Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:23]4[CH2:24][CH2:25][O:26][CH2:27][CH:28]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.C([SiH](CC)CC)C>[Pd]>[F:29][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3=CCOCC3)ccc12
Agent: [Pd]
Agent: CC[SiH](CC)CC
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3CCOCC3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 126 using 6-chloro-2-(3,6-dihydro-2H-pyran-4-yl)-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, palladium on carbon and triethylsilane. 1H NMR (400 MHz, DMSO-d6): δ 8.80 (t, J=5.92 Hz, 1H), 7.97-8.04 (m, 2H), 7.77 (d, J=9.00 Hz, 1H), 7.62 (d, J=8.76 Hz, 1H), 3.96-4.00 (m, 2H), 3.45-3.52 (m, 2H), 3.25-3.27 (m, 2H), 3.11-3.17 (m, 1H), 2.01-2.04 (m, 2H), 1.80-1.90 (m, 7H), 1.74-1.77 (m, 2H), 1.23-1.33 (m, 2H). m/z: 423 [M+H]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([NH:23][C:24](=[O:26])[CH3:25])[CH:10]=1)=[O:8].[Na].[S:28](Cl)([Cl:31])(=[O:30])=[O:29]>C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:11]([N:23]([S:28]([Cl:31])(=[O:30])=[O:29])[C:24](=[O:26])[CH3:25])[CH:10]=1)=[O:8]
Reactant: CC(=O)Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Agent: [Na]
Solvent: c1ccccc1
Product: CC(=O)N(c1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1)S(=O)(=O)Cl

Procedure:
An anhydrous benzene solution of 3-acetamido-4-benzyloxyphenyl 2-pyridyl ketone is heated at reflux with sodium until a suspension is formed. To this suspension is added sulfuryl chloride in benzene and the resulting mixture is filtered to remove sodium chloride. The filtrate is evaporated to give 4-benzyloxy-3-(N-chlorosulfonylacetamido)phenyl 2-pyridyl ketone.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Si:10]([O:17][C@@H:18]([CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@H:19]([CH3:27])/[CH:20]=[CH:21]/[C:22](OCC)=[O:23])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C(Cl)Cl>[Si:10]([O:17][C@@H:18]([CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:35])([CH3:37])[CH3:36])([CH3:32])[CH3:33])[C@H:19]([CH3:27])/[CH:20]=[CH:21]/[CH2:22][OH:23])([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11]
Reactant: CCOC(=O)/C=C/[C@@H](C)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: C[C@H](/C=C/CO)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 96907.8 %

Procedure:
DIBAL-H (26.5 mL, 26.5 mmol, 1.0 M solution in hexane) was added to the ester 10 (3.14 g. 7.30 μmol) in CH2Cl2 (35 mL) at −78° C. dropwise and stirred for 1 h. The reaction mixture was quenched by EtOAc (5 mL) and sat'd sodium potassium tartrate solution (20 mL) followed by vigorous stirring for 4 h. The aqueous phase was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were washed with brine (10 mL). After drying over MgSO4 and evaporation under vacuum, flash column chromatography (hexane/EtOAc 4:1) provided 2.75 g of alcohol 11 (97%) as a colorless oil: IR (CHCl3) 3349, 2956, 2928, 2857, 1471, 1462, 1255, 1099, 836, 774 cm−1; 1H NMR (300 MHz, CDCl3) ε5.57 (m, 2H), 4.03 (m, 2H), 3.70 (ddd, J=9.7, 6.0, 3.8 Hz, 1H), 3.59 (m, 2H), 2.27 (m, 1H), 2.00 (s, 1H), 1.53 (q, J=6.5 Hz, 2H), 0.96 (d, J=6.9 Hz, 3H), 0.85 (s, 9H), 0.84 (s, 9H), 0.00 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 134.7, 129.2, 72.4, 63.6, 60.1, 41.8, 36.3, 25.9, 18.2, 18.0, 15.1, 10.7, −4.6, −5.4; LRMS (EI) 370 (M−H2O), 303, 171, 147; HRMS (EI) calcd for C20H42O2Si2 370.2723 (M−H2O), found 370.2725; [α]20D−3.0 (c 0.57, CHCl3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].FC(F)(F)C([N:12]([C:27]1[CH:42]=[CH:41][C:30]([C:31](ON2C(=O)CCC2=O)=[O:32])=[CH:29][CH:28]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=O.[OH-].[Na+].Cl>O.C(O)C.C(N(CC)CC)C>[CH:21]1([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:27]2[CH:42]=[CH:41][C:30]([C:31]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(N(CCCCCCCCC2CCCCC2)C(=O)C(F)(F)F)cc1
Reactant: NCCS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCCS(=O)(=O)O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of 2.50 g. of taurine and 5.6 ml. of triethylamine in 22.5 ml. of water is added 5.55 g. of N-{p-[2,2,2-trifluoro-N-(8-cyclohexyloctyl)acetamido]benzoyloxy}succinimide as a solution in 45 ml. of ethanol. After 24 hours, the mixture is treated with 20 ml. of 2.0 M sodium hydroxide and 25 ml. of water. After stirring for 10 min., the mixture is acidified with dilute hydrochloric acid, and the crude product is collected by filtration. Recrystallization affords the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][CH2:6][C:7]4=[O:12])[CH2:18][CH2:19]2)=[CH:25][CH:26]=1
Reactant: ClCCCN1CCN(Cc2ccc(Br)cc2)CC1
Reactant: O=C1CCCc2c(O)cccc21
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=C1CCCc2c(OCCCN3CCN(Cc4ccc(Br)cc4)CC3)cccc21
Yield: 50 %

Procedure:
From 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(4-bromobenzyl)-piperazine; yield 50% of theory; m.p. of the dihydrochloride (recrystallized from 1N hydrochloric acid) 256°-259°C (decomposed);
Reaction SMILES: [CH:1]([CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])=O.[C:12]1([C@H:22]([NH2:24])[CH3:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>C(O)C>[C:12]1([C@H:22]([NH:24][CH:1]=[CH:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOP(=O)(CC=O)OCC
Reactant: C[C@@H](N)c1cccc2ccccc12
Solvent: CCO
Product: CCOP(=O)(C=CN[C@H](C)c1cccc2ccccc12)OCC
Temperature: 10 °C

Procedure:
A 1-litre, four-necked flask equipped with a mechanical stirrer, an addition funnel and a nitrogen inlet was charged with diethyl formylmethylphosphonate (100 g) and ethanol (500 mL). Under a nitrogen atmosphere, the resulting mixture was cooled to 10° C. and (R)-1-(1-naphthyl)ethylamine (85.6 g) was added under stirring. The mixture was left under stirring for an additional hour. The solvent was distilled from this mixture under reduced pressure. The resulting residue (180 g) was used in the next step without additional purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:13]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]2([CH3:22])[CH3:21])[N:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:20][C:18]1([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]([CH3:21])([CH3:22])[N:13]1[C:4]1[N:3]=[C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[N:5]=1
Reactant: C1CNCCN1
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)cc(N2CCCC2)n1
Product: CC1(C)CCCC(C)(C)N1c1nc(N2CCCC2)cc(N2CCNCC2)n1
Yield: 80.2 %

Procedure:
4-chloro-2-(2,2,6,6-tetramethyl-1-piperidinyl)-6-(1-pyrrolidinyl) pyrimidine is reacted with piperazine as described in Example 5 to obtain the title compound in a yield of 80.2%, m.p.:134°-137° C.
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][O:9][C:5]=2[CH:4]=1.I>C(O)(=O)C>[OH:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(-c3ccccc3)coc2c1
Agent: I
Solvent: CC(=O)O
Product: Oc1ccc2c(-c3ccccc3)coc2c1

Procedure:
To a stirred solution of 30 g (0.134 mole) of 6-methoxy-3-phenylbenzofuran in 150 ml of acetic acid is added 30 ml of 47% stabilized hydroiodic acid. The mixture is heated to its reflux temperature and maintained at reflux for seven hours. A precipitate is obtained which is separated by filtration, rinsed with water and dried to provide crude 6-hydroxy-3 -phenylbenzofuran, m.p. 138°-143° as an off-white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].Cl.Cl[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1cccnc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2cccnc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
3-Fluoro-4-nitrophenol (7.5 g) is added to a stirred suspension of sodium hydride (2.2 g, 60% dispersion in mineral oil) in DMF (50 mL). The mixture is stirred at ambient temperature for 30 minutes. To this mixture is added a solution prepared by the addition of sodium hydride (2.2 g, 60% dispersion in mineral oil) to a stirred suspension of 3-chloromethylpyridine hydrochloride (8.2 g) in DMF (50 mL). The resulting mixture is stirred at 90° C. for 16 hours then cooled to ambient temperature. The reaction mixture is concentrated in vacuo and the residue partitioned between dichloromethane (100 mL) and water (100 mL). The aqueous phase is extracted four times with dichloromethane (100 mL). The combined organic phases are washed with brine (100 mL), dried over magnesium sulphate, filtered and concentrated in vacuo to give an orange solid. Recrystallisation from ethyl acetate gives 3-(3-fluoro-4-nitrophenoxymethyl)pyridine (4.6 g) as pale orange/brown cystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13](Cl)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:22][C:23]1[CH:27]=[CH:26][N:25]([CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])[N:24]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH2:28][C:29]([OH:31])([CH3:30])[CH3:32])[N:24]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CC(=O)C2)C(=O)Cl)cc1Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclobutyl)-propionyl chloride in methylene chloride (0.036 M solution, 5 mL, 0.18 mmol) was slowly added to a cooled to 0° C. solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 31 mg, 0.20 mmol) and 2,6-lutidine (31 μl, 0.27 mmol) in methylene chloride (6 ml). The reaction continued to stir at 0° C. for 15 min and then at 25° C. for 4 h. After concentration in vacuo it was purified on an AnaLogix Intelliflash system (40 g column, 100% ethyl acetate) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(3-oxo-cyclobutyl)-propionamide (54 mg, 63%) as an off-white solid: [α]30589=−6.60° (c=5.9, CHCl3); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03, 1.04 (2×s, 6H, 2×CH3), 1.93-2.40 (m, 3H, CH and CH2), 2.66-2.85 (m, 2H, 2×CH or 2×CH2), 2.98-3.12 (m, 2H, 2×CH or 2×CH2), 3.34 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH2), 3.85-3.91 (m, 1H, ArCHCO2), 6.46 (d, J=2.3 Hz, 1H, Ar), 7.52 (d, J=2.3 Hz, 1H, Ar), 7.61 (dd, Jm=1.6 Hz, Jo=8.3 Hz, 1H, Ar), 7.73 (d, Jm=1.6 Hz, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.84 (s, 1H, NH).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.B(O)(O)[C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][CH:12]=1.[F-].[K+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[F:18][C:17]([F:20])([F:19])[C:16]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
To a solution of 4-bromobenzaldehyde (1 g, 5.40 mmol) in THF (21.6 mL) is added (2-trifluoromethyl)phenylboronic acid (1.67 g, 8.1 mmol), potassium fluoride (780 mg, 16.2 mmol), palladium(II) acetate (12.1 mg, 0.054 mmol), and 2-(dicyclohexylphosphino)-biphenyl (37.9 mg, 0.108 mmol). The reaction mixture is heated to reflux overnight. After cooling to rt, the reaction mixture is partitioned between dichloromethane and water. The aqueous layer is back-extracted with dichloromethane, the combined organic layers are dried and concentrated, then loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 60% giving 2′-trifluoromethylbiphenyl-4-carbaldehyde (1.0548 g).
Reaction SMILES: [C:1]1([N:7]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[CH:10]=[C:9]([C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31].C(N(CC)CC)C>C1COCC1.[Cu](I)I>[C:1]1([N:7]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[CH:10]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:24][CH:23]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)c1ccc(C2C=C(c3ccc(I)cc3)NN2c2ccccc2)cc1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2C=C(c3ccc(C#C[Si](C)(C)C)cc3)NN2c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
After charging 9.6 parts of 1-phenyl-3-(4-iodophenyl)-5-(4-t-butylphenyl)pyrazoline synthesized by a known method, 2.4 parts of trimethylsilylacetylene, 0.28 parts of bis(triphenylphosphine)palladium(II) dichloroide, 0.04 parts of copper iodide and 40 mL of triethylamine in 80 mL of THF, the mixture was stirred at 60° C. for 10 hours. The reaction mixture was filtered, the obtained filtrate was concentrated, and the precipitate was filtered, washed, recrystallized from methanol and dried at 60° C. to obtain 5.6 parts of 1-phenyl-3-(4-trimethylsilylethynylphenyl)-5-(4-t-butylphenyl)pyrazoline having a melting point of 160-162° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[NH:12][N:11]=2)=[CH:6][CH:5]=1.[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[N:12]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[N:11]=2)=[CH:6][CH:5]=1
Reactant: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
At 0° C., NaH (60 percent, 0.48 g, 12.0 mmol) was added to a THF solution (15 mL) containing 6-(4-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.1 g, 9.7 mmol). Then SEM-Cl (60 percent, 2.4 mL, 12 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% ETOAc in hexane) to give 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.0 g, 6.7 mmol) as brown solid in 69% yield.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].[CH3:12][CH:13]([C@H:15]([NH:26]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C:16](ON1C(=O)CCC1=O)=[O:17])[CH3:14].CCN(C(C)C)C(C)C>ClCCl>[NH2:26][C@@H:15]([CH:13]([CH3:14])[CH3:12])[C:16]([NH:9][C@@H:8]([CH3:10])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])=[O:17]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of the alanine-O-tert-butyl ester hydrogen chloride salt (98) (500 mg, 2.76 mmol) in dichloromethane (5 mL) was added Fmoc-val-OSu (99) (1.09 g, 2.51 mmol). DIPEA (0.96 ml, 5.5 mmol) was added and the reaction mixture was allowed to stir at an ambient temperature for 16 h. The mixture was poured into dichloromethane (100 mL) and washed with 1N HCl (50 mL) and water (50 mL) before being dried over magnesium sulfate. The material was chromatographed on a 2 mm radial chromatotron plate eluting with 1 to 5% methanol/dichloromethane gradient and product containing fractions were combined and concentrated. The resulting residue was dissolved in dichloromethane (16 mL) and piperidine (4 mL) was added. The mixture was stirred for 10 min before being concentrated under reduced pressure. The resulting residue was chromatographed on a 2 mm plate eluting first with ammonia-saturated dichloromethane followed by 5% methanol in ammonia-saturated dichloromethane to give 494 mg (2.02 mmol, 81% for two steps) of 97: 1H-NMR (400 MHz, CDCl3) δ 7.78 (bs, 1H), 4.47 (m, 1H), 3.30 (d, 1H), 2.30 (m, 1H), 1.38 (d, 3H), 1.47 (s, 9H), 1.00 (d, J=7.0 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[CH:31][CH:32]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[C:40](N1C=CN=C1)(=[O:48])[C:41](N1C=CN=C1)=[O:42]>C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:21][CH2:22][N:23]([CH2:26][C:27]5[CH:28]=[C:29]6[C:30](=[CH:31][CH:32]=5)[NH:33][C:41](=[O:42])[C:40](=[O:48])[NH:34]6)[CH2:24][CH2:25]4)[C:13]=3[N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(C(=O)n1ccnc1)n1ccnc1
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc(N)c(N)c5)CC4)cccc3[nH]2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc6[nH]c(=O)c(=O)[nH]c6c5)CC4)cccc3[nH]2)cc1
Yield: 24.4 %

Procedure:
In a round bottom flask under nitrogen was combined 4-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-ylmethyl}-benzene-1,2-diamine (0.17 g, 0.37 mMol), tetrahydrofuran (20 mL), and 1,1′-oxalyldiimidazole (0.284 g, 1.5 mMol) and the solution stirred overnight. Upon arrival the solution was diluted with ethyl acetate (100 mL) and washed with water (100 mL). A precipitate forms and was collected by filtration. The organic layer was concentrated to dryness on a rotary evaporator and combined with the precipitate. Purification by RP-HPLC (Method E) yielded 46 mg (24% yield) of 6-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-ylmethyl}-1,4-dihydro-quinoxaline-2,3-dione as an off-white solid. 1H NMR (DMSO-d6): δ=12.19 (s, 1H), 12.09 (s, 1H), 9.82 (br s, 1H), 8.07 (d, 2H, J=8.6 Hz), 7.58 (d, 2H, J=8.6 Hz), 7.27 (m, 2H), 7.22 (d ,1H, J=8.6 Hz), 7.13 (m, 2H), 6.64 (m, 1H), 4.48 (br s, 2H), 4.44 (s, 2H), 3.50 (br s, 2H), 3.38 (br s, 2H), 3.09 (m, 2H), 1.34 (s, 9H). HPLC: Xterra MS C18, 3.5 μm, 4.6×50 mm, flow=0.8 m/min, 5-95% ACN/PICB6 over 10 mins., rt=5.840 mins., 79% pure @ 210 nm, 77% pure @ 300 nm. LC/MS (Method A), rt=1.05 mins., purity=79.19%, calculated mass=508, [M+H]+=509, [M−H]−=507.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1.[CH2:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22]Br)[CH2:18][CH2:17]1)[CH3:15].[OH-].[Na+].Cl>O>[CH2:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][O:3][C:4]2[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)[CH2:18][CH2:17]1)[CH3:15]
Reactant: CC[C@H]1CC[C@H](CBr)CC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC[C@H]1CC[C@H](COc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of potassium hydroxide (56.1 g) dissolved in 30 ml of water, and methyl 4-hydroxybenzoate (152 g) were suspended in 1500 ml of ethyleneglycolmonoethylether. To this mixture was dropped trans-4-ethylcyclohexylmethylbromide (200 g), and then the mixture formed was stirred under reflux for 4 hours. After cooling to room temperature, a solution of sodium hydroxide (80 g) dissolved in water (400 ml) was added with stirring and was refluxed for 2 hours. After the reaction was completed, the mixture was cooled, added with diluted hydrochloric acid (1 liter), and extracted with toluene (5 liters). The organic layer separated was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 4-(trans-4-ethylcyclohexylmethoxy)benzoic acid (147 g).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH:9]=[C:8]1[CH2:7][C:6](=[O:22])[CH2:5][C@H:4]2[CH3:23].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[CH3:23][C@H:4]1[C@@:3]2([CH2:2][OH:1])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[OH:21])[CH2:7][C@@H:6]([OH:22])[CH2:5]1
Reactant: C[C@@H]1CC(=O)CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](O)CC2=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A tetrahydrofuran solution of 19-hydroxy-1β-methyl-5-androstene-3,17-dione is added under nitrogen to a solution of lithium tri-t-butoxyaluminum hydride in tetrahydrofuran. After stirring at room temperature for about 18 hours, an aqueous solution of potassium sodium tartrate is added with stirring to form a readily filterable white solid. The reaction mixture is filtered, the filtrate dried over magnesium sulfate, and the solvent removed. The residue which remains is crystallized from an acetone-hexane solution to yield 1β-methyl-5-androstene-3β,17β,19-triol.