Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][CH:23](C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Zn](CC)CC>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:22]([C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH3:23]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Pd]
Agent: CC[Zn]CC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCc1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Temperature: 80 °C
Yield: 570.1 %

Procedure:
A suspension of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv), X-phos (14 mg, 0.03 mmol, 0.10 equiv), Pd2(dba)3 (27 mg, 0.03 mmol, 0.10 equiv) in THF (10 mL), and Et2Zn in THF (5.8 mL, 20.00 equiv, 1M was allowed to react, with stifling, overnight while the temperature was maintained at 80° C. in an oil bath. The reaction was quenched by the addition of 2 mL of water. The resulting mixture was concentrated under vacuum and purified by prep-TLC (petroleum ether:ethyl acetate (4:1)) yielding 50 mg (35%) of methyl 3-ethyl-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[N:4][N:5]([CH2:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].[BH4-].[Na+].CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:24]([F:27])([F:25])[F:26])=[N:4][N:5]([CH2:8][CH:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[OH:10])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(O)C1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103.7 %

Procedure:
A solution of tert-butyl 4-(2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)piperidine-1-carboxylate (1.0 g, 2.440 mmol) in anhydrous CH2Cl2 (20 mL) was treated with sodium borohydride (0.055 g, 1.464 mmol), followed by anhydrous MeOH (4 mL). The mixture was stirred at RT for 1.5 h and then concentrated on a rotary evaporator. The resultant residue was treated with 4 M HCl in dioxane (10 mL). After stirring for 2 h, the mixture was concentrated and this residue was made basic with a minimum amount of saturated NaHCO3. The mixture was lyophilized. The resultant lyopholate was treated with CH2Cl2 (50 mL), stirred vigorously for 5 minutes, and then filtered (CH2Cl2 washes). The combined CH2Cl2 filtrates were concentrated to give 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(piperidin-4-yl)ethanol (0.79 g, 2.53 mmol, 104% yield) as an off-white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 4.09-4.17 (1 H, m), 3.95-4.02 (1 H, m), 3.86 (1 H, ddd, J=8.84, 6.21, 2.31 Hz), 3.11-3.19 (2 H, m), 2.62 (2 H, tt, J=12.28, 3.10 Hz), 2.29 (3 H, s), 1.84 (1 H, d, J=12.96 Hz), 1.64-1.71 (1 H, m), 1.55-1.64 (1 H, m), 1.34-1.44 (2 H, m).
Reaction SMILES: [N:1]1([C:6]2[CH:22]=[CH:21][C:9]([C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.B.[Na].CC(C)=O>CO>[OH:11][CH:10]([C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CCCCCC(=O)c1ccc(-n2ccnc2)cc1
Agent: B
Agent: [Na]
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)CCCCCC(O)c1ccc(-n2ccnc2)cc1
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
In methanol (90 ml) was dissolved 9.00 g (30 mmole) methyl 6-[4-(1-imidazolyl)benzoyl]hexanoate, and the solution was stirred under ice-cooling. 0.86 Gram (30×0.75 mmole) of of sodium boron hydride was added to it, and stirring was continued for 30 minutes under ice-cooling. After acetone was added, the solvent was distilled off, and chloroform and water were added to the residue to effect extraction. The chloroform layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated to give 9.10 g (100%) of methyl 7-hydroxy-7-[4-(1-imidazolyl)phenyl]heptanoate (part of the compound was recrystallized from ethyl acetate/isopropyl ether. m.p. 77°-78° C.).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)[C:6]#[N:7])[CH2:3][CH2:2]1.CI.[CH3:16]C([O-])(C)C.[K+]>O1CCOCC1>[CH:1]1([CH2:4][C:5]([CH3:16])([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)[C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: N#CC(CC1CC1)c1cncnc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CI
Product: CC(C#N)(CC1CC1)c1cncnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of 3-cyclopropyl-2-(pyrimidin-5-yl)propanenitrile (1.5 g, 8.67 mmol) and MeI (1.45 g, 13.0 mmol) in 1,4-dioxane (20 ml) was added t-BuOK (9.57 ml, 9.57 mmol) dropwise at room temperature under N2. The mixture was stirred for 1 h at room temperature then quenched by sat.aq NH4Cl (20 ml) and extracted with EtOAc (3×30 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 3-cyclopropyl-2-methyl-2-(pyrimidin-5-yl)propanenitrile (1.5 g), which was used directly for next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][N:33]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]4[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=4[N:10]=[C:4]3[CH:3]=2)[C:32](=[O:36])[CH:31]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3cc(Br)ccn3c2C1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCc2nc3cc(-n4ccc(OCc5ccccc5)cc4=O)ccn3c2C1
Yield: 60.7 %

Procedure:
tert-Butyl 7-bromo-3,4-dihydropyrido[4′,3′:4,5]imidazo[1,2-a]pyridine-2(1H)-carboxylate (591 mg, 1.68 mmol) and 4-(benzyloxy)pyridin-2(1H)-one (338 mg, 1.68 mmol) were reacted according to Example 18 (step g) to provide the title compound (482 mg, 61%) as a brown solid: ESI MS m/z 473 [M+H]+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28])[CH2:19][CH2:18]2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:21][CH2:22]2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1Sc1ccccc1)N1CCN(CCOCCO)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(OCCOCCN1CCN(C(=O)Nc2ccccc2Sc2ccccc2)CC1)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
4-[2-(2-hydroxyethoxy)-ethyl]-piperazine-carboxylic acid (2-phenylsulfanyl-phenyl)-amide (4 g, 10 mmol), triethylamine (2 ml, 15 mmol) and toluene (50 ml) were charged into a reaction flask. Benzoyl chloride (1.7 g, 12 mmol) in toluene (5 ml) was added at 0-10° C. The mixture was stirred for 16 h at 20° C. Cold water (50 ml) and 1 M NaOH (100 ml) were added. The mixture was stirred for 20 min. The water phase was separated. The organic phase was washed with saturated NaCl solution (25 ml) and evaporated in vacuo. The yield of benzoic acid 2-{2-[4-(2-phenylsulfanyl-phenylcarbamoyl)piperazin-1-yl]-ethoxy}-ethyl ester was 4.91 g.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH:10]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:30]=[N+:31]=[N-:32].[Na+].Cl.C(N(CC)CC)C>CN1CCCC1=O>[C:1]1([C:7]2[N:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[NH:32][N:31]=[N:30][N:20]=3)[CH:10]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCCCCOc1cc(-c2ccc3c(c2)OCO3)cc(-c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: c1ccc(-c2cc(-c3ccc4c(c3)OCO4)cc(OCCCCCc3nnn[nH]3)n2)cc1

Procedure:
By using a similar procedure to that described in example 9 but with 2.4 g 6-{[6-phenyl-4-(3,4-methylenedioxyphenyl)-2-pyridyl]oxy}hexanonitrile, 1.65 g of sodium azide, 1.3 g of triethylamine hydrochloride (in place of ammonium chloride) and 90 cc of N-methylpyrrolidone (in place of dimethylformamide) as the starting material (70 hours; 150° C.), and after purification by flash chromatography on silica gel (30-60 mm; eluent: ethyl acetate) and recrystallization from 18 cc of acetonitrile gives 5-{5-{[6-phenyl-4-(3,4-methylenedioxyphenyl)-2-pyridyl]oxy}pentyl }-1H-tetrazole (m.p.=150° C.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[OH:13].C1COCC1>CCO.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[OH:13]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1O
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)cc1O
Yield: 101.1 %

Procedure:
2-Hydroxy-4-nitro-benzoic acid methyl ester (14 g) was dissolved in EtOH (100 ml) and THF (10 ml) and stirred under hydrogen (1 atm) in the presence of PtO2 for 24 h. The reaction mixture was then filtered through a celite bed. The filtrate was concentrated to give 12 g of 4-Amino-2-hydroxy-benzoic acid methyl ester as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5])[CH3:2].[CH3:20][O:21][C:22](=[O:32])[C@@H:23]([NH2:31])[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:31][C@H:23]([C:22]([O:21][CH3:20])=[O:32])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5])[CH3:2]
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)C1Oc2cccc(OC)c2C=C1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1Oc2cccc(OC)c2C=C1CN[C@@H](CC1CCCCC1)C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 46.7 %

Procedure:
To a solution of 5-methoxy-3-formyl-2H-chromene-2-carboxylic acid ethyl ester (1.3 g, 4.96 mmol) in methanol (20 mL) containing molecular sieves (0.7 g) was added commercially available (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.2 g, 5.45 mmol) and N,N′-diisopropylethylamine (1.71 mL, 9.91 mmol). The mixture was stirred at 25° C. for 10 hours. At this time, sodium cyanoborohydride (0.62 g, 9.91 mmol) and acetic acid (0.47 mL, 7.49 mmol) were added simultaneously to the reaction mixture, and the reaction mixture was stirred for additional 16 hours at 25° C. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated in vacuo. Flash column chromatography (eluant-ethyl acetate:petroleum ether 1:19, Rf=0.6) over neutral alumina afforded 5-methoxy-3-[((S)-2-cyclohexyl-1-methoxycarbonyl-ethylamino)-methyl]-2H-chromene-2-carboxylic acid ethyl ester (1.0 g, 45.5%) as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH3:15])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][S:26][CH2:27][C:28]([OH:30])=O)=[C:19]([C:32]([O:34]C)=[O:33])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][S:26][CH2:27][C:28]([N:3]([CH2:1][CH3:2])[C:4]2[CH:9]=[C:8]([C:10]3[CH:14]=[CH:13][O:12][CH:11]=3)[CH:7]=[CH:6][C:5]=2[CH3:15])=[O:30])=[C:19]([CH:18]=1)[C:32]([OH:34])=[O:33]
Reactant: CCNc1cc(-c2ccoc2)ccc1C
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Product: CCN(C(=O)CSCC(=O)Nc1ccc(Cl)cc1C(=O)O)c1cc(-c2ccoc2)ccc1C

Procedure:
Using the same method as in Example 15-(i), N-ethyl-5-(furan-3-yl)-2-methylaniline was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-(([(2-(ethyl[5-(furan-3-yl)-2-methylphenyl]amino)-2-oxoethyl)sulfanyl]acetyl)amino)benzoic acid.methyl ester (yield: 62%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Cl:11][CH2:12][C:13](O)=[O:14]>O>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:13](=[O:14])[CH2:12][Cl:11])([O-:3])=[O:2]
Reactant: O=C(O)CCl
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: O
Product: O=C(CCl)Nc1ccccc1[N+](=O)[O-]

Procedure:
30 Grams of o-nitroaniline and 55.7 g of anhydrous chloroacetic acid were mixed together and the mixture was heated at 70° to 80° C. for 30 minutes with stirring, then water was added to the reaction mixture, the crystals thus formed were collected by filtration and recrystallized from isopropyl ether to obtain 49.42 g of o-nitro-α-chloroacetanilide in the form of light yellow flake-like crystals. Melting point: 85.5°-87.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>O1CCOCC1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:36]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[O:37])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: COc1ccc(N=C=O)cc1
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)Nc2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxan (0.5 mL) and 4-methoxyphenyl isocyanate (0.016 mL, 0.12 mmol) was added. The solution was stirred at 50° C. for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using MeOH/CH2Cl2 1:100 the eluent. This afforded the title compound as oil. 13C NMR (DMSO-d6) δ 195.2, 158.8 (dd), 155.8 (dd), 154.6, 152.7, 149.1, 139.2, 137.6, 133.5, 132.5, 131.5, 129.5, 127.0, 126.4 (dd), 124.4 (dd), 120.4, 120.2, 119.9, 118.5, 114.9, 114.0, 112.0 (dd), 111.9, 105.1 (dd), 55.2, 19.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([CH2:17][C:18]([O:20]C)=[O:19])[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:7]=1.Cl.C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:7]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2cc(Cl)ccc2OCc2ccccc2)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1cccc(NC(=O)c2cc(Cl)ccc2OCc2ccccc2)c1
Temperature: 90 °C

Procedure:
A mixture of methyl {3-[({5-chloro-2-[(phenylmethyl)oxy]phenyl}carbonyl)amino]phenyl}acetate (may be prepared as described in Description 46, 160 mg, 0.39 mmol), 2M HCl (3 ml) and acetic acid (3 ml) was heated at 90° C. for 4 hours and then cooled to room temperature. Water was added and the mixture was filtered to give a white solid. The crude product was purified by MDAP to yield the title compound as a white solid. 53 mg.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][N:4]=1)[NH2:2].[C:13]([C:21]([C:27]#[N:28])=[C:22](SC)[S:23][CH3:24])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.O>[CH3:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([N:1]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:21]([C:27]#[N:28])[C:22]([S:23][CH3:24])=[N:2]2)=[N:4][CH:5]=1)(=[O:10])=[O:11]
Reactant: CSC(SC)=C(C#N)C(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Solvent: O
Solvent: CCO
Product: CSc1nn(-c2ccc(S(C)(=O)=O)cn2)c(-c2ccccc2)c1C#N
Temperature: 25 °C
Yield: 8.7 %

Procedure:
A mixture of the 2-hydrazino-5-methylsulfonyl pyridine (180 mg, 0.81 mmol) and 1-benzoyl-2,2-bis(methylthio)-1-cyano ethene (201 mg, 0.81 mmol) in anhydrous ethanol was refluxed overnight. The resulting solution was cooled to room temperature, diluted with water (25 ml) and extracted with ethyl acetate (2×25 ml). The ethyl acetate layer was dried with sodium sulfate and concentrated to give crude product. Chromatography of the mixture led to the isolation of the desired product (26 mg, 9%) in the form of a white solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:15]([O:17][CH3:18])=[O:16]>O>[CH3:18][O:17][C:15]([N:5]1[CH2:4][CH2:3][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6]1)=[O:16]
Reactant: c1ccc2c(c1)CCNCC2
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N1CCc2ccccc2CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 958.5 %

Procedure:
In 150 ml of water was dissolved 4.13 g (0.10 mol). of sodium hydroxide. To the solution was added 15.27 g (10.4 mmol.) of 2,3,4,5-tetrahydro-1H-3-benzazepine. The reaction mixture was cooled with ice, and there was added dropwise 7.9 ml (0.10 mol.) of methyl chloroformate. The mixture was stirred for 2.5 hours at room temperature, then extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off to leave 20.46 g (96%) of 3-methoxycarbonyl-2,3,4,5-tetrahydro-1H-3-benzazepine as colorless crystals. Recrystallization from diethyl ether--n-hexane gave colorless needles, m.p. 53°-54° C. Elemental Analysis for C12H15NO2 :
Reaction SMILES: Cl.[NH2:2][OH:3].O.[CH:5]1([C:8]([C@H:10]2[C@H:15]([CH3:16])[CH2:14][C@H:13]3[C@H:17]4[C:26]([C@@H:27]([C:29]5[CH:34]=[CH:33][C:32]([C:35]6[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=6)=[CH:31][CH:30]=5)[CH2:28][C@:11]23[CH3:12])=[C:25]2[C:20](=[CH:21][C:22](=O)[CH2:23][CH2:24]2)[CH2:19][CH2:18]4)=[O:9])[CH2:7][CH2:6]1>O1CCOCC1>[CH:5]1([C:8]([C@H:10]2[C@H:15]([CH3:16])[CH2:14][C@H:13]3[C@H:17]4[C:26]([C@@H:27]([C:29]5[CH:34]=[CH:33][C:32]([C:35]6[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=6)=[CH:31][CH:30]=5)[CH2:28][C@:11]23[CH3:12])=[C:25]2[C:20](=[CH:21][C:22](=[N:2][OH:3])[CH2:23][CH2:24]2)[CH2:19][CH2:18]4)=[O:9])[CH2:7][CH2:6]1
Reactant: NO
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4cccnc4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=NO)CCC4=C3[C@@H](c3ccc(-c4cccnc4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Hydroxylamine hydrochloride (20 mg, 0.30 mmol) and water (1 mL) were added to a stirred solution of 100 mg (0.20 mmol) of (11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one in dioxane (2 mL). The reaction mixture was stirred overnight at room temperature and then extracted three times with dichloromethane. The combined organic layers were dried through a phase separate filter and evaporated to dryness. Purification of the crude product by HPLC followed by lyophilisation gave (11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one 3-oxime as an E/Z mixture (2:1) (85 mg, 0.17 mmol, 84% yield). 1H NMR (400 MHz, CDCl3): δ 0.31 and 0.32 (2×s, in total 3H), 0.83-2.95 (m, 25H), 4.37-4.42 (m, 1H), 5.89 and 6.55 (2×s, in total 1H), 7.26-7.32 (m, 2H), 7.35 (dd, J=8 and 5 Hz, 1H), 7.47-7.51 (m, 2H), 7.86 (dt, J=8 and 1 Hz, 1H), 8.57 (dd, J=5 and 1 Hz, 1H), 8.84 (d, J=1 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([C:20](=[O:43])[C@@H:21]([NH:23][C@H:24]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:22])[C:9]1=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[N:10]([C:20](=[O:43])[C@@H:21]([NH:23][C@H:24]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:22])[C:9]1=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCC[C@H](N[C@@H](C)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCC[C@H](N[C@@H](C)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O)C(=O)OCc1ccccc1
Yield: 88.1 %

Procedure:
0.5 g of tert.-butyl (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate and 20 ml of a 13% hydrogen chloride-dioxane solution are treated in the same manner as described in Example 10-(3), whereby 0.4 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless viscous oil. This oil (0.4 g) and 15 mg of palladium black are treated in the same manner as described in Example 10-(5), whereby 0.2 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-carboxy-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless crystals. The physico-chemical properties of this product are identical with those of the sample obtained in Example 9-(2).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[Cl:24][CH2:25][C:26](Cl)=O>ClC(Cl)C>[Cl:24][CH2:25][C:26]1[O:1][N:2]=[C:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[N:4]=1
Reactant: O=C(Cl)CCl
Reactant: N=C(NO)c1ccc2ccccc2c1
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: ClCc1nc(-c2ccc3ccccc3c2)no1
Temperature: 50 °C
Yield: 21.4 %

Procedure:
A solution of N-Hydroxy-naphthalene-2-carboxamidine (364 mg, 1.95 mmol) in dichloroethane (6 mL) and DIEA (683 μL, 3.91 mmol) was treated with a solution of chloroacetyl chloride (157 μL, 2.350 mmol) in dichloroethane (2 mL) which was added dropwise to the reaction vessel at room temperature. After the addition, the reaction mixture was heated at 50° C. for 4 hours. The reaction mixture was then concentrated to dryness and redissolved in dichloromethane. The organic layer was washed with saturated aqueous NaHCO3 and brine, respectively. The organic layer was dried over anhydrous Na2SO4, concentrated onto silica gel and purified by flash chromatography (0-50% ethyl acetate/hexanes gradient) to afford the required intermediate, 5-chloromethyl-3-naphthalen-2-yl-[1,2,4]oxadiazole (102 mg).