Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([N:21]1[CH2:25][CH:24]([CH3:26])[CH2:23][CH:22]1[C:27]1[C:32](F)=[CH:31][C:30]([NH:34][C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=O)=[C:29]([N+:43]([O-])=O)[CH:28]=1)(=[O:20])[CH3:19].O.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C.CN1CCCC1=O>[C:18]([N:21]1[CH2:25][CH:24]([CH3:26])[CH2:23][CH:22]1[C:27]1[C:32]([O:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:31][C:30]2[N:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[NH:43][C:29]=2[CH:28]=1)(=[O:20])[CH3:19]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(=O)N1CC(C)CC1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)N1CC(C)CC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
13.4 mg of 4-(methanesulfonyl)phenol and 44.9 mg of cesium carbonate were added in order to an N-methyl-pyrrolidinone (2 ml) solution of 15 mg of N-(4-(1-acetyl-4-methylpyrrolidin-2-yl)-5-fluoro-2-nitrophenyl)pyridine-2-carboxamide, and the reaction liquid was stirred at 90° C. for 1 hour. 43.8 mg of tin chloride dihydrate was added to the reaction liquid, then heated up to 100° C. and stirred for 2 hours. The reaction liquid was dissolved in ethyl acetate, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[N:2]1.C[C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1.N1C=CC=CC=1>CC#N>[C:22]([N:18]1[CH2:19][CH2:20][N:21]([C:11](=[O:12])[C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:14])[CH2:16][CH2:17]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)C(=O)c1n[nH]c2ccccc12
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
The crude residue containing (1H-Indazol-3-yl)-2-oxo-acetyl chloride (50 mg) was dissolved in dry CH3CN (7 mL), and to the resulting solution was added 3-(R)-methyl-1-benzoyl piperazine (50 mg) and pyridine (1 mL). The reaction mixture was stirred for 1 hour at room temperature then was concentrated in vacuo. The resulting residue was purified using Shimadzu automated preparative HPLC System to give 1-(benzoyl)-4-[(1H-indazol-3-yl)-2-oxoacetyl]piperazine (2.5 mg). 1H NMR (500 MHz, MeOD) δ 8.42 (m, 2H), 7.90 (m, 1H), 7.69 (m, 1H), 7.46 (m, 5H), 5.00-3.00 (m, 8H), 1.30 (m, 3H). MS m/z: (M+H)+ calcd for C21H21N4O3:377.16; found 377.28. HPLC retention time: 1.49 minutes (column A).
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][O:7][C:6]([CH3:11])([CH3:10])[CH2:5]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:10][C:6]1([CH3:11])[CH2:5][CH:4]([CH:3]=[O:2])[CH2:9][CH2:8][O:7]1
Reactant: COC=C1CCOC(C)(C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC(C=O)CCO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.4 %

Procedure:
To a solution of 4-(methoxymethylene)-2,2-dimethyltetrahydro-2H-pyran (4.00 g) in THF (20 mL) were added water (8.0 mL) and p-toluenesulfonic acid (4.90 g), and the mixture was stirred at room temperature for 20 hr. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (2.20 g) as a colorless oil.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[NH:3]1.P(Br)(Br)([Br:18])=O>O>[Br:18][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1
Reactant: COC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Reactant: O=P(Br)(Br)Br
Solvent: O
Product: COC(=O)c1ccc(C(F)(F)F)nc1Br
Temperature: 25 °C
Yield: 13.4 %

Procedure:
A suspension of 22.0 g (0.100 mol) of the product from Example 1 and 28.7 g (0.100 mol) of phosphorous oxybromide was heated at 75°-120° C. over 45 minutes utilizing an oil bath as the heat source. The reaction was also connected to a water scrubber to trap the gas by-products. The mixture was then cooled to room temperature, diluted with water and extracted with methylene chloride. The combined organic layers were washed with saturated sodium bicarbonate solution, washed with brine, dried over magnesium sulfate and evaporated to an oil which was purified by flesh chromatography utilizing 20% ethyl acetate/petroleum ether as the eluent to afford 3.8 g (13.3%) of an oil. 1H NMR (CDCl3) δ4.0 (3H, s), 7.72 (1H, d, J=8 Hz), 8.2 (1H, d, J=8 Hz); IR (neat) 1740, 1590, 1455, 1335, 1275, 1140, 1100, 1050 cm-1.
Reaction SMILES: [C:1]([N:9]1[CH2:24][CH2:23][C:11]2([CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:2]1([C:1]([N:9]2[CH2:24][CH2:23][C:11]3([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[O:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(C(=O)c3ccccc3)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC2(CCNC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl 7-benzoyl-2,7-diazaspiro[4.4]nonane-2-carboxylate (100 mg) was dissolved in 10% TFA solution in CH2Cl2 (10 mL). The reaction was stirred at room temperature for 24 hours. After removal of solvents, the residue, phenyl(2,7-diazaspiro[4.4]nonan-2-yl)methanone, was used in the further reactions without purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1>C(O)(=O)C>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[N:22]3[N:23]=[CH:24][CH:25]=[C:21]3[N:20]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3nccc3n2)c1
Yield: 95.3 %

Procedure:
A mixture of 4,4,4-trifluoro-1-(3-trifluoromethyl-phenyl)-butane-1,3-dione (10.3 g, 36.1 mmol) and commercially available 3-aminopyrazole (3.0 g, 36.1 mmol) in acetic acid (100 mL) was refluxed for 4 h and evaporated. The crude product was further purified by crystallization (ethyl acetate/hexane) to yield 5-(3-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (11.4 g, 95%) as a light yellow solid. MS (ISP) 323.3[(M+H)+]; mp 96° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3][CH:2]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[N:3]1[CH:4]=[C:5]([CH2:7][N:19]2[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21][CH2:20]2)[CH:6]=[N:1][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cncnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cncnc2)CC1
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
A solution of pyrimidine 5-carboxaldehyde (100 mg, 0.92 mmol) in ethanol (2 mL) and acetic acid (0.2 mL) at room temperature was treated with tert-butyl-1-piperazine carboxylate (2.5 eq, 2.31 mmol, 430 mg) and stirred for 5 minutes. Sodium cyanoborohydride (0.95 eq, 0.88 mmol, 55 mg) was added portionwise and the reaction then stirred for 16 h. Concentration in vacuo and preparative tlc purification (EtOAc) gave the product (141 mg, 55%) as a pale yellow oil; δH (500 MHz, CDCl3) 1.47 (s, 9H, C(CH3)3), 1.95 (br, 2H, piperazine NCH2), 2.42 (t, J=4.7 Hz, 2H, piperazine NCH2), 3.45 (t, J=4.9 Hz, 4H, piperazine N(CH2)2), 3.54 (s, 2H, CH2), 8.78 (s, 2H, pyrimidine H-4 & H-6), 9.15 (s, 1H, pyrimidine H-2);
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH:12]([P:15](Cl)(Cl)=[O:16])([CH3:14])[CH3:13]>>[CH:12]([P:15]1(=[O:16])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]1[CH:1]([CH3:3])[CH3:2])([CH3:14])[CH3:13]
Reactant: CC(C)P(=O)(Cl)Cl
Reactant: CC(C)NCc1ccccc1
Product: CC(C)N1Cc2ccccc2P1(=O)C(C)C
Yield: 16 %

Procedure:
The procedure of Example 30 was employed utilizing N-isopropyl-N-benzylamine and isopropyl phosphonic dichloride. The reaction of the dilithio compound and the isopropyl phosphonic dichloride was conducted at -70° C. The crude product produced as a result of the chromatographic separation was distilled at 130° C. and 0.1 mm to yield a colorless oil. This oil was slurried in petroleum ether to yield 1,2-diisopropyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.28 g, 16% yield) as a pale yellow oil having the following analysis:
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[S:14][C:13]([S:15]([OH:18])(=O)=[O:16])=[CH:12][CH:11]=2)[CH:6]=1)([F:4])[CH3:3].CN(C)C=O.S(Cl)([Cl:26])=O>>[F:1][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]2[S:14][C:13]([S:15]([Cl:26])(=[O:18])=[O:16])=[CH:12][CH:11]=2)[CH:6]=1)([F:4])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(F)(F)c1cc(-c2ccc(S(=O)(=O)O)s2)no1
Solvent: CN(C)C=O
Product: CC(F)(F)c1cc(-c2ccc(S(=O)(=O)Cl)s2)no1
Temperature: 80 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a suspension of 5-[5-(1,1-difluoroethyl)-isoxazol-3-yl]-thiophene-2-sulfonic acid (9.5 g, 32 mmol) obtained in Preparation Example 5-10-c) in thionyl chloride (50 mL) was added dimethylformamide (1.0 mL) under argon atmosphere, and the suspension was stirred at 80° C. for 16 hours. The obtained solution was concentrated, and chloroform (100 mL) was added. After azeotropic removal of residual solvent with chloroform, chloroform (50 mL) was added to the residue. The obtained mixture was extracted twice, sequentially washed with water (20 mL) and saturated aqueous sodium chloride solution (10 mL), and dried over magnesium sulfate. After filtration and evaporation, the obtained residue was separated and purified by silica gel chromatography (hexane:ethyl acetate=15:1) to give the title compound (6.9 g, 68%) as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]CN1C(OC)=NC2C1=NC(O[C@@H](C)CC)=NC=2N.FC(F)(F)C(O)=O.[CH3:30][C@H:31]([O:35][C:36]1[N:44]=[C:43]2[C:39]([N:40]=[C:41]([O:45][CH3:46])[NH:42]2)=[C:38]([NH2:47])[N:37]=1)[CH2:32][CH2:33][CH3:34].BrCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][N:42]1[C:41]([O:45][CH3:46])=[N:40][C:39]2[C:43]1=[N:44][C:36]([O:35][C@@H:31]([CH3:30])[CH2:32][CH2:33][CH3:34])=[N:37][C:38]=2[NH2:47]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Agent: ClCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and 1-bromo-3-chloropropane.
Reaction SMILES: [Na].[CH:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl.C(O)(=O)C.C1(C)[C:20]([CH3:25])=[CH:21][CH:22]=[CH:23]C=1>C(O)(C)(C)C.CC1C2C(=CC=CC=2)NC(C)(C)C=1>[CH:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:20]2[CH:21]=[CH:22][CH:23]=[CH:25]2)[CH:2]=[CH:6][CH:5]=[CH:4]1
Reactant: ClCCCCCCCl
Reactant: C1=CCC=C1
Reactant: Cc1ccccc1C
Agent: CC1=CC(C)(C)Nc2ccccc21
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: C1=CC(CCCCCCC2C=CC=C2)C=C1
Temperature: 45 °C
Yield: 90.4 %

Procedure:
A dispersion of 138 g of sodium in 800 g of xylene was mixed with 18 g of tertiary butanol and 436.2 g of monomeric cyclopentadiene were stirred in dropwise at 45° C. The mixture was heated for 2 hours at 45° C., then raised to the boil and 441.6 g of 1,6-dichlorohexane were dropped in. On completion of the dropwise addition 3.0 g of poly(2,2,4-trimethyl-1,2-dihydroquinoline) were added and the whole was heated for another 4 hours at the boil, then cooled, neutralized with a small quantity of glacial acetic acid, the precipitated sodium chloride was filtered off and thoroughly rinsed with xylene. After having distilled off the xylene under a vacuum of 15 mm Hg up to 130° C., there were obtained 552 g of the light-brown oligomeric 1,6-bis(cyclopentadienyl)hexane having a viscosity of 100,000 centipoises at 25° C. and a colour number (according to Gardner and Holdt) of 15. The molecular weight of the oligomer was 1125, corresponding to a polymerization degree of 5.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].[F:30][C:31]1[CH:45]=[CH:44][C:34]([CH2:35][CH2:36][NH:37][CH2:38][CH:39]([O:42][CH3:43])[O:40][CH3:41])=[CH:33][CH:32]=1>O1CCCC1>[CH3:43][O:42][CH:39]([O:40][CH3:41])[CH2:38][N:37]([CH2:36][CH2:35][C:34]1[CH:33]=[CH:32][C:31]([F:30])=[CH:45][CH:44]=1)[C:18](=[O:19])[NH:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: COC(CNCCc1ccc(F)cc1)OC
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(N)sc1C(=O)NCc1cccnc1
Solvent: C1CCOC1
Product: COC(CN(CCc1ccc(F)cc1)C(=O)Nc1nc(C)c(C(=O)NCc2cccnc2)s1)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 19 %

Procedure:
To a solution of 2-amino-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.50 g, 2.01 mmol) in tetrahydrofuran (30 mL) was added 1,1% carbonyldiimidazole (0.39 g, 2.41 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 6 hours and N-(4-fluorophenethyl)-2,2-dimethoxyethanamine (0.59 g, 2.61 mmol) was added. The reaction mixture was stirred for 17 hour at ambient temperature. The solvent was removed in vacuo, and the residue was purified by column chromatography eluted with dichloromethane/methanol (4/1) to afford 2-(3-(2,2-dimethoxyethyl)-3-(4-fluorophenethyl)ureido)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide as an oil in 19% yield (0.19 g): MS (ES+) m/z 502.4 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([CH2:35][CH2:36][CH3:37])[C@@H:3]([NH:10][C:11](=[O:34])[CH2:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]([NH:26]C(=O)OC(C)(C)C)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)=[O:14])[CH2:4][NH:5][CH2:6][CH:7]([CH3:9])[CH3:8]>C(Cl)Cl>[NH2:26][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH2:12][C:11]([NH:10][C@H:3]([C@@H:2]([OH:1])[CH2:35][CH2:36][CH3:37])[CH2:4][NH:5][CH2:6][CH:7]([CH3:8])[CH3:9])=[O:34])[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=1
Reactant: CCC[C@H](O)[C@H](CNCC(C)C)NC(=O)CC(=O)Nc1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: CCC[C@H](O)[C@H](CNCC(C)C)NC(=O)CC(=O)Nc1cc(N)cc(C(F)(F)F)c1

Procedure:
A sample of tert-butyl 3-(3-((2S,3S)-3-hydroxy-1-(isobutylamino)hexan-2-ylamino)-3-oxopropanamido)-5-(trifluoromethyl)phenylcarbamate (86 mg, title compound from Example 24) was dissolved in methylene chloride (2 mL). The resultant solution was cooled to 0° C. and charged with trifluoroacetic acid (1 mL). The mixture was allowed to warm to RT and stirred for 45 min before being concentrated in vacuo. The residue was purified by RP-HPLC to afford the TFA salt of the title compound as a white powder after lyopholization. MS found: (M+H)+=433.3.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][CH2:16][C:17]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18]
Reactant: NC1CCCCC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)NC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
To a cooled (0° C.) solution of cyclohexylamine (2.31 mL, 20 mmol) in DCM (20 mL) was added triethylamine (5.7 mL, 40 mmol) followed by chloro acetylchloride (1.61 mL, 20 mmol). The reaction was warmed to RT and stirred for 3 h. The reaction mixture was concentrated, redissolved in EtOAc (20 mL) and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to yield crude product which was further purified by flash column chromatography using 7:3 Pet. Ether:EtOAc as the eluant. 1.8 g of pure 2-chloro-N-cyclohexylacetamide was isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:27])=[CH:8][N:7]=1)=O.[Si]([N:36]=[C:37]=[O:38])(C)(C)C>C1COCC1.CC(O)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:11]2[C:6]([C:4]3[C:3]4[C:2](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:1][C:37](=[O:38])[N:36]=3)=[N:7][CH:8]=[C:9]([Cl:27])[CH:10]=2)(=[O:15])=[O:14])=[CH:17][C:18]=1[C:23]([F:24])([F:25])[F:26]
Reactant: C[Si](C)(C)N=C=O
Reactant: Nc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1nc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc2[nH]1
Temperature: 65 °C

Procedure:
To a stirred solution of N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide (48 mg, 0.097 mmol) in anhydrous THF (2 mL) and AcOH (400 μL) was added TMSisocyanate (32 μL, 0.22 mmol) and the resulting mixture was heated at 65° C. overnight. The crude reaction mixture was directly purified by HPLC to provide 4-Chloro-N-[5-chloro-2-(2-oxo-1,2-dihydro-quinazolin-4-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([OH:14])=O)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][CH:18]=1>>[CH3:26][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:12](=[O:14])[CH:10]([CH2:9][S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:11][C:24]2=[S:25])=[CH:19][CH:18]=1
Reactant: N[C@@H](CSCc1ccccc1)C(=O)O
Reactant: Cc1ccc(N=C=S)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(N2C(=O)C(CSCc3ccccc3)NC2=S)cc1
Yield: 111.7 %

Procedure:
When 10 g of S-benzylcysteine (0.0473 mole), 1.89 g of sodium hydroxide (0.0473 mole) and 7.05 g of p-tolylisothiocyanate (0.0473 mole) was reacted according to the procedure outlined in the preparation of Example 2, 18.1 g of the crude thiourea was obtained and 14.3 g of pure title compound was obtained: RF on silica gel=approximately 0.33 [ethyl acetate-hexane (3:7)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:7]=1.C(N(CC)CC)C.[Cl:37][CH:38]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:39](Cl)=[O:40]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]([N:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:39](=[O:40])[CH:38]([Cl:37])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])[CH:7]=1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: COc1ccc(CN[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(CN(C(=O)C(Cl)c2ccccc2)[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
A solution of [(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-(4-methoxy-benzyl)-amine (1.035 g, 2.15 mmol) in acetonitrile (16 ml) was treated with triethylamine (0.36 ml, 2.57 mmol). The mixture was cooled to 10° C. and a solution of (RS)-2-chloro-2-phenyl-acetyl chloride (0.34 ml, 2.36 mmol) in acetonitrile (2 ml) was added slowly. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. Because the transformation was not complete, triethylamine (0.33 ml, 2.36 mmol) was again added, the reaction mixture cooled to −5° C., then treated with a solution of (RS)-2-chloro-2-phenyl-acetyl chloride (0.31 ml, 2.15 mmol) in acetonitrile (1 ml). The reaction mixture was allowed to warm to room temperature and was stirred for 22 hours. Thereafter, the mixture was evaporated at reduced pressure and without further workup directly purified by chromatography on Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 70/30 as the eluent. (RS)-N-[(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-2-chloro-N-(4-methoxy-benzyl)-2-phenyl-acetamide was obtained as a white foam (1.068 g, 78% of theory). Mass (calculated) C31H38BrClFNO3 [635.09]; (found) [M+H]+=638, [M+2-H]+=636, [M+4-H]+=634.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:30])[NH2:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:28]([C:26]1[N:27]=[C:23]([N:21]2[CH2:22][CH:19]([OH:18])[CH2:20]2)[S:24][CH:25]=1)(=[O:30])[NH2:29]
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(N)=O)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC(=O)c1csc(N2CC(O)C2)n1
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-carbamoyl-1,3-thiazol-2-yl)azetidine (6.7 g, 15.3 mmol) (obtained as described in Reference Example 3(1)) in anhydrous tetrahydrofuran (200 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (18.4 ml) in an ice bath. The mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→10% methanol in ethyl acetate as the eluant to afford 1-(4-carbamoyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (2.78 g, yield 91%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([B:25]5[O:29]C(C)(C)C(C)(C)[O:26]5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1>CC(C)=O.O>[F:24][C:22]1[CH:21]=[CH:20][C:19]([B:25]([OH:29])[OH:26])=[C:18]2[C:23]=1[C@H:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([O:2][CH3:1])=[O:34])[CH2:6][O:7][C:8]=3[CH:13]=1)[CH2:16][CH2:17]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B(O)O)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
{(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (3.00 g) is dissolved in acetone (20 mL) and water (10 mL). NaIO4 (5.90 g) and NH4O2CCH3 (2.85 g) are added. The mixture is stirred at room temperature for 36 h. Water is added and the resulting mixture is extracted with ethyl acetate. The combined extract is dried (Na2SO4) and concentrated to give the title compound LC (method 12): tR=1.02 min; Mass spectrum (ESI+): m/z=387 [M+H]+.