Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[C:8]([CH3:14])=[C:7]([CH3:15])[C:6]=1[O:16][CH3:17])[OH:4].O=[C:19]([CH3:55])[CH2:20][O:21][C:22]1[CH:54]=[CH:53][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[N:29](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:28]2=[O:52])=[CH:24][CH:23]=1.O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH3:17][O:16][C:6]1[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]([O:12][CH3:13])=[C:10]([CH3:11])[C:5]=1[CH:3]([OH:4])[CH2:2][NH:1][CH:19]([CH3:55])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[NH:29][C:28]2=[O:52])=[CH:53][CH:54]=1
Reactant: CC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Reactant: COc1c(C)c(C)c(OC)c(C(O)CN)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C(O)CNC(C)COc2ccc(CC3SC(=O)NC3=O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
A solution of 1.23 g of 2-amino-1-(2,5-dimethoxy-3,4,6-trimethylphenyl)ethanol [prepared as described in Preparation 14] and 3.0 g of 5-[4-(2-oxopropoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in Preparation 20] in 300 ml of benzene was heated under reflux for approximately 4 hours, during which time the water produced throughout the reaction was eliminated as a benzene azeotrope. The reaction mixture was then freed from benzene by distillation under reduced pressure. The residue was dissolved in a mixture of 100 ml of absolute methanol and 100 ml of absolute ethanol, after which 8.5 g of sodium borohydride were added to the solution. The resulting mixture was then heated under reflux for one hour. At the end of this time, the reaction mixture was freed from the alcohol by distillation under reduced pressure. The residue was then mixed with water and then it was extracted with ethyl acetate. The ethyl acetate layer was then washed twice with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, and 50 ml of trifluoroacetic acid were then added to the residue, whilst ice-cooling. The resulting mixture was then stirred at room temperature for one hour. At the end of this time, the trifluoroacetic acid was distilled off under reduced pressure and the residue was mixed with water. The aqueous mixture thus obtained was then neutralized with an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed twice with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, after which the residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 160 mg of the title compound, having an Rf=0.3 (thin layer chromatography on silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:20])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[NH2:21][C:22]1[C:23]2[C:31](=[O:32])[CH:30]=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:21][C:22]1[C:23]2[C:31](=[O:32])[CH:30]=[CH:29][N:28]([CH:2]([C:4]3[O:5][C:6](=[O:20])[C:7]4[C:12]([C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[C:24]=2[N:25]=[CH:26][N:27]=1
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1ccc(=O)c2c(N)ncnc21
Yield: 52 %

Procedure:
3-(1-Bromoethyl)-4-phenyl-1H-isochromen-1-one (intermediate C7, 50 mg, 0.15 mmol), 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (37 mg, 0.23 mmol), potassium carbonate (31.5 mg, 0.23 mmol) were reacted in DMF (0.5 ml) at 80° C. The crude was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (32 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1/[CH:4]=[C:20](/[N+:17]([O-:19])=[O:18])\[CH3:21]
Reactant: O=Cc1c(Cl)cc(Cl)cc1Cl
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: C/C(=C\c1c(Cl)cc(Cl)cc1Cl)[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 62.1 %

Procedure:
To a stirred solution of 2,4,6-trichloro-benzaldehyde (19 g, 90.69 mmol) and ammonium acetate (16.75 g, 217 mmol) in acetic acid (76 ml, 4 Vol.), nitroethane (45.1 ml, 625 mmol) was added in drops at a temperature of 0° C. The reaction mass was stirred at a temperature of 100° C. for 90 minutes. When the TLC confirmed the completion of the reaction, the reaction mass was allowed to attain ambient temperature and was diluted with ice cold water (700 ml), further aqueous layer was then extracted with ethyl acetate (3×50 ml). Combined ethyl acetate layer was washed with saturated sodium bicarbonate solution to neutral pH, then with water, followed by brine wash and dried under anhydrous Na2SO4 before the complete evaporation of solvents. The resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 1% ethyl acetate in hexane as elution system to give 1,3,5-trichloro-2-((E)-2-nitro-propenyl)-benzene (15 g, 61%)
Reaction SMILES: [O:1]1C=C[CH:3]=[C:2]1B(O)O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([CH2:31][OH:32])[CH:17]=2)=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([C:31]([O:1][CH2:2][CH3:3])=[O:32])[CH:17]=2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccco1
Product: CCOC(=O)c1cc(-c2ccc(Br)cc2)n(-c2ccc(S(C)(=O)=O)cc2)n1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2-furanboronic acid instead of 2-thiophenboronic acid acid and 4-[5-[4-Bromophenyl]-3-hydroxymethy-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole instead of 1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole in step 2.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.Cl[CH:20]([CH3:28])[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][O:24]1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH:20]([CH3:28])[C:21]([N:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[O:22])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CC(Cl)C(=O)N1CCCO1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)N1CCCO1
Reaction time: 5 h
Yield: 92.6 %

Procedure:
A mixture of 4-(5-trifluoromethyl-2-pyridyloxy)phenol (25.6 g), N-[(±)-2-chloropropionyl]isoxazolidine (16.4 g) which was prepared as in Example 1, anhydrous potassium carbonate (15.2 g) and acetonitrile (300 ml) was heated under reflux with stirring for 5 hours. After cooling, the reaction mixture was filtered through a suction filter to remove solid matters and the filtrate was concentrated in vacuo. The residue was washed with the addition of water and benzene and the organic layer formed was separated and dried over anhydrous sodium sulfate. The removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionyl]isoxazolidine (35.5 g) as a pale yellow crystalline solid. Recrystallization from a mixture of n-hexane/ethyl acetate yielded a white crystalline solid. m.p. 83°-85° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)[N:3]=1.[CH2:26]([O:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH3:27]>CS(C)=O>[CH2:26]([O:28][CH2:29][CH2:30][CH2:31][NH:32][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)[N:3]=1)[CH3:27]
Reactant: Cc1cc(Cl)nc(-c2nn(Cc3ccccc3F)c3ncccc23)n1
Reactant: CCOCCCN
Solvent: CS(C)=O
Product: CCOCCCNc1cc(C)nc(-c2nn(Cc3ccccc3F)c3ncccc23)n1
Temperature: 60 °C

Procedure:
35 mg (0.10 mmol) of 3-(4-chloro-6-methyl-2-pyrimidinyl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (example I, step 7) and 52 mg (0.50 mmol) of 3-(ethyloxy)-propylamine are dissolved in 0.40 ml of DMSO and heated at 60° C. for 48 hours. The reaction mixture is diluted with 0.20 ml of DMSO and then purified by preparative
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][C:6]1[N:7]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1.[CH:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH2:25].O>O1CCCC1>[CH3:3][O:4][CH2:5][C:6]1[N:7]([CH2:19][C:20]([CH3:23])([O:22][CH2:25][CH2:24][S:26]([CH3:29])(=[O:28])=[O:27])[CH3:21])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1
Reactant: COCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Reactant: C=CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1nc2cnc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 59 mg, 1.47 mmol) was added to a stirred solution of 1-[2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (4.20 g, 14.7 mmol) in tetrahydrofuran (59 mL). After 5 minutes, methyl vinyl sulfone (3.10 g, 29.4 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 17 hours. Water (5 mL) was added and the mixture was concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 3.7 g of 2-(methoxymethyl)-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.C[C@H]1CNC[C@@H](C)N1>CC(CC(C)=O)C>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: C[C@@H]1CNC[C@H](C)N1
Solvent: CC(=O)CC(C)C
Product: c1ccc2cnncc2c1
Reaction time: 8 h

Procedure:
1,4-dichlorophthalazine (1.6 g, 8 mmol) was slurried in 80 mL of MIBK and 2,6 cis-dimethyl piperazine (3.6 g, 32 mmol, 4 eq) was added. The reaction was stirred overnight and the solvent was removed in vacuo. The crude material was dissolved in 200 mL of CH2Cl2 and washed with 1×30 mL of a 1:1 mixture of H2O and sat. sodium bicarbonate and 1×30 mL of sat. NaCl solution. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (100:5:1 dichloromethane:methanol:triethylamine) afforded 1.6 g (72%) of 1-chloro-4-(cis)-3,5-dimethylpiperazin-1-yl)phthalazine. MS (M+H)+=277.1.
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:6]2[C:11]([C:12]=1[C:13](O)=[O:14])=[CH:10][CH:9]=[C:8]([O:16][CH3:17])[CH:7]=2)([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH2:32][NH2:33])[CH:29]=[N:30][CH:31]=1>>[F:25][C:26]1[CH:27]=[C:28]([CH2:32][NH:33][C:13]([C:12]2[C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=3)[N:5]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:4]=2[CH:1]([CH3:2])[CH3:3])=[O:14])[CH:29]=[N:30][CH:31]=1
Reactant: NCc1cncc(F)c1
Reactant: COc1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Product: COc1ccc2c(C(=O)NCc3cncc(F)c3)c(C(C)C)n(Cc3ccccn3)c2c1

Procedure:
The title compound was prepared from 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139) and (5-fluoropyridin-3-yl)methanamine (Compound 145) by General Procedure C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:31])=[C:8]2[C:15]([C:16]#[N:17])=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:32][Sn](C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:31])=[C:8]2[C:15]([C:16]#[N:17])=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]2=[C:10]([CH3:32])[N:11]=1)=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(C)c2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1

Procedure:
Prepared in analogy to that of Example 103(b) from 7-bromo-3-cyano-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, tetramethyl tin, and Pd(PPh3)2Cl2. The title compound, ESI MS (m/z): 416 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:26])[C:8]([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].[NH4+].[Cl-]>CCO.C(Cl)Cl.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:26])[C:8]([CH:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]2[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1c(C)cc2ccc(Cl)cc2c1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(O)c1c(C)cc2ccc(Cl)cc2c1-c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 107.4 %

Procedure:
A solution of ethyl 2-(7-chloro-1-(4-chlorophenyl)-3-methyl-naphthalen-2-yl)-2-oxoacetate (26 mg, 67 μmol) in EtOH (absolute, 1.0 mL) and DCM (1.0 mL) was treated with NaBH4 (5.1 mg, 0.134 mmol) at 23° C. After 1 h, saturated NH4Cl (1.0 mL) was added. The reaction was stirred overnight, then diluted with H2O (10 mL). The mixture was extracted with DCM (3×), and the combined organics dried (Na2SO4), filtered, and concentrated, giving the title compound (28 mg, >99% yield). 1H-NMR: (400 MHz, CDCl3): δ 7.72 (d, J=8.6 Hz, 1H), 7.65 (s, 1H), 7.51-7.22 (m, 6H), 5.19 (s, 1H), 4.35-4.17 (m, 2H), 2.49 (s, 3H), 1.20 (t, J=7.0 Hz, 3H).
Reaction SMILES: S(=O)(=O)(O)O.O.[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=O)[C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][CH:17]=[CH:16][N:15]=3>[Pd].CO>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[C@@H:19]([C:20]=2[CH:21]=1)[CH2:18][CH2:17][CH2:16][NH:15]3
Reactant: COc1ccc2c(c1)-c1cccnc1C2=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)[C@H]1CCCN[C@H]1C2
Temperature: 60 °C

Procedure:
A mixture of sulfuric acid (98%, 6 kg), water (6 L), and methanol (6 L) is added to an autoclave charged with 6-methoxy-indeno[2,1-b]pyridin-9-one (1.2 kg) and wet 10% palladium on carbon (50%, 0.48 kg). The autoclave is purged with nitrogen and filled then with hydrogen (100 psi). The mixture is heated to 60° C. and maintained at this temperature and hydrogen pressure until the starting material is completely consumed (2-12 h). The mixture is cooled to 50-55° C. and filtered over Celite. The Celite is washed with a warm 1:1 mixture of water and methanol sevaral times (total 20 L). The combined filtrate is added to an autoclave charged with wet 10% palladium on carbon (50%, 0.96 kg). The autoclave is purged with nitrogen and filled then with hydrogen (100 psi). The mixture is heated to 60° C. and maintained at this temperature and hydrogen pressure until the intermediate is completely consumed (12-24 h). The mixture is cooled to ambient temperature and filtered over Celite. The Celite is washed with a mixture of methanol and water (5 L/5 L). The combined filtrate is cooled to 0-10° C. and the pH value is adjusted to 10-11 using 30% aqueous NaOH solution while maintaining the solution temperature below 40° C. Water (10 L) is added and the resulting mixture is extracted with dichloromethane (2×5 L). The combined extract is washed with 10% aqueous NaCl solution and concentrated. The residue is taken up twice in methyl ethyl ketone and concentrated again to give the crude title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[Cl:32])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][NH:38][CH3:39]>>[Cl:32][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:21]=2)=[O:19])=[CH:16][C:11]=1[NH:10][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:38]([CH2:37][CH2:36][CH2:35][N:34]([CH3:40])[CH3:33])[CH3:39])[CH:7]=1)=[O:9]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(N2CCOCC2)c1
Reactant: CNCCCN(C)C
Product: CN(C)CCCN(C)c1cc(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2Cl)ccn1
Yield: 46 %

Procedure:
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give the title compound in 46% yield; NMR Spectrum: (DMSOd6) 1.67 (m, 2H), 2.11 (s, 6H), 2.21 (m, 2H), 3.04 (s, 3H), 3.51 (m, 6H), 3.71 (m, 4H), 6.97 (d, 1H), 7.09 (m, 2H), 7.23 (s, 1H), 7.54 (d, 1H), 7.71 (d, 1H), 8.04 (s, 1H), 8.20 (d, 1H), 8.27 (d, 1H), 10.13 (s, 1H), 10.47 (s, 1H); Mass Spectrum: M+H+ 552.
Reaction SMILES: Br[C:2]#[N:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])=[CH:7][CH:6]=1>CO.O>[NH2:3][C:2]1[O:13][C:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=2)=[N:14][N:15]=1
Reactant: NNC(=O)Cc1ccc(O)cc1
Reactant: N#CBr
Solvent: CO
Solvent: O
Product: Nc1nnc(Cc2ccc(O)cc2)o1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Solid BrCN 6.059 g (57.2 mmol) was added in one portion into ice-cooled slurry of (4-hydroxy-phenyl)-acetic acid hydrazide 8.642 g (52.0 mmol) and KHCO3 6.510 g (65 mmol) in MeOH (100 mL). The mixture was stirred at 0-5° C. for 1 hour, the ice bath allowed to melt and stirred at room temperature overnight (18 hr). The reaction mixture was diluted with water (100 mL), stirred for 1 hour, the precipitate was collected by filtration, washed with water and dried on high vacuum. A second fraction precipitated after concentrating and cooling the supernatants.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][C:23]=1[CH:24]=O.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:24]([C:23]3[CH:26]=[CH:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:29][C:22]=3[CH3:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: Cc1cc(N2CCOCC2)ccc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1cc(N2CCOCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Br)cnc2[nH]1
Yield: 31.5 %

Procedure:
In a similar fashion to compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100.00 mg, 0.29568 mmol), 2-Methyl-4-morpholin-4-yl-benzaldehyde (66.8 mg, 0.325 mmol), and Ammonium acetate (45.6 mg, 0.591 mmol) were reacted to yield 48.7 mg (32%) of the title compound. (300 MHz, DMSO-d6) 12.85 (s, 1H), 8.00 (s, 1H), 7.71 (m, 2H), 7.19 (s, 1H), 6.92 (m, 2H), 6.34 (s, 1H), 6.26 (s, 1H), 5.30 (t, J=17 Hz, 8. Hz, 1H), 3.75 (s, 4H), 3.22 (s, 4H), 2.85 (s, 1H), 2.73 (s, 1H), 2.65 (s, 3H), 2.59 (d, J=8 Hz, 1H) 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=525 (M+H), HPLC: 2.43 min. (G Method)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][CH3:15])[CH2:6]2.[CH3:16][O:17][C:18]1[C:33]([O:34][CH3:35])=[CH:32][C:21]2[CH2:22][C:23](=[O:31])[N:24]([CH2:27][CH2:28][CH:29]=O)[CH2:25][CH2:26][C:20]=2[CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:15])[CH2:29][CH2:28][CH2:27][N:24]1[C:23](=[O:31])[CH2:22][C:21]3[CH:32]=[C:33]([O:34][CH3:35])[C:18]([O:17][CH3:16])=[CH:19][C:20]=3[CH2:26][CH2:25]1)[CH2:6]2
Reactant: CNC[C@H]1Cc2cc(OC)c(OC)cc21
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCC=O)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Temperature: 85 °C
Reaction time: 1 h

Procedure:
1 mmol of [(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine and 1 mmol of 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)propanal are introduced into a clean and dry stainless-steel autoclave under an argon atmosphere. The mixture is degassed by three vacuum/argon cycles and 3 mL of distilled and degassed ethanol are added. The solution is stirred at 85° C. for one hour. The iron complex (5 mol %) is added under argon. The autoclave is then placed under hydrogen pressure (5 bars) and the reaction mixture is stirred at 85° C. for 16 hours and then the autoclave is returned to ambient temperature and decompressed.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Product: CC(F)(F)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1.Cl.O.[NH:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.Cl>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:7]2[NH:10][C:21]3[CH2:22][CH2:23][NH:18][CH2:19][C:20]=3[C:8]=2[CH:9]=1
Reactant: COc1ccc(NN)c(C(F)(F)F)c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: COc1cc(C(F)(F)F)c2[nH]c3c(c2c1)CNCC3
Yield: 41.8 %

Procedure:
A microwave-compatible seal tube was charged with (4-methoxy-2-trifluoromethyl-phenyl)-hydrazine hydrochloride (406 mg, 1.7 mmol), 4-piperidone monohydrate hydrochloride (268 mg, 1.7 mmol), and 2-PrOH (4 mL). The reaction mixture was saturated with HCl gas and the tube was sealed. The reaction mixture was subjected to microwave irradiation at 120° C. for 12 min. The solids were filtered, washed with ether and treated with sat. NaHCO3 (10 mL). The basic solution was extracted with EtOAc (2×25 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by column chromatography [silica gel, 5–75% (80:18:2 CHCl3/MeOH/concd NH4OH)/CH2Cl2] provided 8-methoxy-6-trifluoromethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (192 mg, in 42%) as an off-white solid: mp 140–144° C.; 1H NMR (300 MHz, CD3OD) δ 7.10 (d, J=2.0 Hz, 1H), 6.93 (d, J=2.1 Hz, 1H), 3.97 (s, 2H), 3.83 (s, 3H), 3.16 (t, J=5.8 Hz, 2H), 2.87 (t, J=5.7 Hz, 2H); 19F NMR (282 MHz, CD3OD) δ −61.0; ESI MS 271 [C13H13F3N2O+H]+.