Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1>>[CH3:27][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:17]([C:15]2[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=23)=[O:19])[CH2:22][CH2:23]1
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2cc(Cl)cc3oc(-c4ccccc4)nc23)CC1
Yield: 46 %

Procedure:
This material was prepared from 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid and 4-amino-1-methylpiperidine using the method outlined in Step C of Example 7. This compound was obtained in 46% yield as a tan solid: mp 170-172° C.; 1H NMR (300 MHz, CDCl3) δ 9.14 (d, J=7.8 Hz, 1H), 8.23 (dd, J=6.6, 1.5 Hz, 2H), 8.18 (d, J=1.5 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.65-7.54 (m, 3H), 4.19-4.13 (m, 1H), 2.87 (d, J=1.5 Hz, 2H), 2.37 (s, 3H), 2.32-2.26 (m, 2H), 2.17-2.13 (m, 2H), 1.84-1.72 (m, 2H); MS (ESI) m/z 370 [M+H]+
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1)[OH:6].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CO>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:3][CH2:4][CH:5]([OH:6])[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CSc1nccc(C(O)CN)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CSc1nccc(C(O)CNC2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 8 h
Yield: 75.8 %

Procedure:
2-Amino-1-(2-methylsulfanyl-pyrimidin-4-yl)-ethanol dihydrochloride salt (0.339 g, 1.83 mmol) was dissolved into a minimum of MeOH and diluted with 10 mL of THF. To this was added t-butyl-4-oxo-1-piperidinecarboxylate (0.478 g, 2.40 mmol), AcOH (0.458 mL, 8.00 mmol) and sodium triacetoxyborohydride (1.696 g, 8.00 mmol) and the reaction was stirred overnight. LC-MS analysis indicated complete consumption of the starting material. The mixture was concentrated on a rotary evaporator, the residue dissolved in CH2Cl2 and applied to a SiO2 column and purified (0–10% MeOH/CH2Cl2) to give 511.0 mg, 57.8% yield of 4-[2-hydroxy-2-(2-methylsulfanyl-pyrimidin-4-yl)-ethylamino]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [H-].[Na+].CC[O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([O:34]COC)=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2[CH:30]=O)[CH3:19].O>CN(C)C=O>[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([OH:34])=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2/[CH:30]=[C:8](\[CH3:9])/[C:6]([OH:5])=[O:7])[CH3:19]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 122 %

Procedure:
36 g of 60% sodium hydride was suspended in 500 ml of N,N-dimethylformamide and 268 g of triethyl 2-phosphonopropionate was added at ice bath temperature. After stirring at room temperature for 1 hour, a solution of 206 g of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde was added. After stirring at room temperature for 15 minutes, ice cooled water was gradually added at ice bath temperature. The mixture was extracted with ethyl acetate and the combined organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 262.4 g of the titled compound as a yellow oil (containing a small amount of Z isomer).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)#[N:13].N1C=CC=C[CH:24]=1>>[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:24])=[O:7])=[CH:10][CH:11]=2)=[O:19])=[CH:16][CH:15]=1)#[N:13]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrous pyridine (10 mL) was added dropwise 4-cyanobenzoyl chloride (660 mg) at 0° C. After 5 min the temperature was allowed to warm up to rt. After 90 min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 720 mg) was added and the resulting mixture was stirred overnight at rt. After filtration and rinsing the resin, water (125 mL) was added to the filtrate and a white solid precipated out. Filtration and washing with water gave a solid which was dried under vacuo at 60° C. overnight. The title compound (854 mg) was obtained as a pale yellow solid (92%) in 95.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1O.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.CN(C)C1C=CN=CC=1.CC(O)=O>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[O:15][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@@H]1CCCC[C@H]1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H]1CCCC[C@H]1OC(=O)[C@@H](C)NC(=O)OCc1ccccc1

Procedure:
N-Benzyloxycarbonyl-D-alanine (2.5 mmol. 0.556 g) and trans-2-methylcyclohexanol (3 equivalents, 1 mL) were dissolved in 7 mL THF at room temperature, followed by the addition of 70 mg 4-dimethylaminopyridine. DCC (2.5 mmol, 0.515 g) was then introduced with stirring. The solution turned cloudy immediately and was stirred at room temperature overnight. The reaction mixture was stirred for another 15 min after several drops of HOAc were added to it. Dicyclohexylurea (DCU) was filtered off and the filtrate evaporated to dryness. The residue was dissolved in ethyl acetate. The EtOAc solution was filtered, washed with 0.5N HCl (2×), brine (2×), 5% NaHCO3 (2×) and finally brine (2×). The organic phase, after being dried over anhydrous Na2SO4, showed one UV-positive tlc spot. A second spot, which could only be detected by phosphomolybdic acid (PMA)--Ce(SO4)2 spray, was identified as the unreacted alcohol by tlc comparison with authentic material. The ethyl acetate solution was evaporated to dryness and dried under high vacuum, giving a clear oil weighing 0.965 g. The crude material was chromatographed on a Merck Si--60 size C prepacked column by gradient elution with toluene to toluene:ethyl acetate (9:1). After evaporation, 0.629 g (72.0%) of clear, colorless oil was recovered: nmr (CDCl3, ppm), 0.85-2.05 (13H, m, aliphatic H of cyclohexanol), 0.9 (3H, d, J=6 Hz, CH3) 1.3 (3H, d, J=7 Hz, obscured by other aliphatic protons, β--CH3 of Ala), 4.3 (2H, m, CH--O-- and α--H), 5 (2H, s, ArCH2 --), 5.25 (1H, broad s, amide H), 7.15 (5H, s, ArH5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:35]([BH3-])#[N:36].[Na+].[C:39](O)(=O)[CH3:40].[OH-].[Na+]>CO>[C:1]([O:5][C:6](=[O:34])[N:7]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH3:33])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:11][C:10]2[CH:9]=[CH:8][C:39]([CH3:40])=[CH:35][N:36]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)O
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CNCc2ncc[nH]2)cc1)C(=O)OC(C)(C)C
Reactant: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2ccc(C)cn2)Cc2ncc[nH]2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The compound (61.6 mg) obtained in Example 75-1 was dissolved in methanol (2.0 ml) and then added with the compound (23.8 mg) obtained in Example 56-1, followed by the addition of sodium cyanoborohydride (15.8 mg). The reaction solution was added with acetic acid to adjust the solution to pH 5, followed by stirring at room temperature for 17 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and extracted with chloroform. After that, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (36.7 mg) as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]([CH3:18])[NH:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]([CH3:18])[NH:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:9][C:10]=1[Cl:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1Cl
Yield: 58.1 %

Procedure:
A solution of 6-(4-acetamidophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.5 g) and N-chlorosuccinimide (0.41 g) in dimethylformamide (7 ml) was stirred at 40° C. for 3 hours and then poured into water. The thus-produced crsytals were collected by filtration, washed with water and dried to give 6-(4-acetamido-3-chlorophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.331 g).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C(O)C.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>[F:11][C:12]([F:23])([F:24])[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 25 °C

Procedure:
The mixture of 6-bromo-1H-indole (1.22 g, 6.22 mmol), 4-trifluoromethoxyphenyl boronic acid (1.41 g, 6.84 mmol), tetrakis(triphenylphosphine)palladium (0.213 g, 0.184 mmol) and sodium carbonate (2.64 g, 24.9 mmoles) in water (12.5 mL), ethanol (4 mL), and toluene (25 mL) was heated at reflux for 1.5 hours then cooled to room temperature. The mixture was then evaporated to dryness and the residue was partitioned in methylene chloride and water. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography using 10-30% chloroform in hexane as an eluant. The title compound was obtained as a white solid (0.874 g, 51%), mp: 165-166° C. 1HNMR (300 MHz, DMSO-d6): δ11.25 (s, 1H), 7.8 (d, 2H, J=7.0 Hz), 7.65 (d, 2H, J=7.0 Hz), 7.4-7.5 (m, 3H), 7.3 (d, 1H, J=8.8 Hz), and 6.45 ppm (s, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH3:31])=[CH:21][CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:32](O)=[O:33])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:37])=O.[CH3:39][N:40]([CH:42]=O)[CH3:41]>>[ClH:37].[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:24]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:32]([NH:8][C:14]2[CH:15]=[CH:16][C:17]([CH2:42][N:40]([CH3:39])[CH:41]3[CH2:27][CH2:26][O:25][CH2:22][CH2:21]3)=[CH:18][CH:13]=2)=[O:33])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=S(Cl)Cl
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2)cc1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In DMF (4 ml) was dissolved 1-benzyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.15 g). Under ice-cooling, to the mixture was added thionyl chloride (0.06 ml). The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. In THF (25 ml) was dissolved the residue, and then the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.09 g) and triethylamine (0.23 ml) in THF (10 ml), under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere. The solvent was evaporated under reduced pressure. Water was added to the mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine). The material was dissolved in ethyl acetate, and 4N hydrochloric acid-ethyl acetate was added to the solution. The solvent was evaporated to give 1-benzyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide hydrochloride (Compound 32) (0.14 g) as yellow amorphous.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:42])=[C:18]([CH:28]2[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:29]2)[C:19]([O:25][CH2:26][CH3:27])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1.O>ClCCl>[Cl:15][C:16]1[C:17]([CH3:42])=[C:18]([CH:28]2[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:29]2)[C:19]([O:25][CH2:26][CH3:27])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: CCOc1c(C(C)O)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1c(C(C)Cl)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Yield: 43 %

Procedure:
Cyanuric chloride (200 mg, 1.1 mmol) was added to N,N-dimethylformamide (0.083 mL, 1.1 mmol) at room temperature. After the formation of a white solid (ca. 10 minutes), methylene chloride (5 mL) was added, followed by benzyl 3-[3-chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]azetidine-1-carboxylate (310 mg, 0.77 mmol). After addition, the resultant mixture was stirred at room temperature overnight. Water was added, and then diluted with dichloromethane. The organic phases were washed with sat. NaHCO3 solution, water and brine, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 40% EtOAc/hexanes) to give the desired product (140 mg, 43%). LCMS calculated for C22H26Cl2NO3 (M+H)+: m/z=422.1; Found: 422.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:33]3[CH:32]=[CH:31][C:30]([CH3:34])=[CH:29][N:28]3[N:27]=2)=[CH:6][CH:7]=1.[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:29]3[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][N:28]3[N:27]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc[n+](N)c1
Reactant: COC(=O)C#Cc1ccc(F)cc1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: CC#N
Product: COC(=O)c1c(-c2ccc(F)cc2)nn2cc(C)ccc12
Product: COC(=O)c1c(-c2ccc(F)cc2)nn2cccc(C)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of methyl 3-(4-fluorophenyl)propiolate (Example 1 b) and 1-amino-3-methylpyridinium 2,4,6-trimethylbenzenesulfonate in dry acetonitrile was added, dropwise over 10 min, a solution of 1,8-diazabicycloundec-7-ene in dry acetonitrile. The mixture was allowed to stir at room temperature for about 18 h. The solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate and the organic phase separated. The aqueous was extracted with ethyl acetate and the combined organic extracts are dried (MgSO4), and the solvent removed under vacuum. The residue was purified by chromatography on silica gel using 10:1 hexanes:ethyl acetate as eluent to give the title compound and also methyl 2-(4-fluorophenyl)-4-methyl-pyrazolo[1,5-a]pyridine-3-carboxylate.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.[Br:17][C:18]1[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:21]([F:33])=[CH:20][N:19]=1>C(O)CC.O>[Br:17][C:18]1[CH:23]=[C:22]([C@@H:24]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@@H:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[OH:12])[C:21]([F:33])=[CH:20][N:19]=1
Reactant: Fc1ccccc1/C=C/c1cc(Br)ncc1F
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(C)(C)OCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](c1cc(Br)ncc1F)[C@H](O)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To tert-butyl carbamate (150 mg, 1.28 mmol) in n-propanol (1.75 mL) was added sodium hydroxide (49.8 mg, 1.25 mmol) in water (3.5 mL) followed by tert-butyl hypochlorite (0.141 mL, 1.246 mmol). After 5 min, the solution was cooled to 0° C. and treated with a solution of DHQD2(PHAL) (16.57 mg, 0.021 mmol) in n-propanol (1.75 mL). The reaction was diluted with n-propanol (3.5 mL) and treated with (E)-2-bromo-5-fluoro-4-(2-fluorostyryl)pyridine (90 mg, 0.304 mmol) as a solid in one portion. To this was added potassium osmate dihydrate (5.60 mg, 0.015 mmol) as a solid in one portion. The reaction was allowed to gradually warm to room temperature in the dewar overnight. The reaction was cooled to 0° C. and quenched by addition of sodium thiosulfate (150 mg) in water (3 mL). The ice bath was removed and stirring continued for 30 min. The reaction was diluted with ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25% EtOAc/Hex) gave 93 mg (36%) as a foam solid. Mass spec.: 429.1 (MH)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH3:12].N1CCCC1>C1(C)C=CC=CC=1>[C:14]1([C:11](=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[CH3:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC(=C1C(=O)Nc2ccccc21)c1ccccc1
Yield: 85 %

Procedure:
Oxindole (0.1332 g, 1 mmol) and acetophenone (1.4 ml, 1.2 mmol) were mixed in toluene; then pyrrolidine (0.17 ml, 2 mmol) was added. The mixture refluxed for 3 hand monitored by TLC. When the reaction was finished the solvent was removed under reduced pressure. The residue was separated by flash chromatography column (gradient elution, 10-25% ethyl acetate in petroleum ether) to give 3-(1-phenyl-ethylidene)-1,3-dihydro-indol-2-one as yellow powder (200 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.70 (s, 3H) 5.96 (d, J=7.83 Hz, 1H) 6.51-6.57 (m, 1H) 6.77 (d, J=7.58 Hz, 1H) 7.00-7.10 (m, 1H) 7.30-7.37 (m, 2H) 7.44-7.58 (m, 3H) 10.54 (br. s., 1H). MS calcd. for C16H13NO 235, obsd. (ESI+) [(M+H)+] 236.
Reaction SMILES: [CH:1]1([C:6]([OH:32])([CH2:22][C:23]2[O:24]C(C)(C)O[C:27](=[O:29])[CH:28]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[H][H].[OH-].[Na+]>O.[OH-].[OH-].[Pd+2].C(O)(=O)C>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]4)=[C:11]([F:21])[CH:10]=3)[CH2:22][C:23](=[O:24])[CH2:28][C:27](=[O:29])[O:32]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CCC3)c(F)c2)C2CCCC2)O1
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CCC1
Reaction time: 18 h
Yield: 82.6 %

Procedure:
To a solution of 1-{4-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile (6.0 g, 13.7 mmol) from step 3 below was added Pd(OH)2/C (2.0 g) and ethanol (100 mL). The reaction was placed under a nitrogen atmosphere using a balloon filled with hydrogen. The slurry was stirred vigorously for 18 hours. The reaction was filtered to remove all of the solids, and the liquid was concentrated to an oil. The oil was dissolved in methanol (100 mL), and solution of NaOH (1.64 g, 41 mmol) dissolved in water (30 mL). The reaction was stirred for 18 hours, and then acetic acid (1 mL) was added. The liquid was concentrated to an oil, then redissolved in CH2Cl2, and washed with 1 N HCl. The organic layer was dried over MgSO4, filtered, and then concentrated to give the desired product (4.338 g, 83%). MS (ESI): 382 (M−H+).
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#N.[ClH:12].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C([N:20](CC)CC)C>C(OCC)(=O)C.C(O)C>[ClH:12].[NH:20]=[C:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CCN(CC)CC
Reactant: C1CCNC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: N=C1CCCN1c1ccc(C(=O)O)cc1
Reaction time: 120 h

Procedure:
15.2 g (103 mmol) of 4-cyanobenzoic acid was added to a mixture of a solution of 4 N hydrogen chloride in 200 ml of ethyl acetate and 50 ml of ethanol, and they were stirred for 5 days. The solvent was evaporated under reduced pressure. 100 ml of ethyl acetate was added to the obtained solid, and they were stirred for 30 minutes. The solid was taken by the filtration. The solid was reacted with 15.0 g (211 mmol) of pyrrolidine and 10.0 g (98.8 mmol) of triethylamine in 100 ml of ethanol as the solvent for two days. The solvent was evaporated. 40 ml of 6 N hydrochloric acid was added to the residue, and they were reacted at 85° C. for 4 hours. The solvent was evaporated, 50 ml of 1 N hydrochloric acid was added to the reaction mixture, and they were stirred for 30 minutes. The solid was taken by the filtration and then washed with 20 ml of ice/water. After the drying under reduced pressure, the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[C:30]([CH3:38])[CH:29]=2)=[O:26])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:38][C:30]1[CH:29]=[C:28]([NH:27][C:25](=[O:26])[NH:24][CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][CH:16]([NH:15][S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH2:17][CH2:18]2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(NC(=O)NCCN2CCC(N)CC2)c2ccccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)c2ccccc2n1
Temperature: 40 °C

Procedure:
A solution of 4-trifluoromethyl-benzenesulfonyl chloride (0.03 mmol) in THF (1 mL) is added to a mixture of 1-[2-(4-amino-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea (0.025 mmol), DIPEA (6 μL) and THF (1 mL). The reaction mixture is heated at 40° C. for 18 h, and then is evaporated to dryness. The residue is taken up in formic acid (1 mL), and purified by preparative HPLC to provide the title compound.