Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[O:29])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([O:21][Si](C(C)(C)C)(C)C)[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.Cl.C(OCC)(=O)C.O>C1COCC1>[OH:1][NH:2][C:3](=[O:29])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([OH:21])[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCC=CC(=O)NO)c1ccc2ccccc2c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(C=CCCCCC(O)c1ccc2ccccc2c1)NO
Temperature: 30 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of the silyl ether 186 (300 mg, 0.725 mmol) in THF (3 mL) at room temperature was added 1N aqueous solution of hydrochloric acid (3 mL). The mixture was stirred for 3 hours at 30° C. and then added a large volume of ethyl acetate and water. The water layer was washed with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography (75% to 100% ethyl acetate/hexane) affording unsatisfactory purity. So the compound was purified again using 8% methanol in dichloromethane affording the title compound 187 in 33% yield (77 mg). 1H NMR: (300 MHz, CD3OD) δ: 7.87-7.71 (m, 4H), 7.52-7.40 (m, 3H), 6.77 (dt, J=15.1, 6.9 Hz, 1H), 5.75 (d, J=15.1 Hz, 1H), 4.76 (t, J=6.9 Hz, 1H), 2.17-2.10 (m, 2H), 1.84-1.77 (m, 2H), 1.49-1.27 (m, 4H) 1.88-1.75 (m, 4). MS (ESI)=282 (M+−OH), 322 (M++Na).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:29][N:30]([CH3:40])[C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[CH3:29][N:30]([CH3:40])[C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1
Reactant: CN(C)c1nc2ccccc2[nH]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CN(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.25 g) was reacted with N,N-dimethyl-1H-benzo[d]imidazol-2-amine via General Procedure D to produce 59.5 mg of 153 following reverse phase HPLC purification. MS (Q1) 531.3 (M)+
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:40][C:39]1[CH:43]=[CH:44][C:36]([O:35][CH3:34])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: COc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(F)c23)cc1

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 2-(3) and 4-methoxybenzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 435 (M+NH4)H. 1H-NMR (DMSO-d6) δ 3.21-3.26 (m, 1H), 3.37-3.46 (m, 3H), 3.63-3.68 (m, 2H), 3.70 (s, 3H), 4.02 (s, 2H), 4.53 (t, J=5.4 Hz, 1H), 5.09 (d. J=5.3 Hz, 1H), 5.15 (d. J=5.0 Hz, 1H), 5.20 (d, J=5.9 Hz, 1H), 5.37 (d, J=9.2 Hz, 1H), 6.74 (dd, J=11.2, 7.9 Hz, 1H), 6.83 (d, J=8.5 Hz, 2H), 7.07 (td, J=8.0, 5.2 Hz, 1H), 7.17 (d, J=8.7 Hz, 2H), 7.19 (s, 1H), 7.35 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][C:6]2=[CH2:7].[S:11](=[O:14])([OH:13])[O-:12].[Na+:15]>O>[C:6]1([CH2:7][S:11]([O-:14])(=[O:13])=[O:12])[CH2:8][CH2:9][C@H:3]([CH:2]([CH3:10])[CH3:1])[CH2:4][CH:5]=1.[Na+:15]
Reactant: C=C1CCC2CC1C2(C)C
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)[C@@H]1CC=C(CS(=O)(=O)[O-])CC1
Reaction time: 8 h

Procedure:
In a 1 liter, 3-neck flask, 70 grams (0.51 mole) β-pinene and 325 ml water was heated to reflux. Sodium bisulfite, 70 grams, was added at the rate of 13 grams per hour. The solution was refluxed for 7 hours and allowed to stand overnight.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=O)[O:10][C:8](=O)[C:7]=12.[CH3:14][C:15]1[C:20](C(Cl)=O)=[CH:19][CH:18]=[C:17]([C:24]([F:27])([F:26])[F:25])[N:16]=1.N1C=CC=C[CH:29]=1>>[CH3:29][C:5]1[C:6]2[N:12]=[C:11]([C:20]3[C:15]([CH3:14])=[N:16][C:17]([C:24]([F:27])([F:25])[F:26])=[CH:18][CH:19]=3)[O:10][CH2:8][C:7]=2[CH:2]=[CH:3][CH:4]=1
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Reactant: c1ccncc1
Product: Cc1cccc2c1N=C(c1ccc(C(F)(F)F)nc1C)OC2
Temperature: 25 °C

Procedure:
A mixture of the 6-methyl isatoic anhydride (3.92 g, 22.1 mmol) and the acid chloride from Step A (5.45 g, 24.3 mmol) was heated at reflux in pyridine for 16 hours. The dark brown solution was cooled to room temperature and the solvent was removed under reduced pressure. Excess pyridine was removed by azeotrope with toluene. Ether was added and the resulting brown solid was removed by filtration. The solid was taken up in a mixture of aqueous sodium bicarbonate and chloroform, the chloroform extracts were dried over magnesium sulfate and evaporated. Excess pyridine was again removed by azeotrope with toluene to afford 5.1 g of the title compound as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH2:4]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:1][CH2:2][CH:3]3[CH2:8][CH2:7][CH2:6][N:5]([C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[C:11]([O:13][CH3:14])=[O:12])[CH2:4]3)=[O:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COC(=O)c1ccccc1N1CCCC(CN)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1ccccc1N1CCCC(CNC(=O)c2ccc(-c3ccc(Cl)cc3)cc2)C1
Temperature: 0 °C
Yield: 76.1 %

Procedure:
Methyl 2-[3-(aminomethyl)piperidin-1-yl]benzoate (78.2 mg, 0.315 mmol) was dissolved in N,N-dimethylformamide (3 mL) and the solution was chilled to 0° C. While this solution was stirred, 4′-chlorobiphenyl-4-carboxylic acid (81.1 mg, 0.349 mmol), 1-hydroxybenzotriazole monohydrate (54.1 mg, 0.353 mmol), N-methylmorpholine (90 μL, 0.819 mmol) and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (64.6 mg, 0.337 mmol) were added and the mixture was stirred for 20 min. The reaction mixture was then stirred at room temperature for 12 hours. Subsequently, the mixture was extracted with ethyl acetate and the organic layer washed sequentially with 5% aqueous citric acid, a saturated aqueous sodium bicarbonate solution, water and brine. The washed product was dried over anhydrous sodium sulfate and the solvent was concentrated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=2:1) gave 111 mg (76%) of the desired compound as a colorless powder.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:20](Cl)=[C:19]([C:22](Cl)=[O:23])[S:18][C:17]=2[CH:25]=1.[O:26]1CCCC1>CO.[OH-].[Na+]>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:20]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:19]([C:22]([OH:26])=[O:23])[S:18][C:17]=2[CH:25]=1
Reactant: C1CCOC1
Reactant: OCc1ccccc1
Reactant: COc1ccc2c(Cl)c(C(=O)Cl)sc2c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(OCc3ccccc3)c(C(=O)O)sc2c1

Procedure:
Benzyl alcohol (6.0 mls, 58 mmoles) is added dropwise to a stirred suspension of sodium hydride (2.3 g of a 60% dispersion in mineral oil, 58 mmoles) in tetrahydrofuran (15 mls) under argon. After 20 minutes a solution of 6-methoxy-3-chloro-benzo[b]-thiophene-2-carbonyl chloride (5.0 g, 19 mmoles) in warm tetrahydrofuran (60 mls) is added during 5 minutes, and the mixture is heated under reflux. After 16 hours the mixture is cooled, and stripped of solvent under reduced pressure. The residue is partitioned between water (300 mls) and ether (150 mls). The layers are separated and the aqueous phase extracted twice with ether (100 mls). The combined ether extracts are washed with saturated brine and dried over MgSO4, then stripped of solvent under reduced pressure to leave the crude ester as a syrup which also contains mineral oil. The syrup is stirred in a mixture of methanol (10 mls) and 1N sodium hydroxide (38 mls) and heated under reflux. After four hours heating is discontinued and the methanol is removed under reduced pressure. The residue is diluted with water (300 mls) and extracted twice with ether (100 mls). The aqueous solution is stirred and acidified with concentrated HCl, and the precipitate is filtered off, rinsed with water, and dried. Recrystallization from ethanol gave the pure product (2.1 g): mp=194° C. (dec).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:26])=O>>[ClH:26].[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([Cl:26])=[O:20])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)nc1
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)nc1
Product: Cl
Yield: 96.7 %

Procedure:
30 g (0.102 mol) of the resulting p-(5-octylpyridyl)benzoic acid was added to 24.3 g (0.204 mol) of thionyl chloride and reflux was maintained for 5 hours. The surplus thionyl chloride was removed by distillation and the product was recrystallized from hexane to obtain 34.5 g (0.0986 mol) of p-(5-octylpyridyl)benzoylchloride hydrochloride.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH3:23]>C(#N)C>[Br-:1].[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N+:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[CH3:23])=[CH:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccnc(C)c1
Reactant: CCCCc1ccc(CCCCBr)cc1
Solvent: CC#N
Product: CCCCc1ccc(CCCC[n+]2ccc(C)cc2C)cc1
Product: [Br-]
Yield: 79 %

Procedure:
1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution of 2,4-lutidine (3 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in a vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no lutidine left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (79%). 1HNMR (300 MHz, CDCl3, ppm), 9.51 (d, J=6.2, 1H), 7.67 (d, J=6.2, 1H), 7.54 (s, 1H), 7.05-7.07 (m, 4H), 4.83 (t, J=7.2, 2H), 2.77 (s, 3H), 2.64 (t, J=7.2, 2H), 2.52-2.58 (m, 5H), 1.87-1.92 (m, 2H), 1.76-1.82 (m, 2H), 1.50-1.58 (m, 2H), 1.29-1.37 (m, 2H), 0.91 (t, J=7.8, 3H).
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>>[O:9]=[C:7]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(/C=C(\CSC(C)=O)C(=O)O)cc1
Reactant: NCCC(=O)OCc1ccccc1
Product: COc1ccc(/C=C(\CSC(C)=O)C(=O)NCCC(=O)OCc2ccccc2)cc1

Procedure:
The (Z)-2-acetylthiomethyl-3-(4-methoxyphenyl)propenoic acid obtained in step C is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]2[N:6]([C:8]([S:14](O)(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:29])=O>ClC(Cl)C>[Cl:1][C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]2[N:6]([C:8]([S:14]([Cl:29])(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1
Reactant: CC(C)c1nc2cc(C#N)c(Cl)cn2c1S(=O)(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1nc2cc(C#N)c(Cl)cn2c1S(=O)(=O)Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
6-Chloro-7-cyano-2-isopropylimidazo[1,2-a]pyridine-3-sulfonic acid (2.16 g, 7.21 mmol) obtained in step 2 was dissolved in dichloroethane (20 mL), and the solution was stirred at 100° C. for 4 hours after adding triethylamine (2.01 mL, 14.4 mmol) and phosphorus oxychloride (1.34 mL, 14.4 mL). The reaction mixture was extracted with chloroform after adding water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→80/20) to give 6-chloro-7-cyano-2-isopropylimidazo[1,2-a]pyridine-3-sulfonylchloride (1.73 g, yield 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1.P([O-])(O)(O)=[O:34].[Na+].Cl[O-].[Na+].OO>C(#N)C.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:34])=[O:12])=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1
Reactant: O=P([O-])(O)O
Reactant: COc1c(C)c(Cc2ccc(C=O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CC#N
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Yield: 101.5 %

Procedure:
To a solution of 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (735 mg, 1.69 mmol) in acetonitrile (5 ml) were added an aqueous solution (2 ml) of sodium dihydrogen phosphate (157 mg, 1.31 mmol), an aqueous solution (7 ml) of sodium hypochlorite (795 mg, 80%, 7.07 mmol) and an aqueous hydrogen peroxide (0.5 ml, 30%) and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium hydrosulfite (Na2S2O4) and a saturated saline, dried and concentrated to give the title compound (603 mg, 1.33 mmol, 79%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:23]([F:40])=[C:24](/[CH:28]=[C:29](/[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])\[C:30]#[N:31])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[C:23]=2[F:40])[C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])([C:30]#[N:31])[CH:9]([CH2:10][C:11]([CH3:12])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:19])[NH:8]1)=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C/N=C/CC(C)(C)c1ccccc1
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1NC(CC(C)(C)c2ccccc2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 22.2 %

Procedure:
In a manner similar to the method described in Example 1c, [[3-methyl-3-phenyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 82a (2.3 g, 8.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.4 g, 7.7 mmol) prepared in Example 52a, AgF (0.7 g, 5.5 mmol), and triethylamine (2.1 g, 21 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1 g, 22%).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6]O.O.O.O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH:26]=O>C(O)(=O)C>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[C:26]#[N:6]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#Cc1c(Cl)cccc1Cl
Yield: 61 %

Procedure:
A mixture of 3.7 g of hydroxylamine sulphate, 7 g of sodium acetate trihydrate, 17 g of acetic anhydride, 5 ml of acetic acid and 4.5 g of 2,6-dichlorobenzaldehyde was heated at reflux for 34 hours. Cooling, filtration and washing with water gave 2.7 g of pure 2,6-dichlorobenzonitrile. Stripping of the filtrate gave an additional 1 gram of pure 2,6-dichlorobenzontirile thus producing an overall yield of 84%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[N:12]1[CH:17]=[CH:16][C:15]([C:18]([Cl:20])=O)=[CH:14][CH:13]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[ClH:20].[N:21]1([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][O:8][C:5]2[CH:6]=[CH:7][C:2]3[O:1][C:18]([C:15]4[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=4)=[CH:10][C:9](=[O:11])[C:3]=3[CH:4]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: O=C(Cl)c1ccncc1
Reactant: C1CCNCC1
Product: Cl
Product: O=c1cc(-c2ccncc2)oc2ccc(OCCCCCCN3CCCCC3)cc12

Procedure:
The compound was prepared by the method of Example 11 from 2',5'-dihydroxyacetophenone, 4-pyridylcarbonyl chloride, and piperidine: mp 186°-187° C.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[CH3:7][N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9](Cl)=[O:10]>CCOC(C)=O.CCCCCCC>[N:2]1([O:1][C:9](=[O:10])[N:8]([CH3:7])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: On1ccnn1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)On1ccnn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-1,2,3-triazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (80%, oil). HPLC-MS m/z=219.1 (M+1), Rt: 2.50 min. Mp 105–106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]CC2C=CC=CC=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:21][CH2:20]1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[Cl:16][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:21][CH2:20]1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc(N2CCC(COc3c(Cl)cc(OCc4ccccc4)cc3Cl)CC2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1cc(Cl)c(OCC2CCN(c3ccc(C(F)(F)F)cn3)CC2)c(Cl)c1

Procedure:
This compound was prepared in a manner analogous to that of Example 1 Step B, by the treatment of 2.5 grams (0.0049 mole) of 1,3-dichloro-5-(phenylmethoxy)-2-({1-[5-(trifluoromethyl)(2-pyridyl)](4-piperidyl)}methoxy)benzene with hydrogen gas in the presence of 0.3 gram (catalyst) of 10% palladium on carbon in 25 mL of ethyl acetate and 50 mL of ethanol using a Parr hydrogenation apparatus. The yield of the subject compound was 2.0 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[OH-].[Na+].[CH3:16]OS(OC)(=O)=O.S(=O)(=O)(O)O>O.C(OCC)(=O)C.CCCCCC>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH3:16])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc(O)c(O)c(OC)c1
Reaction time: 1 h
Yield: 79.4 %

Procedure:
Methyl 3,4,5-trihydroxybenzoate(50.0 g, 270 mmol) prepared in Step 1 and borax(54.0 g, 140 mmol) were dissoved in distilled water(1) and the mixture was stirred for 1 hour. To this solution was added sodium hydroxide(13 g, 330 mmol) dissoved in distilled water(100 ml), and the resulting mixture was stirred for 10 minutes. Dimethylsulfate(135 ml, 370 mmol) was added and the mixture was stirred again for 15 hours. The reaction solution was neutralized to pH 7-8 using conc. sulfuric acid, extracted with ethyl acetate and then subjected to silica gel column chromatography(eluent: ethyl acetate/n-hexane, 1/2, v/v) to give methyl 3,4-dihydroxy-5-methoxybenzoate(42.5 g, Yield 79%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[CH:9][N:8]2[CH:12]=[CH:13][N:14]=[C:7]2[CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.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>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][C:20]=2[Cl:22])=[CH:9][N:8]2[CH:12]=[CH:13][N:14]=[C:7]2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2nccn2cc1Br
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Temperature: 150 °C
Yield: 76.8 %

Procedure:
In a sealed tube, a mixture of 6-bromo-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (505 mg, 1.98 mmol), 2,4-dichlorobenzeneboronic acid (416 mg, 2.18 mmol), Pd(PPh3)4 (114 mg, 0.10 mmol) and Na2CO3 (2.0 M solution in water, 3.5 mL) in DME (5 mL) was heated at 150° C. for 17 min in a microwave oven. The reaction mixture was cooled to RT, poured into AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered, and evaporated. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→100% TBME) to yield the title compound (488 mg, 1.52 mmol, 77%). MS: 321 [M+1]+; HPLC: AtRet=1.43; TLC: RF 0.16 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][C:3]([C:4]=23)=[CH:2]1.[CH3:21][C:22]1[CH:23]=[C:24]([S:29]([Cl:32])(=[O:31])=[O:30])[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[ClH:32].[CH3:28][C:26]1[CH:25]=[C:24]([S:29]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[CH2:10][NH:11][CH2:12][CH2:13][C:3]([C:4]=34)=[CH:2]2)(=[O:30])=[O:31])[CH:23]=[C:22]([CH3:21])[CH:27]=1
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]c3cccc(c23)C1
Product: Cc1cc(C)cc(S(=O)(=O)n2cc3c4c(cccc42)CNCC3)c1
Product: Cl

Procedure:
The title compound was prepared from tert-butyl 1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate, Intermediate 12 (14 mg, 0.05 mmol) and 3,5-dimethylbenzenesulfonyl chloride (15 mg, 0.75 mmol) as described in the general procedure above, to give 8.9 mg of product. MS (ESI) m/z 341 [M+H]+.