Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=CC(OCC)=O)=[N-].[CH2:9]([CH:17]1[CH2:19][CH:18]1[C:20]([OH:22])=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O=S(Cl)[Cl:25]>C=CCCCCCCCC.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:9]([CH:17]1[CH2:19][CH:18]1[C:20]([Cl:25])=[O:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCC1CC1C(=O)O
Agent: [Cu+2]
Agent: C=CCCCCCCCC
Agent: CCOC(=O)C=[N+]=[N-]
Product: CCCCCCCCC1CC1C(=O)Cl
Reaction time: 10 h

Procedure:
2 grams of anhydrous CuSO4 was suspended in 9 grams of 1-decene in a 2-neck round bottom flask. To one of the necks was fitted a water cooled condenser; to the other an addition funnel filled with a solution of 7.5 g. or ethyl diazoacetate dissolved in 10 grams of 1-decene. The CuSO4 suspension was heated at 100° C. The dropwise addition of 1-decene solution of ethyldiazoacetate into the suspension was accompanied with nitrogen evolution. The reaction mixture was heated after the completion of addition until nitrogen evolution stopped. After filtering CuSO4, the entire bulk of the reaction products was chromatographed quickly on silica gel, eluting with 1:1 mixture of low boiling petroleum ether and CHCl3. The first fraction was the unreacted 1-decene, followed by 5.5 grams of a mixture of cis and trans ethyl 2-(n-octyl)cyclopropanecarboxylate. 4.0 grams of this mixture was hydrolyzed by refluxing with 2.4 g. of NaOH in 30 ml. of H2O for 10 hours. The hydrolysate was washed with ether to remove unreacted esters, then acidified to pH 1 with HCl, followed by extraction with ether. The concentrated ether extracts gave 2.2 g. of 2-(n-octyl)cyclopropanecarboxylic acid. The entire bulk of this acid was treated with excess amount of SOCl2 at room temperature for 10 hours. Evaporation of excess SOCl2 gave quantitative yield of products.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[C:9](=O)([O:12]C)[O:10][CH3:11]>C[O-].[Na+].CO>[C:9](=[O:12])([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])[O:10][CH3:11]
Reactant: OCC(F)(F)C(F)F
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)OCC(F)(F)C(F)F
Temperature: 120 °C
Yield: 48.5 %

Procedure:
In a flask (500-ml volume) equipped with 10 distillation columns, 2,2,3,3-tetrafluoropropanol (100 g, 0.76 mol), dimethyl carbonate (205 g, 2.3 mol) and a 28% sodium methoxide/methanol solution (1.4 g) were charged. The flask was heated to 120° C. to allow the starting materials to react for 10 hours while removing the methanol from the distillation columns by evaporation. After allowing the mixture to cool to room temperature, an aqueous solution of ammonium chloride was added to the mixture and the mixture was shaken to remove the sodium methoxide. The organic layer was washed with water, dried and distilled to give methyl 2,2,3,3-tetrafluoropropyl carbonate as a colorless liquid (70 g, yield 49%). The chemical structure of the produced compound was determined based on the IR and NMR absorbance spectra shown in FIG. 9 and FIG. 10 respectively and the mass spectrometry spectrum (M/e=190).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:30]=[CH:31][C:32]=1[C:33]([N:35]([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])=[O:34])[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:29])OCC)=[CH:21][CH:20]=1)=[O:6])[CH3:3].[OH-].[Na+].[Cl-].[NH4+].N.Cl.[NH2:48]N=CC1C=CC(OCCCCCOC2C=CC(C(=O)N(C(C)C)C(C)C)=C(C=2)OCC(O)=O)=CC=1.Cl>C(O)C>[ClH:1].[NH2:48][N:29]=[CH:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]2[CH:30]=[CH:31][C:32]([C:33](=[O:34])[N:35]([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])=[C:9]([CH:10]=2)[O:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:20][CH:21]=1
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C=NN)cc2)cc1OCC(=O)O)C(C)C
Reactant: CCOC(=N)c1ccc(OCCCCCOc2ccc(C(=O)N(C(C)C)C(C)C)c(OCC(=O)OCC)c2)cc1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)COc1cc(OCCCCCOc2ccc(C=NN)cc2)ccc1C(=O)N(C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A stirred, 0° C. solution of ethyl 4-[5-[3-ethoxycarbonylmethoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride (400 mg, 0.68 mmol) in 25 mL of anhydrous ethanol is treated with 1.36 mL of 1.0N aqueous sodium hydroxide. After stirring 1.5 hours, the reaction is concentrated in vacuo. The resulting 5-[5-[4-(ethoxyiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxyacetic acid is then dissolved in 50 mL of anhydrous ethanol in a pressure tube, and treated with ammonium chloride (500 mg, 9.4 mmol). This mixture is treated with anhydrous ammonia for 2 minutes at 0° C. The pressure tube is sealed and heated to 50° C. for 1 hour. Upon cooling and concentrating in vacuo, the resulting material is purified by chromatography on silica gel (15 g) with 20-30% methanol/dichloromethane as the eluent to afford a colorless foam. The resulting 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxyacetic acid monohydrochloride is then dissolved in 150 mL of anhydrous ethanol at 0° C. and treated with anhydrous hydrogen chloride gas over 30 minutes. This solution is stirred at room temperature for 20 hours and the resulting solution is concentrated in vacuo. The resulting material is purified by chromatography on silica gel (15 g) with 5-20% methanol/dichloromethane as the eluent to afford ethyl 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxyacetate monohydrochloride as colorless foam; CHN calculated for
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][C@@H:41]3[CH3:50])=[CH:36][N:35]=2)[C:30](=[O:51])[N:29]([CH3:52])[CH:28]=1)(=O)C.O.[Li+].[OH-]>CC(O)C.O1CCCC1>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[CH:32]=[C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH:46]5[CH2:47][O:48][CH2:49]5)[CH2:42][C@@H:41]4[CH3:50])=[CH:36][N:35]=3)[C:30](=[O:51])[N:29]([CH3:52])[CH:28]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCc5c(cc6n5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of 101i (270 mg, 0.38 mmol) in propan-2-ol (8 mL), tetrahydrofuran (8 mL), and water (1.5 mL) was added LiOH (914 mg, 38 mmol). The mixture was stirred at 30° C. for 2 h. It was evaporated and the residue was purified by reverse-phase prep-HPLC to give 101 (127 mg, yield 50%) as a white solid. MS: (M+H)+ 669. 1H NMR (500 MHz, DMSO) δ 8.58 (t, J=2.5, 1H), 8.40 (s, 1H), 7.85 (d, J=3.0, 1H), 7.35-7.38 (m, 2H), 7.22-7.25 (m, 2H), 7.13-7.16 (m, 1H), 6.01 (s, 1H), 4.76 (s, 1H), 4.57-4.54 (m, 2H), 4.47 (t, J=6.0, 1H), 4.42 (t, J=6.5, 1H), 4.29 (s, 2H), 3.98-4.04 (m, 1H), 3.89-3.94 (m, 1H), 3.78-3.83 (m, 2H), 3.67 (s, 1H), 3.58 (s, 3H), 3.37-3.42 (m, 1H), 3.00-3.10 (m, 2H), 2.90-2.95 (m, 2H), 2.71 (t, J=6.0, 2H), 2.52-2.55 (m, 1H), 2.28-2.35 (m, 2H), 2.18 (t, J=8.5, 1H), 1.89-1.94 (m, 2H), 1.72-1.78 (m, 2H), 0.93 (t, J=6.5, 3H)
Reaction SMILES: [CH:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1)([CH3:3])[CH3:2].Cl[C:15]1[N:23]=[C:22]2[C:18]([N:19]=[C:20]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([C:32]([OH:35])([CH3:34])[CH3:33])[CH2:28][CH2:27]3)[N:21]2[CH3:24])=[C:17]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:16]=1>>[OH:35][C:32]([CH:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:20]2[N:21]([CH3:24])[C:22]3[C:18]([N:19]=2)=[C:17]([N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH2:41]2)[N:16]=[C:15]([N:5]2[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:12](=[O:13])[N:4]2[CH:1]([CH3:3])[CH3:2])[N:23]=3)[CH2:31][CH2:30]1)([CH3:34])[CH3:33]
Reactant: CC(C)n1[nH]c2ccccc2c1=O
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CC(C)n1c(=O)c2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-isopropyl-1,2-dihydroindazol-3-one and 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol were reacted to give 443. LCMS m/z: 549.3 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][CH2:18][CH2:19][OH:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:31]([O:20][CH2:19][CH2:18][O:17][CH2:16][C:13]1[N:14]([CH3:15])[C:10]([S:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(C)c1nc(COCCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCOCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To dry methylene chloride solution (5 ml) of 200 mg (0.5 mmol) of 2-{[5-(3,5-dichlorophenylthio)-4-isopropyl-1 methyl-1H-imidazol-2-yl]methoxy} ethanol (25a), 161 mg (1.60 mmol) of triethylamine was added. Under ice-cooling, 63 mg (0.8 mmol) of acetyl chloride was added, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added, neutralized, and extracted with methylene chloride. The extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:1) to obtain 200 mg of 2-[-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methylimidazol-2-ylmethoxy]ethyl acetate (Compound I-60) as oil (yield 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=1)([O-])=O>[Pd].C(O)C>[N:11]1([CH2:10][CH2:9][N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cnn(CCN2CCCC2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnn(CCN2CCCC2)c1
Reaction time: 2 h

Procedure:
A mixture of 4-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazole (4.40 g, 20.9 mmol), ethanol (100 mL) and 10% palladium on carbon (0.41 g, 30.7 mmol) was hydrogenated in a Paar shaker at 30 psi under hydrogen for 2 h. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated in vacuo. 1-(2-Pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-ylamine was isolated as an orange oil, which became a dark gummy material upon standing at room temperature (3.10 g, 82%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.15 (s, 1H), 7.08 (s, 1H), 4.14 (t, J=7.00 Hz, 2H), 2.88 (t, J=6.97 Hz, 4H), 2.52 (s, 4H), 1.765 (s, 4H). MS=181 (MH)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1C=[CH:12][C:11]([CH:14]([C:20]2[CH:25]=[CH:24][C:23](C)=[CH:22][CH:21]=2)[C:15](=O)[CH:16]([CH3:18])[CH3:17])=[CH:10]C=1.[CH3:27]OCCOC.BrC1C=CC=CC=1I>CCOCC.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>[CH3:12][C:11]1[CH:10]=[CH:18][C:16]([CH3:17])=[CH:15][C:14]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([CH3:27])[CH:25]=1
Reactant: COCCOC
Reactant: Cc1ccc(C(C(=O)C(C)C)c2ccc(C)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Brc1ccccc1I
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: Cc1cccc(-c2cc(C)ccc2C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
An oven-dried Schlenk flask was cooled to room temperature under an argon purge, and was charged with tetrakis(triphenylphosphine)palladium (289 mg, 0.25 mmol, 5 mol %) sodium carbonate (2.86 g, 27 mmol), and 1 (1.0 g, 5.0 mmol). The flask was purged with argon and DME (50 mL), ethanol (2 mL), water (15 mL), and 2-bromoiodobenzene (0.83 mL, 6.05 mmol) were added through a rubber septem. The mixture was heated to 85° C. with stirring for 3 days. The mixture was cooled to room temperature, diluted with ether (100 mL), and poured into a separatory funnel. The layers were separated and the organic phase was washed with 1M NaOH (2×50 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 1.23 g (79%) of 2 as a colorless oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.OC(C(F)(F)F)=O.[NH:17]1[C:21]2=[N:22][CH:23]=[CH:24][C:25]([C:26]3[CH:27]=[N:28][N:29]([C:31]4([CH2:35][C:36]#[N:37])[CH2:34][NH:33][CH2:32]4)[CH:30]=3)=[C:20]2[CH:19]=[CH:18]1.[F:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][C:48]=1F)[C:42]([O:44][CH3:45])=[O:43].C([O-])(O)=O.[Na+]>CN1CCCC1=O>[C:36]([CH2:35][C:31]1([N:29]2[CH:30]=[C:26]([C:25]3[CH:24]=[CH:23][N:22]=[C:21]4[NH:17][CH:18]=[CH:19][C:20]=34)[CH:27]=[N:28]2)[CH2:32][N:33]([C:48]2[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][C:39]=2[F:38])[CH2:34]1)#[N:37]
Reactant: COC(=O)c1ccc(F)c(F)c1
Reactant: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)c(F)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
N,N-Diisopropylethylamine (1.6 mL, 9.5 mmol) was added to {3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile TFA salt (2.4 mmol) and methyl 3,4-difluorobenzoate (0.41 g, 2.4 mmol) (Aldrich, Cat. #: 594717) in N-methylpyrrolidinone (NMP) (5.0 mL). The reaction mixture was stirred at 130° C. overnight. The reaction mixture was worked up with saturated aqueous NaHCO3, extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-5%) to afford the desired product (0.34 g, 33%). LCMS (M+H)+: m/z=431.1.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(Br)c1ccc(OC)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Nc1ccccc1)c1ccc(OC)cc1
Temperature: 100 °C
Yield: 64.6 %

Procedure:
Methyl 2-bromo-2-(4-methoxyphenyl)acetate (1.10 g, 4.25 mmol), DIPEA (0.89 mL, 5.09 mmol), and aniline (0.43 mL, 4.67 mmol) are dissolved in acetonitrile (12 mL). The reaction is heated for 18 minutes at 100° C. under microwave irradiation. Acetonitrile is evaporated and the residue is diluted with DCM and washed with water and brine, dried over Na2SO4, filtered and evaporated to dryness. The crude is purified by flash chromatography (Petroleum Ether/EtOAc=9/1) to give intermediate I139 as a yellow oil (745 mg, 65% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:31])=[C:5]([C:24]([O:26]CCC#N)=[O:25])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][Cl:14])[N:9]=1.[OH-].[Na+]>C=C.O>[CH3:1][C:2]1[NH:3][C:4]([CH3:31])=[C:5]([C:24]([OH:26])=[O:25])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][Cl:14])[N:9]=1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc([N+](=O)[O-])c2)C(c2nc(CCl)no2)=C(C)N1
Agent: C=C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(c2nc(CCl)no2)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a stirred mixture of 7.10 g of 2-cyanoethyl 1,4-dihydro-2,6-dimethyl-3-(3-chloromethyl-1,2,4-oxadiazol-5-yl)-4-(3-nitrophenyl)pyridine-5-carboxylate in 30 ml of ethylene glycohol dimethyl ether was added a solution of 1.92 g of sodium hydroxide in 50 ml of water. The reaction mixture was stirred at room temperature overnight and then diluted by adding 40 ml of water. The mixture was washed with methylene chloride and acidified with dilute hydrochloric acid until the pH of the solution was about 1. The precipitate was collected by filtration, washed with water and dried to give 6.1 g of 1,4-dihydro-2,6-dimetyl-3-(3-chloromethyl-1,2,4-oxadiazol-5-yl)-4-(3-nitrophenyl)pyridine-5-carboxylic acid as pale yellow powder, m.p. 196° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][OH:8])=[C:4]([F:12])[CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][O:8][CH:15]=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([F:12])[CH:3]=1
Reactant: N=C(NO)c1ccc(Cl)cc1F
Reactant: C#CC(=O)OCC
Product: CCOC(=O)C=CONC(=N)c1ccc(Cl)cc1F

Procedure:
Scheme 15 shows the synthesis of 5-(2-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)-1-isopropyl-3-methyl-1H-1,2,4-triazole 44 from 4-chloro-2-fluorobenzonitrile 38. Addition of hydroxylamine to the nitrile of 38 gave 4-chloro-2-fluoro-N-hydroxybenzimidamide 39. Michael addition of 39 to ethyl propiolate gave ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40. Heating 40 in diphenyl oxide gave cyclized imidazole, ethyl 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylate 41. Saponification of the ester of 41 with aqueous sodium hydroxide in tetrahydrofuran gave 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylic acid 42. Reaction of 42 with N′-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 2-(4-chloro-2-fluorophenyl)-N-(1-(2-isopropylhydrazinyl)ethylidene)-1H-imidazole-4-carboxamide 43 which cyclizes upon heating to give 44.
Reaction SMILES: [CH2:1]=[C:2]([O:5][Si](C)(C)C)[CH:3]=[CH2:4].[Br:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][C:16](=[CH2:21])[C:17]2=[O:20])=[CH:13][C:12]=1[F:22].B(F)(F)F.CCOCC>C(Cl)Cl>[Br:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][C:16]3([CH2:4][CH2:3][C:2](=[O:5])[CH2:1][CH2:21]3)[C:17]2=[O:20])=[CH:13][C:12]=1[F:22]
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: C=C1Cc2cc(F)c(Br)cc2C1=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=O
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a cold (0° C.) solution of (buta-1,3-dien-2-yloxy)trimethylsilane (1.86 mL, 10.6 mmol) in DCM (80 mL) was 6-bromo-5-fluoro-2-methylene-2,3-dihydro-1H-inden-1-one (Intermediate 5, 2.32 g, 9.62 mmol) added. Boron trifluoride diethyl etherate (0.594 mL, 4.81 mmol) was added at 0° C. The reaction was stirred for 30 min., and then quenched with MeOH (1.0 mL). The reaction mixture was acidified with aq. 2 M HCl solution, and extracted with DCM. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The product was purified by flash column chromatography using a stepwise gradient of heptane/EtOAc (7:1-3.5:1-1:1), to give the title compound (1.60 g, 53% yield). 1H NMR (500 MHz, CDCl3) δ ppm 1.83-1.94 (m, 2 H) 2.17-2.27 (m, 2 H) 2.38-2.51 (m, 2 H) 2.72 (dt, 2 H) 3.18 (s, 2 H) 7.25 (d, 1 H) 8.01 (d, 1 H); MS (ES+) m/z 311,313 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.Cl.[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH2:33].C(Cl)CCl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)C.C(OCC)(=O)C.Cl.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH:33][CH2:32][C:31]([O:30][CH3:29])=[O:34])=[O:27])[CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccc(C(=O)O)c2)c1
Reactant: COC(=O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1cccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A suspension of 3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carboxylic acid (80 mg, 0.178 mmol), glycine methyl ester hydrochloride (24.6 mg, 0.196 mmol), DMAP (2.2 mg, 0.018 mmol), EDC (47.7 mg, 0.249 mmol), and triethylamine (0.074 mL, 0.534 mmol) in DMF (4 mL) was stirred for 15 hours at ambient temperature and then heated to 60° C. for 90 minutes. The reaction mixture was cooled to ambient temperature and then charged with HOBT (12.0 mg, 0.078 mmol), glycine methyl ester hydrochloride (24.6 mg, 0.196 mmol), and triethylamine (0.074 mL, 0.534 mmol). The reaction mixture was heated to 60° C. for 5 hours, cooled to ambient temperature, and diluted with diethyl ether (10 mL), ethyl acetate (10 mL), aqueous hydrochloric acid (1 M, 10 mL), and water (5 mL). The layers were separated, and the organic layer was washed with aqueous hydrochloric acid (1 M, 10 mL), aqueous sodium hydroxide (2×10 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl N-[(3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)carbonyl]glycinate which was used without further purification. MS ESI calc'd. for C22H20F3N4O3 [M+H]+ 445, found 445.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH:5]([OH:7])[CH:4]=[CH:3]1.N1C=CC=CC=1.[C:14](Cl)(=[O:16])[CH3:15]>O1CCCC1>[C:14]([O:1][CH:2]1[CH2:6][CH:5]([OH:7])[CH:4]=[CH:3]1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: OC1C=CC(O)C1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OC1C=CC(O)C1
Yield: 100.5 %

Procedure:
0.70 gram (7.0 mmols) of 3,5-dihydroxycyclopent-1-ene and 0.83 gram (10.5 mmols) of pyridine were dissolved in 20 milliliters of anhydrous tetrahydrofuran, after which a solution of 0.70 g (9.0 mmols) of acetic acid chloride in 6 milliliters of anhydrous tetrahydrofuran was added dropwise over a period of 15 hours at room temperature in a stream of dried nitrogen, using a syringe drive. After concentrating the solvent with a rotary evaporator, 20 milliliters of ethyl acetate was added, following which the reaction mixture was washed with dilute hydrochloric acid (5 ml × 2), saturated sodium bicarbonate solution (5 ml × 2) and saturated sodium chloride solution (5 ml × 2). The organic layer was then separated and dried with anhydrous sodium sulfate. On distilling off the solvent, 1.00 gram of a colorless oil substance was obtained.