Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:9]=[C:10]=[O:11].[Sn]>>[CH2:6]([NH:9][C:10](=[O:11])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][NH:9][C:10](=[O:11])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: [N-]=C=O
Agent: [Sn]
Product: O=C(NCCCCCCNC(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
Into a 16 oz jar equipped with magnetic stir was charged 120 g benzyl alcohol (MW=108 g/mol, 1.11 mmol) and 10 drops of Fascat 4202 catalyst. The jar was placed in an about 130° C. oil bath. Next, 93.3 g HDI (MW=168 g/mol, 0.56 mmol) was added. An exotherm was observed. IR was checked after 1 hour of reaction and showed no isocyanate peak between 2200 and 2400 cm−1, indicating that the reaction was complete. The reaction contents were poured into a tin pan to cool and solidify. DSC was employed to measure thermal properties of the materials. DHDC is a white powdered material having the following structure:
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][NH2:25]>>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([NH:25][CH3:24])=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: CN
Agent: Cl
Product: CNC(=O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2) and methylamine hydrochloride.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:12][C:11]=1[F:32]>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:4]4[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[C:11]([F:32])[CH:12]=3)=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)c(F)c3)CC2)c(C)c1
Yield: 14.5 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (119 mg) described in Preparation Example 4 and (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (230 mg) described in Preparation Example 125 and by the reaction and treatment in the same manner as in Example 4, the title compound (38 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:15]([CH3:23])=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)=[CH:5][N:6]=1>CO.[Pd]>[CH3:23][C:15]1[N:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:14]=1[O:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:4]2[S:3][C:2]([CH3:1])=[N:6][CH:5]=2)[CH:12]=1
Reactant: Cc1ncc(-c2cc(Oc3ccc([N+](=O)[O-])nc3C)ccn2)s1
Agent: [Pd]
Solvent: CO
Product: Cc1ncc(-c2cc(Oc3ccc(N)nc3C)ccn2)s1
Yield: 70.3 %

Procedure:
A solution of 2-methyl-5-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (0.094 g, 0.286 mmol) in MeOH (30 mL) was flushed with Ar, treated with 10% Pd/C (50% wet, 0.305 g, 0.286 mmol) and hydrogenated (1 atm) overnight. The solids were removed via filtration through diatomaceous earth, washed well with MeOH and the filtrate was concentrated to dryness to afford 6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (60 mg, 70%). 1H NMR (400 MHz, DMSO-d6): δ 8.34 (d, J=5.8 Hz, 1H), 8.28 (s, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 6.58 (dd, J=5.8, 2.4 Hz, 1H), 6.34 (d, J=8.7 Hz, 1H), 5.96 (s, 2H), 2.65 (s, 3H), 2.07 (s, 3H); MS (ESI) m/z: 299.1 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][N:6]2[CH:11]=[CH:10][C:9]3=[N:12][CH:13]([N:15]4[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH3:24])[CH2:17][CH2:16]4)[O:14][C:8]3=[CH:7]2)[CH2:3][CH2:2]1.Cl.[CH3:34]O>>[CH:1]1([CH2:4][O:5][N:6]2[CH:11]=[CH:10][C:9]3=[N:12][CH:13]([N:15]4[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:27])[CH3:34])[CH3:24])[CH2:17][CH2:16]4)[O:14][C:8]3=[CH:7]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](COC1CCN(C2N=C3C=CN(OCC4CC4)C=C3O2)CC1)NC(=O)OC(C)(C)C
Reactant: CO
Agent: Cl
Product: CC(=O)N[C@@H](C)COC1CCN(C2N=C3C=CN(OCC4CC4)C=C3O2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl [(1S)-2-({1-[5-(cyclopropylmethoxy)[1,3]oxazolo[5,4-c]pyridin-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate (328 mg) was added 2M hydrogen chloride/methanol (4 mL), and the mixture was stirred at room temperature for 10 min and concentrated. Pyridine (4 mL) and acetic anhydride (0.5 mL) were added to the residue, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated, saturated brine was added to the residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol/ethyl acetate). The obtained solid was washed with diisopropyl ether to give the title compound (197 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH:13]=[CH:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.[F:21][C:22]1[CH:23]=[C:24](I)[CH:25]=[CH:26][CH:27]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:12]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=2)[CH:13]=1
Reactant: Fc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)N1C=CC(c2cc(F)ccc2F)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=CC1c1cccc(F)c1

Procedure:
To a flame dried flask equipped with stir bar was added tert-butyl 3-(2,5-difluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (2-2, 0.088 g, 0.31 mmol), 3-fluoro-1-iodobenzene (0.070 g, 0.31 mmol), triphenylarsine (0.038 g, 0.13 mmol), tributylamine (0.15 mL, 0.62 mmol) and anhydrous DMF (2.0 mL). The resulting solution was purged, and filled with a nitrogen atmosphere. Palladium acetate (0.014 g, 0.06 mmol) was added in one portion, and the reaction was carefully returned to a nitrogen atmosphere. The reaction stirred under nitrogen for 24 h at 65° C. The reaction was then diluted with EtOAc (10 mL) and poured into 5% aq. NaHCO3 in a separatory funnel. The organic layer was washed with brine, separated and dried over magnesium sulfate. The organic layer was then filtered and concentrated to provide crude product. Purification by flash column chromatography (SiO2, 0-20% EtOAc/hexanes gradient) provided tert-butyl 4-(2,5-difluorophenyl)-2-(3-fluorophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4-1). LRMS m/z (M+H) 361.0 found, 361.1 required (M−15). Further transformations followed those described in Scheme 1.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1.COCN[C:23]([C:25]1[C:29]([CH3:30])=[C:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:27]([CH3:38])[N:26]=1)=[O:24].C(O)(=O)C>C1COCC1>[Cl:11][C:12]1[CH:17]=[C:16]([CH2:18][C:23]([C:25]2[C:29]([CH3:30])=[C:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[N:27]([CH3:38])[N:26]=2)=[O:24])[CH:15]=[CH:14][N:13]=1
Reactant: COCNC(=O)c1nn(C)c(-c2ccc(F)cc2)c1C
Reactant: Cc1ccnc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1c(C(=O)Cc2ccnc(Cl)c2)nn(C)c1-c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
To 10 ml of dry THF cooled to −65° C. were added 1.35 ml of a 2M solution of Sodium-bis(trimethylsilyl)amide in THF. Then a solution of 0.32 g 2-Chlor-4-methyl pyridine in 1 ml of dry THF was added dropwise maintaining the temperature at −70° C. for 30 min. Then a solution of 0.50 g of 5-(4-Fluoro-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid methoxymethyl-amide in 5 ml of dry THF was added dropwise over a 10 min period maintaining the temperature below −65° C. The solution was stirred for 2 h at −60° C., and then allowed to warm up to 0° C. and stirred for 20 min at this temperature. Then 0.31 ml of Acetic acid was added dropwise at −50° C., and the solution was allowed to warm up to room temperature and stirred overnight. The mixture was concentrated in vaccuo. The residue was taken up in Ethyl acetate. The organic phase was washed with saturated bicarbonate solution and brine, dried over magnesium sulfate, filtered and evaporated. The crude product (0.67 g, yellow oil) was purified by chromatography on silica gel (Heptane/Ethyl acetate 4:1). The desired product was obtained as a white solid (0.27 g, 70%), MS: m/e=344.0 ([M+1]+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:21](=[O:23])[CH3:22])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[C:21]([NH:20][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][N+:17]([O-:32])=[CH:16][CH:15]=2)=[C:9]([C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)[N:10]=1)(=[O:23])[CH3:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1nc(-c2cc(C)cc(C)c2)c(-c2ccncc2)s1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(-c2cc(C)cc(C)c2)c(-c2cc[n+]([O-])cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a suspension of N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide (1.0 g) in chloroform (30 mL), was added 70% m-chloroperbenzoic acid (0.80 g), and the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was treated with an aqueous saturated solution of sodium hydrogen carbonate. The formed crystalline residue was washed with water, dried and recrystallized from ethanol to obtain the title compound (0.55 g, yield 53%).
Reaction SMILES: B.[Cl:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]=1[C:12](O)=[O:13]>C1COCC1>[Cl:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]=1[CH2:12][OH:13]
Reactant: O=C(O)c1sc2ccccc2c1Cl
Agent: B
Solvent: C1CCOC1
Product: OCc1sc2ccccc2c1Cl
Temperature: 25 °C

Procedure:
Borane (1M in THF, 6.11 mL, 6.11 mmol) was added to a stirred suspension of 3-chloro-1-benzothiophene-2-carboxylic acid (1.00 g, 4.70 mmol) in dry THF (2 mL) at 0° C. under N2. The reaction was allowed to warm to room temperature and was heated at reflux for 1½ h. The reaction was quenched with water (5 mL) and saturated K2CO3 (10 mL), then extracted with EtOAc (3×30 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford (3-chloro-1-benzothien-2-yl)methanol. 1H NMR (500 MHz, CDCl3): δ 7.79-7.77 (m, 2H); 7.45-7.42 (m, 1H); 7.39-7.36 (m, 1H); 4.96 (s, 2H); 2.48 (s, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:8][CH2:9][C:10]2[N:21]=[C:13]3[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[C:17]([CH3:18])[N:12]3[N:11]=2)[N:5]([CH3:7])[CH:6]=1.[O:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>O.[Cl-].[Na+].O.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.CCOC(C)=O>[O:22]1[CH:26]=[CH:25][C:24]([C:2]2[N:3]=[C:4]([CH2:8][CH2:9][C:10]3[N:21]=[C:13]4[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[C:17]([CH3:18])[N:12]4[N:11]=3)[N:5]([CH3:7])[CH:6]=2)=[CH:23]1
Reactant: OB(O)c1ccoc1
Reactant: COc1ccc(C)n2nc(CCc3nc(Br)cn3C)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(C)n2nc(CCc3nc(-c4ccoc4)cn3C)nc12
Temperature: 110 °C
Yield: 14.8 %

Procedure:
A glass vial was charged with 2-[2-(4-Bromo-1-methyl-1H-imidazol-2-yl)-ethyl]-8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine (70 mg, 0.20 mmol), furan-3-boronic acid (33.6 mg, 0.30 mmol), 1,2-dimethoxyethane (0.8 mL), 1M solution of sodium carbonate in water (0.3 mL) and the slurry was deoxygenated by bubbling argon through then tetrakis(triphenylphosphine)palladium(0) (5.2 mg, 0.0045 mmol) was added and the vessel sealed and heated at 110° C. for 12 hours. EtOAc (3 mL) was added followed by brine solution (2 mL). The organic layer was separated and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel (gradient 100% EtOAc to EtOAc:MeOH, 7:3) to yield the title compound (10 mg, 10%). LCMS (MH+): m/z=338.1, tR (minutes, method B)=0.41
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=O)[C:6]=2[CH:5]=[C:4]([CH3:13])[C:3]=1[NH:14][C:15](=[O:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+]>C1(C)C=CC=C(C)C=1>[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][CH:7]2[CH2:8][CH2:9][CH2:10][C:11]3[C:2]([CH3:1])=[C:3]([NH:14][C:15](=[O:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]([CH3:13])=[CH:5][C:6]2=3)=[CH:25][CH:24]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1cccc(C)c1
Product: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)CCCC2Nc1ccc(F)cc1
Temperature: 160 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
A mixture of N-(1,3-dimethyl-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-3,3-dimethylbutanamide (150 mg, 0.52 mmol), 4-fluoroaniline (116 mg, 1.04 mmol), and pTSA (20 mg) in 20 ml of m-xylene was heated at 160° C. for 6 hours. The solvent was removed in vacuo, and the residue was dissolved in a mixture of methanol (10 ml) and acetic acid (2 ml). Sodium cyanoborohydride (49 mg, 0.78 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. After neutralization with saturated sodium bicarbonate, the mixture was extracted with chloroform (×3). The organic layer were combined, dried over anhydrous Na2SO4 and evaporated to dryness in vacuo. The residue was purified by Biotage (hexane/EtOAc, 0-30%, 40 min) to give a white solid (75 mg, 38%). 1H-NMR δ (DMSO-d6, 500 MHz): 9.09 (brs, 1H, exchangeable with D2O), 7.00 (s, 1H), 6.89 (t, J=7.5 Hz, 2H), 6.65 (dd, J=5.7 and 7.5 Hz, 2H), 5.70 (brs, 1H, exchangeable with D2O), 4.45 (m, 1H), 2.61 (m, 1H), 2.51 (m, 1H), 2.20 (s, 2H), 2.06 (s, 3H), 1.99 (s, 3H), 1.84 (m, 1H), 1.73 (m, 3H), 1.04 (s, 9H). MS: 383 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=2[N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)=O)[CH2:4][CH2:3]1>P(Cl)(Cl)(Cl)=O>[Br:17][C:15]1[CH:14]=[CH:13][C:12]2[N:18]3[CH2:19][CH2:20][CH2:21][C:22]4=[CH:23][CH:24]=[CH:25][C:26](=[C:27]34)[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[N:10][C:11]=2[CH:16]=1
Reactant: CN1CCN(C(=O)Nc2cc(Br)ccc2N2CCCc3ccccc32)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3cc(Br)ccc3N3CCCc4cccc2c43)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
A stirred solution of 4-methyl-N-[5-bromo-2-(1,2,3,4-tetrahydro-1-quinolinyl)phenyl]piperazinecarboxamide (8.6 g, 0.020 mole) in phosphorus oxychloride (200 ml) was heated under reflux under nitrogen for 6 hours. The reaction mixture was cooled to room temperature and excess phosphorus oxychloride was removed at aspirator pressure with heating. The residue was chilled in an ice-bath (with exclusion of moisture), and treated with ice-cold 2N sodium hydroxide solution (250 ml) and dichloromethane (250 ml). The mixture was stirred and triturated until the residue dissolved. The organic phase was separated, washed again with 2N sodium hydroxide solution, twice with water, dried over sodium sulfate, and concentrated in vacuo. The residue was taken up in 4N hydrochloric acid (100 ml), filtered, and the filtrate was stirred 15 minutes with charcoal. After filtration, the solution was stirred with dichloromethane (100 ml), and the mixture was made alkaline by the addition of cold 2N sodium hydroxide solution. The organic phase was separated, washed twice with water, dried over sodium sulfate, and boiled 15 minutes with charcoal. After filtration, the solution was concentrated to give 4.6 g (56%) of product, as an oil, which crystallized on standing. The product was taken up in boiling methanol (20 ml) and allowed to crystallize first at room temperature, then in the refrigerator. Recrystallization from methanol afforded the analytical sample, mp 153°-156° C.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25](O)=[O:26])[C:5]1=[O:30])[CH:2]=[CH2:3].[C:31]([NH:34][NH2:35])(=[O:33])[CH3:32].Cl.C(N=C=NCCCN(C)C)C.N1C2C(=NC=CC=2)N(O)N=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C=O)C.Cl>[C:31]([NH:34][NH:35][C:25](=[O:26])[C@@H:24]([N:6]1[C@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH2:9][C@H:4]([CH2:1][CH:2]=[CH2:3])[C:5]1=[O:30])[CH2:28][CH3:29])(=[O:33])[CH3:32]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)O)C1=O
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)NNC(C)=O)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 95 mg (0.213 mmol) of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoic acid (Example 33, Step A) and acetic hydrazide (23.65 mg, 0.319 mmol) in DCM (479 μL) and DMF (53.2 μL) was treated at 0° C. with N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (122 mg, 0.638 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (87 mg, 0.638 mmol), and sodium bicarbonate (53.6 mg, 0.638 mmol) at 0° C., successively. Then the reaction was stirred at 25° C. for 12 h. The reaction was diluted with 1 N aq. HCl and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl and NaHCO3-solutions, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by chromatography on silica gel (60% to 80% EtOAc/Hexanes, gradient elution) provided the title compound as a colorless film. MS (ESI) 502.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][N:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[N:16]=[CH:17][C:18](/[CH:19]=[CH:28]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(N[C@@H]2CCCN(Cc3ccccc3)C2)nc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCCN(Cc3ccccc3)C2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
To a solution of 6-{[(3R)-1-benzyl-3-piperidinyl]amino}nicotinaldehyde (110 mg, 0.37 mmol) in tetrahydrofuran (4 mL) was added (carbethoxymethylene)triphenylphosphorane (260 mg, 0.75 mmol) and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform-MeOH=15-1) to give ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-3-pyridinyl)acrylate (77 mg, 57%) as an oil.
Reaction SMILES: [P:1]([O:13]CCCC)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].COC(=O)[O-].[CH3:23][NH+:24]1[CH2:28][CH:27]([CH3:29])[N:26]([CH3:30])[CH:25]1[CH3:31].O>CO>[CH2:9]([O:8][P:1]([O-:13])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2])[CH2:10][CH2:11][CH3:12].[CH3:23][NH+:24]1[CH2:28][CH:27]([CH3:29])[N:26]([CH3:30])[CH:25]1[CH3:31]
Reactant: CCCCOP(=O)(OCCCC)OCCCC
Agent: CC1C[NH+](C)C(C)N1C
Agent: COC(=O)[O-]
Solvent: O
Solvent: CO
Product: CCCCOP(=O)([O-])OCCCC
Temperature: 100 °C
Reaction time: 20 h

Procedure:
By adding 62 parts of tributyl phosphate to the above-described methanol solution of 46 parts of 1,2,3,4-tetramethylimidazolinium methylcarbonate salt, followed by addition of 5.4 parts of water and stirring at 100° C. for 20 hours, tributyl phosphate was hydrolyzed and a salt exchange reaction was carried out to obtain a methanol solution of 1,2,3,4-tetramethylimidazolinium dibutyl phosphate monoanion. The above-described solution was heated under reduced pressure of 1.0 kPa or less at 50° C. to distill methanol until no distillate of methanol was observed. Thereafter, the temperature was raised from 50° C. to 100° C. and heating was continued for 30 minutes to distill and remove monomethyl carbonate (HOCO2CH3), methanol, and carbon dioxide (slight amounts of methanol and carbon dioxide are formed by thermal decomposition of monomethyl carbonate. Hereinafter, these are abbreviated as by-products). Thus, 1,2,3,4-tetramethylimidazolinium dibutyl phosphate monoanion, electrolyte (C-1), was obtained. The yield was 99 parts (yield based on the weight of 46 parts of 1,2,3,4-tetramethylimidazolinium methyl carbonate salt; hereinafter the same shall apply). The molecular weight of the electrolyte (C-1) was 280.
Reaction SMILES: [CH2:1]([C@H:3]1[C@H:20]([OH:21])[CH2:19][CH2:18][C@@:17]2([CH3:22])[CH:4]1[C@@H:5]([OH:24])[CH2:6][C@@H:7]1[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[OH:23])[CH3:2].C1C(=O)N(Br)C(=O)C1.CCOC(C)=O.[O-]S([O-])=O.[Na+].[Na+]>O1CCOCC1.O.N1C=CC=CC=1>[CH2:1]([C@H:3]1[C:20](=[O:21])[CH2:19][CH2:18][C@@:17]2([CH3:22])[CH:4]1[C@@H:5]([OH:24])[CH2:6][C@@H:7]1[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]1[CH2:9][CH2:10][C:11]2=[O:23])[CH3:2]
Reactant: CC[C@@H]1C2[C@@H](O)C[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC[C@H]1O
Agent: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O
Product: CC[C@H]1C(=O)CC[C@@]2(C)C1[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 72 h
Yield: 57.7 %

Procedure:
To a stirred solution of 4β-ethylandrostan-3α,6α,17β-triol (Preparation 11, 237 mg) in dioxane (5.8 ml), water (1.08 ml), pyridine (0.1 ml) and NBS (249 mg) were added. After 72 h, EtOAc (70 ml), H2O (30 ml) and 10% Na2SO3 aqueous solution (24 ml) were added and the mixture was stirred for 10 min. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with of 5% aqueous NaHCO3, brine, dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (SiO2, EtOAc/n-hexane 70/30) to give the title compound as a white solid (135 mg, 57%).