Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23]([O:25]CC)=[O:24].[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccccn3)c2n1COC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCn1c(C(=O)O)cc2cccc(NS(=O)(=O)c3ccccn3)c21
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.4 %

Procedure:
Ethyl 1-(methoxymethyl)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (7.0 g) was dissolved in a mixed solvent of tetrahydrofuran (30 mL)-methanol (20 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (3.0 g) in water (10 mL)) was added to this solution, and the mixture was stirred at room temperature for 15 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-pink crystals were washed with ethyl acetate-hexane to give the title compound (5.94 g, yield: 91%) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[C@H:10]([C:12]([OH:14])=O)[CH3:11])=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21])#[N:2].[CH3:24][NH:25][CH3:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][C:16]([F:18])([F:19])[F:17])[C@H:10]([C:12]([N:25]([CH3:26])[CH3:24])=[O:14])[CH3:11])=[CH:5][C:4]=1[C:20]([F:22])([F:21])[F:23])#[N:2]
Reactant: CNC
Reactant: C[C@@H](C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Product: C[C@@H](C(=O)N(C)C)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)alanine and dimethylamine: 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.8 Hz, 1H), 7.10 (d, J=2.7 Hz, 1H), 7.01 (dd, J=9.0, 2.7 Hz, 1H), 4.80 (q, J=7.0 Hz, 1H), 4.30 (m, 2H), 3.07 (s, 3H), 2.96 (s, 3H), 1.48 (d, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH3:14])=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=1>[C].[Pd].C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=1
Reactant: CCOC(=O)C=C(C)c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(C)c1cccnc1
Yield: 97.5 %

Procedure:
According to Step 2 of Reference Example 8-65, by use of ethyl 3-(pyridin-3-yl)-2-butenoate (350 mg, 1.8 mmol) obtained in Step 1 of Reference Example 8-66, ethanol (4 mL) and 10% palladium carbon (70 mg), the mixture was stirred and reacted under a hydrogen atmosphere at room temperature for 2 hours. Thus, ethyl 3-(pyridin-3-yl)butanoate (339 mg, yield: 96%) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@:4]([CH:16]=[CH2:17])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].CO.[OH-].[Na+].[ClH:23]>O>[ClH:23].[ClH:23].[CH:16]([C@@:4]([C:3]([OH:18])=[O:2])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5])=[CH2:17]
Reactant: C=C[C@](N)(Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C[C@](N)(Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Treatment of α-vinyltryptophan methyl ester in 1.1 methanol:water with two equivalents of sodium hydroxide, neutralization of the reaction mixture with 1N aqueous hydrochloric acid, and purification of the crude amino acid on DOWEX 50W-X4 cation exchange resin (elution with water and then 2 N aqueous hydrochloric acid) gives α-vinyltryptophan hydrochloride.
Reaction SMILES: [C:1]([CH:9]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][CH:22]=3)=[C:16]([F:35])[CH:15]=2)[C:11](=[O:36])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]2[CH2:13][CH:9]([CH:1]([OH:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10][C:11]2=[O:36])=[CH:15][C:16]=1[F:35]
Reactant: COc1cc2nccc(Oc3ccc(N4CC(C(=O)c5ccccc5)CC4=O)cc3F)c2cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(N4CC(C(O)c5ccccc5)CC4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzoyl-1-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)pyrrolidin-2-one (Example 47, 0.2 g, 0.41 mmol) in 15 mL of MeOH was slowly added solid NaBH4 (50 mg, 1.32 mmol). The reaction was stirred at RT for 1 h. The reaction was quenched with 10 mL of satd. NH4Cl solution. The solution was diluted with 100 mL of EtOAc and was washed with 30 mL of satd. NH4Cl followed by 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The crude solid was purified by chromatography (EtOAc to 5% MeOH/EtOAc) to give a colorless film. MS (ESI pos. ion) m/z: 489.3 (M+H). Calc'd Exact Mass for C28H25FN2O5: 488.51.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([OH:27])=O)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:36](=[N:39]O)([NH2:38])[CH3:37].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:27][N:39]=[C:36]([CH3:37])[N:38]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:34])([F:33])[F:35])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(N)=NO
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)O)cc32)cc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccc3c(c2)N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)Cc2ccc(C(F)(F)F)nc2N3)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carboxylic acid (intermediate 58, 60 mg, 0.119 mmol), acetamide oxime (10 mg, 0.141 mmol), DIPEA (18 mg, 0.141 mmol), HOBt (19 mg, 0.14 mmol), DIC (23 mg, 0.18 mmol) in DCM (0.4 mL) and DMF (0.1 mL) was stirred at rt for 3 h. The reaction was quenched with water and the product was extracted with EtOAc. The combined extracts were washed with 5% NaHCO3, brine, dried (MgSO4) and concentrated. The residue was dissolved in NMP and was heated in a microwave reactor at 120° C. for 1 h. The reaction was quenched with water and the product was extracted with EtOAc. The extracts were washed with water and brine, dried (MgSO4) and concentrated. Flash column purification of the residue on SiO2 afforded the title compound. LC/MS: m/e 544.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.38 (1H, d, J=1.6 Hz), 8.00 (1H, dd, J=8.4, 1.8 Hz), 7.63 (1H, d, J=7.4 Hz), 7.16 (1H, d, J=7.4 Hz), 7.13 (1H, d, J=8.4 Hz), 7.05 (1H, br s), 6.97 (2H, J=8.5 Hz), 6.90 (1H, d, J=8.4 Hz), 4.65-4.95 (2H, br), 2.51 (3H, s), 1.26 (9H, s).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Br:5][C:6]([Br:10])([CH3:9])[CH2:7][OH:8].N1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]([Br:10])([CH3:9])[CH2:7][O:8][C:1]([Cl:4])=[O:2]
Reactant: CC(Br)(Br)CO
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Br)(Br)COC(=O)Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
16 ml (0.22 mol) of liquid phosgene are condensed into 33 g (0.15 mol) of 2,2-dibromopropanol in 150 ml of CH2Cl2, at -20° C, and 12 ml (0.15 mol) of pyridine in 15 ml of CH2Cl2 are then added slowly dropwise at -20° C to -5° C and the mixture is stirred for a further 2 hours at 20° C. The solution is washed, at 0° C, with water, 5% strength sulphuric acid and H2O and dried (Na2SO4) and the solvent is stripped off (46.1 g of crude product). Vacuum distillation gives 36.3 g (86%) of 2,2-dibromopropoxycarbonyl chloride as a colorless liquid. Boiling point12 = 81°-86° C.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][N:8]([C:15](=[O:23])[CH:16]([CH3:22])[CH2:17][S:18][C:19](=[O:21])[CH3:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:19]([S:18][CH2:17][CH:16]([CH3:22])[C:15]([N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:7][C:6]([OH:24])=[O:5])=[O:23])(=[O:21])[CH3:20]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)SCC(C)C(=O)N(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude N-(3-acetylthio-2-methylpropanoyl)-N-phenylglycine tert-butyl ester (25 g, 0.0712 mol) was dissolved in a mixture of anisole (40 ml) and trifluoroacetic acid (125 ml). The resulting red solution was stirred overnight at room temperature. The solvent was evaporated and the residue was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous sodium bicarbonate layer was acidified cautiously with concentrated hydrochloric acid to pH 4-5. The product was extracted several times into chloroform, washed twice with water, and dried over magnesium sulfate. Filtration and evaporation of the extract afforded the crude product as an orange oil which was further purified by HPLC, eluting with ethyl acetate/n-hexane/acetic acid (40:60:1), to afford pure product (7.5 g., 36%) as a pale yellow oil. The product was crystallized from diethyl ether to afford colorless prisms, m.p. 94°-94.5° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH:3]=[N:2]1.O[CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.ClCCl.Cl.O1CCOCC1>O1CCCC1.CO>[NH:15]1[CH2:16][CH2:17][CH:12]([O:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[N:2][NH:1]3)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cccc2[nH]ncc12
Agent: Cl
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: c1cc(OC2CCNCC2)c2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
To a solution of 1H-indazol-4-ol (200 mg, 1.49 mmol) in tetrahydrofuran (10 ml) were added tert-butyl 4-hydroxypiperidine-1-carboxylate (300 mg, 1.49 mmol), triphenylphosphine (430 mg, 1.64 mmol) and a 40%-dibenzyl azodicarboxylate-dichloromethane solution (0.855 ml, 1.79 mmol) at 0° C. After 1 hour, the mixture thus obtained was warmed up to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform (30 ml) and washed with a 1M-aqueous sodium hydroxide solution (20 ml). Extraction with chloroform (30 ml) was carried out again and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The mixture thus obtained was dissolved in methanol (2 ml) and 4N-hydrochloric acid-dioxane (2 ml) was added thereto at room temperature. After 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in methanol (5 ml) and the pH was adjusted to 10 by dropwise addition of a 2M aqueous sodium hydroxide solution. The resulting mixed solution was concentrated under reduced pressure, dried and then purified by a silica gel column chromatography (eluent: chloroform/methanol=10/1→chloroform/methanol/(1%-NH3 aq)=10/1) to obtain 4-(piperidin-4-yloxy)-1H-indazole (103 mg, 32%).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[CH:15]([CH:19]=[O:20])[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:8]3[CH:21]=[O:22]>C(O)(=O)C>[CH:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:15]([CH:19]=[O:20])=[C:14]1[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]1)=[C:8]3[CH:21]=[O:22]
Reactant: O=CC1c2ccccc2C(C=O)c2c1ccc1ccccc21
Solvent: CC(=O)O
Product: O=Cc1c2ccccc2c(C=O)c2c1ccc1ccccc12

Procedure:
A mixture of isomers of 7,12-dihydro-7,12-benz[a]anthracene dicarboxaldehyde [Newman & Din, J. Org. Chem. 36, 967 (1971)] is suspended in 75 ml. of glacial acetic acid, treated with 6 g. of ferric chloride hexahydrate and stirred at room temperature for 3 hours. The remaining yellow solid is filtered off, washed with acetic acid and water leaving the yellow product, m.p. 197°-198° C.
Reaction SMILES: C(O[C:9](=O)[N:10]([CH:12]([C:16](=[O:59])[NH:17][CH:18]([C:22](=[O:58])[N:23]([CH:25]([CH:54]([CH2:56][CH3:57])[CH3:55])[CH:26]([O:52][CH3:53])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH:35]([S:48]([CH3:51])(=[O:50])=[O:49])[CH2:36][C:37](=[O:47])[NH:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:29])[CH3:24])[CH:19]([CH3:21])[CH3:20])[CH:13]([CH3:15])[CH3:14])C)C1C=CC=CC=1.O>CC(O)(C)C.[OH-].[OH-].[Pd+2]>[CH:54]([CH:25]([N:23]([CH3:24])[C:22]([CH:18]([NH:17][C:16](=[O:59])[CH:12]([NH:10][CH3:9])[CH:13]([CH3:15])[CH3:14])[CH:19]([CH3:21])[CH3:20])=[O:58])[CH:26]([O:52][CH3:53])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH:35]([S:48]([CH3:51])(=[O:50])=[O:49])[CH2:36][C:37](=[O:47])[NH:38][CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:29])([CH2:56][CH3:57])[CH3:55]
Reactant: CCC(C)C(C(CC(=O)N1CCCC1C(CC(=O)NCCc1ccccc1)S(C)(=O)=O)OC)N(C)C(=O)C(NC(=O)C(C(C)C)N(C)C(=O)OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCC(C)C(C(CC(=O)N1CCCC1C(CC(=O)NCCc1ccccc1)S(C)(=O)=O)OC)N(C)C(=O)C(NC(=O)C(NC)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
To a stirred solution of the crude {1-[1-({1-sec-butyl-2-methoxy-4-[2-(1-methylsulfonyl-2-phenethylcarbamoyl-ethyl)-pyrrolidin-1-yl]-4-oxo-butyl}-methyl-carbamoyl)-2-methyl-propylcarbamoyl]-2-methyl-propyl}-methyl-carbamic acid benzyl ester (311 mg) obtained above in tBuOH (9 ml) and H2O (1 ml) was added Pd(OH)2 on carbon(ca. 20 wt %, 1 g) at room temperature and then the mixture was set under H2 atmosphere. After being stirred at room temperature for 13.5 hr, the mixture was filtrated through a pad of celite and washed with MeOH. The filtrate and washings were combined and concentrated in vacuo to give the crude gum (285 mg), which was purified by preparative HPLC (column: ODS-80Ts, eluent: 40/30 H2O:CH3CN/0.05% TFA). The appropriate fractions were lyophilized to give the title compound as a white amorphous powder (160 mg, 58%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])/[C:5](=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)=[C:14]([O:24][CH3:25])[CH:13]=1)/[CH2:6][CH2:7][CH2:8][CH:9]=O)[CH3:2].[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(O)(=O)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:26])/[C:5](=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)=[C:14]([O:24][CH3:25])[CH:13]=1)/[CH2:6][CH2:7][CH2:8][CH2:9][NH:32][CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[C:28]([F:27])[CH:29]=1)[CH3:2]
Reactant: NCc1cccc(F)c1
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCCNCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a methylene chloride (6 mL) solution of (E)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-6-oxohexanoic acid ethyl ester (231 mg), 3-fluorobenzylamine (88.7 μL), acetic acid (0.5 mL) and sodium triacetoxy borohydride (165 mg) were added one by one. After agitating the reaction solution at room temperature overnight, a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex NH, elution solvent; heptane-ethyl acetate=1:1->ethyl acetate->ethyl acetate:ethanol=10:1), and 173 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[C:15]([O:22][CH3:23])(=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18].[H-].[Na+]>C1COCC1.CCOC(C)=O>[N+:8]([C:7]1[C:2]([CH:16]([C:15]([O:22][CH3:23])=[O:21])[C:17]([O:19][CH3:20])=[O:18])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 56.2 %

Procedure:
A solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine from Example B16 (400 mg, 1.766 mmol) in THF (5 mL) was treated sequentially with dimethyl malonate (250 μl, 2.187 mmol) and sodium hydride (60%, 85 mg, 2.119 mmol). The resultant mixture was stirred at RT overnight. The mixture was diluted with EtOAc and washed with 0.1 M aq HCl, water, and brine, dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography to provide dimethyl 2-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)malonate (320 mg, 56% yield) of sufficient purity for the next step. MS (ESI) m/z: 323.0 (M+H+).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[CH2:22][C:23](=O)[CH3:24])=[CH:16][C:15]=3[F:27])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH3:28]>CO>[C:1]12([CH2:11][CH2:12][NH:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])/[CH:22]=[C:23](\[NH2:28])/[CH3:24])=[CH:16][C:15]=3[F:27])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC(=O)CC(=O)Nc1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Reactant: N
Solvent: CO
Product: C/C(N)=C/C(=O)Nc1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-((2-(-adamantan-1-yl)ethyl)amino)-3-fluorophenyl)-3-oxobutanamide (0.31 g, 0.83 mmol), MeOH (10 mL) and ammonia (10 mL) was stirred at rt overnight. The mixture was then concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][CH2:5]2.C([Li])CCC.CCCCCC.CN([CH:26]=[O:27])C.[Cl-].[NH4+]>C1COCC1>[S:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:26]=[O:27])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: Brc1ccc2c(c1)CCCS2
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc2c(c1)CCCS2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-thiochromane (1.00 g) was dissolved in THF (15.0 mL), added dropwise with 2.69 mol/L n-butyl lithium/hexane solution (3.24 mL) at −78° C., and stirred for 1 hour at the same temperature. After adding DMF (0.71 mL) at the same temperature, it was stirred for 16 hours while raising the temperature to room temperature. A saturated aqueous solution of ammonium chloride was added, and after extraction with ethyl acetate, the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the residues were purified by silica gel column chromatography (2 to 15% ethyl acetate/hexane) to obtain the title compound (342 mg) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[CH:4]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][C@H:28]1[CH2:33]N[CH2:31][CH2:30][NH:29]1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[F:18][C:19]([F:34])([F:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][C@@H:28]1[NH:29][CH2:30][CH2:31][N:17]([C:6]2[C:5]3[CH:4]=[C:3]([CH3:2])[S:12][C:11]=3[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=2)[CH2:33]1
Reactant: FC(F)(F)c1ccccc1CC[C@H]1CNCCN1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2C(F)(F)F)C1
Temperature: 105 °C
Reaction time: 48 h
Yield: 54.5 %

Procedure:
Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (514.5 mg, 1.94 mmol), (S)-2-[2-(2-trifluoromethyl-phenyl)-ethyl]-piperazine (1.00 g, 3.87 mmol), N,N-diisopropylethylamine (250.2 mg, 1.94 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 497.4 mg (55%) of the title compound as a brown foam: mp 73°, dec; mass spectrum (ion spray): m/z=471.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([S:15]([CH2:18][CH2:19]CC(OC)=O)(=[O:17])=[O:16])[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:11]3[CH2:36][CH2:37][C:38](=[O:39])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].C(S(Cl)(=O)=O)C>>[CH2:18]([S:15]([N:14]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:10]2[C:38](=[O:39])[CH2:37][CH2:36][C:11]=2[N:12]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[C:13]1=[O:25])(=[O:16])=[O:17])[CH3:19]
Reactant: COC(=O)CCCS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Agent: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1

Procedure:
The title compound is prepared in analogy to methyl 4-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl-sulfonyl)butanoate (example 34), substituting 4-(chlorosulfonyl)butanoate with ethane-sulfonyl chloride. Yield: 11 mg; ESI mass spectrum [M+H]+=490; Retention time HPLC: 0.94 min (Z018_S04).
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[CH3:24].O1CCCC1.C(N(CC)CC)C.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>O>[Br:38][C:39]1[CH:44]=[CH:43][C:42]([S:45]([O:1][CH2:2][C:3](=[O:25])[C@@H:4]2[C@:21]3([CH3:22])[C@H:7]([C@H:8]4[C:18](=[CH:19][CH2:20]3)[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]3)[CH2:10][CH2:9]4)[CH2:6][C@H:5]2[CH3:24])(=[O:47])=[O:46])=[CH:41][CH:40]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
To a solution containing 10.0 g (29.4 moles) of 21-hydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione in 100 mol of tetrahydrofuran, first 7,14 ml (51.4 mmoles) of triethylamine, then at 0° C. 13.1 g (51.4 moles) of 4-bromobenzenesulfonyl chloride are added, the reaction mixture is stirred at room temperature for 4 hours, then it is dropwise added to 450 ml of water while stirring. The precipitate is filtered off, dried and recrystallized from ether to obtain 11.0 g (67.07%) of the title compound, m.p.: 124°-129° C.