Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:40])[CH2:14][N:15]2[N:21]=[C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[N:17]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:16]2=[O:39])[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[CH:22]1([C:20]2[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[N:17]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:16](=[O:39])[N:15]([CH2:14][C:13]([NH:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][OH:4])[CH:7]=3)=[O:40])[N:21]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)OCc1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(CO)c2)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Carbonic acid 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzyl ester methyl ester (Example 48, step a) was dissolved in THF-MeOH (1:1/40 ml) and 1% K2CO3 solution (30 ml) was added. The mixture was stirred at room temperature for 2 h. After concentration of the organic solvents, a precipitate formed, which was collected by filtration and dried in vacuo to afford the title compound as a yellow solid (790 mg, 89%). 1H NMR (CDCl3) 8.31 (1H, s), 7.51-7.45 (3H, m), 7.31-7.28 (3H, m), 7.26-7.10 (2H, m), 4.70 (1H, d), 4.67 (2H, s), 4.64 (1H, d), 4.26 (1H, d), 4.22 (1H, d), 2.89 (1H, m), 1.85-1.55 (6H, m), 1.30-1.24 (13H, m). Found: C, 67.70; H, 7.40; N, 10.79%; C29H36N4O4.0.5H2O requires: C, 67.81; H, 7.26; N, 10.91%.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([F:14])([F:13])[C:7]1[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=1.CN1CCOCC1.[OH-].[Na+].Cl>C(Cl)Cl>[F:5][C:6]([F:14])([F:13])[C:7]1[CH:11]=[C:10]([NH:12][C:1](=[O:3])[CH3:2])[NH:9][N:8]=1
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)Nc1cc(C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
Acetyl chloride (7.7 ml, 108 mmol) was added over a period of 45 minutes to a solution of 3-(trifluoromethyl)-1H-pyrazol-5-amine (6.5 g, 43 mmol) and N-methylmorpholine (12.3 ml, 112 mmol) in CH2Cl2 (160 ml) with cooling in an ice bath. The reaction was allowed to warm to room temperature and stirred for 16 h, the solvent was removed in vacuo and the residue dissolved in methanol (150 ml). The solution was cooled in an ice bath and 25% aqueous NaOH (7.3 ml, 65 mmol) was added. After 3.25 h, 25% aqueous NaOH (0.5 ml, 4.4 mmol) was added and the reaction stirred for an additional 1.5 h. 2N HCl (20 ml) was added and the organic solvents were removed in vacuo at below 35° C. Water was added and the crude then extracted EtOAc (×2) and the extracts dried (MgSO4) and concentrated in vacuo. The resultant residue was suspended in CH2Cl2 (20 ml) with stirring. The solid was filtered and washed with CH2Cl2 (2×3 ml) and dried in vacuo to provide the title compound as a white solid (7.3 g) which was used in the subsequent step.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:20][C:19]([CH:33]=[CH2:34])=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:27]1([C:24]2[O:23][C:22]([C:21]3[C:16]([NH2:8])=[N:17][CH:18]=[C:19]([CH:33]=[CH2:34])[N:20]=3)=[N:26][N:25]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c2nnc(-c3ccccc3)o2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Reaction time: 0.33 h
Yield: 84.2 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-vinyl-pyrazin-2-yl]carbamate (138 mg, 0.3 mmol) in DCM (0.7 mL) at room temperature under an atmosphere of N2 was added TFA (338 mg, 228 μL, 3 mmol) and reaction mixture was stirred for 20 minutes. The reaction mixture was diluted with DCM and slowly quenched with satd. NaHCO3. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to yield 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-vinyl-pyrazin-2-amine (67 mg, 85%) as a yellow solid. LC/MS m/z 266.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O>>[F:23][C:15]1[CH:14]=[C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[O:29][CH:33]=[CH:32][CH:31]=4)=[CH:3][CH:4]=3)=[CH:9][C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:11]2)[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CCOC(=O)c1cc(-c2ccc(Br)cc2)n(-c2ccc(S(C)(=O)=O)c(F)c2)n1
Reactant: OB(O)c1ccco1
Product: CCOC(=O)c1cc(-c2ccc(-c3ccco3)cc2)n(-c2ccc(S(C)(=O)=O)c(F)c2)n1

Procedure:
The title compound was prepared according to the procedure of Example 85 using ethyl 5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylate instead of 5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole and 2-furanboronic acid instead of 3-furanboronic acid in step 2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]([N+:13]([O-])=O)=[C:6](/[CH:8]=[CH:9]/N(C)C)[CH:7]=1>[Ni].CCO>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[NH2:16])[NH:13][CH:9]=[CH:8]2
Reactant: CN(C)/C=C/c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc2[nH]ccc2cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.2 %

Procedure:
A suspension of (E)-2-(5-chloro-2,4-dinitrophenyl)-N,N-dimethylethenamine (9.8 g, 36 mmol) and Raney Nickel (9.8 g) in EtOH (140 mL) was stirred under H2 (1 atm) at room temperature for 4 h. After filtration, the filtrate was concentrated and the residue was purified by column chromatograph (petroleum ether/ethyl acetate=10:1) to give 5-chloro-1H-indol-6-amine (0.97 g, 16%) as a gray powder. 1HNMR (CDCl3) δ 7.85 (br s, 1 H), 7.52 (s, 1 H), 7.03 (s, 1H), 6.79 (s, 1H), 6.34 (s, 1H), 3.91 (br s, 1H); MS (ESI) m/e (M+H+) 166.0.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C.Cl>C(#N)C>[CH:26]1([NH:32][C:33]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C=NC1CCCCC1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)NC4CCCCC4)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.43 g, 1.16 mmol) and cyclohexylisocyanate (0.148 mL, 1.16 mmol) in acetonitrile (8 mL), was added triethylamine (0.32 mL, 2.33 mmol) at room temperature under nitrogen. After 2 h, dil. aq. HCl (10 mL) was added. The solids were collected by filtration and washed with dil. aq. HCl (20 mL) and acetonitrile (10 mL). The product was dried in vacuo to give 1-cyclohexyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.24 g, 52% yield): HPLC: Waters Nova-Pak C18 column, 3.9×150 mm, 4 μm; 25/75 CH3CN/0.1% aq H3PO4, 10 min, 1.0 mL/min, 5.94 min (99.50%); mp: 265-267° C.; 1H NMR (DMSO-d6) δ 0.99-1.36 (m, 5H, CH2, CH2, CH), 1.44-1.84 (m, 5H, CH2, CH2, CH), 1.92-2.06 (m, 1H, CH), 2.25-2.47 (m, 1H, CH), 2.59 (d, J=17.4 Hz, 1H, CH), 2.82-3.02 (m, 1H, CH), 3.33-3.47 (m, 1H, CH), 4.22-4.50 (m, 4H, CH2 and CH2), 5.10 (dd, J=5.0, 13.3 Hz, 1H, NCH), 5.88 (d, J=7.9 Hz, 1H, NH), 6.29 (t, J=5.9 Hz, 1H, NH), 7.38 (d, J=7.7 Hz, 1H, Ar), 7.44 (s, 1H, Ar), 7.67 (d, J=7.7 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 24.49, 25.28, 31.20, 33.28, 42.86, 47.09, 47.89, 51.55, 121.76, 122.84, 126.81, 130.13, 142.30, 145.51, 157.26, 167.98, 170.99, 172.85; LCMS: MH=399; Anal Calcd for C21H26N4O4: C, 63.30; H, 6.58; N, 14.06. Found: C, 63.30; H, 6.51; N, 13.76.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([NH:9][CH3:10])=[O:8])[N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31](=O)[CH2:32][C:33](OCC)=[O:34])=[CH:30][C:25]=2[N:24]=[N:23]1>CCCCO>[NH:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[NH:1][C:2]4[N:6]([N:5]=[C:4]([C:7]([NH:9][CH3:10])=[O:8])[N:3]=4)[C:33](=[O:34])[CH:32]=3)=[CH:30][C:25]=2[N:24]=[N:23]1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Reactant: CNC(=O)c1n[nH]c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: CNC(=O)c1nc2[nH]c(-c3ccc4[nH]nnc4c3)cc(=O)n2n1
Reaction time: 12 h
Yield: 18.1 %

Procedure:
To a solution of 5-amino-N-methyl-1H-1,2,4-triazole-3-carboxamide (100 mg, 0.71 mmol) in n-BuOH (3 ml) was added TsOH (4.8 mg, 0.03 mmol), ethyl 3-(1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropanoate (230 mg, 0.88 mmol). The resulting solution was stirred for 12 h at reflux. The solids were collected by filtration to afford 5-(1H-benzo[d][1,2,3]triazol-5-yl)-N-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-α]pyrimidine-2-carboxamide as a white solid (39.8 mg, 18%).
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[O:15]=[S:12]1(=[O:16])[CH2:13][CH2:14][CH:9]([O:8][C:3]2[C:2]([C:22]3[CH:21]=[CH:20][C:19]([C:33]4[CH:38]=[N:37][C:36]([NH2:39])=[N:35][CH:34]=4)=[C:18]([F:17])[CH:23]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:10][CH2:11]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=S1(=O)CCC(Oc2ncccc2Br)CC1
Product: Nc1ncc(-c2ccc(-c3cccnc3OC3CCS(=O)(=O)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-((3-bromopyridin-2-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H19FN4O3S, 414.12; m/z found, 415.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J=1.3, 2H), 8.21 (dd, J=4.9, 1.8, 1H), 7.90 (dd, J=7.4, 1.8, 1H), 7.64 (m, 1H), 7.58 (dd, J=12.4, 1.5, 1H), 7.53 (dd, J=8.0, 1.7, 1H), 7.16 (dd, J=7.4, 4.9, 1H), 6.89 (s, 2H), 5.42 (dd, J=6.3, 3.0, 1H), 3.21 (dd, J=14.5, 8.0, 2H), 3.09-3.01 (m, 2H), 2.34-2.24 (m, 4H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18]>CN(C=O)C>[CH3:16][Si:17]([CH3:19])([CH3:18])[CH2:20][CH2:21][O:22][CH2:23][N:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a flask containing methyl 1H-imidazole-4-carboxylate (5 g, 39.7 mmol) in DMF (70 ml), K2CO3 (13.7 g, 99.1 mmol), SEM-Cl (9.3 ml, 51.6 mmol) were added and stirred at 80° C. overnight. The reaction mixture was quenched by the addition of H2O and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography. Yield 3.8 g. 1H-NMR (400 MHz; DMSO-d6): δ 0.05 (s, 9H), 0.80 (t, 2H), 3.47 (t, 2H), 3.74 (s, 3H), 5.30 (s, 2H), 7.91 (s, 1H), 8.01 (s, 1H). LC-MS: [M+1]=257.27.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:18][C@@H:19]([CH3:33])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CO>[CH3:32][O:31][C:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C@@H:19]([NH:18][CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:33])=[CH:23][CH:24]=1)=[O:30]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](C=O)c1ccccc1
Reactant: COC(=O)Cc1ccc(OC[C@H](C)N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(OC[C@H](C)NC[C@@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1

Procedure:
Following a procedure similar to that described in Preparation 29, but using 1.5 g of (S)-α-(t-butyldimethylsilyloxy)-α-phenylacetaldehyde (prepared as described in Preparation 26), 1.1 g of methyl 4-[2(S)-amino-1-propoxy]phenylacetate (prepared as described in Preparation 28), 10 ml of absolute methanol and 950 mg of sodium cyanoborohydride, the title compound was obtained. [α]D23 +38.30° (c=1.116, chloroform)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH:12]([C:19]([O:21]CC)=O)[CH2:13][C:14]([O:16]CC)=O.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[CH:24]1([NH:30][C:14]([CH2:13][CH:12]([C:19]([NH:3][CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:21])[CH2:11][S:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:16])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)CC(CSc1nc2ccccc2s1)C(=O)OCC
Solvent: Cc1ccccc1
Product: O=C(CC(CSc1nc2ccccc2s1)C(=O)NC1CCCCC1)NC1CCCCC1

Procedure:
18.5 parts of diethyl 3-(benzothiazol-2-ylthio)-propane- 1,2-dicarboxylate are stirred with 31.1 parts cyclohexylamine for 12 hours at 95° C. The mixture is cooled and toluene added with stirring. The resulting solid is filtered off, washed with toluene and dried to give N,N'-dicyclohexyl 3-(benzothiazol-2-ylthio)-1,2-propane dicarboxylic acid diamide, melting at 147°-49° C.
Reaction SMILES: O.[NH2:2][NH2:3].C(O[C:7](=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH3:8])C.O>CCO>[NH2:11][C:10]1[NH:3][N:2]=[C:7]([CH3:8])[C:9]=1[C:12]#[N:13]
Reactant: CCOC(C)=C(C#N)C#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c(N)c1C#N
Temperature: 95 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
Hydrazine monohydrate (6.8 ml, 0.14 mol) was dissolved in EtOH (10 ml) and cooled to 0° C. (1-Ethoxyethylidene)malononitrile (10 g, 0.073 mol) was added slowly and the mixture was heated at 95° C. for 2 h. After cooling to rt, water (20 ml) was added and the mixture was allowed to stand at rt overnight. The mixture was concentrated under reduced pressure and the resulting residue treated with EtOH (6 ml) and water (6 ml). After cooling in an ice/water bath for 10 min, the resulting precipitate was collected by filtration to give 6.34 g of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1Br
Temperature: 0 °C
Yield: 97.3 %

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (25.4 g, 126.2 mmol) and imidazole (9.5 g, 138.9 mmol) in N,N-dimethylformamide (300 mL) was added tert-butyldimethylchlorosilane (20.9 g, 138.9 mmol) under stirring at 0° C., and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=10/1) to give the title compound (38.7 g, yield 97%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[CH:6][N:5]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(F)cc2)c(N)n1
Reactant: CC(=O)N1CCC(N)CC1
Product: CC(=O)N1CCC(Nc2ncc(C(=O)c3ccc(F)cc3)c(N)n2)CC1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(4-fluoro-phenyl)-methanone (Example 366) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(4-fluoro-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 358.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:16]1([CH:22]([N:24]2[CH:28]=[N:27][C:26]([NH2:29])=[N:25]2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:15][C:13]1[N:12]=[CH:11][N:10]([C:5]2[CH:4]=[CH:3][C:2]([NH:29][C:26]3[N:27]=[CH:28][N:24]([CH:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:23])[N:25]=3)=[CH:9][C:6]=2[C:7]#[N:8])[CH:14]=1
Reactant: CC(c1ccccc1)n1cnc(N)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ncn(C(C)c4ccccc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(1-phenyl-ethyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a yellowish solid (Yield=48%). MS ISP (m/e): 370.2 (100) [(M+H)+].
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:16]([C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a solution of o-phenylenediamine (4 mmol) in DCM (20 mL) and pyridine (4 mL) at 0° C., 4-chlorobenzenesulfonyl chloride (4.4 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with water (2×20 mL) and 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 960 mg of N-(2-aminophenyl)-4-chlorobenzenesulfonamide. LC: Tr 0.92 min, MS: 284.0 (M+1)+.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:16](O)[CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][O:12][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:15][CH:14]=1
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cl
Product: O=C(COc1ccc([N+](=O)[O-])cc1)OCCO
Yield: 57.4 %

Procedure:
Dry HCl gas was passed through a mixture of (4-nitrophenoxy) acetic acid 22 (100 g, 507 mmol) and ethylene glycol (300 ml) for 1 hour. During HCl gas bubbling the temperature rose to 60° C. The crude reaction mass was poured onto ice (2 kg). Crude 23 was filtered, dried and purified by column chromatography on silica gel using hexane:ethyl acetate (95:5) to give pure 23 (70 g, 57.4%) as a white powder with an m.p. between 73.5-75.5° C.
Reaction SMILES: [OH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[H-].[Na+].[Cl:13][C:14]1[S:15][C:16]([CH2:20]Br)=[C:17]([Cl:19])[N:18]=1>C1COCC1>[Cl:13][C:14]1[S:15][C:16]([CH2:20][O:1][CH2:2][P:3]([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])=[O:10])=[C:17]([Cl:19])[N:18]=1
Reactant: Clc1nc(Cl)c(CBr)s1
Reactant: CCOP(=O)(CO)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(COCc1sc(Cl)nc1Cl)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of diethyl hydroxymethylphosphonate (1.2 mmol) in THF (10 mL) at 0° C. was added 60% sodium hydride (1.1 mrnol) and allowed to stir for 15 minutes before adding 2,4-dichloro-5-(bromomethyl)thiazole (1 mmol). The mixture was warmed to room temperature and allowed to stir for 3 h. The reaction was extracted and chromatographed to yield 2,4-dichloro-5-(diethylphosphonomethoxymethyl)thiazole.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.I[CH2:15][C:16]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17]2.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:16]12([CH2:15][N:1]3[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]3)[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17]2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: ICC12CCC(CC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(CC23CCC(CC2)O3)C1
Temperature: 75 °C
Reaction time: 32 h
Yield: 52.3 %

Procedure:
The mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (500 mg), 1-(iodomethyl)-7-oxabicyclo[2.2.1]heptane (639 mg) and K2CO3 (742 mg) in DMF (5 mL) was stirred at 75° C. for 32 hours. The resultant was added H2O, extracted with AcOEt. The organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-1-(7-oxabicyclo[2.2.1]hept-1-ylmethyl)-3-pyrrolidinyl]carbamate (416 mg) as orange oil.
Reaction SMILES: C([O:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[N:12]2[C:28](=[S:31])[NH:29][N:30]=[C:11]2[C:10]1=[O:32])C1C=CC=CC=1.[OH-].[Na+]>S(=O)(=O)(O)O>[OH:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=2)[N:12]2[C:28](=[S:31])[NH:29][N:30]=[C:11]2[C:10]1=[O:32]
Reactant: O=c1c2n[nH]c(=S)n2c2cc(-n3ccnc3)c(C(F)(F)F)cc2n1OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1c2n[nH]c(=S)n2c2cc(-n3ccnc3)c(C(F)(F)F)cc2n1O
Temperature: 0 °C
Yield: 24.4 %

Procedure:
A solution of 1.38 g (3 mmol) of 5-benzyloxy-8-(1H-imidazol-1-yl)-1-thioxo-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one in 20 ml of conc. sulfuric acid was stirred at room temperature for 20 min., and poured into 200 ml of ice-water. The stirred mixture was adjusted to pH 5-6 by cautious addition of solid sodium hydroxide at 0° C. Extraction with ethyl acetate (5×100 ml) gave 270 mg (25%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:6]([CH:18]=1)[C:7]([NH:9][CH2:10][C:11]1[NH:16][C:15](=[O:17])[CH:14]=[CH:13][CH:12]=1)=[O:8]>[Rh].CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])=[C:6]([CH:18]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][C:15](=[O:17])[NH:16]1)=[O:8]
Reactant: O=C(NCc1cccc(=O)[nH]1)c1cc(O)ccc1OCC(F)(F)F
Agent: [Rh]
Solvent: CO
Product: O=C1CCCC(CNC(=O)c2cc(O)ccc2OCC(F)(F)F)N1
Reaction time: 0.83 h

Procedure:
A mixture of 0.16 g (0.468 mmole) of 6-[5-hydroxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone, 0.05 g of 5% rhodium on alumina and 50 ml of methanol was hydrogenated on a Parr apparatus for 50 minutes. The mixture was filtered, the filtrate was evaporated, and the residue was dried to provide 5-hydroxy-N-(6-oxo-2-piperidylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide. The structural assignment was confirmed by comparison of infrared and nuclear magnetic resonance spectra.