Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.C(N(C(C)C)CC)(C)C.[Cl:18][C:19]1[C:20](=[O:31])[C:21]2[C:26]([C:27](=[O:30])[C:28]=1Cl)=[CH:25][CH:24]=[CH:23][CH:22]=2.O>C1C=CC=CC=1>[Cl:18][C:19]1[C:20](=[O:31])[C:21]2[C:26]([C:27](=[O:30])[C:28]=1[NH:1][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: NCc1cnccn1
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C(Cl)=C(NCc2cnccn2)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.8 %

Procedure:
2-(Aminomethyl)pyrazine (3.2 g) and diisopropylethylamine (5.8 ml) were added to a solution of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene (3.0 g) in benzene (90 ml) and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction solution and the resulting precipitate was removed by filtration and then the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution with chloroform) to give 2-chloro-1,4-dihydro-1,4-dioxo-3-[(2-pyrazinylmethyl)amino]naphthalene (0.23 g) as a light brown powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:28])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13](Br)=[C:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)=[O:6].[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2B(O)O)[CH:32]=[CH:31][CH:30]=1>>[OH:1][CH2:2][CH2:3][N:4]([CH3:28])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:38]=2[N:29]=[CH:30][CH:31]=[CH:32]3)=[C:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)=[O:6]
Reactant: OB(O)c1cccc2cccnc12
Reactant: CN(CCO)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CN(CCO)C(=O)c1ccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2cccc3cccnc23)cc1

Procedure:
A still further embodiment is directed to a process for preparing N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)piperidin-4-ylidene)methyl)benzamide comprising reacting 2-(methylamino)ethanol with 4-((1-(tert-butoxycarbonyl)piperidin-4-ylidene)bromomethyl)benzoic acid to form tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)bromomethylene)piperidine-1-carboxylate; reacting the tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)bromomethylene)piperidine-1-carboxylate with 8-quinolineboronic acid to form tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)(quinolin-8-yl)methylene)piperidine-1-carboxylate; deprotecting the tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)(quinolin-8-yl)methylene)piperidine-1-carboxylate to form N-(2-hydroxyethyl)-N-methyl-4-((piperidin-4-ylidene)(quinolin-8-yl)methyl)benzamide; and reacting the N-(2-hydroxyethyl)-N-methyl-4-((piperidin-4-ylidene)(quinolin-8-yl)methyl)benzamide with thiazole-4-carbaldehyde to form the N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)piperidin-4-ylidene)methyl)benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:40][C:35]2[C:36]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:37][CH:38]=[CH:39][C:34]=2[CH3:33]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3Br)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 572.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3]([O:5][CH2:6][N:7]1[N:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]3[C:31](=[CH:32][CH:33]=2)[O:30][C:17]2([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH2:16][C:15]3=[O:34])=[N:8]1)=[O:4].[ClH:37]>CCOC(C)=O>[ClH:37].[CH3:1][C:2]([CH3:36])([CH3:35])[C:3]([O:5][CH2:6][N:7]1[N:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]3[C:31](=[CH:32][CH:33]=2)[O:30][C:17]2([CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[CH2:16][C:15]3=[O:34])=[N:8]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3nnn(COC(=O)C(C)(C)C)n3)ccc1O2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCn1nnc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)n1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of tert-Butyl 6-(2-{[(2,2-dimethylpropanoyl)oxy]methyl}-2H-tetrazol-5-yl)-4-oxo-spiro[chroman-2,4′-piperidine]-1′-carboxylate (68.0 g) in EtOAc (1.36 L) was added 4N HCl in EtOAc (340 ml) at 0° C. and the mixture was further stirred for 21 h at room temperature. The resulted precipitate was filtered and washed with EtOAc to give intended compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].[C:8]([Si:12](Cl)([CH3:14])[CH3:13])([CH3:11])([CH3:10])[CH3:9].N1C=CN=C1>CN(C=O)C.[Na+].[Cl-]>[Si:12]([O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H](C)O
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of (R)-(+)-methyl lactate (2.95 g, 28.34 mmol) in DMF (20 mL) was added tert-butyldimethyl silyl chloride (6.41 g, 42.51 mmol) and imidazole (6.75 g, 99.18 mmol). After stirring at a room temperature for 18 hr, the reaction mixture was diluted with a saturated aqueous NaCl solution (90 mL) and extracted with petroleum ether (3×60 mL). The organic layer was washed with a cold 3% HCl solution (30 mL) and a saturated aqueous NaCl solution (30 mL), dried over Na2SO4 and concentrated. The remaining residue was purified by silica gel (105 g) with petroleum ether (300 mL), followed by 3% ethyl acetate in petroleum ether (600 mL). The 3% ethyl acetate in the petroleum ether fractions was collected and the solvent was removed to give 5.26 g of (R)-(+)-Methyl 2-(tert-butyldimethylsilyloxy)propanoate as colorless oil (85% yield). 1H NMR (CDCl3): δ 4.26 (q, 1H, J=6.8 Hz, —CH), 3.65 (s, 3H, —OCH3), 1.32 (d, 3H, J=6.8 Hz, —CH3), 0.83 (s, 9H, Si—(CH3)3), 0.03 (s, 3H, Si—CH3), 0.00 (s, 3H, Si—CH3).
Reaction SMILES: [CH3:1][S:2]([CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([NH:15][C:16](=[O:22])OC(C)(C)C)[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)(=[O:4])=[O:3].N1C=CC=CC=1.ClC([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O>Cl.O1CCOCC1>[CH3:1][S:2]([CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[O:22])[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)Nc1cc2c(ccn2CS(C)(=O)=O)cn1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(=O)Nc2cc3c(ccn3CS(C)(=O)=O)cn2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 30.8 %

Procedure:
A mixture of tert-butyl 1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (8D, 420 mg, 1.3 mmol) in 4M HCl in dioxane (3 ml) was stirred at 50° C. for 3 h. The mixture was concentrated in vacuo and the resulting residue was dissolved in pyridine (3 ml, 37.1 mmol). To the mixture, methyl 4-(chlorocarbonyl)benzoate (385 mg, 1.936 mmol) was added and stirred at room temperature for 3 h. The mixture was extracted with EtOAc/H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (NH—SiO2, EtOAc) to give methyl 4-(1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamoyl)benzoate (8E, 160 mg, 0.40 mmol, 31% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.02 (s, 3H) 3.90 (s, 3H) 5.88 (s, 2H) 6.73 (d, J=2.78 Hz, 1H) 7.49 (d, J=3.28 Hz, 1H) 8.01-8.12 (m, 2H) 8.12-8.19 (m, 2H) 8.46 (s, 1H) 8.70 (s, 1H) 10.93 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1)([O-:3])=[O:2].[CH3:13]N(C)C=O.CI.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:13][N:7]1[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[N:8]1
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])nn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 5-nitro-1H-pyrazole-3-carboxylate (156a) (0.94 g, 5.5 mmol), anhydrous N,N-dimethylformamide (11 mL), methyl iodide (0.85 g, 6 mmol) and potassium carbonate (0.83 g, 6.1 mmol). The reaction was stirred at room temperature for 16 h. After this time the reaction was diluted with water (40 mL) and extracted with methylene chloride (3×25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was subjected to flash chromatography (silica, ethyl acetate/hexanes) to afford methyl 1-methyl-3-nitro-1H-pyrazole-5-carboxylate 156b in 66% yield (0.67 g) as a white solid: MS (ESI+) m/z 186.0 (M+H). Also isolated was the regioisomer methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate in 15% yield (0.15 g) as a white solid: MS (ESI−) m/z 186.0 (M+H).
Reaction SMILES: C1CC1.[H-].[Na+].Cl[C:7]1[N:8]=[CH:9][C:10]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]3[O:42][CH2:41][CH2:40][C@H:23]4[S:24](=[O:39])(=[O:38])[C:25]([CH3:37])([CH3:36])[C:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:27][C@:22]4([CH3:43])[C:20]=3[CH:21]=2)=[O:14])=[N:11][CH:12]=1.[Cl-].[NH4+].[CH2:46]1[CH2:50][O:49][CH2:48][CH2:47]1>>[CH:46]1([CH2:50][O:49][C:7]2[N:8]=[CH:9][C:10]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]4[O:42][CH2:41][CH2:40][C@H:23]5[S:24](=[O:39])(=[O:38])[C:25]([CH3:37])([CH3:36])[C:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:27][C@:22]5([CH3:43])[C:20]=4[CH:21]=3)=[O:14])=[N:11][CH:12]=2)[CH2:47][CH2:48]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(NC(=O)c4cnc(Cl)cn4)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Reactant: C1CCOC1
Agent: C1CC1
Agent: [Cl-]
Agent: [H-]
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(NC(=O)c4cnc(OCC5CC5)cn4)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of hydroxymethyl)cyclopropane (0.10 mL, 1.20 mmol) in THF (1.4 mL) was cooled to 0° C. and treated with sodium hydride (60% wt; 36.1 mg, 0.90 mmol). The reaction was stirred for 30 minutes and then a solution of tert-butyl N-[(4aR,11bR)-10-[(5-chloropyrazine-2-carbonyl)amino]-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]carbamate (113 mg, 0.20 mmol) in 1 mL of THF was added. The reaction was stirred at ambient temperature for 1 hour. The reaction was treated with aqueous ammonium chloride and extracted with ethyl acetate. The organic portion was concentrated. The resulting crude was purified by column chromatography, eluting with 10-50% ethyl acetate/heptane to afford the title compound (100 mg, 0.17 mmol, 83%) as an off-white solid. MS m/z=600.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:51]([F:54])([F:53])[F:52])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:15][CH:14]([N:16]([CH2:18][C@@H:19]4[C@H:23]5[O:24]C(C)(C)[O:26][C@H:22]5[C@H:21]([N:29]5[C:33]6[N:34]=[CH:35][N:36]=[C:37]([NH:38]CC7C=CC(OC)=CC=7OC)[C:32]=6[CH:31]=[CH:30]5)[CH2:20]4)[CH3:17])[CH2:13]3)[NH:7][C:6]=2[CH:50]=1>FC(F)(F)C(O)=O.O>[NH2:38][C:37]1[C:32]2[CH:31]=[CH:30][N:29]([C@@H:21]3[CH2:20][C@H:19]([CH2:18][N:16]([CH:14]4[CH2:13][CH:12]([CH2:11][CH2:10][C:8]5[NH:7][C:6]6[CH:50]=[C:2]([Cl:1])[C:3]([C:51]([F:53])([F:52])[F:54])=[CH:4][C:5]=6[N:9]=5)[CH2:15]4)[CH3:17])[C@@H:23]([OH:24])[C@H:22]3[OH:26])[C:33]=2[N:34]=[CH:35][N:36]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(F)(F)F)c(Cl)cc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
7-((3aS,4R,6R,6aR)-6-(((3-(2-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (60 mg, 0.078 mmol) was dissolved in a mixture of trifluoroacetic acid (3.6 mL) and water (0.4 mL) which had been precooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, and then warmed to room temperature. After 3 h at room temperature, HPLC indicated the reaction was complete. The now very pink reaction mixture was concentrated. The residue was taken up in 10 mL MeOH and concentrated. This procedure was repeated twice and the residue placed on high vac for 1 h. The material was taken up in 7 mL MeOH and was treated with 120 mg K2CO3 and ten drops of water. The mixture was allowed to stir for 1 hr. The mixture was filtered through a fine frit, the solids were washed with 10 mL MeOH and the filtrate was concentrated to yield a nearly colorless solid. The crude material was purified by flash chromatography (30 g silica gel; 10-15% 7N NH3 in CH3OH/CH2Cl2) to yield Compound 7 (31 mg, 69%) as a colorless glass/stiff foam: MS (ESI+) for C27H31ClF3N7O2 m/z 578.3 (M+H)+; MS (ESI−) for C27H31ClF3N7O2 m/z 576.4 (M−H)−; HPLC purity >95% (ret. time, 2.57 min); 1H NMR (400 MHz, d4-MeOD) δH 8.06 (s, 1 H), 7.89 (d, J=2.07 Hz, 1 H), 7.69 (d, J=2.28 Hz, 1 H), 7.21 (dd, J=3.42, 1.76 Hz, 1 H), 6.59 (d, J=3.52 Hz, 1 H), 4.33 (t, J=6.84 Hz, 1 H), 3.89 (q, J=5.25 Hz, 1 H), 3.03 (m, 0.5 H), 2.89 (m, 2 H), 2.70 (m, 0.5 H), 2.49 (m, 1 H), 2.40 (m, 2 H), 2.27 (br. s., 2 H), 2.16 (d, J=7.26 Hz, 4 H), 2.06 (m, 2 H), 1.91 (m, 2 H), 1.62 (m, 1 H), 1.52 (m, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22](Cl)[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH3:57][N:58](C=O)C>[C-]#N.[Zn+2].[C-]#N.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]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:57]#[N:58])[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(Cl)cc21
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(C#N)cc21
Temperature: 150 °C

Procedure:
The mixture of 3-[4-(benzyloxy)phenyl]-6-chloro-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1 g), zinc cyanide (2.474 g), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.216 g), Pd2(dba)3 (0.241 g) and DMF (20 mL) was heated at 150° C. for 1 h under microwave irradiation. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile (710 mg) as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]([OH:38])[CH:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[N:26]=3)[N:21]=[CH:20][C:19]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[OH:17])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:40](OCC)(=[O:42])C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:39])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][CH:15]2[CH:16]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[N:26]=4)[N:21]=[CH:20][C:19]=3[O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:17][C:40](=[O:42])[O:38]2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2ncc(OCc3ccccc3)c(C(O)C(O)C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Reactant: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2ncc(OCc3ccccc3)c(C3OC(=O)OC3C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
N,N′-Carbonyldiimidazole (2.56 g, 15.83 mmol, 5.0 eq) is added at room temperature to a stirred solution of {trans-4-[3-(3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-yl)-2,3-dihydroxy-propyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.70 g, 3.16 mmol, 1.0 eq) in toluene (150 mL). After 2 hours stirring at 70° C., solvent is removed and the crude is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford {trans-4-[5-(3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-yl)-2-oxo-[1,3]dioxolan-4-ylmethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (1.70 g, 96% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](Cl)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19].[NH2:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[N:26][NH:27]2)=[CH:23][CH:22]=1.Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CC(C)=O.CCCCCC.COCCO>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:20][C:21]3[CH:29]=[C:28]4[C:24]([CH:25]=[N:26][NH:27]4)=[CH:23][CH:22]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Temperature: 120 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A mixture of 0.50 g (1 equivalent) of 7-(2-chloro-ethoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.25 g (1.1 equivalents) of 6-aminoindazole, 0.22 g (1.1 equivalents) of pyridine hydrochloride and 15 ml of 2-methoxyethanol was heated in 120° C. oil bath for 2 hours. The reaction progress was monitored by thin layer chromatography (acetone/hexane 1:1). After 2 hours, the reaction mixture was cooled to room temperature; a total of 25 ml of 1M sodium bicarbonate was added and the reaction was stirred for 1 hour. The resultant precipitate was collected, washed with water and dried in vacuo at 60° C. overnight to give 0.645 g (97%) of the desired product. :mass spectrum (electrospray m/e): M+H=393.9 (M+H)+; Analysis calculated for C20H16ClN5O2: 2 H2O: Calculated C:55.88; H:4.69; N:16.29; Found C:55.63; H:4.78; N:15.24
Reaction SMILES: [C:1]([C:3]1[C:7]([N:8]([CH3:16])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:6]([N:17]=CN(C)C)[N:5]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:4]=1)#[N:2].Cl>CO>[NH2:17][C:6]1[N:5]([C:22]2[C:23]([Cl:33])=[CH:24][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][C:27]=2[Cl:28])[N:4]=[C:3]([C:1]#[N:2])[C:7]=1[N:8]([CH3:16])[S:9]([C:12]([F:13])([F:15])[F:14])(=[O:11])=[O:10]
Reactant: CN(C)C=Nc1c(N(C)S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CO
Product: CN(c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N)S(=O)(=O)C(F)(F)F
Yield: 48.4 %

Procedure:
To a solution of N-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)-1,1,1-trifluoro-N-methylmethanesulfonamide (240 mg, 0.45 mmol) in methanol (7 ml) was added hydrochloric acid (4N, 4 ml) and the reaction mixture was heated at reflux for 4 h. The reaction mixture was concentrated under nitrogen and the residue partitioned between ethyl acetate and water. The two layers were separated and the aqueous layer was extracted with ethyl acetate (×2). The combined organic phases were dried (MgSO4) and concentrated under nitrogen. The crude product was dissolved in acetonitrile (4 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm×21.2 mm Phenomonex LUNA 100 Å C18 column) using an acetonitrile:water gradient [50:50 to 98:2]. The appropriate fractions were concentrated in vacuo to give the titled compound (105 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Product: O=[N+]([O-])c1ccc(/C=C/c2ccc(Cl)cc2)cc1

Procedure:
In an analogous manner to that described in Example 36 a), the reaction of diethyl (4-nitrobenzyl)phosphonate with 4-chlorobenzaldehyde yields the (E)-1-chloro-4-[2-(4-nitrophenyl)ethenyl]-benzene as an yellow crystalline solid; MS: m/e=259 (M)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.P(=O)(O)(O)O>C1C=CC=CC=1>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CCl
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Product: Cc1ccccc1Cc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
A solution of 280 parts of o-xylyl chloride in 520 parts of benzene is added to a mixture of 520 parts of benzene and 200 parts of boron fluoride/phosphoric acid (containing 90 parts of boron trifluoride in 110 parts of phosphoric acid) at from 75° to 80°C in the course of one hour. The reaction mixture is stirred for a further three hours at 80°C and allowed to cool, the aqueous solution is separated off and the organic phase is distilled. Yield 322 parts (88.4% of theory) of o-benzyltoluene of boiling point from 145° to 149°C at 17 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[S:21](Cl)(=[O:23])=[O:22]>CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[S:21]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1c(Cl)cc(Cl)cc1Cl
Yield: 74.8 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), 2,4,6 trichlorobenzenesulfonyl chloride (280 mg, 1.03 mmol) and DMAP (cat.) gave the title compound (200 mg, 76%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:19]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=2[Cl:11])(=[O:21])=[O:20])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COc1nc(Br)cnc1N
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.1 g) and 2,3-dichlorobenzenesulphonyl chloride (0.2 g). Yield 0.045 g.,