Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.C1(C)C=CC=CC=1.C[O:15][C:16]([C:18]1[NH:19][C:20]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=2)=[C:21]([C:23]2[CH:33]=[CH:32][C:26]3=[N:27][N:28]([CH2:30]C)[N:29]=[C:25]3[CH:24]=2)[N:22]=1)=O>C1C=CC=CC=1>[CH3:30][N:28]1[N:27]=[C:26]2[CH:32]=[CH:33][C:23]([C:21]3[N:22]=[C:18]([C:16]([NH2:2])=[O:15])[NH:19][C:20]=3[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=3)=[CH:24][C:25]2=[N:29]1
Reactant: [NH4+]
Reactant: CCn1nc2ccc(-c3nc(C(=O)OC)[nH]c3-c3cccc(C)n3)cc2n1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2[nH]c(C(N)=O)nc2-c2ccc3nn(C)nc3c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 17.1 %

Procedure:
Suspension of ammonium chloride (12 mg, 0.21 mmol) in 2 ml dry benzene was cooled to 0° C. 2M solution of trimethylaluminum in toluene (105 μl, 0.21 mmol) was slowly added and the reaction warmed to room temperature and stirred for 2 hours. This suspension was added to separate suspension of 4-(2-ethyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carboxylic acid methyl ester (25 mg, 0.07 mmol) (prepared according to procedures analogous to example 1) in 1 ml dry benzene and the reaction heated at 50° C. overnight. The reaction was quenched by the addition of excess 1M aqueous solution of hydrochloric acid. The reaction was extracted three times with chloroform. Mass spectrometry analysis of organic extracts show no presence of desired product. The remaining aqueous layer was concentrated to dryness. The aqueous extract reside was purified on Biotage Flash 12S silica gel column using chloroform/methanol gradient system (99:1 to 80:20, respectively) as eluent to afford 4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carboxylic acid amide (4 mg, 16% yield). HPLC tR=3.70 min, LC-MS=344 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:43](I)[CH3:44]>CN(C)C=O.O>[CH2:43]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=4)[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)[CH3:44]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (54 mg) was dissolved in dimethylformamide (5 ml), and sodium hydride (60% mineral oil dispersion, 5 mg) was added under ice cooling, followed by stirring at room temperature for 30 minutes. After dropwise addition of ethyl iodide (9 μl), the reaction mixture was further stirred for 10 hours, and subsequently diluted with water (20 ml), followed by extraction with ethyl acetate (10 ml×2). The combined organic layers were washed with brine, and dried with sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/0 to 10/1), to obtain [5-(7-ethyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-bis-(4-methoxy-benzyl)-amine as a colorless solid (49 mg, 86%). The above colorless solid was dissolved in trifluoroacetic acid (2 ml), and concentrated sulfuric acid (1 drop) was added, followed by stirring at 100° C. for 1 hour. The solvent was concentrated under reduced pressure, and the resulting residue was diluted with water (2 ml), to filter the resulting precipitate, followed by washing with water. The crude product was purified by amino silica gel column chromatography (dichloromethane), to obtain a colorless powder (18 mg, 64%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:16]=[CH:15][C:6]2[O:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[C-:17]#[N:18].[Na+]>CN(C)C=O>[C:17]([CH2:2][C:3]1[CH:16]=[CH:15][C:6]2[O:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH:4]=1)#[N:18]
Reactant: CCOC(=O)c1cc2cc(CCl)ccc2o1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(CC#N)ccc2o1
Yield: 90 %

Procedure:
The starting material can be prepared as follows: By the reaction of ethyl 5-chloromethylbenzo[b]furan-2-carboxylate (Chem. Abstr., 1959, 3185d) with excess sodium cyanide in dimethylformamide there is obtained, in a yield of 90% of theory, ethyl 5-cyanomethylbenzo[b]furan-2-carboxylate (m.p. 74°-76° C. after recrystallisation from ethyl acetate) which is hydrogenated in the presence of platinum oxide to give ethyl 5-(2-aminoethyl)-benzo[b]furan-2-carboxylate. From an ethanolic solution thereof, with an ethereal solution of hydrogen chloride there can be precipitated out the hydrochloride; m.p. 188°-190° C.; yield 64% of theory.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:31][NH:32][O:33][CH3:34].Cl>C(Cl)Cl>[CH3:34][O:33][N:32]([CH3:31])[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[CH:15]=1)=[O:18]
Reactant: O=C(O)c1ccc2nc(-c3ccccc3)oc2c1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a suspension of 2-phenylbenzo[d]oxazole-6-carboxylic acid (2.0 g, ca. 8.4 mmol) in CH2Cl2 was added CDI (1.6 g, 9.9 mmol, 1.2 eq) at 0° C. The reaction was warmed to room temperature then stirred for 1 h to give a homogeneous solution. The mixture was cooled to 0° C. before MeNHOMe-HCl (0.98 g, 10.0 mmol, 1.2 eq) was added. After 12 h, the reaction was quenched with H2O and extracted with CH2Cl2 (3×50 mL). Solvent was removed then crude product was purified by flash column chromatography (0-25% EtOAc in hexanes) to afford N-methoxy-N-methyl-2-phenylbenzo[d]oxazole-6-carboxamide (1.57 g, 5.6 mmol, 67% over two steps).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:48][CH:49]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:50]1[CH:51]=[CH:52][C:53]([P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])=[N:54][CH:55]=1>C(OCC)(=O)C>[OH:1][C:2]1[C:7]([C:8]([NH:48][CH:49]([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:50]2[CH:51]=[CH:52][C:53]([P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])=[N:54][CH:55]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1O
Reactant: CCOP(=O)(OCC)c1ccc(C(N)c2ccccc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid, 1-1-h, (1 g, 4.6 mmol) in ethyl acetate (20 ml) was added HATU (1.75 g, 4.6 mmol), Et3N (465 mg, 4.6 mmol) and diethyl {5-[amino(phenyl)methyl]pyridin-2-yl}phosphonate (4-g) (1.47 g, 4.6 mmol). The resulting mixture was stirred at room temperature for 2 hour. Then it was filtered before diluted with saturated NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography to provide the product, 4-1, (360 mg, 15%). 1H NMR (CD3OD, 300 MHz,): δ 10.56 (m, 1H), 8.66 (m, 3H), 8.37 (m, 1H), 7.83 (m, 3H), 7.52 (m, 1H), 7.23 (m, 5H), 6.33 (m, 1H), 4.09 (m, 4H), 1.30 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:11](O)(=[O:18])[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cccc([N+](=O)[O-])c1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccncc1

Procedure:
The general procedure for 8 was followed using 3-nitro aniline 31 and isonicotinic acid to afforded (68%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.67-7.71 (m, 1H), 7.89-7.91 (m, 2H), 8.01 (dd, J, =8.4 Hz, J2=1.6 Hz, 1H), 8.19 (dd, J, =8 Hz, J2=1.6 Hz, 1H), 8.79-8.83 (m, 3H), 10.9 (NH, s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][N:11]2[C:12](=[O:22])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[Cl:21])=O)(C)(C)C.Cl>>[ClH:21].[Cl:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[C:18]2[C:13]=1[C:12](=[O:22])[N:11]1[CH2:23][CH2:24][NH:8][CH2:9][CH:10]12
Reactant: COc1cc(Cl)c2c(c1)C1CN(C(=O)OC(C)(C)C)CCN1C2=O
Agent: Cl
Product: COc1cc(Cl)c2c(c1)C1CNCCN1C2=O
Reaction time: 0.25 h
Yield: 172.9 %

Procedure:
To (±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one (20 mg, 0.06 mmol) was added concentrated hydrochloric acid (1 mL). After 15 min, the resulting solution was concentrated, diluted with water, and lyopholized to give (±)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one hydrochloric acid salt as an off-white solid (15 mg, 91%). MS (ESI) 253.1, 255.1 (M−Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.CO[CH2:16][Cl:17].[Sn](Cl)(Cl)(Cl)Cl.O>ClCCl>[Cl:17][CH2:16][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(OC)cc1
Reactant: COCCl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(OC)c(CCl)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
Ethyl 4-methoxybenzoate (28.0 mL) and 26.0 mL of methoxymethyl chloride were dissolved in 500 mL of dichloromethane, and the solution was cooled to 0° C. To this solution, 10.0 mL of tin (IV) chloride was added dropwise over 15 minutes, and then the mixture was stirred for 5 hours. The reaction mixture was poured into 1 L of water, and the organic layer was separated, whereafter the aqueous layer was extracted twice with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and washed with dichloromethane. The filtrate and the washings were combined, and dichloromethane was distilled off under reduced pressure. The resulting residue was recrystallized from a mixture of n-hexane and ethyl acetate. The resulting crystals were separated by filtration, then washed with n-hexane, and dried under reduced pressure to obtain 23.8 g (60%) of ethyl 3-chloromethyl-4-methoxybenzoate.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]4[CH:32]=[C:31]([N+:33]([O-])=O)[C:30]([C:36]5[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH:41]=5)=[CH:29][C:28]=4[O:43][CH3:44])[N:20]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]4[CH:32]=[C:31]([NH2:33])[C:30]([C:36]5[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH:41]=5)=[CH:29][C:28]=4[O:43][CH3:44])[N:20]=3)=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)n1
Reaction time: 0.08 h
Yield: 140.2 %

Procedure:
A mixture of 4-[1-(benzenesulfonyl)indol-3-yl]-5-chloro-N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]pyrimidin-2-amine (Intermediate 9, 349 mg, 0.47 mmol), iron (157 mg, 2.82 mmol) and NH4Cl (17.60 mg, 0.33 mmol) in ethanol (9 mL) and water (3 mL) was heated at reflux for 1.5 h. The mixture was cooled and concentrated in vacuo. CH2Cl2 (20 mL) and CH3OH (2 mL) were then added and the mixture was stirred for 5 minutes and then filtered. The organic solution was washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (396 mg, 140%) as a green foam which was used without further purification. m/z: ES+ MH+ 601.
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:18]#[N:19])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:20])=O.Cl>C(O)C>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2([C:18]#[N:19])[CH2:8][CH2:7][C:6](=[O:20])[CH2:5][CH2:10]2)=[CH:16][CH:15]=1
Reactant: COC(=O)C1CC(C#N)(c2ccc(F)cc2)CCC1=O
Agent: Cl
Solvent: CCO
Product: N#CC1(c2ccc(F)cc2)CCC(=O)CC1
Yield: 62.3 %

Procedure:
102.5 g of crude 5-Cyano-5-(4-fluoro-phenyl)-2-oxo-cyclohexanecarboxylic acid methyl ester (72) were dissolved in 680 mL of ethanol. 170 mL of conc. hydrochloric acid were added and the reaction mixture was refluxed for 40 h. The mixture was evaporated to dryness, the residue was taken up in water and extracted with dichloromethane. The combined organic layers were extracted with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography to give 50.4 g of the desired product. Rt=1.26 min (Method C). Detected mass: 218.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OC(=O)C)(=O)C>CCOCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][C:12](=[O:14])[O:18][C:16](=[O:17])[CH2:15]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CC(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(c2ccc([N+](=O)[O-])cc2)CC(=O)O1
Temperature: 80 °C
Yield: 70 %

Procedure:
A flask was charged with 20.0 g (79.0 mmol) of 3-(4-nitro-phenyl)-pentanedioic acid (as prepared in the previous step) and 22.4 mL (237 mmol) of acetic anhydride. The mixture was heated to 80° C. for 1 h, cooled to RT, and treated slowly with ether until the product began to precipitate. After allowing the solid to fully precipitate, the solid was filtered, washed with ether, and air-dried to afford 13.0 g (70%) of the title compound as an off-white solid: 1H-NMR (CDCl3; 400 MHz): δ 8.28 (d, 2H, J=8.8 Hz), 7.41 (d, 2H, J=8.8 Hz), 3.64-3.53 (m, 1H), 3.22-3.13 (m, 2H), 2.96-2.85 (m, 2H).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@@H:14]([CH2:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)[C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])[CH2:4]1)=O.[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.C(Cl)Cl.CO.[NH4+].[OH-]>>[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:42][CH2:43][N:44]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@@H:14]([CH2:27][CH:28]4[CH2:29][CH2:30][CH2:31]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:45][CH2:46]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(COC(=O)[C@H](CC2CCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)[C@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Yield: 63.8 %

Procedure:
The title compound was prepared from 25 mg (0.059 mmol) of 2-(S)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, (4-methoxy)benzyl ester (from EXAMPLE 92, Step C) and 14.3 mg (0.059 mmol) of 4-(3-phenylpropyl)piperidine.HCl using a procedures analogous to those described in EXAMPLE 1, Step J and EXAMPLE 10, Step F to 18.4 mg (64%) of the title compound: RF: 0.48 (90:10:1 v/v/v CH2Cl2/MeOH/NH4OH); 1H NMR (300 MHz, CD3OD) δ 0.99-3.67 (m, 33H), 6.96-7.23 (m, 10H); ESI-MS 489 (M+H); HPLC A: 2.69 min.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=[O:12])=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](CC1CCCCC1)C(O)C(=O)O

Procedure:
A solution of Example 3C (75 mg, 0.25 mmol) in 4M HCl in dioxane (2 mL) at room temperature was stirred for 1 hour, concentrated, then purified by reverse phase HPLC with acetonitrile/water to provide the desired product. MS (ESI) m/e 202 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.81 (br s, 2H), 4.07 (d, 1H), 3.35 (m, 1H), 1.80–1.67 (m, 5H), 1.57–1.51 (m, 1H), 1.46–1.17 (m, 5H), 1.00–0.90 (m, 2H); Anal. Calcd. for C10H20ClNO3: C, 50.52; H, 8.48; N, 5.89. Found: C, 50.18; H, 8.56; N, 5.67.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:3].[H-].[Na+].[CH3:16][O:17][C:18](=O)[O:19]C>CCCCCC.C(OCC)(=O)C>[C:4]1([C:2](=[O:3])[CH2:1][C:18]([O:17][CH3:16])=[O:19])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1cccc2ccccc12
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)CC(=O)c1cccc2ccccc12
Yield: 3945.4 %

Procedure:
10.2 g(59.9 mmol) of 1-acetonaphthone and 4.8 g(60% in mineral oi, 120 mmol) of sodium hydride were added to 100 mg of dimethylcarbonate and the mixture was refluxed for 24 hours. The solvent was removed under reduced pressure, 100 ml of 1N aqueous HCl solution was added to the residue, and the resulting mixtrue was extracted with 100 ml of ethyl acetate. The organic layer was washed with water(100 ml×3), dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography(eluent: n-hexane/ethyl acetate=90/10, v/v) to give 10.0 g (43.8 mmol, Yield 73%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8](=O)[N:7]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]=2[C:5]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:8]1[N:7]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]2[C:5]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCCn1c(=O)[nH]c2c(Cl)ccc(C(CC)CC)c21
Product: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 25 °C
Yield: 34 %

Procedure:
The solution of ethyl 4-[4-chloro-7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]butanoate (6.8 g, 19.32 mmol) in phosphorus oxychloride (70 mL) was stirred at 100-110° C. for 2 days. After cooled to room temperature, the excess phosphorus oxychloride was removed by distillation and the residue was poured into water. The aqueous phase was extracted with ethyl acetate (100 mL×3) and the combined extracts were washed with saturated aqueous sodium bicarbonate (100 mL×2) and water (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether/ethyl acetate, 50/1) to afford the title compound (2.4 g, 34%) as light yellow oil.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11]Br)[CH3:8].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11][N:5]1[CH:6]=[C:2]([I:1])[N:3]=[CH:4]1)[CH3:8]
Reactant: Ic1c[nH]cn1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(Cn1cnc(I)c1)OCC
Temperature: 110 °C
Yield: 71 %

Procedure:
To a stirred solution of 4-iodoimidazole (10 g, 51.6 mmol) and bromoacetaldehyde diethyl acetal (9.31 mL) in DMSO (30 mL) was added K2CO3 (10.69 g, 77 mmol). The reaction mixture was heated at 110° C. for 16 h. After cooling to RT, the reaction mixture was diluted with water and extracted with AcOEt. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; AcOEt/Hex:0/100 to 50/50 over 20 CV). The desired fractions were collected and concentrated to afford title compound 260 (11.29 g, 36.4 mmol, 71% yield) as yellow oil. MS (m/z): 310.97 (M+H).
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:19][C:18]1[CH:20]=[CH:21][C:15]([Cl:14])=[CH:16][CH:17]=1)#[CH:3]
Reactant: O=C([O-])OCC=Cc1ccccc1
Reactant: Nc1ccc(Cl)cc1
Product: C#CC(Nc1ccc(Cl)cc1)c1ccccc1
Reaction time: 16 h
Yield: 95.1 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and p-chloroaniline (0.150 g, 11.18 mmol). The reaction was conducted at room temperature for 16 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 98/2. The mixture was purified by flash column chromatography on silica gel (2% ethyl acetate in hexanes) to give the title compound (0.225 g, 95%). HPLC analysis indicated the enantiomeric excess of the product was 96% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99.75/0.25; flow rate=0.6 mL/min; detection wavelength=254 nm; TR=29.6 (major), 46.3 (minor) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.48-7.36 (m, 5H), 7.17 (dt, J=8.8, 2.0 Hz, 2H), 6.59 (dt, J=8.8, 2.4 Hz, 2H), 6.10 (ddd, J=16.8, 10.4, 6.0 Hz, 1H), 5.36 (dt, J=14.8, 1.3 Hz, 1H), 5.33 (dt, J=8.0, 1.2 Hz, 1H), 4.98 (d, J=6.0 Hz, 1H), 4.14 (br s, 1H). 13C NMR (100.59 MHz, CDCl3) δ 145.59, 141.25, 138.51, 128.82, 128.71, 127.52, 127.00, 122.03, 116.20, 114.56, 60.75. Anal. Calcd for C15H14NCl: C, 73.92; H, 5.79; N, 5.75; Cl, 14.55. Found: C, 73.94; H, 5.83; N, 5.83; Cl, 14.67.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH2:22][CH3:23])[CH:4]=1.[OH-].[Na+].Cl>N1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:6]([C:7](=[O:8])[NH:9][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:12]2)=[CH:10][CH:11]=1
Reactant: CCCOc1ccccc1C(=O)Nc1cc(SC)ccc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCOc1ccccc1-c1nc2cc(SC)ccc2c(=O)[nH]1

Procedure:
A stirred solution of 4-methylthio-2-(2-propoxybenzamido)benzamide (0.85 g) and pyridine (1 ml) in 2 Normal aqueous sodium hydroxide was heated under reflux for 2 hours. The cooled reaction mixture was acidified with concentrated hydrochloric acid and the resultant mixture was extracted with chloroform (3×25 ml). The combined extracts were washed with water and then brine, dried (magnesium sulphate) and evaporated under reduced pressure to yield a solid which was recrystallized from ethanol to yield the title compound, 0.61 g, m.p. 156.5°-158.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([CH:14]=[CH:15][N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[N:10]([CH:14]=[CH:15][N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2cccn3ccnc23)cc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2cccn3ccnc23)cc1
Temperature: 5 °C
Reaction time: 12 h

Procedure:
Dissolve 4 g (19.1 mmol) of the product from Example 20, in 100 ml of methylene chloride and cool to 0° C. Add 1.6 ml of methanesulfonyl chloride slowly, maintaining the temperature at 5° C. Stir at r.t. for 12 hr. Extract the reaction mixture with 100 ml of 10% sodium hydroxide. Wash with 100 ml of methylene chloride and with 100 ml of ether. Treat with charcoal and neutralize with ammonium chloride. The resulting precipitate is filtered and washed with water to provide the title compound.