Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.C(OC([NH:33][CH2:34][CH2:35]Br)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH2:33][CH2:34][CH2:35][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH3:12])[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:25])[C:22]2=[O:23]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O)cc2c1=O
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCN)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
N-Cyclopropyl-3-(6-hydroxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (0.621 g), 2-(tert-butoxycarbonylamino)ethyl bromide (0.5 g), potassium carbonate (2.06 g), and potassium iodide (0.025 g) were stirred in DMF (10 ml) at 60° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water (5×), brine (2×), dried (magnesium sulfate) and concentrated. The resulting solid was dissolved in a solution of 4N HCl in dioxane (4 ml) and methanol (3 ml) and stirred at room temperature for 16 hours. The precipitate was collected by filtration and washed with ethyl acetate. Purification by column chromatography on an ion exchange column (isolute SCX-2 column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) washing with methanol initially and then eluting with a 99:1 mixture of methanol and aqueous ammonia solution gave 3-[6-(2-aminoethoxy)-4-oxoquinazolin-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide (AZ12278502) (0.343 g) as a white solid; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.69 (m, 2H), 1.81 (broad s, 2H), 2.14 (s, 3H), 2.87 (m, 1H), 2.93 (t, 2H), 4.08 (m, 2H), 7.52 (m, 2H), 7.59 (s, 1H), 7.73 (d, 1H), 7.84 (s, 1H), 7.91 (d, 1H), 8.19 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 379.
Reaction SMILES: O.Cl.C1(C)C=CC=CC=1.[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=O)[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=2)=[CH:16][C:15]=1[Br:33])(=[O:12])[CH3:11]>[Zn].O1CCOCC1>[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=2)=[CH:16][C:15]=1[Br:33])(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1Br
Agent: Cl
Agent: [Zn]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)Nc1ccc(-c2ccc(CCCC(=O)O)cc2)cc1Br
Reaction time: 8 h
Yield: 35 %

Procedure:
7.5 ml of water, 17.5 ml of concentrated hydrochloric acid, 50 ml of toluene, 30 ml of dioxane and 5 gm of 4-(4'-acetamido-3'-bromo-4-biphenylyl)-4-oxo-butyric acid were added to 10 gm of amalgamated zinc. This reaction mixture was refluxed for 4 hours. After standing overnight at room temperature, the precipitated crystals were collected and recrystallized from ethyl acetate. Yield: 35% of theory; m.p. 155°-156° C. Melting point of the cyclohexylamine salt: 179°-180° C. (precipitated from ethyl acetate).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.OB(O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].C1(C)C=CC=CC=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.O.C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)CCc1oc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Yield: 87.8 %

Procedure:
A mixture of methyl 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionate (1.50 g), dihydroxyphenylborane (650 mg), sodium hydrogen carbonate (1.68 g), tetrakis(triphenylphosphine)palladium (250 mg), toluene (50 mL), ethanol (25 mL) and water (25 mL) was stirred under an argon atmosphere with heating under reflux for 12 hrs. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography. Methyl 3-[4-(4-chlorophenyl)-2-phenyl-5-oxazolyl]propionate (1.50 g, 88%) was obtained as a yellow oil from a fraction eluted with hexane-ethyl acetate (6:1, volume ratio).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[CH2:18]Br)[CH3:2].[CH3:21][O:22][C:23](=[O:36])[CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[CH2:18][N:25]([CH2:24][C:23]([O:22][CH3:21])=[O:36])[S:26]([C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)(=[O:28])=[O:27])[CH3:2]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1cccc(Oc2ccccc2)c1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(Oc2ccccc2)c1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.3 %

Procedure:
A mixture of 2-bromomethyl-3-phenoxy-benzoic acid ethyl ester (6.83 g, 0.02 mol), (toluene-4-sulfonylamino)-acetic acid methyl ester (4.97 g, 0.02 mol), sodium iodide (4.59 g, 0.03 mol), potassium carbonate (4.24 g, 0.03 mol), and anhydrous dimethylformamide (50 mL) was stirred at room temperature for 4 h before it was diluted with water and extracted with ethyl acetate. The organic layer was separated and washed with water and brine. Then it was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (5.10 g): MS: (+) m/z 497.8 (M+1).
Reaction SMILES: [H-].[Na+].[N:3]1[N:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:6]2=[CH:5][CH:4]=1.CI.[C:14](OCC)(=O)C>CN(C)C=O>[CH3:14][N:11]1[CH2:10][CH2:9][CH2:8][N:7]2[N:3]=[CH:4][CH:5]=[C:6]12
Reactant: CCOC(C)=O
Reactant: c1cc2n(n1)CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCCn2nccc21
Reaction time: 1.5 h

Procedure:
To a suspension of 62% sodium hydride (1.41 g) in N,N-dimethylformamide (30 ml) was added 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (4.5 g) under ice-cooling. To this solution was added dropwise methyl iodide (2.27 ml) under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into ethyl acetate (50 ml), and the resulting precipitate was filtered off. The filtrate was evaporated to give 4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (5.05 g).
Reaction SMILES: [F:1][CH:2](F)[C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[O:8])=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=1.C(N(S(F)(F)F)CC)C>C(Cl)Cl>[F:1][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)=[O:8])=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[CH:23]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(C(F)F)c(-c2ccnc(N3CCOCC3)c2)c1
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(CF)c(-c2ccnc(N3CCOCC3)c2)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
To a cooled solution of 4-(difluoromethyl)-3-(2-morpholinopyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)benzamide (1.0 equiv.) in dry CH2Cl2 (0.05 M), (diethylamino)sulfur trifluoride (3.5 equiv.) was added portionwise under vigorous stirring. The resulting reaction mixture was stirred at −78° C. for 3 hrs, Quenched the reaction with sat NaHCO3 and extracted with DCM. The organic layer was washed with Brine, filtered over Na2SO4 and concentrated. The residue was purified by PREP HPLC to yield 4-(fluoromethyl)-3-(2-morpholinopyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)benzamide in 16% yield. 1H NMR (400 MHz, <cd3od>) δ ppm 3.68 (d, J=5.09 Hz, 4H), 3.86 (d, J=5.09 Hz, 4H), 5.40 (s, 1H), 5.52 (s, 1H), 7.01-7.11 (m, 1H), 7.24-7.31 (m, 1H), 7.41-7.48 (m, 1H), 7.52-7.60 (m, 1H), 7.77-7.83 (m, 1H), 7.91-7.98 (m, 1H), 7.99-8.04 (m, 1H), 8.07-8.19 (m, 3H). LC/MS (m/z)=460.1 (MH+), R=0.85 min.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)c(Br)nn2CCN1CCCC1
Temperature: 50 °C
Yield: 133.4 %

Procedure:
A mixture of 3-bromo-5-nitro-1H-indazole (1.8 g, 7.6 mmol) and potassium carbonate (3.1 g 22 mmol) in DMF (20 mL) was stirred for 30 minutes after which 1-(2-chloro-ethyl)-pyrrolidine (0.71 g, 4.2 mmol) was added. The mixture was heated to 50° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The combined filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (1.9 g, 76%). 1H NMR (300 MHz, DMSO-d6) ppm 1.60 (m, 4H), 2.46 (m, 4H), 2.90 (t, 2H, J=6.44), 4.60 (t, J=6.44, 2H), 8.00 (m, 1H), 8.30 (m, 1H), 8.48 (m, 1H); MS (DCI/NH3) m/z 339 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:14][C:15]([N:17]1[CH2:21][CH:20]([CH:22]([OH:24])[CH3:23])[CH2:19][N:18]1[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[C:22]([CH:20]1[CH2:19][N:18]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[N:17]([C:15]([O:14][CH2:11][CH:12]=[CH2:13])=[O:16])[CH2:21]1)(=[O:24])[CH3:23]
Reactant: C=CCOC(=O)N1CC(C(C)O)CN1C(=O)N(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)N1CC(C(C)=O)CN1C(=O)N(C)C
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a solution of oxalyl chloride (7.42 ml) in dichloromethane (250 ml) was added dropwise dimethyl sulfoxide (12.7 ml) at -70° C. To this reaction mixture was added dropwise a solution of 2-allyloxycarbonyl-1-dimethylcarbamoyl-4-(1-hydroxyethyl)pyrazolidine (22 g) in dichloromethane (40 ml), and then was added dropwise triethylamine (56.5 ml) at -70° C. The reaction mixture was allowed to warm to room temperature. The precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was poured into a mixture of ethyl acetate and 1N-aqueous hydrochloric acid, and the organic layer was extracted, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave a residual oil, which was chromatographed on silica gel eluting in turn with a mixture of hexane and ethyl acetate (1:2, V/V) and ethyl acetate to give 4-acetyl-2-allyloxycarbonyl-1-dimethylcarbamoylpyrazolidine (21.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH2:7][N:8]([C:11]([CH:13]3[CH2:18][O:17][CH2:16][CH2:15][O:14]3)=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.O1CCOCC1C=O.Cl[C:30]1[N:35]=[C:34]([NH:36][C:37]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:38]=2[C:39]([NH:41][CH3:42])=[O:40])[C:33]([Cl:48])=[CH:32][N:31]=1>>[Cl:48][C:33]1[C:34]([NH:36][C:37]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:38]=2[C:39]([NH:41][CH3:42])=[O:40])=[N:35][C:30]([NH:1][C:2]2[CH:20]=[CH:19][C:5]3[CH2:6][CH2:7][N:8]([C:11]([CH:13]4[CH2:18][O:17][CH2:16][CH2:15][O:14]4)=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:31][CH:32]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCN(C(=O)C1COCCO1)CC2
Agent: O=CC1COCCO1
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(C(=O)C2COCCO2)CC3)ncc1Cl

Procedure:
(7-Amino-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1,4-dioxinan-2-yl-methanone, prepared in a similar manner as 7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1,4-dioxinan-2-yl-methanone of Example 633b, was reacted with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide, in a similar manner as Example 601b, to yield desired product 2-{5-Chloro-2-[3-([1,4]dioxane-2-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide as a lyophylate (31%); 1H NMR (400 MHz, DMSO-d6) δ 9.39 (d, J=9.23 Hz, 1H), 9.33 (s, 1H), 8.55 (m, 1H), 8.18 (s, 1H), 7.51-7.43 (m, 3H), 7.26 (s, 1H), 7.17 (m, 1H), 6.89 (m, 1H), 4.39 (m, 1H), 3.74-3.4 (bm, H2O+11H), 2.81 (m, 1H), 2.74 (d, J=4.55 Hz, 3H), 2.67 (m, 2H); MS (m/e) 555.14 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[C:10]1=[O:15]
Reactant: BrBr
Reactant: O=C1CCCCC1c1cc(F)cc(F)c1
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1cc(F)cc(F)c1
Temperature: 25 °C
Yield: 112.4 %

Procedure:
2-(3,5-Difluoro-phenyl)-cyclohexanone (50 mg, 0.24 mmol) was dissolved in chloroform (1 mL). To this solution bromine (39.9 mg, 0.25 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (78 mg) which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCC(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)C1CCN(C[C@@H]2CCCNC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
To a solution of tert-butyl (3S)-3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperidin-1-yl)methyl]piperidine-1-carboxylate (2.3 g) in methanol (50 mL) was added 4M HCl in dioxane (15 mL). The mixture was stirred at room temperature for 18 hours and then evaporated. The residue was then partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The layers were separated and the organic extract was evaporated. The residue was triturated with dichloromethane and filtered to give the title compound as a white solid (1.5 g, 83%)
Reaction SMILES: [I-].N([CH:9]=[CH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]=1[CH2:21][CH3:22])C1C=CC=CC=1.[C:23]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[CH3:34])#[N:24].C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C)C=O>[C:23]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[CH:34]=[CH:9][CH:10]=[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH2:21][CH3:22])#[N:24]
Reactant: Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: CC[n+]1c(C=CNc2ccccc2)ccc2ccccc21
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CCN1C(=CC=Cc2ccc([N+](=O)[O-])cc2C#N)C=Cc2ccccc21
Yield: 47 %

Procedure:
The condensation of 4.02 g. (0.01 mole) of 2-(2-anilinovinyl)-1-ethylquinolinium iodide (prepared as described in British Pat. No. 344,409 m.p. 263°-5° C (dec.)) with 2-cyano-4-nitrotoluene (1.67 g., 0.01 mole) was effected in 15 ml. of dimethylformamide containing 2 ml. of acetic anhydride by heating the reaction mixture to reflux, adding 1.01 g. (0.01 mole) of triethylamine, heating at reflux for 1 to 2 minutes and cooling rapidly. The precipitate was collected, washed successively with dimethylformamide, water and ether and then dried to yield 47% of theory of blue dye base m.p. 250°-252° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)(O)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]=1[OH:35]>FC(F)(F)C(O)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)([C:32]2[CH:31]=[C:30]([CH3:34])[C:29]([OH:35])=[C:28]([CH3:27])[CH:33]=2)[C:9]1=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1O
Reactant: Cc1cc(C)cc(C2(O)C(=O)N(Cc3ccccc3)c3ccccc32)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(Cc3ccccc3)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
Dissolve 1-benzyl-3-(3,5-dimethyl-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one (68 mg, 0.2 mmol) and 2,6-dimethylphenol (122 mg, 1.0 mmol) in trifluoroacetic acid (1 mL) and stir at room temperature for 30 min. Pour the reaction over ice water and extract with ethyl acetate (2×). Wash combined organic portions with brine and then dry (Na2SO4), filter and concentrate in vacuo to give an oily residue. Purify with radial chromatography (gradient of 1 EtOAc/9 hexanes and then 1 EtOAc/5 hexanes) to give 55 mg (62%) of the title compound as a white solid. MS (ES): m/z=448 (M+1), 446 (M−1); 1H NMR(DMSO-d6): δ8.29 (s, 1H), 7.38-7.22 (m, 7H), 7.07 (m, 2H), 6.90 (s, 1H), 6.75 (s, 2H), 6.71 (s, 2H), 4.99 (s, 2H), 2.19 (s, 6H), 2.08 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>[Pd].CO>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: Nc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)cc(C(=O)O)c1N
Yield: 95.1 %

Procedure:
2-Amino-5-fluoro-3-nitrobenzoic acid (142; 0.73 g) was dissolved into methanol (10 mL). To this solution was added 5% Pd/C (0.1 g). The resulting reaction mixture was stirred at room temperature under 1 atm of hydrogen for 18 h and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford 2,3-diamino-5-fluorobenzoic acid 143 as a brown solid (0.59 g, 95%).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1)#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=1[O:26][CH:27]([CH3:29])[CH3:28])/[C:19](=[N:21]/O)/[NH2:20].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:19]2[N:21]=[C:10]([C:9]3[CH:8]=[CH:7][C:6]([C:3]4([C:1]#[N:2])[CH2:4][CH2:5]4)=[CH:14][CH:13]=3)[O:12][N:20]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: N#CC1(c2ccc(C(=O)O)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(C4(C#N)CC4)cc3)n2)cc1Cl
Temperature: 160 °C
Yield: 23.7 %

Procedure:
A 20 mL microwave vial was charged with 4-(1-cyanocyclopropyl)benzoic acid (720 mg, 3.85 mmol), (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (880 mg, 3.85 mmol), DCC (873 mg, 4.23 mmol), HOBT (648 mg, 4.23 mmol), ACN (10 ml), and DIEA (1.478 ml, 8.46 mmol). The vial was capped and heated to 160° C. via microwave irradiation for 25 minutes (max 300 W). Solvent was removed under reduced pressure and crude oil was purified by flash column chromatography (Analogix system, heptane/ethyl acetate, 0-45% ethyl acetate over 30 min; 80 g column, 60 mL/min flow rate). Fractions containing product were combined, rotovapped, and dried in a vacuum oven overnight to give 1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)cyclopropanecarbonitrile (347 mg, 23.8%) as a yellow solid. LCMS (Table 1, Method c) Rt=3.19 min, m/z 380.43 (M+H)+; 1H NMR (400 MHz, DMSO)) δ ppm 8.22-8.12 (m, 2H), 8.05 (d, 1H), 7.99 (dd, 2.14 Hz, 1H), 7.62-7.55 (m, 2H), 7.38 (d, 1H), 4.82 (td, 1H), 1.90 (q, 2H), 1.67 (q, 2H), 1.38-1.33 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:20](O)(=O)[CH:21]=[O:22].C(O)C>C(O)(=O)C>[Cl:15][C:14]1[C:9]([C:4]2[CH:3]=[C:2]3[C:7]([N:8]=[CH:20][C:21](=[O:22])[NH:1]3)=[CH:6][CH:5]=2)=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=1
Reactant: O=CC(=O)O
Reactant: Nc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1N
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1cnc2ccc(-c3ncc(C(F)(F)F)cc3Cl)cc2[nH]1
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 87 %

Procedure:
A mixture of 10.0 g of 2-(3,4-diaminophenyl)-3-chloro-5-trifluoromethylpyridine, 5.7 g of a 50% strength by weight aqueous glyoxalic acid solution, 100 ml of ethanol and 50 ml of glacial acetic acid was stirred at 23° C. for 2.5 hours. The solid portion formed was separated off, washed with ethanol and dried. After concentrating, the filtrate gave a further amount of the products. Total yield: 87% (9.9 g of colorless crystals); isomeric ratio according to 1H-NMR=about 1:1).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.N#N.FC(F)(F)C(O)=O.[CH2:17]([N:24]([CH2:30]OC)[CH2:25][Si](C)(C)C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([N:24]1[CH2:30][CH:2]2[C:1](=[O:7])[NH:5][C:4](=[O:6])[CH:3]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(=O)N1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the maleimide (80.4 g, 0.83 mol) in 1.5 L of CH2Cl2 in a 3-neck, 3-L round bottom flask equipped with an addition funnel, internal thermometer, and N2 inlet at 0° C. was added trifluoroacetic acid (TFA) (6.4 mL, 83 mmol). Benzyl(methoxymethyl)trimethylsilylmethylamine (261 g, 1.1 mol) in 500 mL CH2Cl2 was added dropwise via addition funnel over 3 hours with the reaction temperature being maintained below 5° C. After the addition was complete, the mixture was allowed to warm slowly to ambient temperature and then was stirred for 16 h. The mixture was concentrated and the residue was dissolved in 500 mL CH2Cl2 and was washed with 2×50 mL saturated NaHCO3. The layers were separated and the aqueous layer was extracted 2×25 mL CH2Cl2. The combined organics were washed with 25 mL brine, dried over saturated, aqueous Na2SO3, and concentrated under reduced pressure to give the title compound which was carried on to the next step without further purification. MS (DCl/NH3) m/z 231 (M+H)+.