Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:27][C:26]2[CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[S:30][C:25]=2[C:24]=1[CH:35]1[CH2:40][CH2:39][CH2:38][CH:37]=[CH:36]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:27][C:26]2[CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[S:30][C:25]=2[C:24]=1[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)c(C3C=CCCC3)c2s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 13 h
Yield: 82 %

Procedure:
To a solution of methyl 5-(2,4-bisbenzyloxyphenyl)-6-(cyclohex-2-enyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in a mixture of methanol (6 ml) and tetrahydrofuran (16 ml) was added 20% palladium hydroxide/carbon (400 mg, 0.74 mmol). After stirring for 13 hr under hydrogen atmosphere (3.4 atm) at room temperature, the reaction mixture was filtered through celite, and the filtrate was concentrated. The precipitated solid was collected by filtration. The solid was washed with diisopropyl ether (5 ml×3), and dried under reduced pressure to give methyl 5-(2,4-bisbenzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.12 g, yield 82%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17](=[O:19])[CH3:18])[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1)#[N:2]>COC(OC)N(C)C>[CH3:14][N:15]([CH3:16])[CH:11]=[CH:18][C:17]([C:16]1[N:15]2[C:11]([S:12][CH:13]=[CH:14]2)=[N:10][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:19]
Reactant: CC(=O)c1c(-c2cccc(C#N)c2)nc2sccn12
Agent: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1c(-c2cccc(C#N)c2)nc2sccn12

Procedure:
A 100 mL round bottom flask was charged with the 1-[6-(3-cyanophenyl)imidazo [2,1-b][1,3]thiazol-5-yl]ethanone (4.30 g, 16.1 mmol) and dimethylformamide dimethylacetal (40 mL). The mixture was refluxed for 6 hours and then concentrated in vacuo to provide a dark solid. LCMS: 323 [M+H]; purity: 90% by UV at 254 nm. This crude was used for next step reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[C:8]([I:25])=[N:7]1.[NH:36]1[CH2:41][CH2:40][CH:39]([C:42]([OH:44])=[O:43])[CH2:38][CH2:37]1>>[F:1][C:2]([F:34])([F:35])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:36]4[CH2:41][CH2:40][CH:39]([C:42]([OH:44])=[O:43])[CH2:38][CH2:37]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[C:8]([I:25])=[N:7]1
Reactant: O=C(O)C1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(I)nn3Cc2ccc(C(F)(F)F)cc2C(F)(F)F)S1
Product: O=C1N=C(N2CCC(C(=O)O)CC2)SC1=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4-carboxylic acid was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Piperidine-4-carboxylic acid following general procedure C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][O:28][Si](C(C)(C)C)(C)C)[CH:22]=3)=[CH:16][C:15]=2[F:36])=[O:12])[N:7]([C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[N:43]=[CH:42][CH:41]=[CH:40]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][OH:28])[CH:22]=3)=[CH:16][C:15]=2[F:36])=[O:12])[N:7]([C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[N:43]=[CH:42][CH:41]=[CH:40]3)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(CO[Si](C)(C)C(C)(C)C)c3)cc2F)n(-c2ccc3ncccc3c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(CO)c3)cc2F)n(-c2ccc3ncccc3c2)n1
Yield: 90 %

Procedure:
A solution of 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-((tert-butyldimethylsilyloxy)methyl)pyridin-4-yloxy)-2-fluorophenyl)urea (0.12 g, 0.19 mmol) in THF (2 ml) was treated with TBAF (1.0 ml, 1.0 M solution in THF) at RT for 1 hour. Water (10 ml) was added and the separated solid was filtered, washed with water and dried to give desilylated product 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(hydroxymethyl)pyridin-4-yloxy)phenyl)urea as a white solid (0.090 g, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.01 (brs, 1H), 8.97 (dd, J=4.2, 1.6 Hz, 2H), 8.50 (brd, J=8.3 Hz, 1H), 8.36 (d, J=5.5 Hz, 2H), 8.18 (m, 2H), 7.97 (dd, J=9, 2 Hz, 1H), 7.63 (dd, J=9, 4.4 Hz, 1H), 7.22 (dd, J=12, 2.5 Hz, 1H), 6.99 (m, 1H), 6.93 (d, J=2.5 Hz, 1H), 6.82 (dd, J=5.7, 2.5 Hz, 1H), 6.48 (s, 1H), 5.40 (t, J=6 Hz, 1H), 4.50 (d, J=8 Hz, 2H), 1.32 (s, 9H); MS (ESI) m/z: 527.2 (M+H+). The free base was converted to hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (brs, 1H), 9.23 (m, 1H), 9.07 (dd, J=4.2, 1.6 Hz, 1H), 8.70 (brd, J=8.3 Hz, 1H), 8.65 (d, J=6.8 Hz, 2H), 8.32 (d, J=2 Hz, 1H), 8.27 (d, J=9 Hz, 1H), 8.22 (d, J=9 Hz, 1H), 8.09 (dd, J=9, 2.3 Hz, 1H), 7.75 (dd, J=8, 4.5 Hz, 1H), 7.43-7.37 (m, 2H), 7.34 (d, 2.8 Hz, 1H), 7.12 (m, 1H), 6.48 (s, 1H), 4.77 (s, 2H), 1.32 (s, 9H); MS (ESI) m/z: 527.2 (M+H+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH:18]([CH2:20][CH2:21][CH3:22])[CH3:19])([CH2:7][CH2:8][CH3:9])[CH3:6]>O>[CH:18]([O:17][C:12]1[CH:13]=[C:14]([N+:1]([O-:4])=[O:2])[CH:15]=[CH:16][C:11]=1[O:10][CH:5]([CH2:7][CH2:8][CH3:9])[CH3:6])([CH2:20][CH2:21][CH3:22])[CH3:19]
Reactant: O=[N+]([O-])O
Reactant: CCCC(C)Oc1ccccc1OC(C)CCC
Solvent: O
Product: CCCC(C)Oc1ccc([N+](=O)[O-])cc1OC(C)CCC
Reaction time: 1 h

Procedure:
To a mixture of 300 ml. of conc. HNO3 and 300 ml. of H2O was added dropwise 80 g. (0.32 m.) of o-di(sec-amyloxy)benzene (part A) while maintaining a temperature of 10°C. Stirring was continued for an additional 60 minutes at 10°C, then the solution was poured into 2000 ml. addition was poured into 2000 ml. of ice. The aqueous layer was decanted, and the red oil was dissolved in benzene, dried over anhydrous MgSO4 and concentrated to dryness in vacuo. A chromatographic column 32 inches long with O.D. 3/4 inch, was packed with 20 inches of neutral alumina. The crude product was dissolved in a 250 ml. mixture of 50/50 CHCl3 and CCl4. After the solution was placed on the column, it was washed several times with the same solvent mixture. The first fraction was collected and concentrated to dryness in vacuo to yield 10 g. of amber-colored oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[O:16])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([OH:16])[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reaction time: 3 h
Yield: 93.6 %

Procedure:
3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (Compound 1009, 8 g, 35.5 mmol) was dissolved in 100 mL of ethanol. Sodium borohydride (2 g, 53.5 mmol) was added to the solution portionwise at room temperature. After stirring for 3 hours, the reaction was evaporated in vacuo to give clear viscous oil. The oil was dissolved in dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to afford 7.55 g of 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (Compound 1010) as a white crystalline solid; 1H NMR (300 MHz, DMSO-d6): δ 4.23 (dd, J=2.7, 4.6 Hz, 1H), 4.18-4.06 (m, 2H), 2.17-2.06 (m, 1H), 1.99-1.91 (m, 3H), 1.72-1.50 (m, 5H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC2C=CC=CC=2)=[O:11])=[CH:4][CH:3]=1>CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(/C=C/C(=O)OCc2ccccc2)cn1
Solvent: CO
Product: Nc1ccc(/C=C/C(=O)O)cn1
Yield: 71.7 %

Procedure:
A solution of benzyl (E)-3-(6-aminopyridin-3-yl)acrylate (1.3 g, 5.1 mmole) and 1.0 N NAOH(10 mL, 10 mmole) in MeOH was heated at reflux overnight. The solution was concentrated in vacuo, and the residue was dissolved in H2O. The pH was adjusted to 6 with dilute HCl, and the solid precipitate was collected by suction filtration and dried to give the title compound (0.6 g, 72%) as a white solid: MS (ES) m/e 165 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1>[Pd].C(O)C>[NH2:12][C:11]1[C:2]([CH3:1])=[CH:3][C:4]2=[N:8][C:7](=[O:9])[N:6]=[C:5]2[CH:10]=1
Reactant: Cc1cc2c(cc1[N+](=O)[O-])=NC(=O)N=2
Agent: [Pd]
Solvent: CCO
Product: Cc1cc2c(cc1N)=NC(=O)N=2
Reaction time: 4 h

Procedure:
A mixture of (22) (0.25 g, 1.30 mmol) and 10% palladium on carbon (0.05 g) in ethanol (15 ml) was hydrogenated at atmospheric pressure for 4 h. The catalyst was filtered off through Celite, and the solvent was removed in vacuo to give (23) as a white solid.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][C:4]#[N:5].CCN(CC)CC.C[O:25][C:26](=O)[C:27]1[C:32]([NH:33][C:34]([CH:36]2[CH2:38][CH2:37]2)=[O:35])=[CH:31][CH:30]=[C:29]([Cl:39])[C:28]=1[CH2:40]Br>CN(C=O)C>[Cl:39][C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:34]([CH:36]2[CH2:37][CH2:38]2)=[O:35])=[C:27]2[C:28]=1[CH2:40][N:1]([CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][C:4]#[N:5])[C:26]2=[O:25]
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(Cl)c1CBr
Reactant: CCOc1cc(C(N)CC#N)ccc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CC#N)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 90 °C
Yield: 75.5 %

Procedure:
To the DMF solution (20 ml) of 3-Amino-3-(3-ethoxy-4-methoxy-phenyl)-propionitrile (1.55 g, 7 mmol) was added Et3N (1.6 ml, 12 mmol) followed by 2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (2.42 g, 7 mmol). The mixture was heated at 90° C. for 12 hrs then cooled to room temperature. The mixture was extracted with EtOAc (50 ml) and water (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo. The resulted oil was purified by silica gel chromatography to give cyclopropanecarboxylic acid {7-chloro-2-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (2.4 g, 80%): mp 200-202° C.; 1H NMR (CDCl3) δ 0.90-0.94 (m, 2H, c-CH2), 1.09-1.14 (m, 2H, c-CH2), 1.45 (t, J=7.0 Hz, 3H, CH3), 1.64-1.70 (m, 1H, c-CH), 3.12-3.32 (m, 2H, CH2CN), 3.89 (s, 3H), 3.99-4.12 (m, 3H, OCH2CH3+CHHN), 4.37 (d, J=18 Hz, 1H. CHHN), 5.62-5.68 (m, 1H, NCH), 6.87-6.98 (m, 3H, Ar), 7.40 (d, J=9 Hz, 1H, Ar), 8.47 (t, J=9 Hz, 1H, Ar), 10.34 (s, 1H, NH); 13C NMR (CDCl3) δ 8.5, 14.7, 16.2, 21.2, 46.4, 51.8, 56.0, 64.7, 111.7, 112.2, 116.9, 118.4, 119.1, 119.8, 121.9, 127.9, 133.3, 136.9, 138.9, 149.9, 150.0, 169.0, 172.7; Anal Calcd for C24H24ClN3O4: C, 63.50; H, 5.33; N, 9.26. Found: C, 63.43; H, 5.31; N, 9.01
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[N:8]1([C:14]2[C:15]3[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=3[S:17][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>C(Cl)Cl>[C:5]([N:11]1[CH2:12][CH2:13][N:8]([C:14]2[C:15]3[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=3[S:17][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][CH2:10]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(-c2sc3ccccc3c2N2CCNCC2)cc1
Solvent: ClCCl
Product: CC(=O)N1CCN(c2c(-c3ccccc3)sc3ccccc23)CC1
Reaction time: 2 h

Procedure:
6.15 g (60 mmole) of acetic anhydride are mixed with a solution of 11.8 g (40 mmole) of 3-piperazino-2-phenyl-benzo(b)thiophene in 50 milliliters of methylene chloride and left for 2 hours at ambient temperature. After washing with dilute ammonia the organic phase is dried over Na2SO4 and evaporated: 13.2 g (98% of theory) of colourless needles, mp 167°-169° (CCl4).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22](=[O:32])[NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([Cl:33])[CH:7]=1.[OH-].[Na+].Cl>CO>[Cl:33][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([Cl:12])[C:9]=1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22](=[O:32])[NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)[O:5][CH2:4][C:3]([OH:34])=[O:2]
Reactant: COC(=O)COc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc(C)c(C)c4)cc3[nH]2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(Cl)cc(OCC(=O)O)cc4Cl)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {3,5-dichloro-4-[6-(3,4-dimethylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-phenoxy}-acetic acid methyl ester (85 mg, 0.17 mmol) in MeOH (3 mL) was added 1N NaOH (3 mL) and the solution was stirred at ambient temperature for 3 h. The solution was carefully acidified to pH 3-4 with 1N HCl and the resulting suspension was filtered, washed with water, was dried under reduced pressure to give the title compound. 1H NMR (Methanol-d4, 400 MHz): δ 8.29 (d, 1H), 7.96 (dd, 1H), 7.76 (dd, 1H), 7.49 (d, 1H), 7.45 (dd, 1H), 7.23 (s, 2H), 7.15 (d, 1H), 4.84 (s, 2H), 2.30 (s, 3H), 2.27 (s, 3H). MS (m/z) 484.1 (M+1); retention time: 1.18 min (Method 10).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[NH:11][C:10]2=[S:25])[CH:5]=[CH:6][CH:7]=1.[CH3:27]I>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[S:25][CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1Cn1c(=S)[nH]c(=O)c2sc(N3CCOCC3)nc21
Reactant: CI
Solvent: C1CCOC1
Product: CSc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vial containing 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-thioxo-5,6-dihydro[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (25 mg, 0.061 mmol) in Tetrahydrofuran (THF) (607 μl) was added methyl iodide (4.20 μl, 0.067 mmol). The mixture was stirred at room temperature overnight then concentrated. The residue was purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-5-(methylthio)-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (6 mg, 23%); LC/MS: MS (ES+) m/e 423 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H), 2.47 (s, 3H), 3.52 (m, 4H), 3.63-3.73 (m, 4H), 5.50 (s, 2H), 6.61 (d, J=7.6 Hz, 1H), 7.16 (m, 1H), 7.38 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([CH2:23][C@H:24]([NH:32][C:33](=[O:53])[C@@H:34]([NH:41][C:42](=[O:52])[C@H:43]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[NH2:44])[CH2:35][C:36]2[N:37]=[CH:38][NH:39][CH:40]=2)[C@@H:25]([OH:31])[C@H:26]([CH:28]2[CH2:30][CH2:29]2)[OH:27])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:23][C@H:24]([NH:32][C:33]([C@@H:34]([NH:41][C:42]([C@@H:43]([NH:44][C:14]([C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:13])=[O:16])[CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:52])[CH2:35][C:36]2[N:37]=[CH:38][NH:39][CH:40]=2)=[O:53])[C@@H:25]([OH:31])[C@H:26]([CH:28]2[CH2:29][CH2:30]2)[OH:27])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described in Example 21, by replacing Boc-D-proline by N-benzyloxycarbonyl-D-alanine in the condensation with (S)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-α-[(3-phenyl-L-alanyl)amino]imidazole-4-propionamide there was obtained benzyl [(R)-1-[[(S)-α-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]ethyl]carbamate as an amorphous solid, MS: 717 (M+H)+.
Reaction SMILES: ClCCl.[C:4]([O:8][C:9](C(C)(C)C)=[O:10])([CH3:7])([CH3:6])[CH3:5].[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(OCC)(=O)C>[S:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][NH:15][C:9](=[O:10])[O:8][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:23][CH:22]=1)(=[O:25])(=[O:26])[NH2:27]
Reactant: CC(C)(C)OC(=O)C(C)(C)C
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
Dichloromethane (4 mL) and di-tert-butylcarboxylic acid (218 mg, 1.0 mmol) were added to 4-(2-aminoethyl)benzenesulfonamide (200 mg, 1.0 mmol) and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate (100 mL) was added to the reaction mixture and the solid was collected by filtration. Thus, tert-butyl 4-sulfamoylphenethylcarbamate (Compound GI) (160 mg, yield: 53%) was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH3-])(=O)C.[Na+]>>[O:22]=[C:11]1[N:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:3][CH2:4]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[N:13]=[CH:12]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: N#Cc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Product: N#Cc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoxaline-7-carbonitrile (Intermediate 201, 0.11 g) was reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium acetoxyborohydride as described for Example 107 yielding 17 mg of a colorless solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH2:15][CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH:25]C(=O)C(F)(F)F)[CH:23]=2)[CH:18]=[CH:17]1)[C:8]([O:10][CH3:11])=[O:9].O1CCCC1.[ClH:37]>CO>[ClH:37].[NH2:25][C:22]1[CH:23]=[C:24]2[C:19]([CH2:18][CH:17]=[C:16]2[CH2:15][C:14]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=2[O:4][CH3:3])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(CC2C=Cc3ccc(NC(=O)C(F)(F)F)cc32)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(CC2=CCc3ccc(N)cc32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
Sodium borohydride (0.24 g), was added to a 0° C. mixture of methyl 3-methoxy-4-[6-(trifluoroacetamido)-1H-inden-1-ylmethyl]benzoate (1.25 g), tetrahydrofuran (14 ml) and methanol (2 ml). After 15 min, the reaction was stirred at room temperature for 2 h and cooled to 0° C. 1N Hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed (sodium bicarbonate, water, brine) and dried (MgSO4). Evaporation, dissolution in ether (50 ml) and addition of ethereal hydrogen chloride (5 ml) afforded methyl 4-(6-amino-3H-inden-1-ylmethyl)-3-methyoxybenzoate hydrochloride (0.85 g, 79%) as a colorless solid; mp 213.0°-215.0° C.; MS(CI), m/e=310 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8](Cl)([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[O:24]1CCOCC1>>[OH:1][CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([OH:24])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NCC#CCO)C(Cl)(c1ccccc1)C1CCCCC1
Reactant: C1COCCO1
Agent: Cl
Product: O=C(NCC#CCO)C(O)(c1ccccc1)C1CCCCC1
Temperature: 90 °C

Procedure:
A solution of N-(4-hydroxy-2-butynyl)-2-chloro-2-cyclohexyl-2-phenylacetamide (7.88 g) in a mixture of 1N-hydrochloric acid (85 ml) and 1,4-dioxane (180 ml) was heated at 90° C. for 45 minutes and evaporated in vacuo. To the residue was added water and extracted with ethyl acetate. The extract was washed successively with saturated sodium bicarbonate aqueous solution, water, and sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and ethyl acetate (5:1) as an eluent to give N-(4-hydroxy-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide as white powder (6.56 g).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2].C(Cl)(=O)C(Cl)=O.[F:31][CH:32]([F:36])[C:33](O)=[O:34].C(N(CC)CC)C>ClCCl>[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:33](=[O:34])[CH:32]([F:36])[F:31])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2]
Reactant: N#CC=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Reactant: O=C(O)C(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC=C1CCN(c2ccc(N3C[C@H](CNC(=O)C(F)F)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
The mixture of (S)-N-{3-[4-(4-cyanomethylidene-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine (0.5 g, 1.45 mmol), oxalyl chloride (0.150 ml, 1.74 mmol), difluoroacetic acid (0.1 ml, 1.74 mmol) and triethylamine (0.242 ml, 1.74 mmol) in dichloromethane (20 ml) was stirred for 1 hour at room temperature. The reaction mixture was extracted with the dichloromethane water mixture. The combined organic layer was dried and removal of the solvent afforded a residue which was chromatographed over silica gel to give title compound in 48% yield.