Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.[C:11]1([C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH2:19][CH2:20]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:11]1([C:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH2:19][CH2:20][N:1]2[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CC1CCNC1
Reactant: BrCCC=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CC1CCN(CCC=C(c2ccccc2)c2ccccc2)C1

Procedure:
A mixture of 44.5 g. (0.138 mole) of methyl 3-pyrrolidineacetate hexamate, 40.3 g. (0.140 mole) of 4,4-diphenyl-3-butenyl bromide and 38.2 g. (0.276 mole) of potassium carbonate in 400 ml. of acetone was refluxed for 43 hours. The mixture was chilled, filtered, concentrated and chromatographed on silica gel to give methyl 1-(4,4-diphenyl-3-butenyl)-3-pyrrolidineacetate.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[K+]>O>[NH2:10][C:8](=[N:9][C:12](=[O:13])[O:14][CH3:15])[S:7][CH3:6]
Reactant: CSC(=N)N
Reactant: COC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N=C(N)SC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 69.5 parts of 2-methyl-2-thiopseudourea sulfate and 47 parts of methyl chloroformate in 1000 parts of water at 0°C is added dropwise 56.9 parts of potassium hydroxide in 200 parts of water. The reaction mixture is stirred at room temperature for 3 hours and then extracted with methylene chloride. The methylene chloride extract is dried and the solvent evaporated at reduced pressure to give 45 g of methyl N-(1-amino-1-methylthiomethylene)carbamate melting at 72°-77°C.
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[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:28][C:29](O)=[O:30].[NH:32]1[CH2:35][CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:32]1([C:29](=[O:30])[CH2:28][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=4)[CH2:16][CH2:15]3)=[CH:7][C:2]=2[F:1])[CH2:35][CH2:34][CH2:33]1
Reactant: C1CNC1
Reactant: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)c(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2-fluoro-4-{2-[(1S,2R)-2-{1-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetic acid (80.0 mg, 0.185 mmol) in 1 ml anhydrous DMF at RT was added azetidine (12.6.2 mg, 0.221 mmol) and N,N-diisopropylethylamine (0.097 ml, 0.554 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (140 mg, 0.369 mmol) was added into the solution and stirred at RT for 4 hrs. The reaction mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-95% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 473.2 (M+H)+. GPR119 Human EC50: 5.8 nM
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([N:13]2[C:17]3([CH2:21][CH2:20][CH2:19][CH2:18]3)[C:16](=[O:22])[NH:15][C:14]2=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:25][C:26]([NH:28][C:29]1[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[CH:38]([CH3:40])[CH3:39])=[O:27].O>CN(C)C=O>[CH:38]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([CH:35]([CH3:36])[CH3:37])[C:29]=1[NH:28][C:26](=[O:27])[CH2:25][N:15]1[C:16](=[O:22])[C:17]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[N:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:14]1=[O:23])([CH3:39])[CH3:40]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Reactant: O=C1NC(=O)C2(CCCC2)N1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1C(=O)N(c2ccccc2)C2(CCCC2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.6 %

Procedure:
80 mg (0.57 mmol) of potassium carbonate are added to a solution of 120 mg (0.52 mmol) of 1-phenyl-1,3-diazaspiro[4.4]nonane-2,4-dione and 145 mg (0.57 mmol) of 2-chloro-N-(2,6-diisopropylphenyl)acetamide in 20 ml of dimethylformamide. The reaction medium is stirred at room temperature for 24 hours. It is then poured into water and extracted with ethyl acetate. The organic phases are collected, washed with water and dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane and then heptane/ethyl acetate 80/20, v/v). 120 mg of N-(2,6-diisopropylphenyl)-2-(2,4-dioxo-1-phenyl-1,3-diazaspiro[4.4]non-3-yl)acetamide are obtained in the form of a white solid. Yield=51%, m.p.=275-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].CO[CH:19](OC)[N:20](C)[CH3:21].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][C:6](=[CH:19][NH:20][CH3:21])[C:5]2=[O:16]
Reactant: CCC(=O)N1CCC(=O)c2cc(Cl)ccc21
Reactant: COC(OC)N(C)C
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC(=O)N1CC(=CNC)C(=O)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2 g), N,N-dimethylformamide dimethyl acetal (7.009 g), and triethylamine (0.87 g) in benzene (50 m) was refluxed with stirring for 1 hour and then about three-fourths of the solvent was distilled slowly at atmospheric pressure over a period ximately 1 hour. To the residue was added benzene (100 ml) and the solvent was distilled again. The resulting solid was collected by filtration, washed with diethyl ether, and dried to give 6-chloro-3-methylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.02 g).
Reaction SMILES: [NH2:1][CH:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][S:4][C:3]1([CH3:10])[CH3:9].[NH2:11][C@H:12]([C:17]([NH:19][C@@H:20]([C:22](N)=[O:23])[CH3:21])=[O:18])[CH2:13][C:14](=[O:16])[OH:15].C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>>[CH3:9][C:3]1([CH3:10])[CH:2]([NH:1][C:22](=[O:23])[C@@H:20]([CH3:21])[NH:19][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH2:11])[C:6]([CH3:8])([CH3:7])[CH2:5][S:4]1
Reactant: CC1(C)CSC(C)(C)C1N
Reactant: C[C@@H](NC(=O)[C@@H](N)CC(=O)O)C(N)=O
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: C[C@@H](NC(=O)[C@@H](N)CC(=O)O)C(=O)NC1C(C)(C)CSC1(C)C

Procedure:
When levorotatory 3-amino-2,2,4,4-tetramethyltetrahydrothiophene, resolved by standard methods, was employed in the above procedure in place of the racemic amine the resulting L-aspartyl-D-alanine amide was found to be 800 times as sweet as sucrose.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH:30]1[C:38]2[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[C:33]=2[CH:32]=[CH:31]1>>[NH:30]1[C:38]2[C:33](=[C:34]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([CH:18]6[CH2:23][CH2:22][O:21][CH2:20][CH2:19]6)[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCN(C4CCOCC4)CC3)cc2n1
Product: c1cc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C5CCOCC5)CC4)cc3n2)c2cc[nH]c2c1
Yield: 64 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-[4-(tetrahydro-pyran-4-yl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine (100 mg, 0.23 mmol) and indole-4-boronic acid was reacted using Suzuki coupling Method B, to give after silica chromatography, the title compound as a white solid (76 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH2:11][CH2:12][CH3:13]>>[C:10]([C:15](=[CH:21][NH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Reactant: Nc1ccc(CO)cc1
Product: CCCC(=O)C(=CNc1ccc(CO)cc1)C(=O)OCC

Procedure:
4-Aminobenzylalcohol (25 g) and ethyl 2-butyryl-3-ethoxyacrylate (61 g) were heated together on a rotary evaporator (bath temp 100°) for 30 minutes. Ethyl 2-butyryl-3-(4-(hydroxymethyl)phenylamino)acrylate (49.5 g, 84%) crystallized on standing, was filtered off, washed with a little petroleum ether and vacuum dried, m.p. 44°-6°
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[O:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>ClCCl>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[O:6][CH2:5][CH2:4]1)=[O:30]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
(R)-Methyl 4-aminochromane-6-carboxylate hydrochloride (A-03) (0.6 g, 2.462 mmol, 1.0 eq) was dissolved in dichloromethane and DIPEA (2.5 eq) under nitrogen, and 2-chlorobenzoic acid chloride (0.37 ml, 2.954 mmol, 1.2 eq) was added at 0° C. The reaction mixture was stirred for 3 h at RT. Then the reaction mixture was concentrated, and the residue was taken up in ethyl acetate, washed with 10% ammonium chloride solution, sat. NaHCO3 solution and with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, cyclohexane:ethyl acetate 2:1) to yield (R)-methyl 4-(2-chlorobenzamido)chromane-6-carboxylate (B-05). Yield: 92%
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)c1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccccc2C(F)(F)F)CCN1
Yield: 185.1 %

Procedure:
A mixture of (R)-2-methyl-piperazine (300 mg, 2.99 mmol), 2-bromo benzotrifluoride (612 mg, 2.72 mmol), tris(dibenzylidineacetone)dipalladium (0) (24.72 mg, 0.027 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (51.06 mg, 0.082 mmol) and sodium tert-butoxide (326.77 mg, 3.4 mmol) were charged to a microwave vial. Toluene (3.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 30 minutes. Reaction was complete as determined by TLC. The reaction was repeated at (R)-2-methyl-piperazine (1.0 g, 9.98 mmol). Reaction mixtures were combined, diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield (R)-3-methyl-1-(2-trifluoromethyl-phenyl)-piperazine as yellow oil (1.23 g, 39.6% yield). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.07 (d, J=6.32 Hz, 3H) 2.41-2.51 (m, 1H) 2.74-2.84 (m, 1H) 2.90-2.98 (m, 2H) 3.00-3.13 (m, 3H) 7.18-7.25 (m, 1H) 7.35 (d, J=8.08 Hz, 1H) 7.47-7.55 (m, 1H) 7.62 (d, J=7.83 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>CS(C)=O.ClCCl.[Cl-].[NH4+].[Cu]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][N:3]=1
Reactant: Nc1ncc(I)cn1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)c1cnc(N)nc1
Temperature: 80 °C

Procedure:
To the Schlank flask containing 2-amino-5-iodopyrimidine (2.210 g, 10.00 mmol) and copper powder (0.953 g, 15.0 mmol) in anhydrous DMSO (10 mL) was added ethyl bromodifluoroacetate (1.285 mL, 10.00 mmol). The reaction mixture was heated at 80° C. under nitrogen overnight. Reaction mixture was cooled to room temperature and diluted with dichloromethane (80 mL) and 2N aqueous ammonium chloride (150 mL). The mixture was extracted with dichloromethane (2×60 mL). The organic layer was washed with brine (2×50 mL), and concentrated. The residue was purified by Biotage SP1 column chromatography on silica gel [40+M], eluting with 5-60% ethyl acetate/hexanes, 24 CV; 60% ethyl acetate/hexanes, 6 column volumes. 1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 2H), 7.35 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][O:39][C:40](=[O:57])[C:41]1[CH:46]=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][C:42]=1[F:56].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)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>[CH3:38][O:39][C:40](=[O:57])[C:41]1[CH:46]=[CH:45][C:44]([C:20]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:43][C:42]=1[F:56]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(C)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Yield: 82.8 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 128, 1.28 g, 2.4 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.01 mg, 2.4 mmol) and dichlorobis(triphenylphosphine)palladium (II) (170 mg, 0.24 mmol) in dioxane (10 mL) was added an aqueous sodium carbonate solution (2 M, 3.6 mL, 7.2 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-2-fluoro-benzoic acid methyl ester (1.03 g, 83%) as a light yellow solid: LC/MS m/e calcd for C29H27FN2O4S [M+H]+ 519.61, observed 518.8.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH:19]=[CH:18][C:17]2[N:20]([C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[N:21]=[N:22][C:16]=2[CH:15]1[CH3:29])=[O:13]>CO.C1COCC1.[Pd]>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[N:20]([C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[N:21]=[N:22][C:16]=2[CH:15]1[CH3:29])=[O:13]
Reactant: CC1c2nnn(-c3cnccn3)c2C=CN1C(=O)c1cccc(C(F)(F)F)c1Cl
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1c2nnn(-c3cnccn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Reaction time: 8 h

Procedure:
A suspension of the 5-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-methyl-1-pyrazin-2-yl-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine (150 mg, 0.36 mmol) in MeOH (3.0 mL) and THF (1.0 mL) was treated with 10% Pd/C (30 mg), put under an atmosphere of H2 and stirred overnight. The reaction was filtered through Celite© and purified on 12 g SiO2 with 0-70% EA/DCM. MS (ESI): mass calcd. for C18H14ClF3N6O, 422.1. m/z found, 423.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:20].Br[CH2:22][CH2:23][CH2:24][Cl:25].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[N:12]=2)[CH:5]=[CH:4][C:3]=1[O:20][CH2:22][CH2:23][CH2:24][Cl:25]
Reactant: ClCCCBr
Reactant: Oc1ccc(-c2nc(CN3CCCCC3)co2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: ClCCCOc1ccc(-c2nc(CN3CCCCC3)co2)cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A suspension of 2-chloro-4-[4-(piperidin-1-ylmethyl)-1,3-oxazol-2-yl]phenol i66 (0.13 g, 0.44 mmol, 1 eq), 1-bromo-3-chloropropane (57 μl, 0.58 mmol, 1.3 eq) and potassium carbonate (0.12 g, 0.89 mmol, 2 eq) is stirred at 50° C. overnight. The carbonate is then filtered off and the resulting solution is concentrated under reduced pressure to give 0.12 g of crude 1-({2-[3-chloro-4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}methyl)piperidine i71 as an oil, which is directly used in the next step.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]1[O:13][CH3:14].[Cl:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH2:27][C@H:28]([NH2:30])[CH3:29].C(N(CC)CC)C>C(O)C>[Cl:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH2:27][C@H:28]([NH:30][C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:11]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]1[O:13][CH3:14])[CH3:29]
Reactant: C[C@@H](N)Cc1sccc1Cl
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)ncnc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N[C@H](C)Cc3sccc3Cl)ncnc21

Procedure:
A solution of 6-chloro-9-(2'-O-methyl-β-D-ribofuranosyl)-9H-purine (prepared as in EP Publication No. 0378518) (0.28 g), 2-(3-chloro-2-thienyl)-(1R)-1-methylethylamine (0.163 g), and triethylamine (0.5 ml) in ethanol (30 ml) is refluxed for about 18 hours, cooled and concentrated in vacuo. The residue is purified by flash chromatography, eluting with 10% methanol in methylene chloride, followed by crystallization from hexane/ethyl acetate, to give the desired product, m.p. 75°-76° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)(O)[O-].[K+].O>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:16][CH3:17])[C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1[N+](=O)[O-]

Procedure:
1-Benzyl-4-[(N-ethylamino)methyl]piperidine (EXAMPLE 261, 5.68 g) and 2-chloro-3-nitropyridine (3.87 g) are dissolved in 96 ml of acetonitrile and 4.05 g of solid potassium bicarbonate is added. The reaction is refluxed for 20 hr, cooled to 20°-25°, poured into water and extracted with ethyl acetate. The organic extracts are dried (sodium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (15% ethyl acetate/hexane to 80% ethyl acetate/hexane) gives the title compound, HRMS calcd. for C20H26N4O2 =354.2056, found=354.2045.
Reaction SMILES: COC1C=CC=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH3:35])=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: COc1ccccc1C(=O)Cl
Agent: COc1ccccc1C(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4OC)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
2-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (67 mg, yield 85%).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].OC/C=C(/C)\CCC=C(C)C.C(N(CC)CC)C.[C:30](Cl)(=[O:42])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C1(C)C=CC=CC=1>[C:30]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])(=[O:42])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: CC(C)=CCC/C(C)=C\CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)OC/C=C(\C)CCC=C(C)C
Temperature: 25 °C

Procedure:
A mixture of geraniol and nerol (approximately 70:30 by weight) in the amount of 50.00 g (0.324 mol) and triethylamine in the amount of 36.08 g (0.357 mol) are combined with 300 mL of toluene. The reaction mixture is heated to reflux and lauroyl chloride in the amount 70.92 g (0.324 mol) isadded dropwise over 15 min. After heating for an additional 30 min, the product mixture is cooled to room temperature and filtered. The filtrate is washed three times with 100 niL of saturated NaHCO3, 100 mL of water, and dried over MgSO4. After filtration, the filtrate is concentrated by rotary evaporation followed by Kugelrohr distillation. Purity of the product is determined by thin layer chromatography and the structure confirmed by 13C and 1H NMR.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[C:7]([NH:17][C@H:18]([C:22](O)=[O:23])[CH:19]([CH3:21])[CH3:20])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[Br:1][CH2:2][CH:3]([OH:6])[CH2:4][O:5][C:22](=[O:23])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: OCC(O)CBr
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(O)CBr
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 3-bromo-1,2-propanediol (10.85 g, 70mmole), N-CBz-L-valine (10.05 g, 40 mmole) and DMAP (0.49 g, 4 mmol) in 250 ml dichloromethane was added dropwise a solution of DCC (9.1 g, 44 mmol) in 50 ml dichloromethane at about 10° C. The mixture was stirred for two days at room temperature and then cooled to 5° C. The urethane was filtered and the solution was evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 8 g