Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:18][C:19]([O:21]CC)=O)([CH3:17])[CH2:5][N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:4]12[CH2:5][N:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]3[C:3]1=[C:2]([CH:10]=[CH:9][CH:8]=3)[NH:1][C:19](=[O:21])[CH2:18]2
Reactant: CCOC(=O)CN1CC(C)(CC(=O)OCC)c2c(N)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CN1CC2(C)CC(=O)Nc3cccc1c32
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of diethyl 2,2′-(4-amino-3-methyl-2,3-dihydro-1H-indole-1,3-diyl)diacetate from Step D (410 mg, 1.28 mmol) in toluene (100 mL) was added p-toluenesulfonic acid monohydrate (10 mg, 0.052 mmol) and the mixture was heated at reflux. After 20 min, the reaction was allowed to cool to ambient temperature and the mixture was partitioned between EtOAc (300 mL) and aqueous NaHCO3 (50 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 0:100, to give the racemic product. The enantiomers were resolved by HPLC, utilizing a Chiralpak AS column and eluting with hexane:EtOH 40:60. The first major peak to elute was ethyl (2a-methyl-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate, enantiomer A, the title compound, and the second major peak to elute was ethyl (2a-methyl-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate, enantiomer B. MS: m/z=275 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:5][CH:4]=1.CS(Cl)(=O)=O.[CH2:29]([N:31](CC)CC)[CH3:30].C(N)C>C(Cl)Cl.CO.C(OCC)(=O)C>[CH2:29]([NH:31][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:5][CH:4]=1)[CH3:30]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Agent: CCN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCNCc1ccc(-c2ccccc2CNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 68.2 %

Procedure:
4-Hydroxymethyl-2'(t-butoxycarbonylaminomethyl)-1,1'-biphenyl (70 mg; 0.224 mmol) was dissolved in dry methylene chloride and stirred at 0° C. in an iced water bath and methanesulfonyl chloride (22 μl; 0.285 mmol) and triethylamine (39 μl; 0.280 mmol) added. The reaction mixture was stirred for 3 h at 0° C. and then 70% aqueous ethylamine (5 ml) added. The mixture was stirred for 5 h at room temperature vigorously, then partitioned between water and methylene chloride. The organic phase was separated and the aqueous layer extracted with methylene chloride (2×25 ml). The combined methylene chloride layers were dried over potassium carbonate powder, filtered and evaporated under reduced pressure to leave a thick viscous oil. The oil was subjected to a short column chromatography using a solvent gradient initially of ethyl acetate and hexanes (1:1 v/v) then neat ethyl acetate and finally with ethyl acetate and methanol (3:1 v/v). This afforded 52 mg (68%) of the desired product. FAB-MS:- calculated for C21H28N2O2 340.2 found 341.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:17]([CH:30]=[CH2:31])[CH2:18][N:19]1C(=O)C2C(=CC=CC=2)C1=O)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO.CCOCC>[NH2:19][CH2:18][C@H:17]([N:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:30]=[CH2:31]
Reactant: C=C[C@H](CN1C(=O)c2ccccc2C1=O)N(OCc1ccccc1)C(=O)OC(C)(C)C
Agent: NN
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: C=C[C@H](CN)N(OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 80 %

Procedure:
A solution of (R)-tert-butyl benzyloxy(1-(1,3-dioxoisoindolin-2-yl)but-3-en-2-yl)carbamate (Intermediate 155, 80 g, 189.36 mmol) and hydrazine hydrate (47.4 g, 946.86 mmol) in MeOH (800 mL) was stirred at rt overnight. The mixture was diluted with ether and filtered. The filtrate was evaporated and the residue was purified by silica gel column and eluted with MeOH/DCM (0-10%) to give the title compound (44.3 g, 80%) as a colorless oil.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.CN(C)C=O.[N+:14]([C:17]1[O:21][C:20]([CH:22]=[CH:23][C:24]2[N:33]=[C:32](Cl)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>O>[N+:14]([C:17]1[O:21][C:20]([CH:22]=[CH:23][C:24]2[N:33]=[C:32]([NH:7][C:6]3[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=3)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(C=Cc2nc(Cl)c3ccccc3n2)o1
Reactant: Nc1ccc(O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C=Cc2nc(Nc3ccc(O)cc3)c3ccccc3n2)o1
Reaction time: 72 h
Yield: 64.1 %

Procedure:
A 250 ml Erlenmeyer flask equipped with a magnetic stirrer and oil bath for heating was charged with 8.0 g (0.07 mole) of p-aminophenol and 25 ml of dimethylformamide. After the p-aminophenol was dissolved by stirring, 9.05 g (0.03 mole) of 2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline (IV) was added. The reaction mixture was then heated at 70°-90°C for 2 hours after which 60 ml of water was added and the solution after cooling was placed in a refrigerator for crystallization. After three days, the brown yellow solid was collected, washed first with water, then methanol and then dried to obtain 7.20 g of product melting at 250°-60°C with decomposition. Recrystallization from a 1:1 dimethylformamidemethanol mixture gave 6.5 g of orange crystals of the purified product which melted at 270°-2°C with decomposition.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][P:14]([O:20][CH:21]([CH3:23])[CH3:22])([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:8]([P:24]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25])[CH:7]=1.O[Li].O>C1COCC1.O>[CH2:27]([O:26][P:24]([C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:32])=[O:2])[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][P:14]([O:16][CH:17]([CH3:18])[CH3:19])([O:20][CH:21]([CH3:22])[CH3:23])=[O:15])([O:29][CH2:30][CH3:31])=[O:25])[CH3:28]
Reactant: CCOP(=O)(OCC)c1cc(CCC(=O)OC)ccc1OCP(=O)(OC(C)C)OC(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1cc(CCC(=O)O)ccc1OCP(=O)(OC(C)C)OC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
3-(3-Diethylphosphono-4-diisopropylphosphonomethoxyphenyl)propionic acid methyl ester (474 mg, 0.96 mmol) in 5 mL THF at 0° C. was added LiOH.H2O (60 mg, 1.43 mmol) in 1 mL H2O. The reaction mixture was stirred at 0° C. for 1 hr. THF was removed in vacuo and 5 mL 1N HCl was added. Aqueous phase was extracted with DCM (8×10 mL). Combined organic was dried over Na2SO4, concentrated to yield crude product 400 mg (yield 87%) as a clear oil. Electrospray mass spectrum: m/z 479.50 (M−H).
Reaction SMILES: [CH:1]([C:3]1[C@H:8]([C:9]([OH:11])=[O:10])[N:7]2[C:12](=[O:24])[C@@H:13]([NH:14][C:15](=[O:23])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:6]2[S:5][CH:4]=1)=[O:2].O1CCOCC1.CO.[C:33]1([C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[N+]=[N-])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1CCCCC1>[C:33]1([CH:39]([O:10][C:9]([C@@H:8]2[N:7]3[C:12](=[O:24])[C@@H:13]([NH:14][C:15](=[O:23])[CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C@H:6]3[S:5][CH:4]=[C:3]2[CH:1]=[O:2])=[O:11])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCCCC1
Product: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 10 g of 3-formyl-7β-phenylacetylamino-ceph-2-em-4α-carboxylic acid in 250 ml of a 4:1 mixture of dioxane and methanol is treated with a solution of 1.5 mol equivalents of diphenyldiazomethane in cyclohexane. After 2 hours at room temperature, the red-violet solution is evaporated to dryness under reduced pressure. The residue is dissolved in hot methylene chloride; the solution is diluted with cyclohexane whilst warm, and 3-formyl-7βphenylacetylamino-ceph-2-em-4α-carboxylic acid diphenylmethyl ester is obtained in practically quantitative yield in the form of fine colourless felted needles, melting point 175.5°-176° C. (uncorrected, decomposition); [α]D20 =+513°±1° (c=1,084 in chloroform); thin layer chromatogram (silica gel): Rf=0.35 (system: toluene/acetone, 80:20) and Rf=0.58 (system: toluene/acetone 65:35); ultraviolet absorption spectrum (in 95% ethanol): λmax =289 mμ (ε=20,200) and λmin =245 mμ (ε= 2,100); infrared absorption spectrum: characteristic bands at 2.92μ, 3.53μ, 5.59μ, 5.72μ, 5.91μ, 6.34μ, 6.61μ and 6.67μ (in methylene chloride) and at 3.00μ, 5.63μ, 5.76μ, 5.95μ (double band), 5.99μ, 6.07μ and 6.58μ (in mineral oil).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].CN(C=O)C.[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1>CCOC(C)=O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[N:16][CH:17]=1
Reactant: OCC(F)(F)F
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,2,2-Trifluoroethanol (6.15 mL, 84.4 mmol) was placed into a flask with DMF (141 mL). To the reaction mixture was added NaH (3.4 g, 84.4 mmol) in portions. The reaction was then stirred for 30 min at 25° C. At this point, 2,5-dibromopyridine was added and the mixture was heated to 90° C. and stirred at that temperature overnight. The reaction was cooled to rt and diluted with EtOAc (100 mL). The organic layer was washed with H2O (3×150 mL), brine (2×100 mL), dried (MgSO4), filtered, and concentrated. This material was purified by column chromatography (15:1 hexane:EtOAc) to give 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Cl:36])[C:17]=1[CH2:18][CH:19]([C:21]1[C:26]([F:27])=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:22]=1)[OH:20].C(N(CC)CC)C>ClCCl.O>[Cl:36][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([Cl:11])[C:17]=1[CH2:18][C:19]([C:21]1[C:26]([F:27])=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:22]=1)=[O:20]
Reactant: COc1cc(F)c(C(O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(F)c(C(=O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
A solution of oxalyl chloride (0.05 mL) in dichloromethane (3 mL) is cooled to −60° C. and dimethylsulfoxide (1 mL) added. After stirring at this temperature for 0.25 hours, a solution of 2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanol (0.2 g) in dichloromethane (5 mL) is added dropwise. After stirring at −60° C. for 0.25 hours, triethylamine (0.33 mL) is added dropwise and the solution stirred for 0.25 hour at −60° C. and then at room temperature overnight. The solution is then poured into water (30 mL), extracted with ethyl acetate (3×50 mL) and the combined organic extracts washed with brine (30 mL), dried (magnesium sulfate), and concentrated to give a yellow-brown oil. The oil is subjected to mplc on silica gel, using petroleum ether: ethyl acetate (3:1 v/v) as eluent to give 2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanone (0.14 g). m.p. 115-116.5° C. [Elemental analysis:—C, 57.7; H, 4.7; N, 3.5%. calculated:—C, 57.3; H, 4.6; N, 3.5%].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].Cl.[NH2:13][CH2:14][C:15]([NH2:17])=[O:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[S:11])[NH:13][CH2:14][C:15]([NH2:17])=[O:16]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: NCC(N)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=S)NCC(N)=O
Yield: 77.2 %

Procedure:
A mixture of 2,6-dimethylphenyl-isothiocyanate (16.3 g), glycinamide hydrochloride (11.05 g), triethyl amine (12.0 g), and chloroform (250 mL) was heated at reflux for 3 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and washed with 1N HC1 (300 mL) then with water (300 mL). The organic phase was evaporated to dryness, then the residue was stirred with diethyl ether. The solid was collected by filtration and dried to afford 2-[3-(2,6-dimethylphenyl)-thioureido]-acetamide as a solid (18.3 g). Mass spectrum (El, M.+) m/z 237. This compound was used without further purification in the preparation of the title compound.
Reaction SMILES: [Mg].Br[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]=2)[CH:4]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl.[Cl-].[Na+]>O1CCCC1.CCOCC>[CH2:14]([O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([B:22]([OH:27])[OH:23])[CH:12]=[CH:11]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCOc1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCOc1ccc2cc(B(O)O)ccc2c1
Temperature: -78 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
The solution of a Grignard compound is prepared from 2.4 g (99.0 mmol) of magnesium and 30 g (89.6 mmol) of 2-bromo-6-octyloxynaphthalene in 250 ml of tetrahydrofuran at 55° C. over a period of 3hours and then added dropwise to a solution of 41.36 ml (179.2 mmol) of triisopropyl borate in 100 ml of tetrahydrofuran cooled to -78° C., and the mixture is stirred overnight. 130 ml of 10% hydrochloric acid are then added dropwise, and the resulting mixture is stirred at room temperature for 1 hour and then distributed between sodium chloride solution and ether, the organic phase is washed with sodium chloride solution, dried over sodium sulfate, concentrated, and the residue recrystallized from hexane, giving 14.5 g of 6-octyloxynaphthalene-2-boronic acid. ##STR65##
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[CH3:9].P([O-])(O)(O)=[O:11].[Na+].Cl([O-])=O.[Na+].[OH-].[Na+]>C(#N)C.O.OO>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:11])=[O:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(C=O)sc1Br
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(=O)O)sc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 250.9 %

Procedure:
Aluminum chloride (14.6 g) was added portionwise to 2-bromo-3-methylthiophene (8.85 g) and dichloromethyl methyl ether (6.27 g) in dichloromethane (100 ml) under ice-cooling. The mixture was stirred at room temperature for 1 hour and poured into ice water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-bromo-4-methyl-2-thiophenecarbaldehyde (8.0 g). 5-Bromo-4-methyl-2-thiophenecarbaldehyde (6.18 g) was dissolved in acetonitrile (100 ml), and sodium dihydrogen phosphate (1.3 g) in water (20 ml) and 30% aqueous hydrogen peroxide (3.8 ml) were added. Further sodium chlorite (4.07 g) in water (50 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-4-methyl-2-thiophenecarboxylic acid (6.01 g) as crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[C:21]([NH2:33])=[N:22][CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[CH:25]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=O.[NH3:34]>CO>[NH2:33][C:21]1[C:20]([C:7]2[S:6][C:5]([C:3]([NH2:34])=[O:2])=[C:9]([O:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH3:12])[CH:8]=2)=[CH:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)=[CH:23][N:22]=1
Reactant: COC(=O)c1sc(-c2cc(-c3cccc(Cl)c3)cnc2N)cc1OC(C)c1ccccc1Cl
Reactant: N
Solvent: CO
Product: CC(Oc1cc(-c2cc(-c3cccc(Cl)c3)cnc2N)sc1C(N)=O)c1ccccc1Cl
Temperature: 100 °C
Yield: 54 %

Procedure:
5-[2-Amino-5-(3-chloro-phenyl)-pyridin-3-yl]-3-[1-(2-chloro-phenyl)-ethoxy]-thiophene-2-carboxylic acid methyl ester (57 mg, 0.11 mmol, 1.0 Eq.) was suspended in 7M NH3 in MeOH (10 mL) and heated to 100° C. in a pressure tube for 3 days. The reaction was allowed to cool to ambient temperature, the solvent was removed in vacuo and the product purified by column chromatography (ISCO Companion™, 12 g column, 0-10% MeOH/DCM). The solvent was removed in vacuo and the compound was partitioned between DCM (10 mL) and water (10 mL). The organic layer was extracted with DCM (2×7 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow solid (20 mg, 0.08 mmol, 54%); 1H NMR (400 MHz, d-6 DMSO) δ 1.71 (3H, d), 6.04 (1H, q), 6.30 (2H, br s), 7.05 (1H, s), 7.12 (1 h, br s), 7.33-7.36 (2H, m), 7.40-7.48 (3H, m), 7.58-7.63 (2H, m), 7.70-7.72 (1H, br m), 8.35 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH2:21][OH:22])(=[O:12])=[O:11])=[C:5]([CH3:23])[CH:4]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:22][CH2:21][CH2:20][CH2:19][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][N:13]1[S:10]([C:6]1[C:5]([CH3:23])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH3:9])(=[O:11])=[O:12])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCO)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCOS(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
3-(1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propan-1-ol (1.19 mmol, 1 eq) was dissolved in methylene chloride (5 ml), and triethylamine (2.99 mmol, 2.5 eq) and methanesulfonic acid chloride (1.43 mmol, 1.2 eq) were added at 0° C. The mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with methylene chloride (20 ml), washed with water (10 ml) and saturated sodium chloride solution (8 ml), dried over sodium sulfate and concentrated. The crude product was employed in the next stage without further purification. Yield: 89%
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH2:4][S:5][S:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:19][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)SCCCCl)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)SCCCN2CCN(C)CC2)cc1

Procedure:
Toluene-4-thiosulfonic acid S-(3-chloro-propyl) ester (4.9 g, 18.4 mol, 1.00 eq.), N-methylpiperazine (1.9 g, 19.3 mmol) 1.05 eq.) and potassium carbonate (2.7 g, 19.4 mmol, 1.05 eq.) were stirred together in acetonitrile (100 mL) at room temperature for 64 hours. The mixture was concentrated and the residue was partitioned between ethyl acetate (500 ml) and water (250 ml). The organic solution was washed with water (2×200 mL), dried using MgSO4, concentrated and purified by MPLC to give a light yellow oil weighing 2.1 g (36%).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][CH:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][OH:17])[N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24](N)([CH3:26])[CH3:25].C(Cl)(Cl)Cl.CO>CO>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][OH:17])[N:11]([CH:24]([CH3:26])[CH3:25])[CH:10]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1C=C(CO)N=CC1OC(c1ccccc1)c1ccccc1
Reactant: CC(C)N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)n1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO
Reaction time: 144 h
Yield: 45.9 %

Procedure:
To a solution of 3.083 g of 3-diphenylmethoxy-6-hydroxymethyl-4-pyridone in 120 ml of methanol is added 11.082 g of isopropylamine at room temperature, and the mixture is stirred for 6 days. The reaction mixture is condensed to dryness under reduced pressure, and the resulting residue is subjected to flash column chromatography on 120 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of chloroform-methanol (20:1) to perform separation and purification. The title compound (1.608 g) is obtained as colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12]2)[C:3]=1[C:4]#[N:5].[S:17](Cl)(=[O:20])(=[O:19])[NH2:18]>>[S:17]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12]2)[C:3]=1[C:4]#[N:5])(=[O:20])(=[O:19])[NH2:18]
Reactant: CC1CCC(Oc2cccc(N)c2C#N)C1
Reactant: NS(=O)(=O)Cl
Product: CC1CCC(Oc2cccc(NS(N)(=O)=O)c2C#N)C1
Yield: 52 %

Procedure:
Prepared as in Example 215a from 2-amino-6-(3-methylcyclopentyloxy)benzonitrile (Example 251b) and sulfamoyl chloride in 52% yield. MS 296 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([C:28](O)([CH3:30])[CH3:29])[CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O>CCN(CC)CC>[C:28]([C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][NH:7][C:6](=[O:32])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:14][CH:13]=2)[N:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:18]=1)([CH3:30])=[CH2:29]
Reactant: COc1ccc(-n2nc(C(C)(C)O)cc2-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: C=C(C)c1cc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of tert-butyl{4-[3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}-carbamate (1.1 g) and Et3N (1.02 g) was added methane sulfonyl chloride (576 mg). The mixture was stirred at ambient temperature overnight. The mixture was concentrated in vacuo. The residue was partitioned between AcOEt and 1M HCl. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=25%. The pure fraction was collected and concentrated in vacuo to give tert-butyl {4-[3-isopropenyl-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]benzyl}carbamate (857 mg) as a solid.