Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([NH:16][CH2:17][CH2:18][S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH3:15].[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][C:26]=1[C:35]([F:38])([F:37])[F:36].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(OCC)(=O)C.ClCCl.O.C(OCC)(=O)C.CN(C=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([N:16]([CH2:17][CH2:18][S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[C:32](=[O:33])[CH2:31][C:28]1[CH:29]=[CH:30][C:25]([F:24])=[C:26]([C:35]([F:36])([F:38])[F:37])[CH:27]=1)[CH3:15]
Reactant: CCS(=O)(=O)CCNC(C)c1nc2ccc(F)cn2c(=O)c1Br
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCS(=O)(=O)CCN(C(=O)Cc1ccc(F)c(C(F)(F)F)c1)C(C)c1nc2ccc(F)cn2c(=O)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a flask with E4 (310 mg, 0.77 mmol) was added 2-(4-fluoro-3-(trifluoromethyl)phenyl)acetic acid (187 mg, 0.84 mmol), EDC (440 g, 2.3 mmol), HOBt (52 mg, 0.38 mmol), followed by 14 mL of anhydrous DMF and N-methyl morpholine (0.25 mL, 2.3 mmol). The reaction was stirred at room temperature overnight and worked up with ethyl acetate and water. Column chromatography with gradient ethyl acetate/dichloromethane (3:1 to 2:1 to 1:1) gave 460 mg E5 as an yellow foamy solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[NH:19][CH2:18][CH:15]1[CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:17]=2[O:16]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1cccc(C)c1-c1cccc2c1OC(CN)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1-c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2
Yield: 87.2 %

Procedure:
Treatment of (±)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.947 g, 3.73 mmol) with diisopropylethylamine (0.725 g, 5.60 mmol) and benzyl chloroformate (0.7647 g, 4.48 mmol) generally according to the procedure described for Intermediate 12 gave 1.26 g (87%) of (±)-benzyl[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil Rf=0.56 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C25H25NO3: C, 77.49; H, 6.50; N, 3.61. Found: C, 77.42H, 6.57; N, 3.62. Chiral HPLC separation of (±)-benzyl[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, methanol:carbon dioxide 4:6) provided two fractions. Fraction 1 (Rt=2.89 min, Chiralcel OJ, methanol:carbon dioxide 4:6); Fraction 2 (Rt=3.84 min, Chiralcel OJ, methanol:carbon dioxide 4:6).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH:4][N:3]=1.[C:20](OCC)(=[O:25])[CH2:21][C:22]([CH3:24])=O>C(O)(=O)C>[CH2:14]([S:13][CH2:12][CH2:11][S:10][CH2:9][CH2:8][S:7][C:5]1[N:6]=[C:2]2[N:3]([N:4]=1)[C:20]([OH:25])=[CH:21][C:22]([CH3:24])=[N:1]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCSCCSCCSc1nc(N)n[nH]1
Solvent: CC(=O)O
Product: CCCCCCSCCSCCSc1nc2nc(C)cc(O)n2n1
Yield: 78.4 %

Procedure:
A mixture of Compound 12 (3.90 g, 13.3 mmole), ethyl acetoacetate (1.94 g, 14.9 mmole), and acetic acid (8.2 mL) was heated at reflux in a dry nitrogen atmosphere overnight. On cooling, the mixture solidified. The solid was collected, washed with cold ethanol and recrystallized from ethanol to yield Compound 20 (4.03 g, 74% yield), m.p. 119°-121° C. Analysis: Calculated for C10H26N4OS3 : C, 49.71; H, 6.78; N, 14.49. Found: C, 48.98; H, 6.76; N, 14.34.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:28])[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15](=[O:28])[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cccc(OCC(=O)NN)c1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: COC(=O)c1cccc(OCC(=O)NN=C2C(=O)Nc3ccc(I)cc32)c1
Temperature: 100 °C
Yield: 79 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added methyl 3-(2-hydrazino-2-oxoethoxy)benzoate. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 380 mg of the title compound (79%) as a orange powder in 98.9% purity by HPLC (Rt: 4.3, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([N:16]2[N:20]=[CH:19][CH:18]=[N:17]2)=[CH:14][C:13]([N+:21]([O-])=O)=[CH:12][N:11]=1>[Pd].CO.C(OCC)(=O)C>[CH3:5][O:6][CH2:7][CH2:8][O:9][C:10]1[N:11]=[CH:12][C:13]([NH2:21])=[CH:14][C:15]=1[N:16]1[N:20]=[CH:19][CH:18]=[N:17]1
Reactant: COCCOc1ncc([N+](=O)[O-])cc1-n1nccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCOc1ncc(N)cc1-n1nccn1
Yield: 94.6 %

Procedure:
10% Pd/C (200 mg) and ammonium formate (200 mg) were added to an MeOH/ethyl acetate (5 ml/5 ml) solution containing 2-(2-methoxyethoxy)-5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridine (286 mg) obtained in the 1st step, followed by reflux for 1 hour. Insoluble matter was removed using Celite and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:5) and a white solid of 6-(2-methoxyethoxy)-5-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (240 mg) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:14]=[CH:15][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2.C1C(=O)N([Br:24])C(=O)C1>C1COCC1.CN1C(=O)CCC1>[Br:24][C:14]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([Cl:1])[C:3]2=[N:16][CH:15]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=3
Reactant: Cc1cc2nc(Cl)c3nccn3c2cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1cc2nc(Cl)c3ncc(Br)n3c2cc1C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
To a stirred suspension of 4-chloro-7,8-dimethyl-imidazo[1,2-a]quinoxaline (32.2 g, 0.148 mot) in THF/NMP 2:1 (312 mL) was added NBS (26.3 g, 0.148 mot) in one portion at room temperature. After stirred for 18 h, additional NBS (13.1 g, 0.074 mot) was added and the mixture was stirred for additional 2 h at room temperature. After removal of the THF portion of the organic phase by vacuum evaporation, water was added (520 mL). The precipitate was filtered and the residue was washed with water, diethyl ether and dried to give 35 g of the title compound. 1H-NMR (300 MHz, d6-DMSO): δ=8.54 (1H, s), 7.75 (1H, s), 7.40 (1H, s), 2.20 (6H, s) ppm.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[C:17]([O:18][C:2]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Oc1cccnc1Cl
Reactant: N#Cc1cc(F)ccc1F
Product: N#Cc1cc(F)ccc1Oc1cccnc1Cl

Procedure:
2,5-Difluoro-benzonitrile was reacted with 2-chloropyridin-3-ol according to the method of Example 78A to provide the title compound. MS (DCI/NH3) m/z 249 (M)+, 251 (M+2)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH3:8])[O:4][N:3]=1.[CH2:23](O)[CH2:24][OH:25]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:25][CH2:24][CH2:23][O:22]3)[CH:10]=2)[CH3:8])[O:4][N:3]=1
Reactant: OCCO
Reactant: CC(c1cccc(C(=O)c2ccccc2)c1)c1nc(N)no1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(c1cccc(C2(c3ccccc3)OCCO2)c1)c1nc(N)no1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To 3-amino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (1.20 g, 4.09 mmol) in toluene (10 ml) were added ethylene glycol (0.80 g, 12.9 mmol) and p-toluenesulfonic acid monohydrate (0.025 g, 0.15 mmol). After reflux for 10 h, the mixture was cooled at room temperature and extracted with toluene. The extracts were washed with aqueous sodium hydrogen carbonate and then water, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to a residue, which was chromatographed to afford 3-amino-5-(1-(3-(2-phenyl-1,3-dioxolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole (1.06 g, 77% yield) as crystalline material: mp 112.0°-113.5° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=[O:12])[S:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C1CCCCC1.ClC(Cl)(Cl)C(=N)O[C:24]([CH3:27])([CH3:26])[CH3:25]>B(F)(F)F.CCOCC.ClCCl>[C:24]([O:12][C:11]([C:8]1[S:7][C:6]2[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:10]=2[CH:9]=1)=[O:13])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(O)c1cc2c(s1)CCCC2=O
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1cc2c(s1)CCCC2=O
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
4-Oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid (Behringer, H.; Falkenberg, K. Chem. Ber., 1966, 99, 3309) (7.69 g, 39.19 mmol) was suspended in 120 mL 2:1 cyclohexane: dichloromethane. Tert-butyl 2,2,2-trichloroacetimidate (17.13 g, 78.38 mmol) was added in one portion, followed by boron trifluoride diethyl etherate (87.8 mg, 6.19 μmol, 0.16 mol %). The resultant slurry was stirred vigorously for 1.5 hours and a further portion of tert-butyl 2,2,2-trichloroacetimidate (8.57 g, 39.19 mmol) was added. Stirring was continued overnight. Further portions of tert-butyl 2,2,2-trichloroacetimidate (8.57 g, 39.19 mmol) were added at 1.5 hours and 3 hours and after a further 3 hours the reaction was quenched by cautious addition of solid NaHCO3 (˜1 g). Silica was added (˜80 mL) and the resulting suspension was concentrated under reduced pressure. The resulting crude mixture was purified by silica gel chromatography (20% EtOAc in hexanes on 1 L of silica) to afford the title compound as a light yellow solid (8.81 g, 89% yield). MS (ES+) 253. δH (CDCl3) 1.5-1.6 (9H, s), 2.2-2.3 (2H, m), 2.5-2.6 (2H, m), 3.0-3.1 (2H, m), 7.9 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 79 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol) was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (87 mg, 79%) which was obtained as an off white solid. MS: m/e=370.0 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][NH2+:9][CH2:8]1)=[O:6])[CH3:3].Br[CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:15][CH2:14][N:9]1[CH2:10][CH2:11][CH2:12][CH:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:8]1
Reactant: CCOC(=O)C1CCC[NH2+]C1
Reactant: ClCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCCN(CCCl)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-(ethoxycarbonyl)piperidinium hydrochloride (10 g, 65 mmol) in acetone was treated with 1-bromo-2-chloroethane (14.7 g, 0.1 mol) and anhydrous potassium carbonate (13.8 g, 0.1 mol) and the mixture stirred at room temperature for 24 h, the mixture was concentrated and the reside was treated with water and extracted with ether. The extracts were combined and concentrated and the crude was purified by chromatography (silica gel, ethyl acetate:petroleum ether 1:5) to give ethyl 1-(2-chloroethyl)piperidine-3-carboxylate. (3.73 g, Y: 26%). 1HNMR (400 MHz, CDCl3); δ: 1.25 (t, J=7 Hz, 3H), 1.40-3.10 (m, 11H), 3.58 (t, J=7 Hz, 2H), 4.15 (q, 2H). LC-MS (ESI) (m/z): 220 (M+1)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)#[N:22]>CN(C)C(=O)C.O>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:30][NH:29][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:32][CH:31]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(I)c1
Reactant: N#Cc1ccc(C(=O)NN)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(C(=O)NNC(=O)Cc2cccc(I)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Add 1,1-carbonyldimidazole (0.72 g, 4.40 mmol) to a solution of 3-iodo-phenylacetic acid (1.20 g, 4.6 mmol) in 40 mL of N,N-dimethylacetamide, followed by N,N-diisopropylethylamine (0.79 mL, 4.40 mmol). Stir the mixture at room temperature for 2 h, add 4-cyano-benzoic acid hydrazide (0.64 g (4.0 mmol) and heat the mixture to 60° C. for 2 h. Cool the mixture to room temperature and dilute with H2O causing a solid to precipitate from solution. Collect the precipitate by filtration, wash with H2O and diethyl ether dry. Collect any further material that may crystallize from the filtrate. Extract the filtrate with CH2Cl2 and concentrate the combined organic phase provide a clear liquid. Dilute this mixture with H2O resulting in a third crop of material to precipitate from solution. Collect and combine all solid material to give 1.31 g, 71% yield of 4-cyano-benzoic acid N′-[2-(3-iodo-phenyl)-acetyl]-hydrazide as a powder.
Reaction SMILES: [Cl-].[NH4+].C(O)(C)C.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[OH:17]>O>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[C:9]([OH:17])[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: Nc1ccc(Cl)c(O)c1

Procedure:
A suspension (about 600 ml) containing 100 g of reduced iron, 5 g of ammonium chloride, 500 ml of isopropyl alcohol, and 100 ml of water was refluxed with vigorous stirring. To this suspension was added 100 g of 2-chloro-5-nitrophenol in portions. After completion of the addition, the mixture was heated for an additional 1 hour. This suspension was filtered when hot with the aid of Celite and the filtrate was washed with about 500 ml of hot isopropyl alcohol and then concentrated to about one-fifth its original volume under reduced pressure. To the concentrate was added 1 l of ice water and the resulting crystalline precipitate was collected by filtration and washed with water.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-3-trifluoromethylphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H10ClF3N4, 364. Found, 363, 365.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:5][CH:6]([CH2:20][CH3:21])[C:7]([NH:9][C:10]([CH3:19])([CH3:18])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[O:8].I([O-])(=O)(=O)=[O:27].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:5][CH:6]([CH2:20][CH3:21])[C:7]([NH:9][C:10]([CH3:19])([CH3:18])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:17])=[O:27])=[O:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCSC
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCS(C)=O
Reaction time: 2.5 h

Procedure:
To a stirred solution of 2-(3,5-dichlorophenoxy)-N-(6-methyl-1-methylthio-hept-4-yn-6-yl) butyramide (0.21 g) in ethanol (2.5 ml) at ambient temperature was added dropwise a solution of sodium periodate (0.13 g) in water (2.5 ml). The mixture was stirred for 2.5 hours, stored for 18 hours then evaporated under reduced pressure. The residue was extracted with dichloromethane and the organic phase filtered then evaporated under reduced pressure to give the required product as a colourless oil, 0.18 g, 1H NMR (CDCl3) δ: 0.98-1.02(3H, t); 1.56(3H, s); 1.58(3H, s); 1.92-2.00(4H, m); 2.34-2.42((2H, m); 2.62(3H, s); 2.76-2.84(1H, m); 2.90-2.96(1H, m); 4.34-4.38(1H, m); 6.26(1H, s); 6.82(2H, s); 7.02(1H, s).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41]>CN(C)C=O.C(C(C)=O)C>[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41].[C:29]1([CH2:35][C:36]([O:26][CH:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24](=[O:25])[N:16]2[CH2:15][CH2:14][CH2:13][N:10]2[CH2:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)OC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1pyridyl)propyl]-3-hydroxy-1-isoindolinone (7 g) in anhydrous dimethylformamide (75 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (1 g) in anhydrous dimethylformamide (25 cc) at a temperature close to 20° C. in the course of 10 minutes and agitation is continued for 2 hours. Then, 3.5 g of phenylacetyl chloride is added in the course of 5 minutes, and agitation is continued for a further 20 hours. The suspension obtained is poured into distilled water (100 cc) and extracted with methylene chloride (4×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methyl ethyl ketone (30 cc). A solution of oxalic acid (1.1 g) in methyl ethyl ketone (15 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 4.2 g of 3-phenylacetoxy-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 134° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH:33](=O)[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([BH3-])#N.[Na+]>ClC(Cl)C.CO>[CH2:33]([N:16]1[CH2:15][CH2:14][N:13]([C:6]2[C:5]([CH3:19])=[C:4]([NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:26]=3)[C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[N:7]=2)[CH2:18][CH2:17]1)[CH3:34]
Reactant: CC=O
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Product: CCN1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)CC1
Reaction time: 8 h

Procedure:
The 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)-quinolin-4-amine (50 mg, 0.11 mmol) was dissolved in a mixture of dichloroethane (1.3 mL) and MeOH (0.63 mL). The acetaldehyde (6.4 μL, 0.11 mmol) and sodium triacetoxyborohydride (72 mg, 0.34 mmol) were added and the mixture was stirred overnight. A small amount (50 mg) of sodium cyanoborohydride was added to drive the reaction to completion. The reaction was quenched with satd sodium bicarbonate solution and extracted with EtOAc. The organic layer was then dried over magnesium sulfate and the filtrate was cond. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini™ column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 95% over 20 min to provide 2-(4-ethylpiperazin-1-yl)-5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. The salt was then free based by eluting through an SCX column with 0 to 2M ammonia in MeOH to give the desired product as the free base. TFA salt: 1H NMR (CDCl3) δ ppm 7.86 (2H, dd, J=4.3, 2.2 Hz), 7.61 (1H, d, J=9.2 Hz), 7.36-7.43 (1H, m), 7.20 (1H, t, J=2.0 Hz), 6.89 (1H, ddd, J=13.4, 8.5, 2.3 Hz), 4.24 (2H, d, J=14.7 Hz), 3.86-3.95 (4H, m), 3.77 (2H, t, J=13.2 Hz), 3.63 (2H, d, J=12.3 Hz), 3.26-3.38 (4H, m), 3.15 (4H, q, J=7.2 Hz), 2.13 (3H, s), 1.39 (3H, t, J=7.3 Hz). Mass Spectrum (ESI) m/e=469.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([OH:21])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:22]1([CH2:25][NH2:26])[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][NH:26][C:19]([C:12]2[C:13]([C:15]([F:18])([F:16])[F:17])=[N:14][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)=[N:10][CH:11]=2)=[O:21])[CH2:24][CH2:23]1
Reactant: NCC1CC1
Reactant: O=C(O)c1cnc(Nc2cccc(Br)c2)nc1C(F)(F)F
Product: O=C(NCC1CC1)c1cnc(Nc2cccc(Br)c2)nc1C(F)(F)F
Yield: 26.2 %

Procedure:
In a manner similar to Reference Example 1 (c) 2-(3-bromophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (80 mg) and cyclopropylmethylamine (19 mg, ex Lancaster) afforded the title compound (24 mg). Sample purified by mass directed auto-prep.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[C:5](\[NH2:16])/[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[CH3:25][C:24]([NH:16]/[C:5](/[CH2:6][C:7]1[C:8]([F:15])=[CH:9][C:10]([F:14])=[C:11]([F:13])[CH:12]=1)=[CH:4]\[C:3]([O:2][CH3:1])=[O:17])=[O:26]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)/C=C(\N)Cc1cc(F)c(F)cc1F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)/C=C(/Cc1cc(F)c(F)cc1F)NC(C)=O
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A solution of (Z)-methyl-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate (4.90 g, 20 mmol) of Example 2, pyridine (4.8 ml) and acetic anhydride (4.80 g, mmol) in THF (30 ml) was heated to reflux for 16 h. The reaction mixture was stirred at room temperature, quenched with 1N HCl, and extracted with ethyl acetate (3×20 ml). The combined organic phase was washed with saturated sodium bicarbonate, then brine, then dried over sodium sulfate. Concentration was followed by purification by flash chromatography to afford 4.03 g of product (70.3%). 1H NMR (300 MHz, CDCl3) 11.14 (s, 1H) 7.10-7.00 (m, 1H), 6.96-6.87 (m, 1H), 4.81 (s, 1H), 4.14 (s, 2H), 3.70 (s, 3H), 2.14 (s, 3H).