Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].O>N1C=CC=CC=1>[CH2:15]([N:14]([CH2:17][CH3:18])[C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[O:20][CH3:19])[CH:3]=1)[CH3:16]
Reactant: CCN(CC)c1cc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COc1ccccc1C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)c1cc(NC(=O)c2ccccc2OC)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 80.1 %

Procedure:
To a solution of 1-amino-3-diethylamino-4,6-dinitrobenzene (508 mg, 2.0 mmol) in 5 mL of pyridine, 2-methoxybenzoyl chloride (680 mg, 4.0 mmol) was added. After refluxing for 5 h, 50 mL of water was added to the reaction mixture, and the precipitate was collected by filtration and washed with 200 mL of water. Recrystallization from dichloromethane and methanol gave the desired product (622 mg, 80% yield) as a yellow solid: 1H-NMR (300 MHz, CDCl3) δ 1.29 (t, 6H, J=7.2 Hz), 3.39 (q, 4H, J=7.2 Hz), 4.13 (s, 3H), 7.07 (d, 1H, J=8.1), 7.11 (t, 1H, J=9.8 Hz), 7.55 (t, 1H, J=7.8 Hz), 8.23 (d, 1H, J=8.1 Hz), 8.83 (s, 1H), 8.98 (s, 1H); ESI MS m/z 389.1 [M+H]+.
Reaction SMILES: ClC(OC(Cl)C)=O.[CH3:8][N:9](C)[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[NH:20][C:21](=[O:30])[C:22]3[C:27]([CH:28]=2)=[C:26]([CH3:29])[CH:25]=[CH:24][CH:23]=3)=[CH:15][CH:14]=1>ClCCCl>[CH3:29][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[CH:28]=[C:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][NH:9][CH3:8])=[CH:18][CH:17]=1)[NH:20][C:21]2=[O:30]
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(OCCN(C)C)cc3)cc12
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CNCCOc1ccc(-c2cc3c(C)cccc3c(=O)[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 11.9 %

Procedure:
1-Chloro-ethyl chloroformate (97 mg, 0.68 mmol) in 1,2-dichloroethane (0.3 mL) was added to a solution of 3-[4-(2-dimethylamino-ethoxy)-phenyl]-5-methyl-2H-isoquinolin-1-one (35 mg, 0.109 mmol) in 1,2-dichloroethane (0.6 mL) at cooled to 0° C., and stirred for 10 min. The reaction mixture was irradiated using a microwave (300 W, 180° C., 15 min) then concentrated in vacuo and EtOH (0.8 mL) added. The reaction mixture was heated at 80° C. for 15 h, allowed to cool and passed through a SCX-2 cartridge (1 g), eluting with 0.5M NH3 in MeOH. The crude material was concentrated in vacuo and purified by reverse phase preparative HPLC-MS to afford 5-methyl-3-[4-(2-methylamino-ethoxy)-phenyl]-2H-isoquinolin-1-one as a white solid (4 mg, 12%).
Reaction SMILES: [CH2:1]([CH:3]([CH:6]([OH:10])[CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].Cl[Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].C1(NC2CCCCC2)CCCCC1>C(O)C>[CH2:1]([CH:3]([CH:6]([OH:10])[CH2:7][CH2:8][CH3:9])[CH2:4][O:5][Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCCC(O)C(CC)CO
Reactant: CCO[Si](Cl)(OCC)OCC
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCO
Product: CCCC(O)C(CC)CO[Si](OCC)(OCC)OCC
Yield: 50 %

Procedure:
2-Ethyl-1,3-hexanediol was mixed with chlorotriethoxysilane and dicyclohexylamine in a 1:1:1 ratio at 0° C. in absolute ethanol. The resulting product, 2-ethyl-1-triethoxysiloxy-3-hexanol, was obtained in 50% yield and was dissolved to a 10% by weight solution in a 50/50 by volume mixture of ethanol/cyclomethicone.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][C:7]1[C:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C>C1COCC1>[C:1]([NH:5][CH2:6][C:7]1[C:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:3])[CH3:2]
Reactant: NCc1ncccc1CCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1ncccc1CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add dropwise with stirring a solution of 1.24 gm acetyl chloride in 10 ml THF to a cooled solution of 3.2 gm of 2-aminomethyl-3-(2-phenylethyl)pyridine and 2.3 ml triethylamine in 100 ml THF. Warm the reaction mixture to room temperature and then stir for an additional 0.5 hour. Filter off the triethylamine hydrochloride and evaporate the filtrate under reduced pressure. Chromatograph on silica gel using 40% THF in chloroform to obtain 2-acetamidomethyl-3-(2-phenylethyl)pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:28])[C:3]=1[CH2:29][C:30](O)=[O:31].O.ON1C2C=CC=CC=2N=N1.Cl.[OH:45][CH:46]1[CH2:49][NH:48][CH2:47]1.Cl.C(/N=N/CCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[F:28][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:7]=[C:2]([F:1])[C:3]=1[CH2:29][C:30]([N:48]1[CH2:49][CH:46]([OH:45])[CH2:47]1)=[O:31]
Reactant: COc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)nc1
Reactant: OC1CNC1
Agent: CC/N=N/CCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)N4CC(O)C4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-(2,6-difluoro-4-(2-((1S,2R)-2-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethoxy)phenyl)acetic acid (80 mg, 0.179 mmol), 1-hydroxybenzotriazole hydrate (41.1 mg, 0.268 mmol), 3-hydroxyazetidine hydrochloride (29.4 mg, 0.268 mmol) and (E)-3-(ethyldiazenyl)-N,N-dimethylpropan-1-amine hydrochloride (48.2 mg, 0.268 mmol) were dissolved in CH2Cl2 (4 ml). The mixture was stirred at RT for 5 min and triethylamine (0.075 ml, 0.536 mmol) was added. The mixture was stirred at RT overnight and purified by loading directly onto a Preparative TLC plate that was developed with pure EtOAc. The desired product (Rf=0.40 @ pure EtOAc) was collected to give the title compound. 1H NMR (500 MHz, CDCl3) δ 8.15 (s, 2H), 6.50 (d, 2H), 4.60 (m, 3H), 4.40 (m, 1H), 4.30 (m, 1H), 4.05 (m, 2H), 3.90 (m, 11-1), 3.80 (s, 3H), 3.41 (s, 2H), 3.05 (broad, s, 1H), 2.85 (m, 2H), 2.15 (m, 1H), 1.92 (m, 2H), 1.55 (m, 1H), 1.40 (m, 2H), 0.95 (m, 2H), 0.68 (m, 2H), −0.40 (m, 1H). LC/MS (m/z): 503 (M+H)+, GPR119 Human EC50: 0.59 nM.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[CH3:28][C:29]1([CH3:42])[CH2:34][CH:33]([NH:35][C:36]2[NH:40][C:39]([CH3:41])=[N:38][N:37]=2)[CH2:32][CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:42])[CH2:34][CH:33]([N:35]2[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][C:11]=3[F:27])=[C:22]([CH2:23][CH2:24][CH3:25])[N:37]3[N:38]=[C:39]([CH3:41])[N:40]=[C:36]23)[CH2:32][CH2:31][O:30]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Reactant: Cc1nnc(NC2CCOC(C)(C)C2)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCOC(C)(C)C2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (0.87 g) and N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5-methyl-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.34 g, 56%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].C1(C)C=CC(S(O[CH2:28][C@H:29]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)(=O)=O)=CC=1.O>CN(C)C=O>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([CH2:31][CH2:30][C@@H:29]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:28][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)=[CH:10][CH:11]=2)[CH:33]=1
Reactant: N#Cc1cccc(-c2ccc(O)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)OC(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(-c2ccc(OC[C@@H](CCc3cccnc3)OC(=O)c3ccccc3)cc2)c1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Solid 3'-cyanobiphenyl-4-ol (0.20 g, Example 36b)) was added to a suspension of sodium hydride (60%, 0.049 g) in dimethylformamide (5 ml) and the resulting solution stirred for 30 minutes. Solid (2R)-2-benzoyloxy-4-(3-pyridyl)-1-butyl para-toluenesulfonate (0.43 g) was then added and the mixture stirred at 60° C. for 2 hours. The mixture was cooled, poured into water (50 ml) and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography over silica eluting with diethyl ether to give the sub-title compound as an oil (0.34 g).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]1[CH:20]=O)=[O:6])[CH:2]=[CH2:3].C(O)C.[C:25]1([NH2:35])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>C(O)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]1[CH2:20][NH:35][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: Nc1cccc2ccccc12
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1C=O
Solvent: CCO
Solvent: CC(=O)O
Product: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CNc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.1 %

Procedure:
A mixture of (2S,4S)-2-formyl-4-BOCsulfanyl-pyrrolidine-1-carboxylic acid allyl ester (compound(1)) ( 711 mg), ethanol(25 ml), 1-naphthylamine(333 mg) and 3A molecular sieves(4.5 g.) was stirred under an argon atmosphere at ambient temperature for 6 hours. Acetic acid (0.4 ml) was added followed by sodium cyanoborohydride(l70 mg). The mixture was then stirred for a further 20 hours when the sieves were removed by filtration. The filtrate was concentrated under reduced pressure and the residue applied to a silica column and eluted with ethyl acetate/hexane(20:80) to give (2S,4S)-1-allyloxycarbonyl-2[(naphthalen-1-ylamino)-methyl]-4-BOCsulfanylpyrrolidine (compound(31)) as a clear oil (560 mg).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>O1CCCC1>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[O:13][C:27](=[O:30])[CH2:28][CH3:29])=[CH:5][C:4]=1[C:16]([F:19])([F:17])[F:18])#[N:2]
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)On1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(C#N)cc21
Yield: 95 %

Procedure:
A solution of 0.4 g (1.48 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline -2,3(1H,4H)-dione in 50 ml dry tetrahydrofuran was added 0.25 ml (1.82 mmol) dry triethylamine and 0.15 ml (1.72 mmol) propionyl chloride. The mixture was refluxed for 30 min., and then evaporated in vacuo. The residue was stirred with water to give 0.46 g (95%) 7-cyano-1-propionyloxy-6-trifluoromethyl-quinoxaline-2,3(1H,4H)-dione. M.p. 227° C. 1H-NMR (DMSO-d6): 8.37 (1H, s), 7.73 (1H, s), 4.5 (2H, q), 1.35 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([O:11][CH3:12])[C:3]=1[O:13][CH3:14]>C(O)C.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:11][CH3:12])[C:3]=1[O:13][CH3:14])[NH2:8]
Reactant: COc1cc([N+](=O)[O-])cc(F)c1OC
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1cc(N)cc(F)c1OC
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
A mixture of 1-fluoro-2,3-dimethoxy-5-nitrobenzene (91 g, 452 mmol) and platinum(IV) oxide (9 g, 39.6 mmol) in ethanol (500 mL) was hydrogenated with a Par shaker (40 psi) at r.t. for 30 min. LCMS indicated completion of the reaction. The mixture was filtered and the filtrate was concentrated to afford 3-fluoro-4,5-dimethoxyaniline (73 g, 426 mmol, 94% yield) as a brown oil that was directly used in next step. LCMS: (M+H)+:171.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CS(=O)(=O)c1ccc(-c2ccccc2-c2ccc(Cl)cc2)cc1
Yield: 74.9 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 2.3 g (7.4 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Example 4, Step 2) was reacted with 1.7 g (11 mmol) of 4-chlorophenylboronic acid. Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3) and subsequent recrystallization from ethyl acetate/hexane gave 1.90 g (74%) of 1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 180.2-180.6° C.; NMR (CDCl3) δ 3.06 (s, 3H), 7.04 (d, J=8 Hz, 2H), 7.21 (d, J=8 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.38-7.51 (m, 4H), 7.81 (d, J=8 Hz, 2H). MS (EI): m/e (rel intensity) 342 (34), 228 (100); HRMS Calc'd for C19H15ClO2S: 342.0481. Found: 342.0484. Anal. Calc'd for C19H15ClO2S: C, 66.56; H, 4.41; Cl, 10.34. Found: C, 66.45; H, 4.48; Cl, 10.63.
Reaction SMILES: [H-].[Na+].I[CH3:4].[CH2:5]([OH:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15].O>O1CCCC1>[CH2:5]([O:16][CH3:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]
Reactant: C=CCCCCCCCCCO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCCCCCCOC
Temperature: 50 °C
Reaction time: 60 h
Yield: 81.6 %

Procedure:
Under an argon atmosphere a stirred mixture of 15.5 grams (0.375 mole) of sodium hydride (60% in mineral oil) in 180 ml of tetrahydrofuran was warmed to 50° C., and 28 ml (0.45 mole) of iodomethane was added portionwise. Upon completion of addition, 41.1 grams (0.24 mole) of 10-undecen-1-ol in 75 ml of tetrahydrofuran was added dropwise during a one hour period. Upon completion of addition, the reaction mixture was heated at 50° C. for an additional 90 minutes, and then it was allowed to cool to ambient temperature where it stirred for 60 hours. The reaction mixture was cooled in an ice water bath, and cold water was added dropwise until all of the solid material in the reaction mixture was dissolved. The aqueous layer was extracted with two portions of diethyl ether, and the ether extracts were combined with the organic layer from the reaction mixture. The organic layer extract combination was washed in turn with 50 ml of water and 50 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated at atmospheric pressure to a residue. The residue was distilled under reduced pressure, yielding 36.1 grams of methyl 10-undecenyl ether; b.p. 99°-100° C./5.5 mm.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:4]=[C:3]1[C:23]([O:25]CC)=[O:24].Cl>C(O)C.O1CCCC1.[OH-].[Na+]>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:20])[F:21])[CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:4]=[C:3]1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCCn3cccc3)c2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(C(=O)O)cc2c(C(F)(F)F)ccc(OCCn3cccc3)c21
Temperature: 25 °C
Yield: 60.7 %

Procedure:
After 1.94 g (5.10 mmol) of ethyl 1-methyl-7-[2-(1H-pyrrol-1-yl)ethoxy]-4-trifluoromethyl-2-indolecarboxylate was dissolved in a mixture of 100 ml of ethanol and 50 ml of tetrahydrofuran, 10 ml of 3.75 N sodium hydroxide was added thereto. The mixture was stirred at room temperature for an hour. After completion of the reaction, the mixture was rendered acidic with 2 N hydrochloric acid and concentrated under reduced pressure. To the concentrate was added 100 ml of water. The mixture was then extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. Crystallization of the resulting residue from chloroform/ethyl acetate gave 1.09 g of 1-methyl-7-[2-(1H-pyrrol-1-yl)ethoxy]-4-trifluoromethyl-2-indolecarboxylic acid.
Reaction SMILES: [In].[Cl-].[NH4+].[Cl:4][C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1>C(O)C.Cl>[Cl:4][C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1
Reactant: Cc1nc(Cl)sc1-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Agent: [In]
Solvent: CCO
Product: Cc1nc(Cl)sc1-c1ccc(N)cc1
Reaction time: 1.5 h
Yield: 96.3 %

Procedure:
Indium powder (0.64 mg, 2.5 mmol) and saturated ammonium chloride solution (3 ml, 2.5 mmol) are added to a solution of 2-chloro-4-methyl-5-(4-nitro-phenyl)-thiazole (25b) (0.20 g, 0.786 mmol) in ethanol (3 ml). The mixture is heated at reflux with stirring for 90 minutes. When cool the mixture is diluted with 2M aqueous hydrochloric acid to dissolve any product and the mixture is filtered through celite. The filtrate is adjusted to pH 9 with aqueous sodium hydroxide and extracted with dichloromethane (3×30 ml). The combined organic extract is dried (MgSO4) filtered, and the solvent removed to give the title compound as a yellow solid (0.17 g).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[N:12]=1.C1COCC1.[OH-].[Na+]>CCO>[F:21][C:19]([F:20])([F:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:23])=[O:2])[O:9][CH:10]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2C(F)(F)F)co1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCCCc1nc(-c2ccccc2C(F)(F)F)co1

Procedure:
Combine 5-[4-(2-trifluoromethyl-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (3.35 g, 9.9 mmol) with THF (3 mL), EtOH (3 mL) and 2N NaOH (15 mL) and stir until hydrolysis is complete. Concentrate the mixture, dilute the residue with water and adjust the pH to 3.0-4.0 using aq HCl. Extract the mixture with EtOAc and dry the extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) to allow for recovery of 5-[4-(2-trifluoromethyl-phenyl)-oxazol-2-yl]-pentanoic acid (2.36 g, 76%). MS (ES): (M+1)+ 314.2 m/z.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38])#[N:30]>>[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][N:23]([S:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:29]#[N:30])(=[O:39])=[O:38])[CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4C#N)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and 2-cyanobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CN(C=O)C.COS(OC)(=O)=O>O>[Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10][CH3:13])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c(C=O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1ccc(Br)c(C=O)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6-bromo-2-hydroxy-3-methoxybenzaldehyde (66.8 g, 0.29 mole), K2CO3 (powdered, 79 g, 0.57 mole), and dry DMF (250 mL) was stirred under N2 at 110° as dimethylsulfate (33.5 mL, 0.35 mole) was added dropwise. The reaction mixture was stirred at 135° for 5 hours, was cooled to room temperature, and water was added. The aqueous mixture was extracted with CH2Cl2. The combined extracts were washed with water, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated to yield ca 80 g. tan solid. The crude product was recrystallized from 2-propanol to obtain 55.2 g cream colored solid, (77%); mp 92°-3°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10]>>[OH:8][C:4]1[CH:3]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: O=Cc1ccc(-c2cccc(O)c2)cc1
Yield: 65.8 %

Procedure:
In a manner similar to that of Example 1(e), starting with 20 g (115 mmol) of 3-bromophenol and 26 g (173 mmol) of 4-formylbenzene boronic acid, 15 g (65%) of the expected product are obtained.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N(CCCC)C2CCCCC2)CCCCC1.C(=O)CCC=C.C1(N(C2CCCCC2)[CH:46]([CH:53]([O:56][CH3:57])[O:54][CH3:55])[CH2:47][CH2:48][C:49](OC)=O)CCCCC1>>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:46]([CH2:47][CH:48]=[CH2:49])[CH:53]([O:56][CH3:57])[O:54][CH3:55])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: COC(=O)CCC(C(OC)OC)N(C1CCCCC1)C1CCCCC1
Agent: C=CCCC=O
Agent: CCCCN(C1CCCCC1)C1CCCCC1
Product: C=CCC(C(OC)OC)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 24 h
Yield: 63 %

Procedure:
The product was prepared by above general procedure and the same chemicals except employing dibenzylamine (1a′) (98 mg, 0.5 mmol), and pent-4-enal (2d′) (63 mg, 0.75 mmol). After 24 h, the crude product was purified by flash column chromatography (silica gel; ethyl acetate or diethyl ether/hexane=1:100) to afford the desired product 3d as a light yellowish oil (0.102 g, 63% yield); Rf=0.70 (hexane:ethyl acetate=3:1); 1H NMR (CDCl3, 400 MHz) δ 7.38-7.37 (m, 4H), 7.30-7.26 (m, 4H), 7.21-7.18 (m, 2H), 5.89-5.79 (m, 1H), 5.08-5.00 (m, 2H), 4.39-4.38 (d, J=4.93 Hz, 1H), 3.80-3.71 (m, 4H), 3.35 (s, 3H), 3.28 (s, 3H), 2.89-2.84 (m, 1H), 2.44-2.26 (m, 2H) ppm; C NMR (CDCl3, 100 MHz) δ 140.5 (C×2), 137.8, 129.0 (CH×4), 128.0 (CH×4), 126.7 (CH2×2), 115.5, 107.0, 57.8, 54.7, 54.5, 54.4 (CH2×2), 31.2 ppm; FTIR (neat): v=3015, 1454, 1215, 754, 700, 494 cm−1; HRMS (ESI, m/z): calcd for C21H28NO2+ [M+H]+ 326.2120, found: 326.2114.