Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Na+].[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([S:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>CS(C)=O>[CH3:20][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: O=Cc1ccccc1F
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)c2ccccc2C=O)cc1
Temperature: 100 °C
Yield: 38.8 %

Procedure:
To a solution of 2-fluorobenzaldehyde (12.4 g, 100 mmol) in DMSO (75 mL) is added p-toluenesulfinic acid sodium salt (19.6 g, 110 mmol), and the reaction mixture is heated to 100° C. for 16 h. Once complete, the reaction mixture is cooled to room temperature and poured onto ice. The product is then isolated as a white solid by filtration to afford 2-[(4-methylphenyl)sulfonyl]benzaldehyde (10.1 g, 39%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14]>O1CCCC1>[Br:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:12]([CH:13]([OH:14])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:11]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CCCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCCC(O)c1cccc(Br)c1
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
Hexylmagnesium bromide (2.0M in THF, 3.7 mL, 7.4 mmol) was added to a solution of 3-bromobenzaldehyde (1.50 g, 8.11 mmol) in tetrahydrofuran (10 mL) at −78° C. After 10 min, the reaction was quenched by the addition of 2N hydrochloric acid (30 mL) and the product extracted into ethyl acetate (30 mL). The organic layer was washed with sat'd sodium chloride (25 mL), dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with 17% ethyl acetate/hexane gave 1.42 g (5.25 mmol, 65%) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:28](C)=[CH:27][S:26][C:25]=2[C:30]([NH:32][CH3:33])=[O:31])[C:20]([Cl:34])=[CH:19][N:18]=1>>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:28]=[CH:27][S:26][C:25]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)NC(=O)CCc2cc(N)ccc21
Product: CNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)CCC(=O)NC3(C)C)ncc1Cl

Procedure:
Following a procedure analogous to Example 1826d, 7-amino-1,1-dimethyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one and 3-(2,5-dichloropyrimidin-4-ylamino)-N,4-dimethylthiophene-2-carboxamide were converted to 3-(5-chloro-2-(1,1-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)-N-methylthiophene-2-carboxamide, TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.2 (s, 1H), 7.4 (d, 1H), 7.3 (d, 1H), 7.25 (d, 1H), 7.1 (dd, 1H), 3.0 (m, 2H), 2.8 (s, 3H), 2.6 (m, 2H), 2.1 (s, 3H) 1.7 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][N:12]=1)[C:5](O)=[O:6].S(Cl)([Cl:28])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][N:12]=1)[C:5]([Cl:28])=[O:6]
Reactant: CCCCCCCCOc1cnc(-c2ccc(C(=O)O)cc2F)nc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCOc1cnc(-c2ccc(C(=O)Cl)cc2F)nc1

Procedure:
3-Fluoro-4-(5-n-octyloxypyrimidine-2-yl)benzoic acid (1.60 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 3-fluoro-4-(5-n-octyloxypyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:5][CH:4]=1)#[CH:2].S(=O)(=O)(O)O.[H][H]>[Pd].C1C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(-c2ccccc2F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCc1ccc(-c2ccccc2F)cc1
Reaction time: 0.25 h

Procedure:
1-Ethynyl-4-(2-fluorophenyl)benzene, 22 g, was reduced in a Parr Instrument Company Series 3910 Low Pressure Shaker-type Apparatus, using 100 ml of benzene, 2 g of five percent palladium on charcoal, and 0.5 ml of concentrated sulfuric acid. Reduction was carried out at room temperature and at an initial hydrogen pressure of 50 psig. Within 15 minutes, the hydrogen pressure had dropped to 32 psig. Hydrogen pressure was increased to 52 psig and agitation continued for two hours, with no additional hydrogen pressure drop. The reaction mixture was filtered and the filtrate was neutralized with two percent aqueous sodium carbonate. The resulting mixture was washed with water. The benzene phase was separated, dried over anhydrous sodium sulfate, and filtered. The benzene was evaporated and the residue was vacuum distilled to give 17 g of 1-ethyl-4-(2-fluorophenyl)benzene, bp 99°-101°/0.3 mm. The following elemental analysis was obtained:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl-].[OH:28][NH3+:29].C([O-])(=O)C.[Na+]>C(O)C>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[N:29][OH:28])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 25 °C
Yield: 85 %

Procedure:
A suspension of crude 1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-formylindoline (35 g), hydroxylammonium chloride (10.4 g) and anhydrous sodium acetate (12.3 g) in ethanol (400 ml) was stirred at room temperature for a day. Then the reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (500 ml), an 8 N aqueous solution (30 ml) of sodium hydroxide and water (100 ml) and the layers were separated. The organic layer was washed with brine and dried over magnesium sulfate. After removing the solvent, the residue was dissolved in a hot toluene (100 ml)-isopropyl ether (100 ml) mixtures and allowed to cool at room temperature. The resulting crystals were collected by filtration and dried at 50° C. to give the title compound (31 g) as a pale yellow powder (yield: 85%).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[C:5]([OH:10])(=[O:9])/[CH:6]=[CH:7]/[CH3:8].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O1CCOCC1>[C:1]([S:3][CH:7]([CH3:8])[CH2:6][C:5]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: C/C=C/C(=O)O
Reactant: CC(O)=S
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)SC(C)CC(=O)O
Yield: 92 %

Procedure:
40 ml of thioacetic acid are added to 43 g of crotonic acid in 100 ml of dioxane. After adding 20 mg of benzoyl peroxide, the mixture is kept at the boiling point under reflux for 6 hours. The solvent and the excess thioacetic acid are removed by distillation and the product is purified by vacuum distillation. 75 g (92% of theory) of 3-acetylmercapto-butyric acid are obtained; boiling point 94° to 95° C/0.45 mm Hg. nD20 1.4908.
Reaction SMILES: C([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:17][CH3:18])(=O)C.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1CBr>>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:16][O:15][C:13]([C:9]1[CH:8]=[C:7]2[C:12]([CH:4]=[C:5]([CH2:17][CH3:18])[NH:6]2)=[CH:11][CH:10]=1)=[O:14]
Reactant: CCc1[nH]c2cc(C(=O)OC)ccc2c1C(C)=O
Reactant: Clc1ccccc1CBr
Product: CCc1cc2ccc(C(=O)OCc3ccccc3Cl)cc2[nH]1

Procedure:
Methyl 3-acetyl-1-((2-chlorobenzyl)-2-ethylindole-6-carboxylate (170 mg) was prepared from methyl 3-acetyl-2-ethylindole-6-carboxylate (100 mg) and 2-chlorobenzyl bromide (0.06 ml) in a similar manner to that of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:27]=[C:28]([NH2:33])[CH2:29][CH2:30][O:31][CH3:32]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:33]=[C:28]([CH2:29][CH2:30][O:31][CH3:32])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1C
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(C)c(C)c3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
200 mg (0.58 mmol) of the compound from Example 130A and 136 mg (0.87 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 98 mg (40% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([O:30][CH3:31])=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.[CH2:38](I)[CH3:39]>>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:24][CH2:25][N:26]([CH2:38][CH3:39])[CH2:27][CH2:28]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([O:30][CH3:31])=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1
Reactant: CCI
Reactant: COc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)N(C4CCNCC4)C3=O)cc12
Product: CCN1CCC(N2C(=O)S/C(=C\c3ccc4c(c3)c(OC)nn4Cc3ccc(Cl)cc3C(F)(F)F)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methoxy-1H-indazol-5-yl}methylidene)-3-(1-ethylpiperidin-4-yl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-3-methoxy-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 29) and ethyl iodide following General Procedure S.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:12])[F:13])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cc(C(F)(F)F)cnc1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
A solution of 2-chloro-5-(trifluoromethyl)nicotinic acid (500 mg, 2.21 mmole, available from Apollo #PC9219) in a mixture diethyl ether/methanol (5 ml)/(15 ml) was cooled to −20° C. then trimethylsilyldiazomethane (2M solution in diethyl ether) (2.15 ml, 4.43 mmol) was added dropwise. The reaction mixture was stirred at −20° C. for 1 h then allowed to warm to room temperature. After solvent evaporation, the obtained residue was loaded on SPE-Si cartridge (10 g) eluting with a mixture cyclohexane/dichloromethane from 80/20 to 60/40. Collected fractions, after solvent evaporation, afforded the title compound (D66) (300 mg)
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(OCC)(=O)C.O>[CH2:26]([O:25][C:23](=[O:24])[NH:13][C:12]1[CH:14]=[CH:15][C:9]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([NH2:6])=[CH:7][CH:8]=2)=[CH:10][CH:11]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2)cc1

Procedure:
A mixture of 4,4′-methylenedianiline (19.8 g), potassium carbonate (20 g) in ethyl acetate (300 mL) and water (200 mL) was stirred in an ice bath. Benzyl chloroformate (15 mL) was slowly added to the mixture. The resulting mixture was stirred for 1 hour, then the organic layer was separated, and the aqueous layer extracted with additional ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4), and the solvent removed in vacuo. The crude mixture was isolated by column chromatography on silica gel, eluting with 30% ethyl acetate/hexanes, to give 4-(4-aminobenzyl)phenyl-carbamic acid benzyl ester as solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[CH:14][CH:13]=1.[OH-].[Na+]>O>[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH:8]=[O:9])=[CH:17][NH:18]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc2c(C=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phosphorus oxychoride (3.2 ml, 34.3 mmol) was added dropwise to dimethyl formamide (26 ml) over ten minutes at ~5° C. To this solution was added a dimethyl formamide (32 ml) solution of 6-methylindole (3.307 g, 25.2 mmol) over 10 minutes. The mixture was slowly warmed to ambient temperature, then heated to 50° C. for four hours. The mixture was cooled to ambient temperature, then poured onto ice (500 g). The aqueous solution was left to stand for 16 hours. Sodium hydroxide (6.0 g) was dissolved in water (22 ml) and added dropwise to the brown solution. The resultant yellow precipitate was boiled and filtered hot. It was left to cool to room temperature, then to 5° C. The precipitate was filtered off and washed with water (800 ml), dried at the pump, then further dried in vacuo at 50° C. for 16 hours to yield a yellow solid.
Reaction SMILES: F[C:2]1[C:11]2[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)[CH:9]=[C:8]3[C:24](=[O:34])[N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])[N:26]=[C:7]3[C:6]=2[C:5](F)=[CH:4][CH:3]=1.Cl.Cl.[F:38][C:39]1[C:40]([NH:45][C@@H:46]2[CH2:51][CH2:50][CH2:49][CH2:48][C@H:47]2[NH2:52])=[N:41][CH:42]=[CH:43][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:25]1[C:24](=[O:34])[C:8]2=[CH:9][N:52]([C@@H:47]3[CH2:48][CH2:49][CH2:50][CH2:51][C@H:46]3[NH:45][C:40]3[C:39]([F:38])=[CH:44][CH:43]=[CH:42][N:41]=3)[C:5]3[CH:4]=[CH:3][CH:2]=[C:11]([NH:10][CH2:12][C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH:23]=[CH:22][CH:21]=[N:20]5)=[CH:15][CH:14]=4)[C:6]=3[C:7]2=[N:26]1
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3c(F)ccc(F)c3c-2nn1-c1ccccc1F
Reactant: N[C@@H]1CCCC[C@H]1Nc1ncccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c2cn([C@@H]3CCCC[C@H]3Nc3ncccc3F)c3cccc(NCc4ccc(-n5cccn5)cc4)c3c-2nn1-c1ccccc1F
Temperature: 95 °C
Reaction time: 1 h

Procedure:
6,9-Difluoro-2-(2-fluorophenyl)-5-{[4-(1H pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 28, 74 mg, 0.16 mmol), (±)-trans-N-(3-fluoropyridin-2-yl)cyclohexane-1,2-diamine bishydrochloride (43 mg, 0.19 mmol, 1.2 equiv) and potassium carbonate (0.22 g, 1.6 mmol, 10 equiv) were combined in degassed dimethylsulfoxide (5 mL) and placed into an oil bath preheated at 95° C. for 1 hour. Additional (±)-trans-N-(3-fluoropyridin-2-yl)cyclohexane-1,2-diamine bishydrochloride (0.10 g, 0.44 mmol, 2.3 equiv) and potassium carbonate (0.42 g, 3.0 mmol, 16 equiv) were added and the mixture was heated at 95° C. for an additional 2 hours. The mixture was cooled to ambient temperature, filtered and purified by preparative reverse phase HPLC (eluting 70:30 to 5:95; water containing 0.1% TFA: acetonitrile containing 0.1% TFA). The appropriate fractions were poured into sodium bicarbonate (100 mL, aqueous saturated) and extracted with ethyl acetate (1×50 mL). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound as a light yellowish-green solid: 1H-NMR (400 MHz, CDCl3) δ 8.73 (1H, s), 8.32 (1H, br s), 7.85 (1H, d, J=2.8 Hz), 7.77 (1H, d, J=4.6 Hz), 7.69 (1H, d, J=1.8 Hz), 7.61-7.56 (3H, m), 7.44 (2H, d, J=8.6 Hz), 7.30-7.24 (1H, m), 7.21-7.15 (2H, m), 7.11 (1H, dd, J=13.6, 9.8 Hz), 6.90 (1H, ddd, J=11.2, 7.9, 1.3 Hz), 6.83 (1H, dd, J=9.4, 3.0 Hz), 6.44 (1H, dd, J=2.4, 1.9 Hz), 6.39 (1H, ddd, J=7.9, 5.0, 3.5 Hz), 4.77-4.67 (3H, m), 4.56 (1H, br t, J=10.2 Hz), 4.35 (1H, br m), 2.33 (1H, br d, J=10.9 Hz), 2.23 (1H, br d, J=12.8 Hz), 2.01-1.79 (3H, m), 1.67-1.51 (3H, m) ppm; high resolution mass spectrometry (ES+) m/z 661.2621 [(M+H)+; calculated for C37H32F3N8O: 661.2646].
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[N:18]1([C:23]2[CH:24]=[C:25]([CH2:29]O)[CH:26]=[CH:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=[CH:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([N:18]3[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH:24]=2)=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Reactant: OCc1cccc(-n2cccc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc(-n3cccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 3-(1H-pyrrol-1-yl)phenylmethanol (104 mg, 0.600 mmol) were dissolved in tetrahydrofuran (2 mL), and triphenylphosphine (165 mg, 0.629 mmol) and a diethyl azodicarboxylate toluene solution (2.2 M, 290 μL, 0.638 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 90:10 (v/v)), whereby the objective title compound was obtained as a light yellow oily substance (107 mg, yield: 65%).
Reaction SMILES: Cl.C([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[NH:16][C:17]2[CH:22]=[C:21]([OH:23])[C:20]([CH3:24])=[CH:19][C:18]=2[F:25])[N:7]=1)(=O)C.Cl>C(O)C>[NH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[NH:16][C:17]2[CH:22]=[C:21]([OH:23])[C:20]([CH3:24])=[CH:19][C:18]=2[F:25])[N:7]=1
Reactant: CC(=O)Nc1ccc2c(Nc3cc(O)c(C)cc3F)ccnc2n1
Agent: Cl
Solvent: CCO
Product: Cc1cc(F)c(Nc2ccnc3nc(N)ccc23)cc1O
Yield: 76.5 %

Procedure:
A mixture of 2-acetamido-5-(2-fluoro-5-hydroxy-4-methylanilino)-1,8-naphthyridine hydrochloride (170 mg, 0.46 mmol), (prepared as described in Example 53), and concentrated hydrochloric acid (0.5 ml) in ethanol (10 ml) was heated at reflux for 2 hours. The mixture was allowed to cool and the organic volatiles were removed by evaporation. The aqueous residue was basified to pH9 with aqueous sodium hydroxide solution and the resulting precipitate was collected by filtration, washed with water and dried to give 2-amino-5-(2-fluoro-5-hydroxy-4-methylanilino)-1,8-naphthyridine (100 mgs 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.C(OCC)C>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:7]2[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccnc2)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2cccnc2)cc1
Reaction time: 3.5 h
Yield: 95.4 %

Procedure:
A solution of 3-(4-nitrophenoxy)pyridine (5.00 g, 23.13 mmol) in EtOAc (100 mL) in a 250 ml Parr bottle was purged with nitrogen. To this solution was added EtOAc-moistened 10% Pd/C catalyst (500 mg, 10% by weight). The reaction flask was placed in a Parr hydrogenation apparatus, purged with nitrogen (5×), evacuated, and then pressurized to 40 psi with hydrogen and shaken for 3.5 h. The reaction mixture was then purged with nitrogen, and filtered through a pad of Celite®, rinsing with ethyl acetate (3×) and ethanol (3×). The filtrate was evaporated at reduced pressure to give a brown crystalline residue. The residue was stirred in diethyl ether at room temperature for 16 h and then filtered to provide 4.11 g (95%) of the desired product as light brown crystals. 1H-NMR (DMSO-d6) δ 8.21 (m, 2H), 7.30 (ddd, J=8.4, 4.6, 0.7 Hz, 1H), 7.18 (ddd, J=8.4, 2.9, 1.4 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H), 6.58 (d, J=9.0 Hz, 2H), 5.05 (br s, 2H); MS LC-MS [M+H]+=187, RT=1.03 min.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Br[CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]>>[C:12]([C:11]1[C:3]([C:2]([F:14])([F:1])[F:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5]2)#[N:13]
Reactant: COC(=O)C(C)Br
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: COC(=O)C(C)n1ccc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized in a manner similar to Example 1 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile (see, for example, US2008139631A1) and methyl 2-bromopropanoate: MS (ESI): m/z 297 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13](I)[C:11]=1[NH2:12]>C(N(CC)CC)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.[Cu]I>[Cl:17][C:15]1[CH:14]=[C:13]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[C:11]([NH2:12])=[C:10]([F:9])[CH:16]=1
Reactant: C#Cc1cccnc1
Reactant: Nc1c(F)cc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Nc1c(F)cc(Cl)cc1C#Cc1cccnc1

Procedure:
To a mixture of 3-ethynylpyridine (1.13 g, 11 mmol) and 2-fluoro-4-chloro-6-iodoaniline (2.71 g, 10 mmol) in triethylamine (100 mL) is added PdCl2(PPh3)2 (175 mg, 0.25 mmol) and CuI (95 mg, 0.50 mmol) and the mixture is refluxed for 1 h. The solvent is removed in vacuo and the residue is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 24:1) to give 4-chloro-2-fluoro-6-pyridin-3-ylethynyl-phenylamine. MS (ESI) m/z 247 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[O:36][CH3:37].C(#N)C>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][O:26][C:27]4[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=4[O:36][CH3:37])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCN1CCN(c2n[nH]c3cc(Cl)ccc23)CC1
Yield: 41.9 %

Procedure:
A mixture of 6-chloro-[3-(1-piperazinyl)]-1H-indazole (2.1 g, 8.9 mmol), K2CO3 (1.5 g, 10.7 mmol), KI (100 mg), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (2.2 g, 9.8 mml) and acetonitrile (70 ml) was stirred at reflux for 48 hours under N2The cooled reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed with water, dried with MgSO4 and concentrated to yield 6.0 of a light yellow oil. The oil was purified by preparative HPLC (Waters Associates prep LC/System 500, employing 2 silica gel columns and 5.5% methanol/methylene chloride as eluent). Concentration of later fractions provided 1.6 g of an off-white solid. This was combined with an additional sample (3.4 g total) and two consecutive recrystallizations from ethanol yielded 2.1 g (23%) of 1-[4-[2-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphenphenyl]ethanone as an off-white solid, m.p.=154°-156° C.