Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[CH2:9]([O:11][C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].N1C=CC=CC=1C(O)=O>O1CCOCC1.[Cu]I>[CH2:9]([O:11][C:12](=[O:19])[CH:13]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: Brc1ccc(I)nc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
A mixture of 5-bromo-2-iodo-pyridine (56.8 g, 0.2 mol), malonic acid diethyl ester (64 g, 0.4 mol), CuI (3.8 g, 0.02 mol), Cs2CO3 (195.5 g, 0.6 mol) and pyridine-2-carboxylic acid (2.46 g, 0.04 mol) in 1,4-dioxane (400 mL) was stirred at 70 degrees Celsius under N2 for 24 hours. After cooling to room temperature, the solid was filtered and the solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and washed with water, brine, dried over Na2SO4, filtered, concentrated in vacuo, the crude product was purified by flash chromatography (Petroleum Ether:EtOAc=20:1) to obtain an oil (31.6 g, 50%). MS: calc'd 316 (MH+), exp 316 (MH+). 1H NMR (d6-DMSO, 400 MHz), 8.68 (d, 1H, J=2.4 Hz), 8.11 (dd, 1H, J=2.4, 8.4 Hz), 7.45 (d, 1H, J=8.4 Hz), 5.16 (s, 1H), 4.20-4.07 (m, 4H), 1.18 (t, J=8.4 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: Nc1ccccc1
Product: COC(=O)c1cccc(Nc2ccccc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with aniline according to general procedure A provided methyl ester of Compound 3 as a yellow oil (94% yield). 1H NMR (CDCl3, 500 MHz): δ=7.73 (s, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.22-7.35 (m, 4H), 7.10 (d, J=8.5 Hz, 2H), 7.00 (t, J=7.4 Hz, 1H), 5.81 (s, 1H), 3.91 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=167.3, 143.9, 142.6, 131.6, 129.7, 129.6, 122.0, 121.9, 121.7, 118.7, 118.4, 52.3.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]1[CH:16]2[CH2:17][NH:18][CH2:19][CH:15]2[CH2:14][O:13]1.[OH-].[Na+]>>[C:1]1([CH2:7][C:8]([N:18]2[CH2:19][CH:15]3[CH2:14][O:13][CH2:12][CH:16]3[CH2:17]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1NCC2COCC12
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Cc1ccccc1)N1CC2COCC2C1
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
Phenylacetyl chloride (15.46 grams, 0.1 mole), Aldrich Chemical Co., Inc., Milwaukee, Wisconsin, was slowly added to a mixture of hexahydro-1H-furo(3,4-c)pyrrole hydrochloride (14.96 grams, 0.1 mole) and 300 ml aqueous sodium hydroxide (10.0 grams, 0.25 mole NaOH in water) at 10°C. After the phenylacetyl chloride addition, the ice bath was removed and the reaction mixture was stirred for 1.5 hours. The reaction mixture was extracted with diethyl ether (4 × 200 ml) and the extract treated with DARCO G-60 (activated carbon). Removal of diethyl ether gave 5-phenylacetyl-hexahydro-1H-furo(3,4-c)pyrrole (19.35 grams) a clear viscous liquid which solidified on cooling. This product was recrystallized from diethyl ether and had a melting point of 47.5° to 48.5°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:15][C@@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[CH2:11][O:10][NH:9]2>C(O)(=O)C.[Zn]>[NH2:9][C@@:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:15][C@@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[CH2:11][OH:10]
Reactant: CO[C@H]1C[C@H]2CON[C@@]2(c2ccccc2F)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: CO[C@H]1C[C@@H](CO)[C@](N)(c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.4 %

Procedure:
Zinc (533 mg) was added to a solution of (3aR*,5S*,6aS*)-6a-(2-fluorophenyl)-5-methoxy-hexahydrocyclopenta[c]isoxazole (247 mg) in acetic acid (5 mL), and the mixture was stirred at room temperature for 12 hours. Zinc (500 mg) was added to the reaction solution, followed by stirring at room temperature for three hours. Zinc was removed by filtration and the filtrate was poured into a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (245 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:11]([C:10]2[CH:9]=[CH:8][C:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:16])=[CH:15][CH:14]=2)=[O:13])(=[O:25])=[O:26])=[CH:22][CH:23]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A 5-liter 3-neck round bottom flask was equipped with a mechanical stirrer and nitrogen inlet. CH2Cl2 (2 liters) was placed in the reaction flask and terephthalic acid mono-t-butyl ester (127.5 g, 0.574 mol), DMAP (70.06 g, 0.574 mol), and 4-chlorobenzenesulfonamide (110.04 g, 0.574 mol) were added in that order using CH2Cl2 (400 ml) to wash down the solids. WSCDI (110.10 g, 0.574 mol) was added in portions over 10 min using CH2Cl2 (100 ml) to wash down the solid. After the reaction mixture was stirred overnight at room temperature, it was concentrated under vacuum to dryness. The residue was partioned between EtOAc and water. The EtOAc solution was washed (20% aq citric acid, satd aq NaHCO3, brine), dried (Na2SO4), and concentrated under vacuum to a white solid. After drying in a vacuum oven at 50°, the title product (227 g, 100%) was obtained in a sufficiently pure state to be used directly for the next step; TLC, Rf =0.43, MeOH:CHCl3 (15:85). (Further purification was possible by recrystallization from EtOH:water; m.p. above 300°).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=3)[S:28][C:19]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl.CN(C)C=O>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:31][CH:30]=3)[S:28][C:19]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)c(Cl)cc1Cl
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(CN5CCOCC5)cc4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
Morpholine (16 mg, 0.18 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (66 mg, 0.15 mmol) in 5 mL of dichloromethane and 0.5 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (85 mg, 0.40 mmol) is added. After stirring at 0° C. for 1.5 hours, acetic acid (0.02 mL) is added and the reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of water and then partitioned between water and dichloromethane. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography to provide 48 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(4-morpholinylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 244-245° C.; 1H NMR (DMSO-d6) δ 2.36 (m, 4H), 3.50 (s, 2H), 3.57 (m, 4H), 3.85 (s, 3H), 7.31 (s, 1H), 7.42 (d, J=8 Hz, 2H), 7.68 (d, J=8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.73 (s, 1H); MS 525.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[O:17])NCOC)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]([Mg]Cl)([CH3:20])[CH3:19]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12](=[O:17])[CH:18]([CH3:20])[CH3:19])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCNC(=O)C1CN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 4 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
A solution of 3-(methoxymethylcarbamoyl)azetidine-1-carboxylic acid tert-butyl ester (1.06 g, 4.34 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to 4° C. under argon gas. 2M solution of isopropyl magnesium chloride (4.35 mL, 8.68 mmol) was added dropwise and the resulting reaction mixture was stirred at 4° C. for 5 min. The temperature was allowed to rise to RT and stirred for 1 h then the mixture was stirred at 40° C. for 1 h. The reaction mixture was quenched by addition of a saturated solution of ammonium chloride (5 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The organic layer was dried over sodium sulfate, filtered and the solvents reduced in vacuo to afford the title compound as a pale yellow oil (950 mg, 96%) 1H NMR (400 MHz, CDCl3): δ 4.03-4.01 (4H, m), 3.59-3.59 (1H, m), 2.61-2.61 (1H, m), 1.43 (9H), 1.11 (6H, d, J=6.94 Hz).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C@:7]([CH3:17])([C:14]([NH:34][CH2:33][CH2:31][OH:32])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(C(=O)NCCO)O2
Yield: 77.2 %

Procedure:
Following the amide coupling procedure described in protocol A, 5.06 g 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (20.2 mmol), 3.68 g CDI (22.7 mmol) and 2.44 g ethanolamine (39.52 mmol) produced 4.576 g of (S)-6-hydroxy-N-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[NH:10][C:9]=2[CH2:8][NH:7]1)=[O:5])[CH3:2].[S]>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([F:19])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2c([nH]c3ccc(F)cc23)CN1
Agent: [S]
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(F)cc12
Yield: 42.3 %

Procedure:
720 mg of 6-fluoro-1,2,3,4-tetrahydro-β-carbolin-3-carboxylic acid ethyl ester and 130 mg of dry sulphur are heated to boiling under nitrogen in 5 ml of xylene. After cessation of dehydrogenation (about 20 hours, thin-layer chromatography check), the solution is concentrated by evaporation in vacuo, and the residue chromatographed on silica gel with chloroform ethanol (95:5). 300 mg of 6-fluoro-β-carbolin-3-carboxylic acid ethyl ester of melting point 284° C. (decomposition) is obtained. After reaction with hydrochloric acid, the hydrochloride which melts at 295° C., with decomposition, is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1.[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>O1CCCC1.O>[CH2:29]([NH:31][C:32]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1)=[O:33])[CH3:30]
Reactant: CCN=C=O
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4c3)ccc2F)n(C)n1
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cn2cc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.3 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl) oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (70.0 mg, 0.184 mmol) in tetrahydrofuran (3 mL) was added ethyl isocyanate (17.5 μL, 0.221 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate-ethanol to give the title compound (21.0 mg, 25%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12].[NH2:16][C:17]1[N:22]=[C:21](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:20]([CH2:36][C:37]2[CH:52]=[CH:51][C:40]([CH2:41][N:42]([CH2:49][CH3:50])[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][C:38]=2[O:53][CH3:54])=[C:19]([CH3:55])[N:18]=1>C(#N)CC>[NH2:16][C:17]1[N:22]=[C:21]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12])[C:20]([CH2:36][C:37]2[CH:52]=[CH:51][C:40]([CH2:41][N:42]([CH2:49][CH3:50])[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:39][C:38]=2[O:53][CH3:54])=[C:19]([CH3:55])[N:18]=1
Reactant: CCOC(=O)CN(CC)Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Reactant: CCC[C@H](N)CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCC#N
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC)CC(=O)OCC)cc1OC
Temperature: 120 °C
Yield: 78.8 %

Procedure:
Trifluoroacetic acid (0.066 mL) was added to a mixture of (S)-3-aminohexan-1-ol (300 mg) and the product from step (vii) (490 mg) in propionitrile (5 mL). The mixture was heated at 120° C. for 16 h and cooled to RT. The solvent was removed by evaporation. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (330 mg) as a colourless gum; 1H NMR (CDCl3); 6.94 (1H, s), 6.88 (1H, d), 6.79 (1H, d), 4.66 (1H, d), 4.58 (2H, br s), 4.13 (2H, q), 4.11-4.06 (1H, m), 3.88 (3H, s), 3.70 (2H, s), 3.66 (2H, s), 3.42 (1H, ddd), 3.28-3.20 (3H, m), 2.65 (2H, q), 2.34 (3H, s), 1.82-1.74 (1H, m), 1.45-1.33 (1H, m), 1.26-1.21 (5H, m), 1.07-1.02 (5H, m), 0.73 (3H, t).
Reaction SMILES: [ClH:1].[C:2]1([CH:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=O)[CH3:28])=[CH:22][CH:21]=1)([O:16][CH3:17])=[O:15].C([BH3-])#N.[Na+].Cl>CO.ClCCl.C(OCC)C>[ClH:1].[CH3:17][O:16][C:14](=[O:15])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([N:10]2[CH2:11][CH2:12][O:13][CH:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[CH3:28])=[CH:22][CH:21]=1
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-phenylmorpholine hydrochloride (6.05 g), 1-(4-carbomethoxymethoxyphenyl)propan-2-one (6.63 g) and sodium cyanoborohydride (1.61 g) in methanol (100 ml) was stirred at room temperature for 22 hours. The solvent was removed under reduced pressure and aqueous sodium bicarbonate solution added to the residue and extracted with dichloromethane (×2). The extracts were washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated to dryness to give an oil. Chromatography on silica gel in 0→7% methanol in dichloromethane gave an oil which was dissolved in diethyl ether and treated with an ethereal solution of hydrogen chloride. Evaporation to dryness and trituration of the residue with ethyl acetate gave a solid. Recrystallisation of this solid gave the title compound, m.p. 187°-190° C. (methanol-ethyl acetate), of analytical purity.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[C:12]([F:31])[CH:11]=2)=[CH:4][N:3]=1.[F:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36]>O1CCOCC1.Cl>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][CH:18]=[C:17]2[O:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[C:6](=[O:9])[N:7]([CH3:8])[C:2]([NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[C:33]([F:32])[CH:34]=3)=[N:3][CH:4]=2)=[CH:11][C:12]=1[F:31]
Reactant: Nc1cccc(F)c1
Reactant: COc1cc2nccc(Oc3ccc(-c4cnc(Cl)n(C)c4=O)cc3F)c2cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2nccc(Oc3ccc(-c4cnc(Nc5cccc(F)c5)n(C)c4=O)cc3F)c2cc1OC
Temperature: 60 °C

Procedure:
The crude 2-chloro-5-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-3-methylpyrimidin-4(3H)-one from Step 3 was dissolved in 15 mL 1,4-dioxane. To 5 mL of this solution was added m-fluoroaniline (0.2 mL) and concentrated HCl (1 drop). The reaction was heated in the microwave at 60° C. and 60 W for 5 min before being cooled to RT. The mixture was concentrated and filtered through a 1 inch plug of silica gel with EtOAc→2:1 EtOAc/MeOH→3:2 MeOH/EtOAc. The filtrate was concentrated and purified using reverse phase HPLC (10%→95% MeCN/H2O with 0.1% TFA). Finally, the compound was filtered again through a 1-inch plug of silica gel in a pipette column with EtOAc to give the title compound. MS (ESI pos. ion) m/z: 517. Calc'd for C28H22F2N4O4: 516.16.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].CO[C:12]([CH:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1)=[O:13]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][O:5][C:12]([CH:14]1[CH2:15][CH2:16][CH:17]([C:20]([O:22][CH2:23][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])=[O:21])[CH2:18][CH2:19]1)=[O:13])[CH3:2]
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Reactant: CCCCC(CC)CO
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCCCC(CC)COC(=O)C1CCC(C(=O)OCC(CC)CCCC)CC1
Temperature: 180 °C

Procedure:
2-Ethylhexyl alcohol (8.1 mol), dimethylcyclohexane-1,4-dicarboxylate (DMCD, cis 1.7%, trans 98.3%, Eastman, 3.0 mol) and tetraisopropyl titanate catalyst (0.85 g) were added to a 2.5 L reactor equipped with a stirrer and two condensers and heated to 180° C. Di(2-ethylhexyl)cyclohexane-1,4-dicarboxylate (cis 3%, trans 97%) was obtained with a purity of 99.8% in the same manner as in Example 1.
Reaction SMILES: [C:1]([C:4]1[N:5](/[CH:11]=[CH:12]\[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[C:7]([C:9]#[N:10])[CH:8]=1)([OH:3])=O.C(Cl)Cl.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[NH4+]>O>[C:9]([C:7]1[CH:8]=[C:4]2[N:5]([CH:6]=1)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:1]2=[O:3])#[N:10]
Reactant: N#Cc1cc(C(=O)O)n(/C=C\c2ccccc2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: N#Cc1cc2c(=O)c3ccccc3ccn2c1
Reaction time: 0.25 h

Procedure:
A solution of 35 mg. cis-2-carboxy-4-cyano-N-styrylpyrrole in 0.5 ml. of dry methylene chloride was treated with 45 μl. of trifluoroacetic anhydride and stirred for 5 minutes. Stannic chloride (45 μl.) was added and the mixture stirred for 15 minutes. The mixture was poured into water, neutralized with ammonium hydroxide and extracted twice with chloroform. The extract was washed with water, dried over sodium sulfate, and concentrated to dryness. Trituration of the residue with 0.5 ml. of ethyl acetate and filtering gave 2-cyano-11H-pyrrolo[2,1-b][3]-benzazepin-11-one, m.p. 197° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1O.[N+:12]([CH2:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])#[C-:13]>>[CH:13]1[N:1]2[C:10]3[C:5]([N:4]=[CH:3][C:2]2=[C:14]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[N:12]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: Oc1cnc2ccccc2n1
Reactant: [C-]#[N+]CC(=O)OC(C)C
Product: CC(C)OC(=O)c1ncn2c1cnc1ccccc12

Procedure:
M.p. 205°-206° C., from 2-quinoxalinol and isopropyl isocyanoacetate. (Compound 3)
Reaction SMILES: [Cl-:1].[Li+].C1(C)C=CC(S(O[CH2:13][CH:14]([OH:37])[CH2:15][CH:16]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=2)[C:17]([NH:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])(=O)=O)=CC=1.O.C(OCC)(=O)C>CN(C=O)C>[Cl:1][CH2:13][CH:14]([OH:37])[CH2:15][CH:16]([C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1)[C:17]([NH:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CC(C(=O)NNC(=O)OC(C)(C)C)c2cc(F)c(F)c(F)c2)cc1
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NNC(=O)C(CC(O)CCl)c1cc(F)c(F)c(F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
Lithium chloride (818 mg) was added to a solution of 5-(N′-tert-butoxycarbonylhydrazino)-2-hydroxy-5-oxo-4-(3,4,5-trifluorophenyl)pentyl toluene-4-sulfonate (1.03 g) in DMF (8 mL). The reaction solution was stirred at 80° C. for three hours and then left to cool to room temperature. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 734 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:5]([CH3:29])[O:4][N:3]=1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([N:17]2[CH2:22][CH2:21][N:20]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:19][CH2:18]2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)(N1CCNCC1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C2(c3ccccc3)C(=O)Nc3ccc(-c4c(C)noc4C)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
To a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-phenyl-3-(piperazin-1-yl)indolin-2-one (194 mg, 0.5 mmol) in DMF (3.0 mL) was added ethyl 2-bromoacetate (417 mg, 2.5 mmol) and potassium carbonate (208 mg, 1.5 mmol), and the mixture was stirred in RT for 0.5 h, and then saturated NH4Cl (10 mL) was added, and the mixture was extracted with CH2Cl2 (2×10 mL), combined the organic phase, dried with Na2SO4, concentrated in vacuo to give crude product. The mixture was purified with chromatography on column using CH2Cl2/MeOH (50/1, v/v) as eluting to afford a white solid (100 mg, 42%). 1H NMR (400 MHz, DMSO-d6): δH 7.52 (d, J=8.0 Hz, 2H), 7.29-7.37 (m, 5H), 7.17 (d, J=8.0 Hz, 1H), 4.65 (s, 2H), 4.16 (q, J=6.8 Hz, 2H), 2.50-2.52 (m, 4H), 2.36 (s, 3H), 218 (s, 3H), 1.17 (t, J=6.8 Hz, 3H). MS (ESI) m/e [M+1]+ 475.