Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:17]([O:19][CH3:20])=[O:18])[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]=12.C1C(=O)N([Br:28])C(=O)C1>C(#N)C>[Br:28][C:3]1[N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6][C:5]2=[C:1]([C:17]([O:19][CH3:20])=[O:18])[N:2]=1
Reactant: COC(=O)c1ncn2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a stirred solution of Intermediate 1G (2 g, 7.11 mmol) in anhydrous acetonitrile (30 mL) at room temperature, NBS (1.30 g, 7.11 mmol) was added in one portion. The resulting mixture was stirred at room temperature in the dark for 24 hours. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. A saturated aqueous solution of sodium sulfite was added and the biphasic mixture was stirred vigorously at room temperature for 30 minutes. The aqueous phase was separated and the organic layer was washed twice with brine, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica), eluting with ethyl acetate/hexane mixtures to give Intermediate 1H as a white solid at 60% yield. 1H-NMR (400 MHz, CDCl3) δ: 1.52 (s, 9H), 3.85 (m, 2H), 3.89 (s, 3H), 3.93 (m, 2H), 4.89 (s, 2H). LCMS (+ESI) m/z 362.16 [M+H]+, 360.16 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17].[C:19](=O)(OCC)[O:20]CC.CC(C)([O-])C.[K+].O>C1COCC1>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:6]2[C:2]3[N:1]=[C:19]([OH:20])[N:18]=[C:16]([OH:17])[C:3]=3[N:4]=[N:5]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)OCC
Reactant: COc1ccc(Cn2nnc(C(N)=O)c2N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2nnc3c(O)nc(O)nc32)cc1
Temperature: 25 °C

Procedure:
To a solution of 5-amino-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (0.9 g) and diethyl carbonate (1.2 mL) in THF (30 mL) was added potassium tert-butoxide (1.2 g). The mixture was refluxed under nitrogen for 6 h. It was then cooled down to room temperature. Water (20 mL) was added and the reaction mixture was concentrated to about 20 mL. It was neutralized with 1N HCl to pH 6 and filtered. Solid was collected and washed with water, and air dried to give desired product. 1H NMR (400 MHz, MeOD-d4) δ 7.24 (d, 2H), 7.21 (m, 1H), 6.92 (d, 2H), 6.88 (m, 1H), 5.52 (s, 2H), 3.78 (s, 3H) ppm; ESMS calculated for C12H11N5O3 (m/z): 273.0, found (M+H+): 274.0.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[C:7]([F:17])=[C:6]2[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-].C(O)C>O.[Fe]>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[C:7]([F:17])=[C:6]2[C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc2c(F)c(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc2c(F)c(-c3ccc(N)cc3)n(CC3CC3)c2c1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
A mixture of 1-cyclopropylmethyl-6-ethoxy-3-fluoro-2-(4-nitro-phenyl)-1H-indole (161 mg, 0.45 mmol), iron powder (170 mg), NH4Cl (170 mg, 3.2 mmol), ethanol (4 mL) and H2O (1.5 mL) were heated at 80° C. for 90 minutes. The reaction mixture was diluted with H2O and was extracted with CH2Cl2. The organic layer was dried and concentrated to provide 4-(1-cyclopropylmethyl-6-ethoxy-3-fluoro-1H-indol-2-yl)-phenylamine (122 mg, 83%) as a white solid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([C:14]1([OH:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1>>[C:1]([CH2:2][CH2:3][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)([OH:24])[C:15]1=[O:23])#[N:4]
Reactant: COc1cccc(CC2(O)C(=O)Nc3ccccc32)c1
Reactant: C=CC#N
Product: COc1cccc(CC2(O)C(=O)N(CCC#N)c3ccccc32)c1

Procedure:
Reaction of acrylonitrile with -3-(m-anisyl)-3-hydroxyindolin-2-one by a process analogous to that of Example 1 gives 1-(2-cyanoethyl)-3-(m-anisyl)-3-hydroxy-indolin- 2-one. Hydrogenation of the 1-(2-cyanoethyl)- 3-(m-anisyl) 3-hydroxy-indolin-2-one by a procedure analogous to that of Example 2 gives 1-(3-aminopropyl)- 3-(m-anisyl)-3-hydroxy-indolin-2-one. Cyclodehydration of the 1-(3-aminopropyl)-3-(m-anisyl)-3-hydroxy-indolin- 2-one by a procedure analogous to that of Example 3 gives 10-(m-anisyl)-2,3,4,10-tetrahydro-pyrimido[1,2-a] indol 10-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[NH:14]C.[CH3:16][CH:17]1[CH2:22][C:21](=[O:23])[CH2:20][C:19](=O)[CH2:18]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:14][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([CH:9]=[CH:10][C:2]=1[Cl:1])[C:6]([O:8][C:19]1[CH2:18][CH:17]([CH3:16])[CH2:22][C:21](=[O:23])[CH:20]=1)=[O:7]
Reactant: CNc1c(Cl)ccc(C(=O)O)c1[N+](=O)[O-]
Reactant: CC1CC(=O)CC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1CC(=O)C=C(OC(=O)c2ccc(Cl)c(N)c2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg (1.1 mmol) of 4-chloro-3-(methylamino)-2-nitrobenzoic acid, 410.3 mg (3.3 mmol) of 5-methylcyclohexane-1,3-dione, 275.7 mg (1.4 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 13.5 mg (0.1 mmol) of 4-(dimethylamino)pyridine were dissolved in 6 ml of methylene dichloride and stirred at RT for 8 h. This was followed by washing with water and saturated NaHCO3 solution, after which the organic phase was dried over MgSO4 and then the whole was filtered through a small glass frit filled with 1 cm of silica gel, with suction, and the filter product was washed with heptane/ethyl acetate 1:2. The filtrate was concentrated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[ClH:15]>C(O)C.[Pd]>[ClH:15].[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2nnn[nH]2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(-c2nnn[nH]2)c1
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of 5-(3-nitrophenyl)tetrazole (22 g, 0.12 mol) in ethanol (500 mg) was added 10% palladium on carbon (1.5 g, 7% (w/w)) in hydrochloric acid (23 mg of a 5M solution). The mixture was hydrogenated at 40 psi for 10 min, then the catalyst filtered off and washed with water. The solvents were evaporated in vacuo and the brown solid azeotroped with toluene (4×100 mg). The resulting solid was triturated with hot ethanol to give 5-(3-aminophenyl)tetrazole hydrochloride (16.3 g, 71%) as a beige powder, mp 203°-205° C. 1H NMR (360 MHz, D2O) δ 7.63 (1H, d, J=9 Hz), 7.75 (1H, t, J=8 Hz), 8.00 (2H, m).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][CH2:22][N:14]3[C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)[CH2:2]C.Br.Br.O[C:28]1C=CC(C2N=C3CCCN3C=2C2C=CN=CC=2)=CC=1.[H-].[Na+].CC(I)C>CN(C)C=O>[CH3:28][CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][CH2:22][N:14]3[C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCCOc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: Oc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: CC(C)Oc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 0.90 g (2.0 mmoles) of 2 (4 hydroxyphenyl) 3 (4-pyridyl) 6,7 dihydro-[5H]pyrrolo[1,2 a]imidazole dihydrobromide of Example 10 in 20 ml of dry dimethylformamide cooled in an ice bath was treated with 267 mg (6.67 mmoles) of 60% sodium hydride dispersion and allowed to warm to room temperature. A solution of 374 mg. (2.22 mmoles) of 2-propyl iodide in 2 ml of dimethylformamide was added dropwise and the reaction mixture heated at 100° C. for 4 hours. Another 35 mg (0.88 mmole) of 60% sodium hydride suspension was added at room temperature, followed by 113 mg (0.67 mmole) of 2-propyl iodide and the mixture heated at 100° C. for an additional 3 hours. After stirring overnight, the mixture was poured into 10 volumes of ice water and extracted three times with ethyl acetate. The organic phase was washed with water, dried over anhydrous potassium carbonate and concentrated in vacuo. The residue was flash chromatographed on silica and the fraction eluting with 2% methanol in chloroform, concentrated in vacuo, and recrystallized from ethyl acetate to afford the titled compound, mp 148-150° C. Anal. Calcd. for C20H21N3O: C, 75.21; H, 6.63; N, 13.16. Found: C, 75.38; H, 6.58; N, 13.26.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[S:24][CH:25]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccn4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccn4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-[2-(2-pyridyl)-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionate (471 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (2 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(2-pyridyl)-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionic acid (408 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 117–118° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[C:5]([CH3:8])[S:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].C([O-])([O-])=O.[K+].[K+].O.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[C:9]([C:3]1[S:4][C:5]([CH3:8])=[C:6]([NH:7][C:22](=[O:23])[CH2:21][Cl:20])[C:2]=1[CH3:1])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1sc(C)c(N)c1C
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1sc(C)c(NC(=O)CCl)c1C

Procedure:
To 12.25 g (0.066 mol) of methyl 3,5-dimethyl-4-aminothiophene-2-carboxylate, 9.1 g (0.066 mol) of K2CO3, 25 ml of water and 150 ml of methylene chloride are added without cooling 7.5 g (0.066 mol) of chloroacetyl chloride.
Reaction SMILES: [Cl:1][C:2]1C(Cl)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH:23](O)[CH2:24][OH:25])=[C:10]1[C:27]([O:29][CH2:30][CH3:31])=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]([Cl:55])(Cl)(Cl)Cl>O>[Cl:1][C:2]1[C:51]([Cl:55])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH:23]2[CH2:24][O:25]2)=[C:10]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)C1=C(COCC(O)CO)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CCOC(=O)C1=C(COCC2CO2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
A solution of 1- {[4-(2.3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2,3-dihydroxypropane (4.74 g) (see Example 20) and triphenylphosphine (2.62 g) in carbon tetrachloride (60 ml) was heated under reflux for 4 hours and then diluted with dichloroaethane and water. The layers were separated and the aqueous layer was extracted into dichloromethane. The combined organic layers were washed with water, dried over Na2SO4 and evaporated. The residue was purified by chromatography on SiO2 (80 g) using toluene plus 0-20% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated and the residue triturated with diisopropyl ether. The resulting solid was collected, washed with diisopropyl ether and dried to give the title compound (1.40 g), m.p. 103°-104° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][O:8][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[I:17]I>C1COCC1>[I:17][C:4]1[CH:3]=[CH:2][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][O:8][CH2:9]2
Reactant: II
Reactant: Brc1ccc2c(c1)COCC2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Ic1cccc2c1CCOC2
Reaction time: 0.02 h

Procedure:
A solution of 7-bromoisochroman (6.6 g; 30.98 mmol) in THF (100 ml) was cooled to -78° C. and treated with 2.1 eq of tert-butyllithium (40 ml of a 1.7M solution). After stirring the solution for one minute, iodine (8.64 g; 34.08 mmol) was added as a THF solution (50 ml). The reaction mixture was stirred for 30 minutes at -78° C. and one hour at room temperature. It was quenched with saturated aqueous ammonium chloride, and the organic phase was washed with aqueous sodium thiosulfate and brine, dried, and freed of solvent. The crude product was recrystallized from hexane to provide the pure 5-iodoisochroman as a white crystalline solid, mp= 54°-56° C. (4.1 g; 51%). 1H NMR (CDCl3): δ2.79 (t, 2H); 3.94 (t, 2H); 4.70 (s, 2H); 6.85 (d, 1H); 7.32 (s, 1H); 7.46 (d, 1H). IR (nujol): 2931, 2852, 1550, 1252, 1190, 1105, 1005, 987 cm-1.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](Cl)=[O:36]>C(Cl)Cl>[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[CH2:21][N:20]([C:35]([C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)=[O:36])[CH2:19][CH2:18]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: c1cc2c(c(OCCCN3CCCCC3)c1)CNCC2
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccs1)N1CCc2cccc(OCCCN3CCCCC3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a mixture of 8-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride salt (300 mg, 0.86 mmol) and NEt3 (0.36 mL, 2.6 mmol) in CH2Cl2 (10 mL) is added 2-thiophene carbonyl chloride (0.10 mL, 0.95 mmol). After stirring at room temperature overnight, the mixture is partitioned between EtOAc and water. The organic phase is washed with brine, dried (MgSO4), and concentrated. The residue is purified by flash chromatography [Biotage 40S SiO2, elute 20% (90/10/1 CH2Cl2/MeOH/NH4OH)/80% CH2Cl2 to 100% (90/10/1 CH2Cl2/MeOH/NH4OH)] to yield the title compound as a yellow oil (0.181 g, 55%). MS (ES+) 385.3.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[C:33]([C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:34]([O:36][CH3:37])=[O:35])=[CH:28][CH:27]=1>C1COCC1>[CH3:12][C:11]([CH3:14])([O:10][C:8]([N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([CH:32]([C:29]2[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=2)[CH:33]([C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:34]([O:36][CH3:37])=[O:35])[C:2]1=[O:1])=[O:9])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: COC(=O)C(=Cc1ccc(F)cc1)C(=O)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)C(C)C)C(c1ccc(F)cc1)C1CCCN(C(=O)OC(C)(C)C)C1=O
Temperature: -30 °C
Reaction time: 0.42 h
Yield: 77.4 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 2-oxo-1-piperidinecarboxylate (10 g, 50 mmole) in anhydrous THF (50 mL) which had been cooled to −20 to −30° C. was added LiHMDS in THF (55 mL, 1M, 55 mmol) solution, maintaining the temperature between −25 to −35° C. The reaction mixture was stirred for 20-30 minutes then transferred via cannula to a cooled solution (−20° C.) of methyl 3-(4-fluorophenyl)-2-isobutyrylacrylate (12.5 g, 50 mmol) in 75 mL anhydrous THF. When the reaction was complete as judged by TLC monitoring, the reaction was quenched with 100 mL of saturated ammonium chloride and extracted with ethyl acetate (2×200 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to provide an off white solid. Recrystallization from ethyl acetate/hexanes afforded 17.4 g (77% yield) of methyl 1-[(1,1-dimethylethoxy)carbonyl]-β-(4-fluorophenyl)-α-(2-methyl-1-oxopropyl)-2-oxo-3-piperidinepropanoate in as a white crystalline solid. NMR clearly shows a mixture of isomers: IR (KBr) cm−1 2979, 1758, 1755, 1745, 1714, 1671; 1H NMR (CDCl3, 400 MHz) δ 7.21-7.20 (m, 4H), 6.93-6.92 (m, 4H), 4.40 (dd, 2H), 4.09 (m, 2H), 3.66 (s, 3H), 3.58-3.33 (m, 4H), 3.32 (s, 3H), 2.80-2.48 (m, 4H), 2.02-1.60 (m, 6H), 1.47 (s, 18H), 1.43-1.51 (m, 2H), 1.08 (d, J=4 Hz, 3H), 1.05 (d, J=8 Hz, 3H), 0.85 (d, J=4 Hz, 3H), 0.71 (d, J=8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 206.9, 206.8, 171.7, 171.6, 168.4, 168.2, 162.6, 160.2, 151.9, 134.5, 134.3, 131.1, 130.0, 130.8, 130.7, 115.2, 115.1, 115, 114.9, 82.9, 61.5, 60.8, 53.0, 52.6, 48.2, 48.0, 46.3, 45.9, 45.6, 44.9, 41.9, 40.9, 28.63, 24.2, 24.0, 21.9, 21.3, 19.5, 19.0, 18.8, 18.7; HRMS (ES) calcd. for C24H32FNNaO6 (M+Na): 472.2111; found: 472.2100.
Reaction SMILES: [CH2:1]([C:3]([CH2:5][CH3:6])=[O:4])[CH3:2].[N:7](OCCC(C)C)=[O:8].Cl.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>C(OCC)C.CC(=NO)C(=O)CC.C(O)(=O)C>[CH2:1]([C:3]1[O:4][C:21]([C:20]2[CH:23]=[CH:24][C:17]([CH3:16])=[CH:18][CH:19]=2)=[N+:7]([O-:8])[C:5]=1[CH3:6])[CH3:2]
Reactant: CC(C)CCON=O
Reactant: Cc1ccc(C=O)cc1
Reactant: CCC(=O)CC
Agent: CCC(=O)C(C)=NO
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCc1oc(-c2ccc(C)cc2)[n+]([O-])c1C

Procedure:
Diethyl ketone is reacted with isoamyl nitrite and HCl in diethyl ether, resulting in pentane-2,3-dione 2-oxime (G. Buechi, J. Galindo, J.Org.Chem. (1991) 56(8), 2605-2606). The latter is reacted with p-methylbenzaldehyde and HCl in acetic acid to give 5-ethyl-4-methyl-2-p-tolyloxazole 3-oxide (P. M. Weintraub, J. Med. Chem. (1972) 15(4), 419-420). Boiling this compound with phosphoryl chloride in chloroform results in 4-chloromethyl-5-ethyl-2-p-tolyloxazole (M. S. Malamas, R. P. Carlson, D. Grimes, R. Howell, K. Glaser, I. Gunawan, J. A. Nelson, M. Kanzelberger, U. Shah, D. A. Hartman, J. Med. Chem. (1996) 39(1), 237-245). This compound is heated with sodium iodide in acetone under reflux, resulting in 5-ethyl-4-iodomethyl-2-p-tolyloxazole (A., Zlatkov, P., Peikov, J., Rodriguez-Alvarez, N., Danchev, I., Nikolova, J., Mitkov, Eur.J.Med.Chem.Chim.Ther. (2000) 35(10), 941-948).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[CH3:20])[C:6]=2[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:3]=1.C([O:30][B:31]1OC(C)(C)C(C)(C)[O:32]1)(C)C>>[Cl:19][C:15]1[C:14]([CH3:20])=[C:13]([CH2:12][N:7]2[C:6]3[CH:5]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:3]=[C:2]([B:31]([OH:32])[OH:30])[C:10]=3[N:9]=[C:8]2[CH3:11])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(Cl)cccc1Cn1c(C)nc2c(Br)cc(N3CCOCC3)cc21
Product: Cc1c(Cl)cccc1Cn1c(C)nc2c(B(O)O)cc(N3CCOCC3)cc21
Yield: 23.4 %

Procedure:
Several batches were prepared, using additional 77 g of 4-bromo-1-[(3-chloro-2-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole (177.11 mmol), either by the method above or by using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as the quenching agent. After standard work up the batches were combined with the above material and purified first by RP-HPLC (Luna C18(2), 5 u, 101×250 mm, 55:45 300 mM Aqueous ammonium trifluoroacetate (pH 2.8):acetonitrile), followed by purification on chiral phase (Chiralpak AD 101×250 mm, 20 u, 80:20 Heptane/EtOH plus 2% HCO2H and 1% Isopropylamine) and recrystallization from EtOAc to give [1-[(3-chloro-2-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazol-4-yl]boronic acid (18.03 g, 45.17 mmol, 23.4% yield) as a beige powder.
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:20].[Na+].[CH2:22](Cl)Cl>CCOCC>[CH:22]([N:17]1[CH2:18][CH2:19][CH:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16]1)=[O:20]
Reactant: ClCCl
Reactant: c1ccc(Cc2ccccc2C2CCNC2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=CN1CCC(c2ccccc2Cc2ccccc2)C1

Procedure:
A solution of 3.42 g of 3-(α-phenyl-2-tolyl)pyrrolidine hydrochloride of Example 58 in 50 ml of CH2Cl2 is stirred with an excess of 5% NaOH. The organic phase is separated, washed with water, dried (Na2SO4), and evaporated to an oil. This oil is dissolved in 50 ml of ethyl formate and refluxed for 18 hours. The solvent is removed under reduced pressure to give an oil, which is dissolved in 25 ml of ether, and after cooling 16 hours the product is collected by filtration to provide 1-formyl-3-(α-phenyl-2-tolyl)pyrrolidine, mp 70°-71° C.
Reaction SMILES: Br[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH3:15][C:4]1[CH:3]=[C:2]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: Oc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Br)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(-c2ccccc2)cc1C
Yield: 58.1 %

Procedure:
22.6 g of methyl 4-bromo-2-methyl-5-nitrobenzoate, 23 g of K2CO3 and 7.8 g of phenol were stirred at 120° C. for 2 hours in 300 ml of DMF. The solvent was removed in vacuo, 2 l of water were added, and the mixture was adjusted to pH=7 using aqueous HCl solution and extracted 3 times using 500 ml of EA each time. The organic phase was dried over Na2SO4, the solvent was removed in vacuo and chromatography on silica gel using EA/HEP 1:4 yielded 13 g of a colorless oil.
Reaction SMILES: CS(C)=O.[Cl:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.Cl.[CH3:15][NH2:16].[C-:17]#[N:18].[Na+]>O>[Cl:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]([NH:18][CH3:17])[C:15]#[N:16]
Reactant: CN
Reactant: O=Cc1ccccc1Cl
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CNC(C#N)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 76 h

Procedure:
A mixture containing 50 milliliters (ml) of dimethylsulfoxide, 15 ml of water, 29 grams (g) of 2-chlorobenzaldehyde, 15 g of methylaminehydrochloride and 12.5 g of sodium cyanide is stirred at room temperature for approximately 76 hours. The reaction mixture is then diluted with water and extracted with benzene. The benzene extract is washed several times with water and then dried over potassium carbonate. Filtration and evaporation of the filtrate under reduced pressure yields crude 2-(2-chlorophenyl)-2-methylaminoacetonitrile. This material is dissolved in approximately 100 ml of ether and added to a solution of 13 g of lithium aluminum hydride in 300 ml of ether. The reaction temperature is kept between -10° and 5° C at first and is then allowed to warm to room temperature. After stirring for about 20 hours there is added cautiously and dropwise first 13 ml of water, then 13 ml of 15% sodium hydroxide and finally 20 ml of water. The mixture is stirred until the solid is nearly white and the solid is then removed by filtration.