Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)nccc12
Yield: 101.4 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-6, step-1 using 1-chloro-5-nitroisoquinoline (Step-1, Intermediate-1, 500 mg, 2.38 mmol), 4-fluoro-3-(trifluoromethyl)phenol (859 mg, 4.77 mmol) and K2CO3 (821 mg, 5.95 mmol) in CH3CN (5 mL) to afford 850 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.84 (d, J=8.4 Hz, 1H), 8.71 (d, J=7.8 Hz, 1H), 8.19 (d, J=6.3 Hz, 1H), 8.01-7.92 (m, 2H), 7.87 (m, 1H), 7.76 (m, 1H), 7.66 (t, J=9.6 Hz, 1H); MS (m/z): 353.20 (M+H)+.
Reaction SMILES: C(O)(=O)C(O)=O.C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44](Cl)(=[O:49])[CH2:45][CH2:46][CH2:47][CH3:48]>O1CCCC1>[C:44]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:49])[CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(=O)NC1CCN(CCNC(=O)c2nn(C(C)C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise valeryl chloride (0.12 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.385 g oil. Crystallization from diethyl ether provided 0.176 g colorless crystals. Mp 107°-109° C. Mass spectrum, m+ =413. Anal (C23H35N5O2) theory C, 66.80; H, 8.53; N, 16.93; found C, 66.59; H, 8.66; N, 17.04.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH:10]=[CH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.S(O[CH2:30][CH2:31][Cl:32])(C1C=CC(C)=CC=1)(=O)=O>[OH-].[Na+].O>[Cl:32][CH2:31][CH2:30][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]=[CH:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: Oc1ccccc1C=Cc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCOc1ccccc1C=Cc1cccc2[nH]ccc12
Reaction time: 16 h
Yield: 39.5 %

Procedure:
4 g of 2-[(1H-indol-4-yl)-ethenyl]-phenol obtained in Step A of Example 1 in 100 ml of 2N sodium hydroxide after having added 6 g of 2-chloroethanol tosylate were heated for 6 hours at reflux and the mixture was left for 16 hours at ambient temperature, then diluted with water and extracted with ethyl acetate. After eliminating the solvent under reduced pressure and chromatography on silica (eluent: benzene), 2 g of 4-[2-[2-[(2-chloro)-ethoxy]-phenyl]-ethenyl]-1H-indole (trans E) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc(Cl)cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH:13]2[CH2:18][NH:17][C:16](=[O:19])[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:21]([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(OCC)(=O)C>C1(C)C=CC=CC=1>[O:19]=[C:16]1[CH2:15][CH2:14][CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:18][N:17]1[CH:21]([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C1CCC(c2ccccc2)CN1
Reactant: CCOC(=O)C(Br)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC)N1CC(c2ccccc2)CCC1=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
In a 1 l three necked flask fitted with reflux condenser, magnetic stirrer and dropping funnel under inert atmosphere, 9.8 g (87 mmoles) of potassium t-butoxide were suspended in 600 ml of dry toluene. 11.8 g (67 mmoles) of 5-phenyl-2-piperidinone 25 were added, and the mixture stirred for 30 min. 17 g (87 mmoles) of ethyl 2-bromobutanoate were added and the temperature raised to 70° C. for 5 hours. 600 ml of ethyl acetate were added, the solution was washed twice with brine, the organic phase dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by PrepLC (1 kg SiO2, CH2Cl2/EtOH, 97.5/2.5) to give 3.7 g of pure ester 26 as a mixture of diastereomers, 70.4% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11e, and benzenesulfonyl chloride, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.87 (m, 3H), 7.80 (d, 2H), 7.62 (m, 1H), 7.56 (m, 2H), 7.33 (d, 1H), 7.11 (m, 3H), 7.03 (d, 1H), 6.87 (d, 1H), 6.78 (s, 1H), 4.34 (s, 2H), 4.32 (s, 2H), 3.65 (s, 3H), 2.79 (t, 2H), 2.48 (t, 2H); MS 507 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:10]([O:14][C:15]([CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:20]=1[CH:21]=[O:22])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:10]([O:14][C:15]([CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:23][C:20]=1[CH:21]=[O:22])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)COc1ccc(O)cc1C=O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCOc1ccc(OCC(=O)OC(C)(C)C)c(C=O)c1
Temperature: 100 °C
Reaction time: 7 h
Yield: 29.6 %

Procedure:
Ethyl 4-bromobutyrate (1.48 g) and 2-(tert-butoxycarbonylmethoxy)-5-hydroxybenzaldehyde (1.28 g) were dissolved in methyl ethyl ketone (20 ml). To the solution was added powdered potassium carbonate (1.05 g), and the mixture was stirred in an oil bath at 100° C. for seven hours. The reaction mixture was concentrated, diluted with water, and was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration, the crude product was purified by a silica gel column (35 g) eluting with a mixed solvent of toluene and ethyl acetate (from 19:1 to 4:1) to give ethyl 4-(4-tert-butoxycarbonylmethoxy-3-formylphenoxy)butyrate as an oil (0.55 g)
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1>C1COCC1>[CH:1]([O:4][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
iso-Propanol (1.41 mL, 18.48 mmol) was added drop wise into a stirred suspension of sodium hydride (60% dispersion in oil, 0.739 g, 18.48 mmol) in anhydrous THF (20 mL) at 0° C. and the resulting solution stirred for 0.5 hours. To this solution was added 2-fluoro-3-nitropyridine (2.50 g, 17.60 mmol) drop wise in anhydrous THF (10 mL). After complete addition the solution was stirred at 0° C. for 0.5 hours, before being allowed to warm to ambient temperature. The reaction was stirred at ambient temperature for 18 hours, quenched with water (50 mL) and the aqueous layer extracted with diethyl ether (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The title compound was obtained as a yellow solid (1.975 g, 61% yield) after purification by flash-column chromatography (petroleum ether (40-60° C.)/DCM).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26]C1C=C(C=CC=1)CN>>[Cl:26][C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][CH:5]=1)[CH2:1][NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10]
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Reactant: NCc1cccc(Cl)c1
Product: O=C(NCc1cccc(Cl)c1)c1sccc1Nc1ncnc2[nH]ccc12
Yield: 15 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using 3-chlorobenzylamine instead of benzylamine and obtained in 15% yield (HPLC: 94%, RT: 6.54 min). 1H NMR (DMSO-d6) 11.98 (br s, 1H), 11.33 (s, 1H), 8.61 (t, J=6.0 Hz, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.39 (s, 1H), 7.81 (d, J=5.5 Hz, 1H), 7.41-7.29 (m, 5H), 6.43 (dd, J=3.7, 1.8 Hz, 1H), 4.50 (d, J=5.9 Hz, 2H); MS (m/z) 384 [M+H]+ (35Cl).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][NH:24][C@@H:25]([CH2:36][CH2:37][C:38]2[NH:39][CH:40]=[C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:42]=2)[C:26](OCC2C=CC=CC=2)=[O:27])=[CH:15]1.C(N(CC)CC)C>C1COCC1>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][N:24]2[C@@H:25]([CH2:36][CH2:37][C:38]3[NH:39][CH:40]=[C:41]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:42]=3)[C:26](=[O:27])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=3)[C:10]2=[O:11])=[CH:15]1
Reactant: O=C(OCc1ccccc1)[C@H](CCc1nc(-c2ccccc2)c[nH]1)NCc1c[nH]c2ccccc12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1[C@H](CCc2nc(-c3ccccc3)c[nH]2)N(Cc2c[nH]c3ccccc23)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
3-trifluoromethyl-phenylisocyanate (11 mg, 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butanoate (23 mg, 1 eq.) in 2 ml of THF. The mixture is stirred for 2 hours at approximately 20° C. then diluted with 2 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is then concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine) in order to produce the expected compound (25 mg, 92% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12]P(=O)(OCC)OCC)=[N:6][CH:7]=1.[H-].[Na+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C1COCC1.O1CCOCCOCCOCCOCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH:12]=[C:36]2[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cccc(Oc2ccc(C)cn2)c1)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
Diethyl 3-(5-methylpyridin-2-yloxy)benzylphosphonate (1.75 g, 5.22 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.02 mL, 0.10 mmol) were combined in THF (5 mL). Sodium hydride (230 mg, 60% dispersion in mineral oil, 5.74 mmol) was added. The reaction was stirred for 30 min and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.14 g, 5.74 mmol) in THF (5 mL) was added. After 16 h, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30%, EtOAc:heptane) to afford the title compound (1.24 g, 62% yield) as a thick oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:5][NH:4][C:3]1=[S:17].[C:18]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][N:2]1[C:3]([S:17][CH3:18])=[N:4][N:5]=[C:6]1[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1
Reactant: Cn1c(-c2ccc3ccccc3c2)n[nH]c1=S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSc1nnc(-c2ccc3ccccc3c2)n1C

Procedure:
A mixture of 2,4-dihydro-4-methyl-5-(2-naphthyl)-3H-1,2,4-triazole-3-thione (5.26 g, 2.18×10-2 mole), K2CO3 (3.01 g, 2.18×10-2 mole), methyl iodide (1.5 ml, 2.4×10-2 mole), and acetone (65 ml) was stirred and warmed to reflux. After refluxing overnight, the solvent was evaporated at reduced pressure and the concentrate was treated with water. The aqueous mixture was extracted with EtOAc three times. The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure to yield the desired product. Mp 177°-179° C.
Reaction SMILES: I[C:2]1[C:3]([CH3:12])=[N:4][C:5]2[N:6]([N:9]=[CH:10][N:11]=2)[C:7]=1[NH2:8].[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14].C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:12][C:3]1[C:2]([C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:7]([NH2:8])[N:6]2[N:9]=[CH:10][N:11]=[C:5]2[N:4]=1
Reactant: Cc1nc2ncnn2c(N)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2ncnn2c(N)c1C#C[Si](C)(C)C
Yield: 50.1 %

Procedure:
A mixture of Example 4A (275 mg, 1.0 mmol), ethynyltrimethylsilane (283 μL, 2.6 mmol), bis(triphenylphosphine)palladium(II) dichloride (35 mg, 0.05 mmol), CuI (10 mg, 0.05 mmol), and triethylamine (279 μL, 2 mmol) in acetonitrile (4 mL) was heated at 90° C. under an atmosphere of nitrogen for 1 h. The resulting-mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuuo. The residue was purified by flash chromatograph on silica gel (eluting with ethyl acetate) to provide the title compound as a pale yellow solid (123 mg, 50% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].[C:17]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>O1CCOCC1>[C:17]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]([S:23]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([OH:10])=[O:9])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
This compound was prepared from trans-2-amino-1-cyclohexanecarboxylic acid (1.0 g, 7.0 mmol) by reacting it with sodium carbonate (1.48 g, 14.0 mmol) and biphenyl-4-sulfonyl chloride (2.02 g, 8.0 mmol) in dioxane:water (70:35 mL) in the same manner as described in Example 1. The yield was 1.48 g (59%), the melting point was 220-222° C., and mass spectrometry revealed a molecular ion peak (MH)+ at m/z 360.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31]([Cl:33])[C:30]([NH2:34])=[CH:29][C:28]=3[C:35]([F:38])([F:37])[F:36])=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:47](Cl)=[O:48])=[CH:43][N:42]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:39])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[C:31]([Cl:33])[C:30]([NH:34][C:47]([C:44]4[CH:43]=[N:42][C:41]([F:40])=[CH:46][CH:45]=4)=[O:48])=[CH:29][C:28]=3[C:35]([F:37])([F:38])[F:36])=[CH:25][CH:26]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(N)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Reactant: O=C(Cl)c1ccc(F)nc1
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(F)nc4)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of ((S)-1-{(S)-2-[4-(4′-amino-5′-chloro-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (50 mg, 0.09 mmol; Preparation 52) dissolved in DCM (0.3 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (14 mg, 0.091 mmol) dissolved in DCM (0.3 mL). The reaction mixture was stirred at RT for 5 min and concentrated to produce {(S)-1-[(S)-2-(4-{5′-chloro-4′-[(6-fluoro-pyridine-3-carbonyl)-amino]-2′-trifluoromethyl-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)C.Cl.O1CCOCC1>[CH2:24]([O:23][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[CH2:14][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1)[CH3:25]
Reactant: CCOc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)ccc1OC
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Yield: 66.6 %

Procedure:
A solution of [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (9.71 g, 26.64 mmol) in ethanol (50 mL) and 4 M HCl in dioxane (75 mL) was stirred at rt for 2 h. The hydrochloric acid was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (200 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure yielding 4.69 g (89%) of a white solid. The crude material was directly used in the following reaction step. MS (ESI): 265.0 [M+H]+.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16](O)(=[O:20])[CH2:17][CH2:18][CH3:19].[C:22]([O:26][C:27]([NH:29][C@H:30]([C:34]([O:36][CH2:37][CH2:38][C@@H:39]([CH2:52][OH:53])[CH2:40][N:41]1[CH:49]=[N:48][C:47]2[C:46](=[O:50])[NH:45][C:44]([NH2:51])=[N:43][C:42]1=2)=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([O:26][C:27]([NH:29][C@H:30]([C:34]([O:36][CH2:37][CH2:38][C@@H:39]([CH2:52][O:53][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH2:40][N:41]1[CH:49]=[N:48][C:47]2[C:46](=[O:50])[NH:45][C:44]([NH2:51])=[N:43][C:42]1=2)=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: CCCC(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 120 h
Yield: 34.4 %

Procedure:
DCC (110 mg, 0.53 mmol) was dissolved in dichloromethane (10 ml) and butyric acid (82 mg, 0.93 mmol) was added. After 4 hours at room temperature the mixture was filtered and the filtrate was evaporated. The residue was dissolved in pyridine (5 ml) and (R)-9-[4-(N-tert-Butoxycarbonyl-L-valyloxy)-2-hydroxymethylbutyl]guanine (200 mg, 0.44 mmol) (Example 1, step a) was added. The mixture was stirred for 120 hours at room temperature. According to TLC the reaction was incomplete and more anhydride was made using the procedure above. This anhydride was added and the mixture was stirred for an additional 20 hours. The reaction mixture was evaporated and chromatographed first on silica gel and then on aluminium oxide, in both cases eluted with dichloromethane/methanol to give 79 mg of the intermediate product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[N:20]1([C:24](=[O:35])[CH2:25][C:26]2[CH:33]=[CH:32][C:31](O)=[CH:30][C:27]=2[C:28]#[N:29])[CH2:23][CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:20]1([C:24](=[O:35])[CH2:25][C:26]2[CH:33]=[CH:32][C:31]([O:19][CH2:18][CH2:17][C@@H:15]3[CH2:16][C@@H:14]3[CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=4)[CH2:9][CH2:10]3)=[CH:30][C:27]=2[C:28]#[N:29])[CH2:21][CH2:22][CH2:23]1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: N#Cc1cc(O)ccc1CC(=O)N1CCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (22 mg, 0.076 mmol) was dissolved in toluene (1 ml) and 2-[2-(azetidin-1-yl)-2-oxoethyl]-5-hydroxybenzonitrile (15 mg, 0.069 mmol), triphenylphosphine (36 mg, 0.139 mmol), and DIAD (27 μl, 0.139 mmol) added and the mixture stirred at RT overnight. The mixture was diluted with ethyl acetate (20 mL), washed with brine (10 ml), dried over MgSO4, filtered and the solvent removed in vacuo. The reside was purified by column chromatography using a Biotage SiO2 cartridge (25 g) using a gradient eluant of 10-100% EtOAc:hexanes to afford the title compound. LC/MS (m/z): 480 (M+H)+. GPR119 Human EC50: 0.32 nM.
Reaction SMILES: [CH2:1]1[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][C:13](=[O:14])[N:4]3[CH2:3][CH2:2]1)[CH:7]=[CH:8][CH:9]=2.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([C:8]1[CH:9]=[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][C:13](=[O:14])[N:4]3[CH2:3][CH2:2][CH2:1]2)[CH:7]=1)=[O:22]
Reactant: O=C1CCc2cccc3c2N1CCC3
Reactant: O=C(Cl)CCCCCBr
Product: O=C(CCCCCBr)c1cc2c3c(c1)CCC(=O)N3CCC2

Procedure:
Using 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one and 6-bromohexanoyl chloride according to the same method as that of Reference Example 1, the title compound (3.90 g) was obtained as colorless crystals having a melting point of 52–53° C.