Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[N+:5]([C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([N+:20]([O-:22])=[O:21])[C:9]=1[C:10](Cl)=[O:11])([O-:7])=[O:6]>>[OH:2][CH2:1][CH2:3][NH:4][C:10](=[O:11])[C:9]1[C:8]([N+:5]([O-:7])=[O:6])=[CH:16][C:15]([N+:17]([O-:19])=[O:18])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]
Reactant: O=C(Cl)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: NCCO
Product: O=C(NCCO)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
In the method of preparation, one mole of ethanolamine is reacted with each mole of 2,4,6-trinitrobenzoyl chloride to produce N-(2-hydroxyethyl)-2,4,6-trinitrobenzamide which is then nitrated to form the desired N-(2-hydroxyethyl nitrate)-2,4,6-trinitrobenzamide.
Reaction SMILES: [OH-].[K+].Cl.[CH:4]1([CH2:7][NH2:8])[CH2:6][CH2:5]1.[F:9][C:10]([F:35])([F:34])[C:11]1[CH:12]=[CH:13][C:14]2[N:20]3[C:21]([CH2:24]Cl)=[N:22][N:23]=[C:19]3[CH2:18][N:17]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:15]=2[CH:33]=1.[I-].[K+]>CO.O1CCCC1>[F:35][C:10]([F:9])([F:34])[C:11]1[CH:12]=[CH:13][C:14]2[N:20]3[C:21]([CH2:24][NH:8][CH2:7][CH:4]4[CH2:6][CH2:5]4)=[N:22][N:23]=[C:19]3[CH2:18][N:17]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:15]=2[CH:33]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: NCC1CC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNCC3CC3)n1-2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A stirred solution of potassium hydroxide (3.37 g., 0.06 mole) in methanol (30 ml.) is cooled in an ice bath, under nitrogen, and treated with (cyclopropylmethyl)-amine hydrochloride (6.45 g., 0.06 mole). The resulting mixture is kept in the ice bath for 15 minutes, treated with tetrahydrofuran (250 ml.), 8-(trifluoromethyl)-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (6.86 g., 0.02 mole) and potassium iodide (3.32 g., 0.02 mole) and kept at ambient temperature for 18 hours. The mixture is concentrated and the residue is mixed with water and extracted with methylene chloride. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The product is crystallized once from ethyl acetate and once from methylene chloride ethyl acetate to give 8-(trifluoromethyl)-1-[[(cyclopropylmethyl)amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 28 8 -Chloro-1-[[(cyclopropylmethyl)amino] methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1([CH3:22])[CH2:17][O:16][CH:15]([CH2:18][CH2:19][CH2:20][OH:21])[O:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1([CH3:22])[CH2:13][O:14][CH:15]([CH2:18][CH2:19][CH:20]=[O:21])[O:16][CH2:17]1
Reactant: CC1(C)COC(CCCO)OC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC1(C)COC(CCC=O)OC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
DMSO (10.2 ml, 0.14 mol) was added to a solution of oxalyl chloride (5.5 ml, 63.2 mmol) in methylene chloride (25 ml) at −78° C. After stirring for 15 min, a solution of 5,5-dimethyl-1,3-dioxane-2-propanol (Step 1) (10 g, 57.5 mmol) in methylene chloride (100 ml) was added over 10 min. The reaction was stirred for 1 hr and triethylamine (40 ml, 0.2 mol) was added. After stirring at −70° C. for 1 hr, the reaction mixture was warmed to room temperature and stirred for 2 hr. The reaction was quenched with water and extracted with methylene chloride. The organic fractions were washed with aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration, the crude compound was chromatographed (silica gel, hexane/ethyl acetate 7/3) to give 5,5-dimethyl-1,3-dioxane-2-propanal (6.1 g, 61%) as a colorless liquid: Anal Calc'd. for C9H16O3 0.2H2O: C, 61.48; H, 9.40. Found: C, 61.46; H, 9.24.
Reaction SMILES: C(=O)([O-])[O-].[NH4+:5].[NH4+].Cl[C:8]1[S:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([Cl:13])[N:12]=1>C(#N)C>[NH2:5][C:8]1[S:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([Cl:13])[N:12]=1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Nc1nc(Cl)c([N+](=O)[O-])s1
Temperature: 0 °C
Reaction time: 48 h
Yield: 67.9 %

Procedure:
10.1 g (0.105 mol) of ammonium carbonate are added to a solution of 19.9 g (0.1 mol) of 2,4-dichloro-5-nitrothiazole in 200 ml of acetonitrile, while stirring, and stirring is continued at room temperature for two days. The mixture is then stirred into 1 l of ice-water and the precipitate is filtered off, washed with water and dried. To remove unreacted 2,4-dichloro-5-nitrothiazole, the product is stirred into about 100 ml of petroleum ether at room temperature, filtered off, washed with petroleum ether and dried. 12.2 g (68.0% of theory) of 2-amino-4-chloro-5-nitrothiazole of melting point 180° C. (decomposition) are obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=3)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.[CH3:42][CH:43]1[O:48][CH2:47][CH2:46][NH:45][CH2:44]1.[OH-].[Na+].Cl>CS(C)=O.CC(O)C>[CH3:42][CH:43]1[O:48][CH2:47][CH2:46][N:45]([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:21]=[N:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=4)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][NH:15]4)=[O:9])[N:7]=2)[CH2:44]1
Reactant: CC1CNCCO1
Reactant: COc1ncc(-c2cc(NC(=O)c3csc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CS(C)=O
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4CCOC(C)C4)n3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 90 °C
Reaction time: 30 h
Yield: 11.3 %

Procedure:
2-(Chloromethyl)-N-[6-{6-(methyloxy)-5-[(methylsulfonyl)amino]-3-pyridinyl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.079 mmol) was added to 2-methylmorpholine (0.5 ml, 0.079 mmol). The reaction mixture was heated in the microwave for 15 min at 90° C. The solvent was blown off under nitrogen. IPA (2 ml) and 2M NaOH (2 ml) were added to the mixture. The reaction mixture was stirred for 30 hours, then neutralised with 2M HCl aqueous to pH 7. The solvent was blown off under nitrogen. The mixture was dissolved in 2 ml of DMSO. Insoluble matter was removed by filtration and purification was carried out by MDAP (Method E) to afford the title compound (5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[NH:7][C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[H-].[Na+].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[C:25]([F:31])[CH:24]=1.Cl>CN(C)C=O>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:7]2[C:6](=[O:19])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2=[O:18])=[C:25]([F:31])[CH:24]=1
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reactant: Fc1cc(Br)ccc1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To a solution of ethyl 2-(7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl)acetate (176 g) in N,N-dimethylformamide (3.5 l) was added sodium hydride (60% in mineral oil, 32.3 g) at 0° C. and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added a solution of 4-bromo-2-fluorobenzyl bromide (200 g) in N,N-dimethylformamide (100 ml) below 20° C. over a 20-minute period and the resulting mixture was stirred at room temperature for 1 hour. 3N Aqueous hydrochloric acid (62.2 ml) was added to the mixture below 15° C. and the solvent was evaporated in vacuo. The residue was poured into a mixture of ethyl acetate (3 l) and water (3 l), and the resulting mixture was stirred for 15 minutes. The precipitates were filtered off and the organic layer was separated. The solution was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized with addition of isopropyl ether and the crystals were collected by filtration and washed with isopropyl ether. The crude crystals and the precipitates were mixed and recrystallized from a mixture of ether acetate (0.9 l) and n-hexane (0.9 l) to give ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (251 g).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=2)[CH2:15][CH:16]=1
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Reactant: Clc1cccc(CBr)c1
Agent: Cl
Product: Clc1cccc(CN2CC=C(c3cc4ccccc4s3)CC2)c1
Yield: 14.9 %

Procedure:
4-(Benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (250 mg, 0.99 mmol) was reacted with 3-chlorobenzyl bromide (0.2 ml, 1.5 mmol) as exemplified in Example 1. The crude product was triturated with methanol to give the title compound as a pale yellow solid (50 mg, 15%); (Found: C, 69.05; H, 5.03; N, 4.07. C20H18ClNS. 0.5H2O requires C, 68.85; H, 5.49; N, 4.01%). δH (CDCl3), 2.65 (2H, m, NCH2CH2), 2.73 (2H, m, NCH2CH2), 3.18 (2H, m, NCH2CH2), 3.62 (2H, s, NCH2Ar), 6.19 (1H, m, NCH2 CH), 7.12 (1H, s, ArH), 7.28 (5H, m, ArH), 7.39 (1H, s, ArH), 7.67 (1H, d of d, J 6.2Hz, J 1.9Hz, ArH), 7.73 (1H, d of d, J 8.4Hz, J 1.8Hz, ArH). m/z (ES+) 340 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH:9]=[CH:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH:9]=[CH:10][CH2:11][NH:12][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]([C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCC=CCN
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC=CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of (4-amino-but-2-enyl)-carbamic acid tert-butyl ester (1.0 g, 5.36 mmol) in dry CH2Cl2 (40 ml) was added 6,6-bis-(4-fluorophenyl)-hexanoic acid (1.62 g, 5.36 mmol) under nitrogen. To the reaction was added EDC (2.04 g, 10.72 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate:water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give the desired product in 70% yield.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]([C:27]1[CH:36]=[N:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)[NH2:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:26][NH:25][C:27]3[CH:36]=[N:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNc1cnc2ccccc2n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1cnc2ccccc2n1
Reaction time: 2 h
Yield: 17.1 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with a solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) and 2-hydrazinylquinoxaline (0.14 g, 1.2 eq.) in EtOAc. T3P (50% in EtOAc; 0.83 mL, 2.0 eq.) and DIPEA (0.5 mL, 4.0 eq.) were added under nitrogen atmosphere at −55 to −60° C. and the reaction mixture was stirred for 2 hr before being concentrated under reduced pressure (25° C., 20 mmHg) to afford 0.150 g of crude solid. Purification using Combi-Flash column chromatography (eluting with MeOH:CH2Cl2; desired compound started eluting at 5% MeOH in CH2Cl2) afforded 60 mg (yield: 20%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(quinoxalin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ=10.851 (s, 1H), 9.89-9.87 (s, 1H), 9.67 (s, 1H), 8.49-8.54 (m, 3H), 8.26 (s, 1H), 8.28 (s, 1H), 7.86-7.88 (d, J=8 Hz, 1H), 7.45-7.66 (m, 4H), 6.17-6.20 (d, J=10.4 Hz, 1H); LCMS for C21H14F6N7O [M+H]+ 494.37; found 494.19 (RT 2.88 min, purity: 100%).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.C(OC([N:16]1[CH:22]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[C:20]([CH3:30])[CH2:19][CH2:18][CH2:17]1)=O)(C)(C)C>ClCCl>[CH3:30][C:20]12[CH2:21][CH:22]([NH:16][CH2:17][CH2:18][CH2:19]1)[CH2:23][C:24]1[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC1=CC(Cc2ccccc2)N(C(=O)OC(C)(C)C)CCC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CC12CCCNC(Cc3ccccc31)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trifluoromethanesulfonic acid (2.5 mL) is added to a solution of 7-benzyl-5-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester (0.30 g) in dichloromethane (5 mL) chilled in an ice bath. The ice bath is removed and the solution is stirred at room temperature for 5 h. Then, ice-cold water and aqueous K2CO3 solution are added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4), the solvent is evaporated, and the residue is purified by chromatography on silica gel (dichloroemethane/methanol 99:1->9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:17]([Cl:18])=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:4][C:3]=1[OH:19].Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CS(C)=O>[Cl:18][C:17]1[C:9]([C:5]2[CH:4]=[C:3]([O:19][C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:2]([Cl:1])=[CH:7][C:6]=2[F:8])=[N:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=12
Reactant: Clc1ncccn1
Reactant: Oc1cc(-c2nn3c(c2Cl)CCCC3)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCC(C)=O
Product: Fc1cc(Cl)c(Oc2ncccn2)cc1-c1nn2c(c1Cl)CCCC2
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a solution of 2-chloro-5-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)-4-fluorophenol (0.5 g) and 2-chloropyrimidine (0.25 g), in a mixed solvent of 2-butanone:dimethylsulfoxide (1:4) (50 ml) was added potassium carbonate (0.35 g) at room temperature. After addition, the mixture was heated at reflux for 12 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and partitioned between ethyl acetate and brine. The organic phase was washed with brine (×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluent, ethyl acetate:hexane, 2:1) to give the desired compound (0.47 g).
Reaction SMILES: [OH:1][C@@H:2]([C:35]#[C:36][CH3:37])[C@@H:3]([N:16]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:17]1=[O:34])[CH2:4][NH:5]C(=O)OCC1C=CC=CC=1>CO.[Pd]>[NH2:5][CH2:4][C@H:3]([N:16]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[C:17]1=[O:34])[C@@H:2]([OH:1])[CH2:35][CH2:36][CH3:37]
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCC[C@H](O)[C@H](CN)N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.2 %

Procedure:
A solution of benzyl (2S,3S)-3-hydroxy-2-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)hex-4-ynylcarbamate (0.32 g) in MeOH (5 mL) was charged with 10% Pd/C and then stirred under H2 (1 atm) for 5 h at RT, filtered through diatomaceous earth, and concentrated in vacuo to provide N-((S)-1-((2S,3S)-1-amino-3-hydroxyhexan-2-yl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide (0.24 g). MS found: (M+H)+=388.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][CH:42]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:40]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22]([N:39]3[CH2:44][CH2:43][CH:42]([C:45](=[O:46])[NH2:47])[CH2:41][CH2:40]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:3])([CH3:4])[CH3:2]
Reactant: NC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC(C(N)=O)CC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 100.9 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), piperidine-4-carboxylic acid amide (70 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) and 4 mL of N,N-dimethylformamide were then added to the solution successively. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(4-carbamoyl-piperidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 7a (180 mg, yield 98%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].C([C:28]1[C:29]([N:34]=[CH:35][N:36]([CH3:38])C)=[N:30][CH:31]=[CH:32][CH:33]=1)#N.NC1C=C(OCC2C=CC=C(F)C=2)C=CC=1SC1C=CC(O)=CC=1>>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([S:18][C:17]2[CH:16]=[CH:15][C:4]([O:5][CH2:6][C:7]3[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=3)[C:10]#[N:11])=[CH:3][C:2]=2[NH:1][C:38]2[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][C:29]=3[N:34]=[CH:35][N:36]=2)=[CH:24][CH:23]=1
Reactant: N#Cc1cccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)c1
Reactant: CN(C)C=Nc1ncccc1C#N
Agent: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: N#Cc1cccc(COc2ccc(Sc3ccc(O)cc3)c(Nc3ncnc4ncccc34)c2)c1
Yield: 44 %

Procedure:
The product from Example 36H and the product from Example 57A were reacted according to the procedure in Example 57E substituting the product of Example 36H for the product of Example 57D to provide a solid which was triturated with methanol to provide the title compound (44 mg, 44%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.08 (s, 1H), 9.65 (s, 1H), 9.06 (s, 1H), 8.86 (s, 1H), 8.58 (s, 1H), 7.92 (s, 1H), 7.77-7.86 (m, 2H), 7.54-7.70 (m, J=7.72, 7.72 Hz, 2H), 7.28 (s, 1H), 7.07-7.19 (m, 3H), 6.97 (s, 1H), 6.63-6.72 (m, 2H), 5.18 (s, 2H); MS (ESI+) m/z 478.2 (M+H)+, (ESI−) m/z 476.1 (M−H)−.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21][CH3:22])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1.[C:25]([O:33]C(=O)C1C=CC=CC=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[C:25]([O:33][CH2:22][S:21][C:15]1[C@:16]2([CH2:18][C@H:19]([OH:20])[C@@:2]3([F:1])[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=4)[C@@H:12]2[CH2:13][CH:14]=1)[CH3:17])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Reactant: CSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(SCOC(=O)c4ccccc4)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
A solution of 9-fluoro-11β-hydroxy-17-(methylthio)androsta-1,4,16-trien-3-one (100 mg, see Example 1B) in 30 ml of xylene containing 4.0 g of benzoic anhydride and 300 mg of sodium methoxide is stirred at 130° C for 48 hours. The product is then isolated and chromatographed over silica gel to yield 80 mg of the title compound, melting point 220°-222° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].[C:28]1([S:34]([CH2:37][CH2:38][O:39][C:40](=[O:69])[CH2:41][O:42][C:43]2[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][C:44]=2[O:53][CH2:54][C:55]([O:57][CH2:58][CH2:59][S:60]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)(=[O:62])=[O:61])=[O:56])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C(Cl)Cl>[C:28]1([S:34]([CH2:37][CH2:38][O:39][C:40](=[O:69])[CH2:41][O:42][C:43]2[CH:48]=[CH:47][C:46]([S:49]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:50])=[O:51])=[CH:45][C:44]=2[O:53][CH2:54][C:55]([O:57][CH2:58][CH2:59][S:60]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)(=[O:62])=[O:61])=[O:56])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: O=C(COc1ccc(S(=O)(=O)Cl)cc1OCC(=O)OCCS(=O)(=O)c1ccccc1)OCCS(=O)(=O)c1ccccc1
Agent: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)OCCS(=O)(=O)c2ccccc2)c(OCC(=O)OCCS(=O)(=O)c2ccccc2)c1
Reaction time: 3 h
Yield: 78 %

Procedure:
To a heterogeneous mixture of 2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)pyridin-2-ylmethanesulfinyl]-benzimidazole, (LANSOPRAZOLE) (500 mg, 1.35 mmol) in CH2Cl2 (10 mL) was added NaH (40 mg, 1.63 mmol) at room temperature resulting in a clear solution. To this clear mixture was added [2-(2-benzenesulfonyl-ethoxycarbonylmethoxy)-4-chlorosulfonyl-phenoxy]-acetic acid 2-benzenesulfonyl-ethyl ester (Intermediate 29, 1.0 g, 1.63 mmol, 1.2 eq) in CH2Cl2 (5 mL) at room temperature, and the mixture was stirred for 3 h. Thereafter water was added, the mixture was extracted with CH2Cl2, and the organic layers were dried and concentrated under reduced pressure. The residual oil was purified by column chromatography (CH2Cl2 to 2% MeOH in CH2Cl2) to yield Intermediate 30 (1.05 g, 78%) as an off-white foam.