Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]1([CH2:25][CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:27][CH2:26][CH2:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCc1ccccc1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Solvent: CC#N
Product: Clc1cccnc1N1CCc2c(ncnc2NCCc2ccccc2)C1
Temperature: 180 °C
Yield: 57.7 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.025 g, 0.09 mmol) and 2-phenylethanamine (0.065 mL, 0.51 mmol)) in acetonitrile (1 mL) was heated in a sealed vessel via microwave (Emrys Optimizer model, Personal Chemistry) to 180° C. for 10 min. The reaction mixture was cooled to r.t. and concentrated to dryness. The residue was purified by silica gel chromatography using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as a white solid (19 mg).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:18](=[O:19])[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:23][CH:22]=2)/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: COc1ccc(C(=O)NN)cc1
Product: CCCCCCN1C(=O)/C(=N\NC(=O)c2ccc(OC)cc2)c2ccccc21
Yield: 79 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and 4-methoxybenzhydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 79%. 1H NMR (DMSO-d6): δ 0.85 (t, J=6.9 Hz, 3H), 1.26-1.36 (m, 6H), 1.65 (m, 2H), 3.79 (t, J=7.2 Hz, 2H), 3.87 (s, 3H), 7.14-7.24 (m, 4H), 7.48 (t, J=7.8 Hz, 1H), 7.65 (d, J=7.5 Hz, 1H), 7.89 (d, J=9 Hz, 2H), 13.86 (br s, 1H). 13C NMR (DSMO-d6): δ 14.33 (CH3), 22.43 (CH2), 26.39 (CH2), 27.41 (CH2), 31.32 (CH2), 39.77 (CH2), 56.07 (O—CH3), 110.63 (CH), 114.97 (CH), 119.76 (C), 121.13 (CH), 123.64 (CH), 124.46 (C), 129.98 (CH), 132.02 (CH), 143.30 (C═N), 161.63 (C═O), 163.68 (C═O). HRMS (ES+) calcd for C22H26N3O3 (M+H+), m/e, 380.1974; found, 380.1969.
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:33])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:35][CH2:36][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1)[OH:38]>>[Cl:45][C:41]1[CH:40]=[C:39]([C@@H:37]([OH:38])[CH2:36][NH:35][CH:29]2[CH2:30][CH2:31][N:26]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][S:16]([C:13]4[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:33])=[CH:11][CH:12]=4)(=[O:18])=[O:17])=[CH:25][CH:24]=3)[CH2:27][CH2:28]2)[CH:44]=[CH:43][CH:42]=1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Agent: Cl
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4cccc(Cl)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzensulfonamide (which was obtained in Example 225) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol (which was obtained in Example 1) according to the procedure of Example 278 as a brown solid; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, J=6.9 Hz, 3H), 1.20-1.50 (m, 10H), 1.75-1.90 (m, 2H), 2.50-2.80 (m, 5H), 3.00-3.15 (m, 2H), 3.40-3.50 (m, 2H), 4.60 (dd, J=8.1, 3.8 Hz, 1H), 6.29 (t, J=5.7 Hz, 1H), 6.77 (d, J=9.1 Hz, 2H), 6.85 (d, J=9.1 Hz, 2H), 7.25-7.50 (m, 8H), 8.94 (s, 1H), 9.55 (brs, 1H); MS (ES) m/z: 628.1 (MH+); HRMS Calcd. for C32H43ClN5O4S(MH+): 628.2748. Found: 628.2718.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][C:12]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[O:14]3)[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.O>O1CCOCC1>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]([OH:22])=[O:14])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1OC2(CC(c3cccc(C(F)(F)F)c3)=NO2)c2ccccc21
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1-c1cc(-c2cccc(C(F)(F)F)c2)no1
Yield: 89 %

Procedure:
A mixture of 0.28 g. of 3'-(3-trifluoromethylphenyl)-spiro[isobenzofuran-1(3H), 5'(4'H)-isoxazol]-3-one, 0.5 ml. of concentrated HCl, 10 ml. of water and 6 ml. of dioxane was stirred at reflux for one hour. The mixture was cooled and filtered to give 0.25 g. of white solid; m.p. 176.5°-178° C. in 89% yield.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[C:6]([Cl:26])=[N:7][C:8]2[C:13]([C:14]=1[NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:12][CH:11]=[CH:10][CH:9]=2>C(O)C>[NH2:1][C:2]1[N:15]([CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([Cl:26])[C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)c(Cl)nc2ccccc12
Reactant: N#CBr
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCn1c(N)nc2c(Cl)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
Cyanogen bromide (4.6 g, 44 mmol) was added to a solution of tert-butyl 2-[(3-amino-2-chloroquinolin-4-yl)amino]ethylcarbamate (13.46 g, 39.96 mmol) in ethanol (140 mL), and the reaction was heated at reflux overnight. An analysis by LC/MS indicated the presence of starting material, and additional cyanogen bromide (1.25 g, 12.0 mmol) was added. The reaction was heated at reflux for an additional two hours, and the reaction was still incomplete. Additional cyanogen bromide (1.25 g, 12.0 mmol) was added, and the reaction was heated at reflux for two hours and allowed to cool to room temperature. Most of the solvent was removed under reduced pressure, and aqueous sodium hydroxide (700 mL of 2 N) was added. The mixture was stirred for 30 minutes, and the aqueous portion was decanted away. Ethyl acetate (500 mL) was added, and the mixture was stirred for 20 minutes. The ethyl acetate was then decanted away, and the residue was filtered. The filter cake was washed several times with diethyl ether (1 L total), and the resulting solid was stirred vigorously with diethyl ether (500 mL). The solid was collected by filtration and dried under vacuum overnight to provide 7.02 g of tert-butyl 2-(2-amino-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)ethylcarbamate as a reddish-brown solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:17]=2)[N:3]=1.[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]([CH3:43])[C:40]([NH2:42])=[O:41])#[CH:32].F[B-](F)(F)F.CCN(CC)CC>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:42][C:40](=[O:41])[CH:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:31]#[C:32][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:17]=2)[N:3]=1)[CH3:43]
Reactant: C#Cc1ccccc1C(C)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(Cl)n3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C(F)(F)F

Procedure:
A mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate K8 (2.054 g, 4.597 mmol), 2-(2-ethynylphenyl)propanamide K7 (1.027 g, 5.929 mmol), CuI (0.017 g, 0.089 mmol), PdCl2(PPh3)2 (0.062 g, 0.088 mmol) and t-Bu3PH.BF4 (0.025 g, 0.087 mmol) in dioxane (20 mL) and Et3N (2.5 mL, 18 mmol) under a nitrogen atmosphere was heated in the microwave at 110° C. for 40 minutes. The mixture was concentrated under reduced pressure and purified using silica gel column chromatography (50-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A65 (2.121 g, 79%). 1H NMR (400 MHz, d6-DMSO) δ 10.48-10.33 (m, 1H), 8.82-8.73 (m, 1H), 8.09-7.97 (m, 1H), 7.64-7.55 (m, 2H), 7.56-7.44 (m, 2H), 7.41-7.34 (m, 1H), 7.29-7.22 (m, 1H), 7.01 (s, 1H), 4.39-4.29 (m, 1H), 4.18-3.99 (m, 3H), 2.99-2.80 (m, 2H), 2.02-1.94 (m, 2H), 1.83-1.70 (m, 2H), 1.41 (s, 9H), 1.39-1.31 (m, 3H).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[ClH:22].[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[OH:33])[CH2:27][CH2:28][NH2:29].C(O)CCC>Cl.O>[ClH:22].[C:13]1([N:6]([CH2:5][CH:4]2[C:30]3[C:26](=[CH:25][C:24]([OH:23])=[C:32]([OH:33])[CH:31]=3)[CH2:27][CH2:28][NH:29]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CN(c1ccccc1)c1ccccc1)OCC
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: Oc1cc2c(cc1O)C(CN(c1ccccc1)c1ccccc1)NCC2
Yield: 35.4 %

Procedure:
N,N-diphenylaminoacetaldehyde diethyl acetal (3.5 g) and 3,4-dihydroxyphenethylamine hydrochloride (2.1 g) were added to a mixture of n-butyl alcohol (35 ml), water (5 ml) and conc. hydrochloric acid (2 drops) and then the mixture was refluxed for 6.5 hours in a stream of nitrogen. The reaction mixture was concentrated to dryness and the residue was washed with acetone and collected by filtration to recover the starting material, 3,4-dihydroxyphenethylamine (1.2 g). The filtrate was concentrated to give 1-(N,N-diphenylaminomethyl)6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.5 g), oil.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7]Cl)[CH2:3][CH2:4]Cl.[CH2:9]([C:16]#[N:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:7][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]#[N:17])[CH2:4][CH2:3]1
Reactant: N#CCc1ccccc1
Reactant: CN(CCCl)CCCl
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC(C#N)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
To a solution of mechlorethamine (4 g, 25.6 mmol) and benzyl cyanide (4 g, 34.2 mmol) in toluene (25 ml) was added sodium amide (2 g, 51.2 mmol) at 40-50° C. in portions for 1 hour. The reaction mixture was heated to reflux about 2 hours after the addition. The reaction mixture was cooled to room temperature and washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:5) as eluents to give 3 g of desired product.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1>ClCCl>[CH2:2]([C:1]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:4])[CH3:3]
Reactant: Cc1ccncc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Product: CCC(=O)Cc1ccncc1
Reaction time: 8 h

Procedure:
19.8 g of propionyl chloride dissolved in 20 ml of dichloromethane was added dropwise over 1 hour to 10 gm of 4-methylpyridine dissolved in 50 ml dichloromethane and maintained below 10° C. After addition, the reaction was brought to ambient temperature, stirred for 8 hours, then brought to reflux for 1 hour. The reaction mixture was quenched into saturated sodium carbonate solution, the organic layer separated and the solvent removed under reduced pressure. The residual 4-methylpyridine was removed by azeotropic distillation under reduced pressure with toluene. Ethanol was added and the mixture refluxed for 6 hours. The solvent was removed under reduced pressure to give 4.45 g of good (4-pyridinylmethyl) ethyl ketone.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.Cl[CH2:16][C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:20]([S:30][CH2:31][CH2:32][CH3:33])=[N:19][CH:18]=1>CN(C)C=O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][N:21]1[C:17]([CH2:16][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:18][N:19]=[C:20]1[S:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCSc1ncc(CCl)n1Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCSc1ncc(CC(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To dry dimethylformamide (10 mL) under argon was added sodium hydride (0.14 g, 5.83 mmol) followed by diethyl malonate (0.92 g, 5.75 mmol) in dimethylformamide (2 mL) at 0° C. The mixture was stirred at ambient temperature for one hour. A solution of 5-chloromethyl-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole hydrochloride (1.0 g, 2.84 mmol) in dimethylformamide (4 mL) was added over 5 minutes. The reaction mixture was stirred at 25° C. for 18 hours, then partitioned between water and methylene chloride. The organic layer was washed with water, dried, and concentrated. The crude product was flash chromatographed over silica gel with 1:1 hexane/ethyl acetate to give 0.62 g (49.7%) of diethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methylmalonate as a pale yellow syrup.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:55]=[O:56])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:57]=[O:58].N12CCCN=C1CCCCC2>CN(C)C=O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:57][OH:58])[CH:55]=[O:56])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)O[C@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 25i (1.0 g, 1.3 mmol) in N,N-dimethyl formamide (20 mL) was added formaldehyde (2.6 mL, 32.5 mmol, 37 wt % solution) at room temperature, and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mL, 0.78 mmol) was added to adjust the pH to 9. The mixture was stirred at room temperature for 16 hours and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with water (30 mL×2) and saturated aqueous sodium chloride (30 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 25j as yellow oil (1.04 g, 100%). This material was not further purified.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[N+:7]([O-])([OH:9])=[O:8]>S(=O)(=O)(O)O>[Br:1][C:2]1[NH:3][CH:4]=[N:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: Brc1c[nH]cn1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1nc[nH]c1Br
Temperature: 25 °C
Yield: 88.1 %

Procedure:
4-Bromo-1H-imidazole (2.0 g, 13.6 mmol) was reacted with concentrated nitric acid (0.947 mL, 14.96 mmol) in concentrated sulfuric acid (20 mL) at 110° C. for 1 hour. The reaction was cooled to 25° C. and poured into 200 mL of ice water. The resulting white precipitate formed was collected by filtration to give the title compound (2.3 g, 87%). MS (ESI−) m/z 191 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.99 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].C1COCC1.Cl[C:12]1[C:13]([C:19]([N:21]([CH3:33])[C:22]2[CH:27]=[CH:26][C:25]([S:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=1>O>[Cl:18][C:16]1[CH:17]=[C:12]([S:5][CH2:3][CH3:4])[C:13]([C:19]([N:21]([CH3:33])[C:22]2[CH:27]=[CH:26][C:25]([S:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)=[O:20])=[N:14][CH:15]=1
Reactant: CCS
Reactant: CN(C(=O)c1ncc(Cl)cc1Cl)c1ccc(SC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCSc1cc(Cl)cnc1C(=O)N(C)c1ccc(SC(F)(F)F)cc1
Reaction time: 1 h

Procedure:
1.03 g of 60% sodium hydride (oil-based) was added to a mixture of 1.82 mL of ethanethiol and 59 ml of THF under ice cooling, and the mixture was stirred for 1 hour under ice cooling. A mixture of 8.92 g of 3,5-dichloro-N-methyl-N-(4-trifluoromethylsulfanylphenyl)picolinamide and 59 ml of THF was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 7 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 9.02 g of 5-chloro-3-ethylsulfanyl-N-methyl-N-(4-trifluoromethylsulfanylphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 158).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5]2.[CH:30]#[C:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C.[Cu]I>[C:30]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:5]2)#[C:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: C#CCCCCCC
Reactant: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CCCCCCC#Cc1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of the product of Step C (0.2 g; 0.41 mmol), 1-octyne (0.091 ml; 0.62 mmol), Cl2Pd(PPh3)2 (0.02 g; 0.028 mmol) and CuI (0.005 g; 0.026 mmol) in anhydrous DMF (2 ml) was degassed under reduced pressure and saturated with dry N2. After addition of DIPEA (0.5 ml), the resulting mixture was stirred overnight at room temperature under N2. The solvents were removed in vacuo and the residue was diluted to 15 ml with EtOAc and washed with 5% citric acid, 5% NaHCO3, H2O, brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; hexane/EtOAc; 9:1) to give the title compound (0.17 g; 89%) as a colourless syrup. 1H-NMR (CDCl3) 0.93 (m, 3H); 1.34-1.64 (m, 8H); 2.4 (tr, 2H, J=7.1 Hz); 3.94 (s, 4H); 7.0-7.64 (m, 18H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:13])[CH:5]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN1CCOCC1.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:4]([O:13][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)Nc1cc(=O)[nH]c(N)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)n1

Procedure:
A stirred suspension of 500 g of methyl 2-amino-1,6-dihydro-6-oxo-4-pyrimidinecarbamate in 1.45 l of N-methylmorpholine and 9 l of methylene chloride is heated to reflux temperature. Subsequently, 815 g of toluene-4-sulfonyl chloride are added thereto and the mixture is stirred at reflux for 16 hours. The mixture is evaporated at 40° in a water-jet vacuum and the residue is treated with 9 l of water. The insoluble material is filtered off under suction and washed firstly with 5 l of water and thereafter with 5 l of ether. After drying at 40° in vacuo, there is obtained light brown methyl 2-amino-6-[(p-tolylsulfonyl)oxy]-4-pyrimidinecarbamate of melting point 188°-190°. A sample recrystallized from acetonitrile has a melting point of 190°-192°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([N:27]([CH:31]([CH3:33])[CH3:32])[CH2:28][CH2:29]O)([CH3:26])[CH3:25]>S(Cl)(Cl)=O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH2:29][CH2:28][N:27]([CH:31]([CH3:33])[CH3:32])[CH:24]([CH3:26])[CH3:25])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(CCO)C(C)C
Reactant: O=C(O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Solvent: O=S(Cl)Cl
Product: CC(C)N(CCOC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1)C(C)C

Procedure:
Treatment of 4-benzyloxy-5,7-dichloroquinoline-2-carboxylic acid (1 g, Example 33b) with thionyl chloride (10 ml) followed by 2-(diisopropylamino)ethanol (1.63 ml) as described in Example 33c gave 2-diisopropylaminoethyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (0.85 g). δ (360 MHz, DMSO-d6) 0.98 (12H, 2d, CH3), 2.77 (2H, t, CH2N), 3.01 (2H, m, C-H), 4.27 (2H, t, CO2CH2), 5.49 (2H, s, OCH2), 7.38 (1H, d, p-ArH), 7.44 (2H, t, m-ArH), 7.58 (2H, d, o-ArH), 7.72 (1H, s, 3-H), 7.81 (1H, d, 6-H) and 8.21 (1H, d, 8-H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-cyano-phenylboronic acid to give 4-[3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzonitrile. LC-MS m/e 312(MH+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([NH:14][OH:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([CH2:25]Cl)[C:21]([CH3:27])=[C:20]([CH2:28]Cl)[C:19]=1[CH3:30]>CN(C)C=O>[CH2:7]([N:14]([CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([CH2:25][N:14]([OH:15])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:21]([CH3:27])=[C:20]([CH2:28][N:14]([OH:15])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:19]=1[CH3:30])[OH:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ONCc1ccccc1
Reactant: Cc1c(CCl)c(C)c(CCl)c(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CN(O)Cc2ccccc2)c(C)c(CN(O)Cc2ccccc2)c(C)c1CN(O)Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a suspension of 3.87 g of sodium carbonate in 30 ml of dry N,N-dimethylformamide is added 4.50 g of N-benzylhydroxylamine followed by 3.23 g of 2,4,6-tris(chloromethyl)mesitylene. After stirring at 80° C. for 8 hours, dimethylformamide is removed under reduced pressure and the residue is partitioned between methylene chloride and water. The combined organic layers are washed with water, brine, dried and evaporated to give a crude product. Recrystallization from ethyl acetate-heptane affords 4.0 g of white solid, mp 193°-195° C.