Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[CH2:14]([NH:21][C:6]1[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCc2ccccc2)c1C
Temperature: 55 °C
Yield: 45.7 %

Procedure:
2,4-Dichloro-5,6-Dimethyl-3-nitro-pyridine (2 g, 9 mmol) was dissolved in acetonitrile (100 mL) and benzylamine (1.0 mL, 9.5 mmol). Potassium carbonate (1.3 g, 9.5 mmol) was added in one portion, and the whole was heated at 55° C. for 16 h. The reaction mixture was diluted with EtOAc and washed with 50 mL water. The aqueous was re-extracted with EtOAc, the organics were combined and then dried over MgSO4 and evaporated to a dark red residue. This residue was purified by column chromatography on silica gel using 8:1 pentane:EtOAc as eluant to afford the title compound as a bright orange solid (1.2 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:17][C@@H:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])[CH3:19].C[N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:16])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:17][C@@H:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])[CH3:19]
Reactant: CN1CCOCC1
Reactant: C[C@@H](Nc1cc(N2CCC(C(=O)O)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1cc(N2CCC(C(=O)N3CCOCC3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
To a stirred solution of the (R)-1-(4-chloro-3-(1-(2,4-dichlorophenyl)ethylamino)phenyl)piperidine-4-carboxylic acid (0.0.05 g, 0.12 mmol) and N-methylmorpholine (0.01 g, 0.12 mmol) in DMF (1.5 mL) was added HATU (0.049 g, 0.13 mmol) and iPr2NEt (0.75 g, 5.8 mmol). The reaction mixture was stirred at room temperature for 2 h, and quenched with deionzied water. The aqueous layer was extracted with diethyl ether (2×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give a white solid (0.025 g, 0.050 mmol, 43%). 1H NMR (400 MHz, CDCl3) δ 7.36-7.33 (m, 1H), 7.17 (dd, J=1.6, 8.4 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.18 (dd, J=2.8, 8.4 Hz, 1H), 5.78 (d, J=2.4 Hz, 1H), 4.90 (ddd, J=6.4, 6.4, 12.4 Hz, 1H), 4.65 (d, J=5.2 Hz, 1H), 3.68-3.63 (m, 5H), 3.50-3.47 (m, 3H), 2.64-2.48 (m, 3H), 1.92-1.80 (m, 5H), 1.71-1.67 (m, 2H), 1.53 (d, J=6.4 Hz, 3H); MS: (ES) m/z calculated for C24H29Cl3N3O2 [M+H]+496.1. found 496.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][C:9]([Cl:24])=[CH:10][C:11]=2[Cl:23])[N:6]=1)=[O:4].[OH-].[Na+].Cl>C(O)C.O>[CH2:16]([O:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([Cl:24])=[CH:10][C:11]=2[Cl:23])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a suspension of methyl-4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (1.2 g) in ethanol (20 ml) was added a solution of sodium hydroxide (0.53 g) in water (20 ml) and the mixture was stirred at room temperature for 1 h. Hydrochloric acid (11M) was added until pH2 and the resulting precipitate was filtered off, washed with water (20 ml), ethanol (10 ml), diethylether (5 ml) and dried to yield 4-benzyloxy-5,7-dichloroquinoline-2-carboxylic acid (0.95 g). δ (360 MHz, DMSO-d6), 5.49 (2H, s, CH2), 7.40 (3H, m, m,p-ArH), 7.58 (2H, d, o-ArH), 7.71 (1H, s, 3-H), 7.83 (1H, d, 6-H) and 8.81 (1H, d, 8-H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:5][CH:4]=1.[CH3:34][C:35]1([CH3:41])[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:37]3[CH2:38][CH2:39][CH2:40][C:35]([CH3:41])([CH3:34])[CH2:36]3)=[CH:4][CH:5]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:32][CH:31]=1
Reactant: CC1(C)CCCNC1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Solvent: ClCCl
Product: CC1(C)CCCN(Cc2ccc([C@H](c3ccc(Cl)cc3)N3CC(=C(c4cc(F)cc(F)c4)S(C)(=O)=O)C3)cc2)C1
Yield: 69.5 %

Procedure:
The operation is carried out as described in Example 87, starting. with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm3 of dichloromethane and 0.025 g of 3,3-dimethylpiperidine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm3 of dichloromethane and then eluting with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.040 g of 1-{(R*)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 0.94 (s, 6H), 1.21 (mt, 2H), from 1.50 to 1.65 (mt, 2H), 1.99 (broad s, 2H), 2.27 (unresolved complex, 2H), 2.81 (s, 3H), 3.36 (s, 2H), 3.85 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.O>CN(C=O)C>[CH:15]1([NH:18][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: Clc1ccncc1
Reactant: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: c1cc(NC2CC2)ccn1

Procedure:
To a magnetically stirred, 25° C. solution of 2.3 g (0.006 mol) of product of Step A and 0.71 g (0.007 mol) of triethylamine in 40 ml of DMF was added dropwise 0.38 g (0.007 mol) of cyclopropylamine. After 18 hours the reaction mixture was poured into H2O and extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4). The dry ether phase was concentrated in vacuo to 1.95 g of a brown solid. The crude was recrystallized from hexane/EtOAc affording 1.2 g (50%) of product as a beige solid; mp 111°-112° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:14]2[CH2:17][CH2:16][CH2:15]2)=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].C(=O)([O-])[O-:19].[K+].[K+].OO.OP(O)(O)=O>[Cl-].[Na+].O.CS(C)=O>[C:1]([C:3]1[C:4]([CH:14]2[CH2:15][CH2:16][CH2:17]2)=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:19])[NH2:2]
Reactant: COC(=O)c1cc(C#N)c(C2CCC2)cc1C
Reactant: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: OO
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(C(N)=O)c(C2CCC2)cc1C
Yield: 54.7 %

Procedure:
To an 8-mL vial was added methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (152.4, 100 mg, 0.436 mmol, 1.0 equiv), potassium carbonate (181 mg, 1.31 mmol, 3.0 equiv) and DMSO (2.2 mL) and stirring was initiated. Hydrogen peroxide (50 wt %) (176 μL, 3.05 mmol, 7.0 equiv) was added over about 1 minute. The mixture was stirred at room temperature for 29 hours then diluted into brine (10 mL) plus 1 M H3PO4 (1.5 mL). The mixture was extracted with ethyl acetate (10 mL×1, 3 mL×1). The combined organic layers were washed with brine (10 mL) plus a few drops of 1 M H3PO4 followed by a mixture of water (10 mL) plus saturated NaHCO3 (1 mL) and finally brine (5 mL). The organics was dried (Na2SO4), filtered and evaporated to obtain the title compound as a white solid (59 mg, 55%). m/z (ES+) 248.0 (M+H)+.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH:34]([OH:38])[CH:35]([CH3:37])[CH3:36])[CH2:29][CH2:28]1>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH2:29][CH2:28]1
Reactant: CC(C)C(O)CC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)C(=O)CC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C
Yield: 65 %

Procedure:
Pyridinium dichromate (4.0 g, 10.63 mmol) was added to a solution of 1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropanol (0.5 g, 1.5 mmol) in dimethylformamide (25 ml) at 0° C. The resulting solution was stirred at 0° C. until the starting material was consumed and then quenched with water, basified with 2N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over sodium sulfate. The residue was purified on silica gel with 25% acetone, 25% dichloromethane in hexanes to give 1-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-3-methyl-2-butanone (0.32 g) as an oil.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1N=C[N:12](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CCOC(C)=O>[CH:1]1([C:7]([NH2:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 111.8 %

Procedure:
A solution of cyclohexanecarboxylic acid (1.00 g, 7.80 mmol) in EtOAc (10 mL) was treated with CDI (1.581 g, 9.75 mmol), stirred at RT for 20 minutes, treated with ammonium hydroxide (5.00 mL, 70.0 mmol) and stirred for 20 minutes. The mixture was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford cyclohexanecarboxamide (1.109 g, 112%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 5.61 (s, 2H), 2.13 (m, 1H), 1.89 (m, 2H), 1.78 (m, 2H), 1.66 (m, 1H), 1.42 (m, 2H), 1.24 (m, 3H).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].C(O)(=O)C.[CH3:35][NH2:36].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:36][CH3:35])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNC)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (70 mg, 0.16 mmol; Example 91, Step C) and acetic acid (271 μL, 4.73 mmol) in ClCH2CH2Cl (2.6 mL) was added 2 M methylamine in THF (788 μL, 1.58 mmol) and sodium triacetoxyborohydride (100 mg, 0.47 mmol) at rt. After being stirred at rt for 3 h, the reaction was quenched (sat aq. NaHCO3), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the crude title compound as a pale yellow film. The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=2[F:30])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([NH2:20])=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C=O.[OH-].[Na+].[C:35](OCC)(=[O:37])C>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=2[F:30])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([NH:20][CH2:35][OH:37])=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 17 h
Yield: 56 %

Procedure:
To a solution of 5-[[(4-chlorophenyl)sulfonyl](2,3,6-trifluorophenyl)methyl]-4-methylpyridine-2-carboxamide (190 mg, 0.418 mmol) in ethylene glycol dimethyl ether (4 ml), an aqueous solution of formaldehyde (37%, 94.2 μl) and 1 N aqueous sodium hydroxide (21.0 μl) were added at room temperature, and the mixture was stirred for 17 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous ammonium chloride. Subsequently, 1 N hydrochloric acid was added to the organic layer, and the mixture was stirred for 1 hour. After the organic layer was separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of ethyl acetate and diethyl ether, and then was collected by filtration, to obtain the title compound (113 mg, 0.233 mmol, 56%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:7][CH2:6]1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl.C(#N)C>[CH3:1][N:2]([CH3:33])[C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:15][CH2:16][N:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:18][CH2:19]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CCC2(CCN(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)c2ccccc21
Solvent: ClCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)N1CCC2(CCN(C3CCNCC3)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The tert-butyl 4-(1′-(dimethylcarbamoyl)-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline]-1-yl)piperidine-1-carboxylate 2ad (1.34 g, 2.93 mmol) was dissolved in 40 mL anhydrous dichloromethane and cooled to 0° C. The rapidly stirring solution was treated with TFA (20 mL) and allowed to come to room temperature over 2 hours. The reaction was diluted with ˜20 mL acetonitrile and concentrated to an oil. The oil was brought up in 100 mL 1.0 N HCL and washed with diethyl ether (3×30 mL). The aqueous solution was then basified with 5 N NaOH and the product extracted into dichloromethane (3×50 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to yield N,N-dimethyl-1-(piperidin-4-yl)-2′,3′-dihydrospiro[piperidine-4,4′-quinoline]-1′-carboxamide 2ae as a colorless oil. LC/MS (10-99% CH3CN/0.05% TFA gradient over 5 min): m/z 357.2, retention time 0.78 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J=7.8 Hz, 1H), 7.06 (t, J=7.3 Hz, 1H), 6.90 (t, J=7.5 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 3.40 (t, J=5.8 Hz, 2H), 3.13 (d, J=12.4 Hz, 2H), 2.77 (s, 6H), 2.71-2.61 (m, 5H), 2.42 (t, J=10.8 Hz, 3H), 1.92 (t, J=10.7 Hz, 2H), 1.86-1.78 (m, 5H), 1.58-1.45 (m, 4H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@:5]1([CH3:16])[O:9][C:8]2=[N:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][N:7]2[CH2:6]1.Cl[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>CN(C=O)C>[CH3:16][C@@:5]1([CH2:4][O:3][C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[O:9][C:8]2=[N:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][N:7]2[CH2:6]1
Reactant: Clc1nc2ccccc2o1
Reactant: C[C@]1(CO)Cn2cc([N+](=O)[O-])nc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COc2nc3ccccc3o2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
Sodium hydride (0.1 g, 2.4 mmol) was added to a solution of (R)-2-hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 37 (0.40 g, 2.0 mmol) in DMF (4 ml) followed by stirring for 30 minutes with cooling on ice-bath. To the reaction mixture, 2-chlorobenzoxazole (0.38 g, 2.4 mmol) in DMF (4 ml) was added with cooling on ice-bath followed by stirring at room temperature for 48 hours. Ice-water was added to the reaction mixture. The precipitates were filtered off, washed with water, and then recrystallized from acetonitrile-isopropanol to afford (R)-2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)benzoxazole (0.15 g, yield 24%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[F-].[Cs+].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=1)=[O:15]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1C1C=CC=C(C)C=1.O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH3:13])=[CH:17][CH:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cccc(-c2cc(C)ccc2C)c1
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2cccc(C)c2)cc1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
An oven dried resealable Schlenk tube was purged with argon and charged with palladium acetate (4.4 mg, 0.02 mmol, 2 mol %), ligand 2 [Example 1] (11.9 mg, 0.03 mmol, 3 mol %), 3-methylphenylboronic acid (204 mg, 1.5 mmol), and cesium fluoride (456 mg, 3.0 mmol). The tube was purged with argon, and dioxane (3 mL), and 4-chloroacetophenone (0.13 mL, 1.0 mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (20 mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20 mL), and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was then purified by flash chromatography on silica gel to give 195 mg (93%) of a white solid.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[C:24]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=23)=[O:10])=[O:27])[N:25]=1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Reactant: Cc1ccc(-c2sc(C)nc2C(=O)O)cc1
Product: Cc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)cc1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-methyl-5-p-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.89 min; [M+H]+=472.1.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[F:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[NH:18][C:19]1[CH:20]=[C:21]2[C:25]3=[C:26]([CH2:28][O:29][CH2:30][CH2:31][N:24]3[C@H:23]3[CH2:32][CH2:33][NH:34][CH2:35][C@@H:22]23)[CH:27]=1>>[F:7][C:8]1[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[NH:18][C:19]1[CH:20]=[C:21]2[C:25]3=[C:26]([CH2:28][O:29][CH2:30][CH2:31][N:24]3[C@H:23]3[CH2:32][CH2:33][N:34]([CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5])[CH2:35][C@@H:22]23)[CH:27]=1
Reactant: CC(C)=CCBr
Reactant: Fc1c(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)cccc1C(F)(F)F
Product: CC(C)=CCN1CC[C@H]2[C@@H](C1)c1cc(Nc3cccc(C(F)(F)F)c3F)cc3c1N2CCOC3

Procedure:
Using 4-bromo-2-methyl-2-butene and following the procedures described in EXAMPLE 144, (7bR,11aS)-N-[2-fluoro-3-(trifluoromethyl)phenyl]-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-amine free base from EXAMPLE 95 was converted into the title compound of EXAMPLE 146. 1H NMR(CDCl3) δ: 7.22-7.15 (m, 1H), 7.07-6.95 (m, 2H), 6.93 (d, 1H, J=1.9 Hz), 6.79 (d, 1H, J=2.2 Hz), 5.80 (broad s, 1H), 5.36 (t, 1H, J=7.5 Hz), 4.64 (ABq, 2H, JAB=14.3 Hz), 4.27 (app d, 1H, J=13.2 Hz), 3.85-3.70 (m, 2H), 3.54 (d, 1H, J=7.3 Hz), 3.45-3.35 (m, 3H), 3.22 (dd, 1H, J=12.8, 1.4 Hz), 2.92-2.78 (m, 2H), 2.61-2.45 (m, 1H), 2.28 (t, 1H, J=7.9 Hz), 2.18-2.12 (m, 1H), 1.81 (s, 3H), 1.67 (s, 3H). LRMS (ES)+: 476.4 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23](O)=[O:24])=[CH:17]2)=[CH:11][CH:10]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.C1COCC1>[C:9]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]([NH:1][CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)=[O:24])=[CH:17]2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(=O)n(Cc2ccc(-c3ccccc3)cc2)c1
Reactant: NCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCCC1)c1ccc(=O)n(Cc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.4 %

Procedure:
To a solution of 1-(2-aminoethyl)pyrrolidine (230 mg) in acetonitrile (5 ml)/THF (10 ml) were added 1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid (500 mg), WSC (380 mg), HOBt (260 mg), and triethylamine (0.7 ml) at room temperature. After stirring at room temperature for 12 hr, the reaction mixture was diluted with 5% aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried, and the solvent was removed in vacuo. The residue was purified by alumina column chromatography (eluent; THF) and recrystallized from ethyl acetate/diisopropylether to obtain the titled compound (450 mg).