Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][CH2:13][O:14][CH3:15])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C)C=O>[C:4]([C:3]1[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][O:14][CH3:15])[CH:8]=[CH:9][C:2]=1[O:1][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:5]
Reactant: CCOC(=O)CBr
Reactant: COCOCCc1ccc(O)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(CCOCOC)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-hydroxy-5-(2-methoxymethoxyethyl)benzonitrile (496 mg) in N,N-dimethylformamide (5 ml) were added potassium carbonate (435 mg) and ethyl bromoacetate (292 μl), and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, and removal of the solvent under reduced pressure gave ethyl 2-[2-cyano-4-(2-methoxymethoxyethyl)phenoxy]acetate (619 mg). To a solution of the obtained ethyl 2-[2-cyano-4-(2-methoxymethoxyethyl)phenoxy]acetate (522 mg) in ethanol (5 ml) was added concentrated hydrochloric acid (20 μl), and the mixture was stirred for 2 hours at 70° C. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, and removal of the solvent under reduced pressure gave ethyl 2-[2-cyano-4-(2-hydroxyethyl)phenoxy]acetate (449 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[C:28](Cl)=[O:29].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][NH:18][C:28]([C:20]3[O:19][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH:21]=3)=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2(CN)CCCCC2)cc1OC
Reactant: O=C(Cl)c1cc2ccccc2o1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CNC(=O)c3cc4ccccc4o3)CCCCC2)cc1OC
Yield: 44.3 %

Procedure:
C-[1-(3,4-Dimethoxy-phenyl)-cyclohexyl]-methylamine (276 mg, 1.12 mmol) and Benzofuran-2-carbonyl chloride (223 mg, 1.23 mmol) were dissolved in 6 mL of 1,4-dioxane containing triethylamine (312 μL, 2.24 mmol) at 0° C. The reaction mixture was evaporated to dryness, redissolved in dichloromethane, and extracted with 1M hydrochloric acid, 1M sodium hydroxide, and a saturated aqueous solution of sodium chloride. The organic layer dried over sodium sulfate and evaporated to dryness. The crude product was then purified by column chromatography on silica gel using a gradient of 0-20% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (195 mg, 0.496 mmol, 44.2%). ESI-MS m/z calc. 393.2, found 394.2 (M+1)+. Retention time of 2.96 minutes. 1H NMR (400 MHz, CD3CN) δ 1.45-2.20 (m, 10H), 3.48 (d, J=6.5 Hz, 2H), 3.80 (s, 3H), 3.83 (s, 3H), 6.68 (s, 1H), 6.92-7.02 (m, 3H), 7.30-7.38 (m, 2H), 7.42-7.49 (m, 1H), 7.51-7.55 (m, 1H), 7.72 (d, J=7.8 Hz, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].CC([O-])=O.[Na+]>C(OC(=O)C)(=O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11](=[O:17])[CH2:12][CH2:13][C:14]2=[O:16])=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2]
Reactant: O=C(O)CCC(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1CCC(=O)N1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 38.6 %

Procedure:
A solution of 4-(4-nitro-3-(trifluoromethyl)phenylamino)-4-oxobutanoic acid (1.1 g, 3.6 mmol) and NaOAc (1.62 g, 19.75 mmol) in acetic anhydride (15 mL) was stirred overnight at 80° C. The reaction mixture was diluted with water and extracted twice with dichloromethane. The organic layers were combined and washed with NaOH (1 N) until pH was 9. The organic layer was separated, dried with MgSO4, filtered and concentrated in vacuo to provide 1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine-2,5-dione (0.4 g, 39%). LC/MS: m/z 288.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[C:19]1[C:28]2[C:23](=[C:24]([Cl:30])[CH:25]=[C:26]([CH3:29])[CH:27]=2)[N:22]=[C:21]([CH3:31])[C:20]=1[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[C:28]2[C:23]=1[N:22]=[C:21]([CH3:31])[C:20]([CH3:32])=[C:19]2[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:6]=2)[C:2]([CH3:17])([CH3:1])[CH2:3]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Reactant: Cc1cc(Cl)c2nc(C)c(C)c(Cl)c2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(Cl)c2nc(C)c(C)c(N3CC(C)(C)c4ccc(N5CCOCC5)cc43)c2c1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A dry, microwave vial containing 4-(3,3-dimethylindolin-6-yl)morpholine (150.7 mg, 0.65 mmol), 4,8-dichloro-2,3,6-trimethylquinoline (233.8 mg, 0.97 mmol), cesium carbonate (317.0 mg, 0.97 mmol), Pd2(dba)3 (119 mg, 0.13 mmol), rac-BINAP (81.6 mg, 0.13 mmol), and dry 1,4-dioxane (2.2 mL) was evacuated and backfilled with argon. The mixture was heated in the microwave at 140° C. After 2 h, the reaction was filtered then concentrated under reduced pressure. The residue was purified on silica gel (0-100% EtOAc in hexane) to afford an impure film that was triturated with isopropanol to afford 8-chloro-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-2,3,6-trimethylquinoline. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.71 (1H, d, J=1.5 Hz), 7.52 (1H, s), 7.03 (1H, d, J=8.1 Hz), 6.23 (1H, s), 5.44 (1H, s), 3.72 (1H, d, J=9.0 Hz), 3.59 (4H, m), 3.53 (1H, s), 3.33 (2H, s), 2.83 (4H, s), 2.69 (3H, s), 2.40 (3H, s), 2.18 (3H, s), 1.44 (3H, s), 1.39 (3H, s). Mass Spectrum (ESI) m/e=436.1 (M+1).
Reaction SMILES: [F-].[K+].F[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[F:12][C:13](F)([F:22])[O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C1OCCOCCOCCOCCOCCOC1>CS(C)=O.C(OCC)(=O)C>[F:12][CH:13]([F:22])[O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccccc1F
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1Oc1cccc(OC(F)F)c1
Temperature: 140 °C
Yield: 67 %

Procedure:
A mixture of potassium fluoride on alumina (40% w/w, Aldrich, 11 g), 2-fluorobenzonitrile (6.0 ml, 56 mmol), 3-trifluoromethoxyphenol (10 g, 56 mmol), and 18-crown-6 (1.48 g, 5.6 mmol) in dimethylsulphoxide (40 ml) was heated to 140° C. for 20 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (300 ml). The solid was filtered off through a plug of celite. The solution was washed with a mixture of water (100 ml) and brine (100 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (200 g), using ethyl acetate/heptane (1:3) as eluent, to give 9.80 g of 2-(3-(difluoromethoxy)phenoxy)benzonitrile.
Reaction SMILES: CN[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=O.[CH2:20](O)[CH:21]=C>>[CH:18]1[C:19]2[CH:6]([O:5][CH2:3][CH:20]=[CH2:21])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CNC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: C=CCO
Product: C=CCOC1c2ccccc2Oc2ccccc21

Procedure:
9-(N-Methylcarbamoyloxy)xanthene (27.0 g., 0.016 moles) was stirred with 150 ml. of allyl alcohol for 1.5 hours at room temperature, and the mixture was then filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in 200 ml. of ice-cold ether and washed twice each with 100 ml. portions of ice-cold 10% aqueous acetic acid, water and 5% aqueous sodium bicarbonate solution. After drying over potassium carbonate, the solvent was removed in vacuo, and the resulting oil was distilled to give allyl 9-xanthenyl ether, b.p. 100°-105°C. at 0.005 mm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[CH:6]=1.[Si:13]([O:20][CH2:21][CH2:22][C:23]#[CH:24])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:24]#[C:23][CH2:22][CH2:21][O:20][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=1
Reactant: COC(=O)Cc1cccc(I)c1
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccc(C#CCCO[Si](C)(C)C(C)(C)C)c1
Yield: 61.9 %

Procedure:
A mixture of (3-iodo-phenyl)-acetic acid methyl ester (948 mg, 3.4 mmol), 1-(t-butyldimethylsilyloxy)but-3-yne (644 mg, 3.5 mmol), copper(1)iodide (50 mg), and bis(triphenylphosphine)-palladium(II)chloride (50 mg) in Et3N (5 ml) was refluxed, under argon for 2 hr. The reaction was cooled, and the liquid was decanted off, diluted with diethyl ether, and washed with 1N HCl. The organic layer was dried and the solvent was evaporated. The residue was chromatographed on silica gel (hexane/methylene chloride 60/40) to give the title compound as an oil (700 mg, 62%). MS (ESI) 333.0 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][CH:7]([C:9]([O:11][CH3:12])=[O:10])C)[C:3](O)=[O:4].S(Cl)([Cl:15])=O>>[Cl:1][CH:2]([CH2:6][CH2:7][C:9]([O:11][CH3:12])=[O:10])[C:3]([Cl:15])=[O:4]
Reactant: COC(=O)C(C)CC(Cl)C(=O)O
Reactant: O=S(Cl)Cl
Product: COC(=O)CCC(Cl)C(=O)Cl

Procedure:
A mixture of 6.2 g of 2-chloro-4-methoxycarbonyl valeric acid and 12.6 ml of thionyl chloride was refluxed for 30 minutes, then the solvent was distilled off under reduced pressure to leave 2-chloro-4-methoxycarbonyl butyryl chloride. A mixture of this product, 5.0 g of 2-benzylaminodiphenyl methanol, 100 ml of ethyl acetate and 100 ml of a saturated aqueous solution of sodium hydrogencarbonate was stirred for one hour at room temperature. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 5.3 g of 2-[N-benzyl-N-(2-chloro-4-methoxycarbonyl)butyryl]aminodiphenyl methanol as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([OH:26])=O.Cl.[OH:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][NH:33][CH2:34]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)[N:6]=[C:5]2[C:24]([N:33]1[CH2:32][CH2:31][C:30]2[C:35](=[CH:36][CH:37]=[CH:38][C:29]=2[OH:28])[CH2:34]1)=[O:26]
Reactant: Oc1cccc2c1CCNC2
Reactant: COc1cc(-c2nc(C(=O)O)c3cc(F)ccc3n2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(-c2nc(C(=O)N3CCc4c(O)cccc4C3)c3cc(F)ccc3n2)cc(OC)c1OC
Yield: 15.4 %

Procedure:
Reaction of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 107 (15.4% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.80 and 2.89 (2t, 2H), 3.59 and 4.07 (2t, 2H), 3.77-3.3.80 (m, 3H), 3.87 and 3.92 (2s, 6H), 4.51 and 4.95 (2s, 2H), 6.35-6.79 (m, 2H), 6.89-7.11 (m, 1H), 7.64-7.85 (m, 3H), 8.00-8.09 (m, 1H), 8.22-8.29 (m, 1H), 9.51 and 9.53 (2s, 1H); MS (ESI) m/z 490 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]([O-:9])=O.[Na+].CN(C)C=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:47]([NH:49][C:50]([NH:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[N:60]=[C:61]([N:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)[C:62]3[CH2:68][CH2:67][NH:66][CH2:65][C:63]=3[N:64]=2)=[CH:55][CH:54]=1)=[O:51])[CH3:48]>>[CH2:47]([NH:49][C:50]([NH:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[N:60]=[C:61]([N:69]3[CH2:70][CH2:71][O:72][CH2:73][CH2:74]3)[C:62]3[CH2:68][CH2:67][N:66]([C:7]([C:2]4[N:1]=[CH:6][CH:5]=[CH:4][N:3]=4)=[O:9])[CH2:65][C:63]=3[N:64]=2)=[CH:57][CH:58]=1)=[O:51])[CH3:48]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: O=C([O-])c1ncccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2ncccn2)C3)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Sodium pyrimidine-2-carboxylate (0.0229 g, 0.000157 mol) in dry N,N-Dimethylformamide (0.910 mL, 0.0118 mol) was added 1-Hydroxybenzotriazole (0.0313 g, 0.000232 mol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0409 g, 0.000213 mol) then followed by N,N-Diisopropylethylamine (0.0570 mL, 0.000327 mol) and then 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0493 g, 0.000129 mol). The reaction mixture was stirred overnight. The reaction mixture was heated at 40° C. and stirred for 4 days. The reaction mixture was concentrated, chromatographed through silica gel (4 g, 0-10% MeOH in dichloromethane), and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.99-8.94 (m, 1H), 8.68 (d, J=17.8, 1H), 8.24-8.06 (m, 2H), 7.66 (td, J=5.0, 2.2, 1H), 7.54-7.39 (m, 2H), 6.22-6.11 (m, 1H), 4.77 (s, 1H), 4.38 (s, 1H), 3.89 (d, J=5.2, 1H), 3.72 (dd, J=10.3, 5.7, 4H), 3.49 (dd, J=19.3, 4.3, 4H), 3.40 (d, J=5.3, 1H), 3.20-3.03 (m, 2H), 2.80 (s, 1H), 2.69 (s, 1H), 1.13-0.98 (m, 3H). LC/MS-m/z+489.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12]([C:15](Cl)=[O:16])[CH2:13][CH3:14].N1C=CC=CC=1>C1COCC1.CCOC(C)=O>[OH:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[NH:1][C:15](=[O:16])[CH2:12][CH2:13][CH3:14]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1O

Procedure:
To a solution of 2-amino-4-nitrophenol (Aldrich, 1.0 g, 6.5 mmol) in THF (25 ml) was added n-PrCOCl (694 mg, 6.5 mmol) and pyridine (2.6 ml, 32.4 mmol). The reaction was refluxed for 5 days, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH2:6][N:7]=[C:8]=[O:9])[CH3:2].[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH2:6][NH:7][C:8]([NH:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)=[O:9])[CH3:2]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCOC(=O)CCN=C=O
Product: CCOC(=O)CCNC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use 3-isocyanatopropionic acid ethyl ester in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (37% yield). 1H NMR (300 MHz, CDCl3) δ 8.12, 7.92, 7.74, 7.62, 7.55, 7.36, 7.11, 6.65, 3.95-3.90, 3.59, 3.49-3.40, 3.28, 2.36-2.33, 1.63-1.61, 0.94-0.93.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=O.[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=2)[O:15]1.C(=O)([O-])O.[Na+]>C(O)CC>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:3]2[N:27]=[C:24]3[CH:23]=[CH:22][C:21]([B:16]4[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]4)=[CH:26][N:25]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: COc1cccc(-c2cn3cc(B4OC(C)(C)C(C)(C)O4)ccc3n2)c1
Temperature: 80 °C
Yield: 97.8 %

Procedure:
5.00 g of 2-bromo-1-(3-methoxyphenyl)ethanone and 4.80 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylamine are placed in 220 ml of n-propanol in a round-bottomed flask and 2.57 g of sodium hydrogencarbonate are added. The mixture is heated at 80° C. for 20 h and allowed to cool. The reaction mixture is concentrated under reduced pressure. The residue is taken up between water and ethyl acetate, the organic phase is separated by settling and dried over magnesium sulphate and then the solvent is concentrated. 7.47 g of compound are obtained.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH2:11]>C(Cl)Cl>[NH:4]1[C@H:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]2[NH:11][C:1]1=[S:3]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: S=C=S
Solvent: ClCCl
Product: S=C1N[C@H]2CCCC[C@H]2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of carbon disulfide (1.1 mL, 17.9 mmol) and CH2Cl2 (10 mL) was treated dropwise with cis-1,2-diaminocyclohexane 20-1 (Aldrich) (2.0 g, 17.5 mmol) while maintaining the reaction mixture temperature below 20° C. with an ice bath. The reaction mixture was stirred at ambient temperature for 2.0 h after the addition was complete. Concentration followed by refluxing the resulting solid in H2O (20 mL) for 20 h gave a yellow solution. The cooled solution was extracted with CH2Cl2 and the CH2Cl2 portion was dried (MgSO4) and concentrated. The pale yellow solid was recrystallized from CH2Cl2 /ether to give 20-2 as a pale yellow solid. mp=164-166° C.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)/[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])=O.[NH4+]>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cn1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of (E)-3-cyclopentyl-2-(6-methanesulfonylpyridin-3-yl)-N-thiazol-2-ylacrylamide (EXAMPLE 35, 500 mg, 1.3 mmol), ammonium formate (500 mg, 7.9 mmol), and 10% palladium on charcoal (50% H2O, 500 mg) in MeOH (20 mL) was stirred at 80° C. for 20 h. The solvent was removed in vacuo, then the residue was diluted with EtOAc and filtered through Celite. The filtrate was concentrated and once again diluted with EtOAc, filtered through Celite and concentrated. Purification of the crude product by column chromatography (EtOAc-n-C6H14, 3:7 to 1:1) afforded the title compound: δH (CDCl3): 1.05-1.22 (m, 2H), 1.40-1.85 (m, 7H), 1.95 (dt, 1H), 2.29 (dt, 1H), 3.21 (s, 3H), 3.82 (t, 1H), 7.09 (d, 1H), 7.53 (d, 1H), 8.06 (d, 2H), 8.58 (t, 1H); m/z (APCI+)=380 [M+H]+.
Reaction SMILES: Cl.[NH:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][N:5]=1)[NH2:3].[O:14]=[C:15]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:16](O)=[O:17]>O>[O:14]=[C:15]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:16](=[N:2][NH2:3])[OH:17].[NH:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][N:5]=1)[NH2:3]
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: Cl
Agent: NNc1nncc2ccccc12
Solvent: O
Product: NN=C(O)C(=O)CCC(=O)O
Reaction time: 8 h
Yield: 159.2 %

Procedure:
1-hydrazinophthalazine hydrochloride (395 mg; 2 mmol) is dissolved in 5 ml of water. To this an aqueous solution of α-ketoglutaric acid (1 g; 7 mmol) is added and the reaction mixture is allowed to stand overnight at room temperature. The solid precipitate is filtered off and dried in vacuo to yield 510 mg of 1-hydrazinophthalazine α-ketoglutarate hydrazone (88% theoretical yield). [British Journal of Clinical Pharmacology 5: 489-494 (1978)].
Reaction SMILES: [CH:1]([N:4]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].[C:32](Cl)(=[O:37])[CH2:33][C:34](Cl)=[O:35]>C1COCC1>[O:35]=[C:34]1[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:32](=[O:37])[CH2:33]1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: CC(C)N(C(=O)CNc1ccccc1Nc1ccccc1)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.2 %

Procedure:
To 60 mL of THF at 0° C. is added dropwise over 20 min simultaneously a solution of 2.0 g (4.68 mmol) of N-Isopropyl-2-(2-phenylamino-phenylamino)-N-(4-trifluoromethyl-phenyl) acetamide, prepared as in Part A, in 30 mL of THF and 590 μL (6.08 mmol, 1.3 equiv) of malonyl dichloride in 30 mL of THF. The resulting solution is stirred at RT for 20 h and the solvent removed in vacuo. Purification of the resulting brown oil by silica gel flash column chromatography using hexane/EtOAc 3/2 as eluent afforded 1.35 g of the title compound as a light tan solid: mp 186°-188° C.; 1H NMR (CDCl3, 400 MHz) δ7.74 (d, 2H, J=8.1), 7.42 (d, 2H, J=8.1), 7.36 (m, 3H), 7.25 (m, 4H), 7.08 (ddd, 1H, J=1.4, 8.4, 8.4), 6.90 (dd, 1H, J=1.2, 8.2), 5.06 (m, 1H), 4.12 (dd, 2H, J=14.4, 95.5), 3.52 (dd, 2H, J=12.0, 34.5), 1.11 (d, 6H, J=6.6); low resolution MS (FAB)m/e 496 (MH+), 293, 265; Anal. (C27H24F3N3O3) Calcd. C, 65.45; H, 4.88; N, 8.48; Found C, 65.16; H, 4.95; N, 8.33.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11](=[O:20])[CH:12]=[C:13]([C:16]([NH:18][NH2:19])=[O:17])[NH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:21]([O-])=O.[Na+]>O>[N:18]([C:16]([C:13]1[NH:14][CH:15]=[C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:11](=[O:20])[CH:12]=1)=[O:17])=[N+:19]=[N-:21]
Reactant: NNC(=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reaction time: 3.5 h

Procedure:
A solution of concentrated hydrochloric acid (3 ml) in water (10 ml) was cooled to 0° C. and treated with 5-(benzyloxy)-2-(hydrazinocarbonyl)-4-oxo-1,4-dihydropyridine (3 g, 11.58 mmole) to form a thick paste. A solution of sodium nitrite (1.68 g, 23.17 mmole) in water (30 ml) was added in 2 ml portions with mechanical swirling of the reaction vessel. The resulting mixture was stirred for 3.5 hours and filtered. The resulting pasty solid was washed with water, ice-cold ethanol, ether and hexane. After drying thoroughly under high vacuum, the yield of the title compound was 2.6 g.