Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:10]2[N:15]=[C:14]([C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=4)=[N:18][N:17]=3)[C:13]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[N:12][CH:11]=2)=[CH:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH:4]1[CH2:9][CH2:8][C:7]([C:10]2[N:15]=[C:14]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[CH:25][CH:26]=4)=[N:18][N:17]=3)[C:13]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[N:12][CH:11]=2)=[CH:6][CH2:5]1
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(N=[N+]=[N-])CC4)cnc3NC(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(N)CC4)cnc3NC(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[6-(4-azidocyclohexen-1-yl)-3-(tert-butoxycarbonylamino)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (103 mg, 0.17 mmol) in anhydrous THF (1.5 mL) was added triphenylphosphine (67 mg, 0.26 mmol) and the reaction mixture was stirred at room temperature for 1 h. Water (61 μL, 3.41 mmol) was added after 1 h, and the reaction mixture was heated at 65° C. for 3 h. The reaction mixture was allowed to cool to room temperature and was partitioned between EtOAc/aqueous brine. The layers were separated and the aqueous layer was extracted once more with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel column chromatography using 20% MeOH in EtOAc to yield tert-butyl N-[[4-[5-[6-(4-aminocyclohexen-1-yl)-3-(tert-butoxycarbonylamino)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (21 mg, 21%). LC/MS m/z 578.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:31]=[CH:30][C:17]([CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[O:21])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>C1COCC1.[Pd]>[CH2:1]([C:8]1[CH:13]=[N:12][C:11]([C:14]2[CH:31]=[CH:30][C:17]([CH2:18][CH2:19][C:20]([O:22][CH2:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])=[O:21])=[CH:16][CH:15]=2)=[N:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1cnc(-c2ccc(C=CC(=O)OCC(F)(F)C(F)F)cc2)nc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCc1cnc(-c2ccc(CCC(=O)OCC(F)(F)C(F)F)cc2)nc1

Procedure:
0.01 mol of 2,2,3,3-tetrafluoropropyl p-(5-heptyl-pyrimidin-2-yl)-cinnamate (for preparation see Example 21) are hydrogenated in THF with Pd/C in the known manner. Usual working-up gives 2,2,3,3-tetrafluoropropyl β-[p-(5-heptyl-pyrimidin-2-yl)-phenyl]-propionate of m.p. 42° and c.p. 54°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][CH:19]([CH3:23])[C:20](Cl)=[O:21]>>[CH3:18][CH:19]([CH3:23])[C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:21]
Reactant: CC(C)C(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CC(C)C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 756.6 %

Procedure:
Beginning with 0.35 gm (0.154 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.20 mL (0.193 mMol) 2-methylpropanoyl chloride, 0.35 gm (75%) of the title compound were prepared essentially by the procedure described in Example 8.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH2:3][OH:4].C(N(CC)CC)C.[F:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30](Cl)=O>O1CCCC1>[F:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30]1[O:4][CH2:3][CH:2]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[N:1]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NC(CO)COc1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1cccc(F)c1C1=NC(COc2ccc(Oc3ccccc3)cc2)CO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
To a mixture of 1.14 g (4.40 mmol. ) of 2-amino- 3-(4-phenoxyphenoxy)propanol, 0.58 g (5.72 mmol.) of triethylamine and 20 ml of anhydrous tetrahydrofuran, there was added dropwise a solution of 0.78 g (4.40 mmol.) of 2,6-difluorobenzoylchloride in 10 ml of anhydrous tetrahydrofuran with stirring at a temperature of from 5° C. to 10° C. for 5 minutes. After addition, the reaction mixture was stirred at room temperature for 2 hours. The above mixture was filtrated with a filter glass to remove the resultant precipitate and the filtrate was concentrated under reduced pressure. To the residue, there was added 20 ml of toluene and 10 ml of thionyl chloride and the reaction mixture was refluxed by heating with stirring for 5 hours. The reaction mixture was cooled;to room temperature and concentrated under reduced pressure. To the residue, there was added 20 ml of methanol and further added dropwise 1 ml of a 5N aqueous solution of sodium hydroxide with stirring at a temperature of 60° C. for 5 minutes. Then the reaction mixture was stirred at the same temperature for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue, there was added 100 ml of ethyl acetate. The mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 1.28 g of 2-(2,6-difluorophenyl)-4-[(4-phenoxyphenoxy)methyl]-2-oxazoline as a colorless oily substance (nD19.1 1.5814).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[NH:4][N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].[H][H]>[Pd].C(Cl)Cl.O>[O:8]([C:7]1[CH:6]=[N:5][NH:4][C:3](=[O:15])[CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=c1[nH]ncc(Oc2ccccc2)c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=c1cc(Oc2ccccc2)cn[nH]1
Reaction time: 24 h
Yield: 96.9 %

Procedure:
A pressure vial containing a mixture of 4-chloro-5-phenoxy-2H-pyridazin-3-one (1.76 g, 7.90 mmol), water (29.6 mL), and a 2N aqueous sodium hydroxide solution (4.26 mL) was treated with 10% palladium on carbon (174 mg, 10% weight of 4-chloro-5-phenoxy-2H-pyridazin-3-one). The reaction was then pressurized with hydrogen (50 psi), where it shook for 24 h. The resulting reaction mixture was diluted with methylene chloride (100 mL) and water (100 mL), filtered through a pad of diatomaceous earth, and rinsed. The layers were separated, and the organics were concentrated in vacuo. The aqueous layer was then acidified to pH 1-2 with a 2N aqueous hydrochloric acid solution. The resulting mixture was extracted with 90/10 methylene chloride/methanol (3×100 mL). These organics were combined, dried over sodium sulfate, filtered, rinsed, and concentrated in vacuo to afford 5-phenoxy-2H-pyridazin-3-one (1.44 g, 96%) as a white solid; ES+-HRMS m/e calcd for C10H8N2O2 [M+H+] 189.0659, found 189.0658.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32]N)[CH:27]=1>>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][N:19]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[CH:2]([CH3:1])[S:7][C:6](=[O:8])[NH:5][N:4]=4)[CH:10]=3)[NH:14][C:13]2=[O:18])[CH:27]=1
Reactant: NNc1cccnc1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=NNc1cccnc1)C(=O)N2
Yield: 64 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2-one, and 3-pyridylhydrazine and following the method described in Example 21, the desired compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)C(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:5]([C:6](=[O:7])[NH:8][CH3:9])=[CH:4][N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of 8.31 g (31.9 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide, 6.53 g (35.0 mmol) 1-tert-butoxycarbonyl piperazine, 16.7 ml (95.6 mmol) N-ethyldiisopropylamine and a catalytic amount of 4-(N,N-dimethylamino)-pyridine was heated at reflux over night. After cooling to room temperature the mixture was dissolved in dichloromethane and washed with two portions of 0.1 N aqueous hydrochloric acid solution. Drying with sodium sulfate and concentration gave 10.7 g of the crude product. Flash column chromatography afforded 6.28 g (48.0%) of the title compound as an off-white solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:14]=[C:13]3[C:9]([N:10]=[CH:11][N:12]3[CH:15]([CH3:17])[CH3:16])=[C:8](Cl)[N:7]=2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[CH:23]1[C:28]([OH:29])=[CH:27][C:26]2[C:30]([CH2:33][CH2:34][NH2:35])=[CH:31][NH:32][C:25]=2[CH:24]=1>>[S:1]1[CH:5]=[C:4]([C:6]2[N:14]=[C:13]3[C:9]([N:10]=[CH:11][N:12]3[CH:15]([CH3:17])[CH3:16])=[C:8]([NH:35][CH2:34][CH2:33][C:30]3[C:26]4[C:25](=[CH:24][CH:23]=[C:28]([OH:29])[CH:27]=4)[NH:32][CH:31]=3)[N:7]=2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: CC(C)n1cnc2c(Cl)nc(-c3csc4ccccc34)nc21
Product: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(O)cc34)nc(-c3csc4ccccc34)nc21

Procedure:
Following the procedure of Example 15e, 2-(benzo[b]thiophen-3-yl)-6-chloro-9-isopropyl-9H-purine (b) (80 mg, 0.243 mmol) was reacted with serotonin. The reaction mixture was concentrated, then aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate. The organic fractions were combined, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0 to 5% MeOH in DCM eluant) to afford the title compound as an off-white solid. MS m/z 469.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH:13]=O)[CH:3]=1.Cl.[NH2:16]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]#[N:16])[CH:3]=1
Reactant: O=Cc1sccc1-c1cc(Cl)ccn1
Reactant: NO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: N#Cc1sccc1-c1cc(Cl)ccn1
Temperature: 80 °C

Procedure:
A mixture of 3-(4-chloro-pyridin-2-yl)-thiophene-2-carbaldehyde (103 mg, 0.46 mmol) and hydroxylamine hydrochloride (70 mg, 1 mmol) in pyridine (1 mL) was heated at 80° C. for 30 minutes. Acetic anhydride (0.8 mL) was added and the resulting mixture was heated at the temperature for another 3 hours. Ice water was added, the water solution was extracted with EtOAc and organic layer was concentrated. The resulting residue was purified by silica gel column to yield 3-(4-chloro-pyridin-2-yl)-thiophene-2-carbonitrile.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[NH:12][CH2:13][CH2:14][C:3]=12.[H-].[Na+].Cl.[Cl:19][CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>CN(C)C=O.O>[ClH:19].[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[N:12]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)NCC2
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c2n(c3ccccc13)C(=O)N(Cc1ccncc1)CC2
Reaction time: 0.33 h

Procedure:
To a solution of 3,4-dihydro-5-methylpyrimido[1,6-a]indol-1(2H)-one (188 mg) in N,N-dimethylformamide (3 ml) was added sodium hydride (60% in mineral oil, 88 mg) at 5° C. The mixture was stirred at the same temperature for 20 minutes. A solution of 4-chloromethylpyridine hydrochloride in N,N-dimethylformamide (3 ml) was added dropwise at 5° C. over five minutes. The reaction mixture was stirred at the same temperature for 30 minutes and at room temperature for 3 hours. The reaction mixture was diluted with chilled water and extract two times with 5%-methanol-chloroform. The extract was washed twice with water, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was dissolved in 1N-hydrochloric acid (10 ml) and evaporated in vacuo. The residue was pulverized with acetone to give 3,4-dihydro-5-methyl-2-(4-pyridylmethyl)pyrimido[1,6-a]indol-1-(2H)-one hydrochloride (160 mg).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[C:23]([CH3:37])=[C:24]([C:28]3[C:29]([C:35]#[N:36])=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH:25]=[CH:26][CH:27]=2)OC1>>[F:34][C:31]1[CH:30]=[C:29]([C:35]#[N:36])[C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[C:23]=2[CH3:37])=[CH:33][CH:32]=1
Reactant: Cc1c(B2OCC(C)(C)CO2)cccc1-c1ccc(F)cc1C#N
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: Cc1c(-c2ccc(F)cc2C#N)cccc1-c1cnc2nc(C(F)(F)F)ccn12

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 3′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-4-fluoro-2′-methylbiphenyl-2-carbonitrile as described in Example 65 to give 4-fluoro-2′-methyl-3′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as a white solid: δH (360 MHz, CDCl3) 1.94 (3H, s), 7.26 (1H, d, J 7), 7.40-7.51 (6H, m), 8.08 (1H, s), 8.35 (1H, d, J 7); m/z (ES+) 397 (M++H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][C:9](=[O:18])[C:10]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:20]#[N:21].CN1CCCC1=O.N>S([O-])([O-])(=O)=O.[Cu+2].O>[C:20]([C:2]1[C:7]2[CH2:8][C:9](=[O:18])[C:10]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:21]
Reactant: O=C1Cc2c(Cl)cccc2Sc2ccc(F)cc21
Reactant: N#C[Cu]C#N
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc2c1CC(=O)c1cc(F)ccc1S2

Procedure:
The mixture of 3.4g of 9-chloro-2-fluoro-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin, 2.1g of copper cyanide, 0.2g of anhydrous copper sulfate and 50ml of N-methyl pyrrolidone was heated at 200°-210° C overnight. After cooling, to the reaction mixture were added 10ml of conc. aqueous ammonia and 100ml of water and the resulting mixture was extracted with benzene. The benzene layer thus obtained was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue was chromatographed over silica gel, and eluted with chloroform and benzene. There was obtained from benzene eluate 0.3g of 9-cyano-2-fluoro-10,11-dihydro-11 -oxo-dibenzo[b,f]thiepin as yellow needles having a melting point of 174°-175° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[NH2:16].[C:17](OCC)(OCC)(OCC)[CH2:18][CH3:19].Cl.N1C=CC=CC=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:17]1[CH2:18][CH3:19]
Reactant: Nc1cnc2ccccc2c1NCCCCl
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Product: CCc1nc2cnc3ccccc3c2n1CCCCl
Yield: 71.2 %

Procedure:
Using the general method of Example 1 Part D, N4-(3-chloropropyl)quinoline-3,4-diamine (˜37.6 mmol) was cyclized using triethyl orthopropionate (7.96 g, 45.2 mmol) in the presence of pyridine hydrochloride (0.43 g). The crude product was purified by chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 7.33 g of 1-(3-chloropropyl)-2-ethyl-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]2[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]3[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=2)=[CH:13][CH:12]=1
Reactant: COCCCN1C(=O)CCc2ccc(CCl)cc21
Reactant: COc1ccccc1OCCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.200 g of tert-butyl 3-hydroxy-4-{4-[4-(2-methoxyphenoxy)butoxy]phenyl}piperidine-1-carboxylate and 0.125 g of 7-chloromethyl-1-(3-methoxypropyl)-3,4-dihydro-1H-quinolin-2-one (Example 13b) are reacted. The title compound is obtained as a colourless oil. Rf=0.12 (1:1 EtOAc-heptane); Rt=5.86.
Reaction SMILES: C(=[N:14][C:15]1[C:23]2[O:22][CH:21]=[CH:20][C:19]=2[CH:18]=[C:17]([CH3:24])[CH:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[OH-].[Na+]>C1COCC1>[CH3:24][C:17]1[CH:16]=[C:15]([NH2:14])[C:23]2[O:22][CH:21]=[CH:20][C:19]=2[CH:18]=1
Reactant: Cc1cc(N=C(c2ccccc2)c2ccccc2)c2occc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(N)c2occc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2980.1 %

Procedure:
Benzhydrylidene(5-methylbenzofuran-7-yl)amine (17.9 g, 0.57 mmol) was dissolved in THF (150 ml). 5N Hydrochloric acid (50 ml) was added thereto, followed by stirring at room temperature for 2 hours. A 5N aqueous sodium hydroxide solution (40 ml) was added to the reaction mixture, followed by extraction using ethyl acetate. The extract was sequentially washed with an aqueous saturated sodium hydrogen solution and an aqueous saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified using silica gel column chromatography (n-hexane:ethyl acetate=50:1→10:1). The purified product was concentrated to dryness under reduced pressure, giving a dark brown oily substance of 5-methylbenzofuran-7-ylamine (2.5 g, yield: 30%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(=O)O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(C(=O)OCc2ccccc2)c1
Reaction time: 0.17 h
Yield: 8.4 %

Procedure:
To a solution of 3-acetylbenzoic acid (6.00 g, 0.36 mol) in DMF (36 mL) was added Na2CO3 (4.26 g, 0.40 mol) at 0° C. and the reaction stirred for 10 min. After 10 min, benzyl bromide (4.80 mL, 0.40 mol) was added and the reaction stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by combiflash chromatography (silica gel, 40 g, 2-5% ethyl acetate/hexanes) to afford the title compound (7.73 g, 84%) as a white solid.
Reaction SMILES: CO[N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]1[C:13]([F:16])([F:15])[F:14].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>C(OCC)C>[C:17]([NH:21][C:8]1[N:7]=[C:6]2[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[NH:3][C:11]2=[CH:10][C:9]=1[Cl:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: COn1c(C(F)(F)F)nc2ncc(Cl)cc21
Reactant: CC(C)(C)N
Solvent: CCOCC
Product: CC(C)(C)Nc1nc2nc(C(F)(F)F)[nH]c2cc1Cl
Reaction time: 192 h

Procedure:
1-Methoxy-6-chloro-2-(trifluoromethyl)-1H-imidazo [4,5-b] pyridine (2.0 grams) was mixed with tert-butylamine (5 milliliters) in 10 milliliters of diethyl ether. The reaction mixture was permitted to stand for eight days; then solvent was evaporated and the residue taken up in 8 milliliters of chloroform, permitted to stand for two hours, and filtered to separate the desired 5-tert-butylamino-6-chloro-2-(trifluoromethyl)-1H-imidazo [4,5-b] -pyridine, m.p., 252° -4° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:14](=[CH:15][N:16](CC4C=CC(OC)=CC=4)[N:17]=3)[CH:13]=[C:12](Br)[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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.C([SiH](C(C)C)C(C)C)(C)C>O1CCOCC1.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]>[C:1]1([NH:7][C:8]([C:10]2[CH:11]=[C:12]([NH:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][N:16]=[CH:15]3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(Cn2cc3cc(Br)cc(C(=O)Nc4ccccc4)c3n2)cc1
Reactant: Nc1ccncc1
Agent: [Pd]
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)c1cc(Nc2ccncc2)cc2cn[nH]c12
Temperature: 95 °C
Yield: 45.5 %

Procedure:
A mixture of 5-bromo-2-(4-methoxy-benzyl)-2H-indazole-7-carboxylic acid, phenylamide (prepared from preparation #12a using general procedures V and B, 75.0 mg, 0.20 mmol), 4-aminopyridine(24.0 mg, 0.25 mmol), cesium carbonate (195 mg, 0.60 mmol), and XANTPHOS (11.6 mg, 0.02 mmol) was suspended in 1,4-dioxane (2.5 mL) at ambient temperature under an inert atmosphere. Tris(dibenzylideneacetone)dipalladium(0) (9.2 mg, 0.01 mmol) was added and nitrogen gas was bubbled through the resulting suspension for about 5 minutes. The reaction mixture was heated at about 95° C. for about 2 hours. The resulting mixture was allowed to cool to ambient temperature and filtered through a celite pad and the solvent was removed under reduced pressure. The residue was dissolved in trifluoroacetic acid (4.0 mL) containing triisopropylsilane (51.0 uL, 0.25 mmol) and the mixture was heated at about 100° C. in a microwave reactor for about 15 minutes. Solvents were removed under reduced pressure and the residue was purified preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 35 cm; 5-100% acetonitrile/0.1 M ammonium acetate over 20 min, 100% acetonitrile hold 10 minutes, 21 mL/min) to afford N-phenyl-5-(pyridin-4-ylamino)-1H-indazole-7-carboxamide (30 mg, 46%) as an off-white solid, RP HPLC (Table 1, Method e) Rt=1.32; MS m/z: (MH)+ 330.