Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[NH2:24][OH:25].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:24][OH:25])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: NO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ONCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 15, 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a] [1,4]-benzodiazepine is treated with a cold mixture of hydroxylamine and sodium hydride in dimethylformamide to give 8-chloro-1-[(hydroxyamino)methyl]-6-phenyl-4H-s-triazolo [4,3-a][1,4]benzodiazepine.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:16]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][C:13]=2[CH3:15])[CH:8]=[C:9]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]1=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(C)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCCC(=O)O)c(O)c2cc(Cc3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 26.2 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-8-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.097 mmol), β-alanine (3.44 g, 38.6 mmol) and NaOMe solution (58 mL, 29 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was further purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 12 mg of the title compound. MS: (+) m/z 472.18 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[NH2:14][CH:15]([C:18]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](=[O:31])[C:21]2=[CH:32][CH:33]=[CH:34][N:20]2[N:19]=1)[CH2:16][CH3:17].[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][NH:14][CH:15]([C:18]1[N:23]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:22](=[O:31])[C:21]2=[CH:32][CH:33]=[CH:34][N:20]2[N:19]=1)[CH2:16][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(N)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCC(NCC(C)(C)NC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 258 %

Procedure:
(1,1-Dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (88.0 mg, 0.047 mmol) and 2-(1-amino-propyl)-3-benzyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 26, 100 mg, 0.314 mmol) in CH3OH (20 mL) was stirred at 25° C. for 1 h and then treated with NaCNBH3 (29.5 mg, 0.47 mmol). The mixture was stirred for 0.5 h at which time a white precipitate had formed. The precipitate was collected, washed with cold CH3OH and air dried to afford the desired material (55 mg, 39%) as a white crystalline solid: 1H NMR (DMSO-d6, 400 MHz) δ 7.36 (s, 1H), 7.10 (m, 5H), 6.82 (s, 1H), 6.46 (s, 1H), 5.47 (s, 1H), 5.20 (m, 2H), 3.55 (s, 1H), 2.45 (s, 1H), 2.22 (s, 1H), 1.84 (s, 1H), 1.64 (m, 1H), 1.53 (m, 1H), 1.26 (s, 9H), 1.01 (s, 6H), 0.72 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]([CH3:17])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)=[CH:4][C:3]=1[O:18][CH3:19].[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:18][CH3:19])[CH:4]=1)[C:9]1[S:10][C:11]([CH3:17])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1)=[O:24]
Reactant: COc1cc(Nc2nc(C(=O)O)c(C)s2)ccc1Cl
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)O)c(C)s2)ccc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
A mixture of 4.3 g (14 mmol) 2-(4-chloro-3-methoxy-phenylamino)-5-methyl-thiazole-4-carboxylic acid, 7.5 g (35 mmol) 2,4-dichloro-benzoyl chloride and 2.01 g (14.5 mmol) potassium carbonate in 200 mL THF was stirred at 50° C. for 18 h. After evaporation of the volatiles the residue was partitioned between water and ethyl acetate. Organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. Crystallisation from n-heptane/ethyl acetate yielded 6.6 g (97%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C3CCCCO3)[CH:16]=2)([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)([OH:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(OC3CCCCO3)c2)CCCN(Cc2ccccc2)C1
Agent: Cl
Solvent: CCO
Product: Oc1cccc(C2(O)CCCN(Cc3ccccc3)C2)c1
Reaction time: 60 h

Procedure:
8.64 g of 1-benzyl-3-[3-(tetrahydropyrane-2-yloxy)-phenyl]-piperidine-3-ol were dissolved in 30 ml of ethanol and 8.9 ml of HCl were added. The solvent was removed after stirring the mixture for 60 hours. Yield 6 g
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].C([Li])CCC.[Cl:15][C:16]1[C:17]([F:27])=[C:18]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])C(Cl)=O.Cl>O1CCCC1>[Cl:15][C:16]1[C:17]([F:27])=[C:18]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH:22]=[C:23]([F:26])[C:24]=1[F:25]
Reactant: CCOC(=O)CC(=O)O
Reactant: O=C(Cl)c1cc(F)c(F)c(Cl)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Temperature: -5 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a mixture of 2.64 g (20 mmol) of malonic acid monoethyl ester, 0.10 g (catalytic amount) of dipyridyl, and 50 ml of dry tetrahydrofuran at -30° C. is added 13 ml of n-butyllithium (1.55 M, 20.2 mmol) at a rapid rate. When addition is complete, the solution is warmed to -5° C., and another 13 ml of n-butyllithium (1.55 M, 20.2 mmol) is added dropwise until a pale pink color persists for ten minutes. The suspension is then cooled to -78° C. To this mixture is added a solution of 2.3 g (10 mmol) of 3-chloro-2,4,5-trifluorobenzoyl chloride in 3 ml of dry tetrahydrofuran. The reaction mixture is stirred at -78° C. for one hour, then warmed to -35° C. and poured into a mixture of ice (50 g) and 6 N hydrochloric acid (4 ml). This solution is extracted with dichloromethane, and the extracts are washed with water, 5% aqueous sodium bicarbonate, dilute hydrochloric acid, and water. The organic phase is dried over magnesium sulfate, filtered, and concentrated to give 2.5 g of the title compound as an orange solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:31][C:32](=[N:44]O)[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]([F:43])[CH:34]=1>C1(C)C=CC=CC=1>[F:43][C:35]1[CH:34]=[C:33]([C:32]2[N:31]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:44]=2)[CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
Intermediate 28 (4 g; 15.61 mmol) was dissolved in dry Toluene (60 mL) under N2 at RT, then oxalyl chloride (1.98 mL; 23.41 mmol) was added in one portion and then DMF (24.02 μl) was added. The reaction mixture was stirred at RT for 3 hours. The reaction mixture was concentrated to afford a yellow liquid. To a flask containing Intermediate 1 (3.31 g; 15.61 mmol) in Py (20 mL; 5 V) and toluene (20 mL) at RT and under N2 was added dropwise the yellow liquid obtained previously in toluene (40 mL), the addition took 15 min. The reaction mixture was stirred at RT for 12 hours. Then the mixture was refluxed for 24 hours. The reaction mixture was cooled to RT and concentrated affording a beige solid which was washed with MeOH (40 mL). The suspension was filtered affording the title compound as a beige solid (5.58 g, 82%). 1H NMR (DMSO-d6, 300 MHz) δ 8.33 (m, 1H), 8.19-7.98 (m, 4H), 7.44-7.28 (m, 4H), 7.16-7.13 (m, 1H), 4.24-4.14 (m, 2H), 3.91 (s, 3H), 3.25 (s, 3H), 2.03 (s, 3H). LC/MS (Method B): 433.1 (M+H)+ HPLC: Rt 5.94 min (Purity: 94.9%).
Reaction SMILES: Cl[C:2]1[C:11]2[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7](=[O:15])[C:6]=2[C:5]([C:16]([OH:18])=[O:17])=[CH:4][CH:3]=1>[OH-].[K+].[Pd]>[O:15]=[C:7]1[C:6]2[C:5]([C:16]([OH:18])=[O:17])=[CH:4][CH:3]=[CH:2][C:11]=2[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]1
Reactant: O=C(O)c1cc(=O)c2c(C(=O)O)ccc(Cl)c2[nH]1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc(=O)c2c(C(=O)O)cccc2[nH]1

Procedure:
To a solution of 25 (7.90 g, 29.5 mmol) in 10% aqueous KOH solution (100 mL) was added 10% Pd/C (0.500 g). The reaction mixture was hydrogenated (50 psi) on a Parr hydrogenation apparatus at room temperature for 4 h. The catalyst was filtered off on a pad of celite and the filtrate was acidified with 2N HCl to pH=6.5, where a solid precipitated and was collected through a filtration. The solid was washed with H2O (100 mL) and Et2O (100 mL), and dried in vacuum at 60° C. to give an off-white solid (26, 6.79 g, 98.6%). 1H NMR (DMSO-d6, 300 MHz) δ ?8.12 (d, J=8.2 Hz, 1H), 7.76 (t, J=8.2 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 6.74 (s, 1H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:34][NH2:35]>>[CH3:34][NH:35][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=3[F:29])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4cccc(F)c4F)c3O2)cc1
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3cccc(F)c3F)c2O1

Procedure:
The title compound was prepared (0.015 g, 19%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.12 g, 3.9 mmol). mp 123-125° C.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].[CH3:17]OS(OC)(=O)=O>O1CCCC1>[F:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:17])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COS(=O)(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide monohydrate (4.5 g, 1 eq) is added in small portions to a solution of 4-fluoro-3-nitrobenzoic acid (20 g, 1 eq) in tetrahydrofuran (100 ml). After stirring for 1 hour at approximately 20° C., dimethylsulphate (10.2 ml) is added dropwise to the yellow precipitate. The reaction mixture is then heated under reflux for 8 hours then concentrated under reduced pressure at 40° C. The residue is diluted in dichloromethane and Na2C0-3 saturated water. After decanting and extracting, the combined organic phases are washed with salt water, dried over sodium sulphate and concentrated under reduced pressure at 40° C. The yellow solid obtained is recrystallized from a diethyl ether/petroleum ether mixture in order to produce the expected compound in the form of a light yellow powder (16.7 g, 78% yield). Melting point=59° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[N:28][CH:29]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[N:28][CH:29]=2)=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)c1cncc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cncc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (4.52 g), methyl 5-hydroxy-3-pyridinecarboxylate (2.0 g), and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.58 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration. The crystals were subjected to silica gel column chromatography to give crystals (2.41 g, 0.43%) of methyl 5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarboxylate from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 138-139° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([S:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:20])([CH3:19])[O:13][SiH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=1.O.[OH-].[Na+]>C1COCC1>[C:15]([SiH2:14][O:13][C:12]([CH3:20])([CH3:19])[C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH:4]([S:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:3]([OH:31])=[O:2])=[CH:11][CH:10]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)SCCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)O)cc1

Procedure:
3-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid methyl ester (4.93 g, 10.66 mmol) was dissolved in THF (100 mL) and water (50 mL) and cooled down to 0° C. NaOH (6.39 g, 159.88 mmol) was added and the resulting suspension was stirred stirring for 1 h without removing the cooling bath and another 28 h at ambient temperature. 2N HCl was added until pH 2 was reached and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried (MgSO4) and evaporated under reduced pressure to afford the crude product which was directly proceeded to the next step (4.79 g, 95.3%). 1H NMR (400 MHz, CDCl3): δ 7.16 (d, 2H), 7.06 (d, 2H), 6.99 (m, 2H), 6.85 (t, 2H), 4.62 (s, 2H), 3.38 (t, 1H), 3.09 (dd, 1H), 2.71-2.82 (m, 5H), 0.844 (s, 9H), 0.00 (s, 6H). Mass Spectrum: M−H+ 447.10.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])=[C:20]([CH:24]=1)[C:21]([NH:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4])=[O:22]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1cccc(F)c1F
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cccc(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5) and 5-chloro-2-(2,3-difluorophenoxy)benzoic acid (step 2): 1H-NMR (CDCl3) δ 8.15 (1H, d, J=2.6 Hz), 7.96 (2H, d, J=8.4 Hz), 7.62 (1H, d, J=7.4 Hz), 7.44–7.31 (3H, m), 7.14–7.00 (2H, m), 6.85 (1H, d, J=8.7 Hz), 6.81–6.68 (1H, m), 5.33 (1H, dq, J=7.4, 7.1 Hz), 3.90 (3H, s), 1.51 (3H, d, J=7.1 Hz); MS (ESI) m/z 446 (M+H)+, 444 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH2:12].[OH2:13].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O.CCCCCC>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[C:11]([OH:13])=[O:12]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCCC
Product: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-fluoro-4-nitrotoluene (22.45 g, 144.7 mmol) and sodium dichromate dihydrate (60.38 g, 202.6 mmol) in water at 0° C. was added concentrated sulfuric acid (140 mL) dropwise over 3 h. When the addition was complete, the solution was allowed to warm to room temperature over 1 h, and then brought to 90° C. for 1 h. The mixture was allowed to cool to room temperature, diluted with 300 mL water and extracted with ethyl acetate (3×250 mL). The combined organic extracts were concentrated down to 300 mL and extracted with 1 N NaOH (3×250 mL). The aqueous extracts were acidified with 6 N HCl and extracted with ethyl acetate (3×300 mL). The combined organic extracts were dried over MgSO4 and concentrated to give a gummy solid. Trituration with hexane gave the 3-fluoro-4-nitrobenzoic acid as a solid that was collected by filtration (6.51 g, 24%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][N:19]1[CH:23]=[N:22][N:21]=[CH:20]1>>[N:19]1([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:23]=[N:22][N:21]=[CH:20]1
Reactant: Nn1cnnc1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: FC(F)(F)c1cc(Nn2cnnc2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 1-amino-1,3,4-triazole (24 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.61 (brs, 1H), 8.71-8.66 (m, 4H), 7.41 (m, 2H), 6.69 (s, 1H), 5.18 (s, 2H).
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[N:7]=1)C.[O:14]1CCCC1>>[Cl:12][C:8]1[N:7]=[C:6]([CH:5]([OH:14])[CH3:4])[CH:11]=[CH:10][CH:9]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)Cc1cccc(Cl)n1
Product: CC(O)c1cccc(Cl)n1
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of (6-chloro-pyridin-2-yl)-acetic acid ethyl ester (1.8 g, 9.05 mmol) in dry tetrahydrofuran (25 mL) was cooled to 0° C. Borane-dimethylsulfide complex (4.35 mL, 45.25 mmol) was added dropwise and the reaction mixture warmed to room temperature before heating at reflux overnight. The mixture was cooled to room temperature and quenched into saturated ammonium chloride solution and extracted with ethyl acetate. The separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by column chromatography over silica gel (60-120 mesh) using 30% ethyl acetate in chloroform as eluent to afford (6-chloro-pyridin-2-yl)-ethanol (0.76 g, 54%) as a liquid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Reactant: C#CCNC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
Using Method C above, N-methylpropargyl amine (48.4 mg, 0.7 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) using (Ph3P)4Pd (32 mg) and Cul (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[F:16][C:17]([F:24])([F:23])[C:18](B(O)O)=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([C:18]([C:17]([F:24])([F:23])[F:16])=[CH2:19])[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: C=C(B(O)O)C(F)(F)F
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(C(F)(F)F)nc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Yield: 98.8 %

Procedure:
4-bromo-2,6-bis(trifluoromethyl)pyridine (1.53 g), (3,3,3-trifluoroprop-1-en-2-yl)boronic acid (purity: 40%, 2.00 g) and potassium carbonate (1.58 g) were dissolved in the mixed solvent of THF and water, which was then degassed three times. To the solution was added dichlorobis(triphenylphosphine) palladium (II) (0.07 g), and the mixture was heated to reflux for 3 hours under argon atmosphere. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with pentane. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under reduced pressure, and the residue was then purified by silica gel chromatography to obtain 2,6-bis(trifluoromethyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (1.59 g) at a yield of 98%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:8])[CH3:7].[C:33]([O-])(=[O:35])C.[Na+]>CN(C)C=O>[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[C:17]1[CH:18]=[CH:19][C:20]([CH:33]=[O:35])=[CH:21][CH:22]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCCCCCCN(CCCCCCOC(C)=O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCCCCCCN(CCCCCCOC(C)=O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
N,N-Dimethylformamide (DMF, 250 mL) was added dropwise with stirring under nitrogen to phosphorous oxychloride (115 g, 0.751 mol) at 0° C. The resulting orange solution was stirred for 2 hours, then a solution of 236 g (0.626 mol) of N,N-di-(6-acetoxyhexyl)aniline (A2) in 250 mL of DMF was added slowly. The reaction mixture was stirred under nitrogen for 1 hour at 0° C. and then for 6 hours at 80° C. After cooling, the solution was poured onto 500 g of ice plus 200 g of sodium acetate, and the resulting mixture was extracted with dichloromethane (4×250 mL). The combined organic extracts were washed four times with 250 mL portions of water, dried over anhydrous sodium sulfate, and then concentrated at reduced pressure to produce a light brown oil. The oil was fractionally distilled in vacuo to yield 192 g (76%) of A3 as a gold oil, bp 220°-260° C. (0.007 mm).