Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][S:26][CH3:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[OH:30]O>C(O)(=O)C.C(OCC)(=O)C>[O:29]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][S:26]([CH3:27])=[O:30])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: OO
Reactant: CSCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCS(C)=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(methylsulfanyl)ethyl]quinolin-4-amine (300 mg, 0.70 mmol) in acetic acid (2 mL) was added hydrogen peroxide (0.5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with ethyl acetate (10 mL), washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford the desired product. MS obsd. (ESI+) [(M+H)+] 444, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J=7.07 Hz, 1 H), 7.88 (dd, J=7.83, 1.26 Hz, 1 H), 7.70-7.60 (m, 2 H), 7.47 (td, J=7.64, 1.14 Hz, 1 H), 7.34 (d, J=8.34 Hz, 1 H), 7.25 (dd, J=8.34, 1.52 Hz, 1 H), 6.98 (t, J=5.56 Hz, 1 H), 6.14 (s, 1 H), 5.09 (brs, 2 H), 4.5 (brs, 2 H), 3.81-3.56 (m, 4 H), 3.20-3.07 (m, 1 H), 3.04-2.92 (m, 1 H), 2.65 (s, 3 H), 2.35 (s, 3 H).
Reaction SMILES: [F:1][CH:2]([F:41])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:19]([N:21]([CH:35]([CH3:37])[CH3:36])[C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)=[O:20])[C:16]([CH3:18])=[CH:17][C:12]=2[S:11][C:10]([CH3:39])([CH3:38])[C:9]1=[O:40])=[O:4].[ClH:42].O1CCOCC1>C(Cl)(Cl)Cl>[ClH:42].[F:41][CH:2]([F:1])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:19]([N:21]([CH:35]([CH3:36])[CH3:37])[C@@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)=[O:20])[C:16]([CH3:18])=[CH:17][C:12]=2[S:11][C:10]([CH3:39])([CH3:38])[C:9]1=[O:40])=[O:4]
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCNC(=O)C(F)F)C(=O)C(C)(C)S2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCNC1)N(CCNC(=O)C(F)F)C(=O)C(C)(C)S2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R)-3-[[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate (1 g) in chloroform (8 ml) was added a 4N hydrochloric acid/dioxane solution (8 ml), and the mixture was stirred at room temperature for one hour. The mixture was concentrated under reduced pressure to give the title compound (0.9 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17](F)[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Cl:20].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Cl:20]
Reactant: COC(=O)c1ccc(F)cc1Oc1cnc(N)c(Cl)c1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cnc(N)c(Cl)c1
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 318C (8.90 g) and piperazine (10.34 g) in dimethylsulfoxide (100 mL) was heated to 85° C. After stirring for 3 hours, the reaction was cooled, diluted with ethyl acetate (400 mL) and washed with water (2×250 mL), brine (250 mL), dried over magnesium sulfate and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[N:11]=[C:12]([CH3:14])O[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1.[CH2:18]([CH2:20][NH2:21])[OH:19]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[N:11]=[C:12]([CH3:14])[N:21]([CH2:20][CH2:18][OH:19])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1
Reactant: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2o1
Reactant: NCCO
Solvent: O
Product: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2n1CCO
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A mixture of the product from example 42 step (i) (1 g) and ethanolamine (10 ml) was stirred at 90° C. for 14 hours. The mixture was diluted with water (10 ml) and the solid filtered. The solid was further washed with water and then dichloromethane to leave the subtitle product as a beige powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>O.C(=S)=S>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:19](=[O:21])[CH3:20])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 4′-methoxybiphenyl (0.05 mol) and AlCl3 (0.06 mol) were dissolved in boiling CS2 (60 mL) with stirring. Acetyl chloride (0.1 mol) was added dropwise and reflux continued for 1 hour. The mixture was poured onto crushed ice (150 mL) containing water (50 mL) and HCl (50 mL). The organic phase was separated and the CS2 removed by distillation. The residue was recrystallised from aqueous isopropanol to give the title compound. δC (CDCl3, 62.9 MHz): 26.6, 55.4, 114.4, 126.6, 128.4, 129.0, 132.2, 135.3, 145.4, 159.9 and 198.0
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Br[CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]>>[C:12]([C:11]1[C:3]([C:2]([F:14])([F:1])[F:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5]2)#[N:13]
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: COC(=O)C(C)Br
Product: COC(=O)C(C)n1ccc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized in a manner similar to Example 1 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile (see, for example, US2008139631A1) and methyl 2-bromopropanoate: MS (ESI): m/z 297 (MH+).
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[C:9](=[O:28])[CH:8]=1.[H-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]OS(C)(=O)=O)=[CH:34][N:33]=1>C(OCC)(=O)C>[F:31][C:32]1[N:33]=[CH:34][C:35]([CH2:38][O:6][C:7]2[CH:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:17][CH:18]=3)[C:9](=[O:28])[CH:8]=2)=[CH:36][CH:37]=1
Reactant: CS(=O)(=O)OCc1ccc(F)nc1
Reactant: O=c1cc(O)ccn1-c1ccc(OCCN2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2ccc(F)nc2)ccn1-c1ccc(OCCN2CCCCC2)cc1
Reaction time: 0.33 h
Yield: 45.4 %

Procedure:
Into a DMF solution (0.8 mL) of 4-hydroxy-1-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1H-pyridin-2-one (20 mg, 0.065 mmol), NaH (60% oiliness, 3 mg, 0.078 mmol) was added and stinred at room temeture for 20 minutes, followed by addition of DMF solution (0.2 mL) of 2-fluoro-5-methanesulfonyloxymethylpyridine (20 mg, 0.097 mmol), stirring at the same temperature for 2.5 hours and further an overnight stirring at 80° C. Ethyl acetate was added to the reaction liquid, which was then washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-300; methanol:chloroform=1:10) to provide the title compound (12.5 mg, 45%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].CC(C)=O.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>C(N(CC)CC)C>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:1](=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: Nc1ccccc1C(F)(F)F
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccccc1C(F)(F)F
Reaction time: 12 h
Yield: 66 %

Procedure:
33.3 g of propionyl chloride were added over 30 minutes at 20°-30° C to a mixture of 480 ml of acetone, 48.3 g of o-trifluoromethyl aniline and 36.42 g of triethylamine and after standing for 12 hours, the mixture was filtered. The acetone was evaporated from the filtrate and the residue was taken up in 500 ml of ethyl acetate. The solution was washed with 10% potassium carbonate solution, then with water until the pH of the wash waters was 6, then with N hydrochloric acid and then with water until the wash water pH was 6. The solution was dried over magnesium sulfate, treated with activated carbon and then evaporated to dryness to obtain 65 g of raw product which was washed with iced essence G to obtain 43 g of N-(2-trifluoromethylphenyl)-propanamide melting at 86° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:29]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]([F:29])=[O:11])[C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.8 %

Procedure:
(2S,3S)-2-tert-Butoxycarbonylamino-3-phenyl-butyric acid (1.94 g, 6.93 mmol) and pyridine (0.63 mL, 7.74 mmol) were dissolved in dichloromethane (50 mL) at −10° C. Cyanuric fluoride (1.80 mL, 21.1 mmol) was added dropwise. The mixture was stirred for 1 hour and ice-water was added. The mixture was extracted with dichloromethane (2×). The organic extracts were washed with water, brine and dried (sodium sulfate). Evaporation of the solvents gave crude ((1S,2S)-1-fluorocarbonyl-2-phenyl-propyl)-carbamic acid tert-butyl ester (2.2 g) as a cloudy oil which was used in the next step.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[OH-].[Na+]>O>[CH2:5]([O:4][C:2](=[O:3])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: NCCc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)NCCc1ccc(O)cc1

Procedure:
According to scheme 1, ethyl chloroformate is added to a solution of tyramine (1), sodium hydroxide, and water to produce the [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester (2). The carbamate is treated with cesium carbonate and 4-fluorobenzonitrile in DMF to yield the corresponding biarylether 3. The nitrile functionality of the biaryl; ether 3 is converted to the N-acyl compound 4 by reaction with mrethyllithium followed by hydrolysis in aqueous sulfuric acid. The N-acyl compound 4 is converted to the acetate 5 by oxidation with m-chloroperbenzoic acid (MCPBA) in a suitable solvent. The acetate 5 is reduced with lithium aluminum hydride to afford the compound 4-[4-(2-methylamino-ethyl)-phenoxy]-phenol (6). The compound 6 is treated with benzaldehyde in the presence of sodium triacetoxyborohydride to produce the reductive amination product 4-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-phenol 7 of formula I. Compounds of formula I wherein D is acetate and q is 0, may also be prepared according to scheme 2 below.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])(C)C)(C)(C)C.C([Li])CCC.CN(C)[CH:24]=[O:25].Cl>O1CCCC1.O>[Cl:16][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[C:12]([Cl:15])[C:11]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(Cl)ccc(O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl-(2,4-dichloro-phenoxy)-dimethyl-silane (113, 4.00 g, 0.0144 mol) in tetrahydrofuran (50.0 mL), under an atmosphere of nitrogen at −78° C., n-butyllithium (2.50 M in hexane, 6.06 mL) was added slowly. After 30 minutes, N,N-dimethylformamide (1.34 mL, 0.0173 mol) was added to the reaction. After 1 hour, the reaction was allowed to warm to room temperature. 1N HCl (40 mL) was added to the reaction. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a yellow solid (114, 2.0 g, 72.6%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=5)=[C:35]([CH3:49])[CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=5)=[O:59])=[C:35]([CH3:49])[CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)c(C)c2)CCCN3CC(C)C)cc1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)c(C)c2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[[1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (370 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-per-benzoic acid (144 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, the dry ice-acetone bath was removed, and an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:40) and recrystallized from hexane-ethyl acetate to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (289 mg) as yellow crystals (Compound 39).
Reaction SMILES: C(OCC)(=O)C.Br.[NH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>O1CCCC1>[CH2:32]([S:34]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1)(=[O:36])=[O:35])[CH3:33]
Reactant: NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: CCS(=O)(=O)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reaction time: 3 h
Yield: 82.5 %

Procedure:
In a mixed solution of 30 ml of ethyl acetate and 30 ml of tetrahydrofuran was suspended 3.22 g of 2-aminomethyl-5-[pyridazin-3(2H)-on-6-yl]indane hydrobromide. A sodium carbonate aqueous solution (5.30 g/30 ml of water) was added to the suspension. Under ice cooling, 3.32 g of ethanesulfonyl chloride dissolved in 10 ml of tetrahydrofuran was added to the mixture, and the resulting mixture was stirred for 3 hours. 300 ml of ethyl acetate was added to the mixture. After the organic layer was collected by separation, washed with water and dried, and the solvent was removed. The residue was purified by silica gel column chromatography (chloroform-methanol (100:3)) to obtain 2.75 g of 2-(ethylsulfonylaminomethyl)-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:18][CH2:17]2)[CH2:6]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH:27][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:18][CH2:17]2)[CH2:6]1
Reactant: NCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1

Procedure:
A solution of 0.030 g (0.06 mmol) of 1-(2,4-dichlorobenzyl)-3-(S)-(4-(3-aminopropyloxymethyl)piperidinylmethyl)-4-(S)-(3-thienyl)pyrrolidine, 0.02 mL (0.24 mmol) of methanesulfonyl chloride, and 0.03 mL (0.15 mmol) of diisopropylethyl amine in 0.5 mL of CH2Cl2 was stirred at rt for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, CH2Cl2:methanol, 95:5) to give the title compound. Mass Spectrum (ESI) m/e=574 (M+1 35Cl, 35Cl), 576 (M+1 35Cl, 37Cl), and 578 (M+1 37Cl, 37Cl). [a]D=+11.0 (c=0.815, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[C:4]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][C:16]([Cl:22])=[N:15]3)=[O:11])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26].N1C=CC=CC=1>C(Cl)Cl>[Cl:22][C:16]1[CH:17]=[N:18][C:19]2[C:14]([N:15]=1)=[CH:13][C:12]([C:10]([C:4]1[C:3]([F:23])=[C:2]([NH:1][S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[CH:7]=[C:6]([F:8])[C:5]=1[F:9])=[O:11])=[CH:21][CH:20]=2
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Yield: 15.1 %

Procedure:
To a solution of (3-amino-2,5,6-trifluorophenyl)(3-chloroquinoxalin-6-yl)methanone (40 mg, 0.119 mmol, 1.0 eq.) in DCM (5 mL) was added propane-1-sulfonyl chloride (84.6 mg, 0.593 mmol, 5.0 eq.) and pyridine (94 mg, 1.19 mmol, 10.0 eq.). The mixture was heated under reflux overnight, then concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) and Prep-TLC to afford N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)propane-1-sulfonamide (8 mg, 15.2%). LRMS (M−H−) m/z calculated 442.0, found 442.0. 1H NMR (CDCl3, 400 MHz) δ 8.91 (s, 1 H), 8.27-8.41 (m, 3 H), 7.71-7.77 (m, 1 H), 6.63 (s, 1 H), 3.13-3.17 (t, 2 H), 1.86-1.94 (q, 2 H), 1.07-1.11 (t, 3 H).
Reaction SMILES: O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[NH:12]([C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-])=O)[N:20]=1)[C:13]([NH2:15])=[NH:14]>CO.O>[NH:12]([C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])[N:20]=1)[C:13]([NH2:15])=[NH:14]
Reactant: N=C(N)Nc1nc(-c2ccccc2[N+](=O)[O-])cs1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CO
Product: N=C(N)Nc1nc(-c2ccccc2N)cs1
Temperature: 60 °C
Yield: 82.8 %

Procedure:
A solution of 57 gm of sodium sulfide octahydrate in 400 ml of methanol and 120 ml of water was added dropwise over a period of 30 minutes to a hot (60° C.) solution of 16.9 gm of 2-guanidino-4-(2-nitro-phenyl)-thiazole in 120 ml of methanol. After an additional 2 hours of heating at 60° C., the solution was filtered with charcoal and evaporated to dryness. The residual solid was suspended in water, filtered off and dried, yielding 12.4 gm of the title compound, m.p. 198°-200° C.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@@H:13]1[O:23][CH2:24][CH3:25])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@@H:13]1[O:23][CH2:24][CH3:25]
Reactant: CCOC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](OCC)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CC[C@@H](N)[C@@H](OCC)C1
Yield: 89.5 %

Procedure:
Ethyl (3S,4R)-4-{[(benzyloxy)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate (Intermediate 23, 2.4 g, 6.87 mmol) was dissolved in methanol (150 mL) and hydrogenated over 10% palladium on carbon (1.5 g) under 50 psi of hydrogen pressure for 2 h at room temperature. The reaction mixture was then filtered through a celite bed and the filtrate was concentrated under reduced pressure to yield 1.33 g (89.62%) of Ethyl (3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate as liquid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:14]([CH3:47])[C:15](=[O:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C@@H:26]1[CH2:43][C:42]2[CH:41]=[C:40]([OH:44])[CH:39]=[CH:38][C:37]=2[C@@H:36]2[C@@H:27]1[C@H:28]1[C@@:32]([CH2:34][CH2:35]2)([CH3:33])[C@@H:31]([OH:45])[CH2:30][CH2:29]1)[CH2:11][CH2:12][CH3:13].C(=O)(O)[O-].[Na+]>CC(C)=O>[CH2:10]([N:14]([CH3:47])[C:15](=[O:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C@@H:26]1[CH2:43][C:42]2[CH:41]=[C:40]([O:44][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:39]=[CH:38][C:37]=2[C@@H:36]2[C@@H:27]1[C@H:28]1[C@@:32]([CH2:34][CH2:35]2)([CH3:33])[C@@H:31]([OH:45])[CH2:30][CH2:29]1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN(C)C(=O)CCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCN(C)C(=O)CCCCCCCCCC[C@@H]1Cc2cc(OC(=O)c3ccccc3)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Aqueous N-sodium hydroxide solution (0.15 ml.) and benzoyl chloride (0.023 ml.) were successively added at 0° C. to a stirred solution of N-n-butyl-N-methyl-11-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)undecanamide (Example 2; 0.06 g.) in acetone (1 ml.) and the mixture was stirred at 0° C. for 30 minutes and poured into saturated aqueous sodium bicarbonate solution (10 ml.). The mixture was extracted three times with diethyl ether (15 ml. each time) and the combined extracts were washed with water (3 ml.), dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 3:2 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil N-n-butyl-N-methyl-11-(3-benzoyloxy-17β-hydroxyoestra-1,3,5(10)-trien-7α-yl)undecanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([C:15]#[CH:16])[CH:12]=[CH:13][CH:14]=1.C(OC(=O)C)(=O)C>O.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C>[C:15]([C:11]1[CH:10]=[C:9]([N:8]2[C:4](=[O:5])[CH:3]=[CH:2][C:1]2=[O:7])[CH:14]=[CH:13][CH:12]=1)#[CH:16]
Reactant: C#Cc1cccc(N)c1
Reactant: O=C1C=CC(=O)O1
Agent: [Ni+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: C#Cc1cccc(N2C(=O)C=CC2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Maleic anhydride (79.6 g, 0.81 mole) was added to a solution of distilled 3-aminophenylacetylene (95.1 g, 0.81 mole) dissolved in 500 mL of dry N,N'-dimethylacetamide (DMAc) at 5°-10° C. After addition, another 300 mL of DMAc was added and the mixture stirred at room temperature for two hours. Nickel acetate tetrahydrate (0.8 g) and acetic anhydride (300 mL) were added to the reaction mixture and stirring was continued for 12 hours at room temperature to affect cyclodehydration. The crude product was isolated by precipitation in water and recrystallized from methanol to provide N-(3-ethynylphenyl)maleimide (128 g, 80% yield) as a yellow crystalline solid, mp 129°-131° C. Elemental analysis calculated for C12H7NO2 : C, 73.09%; H, 3.58%; N, 7.10%. Found: C, 72.94%, H, 3.61%; N, 7.04%.