Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.CCOCC>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CNS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
1-Boc-4-(2-aminomethyl-phenyl)-piperazine (2.09 g, 7.18 mmol) was dissolved in methylene chloride (50 mL), cooled to 0° C. and treated with triethylamine (1.5 mL, 10.8 mmol) followed by methanesulfonyl chloride (0.67 mL, 8.61 mmol). The resulting mixture was stirred for about 3 hours at r.t., and then diluted with ether (200 mL) and washed with water (50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), which is then dried over anhydrous magnesium sulfate. Concentration under reduced pressure followed by silica gel chromatography (30% ethyl acetate in hexanes) afforded the title compound (2.07 g, 78%) as a clear oil.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[CH:11][C:12]#[N:13])[CH2:3][CH2:2]1>C(O)C.[Pd]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]#[N:13])[CH2:3][CH2:2]1
Reactant: N#CC=C1CCOc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: N#CCC1CCOc2ccccc21
Reaction time: 12 h

Procedure:
The unsaturated compound obtained in Step A (Z+E mixture), solubilized in ethanol (20 ml), is introduced into the reactor of a Parr apparatus. 10% (by weight) palladium-on-carbon is then added. The double bond is hydrogenated at a pressure of 45 psi for 12 hours.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5]O.[OH:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1>C(OCC)(=O)C.CCCCCC>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][C:14]([O:16][CH3:5])=[O:15])=[CH:17][CH:18]=1
Reactant: CO
Reactant: O=C(O)C=Cc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: COC(=O)C=Cc1ccc(O)cc1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
Thionyl chloride (1.33 mL) is added dropwise to methanol (30 mL) under ice-cooling and the solution is stirred for 10 minutes. To the solution is added 4-hydroxycinnamic acid (3.0 g) and the mixture is stirred at room temperature for 4 days. The reaction mixture is concentrated and the residue is diluted with ethyl acetate (50 mL), washed successively with a saturated sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is re-crystallized from ethyl acetate/n-hexane to methyl 4-hydroxycinnamate (2.86 g, yield; 88%) as pale yellow crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1C(=O)N([Cl:25])C(=O)C1>C(#N)C>[C:1]([NH:4][C:5]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=1[Cl:25])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(NC(C)=O)c2c1OCO2
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCO2
Yield: 85.9 %

Procedure:
A mixture of intermediate (2-c) (18.5 g) and NCS (11.4 g) in ACN (130 ml) was stirred and refluxed for one hour. The reaction mixture was cooled. The precipitate was filtered off, washed with ACN, with DIPE, then dried, yielding 18.2 g (87%) of methyl 7-(acetylamino)-6-chloro-1,3-benzodioxole-4-carboxylate (intermediate 2-d).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:10]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: ClC(c1cccnc1)c1cccnc1
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ncccc1OC(c1cccnc1)c1cccnc1
Reaction time: 8 h

Procedure:
To the solution of 2-bromo-3-hydroxypyridine (0.90 g, 5.18 mmol) and 3-[chloro(pyridin-3-yl)methyl]pyridine (2-1) (0.82 g, 3.99 mmol) in DMF (10 mL) at 0° C. was added Cs2CO3 (1.95 g, 5.98 mmol). The mixture was stirred overnight, poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was purified by silica gel chromatography (3% MeOH in CH2Cl2) to give 2-bromo-3-(dipyridin-3-ylmethoxy)pyridine (2-2). LRMS m/z (M+H) Calcd: 343.2, found: 343.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@@H:15]([CH3:33])[CH2:14]2)[C:9](=[O:12])[CH2:10][OH:11])=[CH:4][CH:3]=1.FC1C=C[C:38]([C:39](Cl)=[O:40])=CC=1.C(Cl)(=O)C>>[C:39]([O:11][CH2:10][C:9]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23](=[O:32])[C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C@@H:15]([CH3:33])[CH2:14]1)=[O:12])(=[O:40])[CH3:38]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)CO)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Solvent: CC(=O)Cl
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)COC(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1

Procedure:
N-(4-chlorophenyl)-2-hydroxy-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide was made following general procedure G, substituting 4-methoxybenzoyl chloride for 4-fluorobenzoyl chloride. Procedure A was followed further substituting acetoxyacetylchloride for acetyl chloride in the last step to yield 2-{(4-chlorophenyl)[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-2-oxoethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2].[C:41](=[O:44])([O-])[O-:42].[Na+].[Na+]>C(COC)OC.C(O)C.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24]([C:9]3[CH:14]=[CH:13][C:12]4[O:42][CH2:41][O:44][C:11]=4[CH:10]=3)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 172.5 %

Procedure:
A solution of 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (1.14 g, 1.65 mmol) in dimethoxyethane (15 mL) was stirred for 5 minutes at room temperature under nitrogen atmosphere. Then, tetrakis(triphenylphosphine)palladium(0) (386 mg, 0.33 mmol) was added at room temperature and the resulting light yellow solution was heated to 80° C. and stirred for 5 minutes. At this period, a solution of 3,4-(methylenedioxyphenyl)boronic acid (566 g, 3.3 mmol) in ethanol (16 mL) was added followed by a solution of sodium carbonate (351 mg, 3.3 mmol) in water (1.0 mL). The resulting light yellow suspension was stirred for 15 h at reflux. Then, the reaction mixture was cooled to room temperature and diluted with water (50 mL) and ethyl acetate (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (100 mL) and brine solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent under reduced pressure gave the colored residue which was purified by using an ISCO 80 g column, eluting with 0-20% ethyl acetate in hexanes to afford 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-methanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (972 mg, 86%) as a light brown viscous oil: ES(+)-HRMS m/e calcd for C37H46O10S (M+Na)+ 705.2704, found 705.2703.
Reaction SMILES: ClC(N(C)C)=C(C)C.[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH3:23])[C:18]([OH:20])=O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CC=CC=1.[CH3:30][C:31]1[N:35]=[C:34]([NH2:36])[S:33][N:32]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH3:23])[C:18]([NH:36][C:34]1[S:33][N:32]=[C:31]([CH3:30])[N:35]=1)=[O:20])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11]
Reactant: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: Cc1nsc(N)n1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1nc(C)ns1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
A solution of 1-chloro-N,N,2-trimethylprop-1-en-1-amine (1.521 mL, 11.50 mmol) in DCM (2 mL) was added dropwise to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-methoxypropanoic acid (Intermediate C4c) (2.45 g, 10.45 mmol) in DCM (10 mL) over a period of 1 minute under nitrogen. The resulting pale yellow solution was stirred at ambient temperature for 30 minutes Anhydrous pyridine (1.262 mL, 15.68 mmol) was added in one portion (solution turns deeper yellow) followed by 3-methyl-1,2,4-thiadiazol-5-amine (CAS no. 17467-35-5) (1.204 g, 10.45 mmol) in DCM (3 mL) dropwise over a period of 1 minute. The resulting solution was stirred at ambient temperature for 1 hour. 1M citric acid (50 mL) added and extracted with EtOAc (50 mL). Organic phase washed with water (25 mL) and brine (25 mL), dried (MgSO4), filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane to afford (S)-2-(tert-butyldimethylsilyloxy)-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (390 mg, 11%). 1H NMR (400 MHz, CDCl3) δ 0.11 (6H, dd), 0.89 (9H, s), 2.49 (3H, s), 3.30 (3H, s), 3.61 (2H, t), 4.46 (1H, dd), 9.75-9.90 (1H, s); m/z (ESI+) (M+H)+=332.30; HPLC tR=2.77 min.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.CCN(C(C)C)C(C)C.[O-]S([O-])(=O)=O.[Na+].[Na+].C=O.Cl>O1CCCC1.C1(C)C=CC=CC=1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (1.0 g, 2.2 mmol) is dissolved in 5 mL of anhydrous tetrahydrofuran, add iPr2NEt (370 mg, 2.8 mmol) anhydrous Lithium chloride (49 mg, 1.1 mmol) and anhydrous Na2SO4 (260 mg, 2.2 mmol), reflux for 30 min under nitrogen atmosphere, then add paraformaldehyde (80 mg, 2.7 mmol), reflux for 2 h under nitrogen atmosphere. The reaction mixture is cooled to room temperature, add 20 mL of toluene and 10 mL of 5% HCl(aq), separate the aqueous phase, wash with saturated sodium hydrogen carbonate aqueous solution and brine, dry over anhydrous sodium sulfate and concentrate under vacuum to obtain (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl). Spectroscopic data as Example 23, Method 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH:13]([S:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:24])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25](O)[CH2:26][OH:27].B(F)(F)F.C(OCC)(=O)C.C1CCCCC1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C:12]2([O:27][CH2:26][CH2:25][O:24]2)[C@H:13]([S:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCO
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)C(SC(=O)c2ccccc2)C1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCC2(OCCO2)[C@H](SC(=O)c2ccccc2)C1
Reaction time: 48 h
Yield: 28.1 %

Procedure:
A mixture of the compound of Example 35 Step A (2.00 g, 5.72 mmol), 1,2-ethandiol (2.0 ml, 35.8 mmol), 25 ml of dichloromethane and BF3 (48% purity, 0.60 ml, 4.25 mmol) was stirred for 2 days. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine, dried and stripped of the solvent. After chromatography (silica, ethyl acetate/cyclohexane=1/9->15/85) the title compound (toluene/ethyl acetate=9/1, Rf=0.28, 632 mg, 28% yield) was obtained as foam.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][C:16]#[N:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH4+].[OH-].N>C(O)C.[Ni]>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][CH2:16][NH2:17])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: N#CCc1c2ccccc2cc2ccccc12
Agent: [Ni]
Agent: N
Agent: [NH4+]
Solvent: CCO
Product: NCCc1c2ccccc2cc2ccccc12
Reaction time: 48 h
Yield: 85 %

Procedure:
To a solution of anthracen-9-yl-acetonitrile (3.0 g, 13.82 mmol) in ethanol (150 mL) was added concentrated NH4OH (15 mL) and Raney nickel (15 g), and ammonia gas was bubbled through the mixture at 0° C. for 10 minutes. The suspension was hydrogenated for 48 hours at room temperature. Air was bubbled through the solution and Raney nickel was removed by filtration. The filtrate was concentrated and the oily residue was dissolved in CH2Cl2, washed with an aqueous solution of sodium carbonate (Na2CO3, 10%), dried over MgSO4 and concentrated. The resulting solid was purified by recrystallization from a mixture of hexane and CH2Cl2 (7:3) to give 2-anthracen-9-yl-ethylamine as yellow crystals (2.60 g, 85%). 1H NMR (CDCl3) δ 8.37 (1H, s), 8.33 (2H, d), 8.02 (2H, d), 7.54-7.47 (4H, m), 3.86 (2H, t), 3.19 (2H, t), 1.34 (2H, br-s).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([NH:25][C:26]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=2)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:27])=[CH:21][CH:20]=1
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Reactant: Cc1ccc(N=C=O)cc1
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2ccc(C)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C1(C)C=CC=CC=1.[NH2-].[Na+]>O>[CH2:15]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCBr
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCN(c1ccccc1)c1ccccc1
Temperature: 120 °C

Procedure:
253.8 Grams of diphenylamine, 297.0 g of 1-bromohexane and 1,500 ml of toluene were mixed, and 150 g of sodiumamide was added little by little with stirring. After completion of the addition, the mixture was refluxed under heat on an oil bath at 120° C. with stirring for 10 hours. Then, the reaction mixture was poured into 2,000 ml of water little by little, and the mixture was stirred at room temperature for 1.0 hours. During the stirring, heat generation was observed. The mixture was transferred into a separation funnel, and an organic layer was recovered. The recovered liquid was washed consecutively with water and saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The resultant oily substance was distilled under reduced pressure, to give 337 g of N-hexyldiphenylamine (117) having a boiling point of 173-175° C. (0.4 Torr). The yield thereof was 88.6%.
Reaction SMILES: BrC(Br)[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.[Cl-].[Li+].C(OCC)C.[CH2:33]([Cl:35])[Cl:34]>CN(C)C=O.C(OCC)(=O)C>[Cl:34][CH:33]([Cl:35])[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Br)Br)c3c2)c1=O
Reactant: ClCCl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Cl)Cl)c3c2)c1=O

Procedure:
A solution of 3-[3-(dibromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.750 g, 0.00150 mol) and lithium chloride (0.950 g, 0.0225 mol) in N,N-dimethylformamide is stirred at room temperature for 48 hours and diluted with ethyl acetate. The resultant mixture is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a foam. Column chromatography of the foam using silica gel, methylene chloride, and a 1% diethyl ether in methylene chloride solution gives the title product as a white foam (0.530 g, mp 148-149° C.).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][C:16]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(C(OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>COCCO.O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][CH:16]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:36][CH:37]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: CCOC(=O)C(CCCc1ccccc1)Cc1ccc(OCc2ccccc2)cc1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
Potassium hydroxide (2.00 g) was added to a solution of diethyl 2-(4-benzyloxybenzyl)-2-(3-phenylpropyl)malonate (3.91 g) in a mixture of 2-methoxyethanol (30 ml) and water (3 ml). The mixture was stirred at 130° C. in an oil bath for 1.5 hours. At the end of this time the reaction mixture was partitioned between ethyl acetate and water and the mixture was acidified with aqueous hydrogen chloride solution (6N). The ethyl acetate layer was separated and washed with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated. A solution of the residual syrup in xylene (20 ml) was stirred for 1 hour and then concentrated. Concentrated sulfuric acid (1 ml) was added to a solution of the syrup residue of 2-(4-benzyloxybenzyl)-5-phenylvaleric acid in ethanol (40 ml). The mixture was stirred at 80° C. for 3 hours and allowed to stand at ambient temperature for 16 hours. At the end of this time the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and concentrated to dryness to afford the desired compound (3.32 g) as a syrup.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=3)=[CH:7][C:5]=2[N:6]=1.[Li+].[OH-].O.Cl>C1COCC1.CO>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1ccc(-c2ccc3oc(C)nc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2cc(-c3ccc(C(=O)O)cc3)ccc2o1
Reaction time: 1 h

Procedure:
A room temperature solution of Example 54A (80 mg, 3.0 mmol) and LiOH (630 mg, 15.0 mmol) in a mixture of THF (15 mL), water (4 mL), and methanol (4 mL) was stirred for 1 hour, poured into 1M HCl, and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:27]2[CH2:29][CH2:28]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH:30][NH:31][C:32](=N)[CH2:33][CH3:34]>>[CH:27]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:30][N:31]=[C:32]([CH2:33][CH3:34])[N:2]=3)[CH2:8][CH2:7]2)[C:10]([C:12]2[CH:17]=[N:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=3)=[N:14][CH:13]=2)=[O:11])[CH2:28][CH2:29]1
Reactant: CCC(=N)NO
Reactant: N#Cc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cc1F
Product: CCc1noc(N2CCC(N(C(=O)c3cnc(-c4ccc(C#N)c(F)c4)nc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from 2-(4-cyano-3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide and N-hydroxy-propionamidine following a procedure analogous to that described in Example 6. LC (method 3): tR=1.94 min; Mass spectrum (ESI+): m/z=462 [M+H]+.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][C@H:9]([OH:21])[CH:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:22]>C(Cl)Cl.CC(C)=O.O=[Mn]=O>[OH:20][C@H:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[CH:10]([C:9](=[O:21])[CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C@@H:3]2[OH:22])[CH2:11]1
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@H](O)C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CC(=O)C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 45 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of androstane-3β,6α,17β-triol (3.00 g) in CH2Cl2/acetone/—H2O (300/150/6 mL), activated MnO2 (30.0 g, 345 mmol) was added in three portions over 8 h. The mixture was stirred at 45° C. overnight. After cooling to room temperature, the mixture was filtered through Celite. The filtrate was evaporated and the residue was purified by flash chromatography (SiO2, CH2Cl2/n-n-hexane/i-PrOH 10/5/1) to give 3β,17β-dihydroxyandrostan-6-one (0.89 g, 30%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.54 (d, 1H), 4.48 (d, 1H), 3.45 (m, 1H), 3.30 (m, 1H), 2.27 (dd, 1H), 2.08-0.90 (m, 19H), 0.62 (s, 3H), 0.61 (s, 3H).