Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13]CC)=O)=[C:4]([CH3:17])[CH:3]=1.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>O.C(O)C>[CH2:18]([NH:22][C:11](=[O:13])[CH2:10][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:17])=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Reactant: CCCCN
Solvent: O
Solvent: CCO
Product: CCCCNC(=O)CC(=O)Nc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
A mixture of 4.90 grams (0.02 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate prepared in Example I (Compound No. 75), 358 grams (4.9 moles) of n-butylamine, 150 milliliters of ethanol and 5 drops of water was stirred at room temperature for about 16 hours. After this period, rotary evaporation gave a crude product as a white solid. The white solid was recrystallized from ethyl acetate-hexane to give 3.08 grams (0.009 mole) of N-butyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanamide having a melting point of 123° C.-125° C.
Reaction SMILES: [OH:1][C:2]1[CH:41]=[CH:40][C:5]2[CH:6]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH:18]=3)[CH:7]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1.C[OH:43].O>O1CCOCC1>[OH:1][C:2]1[CH:41]=[CH:40][C:5]2[CH:6]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([CH2:30][CH2:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:35])([F:36])[F:37])=[O:43])[CH:18]=3)[CH:7]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Oc1ccc(C2COc3cc(O)ccc3C2c2cccc(OCCCCCSCCCC(F)(F)C(F)(F)F)c2)cc1
Reactant: CO
Solvent: O
Solvent: C1COCCO1
Product: O=S(CCCCCOc1cccc(C2c3ccc(O)cc3OCC2c2ccc(O)cc2)c1)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
7-Hydroxy-3-(4-hydroxyphenyl)-4-[3-(5-(4,4,5,5,5-pentafluoropentylthio)pentyloxy)phenyl]-2,3-dihydro-4H-benzopyran (90 mg, 0.15 mmol) was dissolved in 1,4-dioxane (1.5 ml), methanol (1.5 ml) and water (0.38 ml), and NaIO4 (35.5 mg, 0.16 mmol) was added dropwise thereto. The reaction solution was stirred for 8 hours at room temperature and then filtered. The filtrate was concentrated and the residue was separated by column chromatography (n-hexane:ethyl acetate=1:1) to obtain 58 mg (yield: 63%, 3RS,4RS/3RS,4SR=1:1) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[N:22]=[C:23]1[N:27]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:26](=[O:36])[CH2:25][S:24]1>FC(F)(F)C(O)=O.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[N:22]=[C:23]1[N:27]([CH2:28][C:29]([OH:31])=[O:30])[C:26](=[O:36])[CH2:25][S:24]1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N=C3SCC(=O)N3CC(=O)OC(C)(C)C)c(Cl)cc2F)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N=C3SCC(=O)N3CC(=O)O)c(Cl)cc2F)c1=O
Temperature: 35 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A solution of tert-butyl 2-{{2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluorophenyl}imino}-4-oxo-3-thiazolidineacetate (41.93 g, 76.1 mmol) in trifluoroacetic acid is stirred at room temperature for 3 hours, stirred at 35° C. for 1 hour, and concentrated in vacuc to obtain a yellow liquid. A solution of the yellow liquid in diethyl ether is cooled and filtered to obtain a solid. The solid is washed with diethyl ether and air-dried to give the title product as a white solid (31.6 g) which is identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: C([O:8][C:9](=[O:42])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16](=[O:34])(=[O:33])[NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][C:24](=[O:32])[N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[O:21])[C:11]=1CC1C=CC=CC=1)C1C=CC=CC=1>C(OC(C)C)(=O)C.[Pd]>[CH2:29]([N:25]([CH2:26][CH2:27][CH3:28])[C:24]([CH2:23][O:22][C:20]([CH2:19][CH2:18][NH:17][S:16]([C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([OH:42])=[O:8])(=[O:34])=[O:33])=[O:21])=[O:32])[CH2:30][CH3:31]
Reactant: CCCN(CCC)C(=O)COC(=O)CCNS(=O)(=O)c1cccc(C(=O)OCc2ccccc2)c1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)OC(C)C
Product: CCCN(CCC)C(=O)COC(=O)CCNS(=O)(=O)c1cccc(C(=O)O)c1
Reaction time: 8 h

Procedure:
A solution of benzyl 3-(2-Dipropylcarbamoylmethoxycarbonyl-ethylsulfamoyl)-benzoic acid benzyl ester (5 g, 33.25 mmol) in isopropyl acetate (82 ml) was treated with 10% Pd/C (0.84 g, 50% wet), and stirred under H2 (3 atm) overnight. The catalyst was removed by filtration. To the filtrate was added 10% Pd/C (1.68 g, 50% wet), and the reaction stirred under H2 (3 atm) for 18 h. The catalyst was removed by filtration and further 10% Pd/C (1.68 g, 50% wet) was added and the reaction stirred under H2 (1 atm) for 18 h. The catalyst was removed by filtration and washed with isopropyl acetate (20 ml). The combined filtrates were concentrated in vacuo and heptane was added to the solution and stirred at RT for 2 hr then −2° C. for 4 h. The solid which formed was collected by filtration and dried under vacuum at 40° C. to afford the title compound; LC-MS; 415.1 [M+H]+, Method (i).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][C:10]([C:20](Cl)=[O:21])=[N:9]2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[N:28][CH:29]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][C:10]([C:20]([NH:23][C:24]3[CH:29]=[N:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[O:21])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1=NN(c2ccc(Cl)cc2)C(c2ccc(F)cc2)C1
Reactant: Nc1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)nc1)C1=NN(c2ccc(Cl)cc2)C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
A solution of 0.9 g of 1-(4-chlorophenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride in 10 mL of THF was added to a solution of 0.4 g of 5-amino-2-chloropyridine, 2.0 mL Of triethylamine and 10 mL of THF. The resulting suspension was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was triturated with 10 mL of methanol to afford 0.66 g of the title compound, mp 191°-193° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27])([CH3:24])([CH3:23])[CH3:22].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[N:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[C:21]([CH3:24])([CH3:23])[CH3:22])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1N
Reactant: Cc1ccc(C(=O)Nc2ccccc2C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=Nc2ccccc2C(C)(C)C)Nc2ccccc2C(C)(C)C)cc1
Reaction time: 1 h
Yield: 93.3 %

Procedure:
2-tert-butyl-N-(chloro(p-tolyl)methylene)benzenamine (HS Imine II) (2.86 g, 10 mmol) was dissolved in 50 mL of toluene. 2-tert-butylaniline (1.56 mL, 10 mmol) was added dropwise at room temperature, resulting in a yellow solution, which was refluxed overnight. Toluene was removed under vacuum. Sodium hydroxide (100 mL of 0.10 M solution, 10 mmol) was added and the solution was stirred for 1 hour. The solid that deposited was extracted into 150 mL of diethylether. The ether layer was dried with MgSO4, filtered, and taken to dryness, leaving 3.72 g (93%) of white solid. The 1H NMR spectrum is complex and is consistent with a mixture of E/Z isomers.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[C:14]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[C:14]([N:18]4[CH2:19][CH2:20][N:21]([CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=5)[CH2:22][CH2:23]4)=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2nc3cccc(N4CCNCC4)c3[nH]2)cc1
Reactant: O=[N+]([O-])c1cc(CBr)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(-c2nc3cccc(N4CCN(Cc5ccc(F)c([N+](=O)[O-])c5)CC4)c3[nH]2)cc1
Reaction time: 1 h
Yield: 33.8 %

Procedure:
2-(4-Ethyl-phenyl)-7-piperazin-1-yl-1H-benzoimidazole (200 mg, 0.65 mmol) and 4-bromomethyl-1-fluoro-2-nitro-benzene (152 mg, 0.65 mmol) were stirred together with DIEA (83 mg, 0.6.5 mmol) in DMF (4 ml) at room temperature. After 1 h, the reaction is complete and it was purified by HPLC Method E to yield the title product (100 mg (34%), 0.22 mmol). 1H NMR (DMSO-d6): δ=12.71 (s, 1H), 8.15 (m, 1H), 8.04 (d, J=8.2 Hz, 2H), 7.83 (m, 1H), 7.59 (m, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.08 (m, 2H), 6.52 (dd, J=6.64, 1.94 Hz, 1H), 3.69 (s, 2H), 3.65 (bs, 4H), 2.75 (bs, 6H), 1.32 (t, J=7.6 Hz, 3H). Calculated mass=457.43, [M+H]+=458.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:17][N:18]([CH3:34])[C:19](=[O:33])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29]Br)=[C:22]([O:31][CH3:32])[CH:21]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:34][N:18]([CH3:17])[C:19](=[O:33])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][N:12]2[CH2:11][CH2:10][CH:9]([C:6]3[C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH2:14][CH2:13]2)=[C:22]([O:31][CH3:32])[CH:21]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(=O)N(C)C)ccc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(=O)N(C)C)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.9 g, 17.7 mmol), N,N-dimethyl-4-bromopropoxy-3-methoxybenzamide (5.54 g, 17.5 mmol) and K2CO3 (3 g) in acetonitrile (250 ml) was heated at reflux for one hour. At the end of the reaction, the insolubles were filtered and washed with dichloromethane. The solvent was removed on a rotary evaporator. The residue was purified by flash chromatography over a silica gel column. The product thus obtained as an oil weighed 7 g. Crystallization from hot ethanol (45 ml) afforded analytically pure N,N-dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide, 3.95 g, 50%, as light yellow crystals, m.p.=126°-127° C.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[CH2:5][O:4][CH2:3]1.Br[CH2:9][CH:10]1[CH2:12][CH2:11]1.[H-].[Na+]>CN(C=O)C>[CH:10]1([CH2:9][O:1][C@H:2]2[C@@H:6]([OH:7])[CH2:5][O:4][CH2:3]2)[CH2:12][CH2:11]1
Reactant: O[C@@H]1COC[C@@H]1O
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O[C@H]1COC[C@H]1OCC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
To a stirred solution of cis-3,4-dihydroxytetrahydrofuran (5.8 g, 56 mmol) and bromomethylcyclopropane (5.0 g, 37 mmol) in DMF (100 mL) at 0° C. was added sodium hydride (1.6 g of a 60% suspension in mineral oil, 40 mmol) in portions over a period of 2 h. The resulting solution was stirred at 0° C. for 1 h and then at ambient temperature for 18 h. The solution was concentrated in vacuo and partitioned between EtOAc and water. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 1:1 EtOAc:hexanes as eluant to give the title compound as a colorless liquid (1.8 g; TLC Rf=0.4, 1:1 EtOAc:hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]([CH3:27])([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:11]3[CH:28]=[CH:29][N:30]=[C:10]23)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[I:31]N1C(=O)CCC1=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1.CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]([CH3:27])([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=3)[N:11]3[C:28]([I:31])=[CH:29][N:30]=[C:10]23)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2nccn21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(I)n21
Temperature: 25 °C
Reaction time: 17 h
Yield: 64.5 %

Procedure:
A solution of (R)-1-(3,5-dichloro-phenyl)-3-methyl-3-(4-trifluoromethoxy-benzyl)-1H-imidazo[1,2-a]imidazol-2-one (Example 1) (1.54 g, 3.38 mmol) in 30 mL of THF was treated with N-iodosuccinimide (0.846 g, 3.76 mmol) and pyridinium p-toluenesulfonate (0.086 g, 0.37 mmol). The mixture was stirred at room temperature for 17 h, then diluted with EtOAc and washed with 10% Na2S2O3 solution and water. The combined aqueous layers were extracted with 10 mL of EtOAc. The combined organic phases were washed with 25 mL of brine, dried over Na2SO4, filtered and concentrated. The crude orange oil was purified by silica gel chromatography to provide 1.27 g (65%) of (R)-1-(3,5-dichloro-phenyl)-5-iodo-3-methyl-3-(4-trifluoromethoxy-benzyl)-1H-imidazo[1,2-a]imidazol-2-one as an off-white oil (582.0, M+1).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:20])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18].[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:20][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[O:30])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]([CH3:18])[CH3:19]
Reactant: CN(C)CCOc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Br)cnn1C
Yield: 40 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-phenylamine (0.034 g, 0.10 mmol) was treated with 4-fluorophenyl isocyanate (0.015 g, 12.5 μL, 0.11 mmol, 1.1 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.47 to afford Compound 70 (0.020 g, 0.04 mmol, 42%). LCMS m/z (%)=476 (M+H79Br, 100), 478 (M+H81Br, 87). 1H NMR (400 MHz, acetone-d6) δ: 8.17 (s, 2H), 7.66 (dd, J=2.7, 9.0 Hz, 1H), 7.50-7.58 (m, 2H), 7.48 (s, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 7.04 (t, J=8.8 Hz, 2H), 3.98-4.20 (m, 2H), 3.73 (s, 3H), 2.49-2.66 (m, 2H), 2.16 (s, 6H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH3:26]>>[C:2]1([O:1][CH2:8][CH2:9][N:10]2[C:11]3[C:20]4[N:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:21]=[C:22]2[CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnc2cccnc2c1NCCOc1ccccc1
Reactant: CCCCC(=O)Cl
Product: CCCCc1nc2cnc3cccnc3c2n1CCOc1ccccc1
Yield: 73.5 %

Procedure:
Using the general method of Example 73 Part A and Part B, N4-(2-phenoxyethyl)[1,5]naphthyridine-3,4-diamine (4.4 g, 15.7 mmol) was reacted with valeryl chloride (1.95 mL, 16.4 mmol) and the resulting amide intermediate was cyclized to provide 4.0 g of 2-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl phenyl ether as a white solid, m.p. 150-150.5° C. Analysis: Calculated for C21H22N4O: % C, 72.81; % H, 6.40; % N, 16.17; Found: % C, 72.78; % H, 6.40; % N, 16.31. 1H NMR (300 MHz, DMSO): δ 9.25 (s, 1H), 9.00 (dd, J=4.3, 1.7 Hz, 1H), 8.52 (dd, J=8.4, 1.7 Hz, 1H), 7.74 (dd, J=8.4, 4.3 Hz, 1H), 7.25-7.20 (m, 2H), 6.91-6.84 (m, 3H), 5.22 (t, J=5.2 Hz, 2H), 4.53 (t, J=5.2 Hz, 2H), 3.09 (t, J=7.7 Hz, 2H), 1.91 (pentet, J=7.6 Hz, 2H), 1.55-1.43 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); MS (EI): m/e 346.1794 (346.1793 calc'd for C21H22N4O).
Reaction SMILES: O.NN.[N+:4]([C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)([O-])=O>[Ni].CO>[NH2:4][C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1cccc2ccoc12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cccc2ccoc12
Temperature: 55 °C
Yield: 98 %

Procedure:
Hydrazine hydrate (0.45 ml) was added dropwise to a stirred mixture of 7-nitrobenzofuran (J. Med. Chem., 1988, 31, 1934; 0.5 g), Raney nickel (0.02 g) and methanol (9 ml) that had been warmed to 55° C. The resultant mixture was heated to reflux for 30 minutes. The catalyst was removed by filtration and the filtrate was evaporated. The residue was partitioned between methylene chloride and water. The organic phase was dried over magnesium sulphate and evaporated to give 7-aminobenzofuran (0.4 g) as an oil; NMR Spectrum: (DMSOd6) 5.25 (br s, 2H), 6.55 (d, 1H), 6.8 (m, 2H), 6.9 (t, 1H), 7.85 (d, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:16]([C:17]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])=[CH:23][CH:22]=4)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:33][N:34](C)C=O.C(Cl)(=O)C(Cl)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:32])([C:28](=[O:29])[NH:34][CH3:33])[CH3:31])=[CH:23][CH:22]=3)=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: CC(C)(C(=O)O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)C(C)(C)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)cc1

Procedure:
2-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-2-methyl-propionic acid (1.00 g) was suspended in anhydrous dichloromethane (20 mL). Anhydrous dimethylformamide (0.02 mL) was added to the suspension, followed by oxalyl chloride (0.391 mL). A 5 mL portion of this 1.15 M solution was transferred to a flame-dried, nitrogen purged round bottom flask. Anhydrous monomethyl amine gas was bubbled in for 5-10 min. The resulting white precipitate was washed with hot dichloromethane, and further purified by silica gel chromatography (ethyl acetate) to yield the title compound (0.127 g).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5]=[C:6]([C:11]([CH:13]([O:16][CH3:17])[O:14][CH3:15])=O)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[NH2:22]/[C:23](/[CH3:31])=[CH:24]\[C:25]([O:27]C(C)C)=[O:26]>C(OCC)(=O)C>[C:1]([C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:11]([CH:13]([O:16][CH3:17])[O:14][CH3:15])[NH:22][C:23]([CH3:31])=[C:24]1[C:25]([OH:27])=[O:26])#[N:2]
Reactant: COC(=O)C(=Cc1ccccc1C#N)C(=O)C(OC)OC
Reactant: C/C(N)=C/C(=O)OC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C(OC)OC)NC(C)=C(C(=O)O)C1c1ccccc1C#N
Temperature: 120 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A mixture of methyl 2-(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (10.1 g) and isopropyl 3-aminocrotonate (5.51 g) was heated for 40 minutes at 78° C. and for 5.5 hours at 120° C. with stirring, followed by heating for an hour at 125° C. without the stirring. After the reaction mixture was allowed to stand overnight, it was dissolved in ethyl acetate. This solution was washed twice with water, dried and then evaporated to dryness under reduced pressure to give a residue, which was crystallized from ethyl ether. The crystals were collected by filtration and washed with a small amount of ethyl ether to give crude powder of isopropyl ester of 4-(2-cyanophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid (8.96 g). Further, the crude product (0.77 g) was recovered from the filtrate. 0.5 g Of this crude product was recrystallized from isopropyl ether to give purified white powder of the same product (0.37 g), mp 171°-172.5° C.
Reaction SMILES: CS([C:5]1[N:6]=[N:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:10]=1)(=O)=O.[OH-:23].[K+].Cl>O.C1COCC1>[C:17]1([C:8]2[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:10][C:5](=[O:23])[NH:6][N:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccccc2)c(-c2cccnc2)n1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1nc(-c2cccnc2)c(-c2ccccc2)n[nH]1
Yield: 92.8 %

Procedure:
To a solution of 3-(methylsulfonyl)-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazine (0.035 g, 0.112 mmol) in a 1:1 mixture of H2O/THF (1.5 mL) was added potassium hydroxide (0.037 g, 0.560 mmol). The reaction was heated at reflux for 2 h. Upon completion, the reaction mixture was cooled to room temperature and neutralized with 1 M HCl, then extracted with EtOAc. The combined organic layers were washed with H2O, brine, dried over MgSO4 and concentrated to give the title compound as a yellow solid (0.026 g) without further purification. LCMS m/z=251.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:16])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH:11]([CH3:15])[CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21].CCN(CC)CC>COCCOC>[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH:21][C:2]1[N:3]=[N+:4]([O-:16])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH:11]([CH3:15])[CH2:12]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)CCN
Reactant: CC1Cc2cc3nc(Cl)n[n+]([O-])c3cc2C1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC1Cc2cc3nc(NCCN(C)C)n[n+]([O-])c3cc2C1
Yield: 150.4 %

Procedure:
A solution of chloride 95 (240 mg, 0.9 mmol), N1,N1-dimethyl-1,2-ethanediamine (0.26 mL, 2.4 mmol) and Et3N (0.33 mL, 2.4 mmol) in DME (50 mL) was stirred at reflux temperature for 4 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 96 (389 mg, 86%) as a yellow solid: mp (MeOH/EtOAc) 119-121° C.; 1H NMR δ 8.03 (s, 1H, H-9), 7.35 (s, 1H, H-5), 5.82 (br s, 1H, NH), 3.52-3.58 (m, 2H, CH2N), 3.07-3.17 (m, 2H, CH2), 2.55-2.67 (m, 5H, CH, CH2, CH2N), 2.28 [s, 6H, N(CH3)2], 1.15 (d, J=6.1 Hz, 3H, CH3); 13C NMR δ 158.7, 154.2, 148.9, 142.9, 129.8, 120.7, 114.8, 57.6, 45.1 (2), 41.2, 40.4, 38.7, 34.9, 20.2. Anal. calcd for C15H21N5O: C, 62.7; H, 7.4; N, 24.4. Found: C, 62.4; H, 7.1; N, 24.1%.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[C:7]([CH3:17])([CH3:16])[CH2:6]1)=[O:4].[CH3:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C>C(#N)C>[C:28]([O:27][C:25]([N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=3)[C:7]([CH3:17])([CH3:16])[CH2:6]2)=[O:4])[CH2:24][C@H:19]1[CH3:18])=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC1(C)CN(C(=O)CCl)c2cc(C#N)ccc21
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(C#N)cc32)CCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 175.7 %

Procedure:
To a solution of 1-(2-chloroacetyl)-3,3-dimethylindoline-6-carbonitrile (0.10 g, 0.40 mmol) and (R)-tert-butyl 2-methylpiperazine-1-carboxylate (0.088 g, 0.41 mmol) in acetonitrile (1.5 mL) was added triethylamine (0.083 mL, 0.6 mmol). The reaction mixture was heated at 50° C. for 3 h. The reaction mixture was then cooled and concentrated. The reaction was repeated on a 0.6 mmol scale and the combined crude material was purified by flash column chromatography, eluting with 20% EtOAc in heptane, to give the title compound (0.29 g) [M+H]+=413.