Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([CH:26]([OH:28])[CH3:27])[NH:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[O:29]1[C:33](=[O:34])[CH2:32][CH2:31][C:30]1=[O:35]>CN(C)C1C=CN=CC=1.C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([CH:26]([O:28][C:33](=[O:34])[CH2:32][CH2:31][C:30]([OH:35])=[O:29])[CH3:27])[NH:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: O=C1CCC(=O)O1
Reactant: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(OC(=O)CCC(=O)O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
N—((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxy-ethyl)-1H-pyrazole-3-carboxamide (1.254 mmol, 0.5 g), dihydrofuran-2,5-dione (1.504 mmol, 0.151 g) and 4-dimethylaminopyridine (0.1254 mmol, 0.015 g) were dissolved in THF (10 ml) and DMF (1 ml). The resulting mixture was stirred at RT for one day after which the temperature was raised to 50° C. for one day. The mixture was stirred at RT over the weekend. During the reaction more dihydrofuran-2,5-dione (50 mg) was added. The solvents were evaporated and the residue was dissolved in EtOAc. The organic phase was washed with 1 M HCl, separated, dried, filtered and evaporated. The crude product was purified by flash chromatography. 352 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.22-1.28 (m, 3H), 1.61-1.69 (m, 3H), 2.54-2.79 (m, 4H), 4.29-4.45 (m, 2H), 4.52-4.64 (m, 1H), 5.97-6.06 (m, 1H), 6.58-6.62 (m, 1H), 6.76-6.80 (m, 1H), 7.50-7.53 (m, 1H), 7.62-7.68 (m, 1H), 7.70-7.77 (m, 1H), 7.90-8.04 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>C1COCC1.CO.[Pd]>[C:21]1([S:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)(=[O:19])=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(c1ccccc1)n1ccc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
Pd/C 10 wt. % (0.10 g, 0.094 mmol) was added to a solution of 5-(benzyloxy)-1-(phenylsulfonyl)-1H-indole (Intermediate 7, 6.00 g, 16.5 mmol) and ammonium formate (15.6 g, 248 mmol) in THF/MeOH 1:1 (300 mL). The reaction mixture was stirred overnight at room temperature and filtered through a short plug of silica gel. The filtrate was evaporated and dissolved in DCM and filtered through a plug of silica gel eluating with 2.5% MeOH in DCM. The purest fractions (monitored by TLC) were evaporated to give the title compound (4.2 g) as a white powder. MS m/z 273 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[C:4]([Br:12])[C:3]=1[OH:13].CC(C)([O-])C.[K+].[Cl:20][C:21]1[N:22]=[N:23][C:24](Cl)=[CH:25][C:26]=1[CH:27]([CH3:29])[CH3:28]>CN(C)C(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[C:4]([Br:12])[C:3]=1[O:13][C:24]1[N:23]=[N:22][C:21]([Cl:20])=[C:26]([CH:27]([CH3:29])[CH3:28])[CH:25]=1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Reactant: OCCCc1cc(Br)c(O)c(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)c1cc(Oc2c(Br)cc(CCCO)cc2Br)nnc1Cl
Temperature: 100 °C
Reaction time: 24 h
Yield: 24.7 %

Procedure:
A mixture of 2,6-dibromo-4-(3-hydroxy-propyl)-phenol (20) (5.0 g, 16.3 mmol) in N,N-dimethyl acetamide (8 mL) was treated with potassium tert-butoxide (1.74 g, 15.48 mmol) under nitrogen at room temperature. The suspension was heated to 100° C. for 15 min and turned brown in color. 3,6-Dichloro-4-isopropyl pyridazine (7) (2.47 g, 12.9 mmol) was added to the suspension and the reaction was stirred at 140° C. for 24 h. The reaction was cooled to room temperature, diluted with water (180 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined and were washed with a 1N aqueous sodium hydroxide solution (1×150 mL), followed by a saturated aqueous sodium chloride solution (1×150 mL). The organic layer was dried with sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (Biotage 40M) eluted with 15% ethyl acetate in hexanes, followed by 25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes. The desired fractions were collected and concentrated under vacuum. The resulting solid was slurried in cold acetonitrile and filtered. The solid was then diluted with a 1:1 mixture of isopropyl acetate:methyl tert-butyl ether (20 mL). The mixture was heated to reflux and then cooled to room temperature. The solvent was decanted. The solid was slurried in heptane, filtered and dried under high vacuum overnight. The filtrate was concentrated. The resulting solid was then diluted with a 1:1 mixture of isopropyl acetate: methyl tert-butyl ether (20 mL). The mixture was heated to reflux and then cooled to room temperature. The solvent was decanted and the solid was slurried in heptane and filtered to afford a second crop of solid which was dried under high vacuum overnight. The solids were combined to afford 3-[3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-propan-1-ol (21) (1.48 g, 20%) as a white solid; LRMS for C16H17Br2ClN2O2 (M+H) m/z=465. Molecular Weight=464.5871; Exact Mass=461.9345
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:33](Br)[CH:34]=[CH2:35]>O1CCCC1>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH2:35][CH:34]=[CH2:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: O=C(CC1CCCCC1)N1C(=O)OCC1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)N1C(=O)OCC1Cc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzyl-3-(2-cyclohexyl-acetyl)-oxazolidin-2-one (16.0 g, 53 mmol) in anhydrous tetrahydrofuran at −78° C. was added a 1.0 M solution of sodium bis(trimethylsilyl)amide (79.0 mL, 79 mmol), and the reaction mixture was stirred for 1 h. To the reaction mixture was then added allyl bromide (18.4 mL, 213 mmol), and the temperature was raised to −45° C. The reaction mixture was stirred at this temperature for 3 h. The reaction was quenched with aqueous saturated NH4Cl solution, and the resulting mixture was warmed to room temperature. The reaction mixture was extracted with ethyl acetate, and the combined extracts were washed with brine. The organic layers were dried (MgSO4) and concentrated in vacuo to yield a residue that was purified by silica gel column chromatography (5:1 hexanes:ethyl acetate) to yield (4-benzyl-3-(2-cyclohexyl-pent-4-enoyl)-oxazolidin-2-one) as a thick liquid that became a solid upon storage.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:13]([O-])=O)[N:3]=1>CO.O1CCOCC1>[OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH2:13])[N:3]=1
Reactant: O=[N+]([O-])c1cccc2nc(O)c(O)nc12
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cccc2nc(O)c(O)nc12
Reaction time: 20 h

Procedure:
2.00 g of 2,3-dihydroxy-5-nitroquinoxaline was dissolved in 1:1 mixed solvent of methanol/dioxane, then the reaction system was sufficiently flushed with argon, and 1.00 g of Pd/C (anhydrous) was added to the reaction mixture. Thereafter, the reaction system was flushed with hydrogen, and reaction was allowed at room temperature for 20 hr. After the reaction was over, the reaction mixture was dispersed in a solution of 6.00 g of potassium carbonate in 130 ml of water, thereby dissolving the reaction product. Filtration was conducted, and 35% hydrochloric acid was gradually added to the solution obtained upon the filtration, to obtain precipitates.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH2:9])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11]>C1COCC1>[CH:4]1[CH:3]=[C:2]([CH2:6][C:7]([NH2:9])=[S:11])[S:1][CH:5]=1
Reactant: NC(=O)Cc1cccs1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: NC(=S)Cc1cccs1
Yield: 54.5 %

Procedure:
To a solution in THF (200 mL) of 2-thiopheneacetamide (4.04 g, 28.6 mmol), prepared as in step 1, was added P4S10 (12,7 g, 28.6 mmol), and the vigorously stirred reaction mixture was placed in a Bransonic 221 bath and irradiated with ultrasound for 30 min. The reaction mixture was filtered and the tiltrate was concentrated in vacuo. The crude product was taken up in CH2Cl2 and decanted from the solid residue. Pure 2-thiophenethioacetamide (2.45 g, 54% yield) was obtained by chromatography on silica gel (CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:34])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][N:15](C(OCC3C=CC=CC=3)=O)[C@H:16]([C:21]([O-:23])=[O:22])[C@H:17]([CH2:19][CH3:20])[CH3:18])[C:9]=2[N:10]=1.[ClH:35]>CO.O1CCCC1.[Pd]>[ClH:35].[NH2:1][C:2]1[NH:3][C:4](=[O:34])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][NH:15][C@H:16]([C:21]([OH:23])=[O:22])[C@H:17]([CH2:19][CH3:20])[CH3:18])[C:9]=2[N:10]=1
Reactant: CC[C@H](C)[C@@H](C(=O)[O-])N(CCOCn1cnc2c(=O)[nH]c(N)nc21)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H](C)[C@H](NCCOCn1cnc2c(=O)[nH]c(N)nc21)C(=O)O
Reaction time: 11 h
Yield: 92 %

Procedure:
A solution of 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)-methoxy]-ethyl-N-[(benzyloxy)carbonyl]-L-isoleucinate (1.11 g, 2.2 mmol) in methanol-tetrahydro furan (1:1, 50 ml) was treated with 0.5N hydrochloric acid (5 ml) and 5% palladium on charcoal (0.30 g; MCB Reagents). The mixture was hydrogenated on a Parr hydrogenator at 50 psi for 11 hours, filtered through a Celite pad and the filtrate was concentrated in vacuo to give 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl-L-isoleucinate hydrochloride (0.86 g, 92%) as an off-white solid; mp 180°-182° C. (effervescent softening ca. 150° C.):
Reaction SMILES: [CH3:1][N:2]([CH3:14])[S:3]([C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[Cl:13])(=[O:5])=[O:4].[C:15](Cl)(Cl)=[O:16]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:14])[S:3]([C:6]1[CH:11]=[C:10]([N:12]=[C:15]=[O:16])[CH:9]=[CH:8][C:7]=1[Cl:13])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1cc(N)ccc1Cl
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1cc(N=C=O)ccc1Cl

Procedure:
50 g of N,N-dimethyl-2-chloro-5-aminobenzenesulfonamide (Example A-3 above) was treated with an excess of phosgene in ethyl acetate as is generally described in "Organic Functional Group Preparations" by S. R. Sandler and W. Karo on pages 364-365 (Academic Press, N.Y., 1983) (preparation of organic isocyanates), which disclosure is herein incorporated by reference. 48 g of the title compound was isolated as a tan solid with a melting point of 82°-85° C.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7](Cl)[N:6]=1.O.[C:14](OCC)(=[O:16])C>CO>[Cl:4][C:5]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:16][CH3:14])[N:6]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
3.24 g of sodium methoxide dissolved beforehand in 13 ml of methanol are added dropwise to a solution of 11 g of 2,4,6-trichloropyrimidine in 140 ml of methanol cooled to 0° C. in an ice bath. The ice bath is withdrawn. The reaction medium is stirred at 0° C. for 45 minutes, and then the cooling bath is removed so as to allow the temperature to rise to ambient temperature. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up with 30 ml of water and 100 ml of ethyl acetate. After settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure so as to give an oil which is left to crystallize for 24 hours at ambient temperature. The product crystallizes in the form of needles in the middle of an oil. The needles are separated so as to give 3.94 g of 2,4-dichloro-6-methoxypyrimidine, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1S(C)(=O)=O
Temperature: 75 °C
Yield: 97.4 %

Procedure:
To a mixture of methyl 3-methyl-4-methylsulfonyl-benzoate (5.8 g, 25.4 mmol) in dioxane (25 mL) was added NaOH (20 g, 125.0 mmol) (aq. 25%) and the reaction mixture was heated at 75° C. for 1 hour. The reaction mixture was cooled and was concentrated in vacuo to half the volume and adjusted to pH 2 with 6N HCl solution. The aqueous layer was extracted with ethyl acetate (3×100 mL). The organics were washed with brine solution (50 mL), dried over MgSO4 and concentrated in vacuo to give 3-methyl-4-methylsulfonyl-benzoic acid (5.3 g, 97%) as a white solid. ESI-MS m/z calc. 214.5. found 215.5 (M+1)+; Retention time: 0.67 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 13.48 (s, 1H), 8.13-7.81 (m, 3H), 3.33 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[C:38]([C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39]>CN(C=O)C.CCOCC.Cl>[C:38]([C:42]1[CH:43]=[CH:44][C:45]([CH2:46][N:19]2[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:34])([O:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][CH:25]=4)[C:4]([OH:3])=[O:35])=[CH:8][CH:9]=3)[N:17]([CH3:22])[C:18]2=[O:21])=[CH:48][CH:49]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1C(=O)N(Cc2ccc(C(C)(C)C)cc2)CC1CCOc1ccc(CC(C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a mixture of 80 mg of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 16 mg of NaH (0.40 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 minute Then 0.07 mL of 4-tert-butylbenzyl bromide is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl. (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.5 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 40 mg (40%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, 2H, J=8.8 Hz), 7.38-7.32 (m, 2H), 7.16 (t, 4H, J=8.8 Hz), 6.95 (d, 2H, J=8.8 Hz), 6.76 (d, 2H, J=8.8 Hz), 4.37, 4.28 (ABq, 2H, J=14.8 Hz), 4.24 (bs, 1H), 3.97 (t, 2H, J=6.0 Hz), 3.74-3.67 (m, 1H), 3.44 (t, 1H, J=9.2 Hz), 3.31, 3.16 (ABq, 2H, J=13.8 Hz), 3.07 (t, 1H, J=9.2 Hz), 2.85 (s, 3H), 2.27-2.18 (m, 1H), 1.98-1.89 (m, 1H), 1.50 (s, 3H), 1.29 (s, 9H). HRMS (ES+) m/z exact mass calcd for C34H40N2O5F3 (m+1) 613.2889, found 613.2872.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[NH:7][CH:6]=1)=O.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([NH2:30])=[S:29])[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C([O-])(O)=O.[Na+]>C1COCC1>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[S:29][CH:2]=[C:3]([C:5]3[C:13]4[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=4)[NH:7][CH:6]=3)[N:30]=2)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CBr)c1c[nH]c2ncc(Br)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3c[nH]c4ncc(Br)cc34)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
To a solution of 70 (1.71 g, 5.38 mmol) in THF (20 mL) was added 1-Boc-4-aminothiocarbonyl piperidine (1.31 g, 5.36 mmol) and the solution was allowed to stir at r.t. for 3 h. The reaction mixture was then poured onto saturated aqueous NaHCO3 (50 mL) and extracted with AcOEt (2×50 mL). The combined organic portions were then evaporated to afford 71 (2.58 g, 5.41 mmol, 100%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 1.64-1.84 (m, 4H), 2.07-2.17 (m, 2H), 2.81-2.94 (m, 2H), 3.13-3.24 (m, 1H), 7.17 (s, 1H), 7.74 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.48 (d, J=2.1 Hz, 1H), 8.97 (br s, 1H).
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])[CH2:15][CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:21])[CH2:5][CH2:4]2.[BH4-].[K+].O.C(O)(=[O:27])C>C(O)C>[OH:27][C@H:15]1[CH2:14][CH2:13][C@H:12]2[C@H:11]3[C@H:20]([CH2:19][CH2:18][C@:16]12[CH3:17])[C@:3]1([CH2:2][OH:1])[C:8](=[CH:7][C:6](=[O:21])[CH2:5][CH2:4]1)[CH2:9][CH2:10]3
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(CO)[C@H]1CC2
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 150 g of 19-hydroxyandrost-4-en-3-one in 6 liters of ethanol is cooled in an ice bath. To this cold solution is added 13.5 g of potassium borohydride, and the reaction mixture is stirred for two hours at about 0 ° C after which a second 13.5 g or potassium borohydride is added. Two hours later a third 13.5 g portion of potassium borohydride is added to the reaction mixture which is stirred for an additional 1 hour then poured into 11 liters of water which 70 ml of acetic acid is added. The ethanol is distilled off under reduced pressure and the aqueous residue cooled to 0° C. The solid which separates is filtered off, dried and dissolved in 25 liters of hot chloroform after which the temperature is adjusted to 25° C. To the chloroform solution is added 250 g of manganese dioxide, and the mixture is stirred for 2 hours then filtered and the solvents removed under reduced pressure. The solid residue is recrystallized from acetonitrile to give 17β,19-dihydroxyandrost-4-en-3-one. M.P. 205°-207° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=2)[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CCOC(=O)c1ccc(N)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Nc2cc(Cl)nc(SC)n2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4,6-dichloro-2-(methylthio)pyrimidine (1 g), ethyl 6-aminonicotinate (0.85 g) and NaHMDS (10.3 mL, 1M in THF) in THF (50 mL) was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc (2×150 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4 and concentrated to give ethyl 6-(6-chloro-2-(methylthio)pyrimidin-4-ylamino)nicotinate which was used as was.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10](=[O:51])/[C:11](/[NH:30][C:31](=[O:50])[C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([OH:48])[CH:43]=2)=[O:39])=[CH:34][C:33]=1[Cl:49])=[CH:12]/[C:13]1[S:17][C:16]([NH:18]C(OC(C)(C)C)=O)=[N:15][C:14]=1[C:26]([F:29])([F:28])[F:27].FC(F)(F)C(O)=O>ClCCl>[CH3:8][O:9][C:10](=[O:51])/[C:11](/[NH:30][C:31](=[O:50])[C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([OH:48])[CH:43]=2)=[O:39])=[CH:34][C:33]=1[Cl:49])=[CH:12]/[C:13]1[S:17][C:16]([NH2:18])=[N:15][C:14]=1[C:26]([F:29])([F:28])[F:27]
Reactant: COC(=O)/C(=C/c1sc(NC(=O)OC(C)(C)C)nc1C(F)(F)F)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)/C(=C/c1sc(N)nc1C(F)(F)F)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Triethylsilane (0.15 mL, 0.94 mmol) was added to a solution of (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[2-(1,1-dimethylethoxycarbonyl)amino-4-trifluoromethylthiazol-5-yl]propenoic acid methyl ester (130 mg, 0.198 mmol) in dichloromethane (1 mL). Trifluoroacetic acid (1 mL, 13.0 mmol) was added and the solution was stirred at room temperature for 2 h and then the solvents were removed under reduced pressure. NMR indicated that the reaction had not gone to completion, so the crude residue was re-dissolved in dichloromethane and treated with triethylsilane and trifluoroacetic acid as before. After the solution was stirred at room temperature for 3 h, the solvents were removed in vacuo and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried (Na2SO4), filtered and evaporated to give (Z)-3-(2-amino-4-trifluoromethylthiazol-5-yl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid methyl ester (100 mg, 91% yield) as a yellow foam.
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:15]([CH3:16])=[N:14][N:13]=[C:12]1[CH2:17]Cl.[NH3:20].[I-].[K+]>O1CCCC1.CO>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]2[N:11]3[C:15]([CH3:16])=[N:14][N:13]=[C:12]3[CH2:17][NH:20][C:3](=[O:19])[C:4]=2[CH:9]=1
Reactant: COC(=O)c1cc(Cl)ccc1-n1c(C)nnc1CCl
Reactant: N
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(=O)NC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A stirred solution of 5-chloro-2-[3-(chloromethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzoic acid methyl ester (VIb)(300 mg., 1 mmole) in tetrahydrofuran (THF) (10 ml.) was cooled, under nitrogen, in an ice bath and treated with 8 ml. of a saturated solution of ammonia in methanol. The mixture was kept in the ice bath for 20 minutes and at ambient temperature for one hour. At this time there was no reaction by thin layer chromatography (TLC). The mixture was therefore treated with potassium iodide (166 mg., 1 mmole) and kept at ambient temperature for 18 hours. It was concentrated in vacuo, and the residue was mixed with water and extracted with chloroform. The extract was washed with brine, dried (Na2SO4) and concentrated. The residue was crystallized from a methanol/ethyl acetate mixture to give 0.169 g., melting point 253.5°-255.5° and 0.026 g., melting point 251°-252.5°. The mixture melting point with that of an authentic sample of the titled compound (VIIa) was 261.5°-264.5°. The first crop was recrystallized from a methanol/ethyl acetate mixture, seeding with an authentic sample, to give 0.110 g., melting point 262°-264°. This was identical to the authentic sample of (VIIa) by ir comparison.