Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][C:14](=[O:20])[NH:15]2.[OH-].[Na+]>O1CCCC1.CN(C)C=O.N1C=CC=CC=1>[O:20]=[C:14]1[CH2:13][C:12]2[C:16](=[CH:17][CH:18]=[CH:19][C:11]=2[CH2:10][CH2:9][O:8][C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[NH:15]1
Reactant: CC(C)(C)N=C=O
Reactant: O=C1Cc2c(CCO)cccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)OCCc1cccc2c1CC(=O)N2
Temperature: 80 °C
Yield: 11.8 %

Procedure:
Tert-butyl isocyanate (0.685 mL, 6 mmol) was added dropwise to a stirred mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (709 mg, 4 mmol) in tetrahydrofuran (8 mL), dimethylforamide (2 mL) and pyridine (3 drops). The mixture was heated at 70° C. for 15 hours and 80° C. for 39 hours. 0.457 mL of tert-butyl isocyanate was added to the reaction and continued to heat at 90° C. for 24 hours. More tert-butyl isocyanate (0.457 mL) was added and continued to heat at 90° C. for 37 hours. The reaction was cooled, poured into 1 N sodium hydroxide solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with 1 N hydrochloric acid (100 mL) and brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from methanol/ethyl acetate/hexane to give 130 mg (12%) of tert-butyl-carbamic acid 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)-ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]2[CH3:22])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:24]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)=[O:15])[C@@H:17]([CH3:22])[CH2:18]1)([CH3:26])[CH3:25]
Reactant: C[C@H]1CNCCN1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)[C@@H](C)C1

Procedure:
(S)-1-[1-(tert-Butoxycarbonyl)-piperidine-4-carbonyl]-2-methylpiperazine (D21)(0.13 g), 2-iodopropane (0.08 ml) and potassium carbonate (0.1 g) in acetonitrile (2 ml) were heated at 120° C. in an Emerys Optimiser microwave for 45 min. The mixture was then filtered and evaporated. The crude product was redissolved in DCM (30 ml) and washed with saturated sodium hydrogen carbonate solution (3×20 ml) and brine (20 ml). The organic layer was dried (MgSO4) and evaporated to give the title compound (D22) as a clear oil (0.11 g)
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1CCCNC1
Product: CC(=O)N1CCCC(C(=O)O)C1
Yield: 97.4 %

Procedure:
Nipecotic acid (3.87 grams) (30.0 mmoles) was reacted with acetic anhydride (9.17 grams) (90 mmoles) as described in Preparative Example 13A to give the title compound (Yield: 5.0 grams, 97%, MH+ 172).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:30][CH:29]4[C:31]([O:33]C)=[O:32])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:35])[CH:8]=1)[CH3:2].[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:35])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:30][CH:29]4[C:31]([OH:33])=[O:32])=[CH:24][CH:23]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(C4CC4C(=O)OC)cc3)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(C4CC4C(=O)O)cc3)c2)c(C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a mixed solution of methyl 2-(4-{[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy}phenyl)cyclopropanecarboxylate (1.33 g, 2.80 mmol) in methanol (6 mL) and tetrahydrofuran (12 mL) was added 2 M aqueous sodium hydroxide solution (3 and the mixture was stirred at 50° C. for 2 hr. Water was added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-70:30) to give the title compound (1.29 g, quantitative) as a colorless oil.
Reaction SMILES: [H-].[Na+].CCO.[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[C:20]([CH2:26]Br)[CH:19]=1>CCOCC>[Br:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:22][CH:23]=1)[CH2:24][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:6]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C1(C(=O)OCC)Cc2ccc(Br)cc2C1
Reaction time: 0.08 h
Yield: 72.3 %

Procedure:
Sodium hydride (60% in mineral oil, 123 mg, 3.1 mmol) was added in small portions to EtOH (2 mL) in Et2O (6 mL) at room temperature under N2. After the addition was complete, the nearly clear and colorless solution was stirred for 5 min. To this solution, diethyl malonate (234 mg, 1.46 mmol) was added followed by the addition of 4-bromo-1,2-bis(bromomethyl)benzene (500 mg, 1.46 mmol). Immediately, a precipitate was formed, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified on silica gel column using 0-10% EtOAc in petroleum ether to afford the title compound (360 mg, 72%). 1HNMR (400 MHz, DMSO-d6): δ 7.44 (d, 1H), 7.35 (d, 1H), 7.20-7.18 (m, 1H), 4.15 (q, 4H), 3.48 (s, 2H), 3.43 (s, 2H), 1.16 (t, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=O)[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:29]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:21])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(=O)O)cs2)CC1
Reactant: C1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(=O)N3CCCCCC3)cs2)CC1
Reaction time: 2 h
Yield: 69.5 %

Procedure:
4-(4-Carboxy-thiophen-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.1 g, 0.35 mmol) was dissolved in DMF (2 mL) and triethylamine (1.0 mmol). Homopiperidine (1.4 mmol) was added with HATU (0.35 mmol) and the mixture stirred for 2 hours. The mixture was diluted with DCM (20 mL) and washed with water. The organic solution was separated, dried with anhydrous magnesium sulphate, filtered and evaporated. The residue was then purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.095 g). LCMS m/z 391.56 [M+H]+ RT=4.09min (Analytical Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([SH:13])[C:6]([CH:14]([CH3:16])[CH3:15])=[N:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][S:13][C:7]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[N:8]=1)[CH3:30]
Reactant: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1S
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCSc1nc2cc(Cl)c(Cl)cc2nc1C(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 6,7-dichloro-3-isopropylquinoxaline-2-thiol (36 mg, 0.13 mmol) in DMF was added potassium carbonate (55 mg, 0.40 mmol) followed by ethyl 3-bromopropionate (0.02 ml, 0.16 mmol). The reaction was stirred at room temperature for 4 days. Purification by flash column chromatography using ethyl acetate:hexanes 1:40 afforded the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([F:10])[C:4]=1[CH2:11][C:12]([OH:14])=O.[CH2:15]([C@H:22]1[CH2:26][NH:25][C@H:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C@H:22]1[CH2:26][N:25]([C:12](=[O:14])[CH2:11][C:4]2[C:5]([F:10])=[CH:6][CH:7]=[C:8]([F:9])[C:3]=2[F:2])[C@H:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)Cc1c(F)ccc(F)c1F
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cc1c(F)ccc(F)c1F
Yield: 49.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,3,6-trifluorophenyl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 84, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(2,3,6-trifluorophenyl)acetyl)pyrrolidine-2-carboxamide (16.8 mg, 49.8%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.93 (s, 1H), 7.52 (d, 2H), 7.39 (m, 1H), 7.32-7.15 (m, 9H), 7.09 (m, 1H), 6.93 (m, 2H), 4.46 (m, 1H), 3.79 (m, 3H), 3.38 (m, 1H), 2.70 (m, 3H), 1.93 (m, 2H). MS (EI) for C32H26F4N2O3. found 563.6 (MH+).
Reaction SMILES: [CH2:1]([C@H:9]([C@H:12]([OH:14])[CH3:13])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(OCC)C.O.C1(C)C=CC=CC=1>[CH2:1]([C@H:9]1[CH2:10][O:11][C@H:20]([C:19]2[CH:22]=[CH:23][C:16]([OH:15])=[CH:17][CH:18]=2)[O:14][C@@H:12]1[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCC[C@@H](CO)[C@@H](C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCC[C@H]1CO[C@H](c2ccc(O)cc2)O[C@@H]1C
Yield: 84.7 %

Procedure:
A mixture of 320 mg of (2S,3R)-2-octyl-1,3-butanediol, 193 mg of p-hydroxybenzaldehyde, 0.1 ml of 1N sulfuric acid and 20 ml of toluene was placed under nitrogen in a round flask having a magnetic stirrer, water separator and condenser. The mixture was heated to reflux for 3 hours while separating water. The cooled reaction mixture was poured into aqueous sodium hydrogen carbonate solution and treated with diethyl ether. The aqueous phase was separated and extracted three times with diethyl ether. The combined organic phases were washed three times with round flask having a magnetic stirrer, water separator and condenser. The mixture was heated to reflux for 3 hours while separating water. The cooled reaction mixture was poured into aqueous sodium hydrogen carbonate solution and treated with diethyl ether. The aqueous phase was separated and extracted three times with diethyl ether. The combined organic phases were washed three times with water, dried over magnesium sulfate, filtered and evaporated. Recrystallization of the yellowish, solid residue (480 mg) from hexane/ethyl acetate (vol. 25:1) gave 410 mg of 4-[(2S,4R,5S)-5-octyl-4-methyl-1,3-dioxan-2-yl]phenol as yellowish crystals with [a]D =+27° (c=1% in chloroform).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][C:11]([CH3:20])([C:13]([O:15]C(C)(C)C)=[O:14])[CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([NH:10][C:11]([CH3:12])([C:13]([OH:15])=[O:14])[CH3:20])=[O:9])=[CH:6][N:5]=[C:4]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1cnc(-n2cccn2)nc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cnc(-n2cccn2)nc1O)C(=O)O

Procedure:
The product of Step A (3.0 g, 8.64 mmol) was combined with DCM (18 ml) and TFA (2.5 mL). The reaction was aged at reflux for about 5 h and then concentrated. The product was then treated with Et2O, isolated by filtration, and washed with hexane to afford the title compound. HPLC/MS: 292.0 (M+1); Rt=1.42 min.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([CH3:19])([O-:18])=[O:17].N12CCCN=C1CCCCC2>ClCCl>[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]([OH:9])[CH2:19][N+:16]([O-:18])=[O:17])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=[N+]([O-])CC(O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Fifty grams (254.78 mmol) of diphenylacetaldehyde (Aldrich) and 18.66 g (305.73 mmol) of nitromethane was dissolved in 635 mL of dichloromethane. The stirred solution was treated with 35 g of 3Å molecular sieves followed by 11.64 g (76.43 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Aldrich) and stirred overnight at room temperature. The reaction mixture was filtered and the filtrate was treated with 700 mL of 2N aqueous HCl. The organic layer was separated and washed with saturated brine solution, dried with sodium sulfate and evaporated in vacuo. The residue was treated with 600 mL of hexane and stirred overnight whereupon crystallization occurred. After isolation there was obtained 38.22 g (58%) of 3,3-diphenyl-2-hydroxy-l-nitropropane as a pale yellow solid which was used directly in the following step.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:16][CH2:17][C:18](=O)[CH2:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:17]([CH:18]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:19][CH3:20])[CH3:16]
Reactant: CCC(=O)CC
Reactant: NCCNC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCC(CC)NCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Benzyl 2-aminoethylcarbamate hydrochloride (2 g, 8.65 mmol) was dissolved in dichloromethane (50 ml) and 3-pentanone (3.7 ml, 35 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature. Sodium triacetoxy borohydride (5.5 g, 26 mmol) was added and the reaction mixture was then stirred for 16 hours at room temperature. The solution was washed with saturated aqueous sodium hydrogen carbonate solution (40 ml). The dichloromethane phase was dried over anhydrous magnesium sulphate and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume). This gave the title compound as an oil (1.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([Br:8])[CH:7]=1.C[Si]([C:14]#[N:15])(C)C.CN(C)C(Cl)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:14]([C:3]1[C:2]([Br:1])=[CH:7][C:6]([Br:8])=[CH:5][N:4]=1)#[N:15]
Reactant: [O-][n+]1cc(Br)cc(Br)c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ncc(Br)cc1Br

Procedure:
A mixture of 3,5-dibromopyridine N-oxide (prepared in the above (1)) 2.26 g, trimethylsilylcyanide 1.06 g and dimethylcarbamic acid chloride 1.15 g in methylene chloride 25 ml is refluxed under heating for 1 day. To the mixture are added trimethylsilylcyanide 443 mg and dimethylcarbamic acid chloride 480 mg, and the mixture is refluxed under heating for 20 hours. An aqueous sodium hydrogen carbonate solution is added to the reaction mixture cooled, and the mixture is extracted with methylene chloride. The combined extract is washed, dried and the solvent is removed in vacuo. The residue is purified by silica gel chromatography (solvent; n-hexane:ethyl acetate=1:1) to give 2-cyano-3,5-dibromopyridine 1.38 g. mp 109-112° C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>ClCCl>[C:12]([O:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn2cccc(O)c2n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cccn2cc(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
A mixture of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (10 g), acetic anhydride (10.3 g) and pyridine (10.7 g) in anhydrous dichloromethane (100 ml) was stirred for 1 hour at ambient temperature and allowed to stand overnight. The 30 mixture was washed with water, and the organic layer was separated. The aqueous layer was neutralized with sodium bicarbonate and extracted with chloroform. The combined organic layers were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo to give 8-acetoxy-2-methylimidazo[1,2-a]pyridine (13.1 g) as oil.
Reaction SMILES: [C:1]1([C:7]([OH:9])=O)([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.CN1CCOCC1.S(Cl)(Cl)=O.[NH2:21][C:22]1[C:37]([F:38])=[CH:36][C:25]([O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=2)=[C:24]([F:39])[CH:23]=1>O1CCCC1>[C:33]([C:29]1[CH:28]=[C:27]([O:26][C:25]2[C:24]([F:39])=[CH:23][C:22]([NH:21][C:7]([C:1]3([C:4]([OH:6])=[O:5])[CH2:2][CH2:3]3)=[O:9])=[C:37]([F:38])[CH:36]=2)[CH:32]=[CH:31][N:30]=1)(=[O:34])[NH2:35]
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)O)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a solution of 1,1-cyclopropanedicarboxylic acid (492 mg) in tetrahydrofuran (15 ml) was added dropwise 4-methylmorpholine (0.416 ml) while cooling in an ice water bath under a nitrogen atmosphere, followed by stirring for 15 min. To the reaction mixture, was then added thionyl chloride (0.276 ml), followed by stirring at the same temperature for 30 min. To the reaction mixture were added 4-(4-amino-2,5-difluorophenoxy)pyridine-2-carboxamide (500 mg) and 4-methylmorpholine (0.416 ml) in this order while cooling in an ice water bath under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned after addition of a 1N aqueous solution of sodium hydroxide (15 ml) and tert-butyl methyl ether (30 ml). The separated aqueous layer was treated with 1N hydrochloric acid (15 ml) to precipitate a solid. The solid was collected by suction filtration and washed with water (10 ml, three times). Hot air drying at 60° C. provided 1-[4-(2-carbamoylpyridin-4-yl)oxy-2,5-difluorophenylaminocarbonyl]cyclopropanecarboxylic acid as a pale purple solid (674 mg, 95%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18][OH:19])[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[CH3:30]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18][O:19][CH3:30])[C@@H:12]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCO)[C@H]1Oc1ccccc1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]1Oc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)carbamate (400 mg, 0.982 mmol) and Proton Sponge® (841 mg, 3.93 mmol) in anhydrous CH2Cl2 (10 mL) at 0° C. (icewater bath) was added trimethyloxonium tetrafluoroborate (290 mg, 1.963 mmol; weighed under N2), and the resulting mixture was stirred at 0° C. for 3 h, quenched with 1N HCl (20 mL), and extracted with CH2Cl2 (3×20 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to provide an oily white solid, which was purified by column chromatography on SiO2 (5→20% acetone/hexanes) to provide the title compound as a white, crystalline solid (321 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 7.27 (t, J=8.0 Hz, 2H), 6.94 (dd, J=7.7, 3.3 Hz, 3H), 5.10 (d, J=8.1 Hz, 1H), 5.08-4.98 (m, 1H), 4.20 (q, J=7.9, 6.9 Hz, 2H), 3.36 (t, J=6.5 Hz, 2H), 3.25 (s, 3H), 2.27 (dt, J=13.3, 6.8 Hz, 1H), 1.88 (ddt, J=10.8, 6.9, 3.9 Hz, 2H), 1.83-1.71 (m, 1H), 1.70-1.61 (m, 1H), 1.60-1.52 (m, 1H), 1.44 (s, 10H), 1.28 (d, J=6.5 Hz, 3H), 1.25-1.16 (m, 1H), 1.16-1.05 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 173.28, 159.46, 154.90, 129.61, 121.05, 115.38, 81.12, 79.86, 74.71, 70.79, 58.42, 52.99, 40.09, 34.12, 30.53, 28.33, 28.15, 19.07, 18.36; ESIMS m/z 422.3 ([M+H]+), 444.3 ([M+Na]+).
Reaction SMILES: [O-]Cl.[Na+].[OH-].[Na+].[F:6][C:7]([F:22])([F:21])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH:18]=[N:19][OH:20])=[CH:15][C:16]=1[CH3:17])=[O:11].[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1>C1COCC1.C(OCC)C>[F:22][C:7]([F:6])([F:21])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([C:18]2[CH2:31][C:30]([C:28]3[CH:27]=[C:26]([Cl:36])[CH:25]=[C:24]([Cl:23])[CH:29]=3)([C:32]([F:33])([F:35])[F:34])[O:20][N:19]=2)=[CH:15][C:16]=1[CH3:17])=[O:11]
Reactant: Cc1cc(C=NO)sc1C(=O)NCC(F)(F)F
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(=O)NCC(F)(F)F
Reaction time: 21 h
Yield: 15.7 %

Procedure:
Chlorox (4%, 1.02 ml) and NaOH (1N, 0.1 ml) are premixed and then added to a solution of 5-(hydroxyimino-methyl)-3-methyl-thiophene-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (200 mg) and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (170 mg, example 1, Step A) in THF (3 ml) and diethyl ether (3 ml) at 5° C. The cold bath is then removed. After 21 hours, water is added and the reaction mixture is extracted three times with ethyl acetate. The organic phases are combined, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl thiophene-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (56 mg) as light yellow oil. MS (HPLC/MS): 505 (MH+). Retention time: 4.38 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: CCCCCCCN
Solvent: CN(C)C=O
Product: CCCCCCCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 1.07 g (7.5 mmol) of heptylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 1.00 g (yield: 100%) of the title compound.