Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([O:11][CH3:12])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[CH:15][CH:14]=2)=[CH:21][CH:22]=1)#[N:2]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1
Reactant: CN1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC2CCN(C)CC2)cc1
Temperature: 0 °C
Reaction time: 120 h
Yield: 44.7 %

Procedure:
(RS)-N-(4-Cyano-benzyl)-2-(4-hydroxy-phenyl)-2-methoxy-acetamide (example 21.2, 0.406 g) was dissolved in THF (12 ml). Triphenylphosphine (0.539 g) and 4-hydroxy-N-methylpiperidine (0.237 g) were added. The reaction mixture was cooled to 0° C. Slowly, DEAD (0.384 g) was added. The reaction mixture was stirred at 0° C. for 30 min and at rt for 5 days. The solvent was evaporated and the product was purified by chromatography (silicagel, mobile phase: gradient from CH2Cl2 to CH2Cl2/MeOH 4:1) to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-[4-(1-methyl-piperidin-4-yloxy)-phenyl]-acetamide as a colorless foam (0.241 g). MS 394.4 ([M+H]+)
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([CH3:12])[N:3]=1.Cl.[NH:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=2)=[N:17][N:16]=[N:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:17]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:2]3[C:11]4[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=4[N:5]=[C:4]([CH3:12])[N:3]=3)=[CH:27][CH:26]=2)=[N:14][N:15]=[N:16]1
Reactant: NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: Cc1nc(Cl)c2c(n1)CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c(c(NCc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)n1)CCCC2
Temperature: 95 °C
Yield: 30.6 %

Procedure:
To 10 mL of dimethylformamide were added 0.57 g of 4-chloro-5,6,7,8-tetrahydro-2-methylquinazoline, 0.45 g of N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amine hydrochloride and 1.30 g of anhydrous potassium carbonate. The resulting mixture was heated at 95° C. for 5 days and then cooled to room temperature. The resulting mixture was run through a silica plug (methanol/chloroform/ammonia eluant) and after all solvent was removed by evaporation the resulting residue was purified on silica to yield 0.19 g (31%) of the desired product. The compound was characterized as its potassium salt: 1H NMR (DMSO-d6, 400 MHz) δ 7.50 (m, 1H), 7.32 (m, 3H), 7.11 (d, J=8.2 HZ, 2H), 7.02 (m, 3H), 4.57 (d, J=6.0 Hz, 2H), 2.48 (m, 4H);, 2.24 (s, 3H), 1.71 (m, 4H); negative FAB-MS m/e 433(M-H); 396(M-K). Anal. calcd for C23H22KN7.0.85H2O: C, 61.53; H, 5.30; N, 21.84. Found: C, 61.74; H, 5.25; N, 21.47.
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[N:24][N:25]([CH3:27])[CH:26]=3)=[CH:18][CH:17]=2)=[CH:9][C:4]=1[C:5](OC)=[O:6])=[O:2].[O:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][NH2:34].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.C(OCC)(=O)C>[OH:2][CH:1]1[C:3]2[C:4](=[CH:9][C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:23]=[N:24][N:25]([CH3:27])[CH:26]=4)=[CH:18][CH:17]=3)=[C:11]([CH3:14])[C:12]=2[CH3:13])[C:5](=[O:6])[N:34]1[CH2:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][O:28]1
Reactant: COC(=O)c1cc(Cc2ccc(-c3cn(C)nn3)cc2)c(C)c(C)c1C=O
Reactant: NC[C@@H]1CCCO1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-c3cn(C)nn3)cc2)cc2c(c1C)C(O)N(C[C@@H]1CCCO1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-formyl-3,4-dimethyl-5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)benzoate (0.13 g) in THF (3.00 mL) were added 1-((2S)-tetrahydrofuran-2-yl)methanamine (0.04 mL) and anhydrous magnesium sulfate (0.04 g), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3([C:26]([NH:30][C@@H:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]4[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Reactant: CCOC(=O)[C@H]1CCCC[C@@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCC[C@H]1NC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), (1S,2S)-ethyl 2-aminocyclohexanecarboxylate hydrochloride (9.08 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC to give the title compound. LCMS m/z=531.6 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]2[CH2:39][CH2:38][CH2:37]2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]5[CH2:39][CH2:38][CH2:37]5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(OC2CCC2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OC5CCC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-cyclobutoxy-pyridine.
Reaction SMILES: [F:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]3[N:15]([CH3:16])[C:14]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:13]=4[N:12]=3)=[N:7][C:6]=2[CH:24]=1.CN.[CH3:28][N:29](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:28][NH:29][C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([NH:10][C:8]3[S:9][C:5]4[CH:4]=[C:3]([F:25])[C:2]([F:1])=[CH:24][C:6]=4[N:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:23]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(Nc2nc3cc(F)c(F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)c(F)cc3s1)n2C
Yield: 69.7 %

Procedure:
2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid methylamide (26 mg) was prepared by following General Procedure F using 2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (36 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.2 ml). LCMS: m/z 375; and 1H NMR (DMSO-d6, 400 MHz): δ 8.30 (d, 1H), 8.04 (s, 1H), 7.93 (d, 1H), 7.60 (d, 1H), 7.49 (m, 2H), 7.29 (d, 1H), 3.62 (s, 3H), and 2.80 (d, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10](=[CH:15][CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:12][CH2:13][NH2:14])[CH3:9].Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>ClCCl>[CH2:8]([C:10](=[CH:15][CH:16]([CH3:17])[CH3:18])[CH:11]=[CH:12][CH2:13][NH:14][C:20]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:27])[CH3:9]
Reactant: CCC(C=CCN)=CC(C)C
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C=CCNC(=O)c1cccnc1)=CC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a solution of triethylamine (5.06 g) and 4-ethyl-6-methyl-2,4-heptadiene-1-ylamine (3.06 g) in dichloromethane (50 ml) at 0° C. was added nicotinic acid chloride hydrochloride (3.56 g) in small portions during 5 minutes. The mixture was stirred for 30 minutes at 0° C. The reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was dissolved in isopropyl ether (20 ml) and allowed to stand at 5° C. overnight to give 4.46 g of N-(4-ethyl-6-methyl-2,4-heptadiene-1-yl)-3-pyridinecarboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:21])[C:7](=[O:20])[NH:8][N:9]=1.[H-].[Na+].Cl[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]([F:17])([F:18])[F:19])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:21])[C:7](=[O:20])[N:8]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(Br)cc3N21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(Br)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a 0° C. solution of 6-bromo-4-methyl-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.364 g, 1.0 mmol) in THF (50 mL) was added sodium hydride (60% in mineral oil, 0.080 g, 2 mmol) and the reaction mixture was stirred for 0.5 h. (2-(chloromethoxy)ethyl)trimethylsilane (0.250 g, 1.5 mmol) was added and the mixture was stirred at ambient temperature for 2 h. The reaction was quenched with water (100 mL) and the aqueous mixture was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 3-20% EtOAc in petroleum ether) to give 6-bromo-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a white solid (0.330 g, 67%). 1H NMR (CDCl3, 400 MHz): δ 7.32 (s, 1H), 7.16 (s, 1H), 5.11 (q, J=8.8 Hz, 2H), 4.75 (d, J=12.6 Hz, 1H), 4.69 (q, J=6.4 Hz, 1H), 4.57 (d, J=12.6 Hz, 1H), 3.65 (t, J=8.4 Hz, 2H), 1.51 (d, J=6.8 Hz, 3H), 0.99 (t, J=8.4 Hz, 2H), 0.01 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: C1COCCN1
Reactant: CSc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCC(C)CC4)c3)c3ccccc23)n1
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(Oc4ccnc(N5CCOCC5)n4)c4ccccc34)c2)CC1

Procedure:
Compound is prepared from 3-fluoro-5-(4-methylpiperidin-1-yl)-N-(4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)benzamide (0.1 g, 0.2 mmol) and morpholine (10 mmol) according to conditions described in Step 4 of Example 3 and general procedure C. A pink solid is produced (15 mg). Mp: 88-89° C.; 1H NMR (300 MHz, CDCl3) δ 0.98(d, J=6.6 Hz, 3H), 1.25-1.38(m, 3H), 1.75 (d, J=12.6 Hz, 2H), 2.78-2.86(m, 2H), 3.64(s, 9H), 3.77(d, J=12 Hz, 1H), 6.07(d, J=5.7 Hz, 1H), 6.77(d, J=12 Hz, 1H), 6.98(d, J=7.8 Hz, 1H), 2.30-7.33(m, 2H), 7.49-7.60(m, 2H), 7.89-7.99(m, 3H), 8.13(s, 1H), 8.18(d, J=5.7 Hz, 1H); MS 542 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:16][CH2:17][CH2:18][NH:19][CH3:20].C(N(CC)CC)C>O1CCOCC1>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([N:19]([CH2:18][CH2:17][Cl:16])[CH3:20])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: CNCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(CCCl)C1CC(=O)N(Cc2ccccc2)C1=O
Temperature: 0 °C

Procedure:
74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 308, 489 (1975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methylamine hydrochloride are initially introduced into 400 ml of dioxane and 40.4 g (0.4 mol) of triethylamine are added dropwise at 20° C. The mixture is then boiled under reflux for 5 hours. The batch is subsequently poured into 2 l of ice-water and extracted with 3 portions of 400 ml of chloroform and the extract is washed with water, dried over sodium sulphate and concentrated on a rotary evaporator. Chromatography of the residue (101.1 g) on silica gel using ethyl acetate:petroleum ether (1:2) gives 56.8 g (51% of theory) of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N+]([C:14]1[CH:19]=CC(O)=C[CH:15]=1)([O-])=O.S(=O)(=O)(O)O.OCC(CO)O.[OH-].[Na+]>>[N:1]1[C:2]2[C:10](=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:19]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: O=C(O)c1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 112.8 %

Procedure:
To a mixture of 4-aminobenzoic acid (175 g, 1.28 mol), 4-nitrophenol (88.75 g, 0.64 mol) and sulphuric acid (1.2 lit.), glycerol (234.8 g, 2.55 mol) was added dropwise at 135° C. After 48 h, the reaction mixture was cooled to 0° C. and the pH adjusted to 3-5 with 10% sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water and dried under vacuum to afford the title compound as a black solid (125 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[N:7][C:6]=2[C:5]([Cl:15])=[CH:4][C:3]=1[Cl:16].[O:17]=[C:18](Cl)OC(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:15][C:5]1[C:6]2[N:7]=[C:8]([S:11]([CH3:14])(=[O:12])=[O:13])[S:9][C:10]=2[C:2]([N:1]=[C:18]=[O:17])=[C:3]([Cl:16])[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1nc2c(Cl)cc(Cl)c(N)c2s1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1nc2c(Cl)cc(Cl)c(N=C=O)c2s1

Procedure:
5 g (17 mmol) of 7-amino-4,6-dichloro-2-(methylsulfonyl)benzothiazole and 17 g (85 mmol) of diphosgene in 200 ml of toluene were refluxed for 8 hours, after which the reaction mixture was evaporated down.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:17]#[N:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]([C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][N:20]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH3:19])#[N:18]
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: CNCCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc(F)cc1)CCC(C#N)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 3-bromo-1-cyano-1,1-diphenylpropane (1.5 g)--see Preparation 4), N-methyl-4-fluorophenethylamine (0.766 g--see CA 80:PIZ0985y), anhydrous potassium carbonate (1.38 g) and acetonitrile (50 ml) was heated under reflux for 24 hours then concentrated in vacuo. The residue was dissolved in water (40 ml) and extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 100%) and then with dichloromethane containing methanol (0% up to 3%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield, 0.51 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=23)=[CH:4][CH:3]=1.[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O.O1CCOCC1.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:22]1[C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[N:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=34)=[CH:4][CH:3]=2)=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc(Br)cc3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc(-c4cc5ccccc5s4)cc3)c12
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
A mixture of 1-(4-bromophenyl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine (30.0 mg, 0.0874 mmol), 1-benzothiophen-2-ylboronic acid (18.7 mg, 0.105 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) in 1,4-dioxane (2 mL, 30 mmol) and H2O (0.2 mL, 9 mmol) was degassed and refilled with nitrogen (3×). The reaction was microwaved on 300 watts, PowerMAX enabled, 100° C. for 30 min. For the workup, the reaction was concentrated in vacuo to a solid and purified by 10 g Jones Chromatography column wetted with DCM, dried loaded the product, eluted with DCM to 5% MeOH in DCM], which afford 8.4 mg (24%) of the desired product as a yellow solid. 1H NMR (400 MHz, CDCl3); 6=2.03-2.14 (m, 1H), 2.16-2.27 (m, 1H), 2.48-2.59 (m, 2H), 2.61-2.74 (m, 2H); 3.78-3.89 (m, 1H), 6.93 (d, J=5.56 Hz, 1H), 7.14 (d, J=5.56 Hz, 1H), 7.33-7.43 (m, 2H), 7.66 (s, 1H), 7.74 (d, J=8.59 Hz, 2H), 7.80-7.92 (m, 4H). HPLC: tR=2.71 min. (Open Lynx polar—5 min.). MS (ES+): m/z 379.80/380.91 (100/60) [MH+].
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:24]3[C:23]4[CH:22]=[C:21]([C:25]5[CH:26]=[N:27][C:28]6[C:33]([CH:34]=5)=[CH:32][CH:31]=[CH:30][CH:29]=6)[CH:20]=[CH:19][C:18]=4[N:17]=[CH:16][C:15]=3[N:14]([CH3:35])[C:13]2=O)=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>O1CCOCC1>[CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:24]3[C:23]4[CH:22]=[C:21]([C:25]5[CH:26]=[N:27][C:28]6[C:33]([CH:34]=5)=[CH:32][CH:31]=[CH:30][CH:29]=6)[CH:20]=[CH:19][C:18]=4[N:17]=[CH:16][C:15]=3[N:14]([CH3:35])[C:13]2=[S:46])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4]
Reactant: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4cnc5ccccc5c4)ccc3ncc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cn1c(=S)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4cnc5ccccc5c4)ccc3ncc21

Procedure:
100 mg (0.213 mmol) of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile (Example 7) and 95 mg (0.234 mmol) Lawesson reagent (Fluka, Buchs, Switzerland) in 1 ml of dioxane are heated at 100° C. for 96 h. The reaction mixture is quenched with sat. aqueous NaHCO3 and extracted with CH2Cl2 (2×). The organic layers are washed with sat. aqueous NaHCO3, dried over Na2SO4, filtered and evaporated. The residue is purified by preparative HPLC to provide the title compound as an off-white solid. ES-MS: 486 (M+H)+; analytical HPLC: tret=3.29 minutes (Grad 1).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14]>C1CCCCC1.CCCCCCC>[CH2:3]([C:4](=[N:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:2][CH3:1]
Reactant: CCCCCCC(=O)CCC
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCCCC1
Solvent: CCCCCCC
Product: CCCCCCC(CCC)=NNC(=O)OC(C)(C)C
Yield: 92.9 %

Procedure:
24.76 g (158 mmol) of 4-decanone and 20.94 g (158 mmol) of tert-butyl carbazate are heated for 90 minutes at 80° C. in 250 ml of cyclohexane/heptane mixture (1:1). After cooling, 39.71 g (93%) of a white solid are obtained by crystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][NH:30]C(OC(C)(C)C)=O)[CH:25]=[CH:26][C:27]=1[CH3:28].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:29]([C:24]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:22]([Cl:21])[CH:23]=2)[N:30]=1
Reactant: Cc1ccc(NNC(=O)OC(C)(C)C)cc1Cl
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1Cl
Yield: 26.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl 2-(3-chloro-4-methylphenyl)hydrazinecarboxylate (Intermediate-87, 0.450 g, 1.55 mmol), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.180 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]([N:16]=[C:17]=S)([CH3:15])[CH3:14]>C(OCC)(=O)C>[CH:13]([NH:16][C:17]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9](=[O:10])(=[O:11])[N:12]=1)([CH3:15])[CH3:14]
Reactant: Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CC(C)N=C=S
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)S(=O)(=O)N=C(NC(C)C)N2

Procedure:
The title compound was prepared from 2-amino-5-methylbenzenesulfonamide and isopropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 266-268° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 1.16 (d, 6H, CH(CH3)2), 3.91 (m, 1H, CH(CH3)2), 6.92 (br.d, 1H, NH), 7.06 (d, 1H, ArH), 7.35 (dd, 1H, ArH), 7.45 (d, 1H, ArH), 10.20 (br.s, 1H, NH); MS: m/e 253 (M+, 44%); (C11H15N3O2S1) calc. C, 52.16; H, 5.97; N, 16.59; found C, 52.28; H, 6.19; N, 16.49.