Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:3])C.[C:4]1([S:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:36]=[CH:37][C:38]=2[N+:39]([O-])=O)[O:21][CH:22]([CH3:35])COS(C2C=CC(C)=CC=2)(=O)=O)(=[O:16])=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[CH2:42]1[CH2:46]O[CH2:44][CH2:43]1>[Pd]>[NH2:39][C:38]1[CH:37]=[CH:36][C:20]([O:21][CH2:22][CH2:35][CH2:1][O:3][S:14]([C:42]2[CH:46]=[CH:5][C:4]([CH3:13])=[CH:44][CH:43]=2)(=[O:16])=[O:15])=[CH:19][C:18]=1[CH2:17][S:14]([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:15])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)Oc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1
Reactant: CCO
Reactant: C1CCOC1
Agent: [Pd]
Product: Cc1ccc(S(=O)(=O)OCCCOc2ccc(N)c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1
Reaction time: 2 h
Yield: 84.4 %

Procedure:
Ethanol (30 mL) and 10% palladium on carbon (0.439 g) were added to a hot solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-propyl ester (0.785 g, 1.41 mmol) in hot, anhydrous THF (40 mL). The reaction mixture was hydrogenated on the Parr apparatus for 2 hours (starting pressure of 43 psi). The reaction mixture was then filtered over Celite and concentrated. It was dried at 75° C. in vacuo for 20 minutes to yield toluene-4-sulfonic acid 3-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-propyl ester as a brown-green semi-solid (0.627 g, 84.4%). Mass Spectrum (+EI, [M+H]+) m/z 526.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[N:16]([CH3:17])[N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[N:30][CH:31]=1>CN(C)C=O>[CH3:17][N:16]1[C:12]([C:10]([NH:9][C:4]2[CH:3]=[C:2]([O:1][C:26]3[CH:31]=[N:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[O:11])=[CH:13][C:14]([CH3:18])=[N:15]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Cc1cc(O)cc(NC(=O)c2cc(C)nn2C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc([N+](=O)[O-])nc2)c1
Yield: 64.9 %

Procedure:
In the same manner as in Reference Example 12 and using N-(3-hydroxy-5-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (8.30 g, 33.8 mmol), cesium carbonate (16.5 g, 50.8 mmol), 5-bromo-2-nitropyridine (6.54 g, 32.2 mmol) and N,N-dimethylformamide (40 mL) as starting materials, the title compound (7.68 g, 54%) was obtained as a pale-yellow oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[C:12]([O:21][C:22]2[CH:23]=[N:24][C:25]([O:29][C@@H:30]([CH3:35])[C:31]([F:34])([F:33])[F:32])=[C:26]([Cl:28])[CH:27]=2)=[CH:13][C:14]([F:20])=[C:15]([CH:19]=1)[C:16](O)=[O:17].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:60][S:61]([NH2:64])(=[O:63])=[O:62]>ClCCl>[Cl:10][C:11]1[C:12]([O:21][C:22]2[CH:23]=[N:24][C:25]([O:29][C@@H:30]([CH3:35])[C:31]([F:34])([F:33])[F:32])=[C:26]([Cl:28])[CH:27]=2)=[CH:13][C:14]([F:20])=[C:15]([CH:19]=1)[C:16]([NH:64][S:61]([CH3:60])(=[O:63])=[O:62])=[O:17]
Reactant: CS(N)(=O)=O
Reactant: C[C@H](Oc1ncc(Oc2cc(F)c(C(=O)O)cc2Cl)cc1Cl)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ncc(Oc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
Diisopropylethyl amine (11.7 mL, 66.8 mmol) was added to a solution of (S)-5-chloro-4-((5-chloro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)oxy)-2-fluorobenzoic acid (Preparation 299, 6.9 g, 16.7 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (9.5 g, 25.1 mmol) and methylsulfonamide (2.4 g, 25.1 mmol) in dichloromethane (125 mL). The reaction mixture was stirred at room temperature for 20 hours, then quenched with an aqueous solution of hydrogen chloride (2M, 50 mL). Organics were removed in vacuo and the aqueous residue was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude compound was purified by silica gel chromatography, eluting with dichloromethane:methanol (from 100:0 to 96:4), followed by reverse phase chromatography, eluting with acetonitrile:water (from 5:95 to 95:5) to provide the title compound as a white solid (4.8 g, 56%).
Reaction SMILES: [O:1]1CCC[CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([O:13]C(=O)C)[CH:10]=[CH:9]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].C(=O)(O)[O-]>C(O)C.C(Cl)(Cl)Cl>[C:2]([O:7][C@@H:8]1[CH2:12][C@H:11]([OH:13])[CH:10]=[CH:9]1)(=[O:1])[CH3:3]
Reactant: CC(=O)O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H]1C=C[C@@H](O)C1
Yield: 74.5 %

Procedure:
Dissolve (-)-acetic acid cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enyl ester (192 mg, 0.85 mmol, prepared in example 11) in ethanol (1.5 mL) and treat with p-toluenesulfonic acid (11.7 mg). Stir the reaction at room temperature for 2 hours. Add carbonate or bicarbonate to neutralize the reaction mixture and concentrate under vacuum. Purify the residue by chromatography (silica gel, 3 g, 1.5×3 cm column, 33% ethyl acetate/hexane, 80 mL), to provide the title compound (90 mg, 75% yield, 91% ee), [α]20 D =-66.1°, (c=0.63, chloroform).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:22])([C:14]([NH:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:6][CH2:5]2.[O:24]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:24][C:7]([CH3:22])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:23])[C:14]([NH:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCC(C)C)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCC(C)C)=C(C)C1=O
Yield: 95.5 %

Procedure:
Oxidation as described in protocol B, using 101 mg (0.316 mmol) of 6-hydroxy-N-isopentyl-2,5,7,8-tetramethylchroman-2-carboxamide and 380 mg CAN (0.694 mmol) yielded 101.2 mg of 2-hydroxy-N-isopentyl-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[C:7]([F:13])[CH:6]=2.[Cl:14][C:15]([Cl:21])([Cl:20])[C:16](=[NH:19])[O:17]C.[CH2:22]([OH:24])[CH3:23]>C(O)(=O)C>[C:16]([OH:17])(=[O:24])[CH3:15].[C:22]([OH:17])(=[O:24])[CH3:23].[NH2:12][C:11]1[C:10]2[C:5](=[CH:6][C:7]([F:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:16](=[NH:19])[C:15]([Cl:21])([Cl:20])[Cl:14]
Reactant: Nc1cnc2cc(F)ccc2c1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: CCO
Solvent: CC(=O)O
Product: N=C(Nc1cnc2cc(F)ccc2c1N)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 1.77 g of 3,4-diamino-7-fluoro-quinoline (V-4) in 20 ml of acetic acid was added 1.94 g of methyl trichloroacetimidate and the mixture was stirred for two hours at room temperature. After concentration under reduced pressure, 10 ml of ethyl acetate was added to the residue, and the mixture was allowed to stand overnight. The crystals precipitated were collected by filtration and washed with ethyl acetate and then a small quantity of ethanol to give 3.75 g (yield: 87%) of the titled compound (VIII-1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:21][CH3:22]>CC(C)=O>[CH2:21]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)[CH3:22]
Reactant: Ic1ccc(N2CCNCC2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCN(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 84.9 %

Procedure:
To a stirred mixture of 1-(4-iodophenyl)piperazine (5.76 g, 20 mmol) and K2CO3 (5.44 g, 40 mmol) in acetone (200 mL) was added iodoethane (2.58 mL, 32 mmol) dropwise over 1 min. After addition, the resulting mixture was stirred at rt for 21 h. The resulting precipitate was filtered off and rinsed with EtOAc (2×60 mL). The filtrate was concentrated to dryness to give a whiteish yellow solid. Trituration with MeOH (10 mL) and H2O (250 mL), followed by suction filtration (rinsed with H2O) gave the title compound as a yellow solid (5.37 g, 85%) after drying. 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=7.6 Hz, 2H), 6.76 (d, J=8.0 Hz, 2H), 3.13-3.07 (m, 4H), 2.48-2.43 (m, 4H), 2.34 (q, J=7.2 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H); MS ESI 317.0 [M+H]+, calcd. for [C12H17IN2+H]+ 317.0.
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=[O:5].[C:16]([O:19][C:20](=O)C)(=O)C>>[F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[CH:9][C:3]=1[C:4]([C:6](=[CH:16][O:19][CH3:20])[C:7]#[N:8])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: N#CCC(=O)c1cc(F)c(F)c(F)c1F
Product: COC=C(C#N)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 150 °C
Yield: 95.3 %

Procedure:
A mixture of 16 g of 2,3,4,5-tetrafluorobenzoylacetonitrile, 15.6 g of trimethyl o-iformate and 18.8 g of acetic anhydride is heated at 150° C. (bath temperature) for 3 hours. The solvent mixture is distilled off completely under a waterpump vacuum and finally under a high vacuum, at a bath temperature of 120° C. 18.2 g of 2-(2,3,4,5-tetrafluorobenzoyl)-3-methoxy-acrylonitrile are obtained as a dark brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1B1OC(C)(C)C(C)(C)O1)[C:5]#[N:6].Br[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=1)[C:5]#[N:6]
Reactant: CC1(C)OB(c2ccc(C#N)cc2F)OC1(C)C
Reactant: Cc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(C#N)cc2F)ccn1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (14.0 g), 4-bromo-2-methylpyridine (5.84 mL), tetrakis(triphenylphosphine)palladium(0) (5.24 g) and 2N aqueous sodium carbonate solution (91 mL) in 1,2-dimethoxyethane (20 mL) was stirred at 80° C. for 30 min under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was separated, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.41 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[Br:16]C1C=C(CC(OCC)=O)C=CC=1>>[Br:16][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:2]=1
Reactant: CCOC(=O)CCCc1ccc(Br)cc1
Reactant: CCOC(=O)Cc1cccc(Br)c1
Product: CCOC(=O)CCCc1cccc(Br)c1

Procedure:
Employing the same general multistep preparation as for ethyl 4-(4-bromophenyl)butanoate (Compound C), 60 g (246 mmol) of ethyl (3-bromophenyl)acetate (Compound B) was converted into the title compound (oil) using 255 ml (255 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M in hexane), 85.8 g (250 mmol) of (carbethoxymethylene) triphenylphosphorane and 1.7 g of 10% Pd/C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]12[CH2:33][C:30]([CH2:34]O)([CH2:31][CH2:32]1)[CH2:29][CH2:28][CH2:27]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:26]12[CH2:33][C:30]([CH2:34][O:12][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[O:13])([CH2:31][CH2:32]1)[CH2:29][CH2:28][CH2:27]2
Reactant: OCC12CCCN(CC1)C2
Reactant: Cn1cc(C(=O)O)c2ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1cc(C(=O)OCC23CCCN(CC2)C3)c2ccccc21
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of 1-methyl-1H-indole-3-carboxylic acid (1.75 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.79 g, 11 mmol), stirred for one hour, and degassed under a stream of nitrogen over 10 minutes. Meanwhile a cooled (-10° C.) solution of 1-azabicyclo[3.2.1]octane-5-methanol (1.55 g, 11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5 N n-butyllithium/hexane (10.5 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The suspension of the acid/1,1'-carbonyldiimidazole adduct was transferred into this solution, and the mixture was stirred 18 hours at room temperature and 4 hours at 55° C., and concentrated in vacuo. The residue was partitioned between toluene (150 mL) containing some 2-propanol and saturated aqueous sodium carbonate (100 mL). The organic layer was separated and the aqueous solution was extracted with toluene (2×100 mL) containing some 2-propanol. The combined organic solution was dried (Na2SO4), concentrated in vacuo, and filtered through alumina (eluted with 20% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, triturated with petroleum ethers (30°-60°), and recrystallized from ether/petroleum ethers (2 crops) to afford 1.72 g (58%) of colorless solid; mp 94.5°-96.5° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:8][CH2:7]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:3]([CH3:2])[CH2:4][CH2:5][C@H:6]2[CH2:11][CH2:10][C@H:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:8][CH2:7]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CNCC[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Agent: Cl
Product: CN(CC[C@H]1CC[C@H](COS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 11.15, trans-methanesulfonic acid 4-(2-methylamino-ethyl)-cyclohexylmethyl ester HCl salt was reacted with 4-chloro-benzene sulphonyl chloride to yield trans-methanesulfonic acid 4-{2-[(4-chloro-benzenesulfonyl)-methyl-amino]-ethyl}-cyclohexylmethyl ester as colorless viscous oil, MS: 424 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][C:4]=1[F:19])[CH3:2].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:22])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][C:4]=1[F:19])[CH3:2]
Reactant: CCc1ccc(C2CNCC(C(=O)OC)C2)cc1F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cc1F

Procedure:
According to General Method 3A, 1.5 g (4.8 mmol) of methyl 5-(4-ethyl-3-fluorophenyl)piperidine-3-carboxylate and 1.3 g (6.3 mmol) of 4-nitrophenyl chloroformate were reacted. Yield: 2.1 g (92% of theory)
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[C:31](Cl)(Cl)=[O:32].[NH2:35][OH:36].Cl>C1(C)C=CC=CC=1.C(Cl)Cl>[OH:36][NH:35][C:31]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)=[O:32]
Reactant: O=C(Cl)Cl
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)NO)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a 0° C. solution of COMPOUND 249 (144 mg, 0.465 mmol) in toluene (20 mL) and Et3N (0.40 mL, 3.34 mmol) was added phosgene solution in toluene (20 wt %, 0.317 mL, 0.697 mmol). The mixture was stirred at 0° C. for 3 hours, was then warmed up to room temperature and solvent was removed under reduced pressure (high vac.) to yield a yellow solid. The solid was dissolved in CH2Cl2 (15 mL) and Et3N (0.194 mL, 1.40 mmol) was added followed by NH2OH.HCl (48 mg, 0.700 mmol). The mixture was stirred at room temperature for 17 hours. Solvent was removed under reduced pressure and the residue was purified by radial chromatography on silica gel (9:1:0.2 CH2Cl2:MeOH:NH4OH) to provide COMPOUND 324 as white solid (112 mg, 60%). 1H NMR (CDCl3) δ 1.61-1.73 (m, 3H), 1.92-2.00 (m, 2H), 2.08 (s, 6H), 2.65-2.72 (m, 3H), 3.81 (s, 4H), 4.01-4.06 (m, 2H), 6.72 (br s, 1H), 7.09 (dd, 2H, J=4.8, 7.8 Hz), 7.37 (d, 2H, J=7.8 Hz), 8.34 (d, 2H, J=4.8 Hz); 13C NMR (CDCl3) δ 18.0, 26.9, 43.8, 54.6, 57.3, 122.5, 133.4, 138.1, 145.9, 157.0, 160.7; ES-MS m/z 370 (M+H). Anal. Calcd. for C20H27N5O2.0.4 CH2Cl2: C, 60.73; H, 6.95; N, 17.36. Found: C, 61.07; H, 7.19; N, 17.09.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@H:11]([C:18]([O:20]CC)=[O:19])[N:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P([O-])([O-])([O-])=O>[CH2:1]([N:8]1[C@@H:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:11]([C:18]([OH:20])=[O:19])[N:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1[C@H](C(=O)OCC)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: CCOC(=O)[C@H]1[C@@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Yield: 85.9 %

Procedure:
A suspension of diethyl cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylate (500 mg) in 0.1M phosphate buffer (pH 8.0, 50 ml) was treated with Pig Liver Esterase (manufactured by Sigma Lab., 1600 units, 10 mg) in a manner similar to that in Example 1 (1) to give (4S,5R)-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (400 mg). M.P., 108°-112° C. [α]D20 =+4.4° (c=1, CHCl3).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5](C(O)=O)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1C(O)=O.NCCO>O>[CH3:1][N:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[C:6]1[CH3:7]
Reactant: Cc1c(C(=O)O)c(-c2ccccc2)c(C(=O)O)n1C
Solvent: NCCO
Solvent: O
Product: Cc1cc(-c2ccccc2)cn1C
Temperature: 175 °C
Yield: 77.4 %

Procedure:
A suspension of 1,5-dimethyl-3-phenyl-pyrrole-2,4-dicarboxylic acid (60 g, 0.23 mol) and 2-aminoethanol (300 mL) was heated to 175° C. under a nitrogen atmosphere for 30 min. The mixture was allowed to cool to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed successively with water (3×100 mL) and brine (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo at a temperature below 40° C. to afford the crude product. Flash column chromatography over neutral alumina using 5% ethyl acetate in petroleum ether as eluent afforded 1,2-dimethyl-4-phenyl-pyrrole (30.5 g, 78%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][C:15](=[O:20])[N:16]3[CH3:19])=[CH:11][CH:10]=2)=[O:7])=[C:4]([NH:23][CH2:24][CH2:25][OH:26])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>O1CCCC1>[CH3:36][S:37]([O:26][CH2:25][CH2:24][NH:23][C:4]1[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=1[C:6](=[O:7])[NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:20])[N:16]2[CH3:19])=[CH:11][CH:10]=1)(=[O:39])=[O:38]
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCO)cc21
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCOS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Chloro-2-[(2-hydroxyethyl)amino]-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)benzamide was dissolved in tetrahydrofuran, diisopropylethylamine and methanesulfonyl chloride were added, followed by stirring at room temperature for 3 hours. By post-treating the reaction liquid, 2-({5-chloro-2-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamoyl]phenyl}amino)ethyl methanesulfonate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[OH:30][C:31]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:34]2[CH2:35][CH2:36][C:31]([OH:30])([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:32][CH2:33]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCC(O)(c4ccccc4)CC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 4-hydroxy-4-phenylpiperidine (35 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(4-hydroxy-4-phenylpiperidinomethyl)indol-2-yl]isoindolinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[C:9](=O)[NH:8][C:5]2=[CH:6][CH:7]=1.[BH4-].[Na+].II>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)C(=O)Nc1ccc(Cl)cc12
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(Cl)cc32)C1
Temperature: 0 °C
Yield: 101.7 %

Procedure:
To a stirred solution of tert-butyl 5-chloro-2-oxospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (0.530 g, 1.64 mmol) in UV (5 mL) was added NaBH4 (0.311 g, 8.21 mmol). The reaction was cooled to about −20° C. to −10° C. A solution I2 (0.833 g, 3.28 mmol) in THF (3 mL) was added to the mixture dropwise. The reaction was stirred with warming to about room temperature overnight. The reaction was cooled to about 0° C. and quenched by the addition of saturated NH4Cl, and diluted with DCM. The organics were washed with Na2SO3 and brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography to yield tert-butyl 5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (0.515 g, 100%). LCMS (APCI+) m/z 209, 211 [M+H−Boc]+; Rt=3.67 min.