Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:9]=2)=[CH:4][CH:3]=1.CN(C([O:26][N:27]1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.NO>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]([NH:27][OH:26])=[O:18])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1cccc(-c2ccc(O)cc2)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccc(-c2ccc(O)cc2)c1)NO
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.4 %

Procedure:
70 mg (0.29 mmol) of E-3-(4′-hydroxybiphenyl-3-yl)-acrylic acid were dissolved under nitrogen in 3 ml of DMF, then 109 mg (0.29 mmol) of HBTU and 100 μL (0.57 mmol) of DIPEA were added at 0° C. After 5 min hydroxylamine hydrochloride (20 mg, 0.29 mmol) was added and the mixture was stirred at 0° C. for 10 min., then at room temperature for 4 h. DMF was removed under reduced pressure and the residue was washed with water to obtain, after filtration, 73 mg of a crude product. Purification by flash chromatography on KH2PO4 buffered silicagel using as eluent CH2Cl2/MeOH 95:5 afforded 24 mg of the title compound as a white solid. M.p. 127-128° C. Rf=0.26 (Merck silica gel 60F254, CH2Cl2:/MeOH 90:10)
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26].CO.C(Cl)Cl>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH3:23])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: CC(C)(C)CN
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NCC(C)(C)C
Temperature: 80 °C
Yield: 95.6 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.090 mmol) and 2,2-dimethylpropan-1-amine (TCI America, Portland, Oreg.; 0.032 mL, 0.271 mmol) in DMSO (0.8 mL), heating at 80° C. for 2 h. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(2-methyl-3-(neopentylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (31.4 mg, 0.086 mmol, 96% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (1H, br. s.), 7.85 (1H, dd, J=7.7, 0.8 Hz), 7.55 (1H, dd, J=8.0, 0.9 Hz), 7.30 (1H, t, J=7.7 Hz), 7.21 (1H, d, J=2.2 Hz), 7.02 (1H, t, J=6.4 Hz), 6.92 (1H, br. s.), 3.41-3.48 (4H, m), 2.88 (2H, t, J=6.8 Hz), 2.57 (3H, s), 0.99 (9H, s). m/z (ESI, +ve) 364.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH2:30])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)=[CH:12][CH:13]=3)[C@@:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1.O.S(=O)(=O)(O)[OH:33].C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:29][C:26]1[O:27][CH2:28][C@:8]2([N:25]=1)[C:9]1[CH:10]=[C:11]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[C:7]2=[CH:6][C:5]([O:4][CH2:3][C:2]([CH3:1])([OH:33])[CH3:30])=[CH:18][CH:17]=1
Reactant: O=S(=O)(O)O
Reactant: C=C(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(O)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 25 °C

Procedure:
A vial was charged with (S)-2′-(2-methylallyloxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (41.17 mg, 0.103 mmol) and water (0.5 mL) giving a suspension. Sulfuric acid (110 μL, 2.061 mmol) was added, and the mixture became a cloudy solution. The vial was sealed and placed in a 70° C. oil bath for 8 h. The mixture was cooled to RT, and potassium carbonate was added until bubbling ceased. The resulting suspension was extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 12-g Redi-Sep column eluting with 0-10% MeOH/DCM to give a white solid. The solid was dissolved in methanol and purified further by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA). The fractions containing product were combined in saturated aq. sodium bicarbonate solution and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (S)-1-(2-amino-2′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)-2-methylpropan-2-ol as a white solid. MS m/z=418.2 [M+H]+. Calculated Mass for C24H24N3O4: 418.2.
Reaction SMILES: [C:1](#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N[CH2:15][CH:16]([NH2:18])[CH3:17].NC(N)(C)C>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O>[CH2:2]([C:1]1[NH:13][CH2:15][CH:16]([CH3:17])[N:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(N)CN
Reactant: CCCCCCCCCCCC#N
Agent: [Ti+4]
Agent: CC(C)(N)N
Agent: CC(C)[O-]
Solvent: O
Product: CCCCCCCCCCCC1=NC(C)CN1
Temperature: 120 °C
Yield: 92 %

Procedure:
In a 500 ml four-necked flask equipped with a reflux condenser and a thermometer were charged 181 g of lauronitrile and 2 g of titanium tetraisopropoxide. Further, 1 g of water was added with stirring and the mixture was heated up to about 120° C. with stirring for 10 minutes. Thereafter, while maintaining the temperature at about 120° C., the mixture was heated for 30 minutes under a reduced pressure to remove isopropanol formed in situ and unreacted water therefrom. After heating the mixture up to 200°-210° C., 74 g of 1,2-diaminopropane were added dropwise for 120 hours with stirring while maintaining the temperature at 200° C. or above. After the addition of the diaminopropane had been completed, the reaction mixture was heated at 210°-220° C. for 4 hours for the completion of the reaction. The resulting mixture was then subjected to vacuum distillation at 1.0 mmHg and at 160°-165° C. to obtain 219 g of 2-undecyl-4-methyl-2-imidazoline with a yield of 92%.
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14](N)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].S(O)(O)(=O)=O.Cl[C:26]1[NH:27][CH2:28][CH2:29][N:30]=1>C(O)(C)C>[CH:1]([O:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:26]3[NH:30][CH2:29][CH2:28][N:27]=3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCc1ccc(Cc2ccc(N)cc2)cc1
Reactant: ClC1=NCCN1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)OCc1ccc(Cc2ccc(C3=NCCN3)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 4-(4-isopropoxymethylbenzyl)-phenylamine (400 mg, 1.57 mmol) in isopropanol (4.8 mL) at 20° C. under argon atmosphere was added 2-chloro-2-imidazoline sulfate (382 mg, 1.88 mmol). The mixture was heated to 80° C. and stirred for 3 hours. The solvent was evaporated in vacuo, and water and 10% sodium hydroxide was added to pH 11-12. The basic aqueous phase was extracted with dichloromethane (3x 20 mL), and the combined organic layers were washed with water, dried (Na2SO4), and evaporated in vacuo. The crude product was purified by flash chromatography, washed with 0.07M potassium carbonate, and concentrated to give pure 2-[4-(4-isopropoxymethyl-benzyl)-phenyl]-imidazoline (463 mg, 91%) as a clear oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[F:16][CH:17]([F:34])[C:18]1[N:26]=[CH:25][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[CH:23][C:19]=1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[F:34][CH:17]([F:16])[C:18]1[N:26]=[CH:25][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH:30]([CH3:31])[CH3:32])=[CH:23][C:19]=1[C:20]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][N:6]=[C:5]2[NH:4][CH:1]([CH3:3])[CH3:2])=[O:21]
Reactant: CC(C)Nc1ncnc2c(N)cccc12
Reactant: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Nc1ncnc2c(NC(=O)c3cc(CNC(=O)C(C)C)cnc3C(F)F)cccc12
Yield: 4.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-isopropylquinazoline-4,8-diamine (Intermediate-57, 100 mg, 0.50 mmol), 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid (Intermediate-66, 161 mg, 0.60 mmol), oxalyl chloride (113 mg, 0.90 mmol), DMF (1 drop) and DIPEA (192 mg, 1.49 mmol) in CH2Cl2 (2 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H), 8.71 (s, 1H), 8.64 (m, 1H), 8.48 (m, 2H), 8.08 (m, 3H), 7.53 (m, 1H), 7.23 (t, J=54 Hz, 1H), 4.44 (m, 1H), 4.41 (d, 2H), 2.50 (m, 1H), 1.27 (d, J=6.9 Hz, 6H), 1.04 (d, J=7.5 Hz, 6H); MS [M+H]+: 457.47.
Reaction SMILES: [CH:1]([C:3]1[CH:32]=[CH:31][C:6]([NH:7][C:8]2[N:9]=[C:10]3[C:16]([C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[O:33]1[CH2:38][CH2:37][N:36]([C:39](=[O:43])[CH2:40][C:41]#[N:42])[CH2:35][CH2:34]1.N1CCCCC1>C(Cl)Cl>[C:41]([C:40]([C:39]([N:36]1[CH2:35][CH2:34][O:33][CH2:38][CH2:37]1)=[O:43])=[CH:1][C:3]1[CH:32]=[CH:31][C:6]([NH:7][C:8]2[N:9]=[C:10]3[C:16]([C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:11]3=[N:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:42]
Reactant: N#CCC(=O)N1CCOCC1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCOCC4)cc3)nc12
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a 20 ml vial 2-(4-formylanilino)-N-isopropyl-5-(2-trimethylsilylethoxymethyl)-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 0.11 mmol), 3-morpholino-3-oxopropanenitrile (33.99 mg, 0.22 mmol) and piperdine (0.02 ml, 0.22 mmol) were mixed and stirred overnight. The residues was dissolved in minimum CH2Cl2, loaded on silica gel column, and eluted with EtOAc:hexane, 0, 50, 80, 100% to get 60 mg of 2-[4-(2-cyano-3-morpholino-3-oxo-prop-1-enyl)anilino]-N-isopropyl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-carboxamide as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.CN(C)C=O.[H-].[Na+].[C:13]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]2[N:31]([CH2:32][CH2:33]OS(C)(=O)=O)[C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]=3[N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]2[N:31]([CH2:32][CH2:33][N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)[C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]=3[N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCn2cccn2)CC1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
Treat a stirred solution of pyrazole (0.22 g, 3.18 mmol, Aldrich Chemical Company) and dimethylformamide (5 mL) at room temperature portionwise with sodium hydride (0.15 g, 3.18 mmol). After 30 minutes, slowly add a solution of 1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)-[1,4]diazepane (0.93 g, 2.12 mmol, Preparation 28) and dimethylformamide, and then heat at 75° C. for 12 hours. Cool, add dichloromethane (100 mL) and wash with water (2×20 mL). Dry (Na2SO4) the organic phase, filter and concentrate. Dry the residue under high vacuum at 100° C. to remove residual dimethylformamide. Purify the residue by radial chromatography (silica gel, ethyl acetate:hexane, 1:1) to afford 4-[1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.71 g), Rf=0.44 (silica gel, ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C@H:15]2[CH2:18][C@H:17]([CH3:19])[CH2:16]2)[C:11]([OH:13])=O)[C:7](=[O:20])[CH:6]=1.[C:25](Cl)(=O)C(Cl)=O.Cl.[OH:32][C@@H:33]([CH2:63]O)[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:36]1.N1C(C)=CC=CC=1C>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C@H:15]2[CH2:16][C@H:17]([CH3:19])[CH2:18]2)[C:11]([NH:40][C:37]2[CH:38]=[CH:39][N:35]([CH2:34][C:33]([OH:32])([CH3:63])[CH3:25])[N:36]=2)=[O:13])[C:7](=[O:20])[CH:6]=1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H]1C[C@H](CC(C(=O)O)N2CC(Oc3ccccc3Cl)=CC2=O)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(C[C@H]2C[C@H](C)C2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(trans-3-methyl-cyclobutyl)-propionic acid (100 mg, 0.29 mmol), dichloromethane (5 mL) and N,N-dimethylformamide (3 drops) at 25° C. To this mixture was added a 2.0M solution of oxalyl chloride in dichloromethane (180 μL, 0.36 mmol) dropwise, which resulted in gas evolution. The mixture was stirred for 15 min at 25° C. and then concentrated in vacuo. This residue was taken up in dichloromethane (5 mL) and added dropwise into another flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in US20080021032, Example 80, 55 mg, 0.35 mmol), dichloromethane (5 mL) and 2,6-lutidine (180 μL, 0.58 mmol) at 25° C. and stirred for 1.5 h at 25° C. and then quenched with methanol. The mixture was diluted with dichloromethane and washed with a 1N aqueous hydrochloric acid solution. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 25% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(trans-3-methyl-cyclobutyl)-propionamide (51 mg, 36%) as a light amber foam: HR-ES-MS m/z calculated for C25H31N4O4Cl [M+H]+ 487.2107, observed 487.2107; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06 (d, J=6.8 Hz, 9H), 1.48-1.57 (m, 1H), 1.65-1.73 (m, 1H), 1.75-1.83 (m, 1H), 1.88-2.01 (m, 3H), 2.14-2.26 (m, 1H), 2.28-2.37 (m, 1H), 3.90 (s, 2H), 4.20 (d, J=18.6 Hz, 1H), 4.58 (d, J=18.6 Hz, 1H), 4.66 (s, 1H), 4.73 (dd, J=9.3, 6.3 Hz, 1H), 4.78 (s, 1H), 6.44 (d, J=2.4 Hz, 1H), 7.37 (td, J=7.8, 1.5 Hz, 1H), 7.47 (td, J=7.8, 1.5 Hz, 1H), 7.51 (dd, J=7.8, 1.5 Hz, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.65 (dd, J=7.8, 1.5 Hz, 1H), 10.75 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[NH:7][C:6]2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:11][C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=1[CH3:41]>CN(C=O)C>[F:22][CH:2]([F:1])[C:3]1[N:4]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[C:32]=2[CH3:41])[C:5]2[CH:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[C:8]([C:18]([O:20][CH3:21])=[O:19])[C:6]=2[N:7]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)F)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 70 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of methyl 2-(difluoromethyl)-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 68 (500 mg, 1.6 mmol), K2CO3 (442 mg, 3.2 mmol) and 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (480 mg, 19 mmol) in DMF (15 mL). was stirred at 70° C. for 18 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was poured into water (100 mL) and filtered, the filter cake was collected and purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:1 to give the desired product (710 mg, 98%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.53 (s, 3H), 3.14 (t, 4H, J=4.5 Hz), 3.73 (t, 4H, J=4.5 Hz), 3.93 (s, 3H), 5.75 (s, 2H), 6.27 (d, 1H, J=7.8 Hz), 7.22 (t, 1H, J=7.8 Hz), 7.30 (d, 1H, J=2.1 Hz), 7.36 (t, 1H, J=51.6 Hz), 7.58-7.61 (m, 2H); LC-MS: m/e=484 [M+1]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]#[N:11])=[C:4]([Cl:19])[CH:3]=1.Cl.[N:21]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH2:30]([O:32][C:33](=[O:40])[NH:34][C:35](=[O:39])[CH2:36][C:37]#[N:38])[CH3:31]>O.C(O)(=O)C>[CH2:30]([O:32][C:33](=[O:40])[NH:34][C:35](=[O:39])[C:36](=[N:21][NH:1][C:2]1[CH:3]=[C:4]([Cl:19])[C:5]([CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]#[N:11])=[C:6]([Cl:8])[CH:7]=1)[C:37]#[N:38])[CH3:31]
Reactant: O=N[O-]
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(N)cc1Cl
Reactant: CCOC(=O)NC(=O)CC#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)NC(=O)C(C#N)=NNc1cc(Cl)c(C(C#N)c2ccc(Cl)cc2)c(Cl)c1

Procedure:
To a stirred and cooled (5-10 degrees C) mixture of 15.2 parts of 4-amino-2,6-dichloro-α-(4-chlorophenyl)-benzeneacetonitrile (intermediate 2), 14.4 parts of concentrate hydrochloric acid and 125 parts of acetic acid is added dropwise, during a 30 minutes period, a solution of 3.5 parts of sodium nitrite in 15 parts of water at about 10 degrees C. Upon completion, the whole is stirred for 30 minutes and then 10 parts of sodium acetate and 7.8 parts of ethyl(2-cyanoacetyl)carbamate are added, during a period of 2 hours, at room temperature. The reaction mixture is poured into 500 parts of water. The product is filtered off, washed with water and dissolved in dichloromethane. The organic layer is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated in vacuo. The residue is stirred in 2-propanol. The product is filtered off, washed with 2,2'-oxybispropane and dried, yielding ethyl[2-[[3,5-dichloro-4-[(4-chlorophenyl)cyanomethyl]phenyl]hydrazono]-2-cyanoacetyl]carbamate (intermediate 3).
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][CH:15]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:15][CH2:14][CH2:13][CH2:12][CH:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:11]3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=CCCCC1CC(c2ccccc2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(C2=NOC(CCCCN3CCN(c4ccccc4)CC3)C2)cc1
Yield: 79.8 %

Procedure:
4-(3-Phenyl-4,5-dihydroisoxazol-5-yl)butanal (29.4 mg, 0.135 mmol), 1-phenylpiperazine (20.0 mg, 0.123 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (78.4 mg, 0.369 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 35.7 mg (68.4%) of the target compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([Br:20])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(F)cc1
Yield: 102.1 %

Procedure:
To a solution of methyl-4-fluorphenylacetate (10 g) in carbontetrachloride (80 mL) was added NBS (11.64 g) and AIBN (0.976 g) at RT. The reaction was then heated to reflux for 3 days. The reaction mixture was filtered and the solid washed with further carbontetrachloride. The filtrate was reduced in vacuo and the diluted with water (50 mL) and EtOAc (100 mL). The phases were separated and the aqueous phase was extracted with further EtOAc (100 mL). The combined organic phases were dried over sodium sulphate, filtered and evaporated in vacuo to afford the desired bromo-(4-fluoro-phenyl)-acetic acid methyl ester (15.0 g) as a yellow oil which was taken into the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.O.[SH-:13].[Na+].CN1CCCC1=O.O>C(OCC)(=O)C>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=[S:13])[C:5]=2[S:4][CH:3]=1
Reactant: [SH-]
Reactant: Clc1ncnc2c(Br)csc12
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: S=c1[nH]cnc2c(Br)csc12
Reaction time: 1 h

Procedure:
A solution of 7-bromo-4-chlorothieno[3,2-d]pyrimidine (see below for preparation) (2.0 g), sodium hydrosulfide hydrate (0.66 g) and N-methylpyrrolidinone (10 ml) was heated at 102° C. for 1 hour. Water (500 ml) and ethyl acetate (500 ml) were added and stirred for 1 hour. The layers were separated and the aqueous phase extracted with ethyl acetate (300 ml). The combined organic extracts were washed with brine (300 ml), dried (MgSO4), treated with activated charcoal, then filtered through a silica pad and the solvent removed to give the title product, m.p. 328° C.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=O>>[CH2:1]([N:5]1[C:14]2[CH2:13][CH2:12][N:11]([CH2:27][C:26]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:10][CH2:9][C:8]=2[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCCCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Product: CCCCn1nc(-c2ccc(Cl)cc2)c2c1CCN(Cc1ccc(OC)c(OC)c1)CC2
Yield: 38.2 %

Procedure:
The title compound (8 mg) was prepared from 1-butyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 67, 14 mg) using 3,4-dimethoxy-benzaldehyde (0.2 mmol) in place of formaldehyde. MS (ESI): exact mass calculated for C26H32ClN3O2, 453.22. found, m/z 454.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.38 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.20 (s, 1H), 6.91-6.90 (br m, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 3.98 (t, J=7.3 Hz, 2H), 3.82 (d, J=7.0 Hz, 6H), 3.66 (s, 2H), 2.78-2.72 (br m, 8H), 1.67 (m, 2H), 1.27 (m, 2H), 0.86 (t, J=7.3 Hz, 6H).