Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[F:19][C:20]([F:31])([F:32])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=23)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1nn2cccnc2c1Br
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CC(C)(C)OC(=O)Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1

Procedure:
The product from Example 148A and 4-trifluoromethoxyphenylboronic acid were processed using the method analogous to that described in example 110C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.52-9.54 (bs, 1H), 9.08 (dd, J=6.9, 1.7 Hz, 1H), 8.61 (dd, J=4.1, 1.7 Hz, 1H), 7.87-7.90 (m, 2H), 7.44-7.46 (m, 2H), 7.12 (dd, J=6.9, 4.1 Hz, 1H), 1.25 (s, 9H); MS (ESI) m/z 393 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1COCCC)[C:7]([O-:9])=[O:8])([O-:3])=[O:2].[Li+].[OH-].[CH2:20]1C[O:23][CH2:22][CH2:21]1>CCO.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:23][CH2:22][CH2:21][CH3:20])[C:7]([OH:9])=[O:8])([O-:3])=[O:2]
Reactant: CCCOCc1ccc(C(=O)[O-])cc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCOc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a stirred solution of 3-nitro-4-propoxymethylbenzoate (0.35 g, 1.46 mmol) in a mixture of THF and EtOH (3 ml:1 ml) the solution of LiOH (0.345 g; 15 mmol) in H2O (1 ml) was added and the mixture was stirred for 4 h at room temperature. The solvent was distilled off and the residue was treated with 1 M HCl and extracted with EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.32 g, 97%), as creamy solid. 1H NMR (CDCl3) 8.53 (d, 1H, J=1.65 Hz); 8.21 (dd, 1H, J=8.79, 1.62 Hz); 7.12 (d, 1H, J=8.82 Hz); 4.14 (t, 2H, J=6.39 Hz); 1.94-1.82 (m, 2H); 1.07 (t, 3H, J=7.35 Hz).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.[NH2:27][OH:28]>C(O)C>[OH:28][N:27]=[CH:1][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1
Reactant: NO
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(4-formyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 2, Step B) (0.8 g, 2.07 mmol) in ethyl alcohol (15 mL) was added hydroxylamine (50% aqueous solution, 0.136 g, 4.1 mmol), and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give a yellow oil, which was purified by flash column chromatography on silica gel using 50% ethyl acetate in hexanes as eluant to give 0.7 g of the title compound as a white solid.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8][O:9][C:10]([CH:12]1[CH2:17][CH:16]2[C:18](=[O:21])[C:19](=[O:20])[CH:13]1[CH:14]=[C:15]2[Br:22])=[O:11].B(F)(F)F.[CH3:27]COCC>ClCCl>[CH3:8][O:9][C:10]([CH:12]1[CH2:17][CH:16]2[C:15]([Br:22])=[CH:14][CH:13]1[C:19](=[O:20])[CH2:27][C:18]2=[O:21])=[O:11]
Reactant: COC(=O)C1CC2C(=O)C(=O)C1C=C2Br
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: FB(F)F
Solvent: ClCCl
Product: COC(=O)C1CC2C(=O)CC(=O)C1C=C2Br
Temperature: 20 °C
Reaction time: 4 h

Procedure:
4.2 ml of trimethylsilyl-diazomethane are added dropwise at a temperature of −10° C. to a solution of 1.91 g (7 mmol) of 5-bromo-7,8-dioxo-bicyclo[2.2.2]oct-5-ene-2-carboxylic acid methyl ester in 20 ml of dichloromethane and 0.089 ml (0.7 mmol) of boron trifluoride etherate. The cooling is removed and the reaction mixture is stirred for 4 hours at a temperature of 20° C. The reaction solution is then extracted with water, the organic phase is dried over sodium sulfate and concentrated by evaporation using a rotary evaporator, and the residue is purified by silica gel chromatography. An isomer of 8-bromo-2,4-dioxo-bicyclo[3.2.2]non-8-ene-6-carboxylic acid methyl ester is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.B(O)(O)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[N:32][CH:31]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:30]3[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: COc1ccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)cn1
Yield: 68 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 6-methoxypyridin-3-yl-3-boronic acid instead of phenyl boronic acid, to obtain the title compound (68%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[Br:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cnc(Br)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
A solution of 2-amino-5-bromopyrazine (10.00 g, 57.47 mmol) and pyridine (5.6 mL, 68.96 mmol) in methylene chloride (144 mL) was cooled to 0° C. and then was treated slowly with trimethylacetyl chloride (8.6 mL, 68.96 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min and then was allowed to warm to 25° C. where it was stirred for 18 h. At this time, the reaction mixture still contained the starting material 2-amino-5-bromopyrazine. The reaction mixture was treated with an additional amount of trimethylacetyl chloride (4.3 mL, 34.48 mmol) and then stirred at 25° C. for 4 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The resulting residue was diluted with ethyl acetate (700 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (2×200 mL) and a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 65M, Silica, 1/9 ethyl acetate/hexanes) afforded N-(5-bromo-pyrazin-2-yl)-2,2-dimethyl-propionamide (12.19 g, 82%) as a white solid: mp 122–124° C.; (ES)+-HRMS m/e calcd for C9H12BrN3O (M+H)+ 258.0237, found 258.0240.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][NH:12]2)[CH2:10][CH2:9]1.CO.C=O.[C:28]([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][N:12]2[CH3:28])[CH2:9][CH2:10]1
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1C)CCNC2C1(c2ccccc2Cl)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2c(cc1C)CCN(C)C2C1(c2ccccc2Cl)CC1
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
A mixture of 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline (6.2 g), methanol (160 ml) and 37-40% aqueous formaldehyde solution was stirred for 15 minutes. Sodium cyanoborohydride (5.13 g) was added and the mixture was stirred for a further 10 minutes. The reaction was then neutralised with acetic acid and stirred for 45 minutes. The methanol was removed in vacuo and the residue treated with aqueous sodium hydroxide solution. The product was extracted with ethyl acetate. The extracts were washed with aqueous ammonia solution, water and brine, then dried over magnesium sulphate. Concentration yielded 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinoline as a gum (5.02 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:29]1(=[O:36])[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH2:30]1>CN(C)C1C=CN=CC=1.ClC(Cl)C>[OH:36][C:29]1[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[C:30]=1[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C1CCCC(=O)C1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: O=C1CCCC(O)=C1C(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 66.8 %

Procedure:
4-Nitrophenylacetic acid (8.1 g, 45 mmol) and then dicyclohexylcarbodiimide (9.7 g, 47 mmol) were added to a dichloroethane (150 ml) suspension of 1,3-cyclohexanedione (5.00 g, 44.6 mmol) at room temperature, after which 4-dimethylaminopyridine (0.27 g, 2.2 mmol) was added and stirring carried out for 1 hour at 60° C. and then further 4-dimethylaminopyridine (0.54 g, 4.4 mmol) added and stirring carried out for 23 hours at 85° C. The dicyclohexylurea was filtered off while the solution was still warm, then the reaction solution washed with dilute hydrochloric acid (50 ml), after which the aqueous layer was extracted with dichloromethane. After drying with anhydrous sodium sulphate, the solvent was distilled off and separation and purification performed by column chromatography. When recrystallization was performed from ethanol, 3-hydroxy-2-(4-nitrophenylacetyl)-2-cyclohexenone (8.2 g, 67%) was obtained as yellow crystals. Tetrahydrofuran (100 ml), methanol (35 ml) and concentrated hydrochloric acid (10 ml) were added to the compound obtained (2.00 g, 7.3 mmol), then Pd-C (5%, containing 100% of water, 300 mg) added and the atmosphere replaced by hydrogen. The raw material was consumed in 4 hours and then the hydrogen replaced by argon. The precipitate was filtered off, washed with hot methanol, and the filtrate concentrated. When the solid obtained was recrystallized from ethanol, 2-(4-aminophenylacetyl)-3-hydroxy-2-cyclohexenone hydrochloride (1.3 g, 64%) was obtained. A chloroform (15 ml) solution of the compound (500 mg, 1.77 mmol) obtained was ice-cooled and 2-thiopheneacetyl chloride (0.26 ml, 2.1 mmol) added. Next, pyridine (0.44 ml, 5.5 mmol) was added and stirring carried out for 3 hours. After returning to room temperature, stirring was carried out for 15 hours, then dilute hydrochloric acid added and extraction performed with dichloromethane. The organic layer was dried with anhydrous sodium sulphate, and the solvent distilled off. When recrystallization was performed from ethanol, Compound 4 (245 mg, 37%) was obtained as pale yellow crystals.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:24][CH3:25])[C:20]=1[CH:21]([CH3:23])[CH3:22])[C:14]([O:16]C)=O.O.Cl>CCOCC>[CH3:25][O:24][C:19]1[CH:18]=[C:13]([C:14]([OH:16])([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=[C:11]([O:10][CH3:9])[C:20]=1[CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)c1cc(OC)c(C(C)C)c(OC)c1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COc1cc(C(O)(Cc2ccccc2)Cc2ccccc2)cc(OC)c1C(C)C
Temperature: 25 °C
Yield: 79 %

Procedure:
To Mg (0.252 g, 10.4 mmol) in dry ether (5 mL) was added benzylbromide (1 mL, 8.41 mL) in dry ether (3 mL) dropwise under reflux. After the addition was complete, the reaction mixture was further refluxed for 1 h. Methyl 3,5-dimethoxy-4-i-propylbenzoate (1.00 g, 4.20 mmol) in ether (15 mL) was added. After the ester completely disappeared, the reaction mixture was cooled to room temperature. Water (10 mL) was added followed by addition of 2N HCl (10 mL) to dissolve precipitate. The organic layer was separated and the aqueous layer was extracted with ether (3×50 mL). The extract was dried over anhydrous Na2SO4. Evaporation of solvent followed by flash chromatography using ethyl acetate:hexane (1:9) afforded 2-(3,5-dimethoxy-4-i-propylphenyl)-1,3-diphenylpropan-2-ol (1.29 g, 79%) as a white solid. 1HNMR (CDCl3, ppm): δ 1.28 (d, J=7.2 Hz, 6H), 3.08 (d, J=13.3 Hz, 2H), 3.35 (d, J=13.3 Hz, 2H), 3.6 (m, 1H), 3.95 (s, 6H), 6.44 (s, 2H), 6.9-7.5 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=[O:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]C#N)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:21][N:20]=[C:17]3[CH:18]=[CH:19][C:14]([C:13]4[N:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[N:10]=[CH:11][CH:12]=4)=[CH:15][C:16]=23)=[CH:27][CH:26]=1
Reactant: COc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1ccc(CC#N)cc1
Product: COc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(OC)cc4)cc23)cc1

Procedure:
The title compound, yellow solid (7 mg, 5%), MS (ISP) m/z=398.2 [(M+H)+], mp 133° C., was prepared in accordance with the general method of example 1 from 1-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate G) (100 mg, 353 μmol) and commercially available 2-(4-methoxy-phenyl)-acetonitrile.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.O.[NH2:17][NH2:18]>>[NH:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1)[NH2:18]
Reactant: COc1ccc(-c2ccc(Cl)nc2)cc1
Reactant: NN
Solvent: O
Product: COc1ccc(-c2ccc(NN)nc2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A round-bottom flask was charged with 2-chloro-5-(4-methoxyphenyl)pyridine (260 mg, 1.19 mmol) and hydrazine hydrate (4 mL) at room temperature. The reaction mixture was heated at 100° C. for 48 h. It was cooled to room temperature, then was kept in a refrigerator for 3 h. The precipitate was filtered, washed with cold water, and dried to give the title compound as gray solids (200 mg, 78.0% yield). MS: m/z 216.1 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.Cl>[CH2:22]([O:21][C:19]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)n1ccc2cc(N)ccc21
Temperature: 0 °C
Yield: 112.2 %

Procedure:
To a solution of 4.27 gm (32.3 mMol) 5-amino-1H-indole in 50 mL tetrahydrofuran were added 5.4 ML (38.8 mMol) triethylamine and the reaction mixture was then cooled to 0° C. To this solution were then added dropwise 3.4 mL (35.5 mMol) ethyl chloroformate. After 4 hours the reaction mixture was diluted with 1N HCl and was then extracted with ethyl acetate. The organic phase was washed sequentially with 1N HCl, water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to give 7.4 gm of a dark oil. This oil was purified by flash chromatography, eluting with a gradient of dichloromethane containing 0-2.5% methanol, to give 4.95 gm (75%) of the title compound as a tan solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[N:7][C:6]=2[Cl:12].CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:64]([SH:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:64]([S:71][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[N:7][C:6]=2[Cl:12])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: SCc1ccccc1
Reactant: Clc1nccc2cc(Br)cnc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc2cc(SCc3ccccc3)cnc12
Temperature: 40 °C
Yield: 51.4 %

Procedure:
To a vial charged with 3-bromo-8-chloro-1,7-naphthyridine (Anichem, North Brunswick, N.J.) (360 mg, 1.479 mmol) was added dioxane (5914 μl), DIEA (516 μl, 2.96 mmol), Xantphos (171 mg, 0.296 mmol), Pd2(dba)3 (135 mg, 0.148 mmol) and benzyl mercaptan (184 μl, 1.552 mmol). The vessel was sealed and heated to 40° C. overnight. The mixture was cooled to RT, filtered through diatomaceous earth and dried under reduced pressure. The crude residue was purified with a 25 g silicycle HP column (25 μm spherical silica) ramping EtOAc in heptane (0 to 100%, 10% DCM throughout) to provide 3-(benzylthio)-8-chloro-1,7-naphthyridine (0.218 g, 0.760 mmol, 51.4% yield) as a light yellow solid. m/z (ESI) 287.1 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1)=[O:2].[CH3:16][Mg]Cl>O1CCCC1>[OH:2][CH:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1)[CH3:16]
Reactant: CC(C)(C)C(=O)Nc1cccc(C=O)n1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)c1cccc(NC(=O)C(C)(C)C)n1
Temperature: 0 °C
Yield: 13 %

Procedure:
To an ice-cooled solution of N-(6-formylpyridin-2-yl)-2,2-dimethylpropanamide (4.0 g, 19.4 mmol) in tetrahydrofuran (30 mL) was added methylmagnesium chloride (13.6 mL, 40.7 mmol, 3 M in THF) dropwise. After 2 h the reaction was quenched with saturated aqueous NH4Cl solution (10 mL) and diluted with ethyl acetate (50 mL). The mixture was washed with saturated aqueous NaHCO3 solution (2×50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (2:1 hexanes/EtOAc) to afford the intermediate as a clear oil (0.56 g, 49%). 1H NMR (400 MHz, CDCl3), δ: 8.14 (d, J=8.1 Hz, 1H), 8.00 (br s, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.00 (d, J=7.5 Hz, 1H), 4.82 (m, 1H), 3.81 (d, J=5.0 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H), 1.35 (s, 9H); LRMS (ESI): m/z: 223.2.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:28][C:25]3[CH:26]=[CH:27][N:23]([CH3:22])[N:24]=3)=[O:18])=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cn1ccc(N)n1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)Nc2ccn(C)n2)cn1
Yield: 55 %

Procedure:
As described for example 19b, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted, using 1-methyl-1H-pyrazol-3-ylamine instead of L-2,2,2-trifluoro-1-(methyl)ethylamine, to the title compound (70 mg, 55%) which was obtained as a yellow oil after purification by chromatography (silica, heptane:ethyl acetate 9:1 to 1:1). MS: m/e=370.2 [M+H]+.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH3:13].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>ClCCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:1][N:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]2[CH3:13])=[O:23])=[CH:17][CH:16]=1
Reactant: Cc1nc2ccccc2c(=O)n1N
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCCl
Product: Cc1nc2ccccc2c(=O)n1NC(=O)Nc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A mixture of 3-amino-2-methyl-4-quinazolone (1.60 g, 9.10 mmol) and 4-chlorophenyl isocyanate (1.54 g, 10.0 mmol) in 1,2-dichloroethane is heated at reflux for 22 hours, concentrated in vacuo, cooled to 0° C. and filtered. The filter cake is washed with ether and dried to give the title product as a white solid, 2.45 g (82%), mp 228°-229.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]([C:12]([OH:14])=O)[CH2:3]1.[CH2:15]([NH2:18])[CH:16]=[CH2:17]>C(O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]([C:12]([NH:18][CH2:15][CH:16]=[CH2:17])=[O:14])[CH2:3]1
Reactant: CN1CC(C(=O)O)Oc2ccccc21
Reactant: C=CCN
Solvent: CCO
Product: C=CCNC(=O)C1CN(C)c2ccccc2O1

Procedure:
A solution of 1.1 g of 2A, and 5 ml of 2-propenamine in 25 ml of ethanol was refluxed for 16 hours. The solvent and excess amine were stripped off and the residue was passed through a silica gel column using Solvent No. 3 as eluent. The solvent was stripped off to give 2, as light yellow liquid, boiling point not determined.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[N:17]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN(C)C=O>[CH:13]1[C:4]2[CH:5]=[CH:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([N:20]3[CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21]3)[C:3]=2[CH:16]=[CH:15][CH:14]=1
Reactant: ClC1c2ccccc2C=Cc2ccccc21
Reactant: CCOC(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 gram (44 millimoles) of 5-chloro-5H-dibenzo-[a,d]cycloheptene prepared in a manner similar to that previously described was added to a solution of 1.4 grams of ethyl N-piperazinecarboxylate in 10 milliliters of dimethylformamide and the resulting mixture allowed to stir overnight at room temperature. At the end of this period, the mixture was subjected to reduced pressure to remove most of the dimethylformamide. Aqueous saturated sodium bicarbonate solution was added, mixed and then extracted with diethyl ether. The ether extract was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, the dried solution subjected to reduced pressure to remove the ether and to obtain the ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-piperazinecarboxylate product as residue. The crude product was treated with and crystallized from acetonitrile. The product after several recrystallizations had a melting point of 159°-160° C. and elemental analyses as follows:
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:10]([N:17]1[C:21]2[N:22]=[CH:23][N:24]=[C:25](Cl)[C:20]=2[CH:19]=[CH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C1COCC1>[CH2:10]([N:17]1[C:21]2[N:22]=[CH:23][N:24]=[C:25]([O:9][CH:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[C:20]=2[CH:19]=[CH:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OC1CCCCC1
Reactant: Clc1ncnc2c1ccn2Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(Cn2ccc3c(OC4CCCCC4)ncnc32)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a flame dried flask under nitrogen was charged 84 mg (2.10 mmol) of 60% sodium hydride in mineral oil and 3.0 mL of THF and the mixture cooled to 0° C. Cyclohexanol (0.18 mL/1.70 mmol) was added and the reaction mixture stirred for 5 min. A solution of 102 mg (0.419 mmol) of the product from Method L in 1.0 mL of THF was added and the mixture heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was acidified to pH 1 with 2 N HCl and concentrated in vacuo. The resulting residue was then slurried in ethyl acetate, filtered and the filtrate concentrated in vacuo to provide 76 mg (59%) of the title compound as an oil. LRMS: 308 (M+1).