Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:14]S(C(C)(C)C)=O)[CH2:12][CH3:13])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].[ClH:21].O1CCOCC1>CO>[ClH:21].[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH2:14])[CH2:12][CH3:13])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(S(C)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@H](N)c1ccnc(S(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(2-methanesulfonyl-pyridin-4-yl)-propyl]-amide (26 g, 82 mmol) in methanol (150 mL) was added a solution of 4 N HCl in dioxane (22.5 ml, 89.8 mmol) and stirred for 1 hour. The solution was concentrated to half the original volume and diluted with toluene (100 mL), and concentrated. The crude material was co-evaporated from toluene (3×100 mL) and dried in vacuo for 18 hours to afford the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[CH3:16]N1C=CN=C1.O>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13](=[O:15])[CH3:16]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Reactant: Cn1ccnc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Treat a solution of 2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid (30.0 g, 0.11 mol) in acetic anhydride (30 mL) with 1-methylimidazole (4.5 g, 55 mmol), stir at RT for 2 h, treat with water, stir for 5 min, and extract with EtOAc. Wash the combined organics with water, saturated. Na2CO3, then brine, dry over Na2SO4, concentrate and purify via silica gel chromatography (EtOAc/petroleum ether) to afford the title compound (12 g, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.19 (d, J=8.0 Hz, 1H), 8.02 (d, J=10.8 Hz, 1H), 4.09 (s, 2H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:20][C:21](=[O:26])[CH:22](Cl)[CH:23]=O)[CH3:19]>O1CCOCC1.CCOC(C)=O>[CH2:18]([O:20][C:21]([C:22]1[N:12]2[CH:13]=[C:14]([Br:15])[C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])=[CH:10][C:11]2=[N:16][CH:23]=1)=[O:26])[CH3:19]
Reactant: CCOC(=O)C(Cl)C=O
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ncc1Br
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(CNC(=O)OC(C)(C)C)c(Br)cn12
Yield: 41 %

Procedure:
A solution of (2-amino-5-bromo-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (3.5 g, 11.6 mmol, prepared according to Example 1, Step 1.3) and freshly prepared 2-chloro-3-oxo-propionic acid ethyl ester (8.97 g, 59.6 mmol, prepared according to a patented procedure U.S. Pat. No. 5,559,158-A1) in dioxane (60 mL) was stirred at RT for 14 h. The reaction mixture was diluted in AcOEt (400 mL) and washed with a 2.0 M aqueous Na2CO3 solution (2×200 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→2:8) to yield the title compound (1.31 g, 4.83 mmol, 41%) as a light yellow solid. MS: 398 [M+1]+; HPLC: AtRet=1.85; TLC: RF 0.47 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([OH:8])([CH3:7])[CH3:6])=[O:3].[OH:9][CH2:10][C:11]([C@H:13]([C@@H:15]([C@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])=[O:12].Cl[O-].[Na+]>[Ni](Cl)Cl>[CH3:1][C:2]([CH2:4][C:5]([OH:8])([CH3:7])[CH3:6])=[O:3].[CH2:19]([OH:20])[C@H:17]([OH:18])[C@@H:15]([OH:16])[C@H:13]([OH:14])[C:11]([C:10]([OH:3])=[O:9])=[O:12]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl[Ni]Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)CC(C)(C)O
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 6 h

Procedure:
For a comparison, the same reaction vessels as above were placed on a water bath at 70° C., and the aqueous solutions of diacetone-L-sorbose, nickel chloride and sodium hypochlorite were fed into the first reaction vessel in the same manner as above, to start the reaction under atmospheric pressure. The reaction temperature was found to temporarily rise to 70°-75° C. After 6 hour, the effluent from the second reaction vessel was sampled for 1 hours, and was worked up in the same manner as in Example 1, to provide diacetone-2-keto-L-gulonic acid.
Reaction SMILES: [CH:1]([C:4]([OH:27])([CH:15]([CH3:26])[C:16]([O:18]CC1C=CC=CC=1)=[O:17])[C:5]([O:7]CC1C=CC=CC=1)=[O:6])([CH3:3])[CH3:2]>O1CCCC1.[Pd]>[OH:27][C:4]([CH:1]([CH3:3])[CH3:2])([CH:15]([CH3:26])[C:16]([OH:18])=[O:17])[C:5]([OH:7])=[O:6]
Reactant: CC(C)C(O)(C(=O)OCc1ccccc1)C(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)C(O)(C(=O)O)C(C)C(=O)O

Procedure:
The dibenzyl 2-isopropyl-2-hydroxy-3-methylsuccinate thus obtained was dissolved in tetrahydrofuran (25 mL), and the solution was stirred in the presence of 10% palladium/carbon (120 mg) under hydrogen stream at room temperature for 15 h. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 748 mg of 2-hydroxy-2-isopropyl-3-methylsuccinic acid as oil (quantitative).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([CH2:13][C:14]#[N:15])(=[O:12])=[O:11].ClC1C=C[C:20]([S:23]([CH2:26]C#N)(=[O:25])=[O:24])=CC=1>>[Cl:8][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([S:10]([C:13](=[C:26]([S:10]([CH3:3])(=[O:12])=[O:11])[S:23]([CH3:20])(=[O:25])=[O:24])[C:14]#[N:15])(=[O:12])=[O:11])=[C:2]([CH3:1])[CH:7]=1
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(S(=O)(=O)CC#N)c(C)cc1Cl
Product: Cc1cc(S(=O)(=O)C(C#N)=C(S(C)(=O)=O)S(C)(=O)=O)c(C)cc1Cl

Procedure:
The titled compound was prepared in an analogous fashion to Intermediate 2 except that 2-(2,5-dimethyl-4-chlorobenzenesulfonyl) acetonitrile was utilized in place of 2-(4-chlorobenzenesulfonyl) acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C:5]1O[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].BrBr.C1(O)C=CC=CC=1.O.[NH2:30][NH2:31].Cl>CO.O>[CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C:5]1[N:30]=[N:31][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccccc1Cc1ccco1
Reactant: NN
Agent: BrBr
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Oc1ccccc1
Solvent: CO
Product: Cc1ccccc1Cc1cccnn1
Reaction time: 0.08 h

Procedure:
A mixture of 2-(2-methylbenzyl)furan (5.2 g.), anhydrous sodium carbonate (12.8 g.) and methanol (120 ml.) was stirred at -2° C. during the addition, over 40 minutes, of a solution of bromine (1.6 ml.; 9.3 g.) in methanol (24 ml.). The mixture was stirred for a further 5 minutes, diluted with water (300 ml.) and extracted with toluene (4 × 35 ml.). The combined toluene extracts were dried over magnesium sulphate and evaporated to dryness to give crude 2-(2-methylbenzyl)-2,5-dimethoxy-2,5-dihydrofuran (7.2 g.) in the form of a pale brown coloured oil, which was then heated under reflux with phenol (20 g.) and hydrazine hydrate (2.6 ml.) for 70 hours in an oil bath at 120° C. Hydrochloric acid (100 ml. of 2N and 10 ml. of concentrated hydrochloric acid) was added and the mixture was steam-distilled to remove phenol. The mixture was then cooled and extracted with diethyl ether (50 ml.). The ether solution was extracted with N hydrochloric acid (5 × 10 ml.). Dissolved diethyl ether was removed from the combined aqueous acid extracts by the passage of a stream of air. The aqueous acid solution was then treated with charcoal, filtered, neutralised with solid sodium bicarbonate, basified by the addition of aqueous sodium hydroxide solution (2N; 10 ml.) and extracted with chloroform (5 × 20 ml.). The combined chloroform extracts were washed with water, dried over magnesium sulphate and distilled to give 3-(2-methylbenzyl)pyridazine (2.7 g.) as a white solid, m.p. 86°-89° C. [b.p. 115°-125° C. (bath temperature)/0.1 mm.Hg], the melting point of which was raised to 89°-91° C. by dissolution in 2N hydrochloric acid, filtration and precipitation from the clarified solution by the addition of solid sodium carbonate.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](Cl)=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH3:12][Zn]C>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[C:9]([C@H:6]1[CH2:7][CH2:8][C@H:3]([C:1]#[N:2])[CH2:4][CH2:5]1)(=[O:10])[CH3:12]
Reactant: C[Zn]C
Reactant: N#C[C@H]1CC[C@H](C(=O)Cl)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)[C@H]1CC[C@H](C#N)CC1
Temperature: 38 °C

Procedure:
To the product from step 1 (1.44 g, 8.42 mmol) was added dioxane (56 mL) and the solution was degassed via subsurface bubbling with argon for 30 minutes. Pd(OAc)2 (95 mg, 0.42 mmol) was added and argon was bubbled through the solution for 15 minutes. Dimethylzinc (2.0 M in toluene, 4.21 mL, 8.42 mmol) was added and the solution was evacuated and then purged with argon 5 times. The reaction was heated overnight at 38° C. The mixture was then cooled to room temperature, diluted carefully with water and ethyl acetate, filtered through a pad of CELITE and washed with ethyl acetate. The organic layer of the filtrate was then dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford trans-4-acetylcyclohexanecarbonitrile. 1H NMR (500 MHz, CDCl3) δ 2.52-2.32 (m, 2H), 2.23-2.12 (m, 5H), 2.07-1.93 (m, 2H), 1.72-1.53 (m, 2H), 1.48-1.33 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1[C:17]([N+:18]([O-])=O)=CC=C(O)C=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:17][NH:18][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CNC(=O)Cc1ccc(O)cc1
Yield: 48.5 %

Procedure:
To a solution of 7.6 g of p-hydroxyphenylacetic acid in 100 ml of acetonitrile were added 8.4 g of p-nitrophenol and 10.3 g of dicyclohexylcarbodiimide at room temperature with stirring, and the resulting crystals of dicyclohexylurea were filtered out. An ethereal solution of 7.8 g of methylamine was added to the filtrate containing p-nitrophenyl p-hydroxyphenylacetate, the mixture was allowed to stand to precipitate crystals. The crystals obtained were filtered out and washed with diethyl ether to obtain 4.0 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(C(=O)NCCS(C)(=O)=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 30.2 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.084 mmol) described in example 92, triethylamine (0.05 mL, 0.364 mmol) and [2-(methylsulfonyl)ethyl]amine hydrochloride (174 mg, 1.08 mmol) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-[2-(methylsulfonyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (11 mg, 22% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.61 (br s, 1 H), 8.56 (s, 1 H), 7.39 (s, 1 H), 7.16-7.12 (m, 2 H), 7.04-6.99 (m, 2 H), 4.13 (s, 2 H), 3.95 (m, 2 H), 3.57 (s, 3 H), 3.37 (m, 2 H), 2.98 (s, 3 H); MS m/z 434 (M+1).
Reaction SMILES: [C:1]([O-])(=[O:4])[CH2:2]C.[Sc+3:6].[C:7]([O-])(=[O:10])[CH2:8]C.[C:12]([O-])(=[O:15])[CH2:13]C.C1C=CC=CC=1.[Li]>C(O)C>[O-:4][CH2:1][CH3:2].[Sc+3:6].[O-:10][CH2:7][CH3:8].[O-:15][CH2:12][CH3:13]
Reactant: CCC(=O)[O-]
Agent: [Li]
Agent: [Sc+3]
Solvent: c1ccccc1
Solvent: CCO
Product: CC[O-]
Yield: 118.4 %

Procedure:
Scandium propionate (0.03 mol.), benzene (50 ml) and ethanol (10 ml) were placed in a round-bottomed flask of 100 ml-capacity, to which was then added slowly 0.6 g (0.09 mol.) of metallic lithium under stirring. After the addition of the metallic lithium, the admixture in the flask was refluxed for 1 hour by heating with aid of a mantle heater, and then the reaction solution was processed in the same manner as in Example 1 to afford 6.4 g of scandium ethoxide as a white colored crystal. Yield 95.6%
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].CO.Cl>C1COCC1>[C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2F)noc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cc2F)c1C(=O)O
Yield: 104.9 %

Procedure:
4-Ethoxycarbonyl-5-methyl-3-(2,4-difluorophenyl)isoxazole (305 mg, 1.14 mmol), 5N NaOH (1.0 ml, 5 mmol), methanol (5 ml), and THF (1 ml) were heated at 50° C. for 16 h. Ice was added and the pH was adjusted to 2-3 with 1N HCl. Extraction with EtOAc followed by washing (brine), drying (Na2SO4), filtering, and concentration gave the crude 4-carboxy-5-methyl-3-(2,4-difluorophenyl)isoxazole (286 mg, 99%) which was used without further purification.
Reaction SMILES: C(O[CH2:5][CH:6]=[CH2:7])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:27]([C:30]1[C:31](=[O:40])[NH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1)([O-:29])=[O:28]>C1COCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:27]([C:30]1[C:31](=[O:40])[N:32]([CH2:7][CH:6]=[CH2:5])[C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: C=CCOC(C)=O
Reactant: O=c1[nH]c(C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCn1c(C(F)(F)F)ccc([N+](=O)[O-])c1=O
Reaction time: 24 h
Yield: 33.8 %

Procedure:
A solution of allyl acetate (13.5 ml, 125 mmol) in THF (8 ml), was evacuated and purged with argon (3 times). Palladium acetate (122 mg, 0.50 mmol) and triphenylphosphine (525 mg, 2.0 mmol) were added as solutions in tetrahydrofuran (1.5 ml each), followed by 3-nitro-6-trifluoromethyl-2-pyridinone (2.6 g, 12.5 mmol) in THF (2 ml). The reaction was heated to reflux for 64 h, and more allyl acetate (13.5 ml, 125 mmol), triphenylphosphine (525 mg, 2.0 mmol), palladium acetate (122 mg, 0.5 mmol), and tetrahydrofuran (13 ml) were added. After a further 24 h and 48 h at reflux addditional allyl acetate (13.5 ml, 125 mmol), palladium acetate (122 mg, 0.5 mmol), and triphenylphosphine (525 mg, 2.0 mmol) were added and the reaction was heated to reflux for a further 24 h. The reaction was cooled and evaporated in vacuo to a gum which was purified by flash column chromatography on silica (15% ethyl acetate/hexane) to give the product contaminated with unreacted 3-nitro-6-trifluoromethyl-2-pyridinone. This material was diluted with ethyl acetate and washed with water adjusted to pH 12 with sodium carbonate, dried (Na2SO4), and evaporated in vacuo to give the title compound (1.05 g): 1H NMR (CDCl3) selected signals at δ 4.80 (d, J=5.8 Hz, 2H), 5.28-5.33 (m, 2H), 5.86-5.96 (m, 1H), 6.80 (d, J=7.9 Hz, 1H), 8.22 (d, J=7.9 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]([CH3:17])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:2].[NH2:21][OH:22]>C(O)C>[NH2:2][C:1](=[N:21][OH:22])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]([CH3:17])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11]
Reactant: NO
Reactant: CN(CCC(=O)OC(C)(C)C)Cc1cccc(C#N)c1
Solvent: CCO
Product: CN(CCC(=O)OC(C)(C)C)Cc1cccc(C(N)=NO)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl 3-[(3-cyanobenzyl)(methyl)amino]propanoate (4.5 g, 0.0164 mol) in ethanol (60 mL) under N2, was added hydroxylamine (2.5 mL, 0.082 mol) in one portion. After being stirred at RT for 12 h, the reaction mixture was concentrated under reduced pressure to afford the title compound as a white gummy solid (4.5 g, 84%). 1H NMR (DMSO-d6, 400 MHz) δ 9.56 (s, 1H), 7.51-7.53 (m, 2H), 7.27-7.31 (m, 2H), 5.74 (s, 2H), 3.44 (s, 2H), 2.55-2.59 (m, 2H), 2.34-2.38 (m, 2H), 2.09 (s, 3H), 1.37 (s, 9H). LC/MS (Method A): 308.2 (M+H)+. HPLC (Method B) Rt 5.18 min (Purity: 96.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH:11]3[N:10]([CH2:16][CH2:17][O:18][CH3:19])[C:9]2=[O:20])=[N:6][CH:7]=1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[CH:22]>>[CH3:19][O:18][CH2:17][CH2:16][N:10]1[CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[N:8]([C:5]2[N:4]=[CH:3][C:2]([C:22]#[C:21][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][N:6]=2)[C:9]1=[O:20]
Reactant: COCCN1C(=O)N(c2ncc(Br)cn2)C2CCCC21
Reactant: C#Cc1ccccc1
Product: COCCN1C(=O)N(c2ncc(C#Cc3ccccc3)cn2)C2CCCC21

Procedure:
The title compound was prepared in accordance with the general method of Example 1, step 5 starting from (rac)-(3aSR,6aRS)-1-(5-bromo-pyrimidin-2-yl)-3-(2-methoxy-ethyl)-hexahydro-cyclopentaimidazol-2-one (Example 10, step 3) and ethynylbenzene to yield racemic (rac)-(3aRS,6aSR)-1-(2-methoxy-ethyl)-3-(5-phenylethynyl-pyrimidin-2-yl)-hexahydro-cyclopentaimidazol-2-one as an light yellow oil; MS: m/e=363.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27].C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([O:24][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(C4(O)CCCC4)n3)c2n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1(c2cccc(Cn3nnc4c(Cl)nc(N)nc43)n2)CCCC1
Yield: 87.7 %

Procedure:
A solution of 7-chloro-3-{6-[1-hydroxy-1-cyclopentyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine (0.5 g, 1.5 mmol) in dry THF (15 mL) at room temperature was treated with trimethylsilyl chloride (0.38 mL, 3.0 mmol) then triethylamine (0.42 mL, 3.0 mmol), stirred at 35° C. overnight, treated with additional quantities of trimethylsilyl chloride (0.19 mL, 1.5 mmol) then triethylamine (0.21 mL, 1.5 mmol) and stirred at 35° C. for 24 h. The mixture was poured into water (60 mL), extracted with EtOAc (×2), concentrated in vacuo and purified by chromatography (SiO2: isohexane—EtOAc (3:1)) to give the title compound (0.55 g, 88%); NMR δH (400 MHz, DMSO) 7.78 (1H, t, J 7.8 Hz), 7.59 (2H, br s), 7.43 (1H, d, J 7.8 Hz), 7.19 (1H, d, J 7.8 Hz), 5.79 (2H, s), 1.68 (7H, m), 1.40 (2H, m), −0.11 (9H, s); (M+H)+ 418.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[N:24][N:23]=[N:22]1)[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]1.Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][O:34][CH3:35])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.O>[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[N:24][N:23]=[N:22]1)[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][N:15]([C:27]2[N:32]=[CH:31][C:30]([CH2:33][O:34][CH3:35])=[CH:29][N:28]=2)[CH2:14][CH2:13]1
Reactant: COCc1cnc(Cl)nc1
Reactant: Fc1cc(COC[C@@H]2C[C@@H]2C2CC[NH2+]CC2)ccc1-n1cnnn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(-n4cnnn4)c(F)c3)CC2)nc1
Temperature: 55 °C
Yield: 57.8 %

Procedure:
4-((1R,2R)-2-((3-fluoro-4-(1H-tetrazol-1-yl)benzyloxy)methyl)cyclopropyl)piperidinium chloride (Step D product, 45 mg, 0.122 mmol) and 2-chloro-5-(methoxymethyl)pyrimidine (Intermediate 18, 22 mg, 0.136 mmol) were dissolved in DMF (600 uL), to which was added cesium carbonate (100 mg, 0.306 mmol). The reaction was heated at 55° C. overnight. The reaction mixture was cooled to rt and diluted with EtOAc (5 mL) and water (5 mL). The layers were cut and the aqueous phase extracted with EtOAc (5 mL×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was loaded onto 2×2000 micron silica preparative TLC plates (uv 254 active) which were developed using 50% EtOAc/Hex as the solvent system. The desired silica (Rf=0.4 @ 50% EtOAc/Hex) was collected and extracted to give the title compound (32 mg, 57%). 1H NMR (500 MHz, CDCl3) δ 9.14 (s, 1H), 8.39 (s, 2H), 7.94 (t, 1H), 7.40 (dd, 2H), 4.73 (t, 2H), 4.65 (q, 2H), 4.29 (s, 2H), 3.61 (td, 2H), 3.38 (s, 3H), 2.95 (m, 2H), 1.95 (dd, 2H), 1.43 (m, 2H), 1.28 (m, 1H), 1.22 (m, 1H), 0.85-0.73 (m, 2H), 0.11 (q, 1H). LC/MS (m/z): 454 (M+H)+, GPR119 Human EC50: 1.1 nM.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)=[O:3].[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:25][CH2:24]1.[K+].[Br-].C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1O>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][NH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][CH:23]4[CH2:25][CH2:24]4)[CH2:28][CH2:29]3)=[O:3])=[CH:6][CH:7]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Reactant: C1CN(CC2CC2)CCN1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Br-]
Agent: [K+]
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(OC(=O)N2CCN(CC3CC3)CC2)cc1
Yield: 18 %

Procedure:
The title compound was prepared from 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, yield 18%. White crystals, m.p. 225-226° C.; IR (KBr): ν 1710 (ester C═O), 1661 (amide C═O) cm−1.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[N:22]([C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:21][CH2:20]2
Reactant: Clc1cc(Br)cc2c1NCC2
Reactant: CC[C@@H](COC)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@@H](COC)n1cc(Cl)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 121-122° C.; 1H NMR (300 MHz, CDCl3) δ 7.24 (s, 1 H), 7.18 (s, 1 H), 6.99 (s, 1 H), 4.90-4.80 (m, 1 H), 4.26 (t, J=8.1 Hz, 2 H), 3.60 (dd, J=10.2, 5.5 Hz, 1 H), 3.49 (dd, J=10.6, 3.3 Hz, 1 H), 3.28 (s, 3 H), 3.06 (t, J=8.1 Hz, 2 H), 1.83-1.65 (m, 2H), 0.86 (t, J=7.4 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2BrCl2 (M+H)+: 446.0038; Found m/z 446.0048.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH2:19](Br)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Product: CCCCn1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-(n-Butyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and n-butyl bromide.