Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[S:47][C:46]([S:48](Cl)(=[O:50])=[O:49])=[CH:45][CH:44]=1>ClC(Cl)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:48]([C:46]2[S:47][C:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=3)=[CH:44][CH:45]=2)(=[O:49])=[O:50])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(-c3ccccn3)s2)c1
Reaction time: 72 h
Yield: 33.9 %

Procedure:
To a solution of {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (111 mg, 0.270 mmol), prepared in Step A of Example 13i, triethylamine (120 mg, 1.19 mmol) and dichloroethane (10 mL) was added 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (77.2 mg, 0.297 mmol). The reaction was stirred for 72 h and additional 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (38.5 mg) was added. The reaction was stirred for an additional 48 h. The organic solution was washed sequentially with 5.5% HCl, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3:MeOH 99:1) provided the title compound of Step A (58 mg). MS 633 (M+1).
Reaction SMILES: [B-](F)(F)(F)F.[N+:6](=[O:8])=[O:7].N1C(C)=CC(C)=CC=1C.[CH3:18][C@H:19]([NH:22][C:23]([C@@H:25]1[CH2:29][S:28][C:27](=[O:30])[NH:26]1)=[O:24])[CH2:20][OH:21]>C(#N)C>[CH3:18][C@H:19]([NH:22][C:23]([C@@H:25]1[CH2:29][S:28][C:27](=[O:30])[NH:26]1)=[O:24])[CH2:20][O:21][N+:6]([O-:8])=[O:7]
Reactant: C[C@@H](CO)NC(=O)[C@@H]1CSC(=O)N1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: Cc1cc(C)nc(C)c1
Product: C[C@@H](CO[N+](=O)[O-])NC(=O)[C@@H]1CSC(=O)N1
Yield: 29.2 %

Procedure:
In 10 ml of dry acetonitrile were dissolved 478 mg of nitronium tetrafluoroboron (85% content), 0.43 ml of 2,4,6-collidine was added thereto with stirring under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. To the resulting mixture were added 500 mg of (4R)-N-[(1S)-1-methyl-2-hydroxyethyl]-2-oxothiazolidin-4-yl-carboxamide, and the mixture was stirred at room temperature for 1 hour and 45 minutes. Then, the solvent was distilled off under reduced pressure and the thus obtained residue was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (3:7) as an eluent to obtain 178 mg of the desired compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:9]2[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:38])=[CH:32][CH:31]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)Nc2ccc(Cl)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) and 1-chloro-4-isocyanato-benzene (Aldrich, 45.0 mg, 0.30 mmol) in CH2Cl2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (4-chloro-phenyl)-amide (35.9 mg, 59.3%) as a white amorphous. HRMS (ES+) m/z Calcd for C29H26Cl2F2N3O+H [(M+H)+]: 576.1183, found: 576.1183.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)[N:10]=2)[N:7]=1.Cl.[CH3:18][NH:19][CH3:20].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:16])([CH3:15])[C:12]([N:19]([CH3:20])[CH3:18])=[O:14])[N:10]=2)[N:7]=1
Reactant: CNC
Reactant: CC(C)(C(=O)O)c1cn2nc(Cl)ccc2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
0.959 g of 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionic acid was dissolved in 6 ml of N,N-dimethylformamide; 0.714 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 60 minutes. To this mixture, 0.392 g of dimethylamine hydrochloride and 0.665 ml of triethylamine were added under ice cooling conditions, followed by stirring at room temperature for 3 hours. Saline was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol (95:5). The desired fraction was collected and concentrated; the crystal obtained was collected by filtration to yield 0.608 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[NH2:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[NH2:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]([N:17]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:26]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccc(N)c3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Examples 44 and 60 and General Procedure C, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and 3-aminophenyl boronic acid were reacted to give 124. MS: (ESI+) 461.1
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[C:13]1(B(O)O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:21]3[C:22]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:18]=[CH:19][CH:20]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CC1Cc2cccc(Br)c2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1Cc2cccc(-c3cccc4ccccc34)c2C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Using a method similar to Example 15a), 56.3 g (0.25 mol) of 7-bromo-2-methyl-1-indanone (2), 47.3 g (0.275 mol) of 1-naphthylboronic acid and 58 g (0.55 mol) of sodium carbonate were placed in 950 ml of dimethoxyethane and 300 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. 560 mg (2.5 mmol) of palladium acetate and 1.31 g (5 mmol) of triphenylphosphine (TPP) were added and the reaction mixture was stirred for 2 hours at 80° C. After addition of 700 ml of water, the mixture was extracted 5 times with 300 ml each time of diethyl ether, the ether phase was washed twice with 300 ml each time of water and with 300 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 63.3 g of (16) as solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>N1CCCCC1>[C:14]([C:13]1[C:12](=[O:17])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[C:8]([O:10][CH3:11])[CH:9]=2)(=[O:15])[CH3:16]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(C=O)c(O)c1
Solvent: C1CCNCC1
Product: COc1ccc2cc(C(C)=O)c(=O)oc2c1

Procedure:
A mixture of 15.2 g 2-hydroxy-4-methoxybenzaldehyde and 13.5 g ethyl acetoacetate was warmed on a hot plate until solution was attained. Thirty drops of piperidine were added and the reaction mixture continued to be heated gently. After several minutes the reaction mixture solidified. After cooling, the product was recrystallized from a mixture of alcohol and acetonitrile. Yield 20 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([O:26][CH3:27])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[S:36](Cl)(=[O:38])=[O:37]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([O:26][CH3:27])=[C:21]([NH:22][S:36]([C:30]3[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=3[F:28])(=[O:38])=[O:37])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1c(N)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(Cl)n1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Product: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(Cl)n1
Yield: 27.2 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-methoxyaniline (26.1 g, 64.7 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (13.8 g, 64.7 mmol) the title compound of Step C was obtained (10.2 g, 27.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J=5.5 Hz, 1H), 7.62-7.71 (m, 1H), 7.38-7.45 (m, 1H), 7.15-7.30 (m, 4H), 6.40 (d, J=5.5 Hz, 1H), 3.67-3.78 (m, 4H), 3.50-3.61 (m, 4H), 3.18 (s, 3H). MS (ES+): 580 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19][C:20](NC1SC=CN=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][N:36]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.Cl>[CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19][C:20]([NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][N:36]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1nccs1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1ccc(C(=O)O)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Example 1, Part E (300 mg, 1.02 mmol) was taken up in 4 mL CH2Cl2 and cooled to 0° C. Oxalyl chloride (0.1 mL, 1.22 mmol) was added slowly and stirring continued for 0.5 h. A slurry of 6-aminonicotinic acid (211 mg, 1.53 mmol) and diisopropylethylamine (0.27 mL, 1.53 mmol) was added slowly and stirring continued at room temperature for 16 h. Three drops of conc. HCl was added and the organic phase was washed with brine. The organic phase was dried (Na2SO4), filtered and evaporated. The product was purified by silica gel chromatography (12 mg, 3%). 1H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 8.70 (m, 1H), 8.32 (m, 1H), 7.87 (m, 1H), 7.52 (m, 3H), 7.34 (m, 6H), 5.46 (m, 1H), 4.60 (br s, 1H), 4.31 (m, 1H), 2.54 (m, 2H), 2.09 (m, 2H). MS: m/z (MH+) 416.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14](=[O:39])[C:15]3[CH:20]=[C:19]([CH2:21][C:22]4[C:23](=[O:34])[C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[C:26](=[O:29])[C:27]=4[CH3:28])[CH:18]=[CH:17][C:16]=3[O:35]C(=O)C)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+]>CO.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14](=[O:39])[C:15]3[CH:20]=[C:19]([CH2:21][C:22]4[C:23](=[O:34])[C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[C:26](=[O:29])[C:27]=4[CH3:28])[CH:18]=[CH:17][C:16]=3[OH:35])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3N3CCOCC3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3N3CCOCC3)c2)=C(C)C1=O
Yield: 99 %

Procedure:
N-(2-Morpholinopyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.110 g, 0.205 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.100 g, 0.203 mmol, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C@@H:17]([OH:20])[CH2:18][OH:19])[CH:11]=2)[CH:6]=1)=[O:4].CO[C:23](OC)([CH3:25])[CH3:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C@@H:17]3[CH2:18][O:19][C:23]([CH3:25])([CH3:24])[O:20]3)[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc(OC[C@@H](O)CO)ccc2c1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(OC[C@@H]3COC(C)(C)O3)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 6-((S)-2,3-dihydroxy-propoxy)-naphthalene-2-carboxylic acid methyl ester (0.9 g, 3.26 mmol) in anhydrous DMF (10 ml) is added 2,2-dimethoxypropane (2.0 ml, 16.3 mmol) and pyridinium p-toluenesulfonate (0.08 g, 0.32 mmol) and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in EtOAc. The EtOAc layer is washed with 10% NaHCO3, water, and brine, dried over anhydrous Na2SO4 and the solvent is evaporated in vacuo to obtain 6-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-naphthalene-2-carboxylic acid methyl ester as solid; 1H NMR (DMSO-d6): 1.32 (3H, s), 1.37 (3H, s), 3.78-3.82 (1H, m), 3.88 (3H, s), 4.11-4.20 (3H, m), 4.45-4.50 (1H, m), 7.26 (1H, dd, J=9.0, 2.0 Hz), 7.45 (1H, d, J=2.0 Hz), 7.88 (1H, d, J=9.0 Hz), 7.93 (1H, d, J=9.0 Hz), 8.04 (1H, d, J=9.0 Hz), 8.55 (1H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[F:25][C:26]1[CH:27]=[C:28]([OH:34])[CH:29]=[C:30]([F:33])[C:31]=1[F:32]>C(OCC)(=O)C>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([O:34][C:28]3[CH:27]=[C:26]([F:25])[C:31]([F:32])=[C:30]([F:33])[CH:29]=3)[N:3]=2)[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: Oc1cc(F)c(F)c(F)c1
Solvent: CCOC(C)=O
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(Oc2cc(F)c(F)c(F)c2)n1
Yield: 25 %

Procedure:
This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 3,4,5-trifluorophenol in analogy to example 3. Chromatography on silica gel using ethyl acetate as an eluent gave the title compound as a colorless solid in 25% yield.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[NH2:2].[CH2:10]([CH2:17][C:18](=O)[CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:19][C:18](=[N:2][NH:1][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[CH2:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNc1cc[nH]c(=O)c1
Reactant: CC(=O)CCc1ccccc1
Product: CC(CCc1ccccc1)=NNc1cc[nH]c(=O)c1

Procedure:
In accordance with the same procedures as in Step 2 of Preparation 1, except for using 4-hydrazino-1H-pyridin-2-one (5.39 g, 43.1 mmol) prepared in Step 1 of Preparation 1 and benzylacetone (9.70 ml, 64.6 mmol), the titled compound was obtained as a white solid. (Yield: 66.5%) The product was used in the subsequent reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1
Yield: 90.4 %

Procedure:
To a mixture of 4-nitrophenol (10.0 g, 71.9 mmol), K2CO3 (19.9 g, 143.9 mmol) and KI (2.6 g, 15.8 mmol) in acetonitrile was added chloromethylbenzene (10.0 g, 79.1 mmol) at RT. The resultant mixture was heated to reflux for 3 h. After removal of the solvent, the residue was dissolved in EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to afford 4-benzyloxynitrobenzene (14.9 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J=8.0 Hz, 2H), 7.43-7.37 (m, 5H), 7.03 (d, J=8.0 Hz, 2H), 5.17 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC(C)([O-])C.[K+]>>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:10]1
Reactant: Brc1ccccc1
Reactant: CN1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CN1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
A 1 L flask was charged with 141.3 g of bromobenzene, 30.1 g of 1-methylpiperazine and 43.8 g of potassium tert-butoxide. The flask was then placed on an ice bath for 10 minutes and the contents rapidly stirred. 2.04 g of “PEPPSI” catalyst[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)-palladium (II) dichloride was then added and the flask fitted with a reflux condenser. The reaction was refluxed under a nitrogen atmosphere for 2 hours and then cooled to room temperature. The reaction mixture was then filtered through a pad of 800 mL of silica gel in a 2 L D-filter flask and the pad subsequently rinsed with 600 mL of ether. Then the product was extracted from the pad with ethanol. Evaporation of the ethanol gave 39.4 g of 1-methyl-4-phenylpiperazine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl)[N:9]=[CH:8][CH:7]=[C:6]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:28])=[CH:22][CH:21]=1)#[N:2].[CH3:38][NH:39][CH3:40]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:39]([CH3:40])[CH3:38])[N:9]=[CH:8][CH:7]=[C:6]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:28])=[CH:22][CH:21]=1)#[N:2]
Reactant: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCCCl)c(C#N)cc34)cc2)cc1
Reactant: CNC
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCCN(C)C)c(C#N)cc34)cc2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
N-(4-(6-Cyano-7-(4-chlorobutoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea (120 mg) was dissolved in dimethylformamide (3 ml), and then a 50% dimethylamine solution (93 μl) was added and the mixture was heated and stirred at 70° C. for 5 hours. The reaction solution was poured into saturated saline and extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated. The residue was passed through NH silica gel (Fuji Silicia Chemical) and eluted with a solvent (ethyl acetate), and then further eluted with another solvent (ethyl acetate:methanol=10:1) and concentrated. The obtained solid was passed through Merck Silica Gel using tetrahydrofuran, and after eluting the insoluble portion with tetrahydrofuran and ethyl acetate, it was further eluted with solvents (tetrahydrofuran:methanol:triethylamine=10:1:1, ethyl acetate:methanol:triethylamine=10:1:1) and concentrated to obtain 10 mg of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(CO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a solution of 2-fluoro-5-nitro-benzoic acid (2.9 g, 15.7 mmol) in THF (20 ml) was slowly added 1M BH3.THF (30 ml, 30 mmol) at 0° C. The reaction mixture was stirred at rt overnight, quenched carefully with MeOH until no H2 evolution, evaporated and redissolved in MeOH, evaporated again to give 394A (2.7 g, 100%) as a yellow solid.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[OH-].[K+].[C:13](=S)=[S:14]>>[SH:14][C:13]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: NC(=O)c1ccccc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c(S)nc2ccccc12
Yield: 91 %

Procedure:
Aminoalcohol VIII was then allowed to react with 2,4-dimethylthioquinazoline (IX) in acetonitrile at reflux to give 4-[(3-(4-methoxyphenyl)piperazine-1-yl)propan-2-ol-1-yl]amino-2-methylthioquinazoline (XI). But the results were variable in the yields ranging from 24 to 56% and the reaction released notorious methylthiol. The possibility of synthesizing compound XI by using 4-chloro-2-methylthioquinazoline (X) was also investigated. Compound X was obtained in good yield (90-93%) starting from anthranilamide by heating with carbon disulfide in water-alcohol solution of potassium hydroxide to afford 2-mercaptoquinazolin-4-one (XII) in 91% yield. (Zakerinia, M. et. al. Helv. Chim. Acta. 1990, 73, 912-915) Compound XII was then methylated with methyl iodide to give 2-methylthioquinazolin-2-one (XIII) which was subsequently converted to 4-chloro-2-methylthioquinazoline (X) in high yield (90-93%) by treating with POCl3, followed by precipitation with water from acetone solution. Compound X was reacted smoothly with amino alcohol VIII in the presence of triethylamine to give compound XI in 72% yield. The cyclization of XI to compound I was achieved by methanesulphonylchloride (MsCl) and triethylamine. The cyclization reaction proceeded in 12-17 hours to give compound I with 47-69% chemical yield after chromatographical purification. The addition of potassium carbonate to the reaction mixture to trap hydrogen chloride formed allowed to obtain a chromatographically pure compound I in 77% yield without column chromatography. ##STR7##