Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:23]([NH2:25])=[O:24])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][O:20][S:21][NH2:22])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].N1C=CC=CC=1>CN(C=O)C.O>[C:28]([NH:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:23]([NH2:25])=[O:24])=[N:10][N:11]([C:13]4[CH:14]=[CH:15][C:16]([O:19][O:20][S:21][NH2:22])=[CH:17][CH:18]=4)[C:12]=3[C:4]=2[CH:3]=1)(=[O:30])[CH3:29]
Reactant: NSOOc1ccc(-n2nc(C(N)=O)c3c2-c2cc(N)ccc2CC3)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)-c1c(c(C(N)=O)nn1-c1ccc(OOSN)cc1)CC2
Reaction time: 8 h
Yield: 90 %

Procedure:
To the material of Example 4b (1.0 g, 0.0026 mol) in DMF (15 mL) was added dropwise a mixture of acetic anhydride (0.283 mL, 0.003 mol) and pyridine (0.243 mL, 0.003 mol) in DMF (5 mL). Contents were stirred overnight, diluted with water (75 mL), and filtered to give the desired as a white solid, 1.0 g (90% yield). FABHRMS m/z 426.1235 (M+H, C20H20N5O4S requires 426.1236). 1H NMR (DMSO-d6/300 MHz) 9.80 (s, 1H); 8.00 (d, 2H); 7.75 (d, 2H); 7.60 (s, 1H); 7.48 (s, 2H); 7.39 (s, 1H); 7.30 (d, 1H); 7.15 (s, 1H); 2.90 (s, 4H); 1.92 (s, 3H). Anal. Calcd for C20H19N5O4S (1H2O): C, 54.17; H, 4.77; N, 15.79. Found: C, 54.20; H, 4.97; N, 15.77.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][C:16]([CH3:38])([CH3:37])[C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:21][CH2:20]1)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1.O>[CH2:7]([O:14][CH2:15][C:16]([CH3:38])([CH3:37])[CH2:17][N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:32][C:33]([F:34])([F:36])[F:35])[CH2:23][CH2:24]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(COCc1ccccc1)C(=O)N1CCN(c2ccccc2OCC(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(COCc1ccccc1)CN1CCN(c2ccccc2OCC(F)(F)F)CC1
Temperature: 0 °C
Yield: 96.9 %

Procedure:
A suspension of lithium aluminum hydride (0.49 g, 12.8 mmol) and THF (5 mL) was cooled to 0° C. and added to a solution of 3-benzyloxy-2,2-dimethyl-1-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}-1-propanone (2.8 g, 6.4 mol) in 12 mL of THF. The mixture was heated 2 hours at reflux, slowly diluted with water, filtered and concentrated. The residue was dissolved in water and the solution was extracted with methylene chloride (4×30 mL). The combined extracts were washed with water (1×25 mL), dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (8:2) to give 3-benzyloxy-2,2-dimethyl-1-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propane (2.6 g, 6.2 mol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.N[CH2:31]C1C=CC(C(OC)=O)=C(C)C=1>>[F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:28]([CH3:31])[CH:29]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Reactant: COC(=O)c1ccc(CN)cc1C
Product: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1C

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 3 of Example 1) and methyl 4-(aminomethyl)-2-methylbenzoate: 1H-NMR (CDCl3) δ 8.38 (1H, dd, J=8.1, 3.1 Hz), 8.30–8.24 (1H, m), 8.05 (1H, d, J=3.1 Hz), 7.88 (1H, d, J=8.1 Hz), 7.26–7.08 (6H, m), 4.71 (2H, d, J=5.9 Hz), 3.90 (3H, s), 3.87 (3H, s); MS (ESI) m/z 413 (M+H)+, 411 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=O.C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C(OC(=O)C)(=O)C>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[O:14][C:12](=[O:13])/[C:11](=[C:16](/[C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)\[CH3:15])/[N:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)CNC(=O)c1cccnc1Cl
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: C/C(=C1/N=C(c2cccnc2Cl)OC1=O)c1ccc([N+](=O)[O-])cc1
Yield: 20.8 %

Procedure:
A mixture of 2-{[(2-chloro-3-pyridinyl)carbonyl]amino}acetic acid (6.44 g, 30 mmol, prepared from glycine and 2-chloronicotinoyl chloride), 4-nitroacetophenone (2.48 g, 15 mmol), lead (IV) acetate (3.33 g, 7.5 mmol) and acetic anhydride in THF (30 ml) was heated at reflux for 4 days. The mixture was poured onto crushed ice, the solid filtered off, washed with water and dried. The brown solid was triturated twice with boiling ethanol and filtered off to give the title compound as a brown solid (1.07 g). δH (CDCl3), 8.57 (1H, dd, J 4.8, 2.1 Hz, PyH), 8.34-8,29 (3H, m, ArH+PyH), 8.05 (2H, d, J 9.1 Hz, ArH), 7.41 (1H, dd, J 7.9, 4.8 Hz, PyH) and 2.84 (3H, s, Me).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[CH:39]1([NH:42][CH2:43][CH2:44][C:45]#[N:46])[CH2:41][CH2:40]1>CN(C=O)C>[C:45]([CH2:44][CH2:43][N:42]([CH:39]1[CH2:41][CH2:40]1)[C:16]1[C:17]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:8][CH:9]=2)[N:15]=1)#[N:46]
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: N#CCCNC1CC1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCC#N)C4CC4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). 3-(cyclopropylamino)propanenitrile (49.7 mg, 0.45 mmol) was added and the reaction mixture was stirred at 85° C. overnight. The mixture was allowed to reach room temperature and the solvent was evaporated under reduced pressure. The crude tert-butyl 4-((2-cyanoethyl)(cyclopropyl)amino)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5H)-carboxylate (241 mg, 104%) was used as such in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:48]=[CH:47][C:14]([CH2:15][N:16]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:17]2[N:22]=[CH:21][C:20]([C:23]3[C:24]4[CH2:37][CH2:36][NH:35][C:25]=4[N:26]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:28]=3)=[CH:19][N:18]=2)=[CH:13][CH:12]=1.C(Cl)(Cl)Cl.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([N:35]2[C:25]3[N:26]=[C:27]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[N:28]=[C:23]([C:20]4[CH:21]=[N:22][C:17]([N:16]([CH2:38][C:39]5[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=5)[CH2:15][C:14]5[CH:47]=[CH:48][C:11]([O:10][CH3:9])=[CH:12][CH:13]=5)=[N:18][CH:19]=4)[C:24]=3[CH2:37][CH2:36]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Clc1ccc(I)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Temperature: 100 °C
Reaction time: 14 h
Yield: 36.7 %

Procedure:
A toluene solution (10 ml) of 2-chloro-5-iodopyridine (67 mg, 0.27 mmol), bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg, 0.18 mmol), Pd2(dba)3.CHCl3 (19 mg, 0.018 mmol), BINAP (17 mg, 0.02 mmol) and cesium carbonate (181 mg, 0.55 mmol) was degassed under ultrasonic irradiation, followed by stirring at 100° C. for 14 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and subsequently magnesium sulfate was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1), to obtain {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine as a yellow solid (43 mg, 36%).
Reaction SMILES: CS(O[CH2:6][C:7]([N:10]1[CH:14]=[C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:12]=[N:11]1)([CH3:9])[CH3:8])(=O)=O.[I-].[Na+].[CH3:25][S:26]([O-:28])=[O:27].[Na+].O>CN(C)C=O>[C:19]([O:18][C:16](=[O:17])[NH:15][C:13]1[CH:12]=[N:11][N:10]([C:7]([CH3:9])([CH3:8])[CH2:6][S:26]([CH3:25])(=[O:28])=[O:27])[CH:14]=1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1cnn(C(C)(C)COS(C)(=O)=O)c1
Reactant: CS(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cnn(C(C)(C)CS(C)(=O)=O)c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
To a solution of the crude 2-(4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)-2-methylpropyl methanesulfonate (1.1 g) obtained in Step B of Example 114 in N,N-dimethylformamide (10 mL) were added sodium iodide (740 mg) and sodium methanesulfinate (1.0 g), and the mixture was stirred overnight at 140° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (250 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C.O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2cc(O)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2cc(OCCN3CCOCC3)ccc21
Temperature: 80 °C
Yield: 68.1 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-5-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one (60 mg, 0.18 mmol) obtained in Step 5 in DMF (2 mL) was added K2CO3(75 mg, 0.54 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (50 mg, 0.27 mmol). The mixture was heated to 80° C. for 3 h and cooled to room temperature. The resulting solution was diluted with H2O and extracted with EtOAc (5 mL×3). The extracts were washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2% MeOH/CH2Cl2) to afford the title compound (55 mg, 68%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].Cl.Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]3[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]3[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])[CH2:12][CH2:11]1)(=[O:5])=[O:4]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(S(=O)(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
Dimethylsulfamoyl chloride (90 mg) was added to a solution of 6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline dihydrochloride (250 mg) (starting material Example 16) and diisopropylethylamine (184 mg) in methylene chloride (10 ml). The reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was adsorbed onto silica and the residue was purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the expected product were combined and evaporated under vacuum and the residue triturated with diethylether to give the title product as a white solid (0.23 g); 1H NMR. Spectrum: (DMSO d6) 1.72-1.86 (m, 2H), 2.00-2.12 (m, 2H), 2.76 (s, 6H); 3.12-3.23 (m, 2H), 3.40-3.51 (m, 2H), 3.94 (s, 3H), 4.68 (m, 1H), 7.19-7.30 (m, 2H), 7.43-7.54 (m, 2H), 7.85 (s, 1H), 8.37 (s, 1H), 9.52 (s, 1H); Mass Spectrum: (M+H)+ 510.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:35][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCCCC1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)NC3CCCCCC3)c(=O)n12
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, 9.96 g (0.088 mol) of cycloheptylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -12° C. and -15° C. during 40 minutes. The reaction mixture is stirred for 1 hour below -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to obtain 20.4 g (85.2%) of the named compound as yellow crystals, m.p.: 172°-174° C.
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][C:9]1[C:21]2[C:20]3[CH:19](N4CCN(C)CC4)[CH2:18][CH2:17][CH2:16][C:15]=3[C:14](=[O:29])[NH:13][C:12]=2[N:11](C)[N:10]=1.[OH-].[Na+]>ClCCl.O>[CH3:8][C:9]1[C:21]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14](=[O:29])[NH:13][C:12]=2[NH:11][N:10]=1
Reactant: Cc1nn(C)c2[nH]c(=O)c3c(c12)C(N1CCN(C)CC1)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1n[nH]c2[nH]c(=O)c3c(c12)CCCC3
Temperature: 230 °C
Yield: 85.1 %

Procedure:
A mixture of 8.5 g of pyridine and 10 mL of concentrated hydrochloric acid was heated to 230° C., added to EXAMPLE 1 (217 mg, 1.0 mmol) and the mixture heated at 230° C. for 2 hours. After cooling, water was added and the suspension neutralized with 10% sodium hydroxide. Dichloromethane (50 mL) was added, the mixture was filtered and the solid collected, washed with dichloromethane and water and dried. Purification by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% trifluoroacetic acid in water; B: 0.1% trifluoroacetic acid in acetonitrile; 0-100% gradient) provided 173 mg (73%) of the title compound as the trifluoroacetate salt. 1H NMR (DMSO-d6) 1.63-1.73 (m, 4H), 2.29-2.34 (m, 2H), 2.46 (s, 3H), 2.75-2.80 (m, 2H), 11.28 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[Cl:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(OCC)(=O)C>[Cl:14][C:15]1[C:16]([C:17]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[CH:3]=2)=[O:18])=[CH:20][CH:21]=[CH:22][N:23]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-aminobenzotrifluoride (Ruka, Buchs, Switzerland; 2.5 mL, 2.90 g, 18 mmol) in ethyl acetate (40 mL) is added to a stirred aqueous solution of sodium hydroxide (40 mL of 1 M, at room temperature. This stirred solution is then treated dropwise over 30 minutes with a solution of 2-chloronicotinoyl chloride (Lancaster Synthesis, Lancashire, England; 3.52 g, 20 mmol) in dry ethyl acetate (25 mL). The resulting mixture is then stirred for 2 h at ambient temperature. The mixture is then extracted with ethyl acetate (3×100 mL) and the combined extracts are sequentially washed with water (2×100 mL), hydrochloric acid (2×100 mL of 2M), water (2×100 mL), saturated aqueous sodium hydrogen carbonate solution (2×100 mL) and saturated aqueous sodium chloride (1×100 mL), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate-hexane to give the title compound as a colourless crystalline solid, m.p. 117-118° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:12]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:11]2[CH:10]=[C:9]([OH:17])[CH:8]=[CH:7][C:6]=2[CH2:5][C@@H:4]1[O:18][CH3:19].C[O:21][C:22](=[O:34])[C@H:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:24][CH:25]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CCOC(C)=O>[CH:28]1([CH2:27][C@H:23]([CH2:24][CH2:25][NH:2][C@@H:3]2[C@@H:4]([O:18][CH3:19])[CH2:5][C:6]3[C:11](=[CH:10][C:9]([OH:17])=[CH:8][CH:7]=3)[C:12]2([CH2:15][CH3:16])[CH2:13][CH3:14])[C:22]([OH:34])=[O:21])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COC(=O)[C@@H](CC=O)CC1CCCCC1
Reactant: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1NCC[C@@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 125.8 %

Procedure:
(6S,7S)-7-Amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalen-2-ol hydrochloride salt (100 mg, 0.35 mmol), (R)-2-cyclohexylmethyl-4-oxo-butyric acid methyl ester (90 mg, 0.42 mmol) and triethylamine (35 mg, 0.035 mmol) were dissolved in dichloromethane (2.0 mL) and stirred at room temperature for 30 min. Sodium triacetoxyborohydride (1.03 g, 4.85 mmol) was added and the reaction was monitored by HPLC. After 3 h, additional (R)-2-cyclohexylmethyl-4-oxo-butyric acid methyl ester (20 mg, 0.1 mmol) and sodium triacetoxyborohydride (30 mg, 0.14 mmol) were added. Thirty minutes after the last addition, EtOAc (15 mL) was added and the mixture was washed with 5% aqueous sodium carbonate (2×5 mL) and saturated sodium chloride (5 mL). The organic layer was dried with Na2SO4) and concentrated to give the title compound (190 mg). (m/z): [M+H]+ calcd for C27H43NO4, 446.33; found, 446.6.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:35])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:35])=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2c(CO)n(CC(C)C)c(=O)c3ccc(OCc4ccccc4)cc23)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2c(CCl)n(CC(C)C)c(=O)c3ccc(OCc4ccccc4)cc23)cc1
Yield: 95.5 %

Procedure:
To a suspension of 6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinone (4.28 g, 10 mmol) in toluene (50 ml) was added thionyl chloride (1.5 ml, 20 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-3-chloromethyl-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinone (4.26 g, 95.5%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Br:25])[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)=[O:6].[N:26]1[N:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]2=[C:28]([C:35](Cl)=[O:36])[CH:27]=1>>[Br:25][C:24]1[CH:23]=[CH:22][C:4]([C:5](=[O:6])[NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)=[CH:3][C:2]=1[NH:1][C:35]([C:28]1[CH:27]=[N:26][N:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=12)=[O:36]
Reactant: CN1CCN(c2ccccc2CNC(=O)c2ccc(Br)c(N)c2)CC1
Reactant: O=C(Cl)c1cnn2ccccc12
Product: CN1CCN(c2ccccc2CNC(=O)c2ccc(Br)c(NC(=O)c3cnn4ccccc34)c2)CC1

Procedure:
The title compound was prepared from 3-amino-4-bromo-N-(2-(4-methylpiperazin-1-yl)benzyl)benzamide (Ex 5.1, step 1) and pyrazolo[1,5-a]pyridine-3-carbonyl chloride (commercially available) analogously to Example 5.1;
Reaction SMILES: [C:1]1([CH2:7][CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[C:1]1([CH2:7][CH2:8][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cccc(N)c1
Reactant: OCCc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: Cc1cccc(NCCc2ccccc2)c1
Temperature: 236 °C
Yield: 90 %

Procedure:
260 parts of phenylethyl alcohol, 428 parts of m-toluidine and 20 parts of triphenyl phosphite are mixed and heated, using a water separator, initially to 210° C, at which temperature the elimination of water commences. The internal temperature is raised to 236° C in the course of 8 hours. After this time, the elimination of water has ended (36 parts of water). After distilling off excess alcohol and amine, the N-(2-phenylethyl)-m-toluidine distils at a boiling point of 167° C/5 mm Hg. 402 parts of N-(2-phenylethyl)-m-toluidine (90% of theory) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].O.O.[Cl-].[Ca+2].[Cl-].Cl.N[CH2:16][C:17]1[S:21][C:20]([Cl:22])=[N:19][CH:18]=1.[OH-].[Na+]>O>[CH3:1][O:2][C:3](=[N:4][N+:5]([O-:7])=[O:6])[NH:8][CH2:16][C:17]1[S:21][C:20]([Cl:22])=[N:19][CH:18]=1
Reactant: COC(=N)N[N+](=O)[O-]
Reactant: NCc1cnc(Cl)s1
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 19 h
Yield: 58.9 %

Procedure:
O-methyl-N-nitroisourea (2.0 g, 0.0168 mol) was added to water (40 ml) dissolving calcium chloride dihydrate (8.0 g). Then, 36% hydrochloric acid (1.5 ml, 0.0176 mol, 1.05 equivalents) was added, and 5-(aminomethyl)-2-chlorothiazole (2.5 g, 0.0168 mol, 1.00 equivalent) was added at 24° C. The mixture was adjusted to pH 7 with 30% aqueous sodium hydroxide solution. After 19 hours of stirring at room temperature, the resulting crystals were collected by filtration to provide 2.48 g (59.1% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.