Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+].[C:2]([O:6][C:7]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14](/[CH:18]=[CH:19]/[C:20]2[CH:28]=[CH:27][C:23]([C:24]([O-:26])=O)=[CH:22][C:21]=2[N+:29]([O-:31])=[O:30])=[C:13]([Cl:32])[CH:12]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:66][C:67]1[CH:76]=[CH:75][C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[N:68]=1>C(Cl)Cl>[C:2]([O:6][C:7](=[O:8])[CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14](/[CH:18]=[CH:19]/[C:20]2[CH:28]=[CH:27][C:23]([C:24](=[O:26])[NH:66][C:67]3[CH:76]=[CH:75][C:74]4[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=4)[N:68]=3)=[CH:22][C:21]=2[N+:29]([O-:31])=[O:30])=[C:13]([Cl:32])[CH:12]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(/C=C/c2ccc(C(=O)[O-])cc2[N+](=O)[O-])c(Cl)c1
Reactant: Nc1ccc2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCc1cc(Cl)c(/C=C/c2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[N+](=O)[O-])c(Cl)c1
Reaction time: 0.5 h

Procedure:
To 4-{(E)-2-[4-(2-tert-butoxycarbonylethyl)-2,6-dichlorophenyl]-vinyl}-3-nitrobenzoic acid potassium salt (280 mg, 0.56 mmol) in DCM (6 mL) was added diisopropylethylamine (292 μL, 1.68 mmol) and HATU (320 mg, 0.84 mmol) and the solution was stirred for 30 min. To this was added 2-aminoquinoline (96 mg, 0.66 mmol) and the mixture was stirred 18 h. The reaction mixture was partitioned between ethyl acetate and water, the organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate/heptane to obtain 3-(3,5-dichloro-4-{(E)-2-[2-nitro-4-(quinolin-2-ylcarbamoyl)-phenyl]-vinyl}-phenyl)-propionic acid tert-butyl ester as a white solid. MS (m/z) 592.1 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 11.58 (s, 1H), 8.74 (d, J=1.89 Hz, 1H), 8.43-8.48 (m, 2H), 8.36-8.41 (m, 1H), 8.16 (d, J=8.34 Hz, 1H), 7.99 (d, J=7.33 Hz, 1H), 7.91 (d, J=8.21 Hz, 1H), 7.77 (ddd, J=8.40, 6.95, 1.33 Hz, 1H), 7.56 (dd, J=15.03, 1.14 Hz, 1H), 7.49 (s, 2H), 7.48 (d, J=16.82 Hz, 1H), 7.36 (d, J=16.82 Hz, 1H), 2.85 (t, J=7.26 Hz, 2H), 2.59 (t, J=7.39 Hz, 2H) 1.38 (s, 9H).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl>O1CCOCC1>[CH3:3][CH:2]([CH3:4])[C:1]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=1)=[O:5]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Into a stirred solution of 2.20 (6.50 mmol) of tert-butyl 4-[3-(isobutyrylamino)phenyl]-1-piperidinecarboxylate in 100 ml of 1,4-dioxane at 0° C. was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HCl gas was continued for 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets. The aqueous solution was extracted with 3×80 mL of dichloromethane, the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9:1, dichloromethane:methanol+1% isopropyl amine) to afford 0.700 g (46.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.40 (d, 1H, J=7.8 Hz), 7.24 (t, 1H, J=7.8 Hz), 7.00 (d, 1H, J=7.8 Hz), 3.23–3.14 (m, 5H), 2.82–2.57 (m, 4H) 1.20 (d, 6H, J=6.8 Hz); ESMS m/e: 247.2 (M+H)+; The hydrochloride salt was used for the combustion analysis: Anal. Calc. for C15H22N2O+HCl+0.15 CHCl3: C, 60.51; H, 7.76; N, 9.32. Found: C, 60.57; H, 7.83; N, 8.88.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32]([NH:35][C:37](=[O:39])[CH3:38])=[N:33][CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cnc(-c2cnc(N)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Solvent: c1ccncc1
Product: COc1cnc(-c2cnc(NC(C)=O)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
1-(benzoyl)-4-[(4-methoxy-7-(2-amino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine (4 mg) and acetic anhydride (20 mg) were dissolved in pyridine (0.5 ml). The reaction was stirred for three hours at room temperature. After reaction was quenched with MeOH (1 ml), solvents were concentrated to give a residue which was purified using a Shimadzu automated preparative HPLC System to provide 3.0 mg of the desired compound, 1-(benzoyl)-4-[(4-methoxy-7-(2-acetylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. 1H NMR (500 MHz, CD3OD) δ9.58 (s, 1H), 9.25 (s, 1H), 8.45 (s, 1H), 8.10 (s, 1H), 7.49 (m, 5H), 4.12 (s, 3H), 3.84-3.35 (m, 8H), 2.27 (s, 3H). MS m/z: (M+H)+ Calc'd for C27H26N7O5: 528.20; found 528.22. HPLC retention time: 1.33 minutes (column A).
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(N(CC)CC)C>[CH3:15][S:16]([O:11][CH2:10][CH2:9][CH2:8][O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:18])=[O:17]
Reactant: OCCCOC1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCOC1CCCCC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 57.8 %

Procedure:
To a solution of 10 parts of 3-(cyclohexyloxy)-1-propanol in 160 parts of dichloromethane there were added 11.2 parts of N,N-diethylethanamine and dropwise 8.14 parts of methanesulfonyl chloride. The whole was stirred for 9 hours at room temperature. The reaction mixture was washed with Na2CO3 (aq.) and water and was then dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 99:1). The eluent of the desired fraction was evaporated and the residue was co-evaporated with methylbenzene. The product was filtered off and dried, yielding 8.6 parts (57.8%) of 3-(cyclohexyloxy)-1-propanol methanesulfonate (ester) (interm. 21).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[CH3:8][C:9]([CH3:11])=[O:10].C(O)C.[ClH:15]>C[Si](C)(C)N[Si](C)(C)C.O>[ClH:15].[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:9]([OH:10])([CH3:11])[CH3:8])(=[O:7])[OH:6]
Reactant: CC(C)=O
Reactant: NCCCP(O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(O)P(=O)(O)CCCN
Temperature: 25 °C

Procedure:
A suspension of 1.23 g 3-aminopropylphosphonous acid in 25 ml of hexamethyldisilazane is heated to reflux under an inert gas for 20 hours. After this time a clear solution results and the reaction mixture is cooled to room temperature under inert gas and 50 ml of anhydrous acetone is added and an exothermic reaction results. The reaction mixture is allowed to cool to room temperature and the volatile components removed in vacuo to afford a clear oil. This oil is dissolved in 50 ml of a 2.0M hydrochloric acid solution in water and washed with 2×100 ml of dichloromethane and 1×100 ml of ether. The aqueous layer is evaporated to dryness to give a semi-solid residue which is co-evaporated with water (10×20 ml) and absolute ethanol (10×20 ml) yielding 3-aminopropyl(2-hydroxyprop-2-y)phosphinic acid hydrochloride m.p. 159°-161° as a white solid. This is suspended in absolute ethanol and treated with propylene oxide. Filtration and drying of the solid affords 3-aminopropyl(2-hydroxyprop-2 -yl)phosphinic acid; m.p. 243°-244°.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[Si:10]([O:17][CH:18]1[CH2:21][N:20]([CH2:22][C@H:23]([O:28][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:45])[N:36]=[CH:37][C:30]=23)[C:24](OC)=[O:25])[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][CH:18]1[CH2:19][N:20]([CH2:22][C@H:23]([O:28][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[C:39]([Cl:45])=[CH:40][CH:41]=[CH:42][C:43]=4[Cl:44])[N:36]=[CH:37][C:30]=23)[C:24]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[O:25])[CH2:21]1)([C:13]([CH3:15])([CH3:16])[CH3:14])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@H](CN1CC(O[Si](C)(C)C(C)(C)C)C1)Oc1ncnc2c1cnn2-c1c(Cl)cccc1Cl
Reactant: N#Cc1ccc(N)nc1
Product: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](Oc2ncnc3c2cnn3-c2c(Cl)cccc2Cl)C(=O)Nc2ccc(C#N)cn2)C1

Procedure:
Using a procedure analogous to that described for Intermediate BD12 using 6-aminonicotinonitrile and (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate BJ1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27](=O)[NH:26][CH:25]=[N:24]2)=[CH:19][CH:18]=1.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C=NN(C2C=CC(C(F)(F)F)=CC=2)C1=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:27]2[N:23]([C:20]3[CH:19]=[CH:18][C:17]([C:16]([F:29])([F:15])[F:30])=[CH:22][CH:21]=3)[N:24]=[CH:25][N:26]=2)[CH3:13])[CH2:11][O:10]1
Reactant: O=c1[nH]cnn1-c1ccc(C(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[C@@H](n1cnn(-c2ccc(C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1ncnn1-c1ccc(C(F)(F)F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 13.7 %

Procedure:
In the same manner as in Reference Example 5, starting from 2.49 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 2.52 g of 2-(4-trifluoromethylphenyl)-3(2H,4H)-1,2,4-triazolone, 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-(4-trifluoromethylphenyl)-3(2H,4H)-1,2,4-triazolone (1.13 g) and 618 mg of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-trifluoromethylphenyl)-1H-1,2,4-triazol-5-yloxy]ethyl]oxirane were obtained.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H].Cl>O1CCCC1>[C:13]1([CH:12]=[CH:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[CH2:4][OH:3])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cccc(C=Cc2ccccc2)c1
Reactant: [H][H]
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cccc(C=Cc2ccccc2)c1
Temperature: 0 °C
Yield: 79.3 %

Procedure:
10 g (0.03 mol) of 3-(2-phenyl-vinyl)-benzoic acid ethyl ester, dissolved in 50 ml of dry tetrahydrofuran, were added dropwise to 2.5 g of lithium aluminium hydride in 50 ml of anhydrous tetrahydrofuran at 25°-30° C., whilst stirring thoroughly. The reaction mixture was then subsequently stirred at 22° C. for 10 hours and then cooled to 0° C. and ice-water was added dropwise, whilst stirring, until no further evolution of hydrogen could be observed (60 ml). The precipitate which had formed was dissolved by adding 30 ml of concentrated hydrochloric acid dropwise, and the reaction mixture was then extracted twice with 100 ml of toluene each time. The organic phase was separated off and dried over sodium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by subjecting the product to brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 5 g (61% of theory) of 3-(2-phenyl-vinyl)-benzyl alcohol were obtained as a yellow oil with the refractive index nD22 : 1.6286 (isomer mixture with a cis proportion of about 90%). ##STR62##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([F:27])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 36.9 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), 4-fluoro-3-(trifluoromethyl)aniline (0.069 g, 0.38 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.050 g of desired product. 1HNMR (DMSO-d6): δ 4.09 (s, 3H), 7.52 (t, J=9.6 Hz, 1H), 7.88-7.68 (m, 6H), 8.25 (s, 1H), 8.25 (d, J=6.9 Hz, 1H), 10.37 (s, 1H), 12.74 (s, 1H); MS (m/z): 540.91 [M]+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCl
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1CCC(Cc2ccccc2)CC1
Temperature: 110 °C
Yield: 40.7 %

Procedure:
To a solution of 4-benzylpiperidine (0.50 mL, 2.8 mmol) in DMF (15 mL) were added 2-chloroethanol (0.25 mL, 3.70 mmol) and K2CO3 (0.79 g, 5.70 mmol). The heterogeneous mixture was heated at 110° C. for 2 h. It was then cooled to 25° C. and was diluted with water (100 mL) and extracted with ether (2×70 mL). The collected organic phase was washed with water (2×100 mL), dried and concentrated in vacuo. The crude compound was purified by filtration on silica gel using CH2Cl2/MeOH as eluant to afford the title compound as a colorless solid (0.25 g, 40%): mp 62-64° C.; 1H NMR (CDCl3) δ 1.15-1.35 (m, 2H), 1.45-1.60 (m, 1H), 1.63 (bd, J=13.8 Hz, 2H), 1.99 (t, J=11.7 Hz, 2H), 2.48 (t, J=5.7 Hz, 2H), 2.53 (d, J=6.9 Hz, 2H), 2.87 (bd, J=11.7 Hz, 2H), 2.9 (bs, 1H), 3.574 (t, J=5.4 Hz, 2H), 7.14 (d, J=7.2 Hz, 2H), 7.20 (d, J=6.9 Hz, 1H), 7.28 (t, J=6.2 Hz, 2H); MS (m/z) 219, 188, 91. Anal. Calcd for C1-4H21NO: C, 76.71; H, 9.65; N, 6.40. Found: C, 74.49; H, 9.29; N, 6.08.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[CH:2]=[CH2:3].C(N(CC)CC)C>CS(C)=O>[CH2:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[O:11])[N:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(CO)cs1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C=CCNc1nc(C=O)cs1

Procedure:
The reaction described in Preparation 44 was repeated, but using 11 g of 2-allylaminothiazol-4-ylmethanol, 31 g of sulfur trioxide pyridine complex, 20 g of triethylamine and 100 ml of dimethyl sulfoxide, giving the title compound as pale brown needles.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[Br:11][C:12]1[CH:13]=[C:14]2[CH:20]=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1.C[C:22](O)=[O:23]>O>[Br:11][C:12]1[CH:13]=[C:14]2[C:20]([CH:22]=[O:23])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1
Reactant: CC(=O)O
Reactant: Brc1cnc2[nH]ccc2c1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2ncc(Br)cc12
Temperature: 100 °C
Yield: 33 %

Procedure:
Hexamethylenetetramine (1.08 g, 7.61 mmol) was added to a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5 mol) in HOAc (6.34 mL). The mixture was heated at 100° Celsius for 6 hours. The reaction mixture was then cooled to rt and diluted with water. The mixture was extracted with EtOAc, dried (Na2SO4), filtered and concentrated to dryness. The residue was purified by FCC to provide the title compound (379 mg, 33%). 1H NMR (500 MHz, CDCl3) δ 10.02 (s, 1H), 8.77 (d, J=2.2, 1H), 8.48 (d, J=2.2, 1H), 7.99 (d, J=2.7, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=2)[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:18])[CH3:2]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccc(Cl)cc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
A solution of ethyl-N-boc-nipecotate (45 g, 0.18 mole) in tetrahydrofuran (200 mL) at -40° C. was treated with a solution of lithium bis (trimethylsilyl)amide in tetrahydrofuran (320 mL of a 1M solution). The solution was stirred at -40° for 15 minutes at which time 4-Chlorobenzyl chloride (34.59 g, 0.215 moles) was added and the reaction warmed to room temperature over 1.5 hours. The reaction was poured into saturated aqueous sodium bicarbonate (1 L) and extracted with ethyl acetate (3×500 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel with 30% ethyl acetate/hexane as eluent to give 36.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH:24]=[CH:23][CH2:22]4)=[O:20])=[C:15]([CH3:26])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH:22]=[CH:23][CH:24]=[CH:25]4)=[O:20])=[C:15]([CH3:26])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CC=CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)n1cccc1

Procedure:
200 mg (0.49 mmol) of rac.-N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-methyl-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzamide and 167 mg (0.73 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone are stirred in 5 mL dioxane for 10 hours at 100° C. Then the solvent is distilled off and the residue is chromatographed on silica gel, eluting with dichloromethane/methanol (0%-6%). Yield: 30 mg (15%); Rf value: 0.62 (silica gel: dichloromethane/ethanol=9:1); C22H19ClN4O2 (406.875); mass spectrum: (M+H)+=407/409 (chlorine isotope).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([N:21]([CH2:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([OH:38])=[O:37])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])(=[O:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.NN.Cl>C(O)C>[NH2:3][CH2:12][CH:13]([N:21]([CH2:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([OH:38])=[O:37])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])(=[O:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccccc1S(=O)(=O)N(Cc1ccccc1C(=O)O)C(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccccc1S(=O)(=O)N(Cc1ccccc1C(=O)O)C(CN)Cc1ccccc1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
The mixture of compound 2e (100 mg, 0.17 mmol) and hydrazine monohydrate 98% (85 mg, 1.7 mmol) in ethanol (5 mL) was heated to reflux for 2 hr. The reaction mixture was cooled down to rt and acidified to pH=3 with 1N aqueous HCl. The precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to give compound 2f as a white solid (30 mg, 39% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([F:12])=[CH:7][CH:6]=2.[CH3:14][O-:15].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:3]([O:15][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([F:12])=[CH:7][CH:6]=2
Reactant: C[O-]
Reactant: Nc1nc2cc(F)ccc2nc1Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc2ccc(F)cc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To 3-amino-2-chloro-6-fluoroquinoxaline (550 mg, 2.78 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (6.01 g, 27.8 mmol) in methanol was added at room temperature and stirred further at room temperature for 1 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with dichloromethane and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 491 mg of the titled compound (yield, 91%).
Reaction SMILES: [Na].Cl[C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH:9]=2)[N:4]=1.[CH2:20]([OH:23])[CH2:21][CH3:22]>>[N:15]1([CH2:14][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[C:3]([O:23][CH2:20][CH2:21][CH3:22])[CH:12]=[C:11]3[CH3:13])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CCCO
Reactant: Cc1cc(Cl)nc2ccc(Cn3ccnc3)cc12
Agent: [Na]
Product: CCCOc1cc(C)c2cc(Cn3ccnc3)ccc2n1
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a stirred solution of 2 parts of sodium in 24 parts of 1-propanol was added a solution of 5.2 parts of 2-chloro-6-(1H-imidazol-1-ylmethyl)-4-methylquinoline in 16 parts of 1-propanol at room temperature under nitrogen atmosphere. After stirring for 2 hours at reflux temperature, the mixture was evaporated. The residue was taken up in a potassium carbonate solution and the product was extracted with ethyl acetate. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 1.8 parts (31.9%) of 6-(1H-imidazol -1-ylmethyl)-4-methyl-2-propoxyquinoline; mp. 137.9° C. (compound 35).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH:34]([CH3:36])[CH3:35]>C(OCC)(=O)C.CCCCCC.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([O:21][CH:34]([CH3:36])[CH3:35])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)Br
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccc(C=C2Oc3cc(OC(C)C)ccc3C2=O)cc1C
Reaction time: 4 h
Yield: 47.9 %

Procedure:
To a solution of 2-[(3-methyl-4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g, potassium carbonate 0.61 g and dimethylformamide 5 ml, 2-bromopropane 0.306 g was added. After the mixture was refluxed for 2.5 hours, water 50 ml was added. The resulting compound was extracted with ethyl acetate 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dissolved in ethyl acetate 2 ml and hexane 5 ml, and the solution was allowed to stand at room temperature for four hours. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 275.1 mg.