Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH2:13]([N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[CH2:13]([N:20]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=2)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2cnn(Cc3ccccc3)c2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 72 h
Yield: 77.6 %

Procedure:
An oven-dried resealable Schlenk tube was charged with 5-bromo-2-methoxy-3-nitropyridine (3.58 g, 15.36 mmol), 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.23 g, 18.43 mmol), potassium carbonate (4.24 g, 30.72 mmol), 1,4-dioxane (50 mL) and water (5 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and tetrakis(triphenylphosphine)palladium(0) (1.77 g, 1.53 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 100° C. After 3 days, the mixture was cooled, filtered through diatomaceous earth (Celite®) and the filter cake was washed with methylene chloride (300 mL). The combined filtrate and washings were concentrated in vacuo and the residue was purified by flash chromatography (20-50% ethyl acetate in hexanes) to give the title compound (3.70 g, 84%) as a yellow solid.
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[CH3:8][CH2:9][C:10](=[O:16])[CH2:11][C:12](=[O:15])[CH2:13][CH3:14].IC>O>[CH3:4][CH:11]([C:10](=[O:16])[CH2:9][CH3:8])[C:12](=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)CC(=O)CC
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCC(=O)C(C)C(=O)CC
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To 0.02 mol sodium hydride was added 100 ml anhydrous tetrahydrofuran, slowly added dropwise 0.02 mol 3,5-heptandione at room temperature. Upon completion, the mixture was stirred for 0.5 hours, then 0.04 mol iodomethane was slowly added dropwise. After stirred at room temperature for 10 hours, 20 ml water was added. White solid was precipitated. The solid was filtered, washed with water, and dried to give 4-methyl-3,5-heptandione as a white solid, and the yield was 94%. m.p. was 91-92° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Yield: 87.5 %

Procedure:
A mixture of 5.0 parts of 2,5-dichloro-3-nitrobenzoic acid and 16.2 parts of thionyl chloride was refluxed for 24 hours under argon. The reaction mixture was evaporated, yielding 4.74 parts (87.5%) of 2,5-dichloro-3-nitrobenzoyl chloride (interm. 66).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[C:7](=[O:16])[CH2:6]1)=[N+:2]=[N-:3].[C:17]1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=CC(C)=O)[CH:22]=CC=C[CH:18]=1>C1(C)C=CC=CC=1>[CH3:22][C:17]1[N:1]([CH2:4][CH:5]2[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[C:7](=[O:16])[CH2:6]2)[N:2]=[N:3][CH:18]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC[C@@H](C(N)=O)N1CC(CN=[N+]=[N-])CC1=O
Solvent: Cc1ccccc1
Product: CC[C@@H](C(N)=O)N1CC(Cn2nncc2C)CC1=O
Temperature: 80 °C

Procedure:
In a 50 ml 3 necked flask, fitted with magnetic stirrer and reflux condenser under inert atmosphere, 1 g (4.44 mmoles, 1 eq) of (2S)-2-[4-(azidomethyl)-2-oxo-1-pyrrolidinyl]butanamide 32 is suspended in 20 ml of toluene. 1.55 g (4.88 mmoles, 1.1 eq) of 1-(triphenylphosphoranylidene)acetone are added, and the mixture is heated up to 80° C. for 24 hours. After cooling down, the mixture is concentrated to dryness and purified by Prep LC (1 kg SiO2, CH2Cl2/MeOH/NH4OH, 94.5:5:0.5). It is suspended in 15 ml of water and lyophilised to give 240 mg of pure 52 as a clear oil, 42%.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Cl)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.O.[NH2:23][NH2:24]>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:23][NH2:24])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2Cl)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2NN)CC1
Yield: 36.5 %

Procedure:
A 500 mL 3-necked round bottom flask was charged with tert-butyl 4-(5-bromo-3-chloropyrazin-2-yl)piperazine-1-carboxylate (16.1 g, 42.6 mmol), hydrazine hydrate (4.2 mL, 85.2 mmol) and ethanol (200 mL). The resulting solution was refluxed overnight. TLC indicated an incomplete conversion. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether then 2% methanol in dichloromethane, to afford 5.8 g (47%) of the product as a yellow solid. MS m/z: 373 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH2:22][CH2:23][CH3:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=O)=[CH:7][CH:6]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:1][CH:2]([CH2:22][CH2:23][CH3:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)=[CH:7][CH:6]=1
Reactant: CN1CCNCC1
Reactant: CCCC(C)COc1ccc([C@H](C=O)NC(=O)OC(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCC(C)COc1ccc([C@H](CN2CCN(C)CC2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of t-butyl (1R)-1-(4-(2-methylpentyloxy)phenyl)-2-oxoethylcarbamate (80 mg, 0.238 mmol) in dichloroethane (1 mL) was added 1-methylpiperazine (0.032 mL, 0.286 mmol) followed by sodium triacetoxyborohydride (70.8 mg, 0.334 mmol). The mixture was stirred at room temperature for 3 h. Additional 1-methylpiperazine (0.064 mL, 0.572 mmol) and sodium triacetoxyborohydride (71 mg, 0.334 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (5 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (5 mL), dried over MgSO4, filtered and concentrated. The product, t-butyl 1-(4-(2-methylpentyloxy)phenyl)-2-(4-methylpiperazin-1-yl)ethylcarbamate, was used directly in the next step: LRMS (ESI) m/e 420.3 [(M+H)+, calcd for C24H42N3O3 420.3].
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:28])[O:4][N:3]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.Br[CH2:42][CH:43]([CH3:46])[CH2:44][CH3:45]>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:21][N:20]=3)[CH2:42][CH:43]([CH3:46])[CH2:44][CH3:45])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: CCC(C)CBr
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: CCC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (156 mg, 0.389 mmol) in acetonitrile (4 mL) stirred in air at 20° C., was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (133 mg, 0.777 mmol). The reaction mixture was stirred at 20° C. for 1 hour, then 1-bromo-2-methylbutane (117 mg, 0.777 mmol) was added. The reaction then heated by microwaves to 150° C., for 30 minutes. After cooling the solvent was removed in vacuo and diluted with ethyl acetate. The organic phase was washed with water (5 mL), then dried using a hydrophobic frit. The solvent was removed in vacuo to give the crude product as an orange oil. Purification of the crude was attempted using flash silica (Si) chromatography (0-25% ethylacetate-cyclohexane gradient) followed by mass directed autoprep (ammonium carbonate modifier), however impurities still remained. A final purification using a silica (Si) cartridge (eluting with a gradient of 0-25% ethyl acetate-cyclohexane) provided a small amount of clean product (8.5 mg) as a colourless oil. LCMS (2 min, High pH) Rt 1.48 mins, m/z (ES+) 472 (M+H).
Reaction SMILES: [CH:1]1([NH:5][CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:17](C)=O.[Na+]>C1COCC1>[CH:1]1([N:5]([CH3:17])[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)/C=C/CNC1CCC1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/CN(C)C1CCC1
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of (E)-methyl 4-(cyclobutylamino)but-2-enoate (19) (1.7 g, 10 mmol) in THF (30 mL) was added HCHO solution (3 g, 40 mmol, 40% solution in water). The resulting mixture was stirred for 30 min before introducing NaBH(OAc)3 (3.18 g, 15 mmol). Stirring was continued at RT overnight. After quenching with sat. aq. NaHCO3 solution, the reaction mixture was extracted with EA (3×). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (0-5% methanol in DCM) to provide (E)-methyl 4-(cyclobutyl(methyl)amino)but-2-enoate (20) (1.47 g, 80%) as an oil. LC-MS (ESI): m/z (M+1) 184.3.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12]Cl)=[CH:5][CH:4]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([CH2:12][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([C:32]4[S:33][CH:34]=[CH:35][N:36]=4)[CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)CC(c1ccc(O)cc1)c1nccs1
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: O=C(O)CC(c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1)c1nccs1
Temperature: 50 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
Benzyl chloride 2.3 (123 mg, 0.456 mmol) and phenol 53.1 (100 mg, 0.380 mmol) were dissolved in acetone (1 mL) and treated with Cs2CO3 (371 mg, 1.14 mmol). The reaction was stirred at 50° C. for 16 h, filtered and concentrated. The residue was purified by column chromatography (silica gel, 30% to 70% ethyl acetate in hexanes). Eluant containing desired compound was concentrated and dissolved in a THF/MeOH/2N LiOH(aq) (1:1:1) solution (2 mL). The mixture was stirred at room temperature for 90 min., and the solution was poured into 0.65 N HCl(aq.) (2 mL). The aqueous phase was extracted with dichloromethane (3×10 mL) and the combined organic phases were dried over Na2SO4. After filtration and drying, 150 mg (0.311 mmol) of carboxylic acid 53 was obtained. 1H NMR (400 MHz) (CDCl3) δ 7.47-7.77 (m, 9H), 7.24-7.27 (m, 3H), 6.99-7.00 (m, 2H), 5.14 (s, 2H), 4.78 (dd, 1H, J=6.8, 4.4 Hz), 3.47 (dd, 1H, J=12.8, 6.8 Hz), 3.09 (dd, 1H, J=12.8, 4.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:13]([Cl:22])=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=2)[C:17](Cl)=[O:18])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[N:23]1([CH2:29][CH2:30][OH:31])[CH2:27][CH2:26][CH2:25][C:24]1=[O:28]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([Cl:22])=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=2)[C:17]([O:31][CH2:30][CH2:29][N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[O:18])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: O=C1CCCN1CCO
Reactant: Cn1nc(-c2cc(C(=O)Cl)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Solvent: c1ccncc1
Product: Cn1nc(-c2cc(C(=O)OCCN3CCCC3=O)c(Cl)cc2Cl)c(Cl)c1OC(F)F

Procedure:
A solution of 1 g (2.6 mmol) of 5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-2,4-dichlorobenzoyl chloride and 0.5 g (3.8 mmol) of 2-(2-pyrrolidon-1-yl)ethanol in 20 ml of pyridine was stirred for approximately 15 hours, whereupon the reaction mixture was concentrated. The residue was treated with 10 ml of water and 20 ml of ethyl acetate. The organic phase was then separated off, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (eluent: initially hexane/ethyl acetate=1:1, then ethyl acetate). Yield: 0.8 g.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][NH:8][C:9]1[N:14]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[C:27]([O:29][CH2:30][CH3:31])[C:26]([F:32])=[C:25]([O:33][CH2:34][CH3:35])[CH:24]=3)[CH2:18][CH2:17]2)[N:12]=[C:11]([O:36][CH3:37])[N:10]=1)(C)(C)C.[Li+].[OH-].O.Cl>C1COCC1.CO>[CH2:34]([O:33][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([O:29][CH2:30][CH3:31])[C:26]=1[F:32])[CH2:22][N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:13]2[N:12]=[C:11]([O:36][CH3:37])[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:38])=[O:5])[N:14]=2)[CH2:17][CH2:18]1)[CH3:35]
Reactant: CCOc1cc(CN2CCC(Nc3nc(NCC(=O)OC(C)(C)C)nc(OC)n3)CC2)cc(OCC)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOc1cc(CN2CCC(Nc3nc(NCC(=O)O)nc(OC)n3)CC2)cc(OCC)c1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 32.4 %

Procedure:
To a stirred solution of {4-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-6-methoxy-[1,3,5]triazin-2-ylamino}-acetic acid tert-butyl ester (0.09 g, 0.2 mmol, 1.0 equiv; example 297) in THF/methanol (1:1) (4 mL) was added drop by drop a 1 M solution of LiOH in water (0.42 mL, 0.42 mmol, 2.1 equiv). After 16 h, the reaction mixture was poured into ice water, the pH adjusted to 3-4 with diluted HCl and the mixture extracted three times with dichloromethane/isopropanol (4:1). The combined organic layers were concentrated by evaporation under reduced pressure to yield 0.031 g (32%) of the title compound as a colorless solid. MS (ISN): 477.2 [M−H]−.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][C:7]=1[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]([C:23]([O:25]CC)=[O:24])=[CH:13]2)=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].O.Cl>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][C:7]=1[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]([C:23]([OH:25])=[O:24])=[CH:13]2)=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(C(=O)c3ccc(OCC(C)C)cc3OCC(C)C)ccc2n1CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)COc1ccc(C(=O)c2ccc3c(c2)cc(C(=O)O)n3CC(C)C)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
In 2 ml of ethanol is dissolved 0.18 g of ethyl 5-(2,4-diisobutoxybenzoyl)-1-isobutyl-1H-indole-2-carboxylate. After adding 0.3 ml of 5 mol/L sodium hydroxide, the mixture thus obtained is stirred at ambient temperature for one hour. Water and chloroform are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1). Thus, 0.15 g of 5-(2,4-diisobutoxybenzoyl)-1-isobutyl-1H-indole-2-carboxylic acid is obtained as a white solid product.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>O1CCOCC1.C(N(CC)CC)C>[CH:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: [H][H]
Reactant: O=C=Nc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=CNc1ccccc1
Yield: 98 %

Procedure:
A solution of phenyl isocyanate (1.2 g.; 0.01 mole in 100 ml. anhydrous 1,4-dioxane containing two drops of anhydrous triethylamine was mixed with 500 mg. of 10% Pd-on-carbon and shaken at a pressure of 50 p.s.i. of hydrogen on a Parr low pressure hydrogenator. The uptake of hydrogen was complete in 5 minutes. The catalyst was collected and washed with 50 ml. of 1,4-dioxane. The solvent was evaporated to give 1.2 g. (98% yield) of slightly yellow oil which slowly crystallized. The product was confirmed to be formanilide by ir, nmr and glc analyses.
Reaction SMILES: Cl.C(Cl)Cl.[CH:5]([Si:8]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:9][CH:10]([C:15]1[C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:11][CH2:12]C=C)([CH3:7])[CH3:6].N#N>CCCCCC.CCOCC>[CH:23]([Si:8]([CH:26]([CH3:28])[CH3:27])([CH:5]([CH3:7])[CH3:6])[O:9][CH:10]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:20]2[CH:21]=[CH:22][CH2:12][CH2:11]1)([CH3:25])[CH3:24]
Reactant: C=CCCC(O[Si](C(C)C)(C(C)C)C(C)C)c1ncccc1C=C
Agent: Cl
Agent: N#N
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)[Si](OC1CCC=Cc2cccnc21)(C(C)C)C(C)C
Temperature: 40 °C
Yield: 70.9 %

Procedure:
Hydrogen chloride (5.64 mL, 11.28 mmol) (10 mL, 2M diethyl ether solution) was added to the CH2Cl2 (25 mL) solution of 2-(1-(triisopropylsilyloxy)pent-4-enyl)-3-vinylpyridine (3.9 g, 11.28 mmol). The solvent was removed via vacuum and the corresponding HCl salt was azeotroped by benzene twice. The reaction was charged with CH2Cl2 (500 mL) and purged with N2 for 10 min before addition of Grubb II (0.192 g, 0.226 mmol). The reaction was heat to 40° C. for 3 hours, LCMS showed no starting material left. The reaction was washed with saturated NaHCO3 solution once. The CH2Cl2 was separated, dried (Na2SO4), filtered and concentrated. Flash column by ether in hexane from 0 to 25% gave the desired product as yellow oil (2.54 g, 71% yield). MS (ESI)[M+H+]=318.35.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([F:16])[CH:7]=1.[C:20]([NH2:23])(=[S:22])[CH3:21]>>[CH3:1][O:2][C:3]([C:4]1[N:23]=[C:20]([CH3:21])[S:22][C:5]=1[C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([F:16])[CH:7]=1)=[O:19]
Reactant: COC(=O)C(=O)C(Cl)c1cc(F)cc(C(F)(F)F)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1cc(F)cc(C(F)(F)F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-5-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=1.03 min; [M+H]+=319.8.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.ClC(Cl)(Cl)C#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCNCC1.[NH2:55][C@@H:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH3:57]>ClCCl.O>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:55][C@@H:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH3:57])=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCCCCC[C@@H](C)N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: N#CC(Cl)(Cl)Cl
Solvent: C1CCNCC1
Product: CCCCCC[C@@H](C)NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) was suspended in dichloromethane (1 mL). To the suspension, trichloroacetonitrile (31.0 μL) and triphenylphosphine (81.1 mg) in dichloromethane (0.5 mL) were added and the mixture was stirred at room temperature for 2 hours. Subsequently, (piperidinomethyl)polystyrene (150 mg) and (2R)-2-aminooctane (57.1 μL) were sequentially added at 0° C. and the mixture was stirred at room temperature for 21 hours. This was followed by addition of (isocyanatomethyl)polystyrene (232 mg), stirring at room temperature for 1 hour, addition of water (3 mL) and dichloromethane (2 mL), and further stirring at room temperature for 50 minutes. The reaction mixture was then loaded onto an Isolute HM-N column and was extracted 5 times with 2 ml dichloromethane. The dichloromethane extracts were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column (eluant:dichloromethane:methanol=50:1) to give (2S,4S)-4-fluoro-1-[[N-[4-[(2R)—N-(2-octyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (30.3 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.CN(C=O)C.[H-].[Na+].[CH:18]([OH:21])([CH3:20])[CH3:19]>>[CH:18]([O:21][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 2-chloro-5-nitro-pyridine (450 mg, 2.84 mmol) in isopropanol (10 mL)/DMF (7 mL) was added 60% NaH (57 mg). The mixture was stirred at 80° C. for 4 h and the organic solvents were evaporated under reduced pressure. The residue was partitioned between EtOAc and water. The EtOAc extracts were dried (Na2SO4) and evaporated. The crude product was used for the next step reaction without further purification. 1H NMR (300 MHz, CDCl3) δ 9.06 (d, J=2.81 Hz, 1H), 8.32 (dd, J=8.79 and 2.53 Hz, 1H), 6.74 (d, J=8.61 Hz, 1H), 5.43 (m, 1H), 1.38 (d, J=6.20 Hz, 6H).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([N:24]2[C:28]([C:29]3[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=3)=[CH:27][C:26]([O:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[N:25]2)=[CH:20][CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:32]1[CH:31]=[CH:30][C:29]([C:28]2[N:24]([C:21]3[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[N:25]=[C:26]([O:36][CH2:37][C:38]([F:40])([F:39])[F:41])[CH:27]=2)=[CH:34][CH:33]=1)(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(-n2nc(OCC(F)(F)F)cc2-c2ccc(O)cc2)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2nc(OCC(F)(F)F)cc2-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cn1
Reaction time: 1 h

Procedure:
A solution of trifluoromethanesulfonic anhydride (207 μl) in CH2Cl2 (1 mg) was added to a solution of 4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]phenol (300 mg) and pyridine (199 μl) in CH2C12 (3 ml) under ice-bath cooling. The mixture was stirred at same temperature for 1 hour. The reaction was quenched by adding saturated aqueous ammonium chloride solution (5 ml) The mixture was partitioned between AcOEt and 1M HCl. The mixture was washed with saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give 4-[l-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1H-pyrazol-5-yl]phenyl trifluoromethane-sulfonate (439 mg) as an oil.