Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[C:29]([CH3:33])=[N:28]1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:10][CH:11]3[CH2:15][NH:14][CH2:13][CH:12]3[CH2:23]2)=[N:7][C:2]([NH:32][C:30]2[C:29]([CH3:33])=[N:28][N:27]([CH3:26])[CH:31]=2)=[N:3][CH:4]=1
Reactant: Cc1nn(C)cc1N
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CC3CNCC3C2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole2(1H)-carboxylate (573.1 mg, 1.54 mmol) and 1,3-dimethylpyrazol-4-amine hydrochloride (458.8 mg, 3.11 mmol) in dioxane (10 mL) was added trifluoroacetic acid (856.4 mg, 7.51 mmol). The reaction mixture was stirred at 100° C. overnight and adjusted to pH=10 with a saturated Na2CO3 solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM=1/10) to give the title compound as a beige solid (256.8 mg, 48.1%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][C@H:21]([N:23]3CCO[C:24]3=[O:28])[CH2:20][C@@H:19]([CH3:29])[CH2:18]2)[N:3]=1.[CH2:30]([OH:32])[CH3:31].O.[NH2:34][NH2:35].[NH4+].[OH-]>C(Cl)Cl.CO>[NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:18][C@H:19]([CH3:29])[CH2:20][C@@H:21]([N:23]3[CH2:31][CH2:30][O:32][C:24]3=[O:28])[CH2:22]2)[CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:34][NH:35]3)=[CH:14][CH:15]=2)[N:7]=1
Reactant: CCO
Reactant: NN
Reactant: C[C@@H]1C[C@@H](N2CCOC2=O)CN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: C[C@@H]1C[C@@H](N2CCOC2=O)CN(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 100 °C

Procedure:
Into a 5 mL sealable vial were added 4-{2-amino-6-[(3R,5R)-3-methyl-5-(2-oxo-1,3-oxazolidin-3-yl)-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (96 mg, 0.242 mmol) and ethanol (10 mL) followed by hydrazine monohydrate (0.356 mL, 7.27 mmol). The reaction vial was capped and was heated at 100° C. overnight. The reaction was concentrated, then dissolved in 2 mL of DMSO and purified on HPLC (HPLC condition: open-access Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 mL/min, 10% CH3CN/H2O, 0.1% TFA to 25% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the CH3CN. The water left behind was freeze dried, and the solid obtained was then dissolved in 2 mL of 9:1 CH2Cl2:CH3OH and then loaded on to a 10 g Biotage SNAP column. The product was then eluded off the column with a gradient of 0 to 100% 95:5:1 CH2Cl2:CH3OH:NH4OH in CH2Cl2 over 25 minutes. The product fractions were combined, concentrated, and then transferred into haystack vial. Water (1 mL) was added, and the resulting mixture was freeze dried to afford the title compound (55 mg) as a light yellow solid. LC-MS (ES) m/z=409 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.97 (d, J=6.6 Hz, 3H), 1.51-1.59 (m, 1H), 1.96 (ddd, J=12.8, 8.1, 4.4 Hz, 1H), 2.00-2.07 (m, 1H), 3.36-3.45 (m, 1H), 3.50-3.72 (m, 4H), 3.80-3.87 (m, 1H), 3.89-3.98 (m, 1H), 4.18-4.26 (m, 2H), 5.38 (s, 2H), 6.11 (s, 2H), 6.64 (s, 1H), 7.58 (dd, J=8.6, 1.3 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.95 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:17]1C=CC=CC=1C1(C(OC)=O)CCNCC1>>[C:14]([C:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)#[N:15]
Reactant: N#CC1(c2ccccc2Cl)CCNCC1
Reactant: COC(=O)C1(c2ccccc2Cl)CCNCC1
Product: Cc1ccccc1C1(C#N)CCNCC1

Procedure:
4-(2-chlorophenyl)-4-cyanopiperidine or 4-(2-chlorophenyl)-4-(methoxycarbonyl)piperidine
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[NH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N:42]1([CH2:47][CH2:48][O:49][CH2:50][CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[C:1]1([C:7]2[C:15]3[C:14]([N:54]4[CH2:55][CH2:56][CH:51]([CH2:50][O:49][CH2:48][CH2:47][N:42]5[CH2:46][CH2:45][CH2:44][CH2:43]5)[CH2:52][CH2:53]4)=[N:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(C(F)(F)F)nc2scc(-c3ccccc3)c12
Reactant: C1CCN(CCOCC2CCNCC2)C1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: FC(F)(F)c1nc(N2CCC(COCCN3CCCC3)CC2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
5-Phenyl-2-(trifluoromethyl)thieno[2,3-d]pyrimidin-4-one (0.20 g, 0.67 mmol) was stirred in dichloromethane (5 mL) at 0° C. Pyridine (0.11 mL, 1.3 mmol) was added, followed by trifluoromethanesulfonic anhydride (0.14 mL, 0.81 mmol) and stirring continued for 30 mins and the mixture allowed to warm to room temperature. 4-(2-Pyrrolidin-1-ylethoxymethyl)piperidine (0.29 g, 1.3 mmol) was added and the reaction stirred for 1 hour at room temperature. The reaction mixture was diluted with DCM (20 mL), washed with water (20 mL), dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of petroleum ether to 50/50 petroleum ether/ethyl acetate to afford 5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]-2-(trifluoromethyl)thieno[2,3-d]pyrimidine (0.16 g). LCMS: purity 98%, RT=4.28 min, M+1=491.2
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]([SH:15])([CH3:14])[CH3:13].[OH-].[Na+]>CS(C)=O.O>[CH:12]([S:15][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])([CH3:14])[CH3:13]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)S
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Sc1ccc(N)cc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 96.8 %

Procedure:
To a stirred solution containing 34.5 g (0.20 mole) of 4-chloro-3-nitroaniline and 24 g (0.30 mole) of isopropyl mercaptan in 200 ml of DMSO was added dropwise at ambient temperature a solution of 8.0 g (0.20 mole) of sodium hydroxide in 10 ml of water. The addition was exothermic to 60° and the mixture became deep red in color. After three days, the reaction mixture was poured into water and extracted with methylene chloride. The combined extracts were washed with water, dried with anhydrous MgSO4, filtered and concentrated to give 41.1 g (97%) of product as a red-brown syrup.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[C:14]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=1)[CH3:2].[CH3:34][C:35](C)=O.[OH:38]S(O)(=O)=O.O=[Cr](=O)=O>CCOCC>[CH2:34]([O:21][C:20](=[O:38])[CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[O:33])=[CH:13][C:14]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:35]
Reactant: CCCCCCCCCCOc1cc(Oc2ccccc2C(=O)OCC)ccc1CCCO
Reactant: CC(C)=O
Reactant: O=S(=O)(O)O
Agent: O=[Cr](=O)=O
Solvent: CCOCC
Product: CCCCCCCCCCOc1cc(Oc2ccccc2C(=O)OCC)ccc1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 490 mg of 2-[3-(decyloxy)-4-(3-hydroxypropyl)phenoxy]benzoic acid ethyl ester in ether were added 1 ml of Jones reagent (chromic acid solution). After stirring for 1 hour, additional ether was added and the solution washed with a sodium bisulfite solution. The organic layer was dried and concentrated in vacuo. To the residue were added ethanol and a few drops of sulfuric acid. The mixture was refluxed overnight, cooled to room temperature, and concentrated in vacuo. Ethyl acetate was added and the organic solution washed with water. The organic layer was dried, concentrated in vacuo, and the residue purified by column chromatography eluting with 5% ethyl acetate in hexane. Combination concentration of the appropriate fractions yielded 110 mg of the desired subtitled intermediate as an oil. MS, IR, NMR.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24]([S:27][CH2:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])(=[O:26])[CH3:25]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[CH2:7][N:8]([C:30](=[O:31])[CH:29]([CH3:33])[CH2:28][S:27][C:24](=[O:26])[CH3:25])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)CNC1CCCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCCCC1
Yield: 98.7 %

Procedure:
To a stirred and chilled (0°-5° C.) solution of N-cycloheptylglycine t-butyl ester (32.9 g, 0.12 mol) and triethyl amine (13.2 g, 0.13 mol) in methylene chloride (150 ml) was added dropwise 3-acetylthio-2-methylpropanoyl chloride (21.6 g, 0.12 mol) dissolved in 50 ml methylene chloride. The reaction mixture was stirred overnight. Filtration of the reaction mixture followed by washing the filtrate with saturated sodium bicarbonate (500 ml), brine (500 ml), 5% HCL (4×500 ml), brine (500 ml), saturated aqueous sodium bicarbonate (3×500 ml), brine (500 ml); drying the organic layer over Na2SO4 and MgSO4 ; filtration; and solvent evaporation afforded a nearly quantitative yield of the desired compound (44 g, crude).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]([CH2:14][OH:15])[CH2:10][O:11][CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.O>[CH3:23][S:24]([O:15][CH2:14][CH:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[CH:13][CH2:12][O:11][CH2:10]1)(=[O:26])=[O:25]
Reactant: OCC1COCC=C1c1cccc(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1COCC=C1c1cccc(Br)c1
Yield: 115.2 %

Procedure:
A 0° C. solution of (4-(3-bromophenyl)-3,6-dihydro-2H-pyran-3-yl)methanol (0.305 g, 1.08 mmol) in CH2Cl2 (10 mL) is treated with triethylamine (0.218 g, 2.15 mmol) and then methanesulfonyl chloride (0.148 g, 1.29 mmol) and the reaction is stirred at 0° C. for 30 min. The reaction is diluted with water and extracted with CH2Cl2. The organic layer is dried over Na2SO4 and the solvent is removed under reduced pressure to afford the title compound (0.432 g, 97%). 1H NMR (400 MHz, CDCl3) δ 7.51 (t, J=1.8 Hz, 1H), 7.44-7.41 (m, 1H), 7.31-7.29 (m, 1H), 7.25-7.21 (m, 1H), 6.18 (t, J=2.6 Hz, 1H), 4.33-4.31 (m, 2H), 4.20 (dd, J=1.5, 11.6 Hz, 2H), 4.14-4.08 (m, 1H), 3.72-3.68 (m, 1H), 3.01-2.98 (m, 1H), 2.95 (s, 3H).
Reaction SMILES: [CH2:1]1[O:20][C:19]2[CH:18]=[CH:17][C:5]([C:6]([C:8]3[CH:13]=[C:12]4[O:14][CH2:15][O:16][C:11]4=[CH:10][CH:9]=3)=O)=[C:4]([NH2:21])[C:3]=2O1.[O-:22][C:23]#[N:24].[Na+].[OH2:26]>CC(O)=O>[CH2:1]1[O:20][C:19]2[CH:3]=[C:4]3[C:5]([C:6]([C:8]4[CH:9]=[CH:10][C:11]5[O:16][CH2:15][O:14][C:12]=5[CH:13]=4)=[N:24][C:23](=[O:22])[NH:21]3)=[CH:17][C:18]=2[O:26]1
Reactant: O
Reactant: Nc1c(C(=O)c2ccc3c(c2)OCO3)ccc2c1OCO2
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2[nH]1)OCO3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3,4-(Methylenedioxy)-2-amino-4′,5′-(methylenedioxy)benzophenone 15.0 g, 52.63 mmol) was dissolved in AcOH (250 mL) by heating, then sodium cyanate (4.1 g, 63.16 mmol) and water (25 mL) was added. The resulting mixture was stirred at rt for 18 h, then excess water (120 mL) was added. The precipitate was collected by filtration, washed with water, acetone, and dried to give 6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one as yellow solid (15.7 g); mp >300° C. 1H NMR (DMSO) 7.18 (s, 1H), 7.14 (d, J=9.12, 1H), 7.07 (d, J=7.95, 1H), 7.04 (s, 1H), 6.82 (s, 1H), 6.16 (s, 2H), 6.14 (s, 2H), 1.90 (s, 1H). Anal. calcd. for C16H10N2O5(1/4)H2O: C, 60.99, H, 3.34, N, 8.90. Found: C, 60.92, H, 3.14, N, 8.47.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:21])[S:13][C@@H:12]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:11]2[C@H:10]1[C:18]([OH:20])=[O:19].C[Si](C)(C)Cl.[C:27]1([O:33][C:34](=[O:45])[CH:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:36](O)=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)(O)[O-].[Na+:50]>C(Cl)Cl>[Na+:50].[O:33]([C:34]([CH:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:36]([NH:17][CH:14]1[C:15](=[O:16])[N:11]2[CH:10]([C:18]([O-:20])=[O:19])[C:9]([CH3:21])([CH3:8])[S:13][C@H:12]12)=[O:37])=[O:45])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)C(C(=O)Oc1ccccc1)c1ccccc1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccccc3)c3ccccc3)C(=O)N2C1C(=O)[O-]
Temperature: 35 °C
Reaction time: 1 h

Procedure:
56 ml. (0.4 moles) of triethylamine are added to a suspension of 42 g. (0.2 moles) of 6-APA in 600 ml. of methylene chloride. Subsequently 430 g. (0.4 moles, 50 ml.) of trimethyl chlorosilane are added to the obtained solution at 10° C., and the mixture is stirred for 60 minutes. Thereafter the mixture is heated to 35° C., 104 g. (0.2 moles) of phenylmalonic acid phenylester pnetachlorophenyl ester are added, and subsequently 28 ml. (0.2 moles) of triethylamine are introduced dropwise into the mixture. The reaction mixture is stirred at room temperature for 3 hours, thereafter it is neutralized to pH=7 with 200 ml. of 8% aqueous sodium bicarbonate solution.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].CC(C)([O-])C.[K+].[N:27]1([C:31](=[O:40])[CH2:32][C:33]2[CH:34]=[N:35][C:36](Cl)=[CH:37][CH:38]=2)[CH2:30][CH2:29][CH2:28]1>CN(C=O)C.CC#N>[N:27]1([C:31](=[O:40])[CH2:32][C:33]2[CH:34]=[N:35][C:36]([O:20][CH2:19][CH2:18][C@@H:16]3[CH2:17][C@@H:15]3[CH:12]3[CH2:13][CH2:14][N:9]([C:6]4[N:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=4)[CH2:10][CH2:11]3)=[CH:37][CH:38]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: O=C(Cc1ccc(Cl)nc1)N1CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)cn3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-((1S,2R)-2-(1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethanol (40 mg, 0.145 mmol) was dissolved in DMF (2 ml) at RT under N2 and potassium tert-butoxide (0.218 ml, 0.218 mmol) was added. The mixture was stirred at RT for 5 min and 1-(azetidin-1-yl)-2-(6-chloropyridin-3-yl)ethanone (36.7 mg, 0.174 mmol) was added. The mixture was microwaved at 100° C. for 30 min. and 150° C. for 30 min. The mixture was diluted with CH3CN, filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD Sum 19×100 mm column; 25-95% acetonitrile in 0.1% formic acid in water gradient) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 2H), 8.01 (s, 1H), 7.61 (d, 1H), 6.75 (d, 1H), 4.70 (m, 2H), 4.39 (t, 2H), 4.21 (t, 2H), 4.03 (t, 2H), 3.38 (s, 2H), 2.85 (m, 2H), 2.45 (m, 2H), 2.31 (m, 2H), 2.18 (m, 1H), 1.84 (m, 2H), 1.58 (m, 1H), 1.40 (m, 2H), 1.10-1.20 (m, 5H), 0.95 (m, 2H), 0.68 (m, 2H), −0.40 (m, 1H). LC/MS (m/z): 450 (M+H)+, GPR119 Human EC50: 7.4 nM.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:30]([Cl:33])(=[O:32])[CH3:31]>ClCCl>[C:30]([Cl:33])(=[O:32])[CH3:31].[C:30]([N:17]1[CH2:18][CH2:19][C@@H:15]([CH2:14][C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([Br:2])=[CH:4][CH:5]=3)[C:10](=[O:20])[NH:11][N:12]=2)[CH2:16]1)(=[O:32])[CH3:31]
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)Cl
Product: CC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reaction time: 0.02 h
Yield: 101.1 %

Procedure:
In 4 mL screwcap vial was placed 4-(4-bromophenyl)-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.417 mmol) and 1 mL dichloromethane. N,N-Diisopropylethylamine (1.374 mmol) was added. The vial contents were stirred for 1 min. In a separate vial, acetyl chloride (0.417 mmol) was diluted with 1 mL dichloromethane and added to the prior solution dropwise via pipette. The vial was capped and the reaction was stirred at room temperature overnight. Analysis by LCMS displayed the reaction had only progressed to 70% completion. A solution of acetyl chloride (0.050 mL) in 1 mL dichloromethane was prepared and 0.100 mL of this solution was added to the reaction. After 1 h, the reaction had progressed to 90% completion via LCMS analysis. Another 0.100 mL of the acetyl chloride solution in dichloromethane was added to the reaction. After 1 h, LCMS analysis displayed the reaction was complete. The solution was washed with saturated aq NH4Cl. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-20% methanol:ethyl acetate) afforded the title compound (77 mg, 50% yield). MS(ES)+ m/e 365.0, 366.7 [M+H]+.
Reaction SMILES: [O-]S(OOS([O-])(=O)=O)(=O)=O.[K+].[K+].S(=O)(=O)(O)O.CN(C)C=O.[Br:23][C:24]1[CH2:28][CH:27]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[C:39](=[O:46])[NH:40][CH:41]([CH:43]2[CH2:45][CH2:44]2)[CH3:42])=[O:30])[N:26]([C:47]2[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][N:48]=2)[N:25]=1>C(OCC)(=O)C.O>[Br:23][C:24]1[CH:28]=[C:27]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[C:39](=[O:46])[NH:40][CH:41]([CH:43]2[CH2:45][CH2:44]2)[CH3:42])=[O:30])[N:26]([C:47]2[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][N:48]=2)[N:25]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
0.24 g of potassium peroxodisulfate and 0.02 g of sulfuric acid were added to 3 ml of an N,N-dimethylformamide solution containing 0.10 g of 3-bromo-N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxamide, followed by heating and refluxing. After 1.5 hours, the reaction liquid was left to cool and introduced into 10 ml of water, and then ethyl acetate was added, followed by extraction. The organic layer (the ethyl acetate layer) was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/2) to obtain 0.09 g of the desired product (melting point: 231-233° C.).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=CC=CC=2)[C:5]=1CCC.Cl.[O:18]=[C:19]1[NH:28][C:27]2[N:26]=[CH:25][C:24](/[CH:29]=[CH:30]/[C:31]([OH:33])=O)=[CH:23][C:22]=2[CH2:21][CH2:20]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2[NH:39][C:38](=[O:52])[CH2:37]1>>[C:38]([NH:39][C:11]1[CH:6]=[CH:5][C:4]([CH2:3][N:2]([CH3:1])[C:31](=[O:33])/[CH:30]=[CH:29]/[C:24]2[CH:25]=[N:26][C:27]3[NH:28][C:19](=[O:18])[CH2:20][CH2:21][C:22]=3[CH:23]=2)=[CH:13][CH:12]=1)(=[O:52])[CH3:37]
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CCCc1c(CNC)ccc2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: Cl
Product: CC(=O)Nc1ccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)cc1
Yield: 53 %

Procedure:
According to the procedure of Example 1 (a), except substituting 4-acetamidobenzyl methyl amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride for (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.283 g, 53%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.66-10.64 (m, 1H), 9.94-9.92 (m, 1H), 8.36-8.33 (m, 1H), 8.07-8.06 (m, 1H), 7.56-7.48 (m, 3H), 7.33-7.13 (m, 3H), 4.74-4.54 (m, 2H), 3.07-2.86 (m, 5H), 2.53-2.49 (m 2H), 2.01 (s, 3H); MS (ESI) m/e 379 (M+H)+.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:36]([O:38][C:39](=[O:50])[CH2:40][C:41]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)=O)[CH3:37].C(N(CC)CC)C>ClCCCl>[CH2:36]([O:38][C:39](=[O:50])[C:40]#[C:41][C:43]1[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=1)[CH3:37]
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C#Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
Prepared in analogy to Synthesis Communications (1989) 3:217-218. To a solution of triphenylphosphine oxide (3.77 g, 14 mmol) in 1,2-dichloroethane (42 mL) was added trifluoromethanesulfonic anhydride (2.25 mL, 14 mmol) dropwise at 0° C. and the grey suspension was stirred at 0° C. for 15 min. Then a solution of 3-(4-fluoro-phenyl)-3-oxo-propionic acid ethyl ester (2.85 g, 14 mmol) in 1,2-dichloroethane (14 mL) was added followed by a dropwise addition of triethylamine (3.78 mL, 28 mmol) at 0° C. The brown solution was refluxed for 2.5 h. After cooling the mixture was poured onto ice-water and the organic layer separated and washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 20% ethyl acetate in heptane) afforded the title compound (1.53 g, 59%) as a yellow solid. MS: m/e=193.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([S:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)([F:4])[F:3].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[S:19]([O:26]S(C(F)(F)F)(=O)=O)([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20]>>[O-:26][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20].[C:7]1([S+:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:2]([F:4])([F:3])[F:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccccc1
Reactant: O=S(c1ccccc1)C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: FC(F)(F)[S+](c1ccccc1)c1ccccc1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Phenyl trifluoromethyl sulfoxide (0.4 g, 2.1 mmol) and then benzene (4.9 g, 64 mmol) are introduced, under an inert atmosphere and at approximately 0° C. (lower limit below which benzene crystallizes), into a Schlenck tube purged beforehand with argon. Five equivalents of triflic anhydride (2.82 g, 10 mmol) are gradually added. The mixture is stirred for 1 h at 0° C. and then for 24 h at ambient temperature. The medium is evaporated and the residue is purified by chromatography with the CH3CN/CH2Cl2 (1/4) mixture as eluent. White crystals, having a melting point of 69-70° C., are obtained with a yield of 40%.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]([CH3:3])([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)[C:4]#[CH:5]
Reactant: C#CC(C)(C)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C#CC(C)(C)OC1CCCCO1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 2-methyl-3-butyn-2-ol (17.0 g, 202.1 mmol) in dichloromethane (200 mL) cooled to 0° C. was added 2,3-dihydropyran (22.0 mL, 258.4 mmol), followed by para-toluenesulfonic acid (10 mg, 0.05 mmol). The mixture was allowed to slowly warm to room temperature over 3 h, then washed with a saturated aqueous solution of sodium bicarbonate, followed by brine, then dried (sodium sulfate), and concentrated to provide 34.0 g (97%) of 2-(1,1-dimethyl-prop-2-ynyloxy)-tetrahydropyran as a clear oil.