Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:28]=[CH:27][C:21]([O:22][CH:23]2[CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I.C(OCC)(=O)C>[C:14]([C:18]1[CH:28]=[CH:27][C:21]([O:22][CH:23]2[CH2:26][N:25]([C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=3)[CH2:24]2)=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)N[C@@H](C)c1ccc(I)cc1
Reactant: CC(C)(C)c1ccc(OC2CNC2)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(C(C)(C)C)cc3)C2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Under an argon atmosphere a mixture of 0.28 g (0.97 mmol) (S)—N-[1-(4-iodo-phenyl)-ethyl]-acetamide (III.1), 0.20 g (0.98 mmol) 3-(4-tert-butyl-phenoxy)-azetidine, 0.0093 g (0.049 mmol) CuI, 0.41 g (1.95 mmol) K3PO4 and 0.12 g (1.95 mmol) ethyleneglycol in 1.0 mL isopropanol is stirred for 12 h at 80° C. 100 mL Ethyl acetate are added and the mixture is washed with ammonia solution (5%, 2×). The aq. layer is extracted with ethyl acetate (1×) and the combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified by HPLC (XBridge, MeOH/water (+0.3% NH4OH)) to yield the desired product.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].C(N(CC)CC)C.[C:19](ON1C(=O)CCC1=O)(=[O:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].O.CC(C)=O.C(N(CC)CC)C>O.CC(C)=O>[C:19]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])(=[O:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O

Procedure:
To a vigorously-stirred solution of L-lysine monohydrochloride (13 mmol, 2.4 g, commercially available) and triethylamine (39 mmol, 3.9 g) in 50 mL of water-acetone (1:1), was added succinimidyl nervonate (13 mmol, 6.0 g, prepared as in Example 1A) in portions during 0.5 h. During the addition, more water-acetone-triethylamine (10:10:2) was added in order to prevent the product from precipitating as a thick voluminous mass. Stirring was continued for an additional hour. The mixture was then acidified with hydrochloric acid in water (1:1, v/v) to pH 4 and chilled. The light foamy product was separated by filtration and washed with water and hot dioxane to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1.N1C(C)=CC=CC=1C>CN(C)C=O.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1C#N
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(C#N)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
In a round bottom flask was placed (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared in Example 114, 65 mg, 0.20 mmol), methylene chloride (2 mL) and N,N-dimethylformamide (2 drops). To this solution was then added a solution of oxalyl chloride in methylene chloride (2.0 M solution, 110 μL, 0.22 mmol). Upon addition there was gas evolution. This was stirred for 30 min at 25° C. after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 29 mg, 0.19 mmol), 2,6-lutidine (46 μL, 0.40 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol, diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) to afford (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (57 mg, 62%) as a white foam: [α]25589=−5.3° (c=0.17, methanol); ES-HRMS m/e calcd for C23H30N4O4S (M+H)+ 459.2061, observed 459.2060; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.11 (m, 2H, CH2), 1.38-1.80 (m, 8H, 4×CH2), 2.11 (m, 1H, CH), 3.36 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH2), 3.99 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.44 (d, J=2.2 Hz, 1H, Ar), 7.51 (d, J=2.2 Hz, 1H, Ar), 7.95 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 8.10 (d, Jm=1.6 Hz, 1H, Ar), 8.10 (d, Jo=8.2 Hz, 1H, Ar), 10.84 (s, 1H, NH).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.O>ClCCl>[CH3:21][C@H:19]1[NH:20][C:24](=[O:26])[N:17]([C:14]2[CH:13]=[N:12][C:11]([O:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=3)=[N:16][CH:15]=2)[C:18]1=[O:22]
Reactant: CC(C)c1cccc(Oc2ncc(NC(=O)[C@@H](C)N)cn2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cccc(Oc2ncc(N3C(=O)N[C@H](C)C3=O)cn2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 230.4 %

Procedure:
To a solution of N1-(2-{[3-(1-methylethyl)phenyl]oxy}-5-pyrimidinyl)-D-alaninamide (Intermediate 87, 100 mg) in dichloromethane (30 mL) were added triphosgene (40 mg, 0.133 mmol) and triethylamine (51 mg, 0.5 mmol). The resulting mixture was stirred at 0° C. for 30 minutes and water (30 mL) was added. It was extracted with dichloromethane (3 times 30 mL) and the combined organic layer was dried over sodium sulphate and evaporated to afford the title compound (100 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=C2C2C=CC(Cl)=CC=2)=[CH:4][CH:3]=1.BrC1C=C2C(C=C(C)C(C(O)C(OCC)=O)=[C:39]2[C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)=CC=1.Cl(O)(=O)(=O)=O.[OH2:62]>C(OC(C)=O)(C)(C)C>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:4](=[CH:3][C:2]([C:3]#[C:4][C:5]([OH:62])([CH3:10])[CH3:6])=[CH:11][CH:10]=2)[C:39]=1[C:42]1[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C(O)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: Cc1cc2ccc(C#CC(C)(C)O)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Reaction time: 3 h

Procedure:
Preparation of ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate: To a solution of ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate (˜2.78 mmol) in t-BuOAc (14 mL) was added perchloric acid (HClO4) (334 μL, 5.56 mmol). After 3 h, water was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 877 mg of the titled compound. 1H-NMR: 400 MHz, (CDCl3) δ: 7.62 (m, 2H), 7.51 (m, 4H), 7.27 (m, 2H), 5.09 (s, 1H), 4.15 (m, 2H), 2.59 (s, 3H), 1.19 (t, J=7 Hz, 3H), 1.00 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH:5]=O)[CH3:2].C1(P(=[CH:29][C:30]([O:32][CH3:33])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH3:33][O:32][C:30](=[O:31])/[CH:29]=[CH:5]/[CH:4]([O:3][CH2:1][CH3:2])[O:7][CH2:8][CH3:9]
Reactant: CCOC(C=O)OCC
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(/C=C/C(=O)OC)OCC
Reaction time: 8 h

Procedure:
The mixture of 10.2 g of 2,2-diethoxy acetaldehyde, 27.8 g of methyl triphenylphosphoranylidene-acetate and 130 ml of benzene is refluxed for 15 hours and evaporated. The residue is triturated with diethyl ether, filtered and the filtrate evaporated. The residue is allowed to stand overnight in the refrigerator, triturated with the minimum amount of diethyl ether, the suspension filtered, the filtrate evaporated, the residue distilled and the fraction boiling at 50°-54°/0.1 mm Hg collected, to yield the 4,4-diethoxy-crotonic acid methyl ester.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:12][OH:13]>>[CH3:12][O:13][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[CH2:2][Cl:1]
Reactant: CO
Reactant: O=C(Cl)c1ccccc1CCl
Product: COC(=O)c1ccccc1CCl
Reaction time: 10 h
Yield: 94 %

Procedure:
180 g of o-(chloromethyl)benzoyl chloride was placed in a double-neck 500 ml flask equipped with a thermometer, cooler and dropping funnel. While maintaining the internal temperature of a reactor at 40˜50° C., 50 ml of methanol was added dropwise. After all amounts of methanol were infused, the reacting mixture was stirred for 10 hours, while maintaining the internal temperature of a reactor at 40˜50° C. After a distillator was equipped, a fractional distillation under reduced pressure was made to afford 165 g of desired compound (yield 94%) as oil.
Reaction SMILES: [P:1]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2]C1C=CC=CC=1.[CH:23](=O)[CH2:24][CH2:25][CH3:26].[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:33][CH:34]=1>ClC1C=CC=CC=1>[C:29]1([CH3:28])[CH:30]=[CH:31][C:32]([S:35]([NH:38][CH:23]([P:1](=[O:2])([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:24][CH2:25][CH3:26])(=[O:37])=[O:36])=[CH:33][CH:34]=1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: CCCC=O
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Solvent: Clc1ccccc1
Product: CCCC(NS(=O)(=O)c1ccc(C)cc1)P(=O)(Oc1ccccc1)Oc1ccccc1
Reaction time: 0.75 h
Yield: 88 %

Procedure:
A mixture of 0.5 mole each of triphenyl phosphite, n-butyraldehyde and p-toluenesulfonamide in 150 g of chlorobenzene is stirred and warmed under nitrogen. An exothermic reaction is detectable at 85° C., and cooling is used for a few minutes to keep the temperature below 93°. Heating is then continued at 95°-100° for 0.75 hr to ensure complete reaction. The reaction mixture is cooled to 25° and filtered. The product is recrystallized from acetonitrile, giving 202 g (88% yield) of white solid: mp 178°-180°; 31P nmr(DMSO-d6)- 17.7 ppm.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][P:5]([O-:12])[O:6][CH2:7][C:8]([F:11])([F:10])[F:9].C1CCN2C(=NCCC2)CC1.[C:26]1([C:32]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:33]2[CH:37]=[C:36]([CH2:38]Cl)[N:35]=[CH:34]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[F:14][C:2]([F:1])([F:13])[CH2:3][O:4][P:5]([CH2:38][C:36]1[N:35]=[CH:34][N:33]([C:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:37]=1)(=[O:12])[O:6][CH2:7][C:8]([F:11])([F:9])[F:10]
Reactant: [O-]P(OCC(F)(F)F)OCC(F)(F)F
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=P(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)(OCC(F)(F)F)OCC(F)(F)F
Yield: 29.9 %

Procedure:
To a solution of bis(2,2,2-trifluoroethyl)phosphite (0.11 ml, 0.6 mmol) in THF (1.5 ml) were added 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) (0.09 ml, 0.6 mmol) and (1-triphenylmethylimidazol-4-yl)methyl chloride (71.8 mg, 0.2 mmol). The reaction mixture was refluxed under argon flow for 22 hours. The solvent was removed under reduced pressure, and water (10 ml) was added to the residue, which was then extracted 3 times with ethyl acetate (10 ml). The resultant organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained white solid was purified through chromatography on silica gel column using ethyl acetate-hexane (3:2) to give bis(2,2,2-trifluoroethyl)(1-triphenylmethylimidazol-4-yl)methylphosphonate (34 mg, 30%) as a white powder. This powder was recrystallized from a mixture of ethyl acetate and hexane to provide a white small needle crystal (m.p. 145-148° C.).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[C:8]([F:14])=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)=[C:4]([C:17](=[O:23])[N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:3]=1.P(Cl)(Cl)([Cl:26])=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[C:8]([F:14])=[N:9][C:10]([Cl:26])=[CH:11][CH:12]=2)=[C:4]([CH:3]=1)[C:17]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:23]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc[n+]([O-])c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc(Cl)nc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-bromo-2-(diethylcarbamoyl)phenoxy)-2-fluoropyridine 1-oxide (420 mg, 1.096 mmol) in 15 mL of DCM was added dropwise phosphorus oxychloride (301 μL, 3.29 mmol) followed by 2 drops of DMF. After stirring at rt for 1 h, the reaction was quenched with sat. NaHCO3, extracted with EA, dried over Na2SO4, filtered and evaporated to dryness. CC (DCM to DCM/EA=10:1 to 5:1 to 3:1) gave 5-bromo-2-(6-chloro-2-fluoropyridin-3-yloxy)-N,N-diethylbenzamide as a colorless gum.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N+:3]=1[O-:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1nccc2ccccc12
Solvent: ClCCl
Product: [O-][n+]1ccc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.1 %

Procedure:
To a solution of 1-chloroisoquinoline (3.0 g, 18 mmol) in DCM (50 mL) was added m-CPBA (9.5 g, 55 mmol). The mixture was stirred at room temperature for 48 h. The mixture was diluted with DCM, and then washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography eluting with a gradient of petroleum ether: EtOAc (5:1 to 0:1) to afford the title compound (1.2 g, 36%) as a yellow solid.
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([CH3:10])=[O:9].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>C(O)C.O>[O:9]=[C:8]([CH3:10])[CH:7]([C:6]([O:12][CH2:13][CH3:14])=[O:11])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCCCCN1C(=O)c2ccccc2C1=O)C(C)=O
Reaction time: 8 h

Procedure:
A solution of sodium ethoxide in ethanol, prepared by dissolving 23.69 g (1.03 moles) of sodium in 800 ml of absolute alcohol, was treated slowly with ethyl acetoacetate. To this solution was added, in one portion, 308 g (1.04 moles) of N-(5-bromopentyl)phthalimide and the resulting mixture was refluxed for two hours and stirred overnight at 25°. The ethanol was stripped, 1500 ml of water was added to the residue, and the resulting mixture was extracted with 3×400 ml of ether. The ether layers were combined, dried over anhydrous sodium sulfate, filtered and stripped to give 350 g of light brown oil. This material was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of 3-fluoro-4-nitrobenzaldehyde (0.5 g, 2.96 mmol) and 2-(piperidin-4-yl)propan-2-ol (0.466 g, 3.25 mmol) in DCM (25 mL) was added AcOH (0.017 mL, 0.296 mmol) and sodium triacetoxyborohydride (0.689 g, 3.25 mmol), and the reaction was stirred at RT for 1 hour. After 1 hour, the reaction was quenched by the addition of 1 N aqueous NaOH (15 mL), and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residual product was adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide 2-(1-(3-fluoro-4-nitrobenzyl)piperidin-4-yl)propan-2-ol as a yellow oil (0.75 g, 86% yield).
Reaction SMILES: O=[C:2]([C:23]#[C:24][CH3:25])[CH2:3][N:4]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[CH2:5][CH2:6][NH:7]C(=O)OC(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:23]([CH:2]1[NH:7][CH2:6][CH2:5][N:4]([S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])[CH2:3]1)#[C:24][CH3:25]
Reactant: CC#CC(=O)CN(CCNC(=O)OC(C)(C)C)S(=O)(=O)c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CC1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2-((2-oxo-3-pentyn-1-yl)(2-thiophenylsulfonyl)amino)ethyl)carbamate (330 mg, 0.854 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.0 g, 4.72 mmol, Sigma-Aldrich, St. Louis, Mo.) followed by TFA (2.5 mL, 32.4 mmol). The mixture was stirred at room temperature for 1 h and then concentrated to half the original volume. MeOH (5 mL) was added and the solution was concentrated by one-third and then partitioned between NaOH (0.5 N, 20 mL) and CHCl3 (containing 10% i-PrOH) (20 mL). The aqueous layer was extracted twice with CHCl3 (containing 10% i-PrOH) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated to orange oil. The residue was purified by chromatography on silica gel using (1 to 5% MeOH in EtOAc) to give 3-(1-propyn-1-yl)-1-(2-thiophenylsulfonyl)piperazine as a light-yellow film (150 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C@H:17]3[CH2:19][C@H:18]3[CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[C:25]([F:33])[CH:24]=3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1)[CH3:2].Cl.[OH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C@H:17]3[CH2:19][C@H:18]3[CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]([N:38]4[CH2:39][CH:36]([OH:35])[CH2:37]4)=[O:31])=[C:25]([F:33])[CH:24]=3)[CH2:13][CH2:12]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: OC1CNC1
Reactant: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CC(O)C4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-{2-[(1S,2R)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethoxy}-2-fluorophenyl)acetic acid (50, 0.109 mmol) and 3-hydroxy azetidine hydrochloride (11.97 mg, 0.109 mmol) were dissolved in DMF (1 ml) and HATU (83 mg, 0.219 mmol) and DIEA (0.057 ml, 0.328 mmol) added. The mixture was stirred at RT for 2 hr. The mixture was diluted with ethyl acetate (20 mL), washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, Biotage 25M, using a gradient eluant of MeOH/DCM (0-10%) to to provide the title compound. LC/MS (m/z): 513 (M+H)+. GPR119 Human EC50: 1.9 nM
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH3:27][O:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:31]([CH2:30][CH2:29][O:28][CH3:27])(=[O:33])=[O:32])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Reactant: COCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CCOC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 0.11 g, 0.40 mmol) in dichloromethane (1.5 ml) was added pyridine (64 mg) in dichloromethane (0.75 ml) and 2-methoxy-1-ethanesulfonyl chloride (J. F. King, J. Y. L. Lam, S. Kronieczny, J. Am. Chem. Soc., 1992, 114 (5), 1743; 0.96 g, 0.60 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The crude residue was purified by chromatography on silica gel eluting with ethyl acetate: 2M ammonia in methanol (99:1).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.C(C1CCN(N)C1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O.C[N:23]([CH:25]=[O:26])[CH3:24]>>[C:12]([O:11][C:25](=[O:26])[NH:23][CH:24]1[CH2:7][CH2:2][N:3]([C:2]2[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:4]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CN(C)C=O
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)C1CCN(N)C1
Product: CC(C)(C)OC(=O)NC1CCN(c2nccnc2Cl)C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 2,3-Dichloro-pyrazine (3 g, 20.2 mmol) and dry DMF (50 mL). 3-Boc-aminopyrrolidine (8.2 g, 44.5 mmol) was dissolved in dry DMF (50 mL) and added to the round bottom flask. The reaction mixture was allowed to continue to stir overnight at 100° C. LC/MS analysis indicated the desired product as the main component. The reaction mixture was cooled to room temperature and poured on ice. The mixture was extracted with EtOAc and the EtOAc layer was washed with water and brine and dried on sodium sulfate. After removal of solvent in vacuo the desired product [1-(3-Chloro-pyrazin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (6.8 g, 99% yield) was obtained.