Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:15]=[CH:16][C:17]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1OCc1ccccc1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CO)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a solution of 3-(benzyloxy)-4-methylbenzoic acid (2.80 g) in THF (10 mL) was added dropwise a 1.0 M solution of borane-THF complex in THF (23 mL) at room temperature over 30 min, and the mixture was stirred for 2 hr. Methanol (20 mL) was added dropwise to the reaction mixture over 20 min, and water was further added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.60 g) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([S:4][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:39])[CH2:6]1)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:45]>C(OCC)(=O)C>[CH2:1]([S:4]([CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[S:11])[C:7](=[O:39])[CH2:6]1)=[O:45])[CH:2]=[CH2:3]
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(OC)cc1)C(=O)C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: C=CCS(=O)C1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(OC)cc1)C(=O)C(C)(C)C
Yield: 62 %

Procedure:
To a solution of 0.35 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-methoxyphenoxy)-3-trimethylacetylthio-propenate in ethyl acetate at -78° C. was added a solution of 0.128 g of 80% m-chloroperoxybenzoic acid in ethyl acetate over 10 minutes. The reaction mixture was washed with saturated sodium bicarbonate solution, was dried over MgSO4 and evaporated in vacuo to dryness. Chromatography over silica gel and elution with ethyl acetate-hexane mixtures afforded 0.223 g of the title compound as a yellow oil (62% of the theoretical yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:31])[CH3:30].CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[CH2:29]([NH:31][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1)[CH3:30]
Reactant: CCN
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: CCNc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 160 °C
Yield: 3.2 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.90 mmol, prepared as described in Example 18) in DMSO (14 ml). Ethylamine (0.021 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Further ethylamine (0.021 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Again, ethylamine (0.021 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 1 h under microwave irradiation. After this time ethylamine (0.021 ml, 0.26 mmol) and DIPEA (0.113 ml) were both added to the mixture and it was heated at 160° C. for 2 h under microwave irradiation. Finally, additional ethylamine (0.021 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 170° C. for 1 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was re-purified by Mass Directed Automated Preparative HPLC (Method E, using Waters Atlantis column 100 mm×19 mm, 5 um). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (3.3 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]1=[O:23].[OH-:24].[Na+]>O1CCOCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH3:12])[C:9]([OH:23])=[O:24])=[CH:17][CH:18]=1
Reactant: [OH-]
Reactant: C[C@H]1[C@@H](CCCc2ccc(Cl)cc2)C(=O)N1OC1CCCCO1
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](NOC1CCCCO1)[C@@H](CCCc1ccc(Cl)cc1)C(=O)O
Temperature: 23 °C
Reaction time: 72 h
Yield: 99 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-(4-chlorophenyl)-1-propyl)-4-methylazetidin-2-one (360 mg, 1.07 mmol) in dioxane (3.2 mL) is added 1 M aqueous sodium hydroxide (1.6 mL). The solution is stirred at 23° C. for 72 h, then extracted with hexanes (20 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 30 mL portions of ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(3-(4-chlorophenyl)-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as an oil (380 mg, 99% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]([NH:13][C:14]1[C:15]([NH:24][CH2:25][CH2:26][OH:27])=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=S.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[N:24]([CH2:25][CH2:26][OH:27])[C:15]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=[CH:23][C:14]=2[N:13]=1
Reactant: COC(=O)c1cccc(NC(=S)Nc2c(C)cc(Cl)cc2Cl)c1NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cccc2nc(Nc3c(C)cc(Cl)cc3Cl)n(CCO)c12
Temperature: 50 °C
Reaction time: 14 h
Yield: 75.7 %

Procedure:
To a solution of methyl 3-{[(2,4-dichloro-6-methylphenyl)carbamothioyl]amino}-2-[(2-hydroxyethyl)amino]benzoate (300 mg, 0.70 mmol) in tetrahydrofuran (7.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (148 mg, 0.77 mmol) and triethylamine (0.108 mL, 0.77 mmol) at room temperature. The mixture was stirred at 50° C. for 14 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give methyl 2-[(2,4-dichloro-6-methylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazole-7-carboxylate (210 mg, 0.53 mmol, 76%) as a pale yellow solid. To a solution of methyl 2-[(2,4-dichloro-6-methylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazole-7-carboxylate (200 mg, 0.507 mmol) and triethylamine (0.28 mL, 3.8 mmol) was added methanesulfonyl chloride (0.079 mL, 1.02 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hr and at room temperature for 14 hr. Then the mixture was warmed to 45° C. and stirred at 45° C. for 8 hr. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-70% ethyl acetate/n-hexane gradient mixture to give the title compound (170 mg, 0.45 mmol, 89%) as colorless crystals.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:23](=[O:25])[CH3:24])=[N:20][C:21]=1[Cl:22]>CN(C=O)C>[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH:10][CH2:15][C:16]1[C:21]([Cl:22])=[N:20][C:19]([C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(=O)c1ccc(CBr)c(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(CNCCC(=O)OC(C)(C)C)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-amino-propionic acid tert-butyl ester hydrochloride (1.5 eq) in DMF is added NaH (3.5 eq). The resulting mixture is stirred at room temperature for 15 minutes and a solution of 1-(5-bromomethyl-6-chloro-pyridin-2-yl)-ethanone (1 eq) in DMF is then added. After stirring for 3 hours, it is partitioned with 20% EtOAc/hexane and H2O. The organic layer is washed with brine and dried. After concentration, 3-[(6-acetyl-2-chloro-pyridin-3-ylmethyl)-amino]-propionic acid tert-butyl ester is isolated by flash column chromatography. MS: (ES+): 313.1 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[O:17]CCCO2)[CH:6]=[C:7](I)[C:8]=1[O:9][CH3:10].C([Li])CCC.[C:23](=[O:25])=[O:24].C(OCC)C>C1COCC1.O>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH:12]=[O:17])=[CH:6][C:7]=1[C:23]([OH:25])=[O:24]
Reactant: COc1cc(C2OCCCO2)cc(I)c1OC
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1cc(C=O)cc(C(=O)O)c1OC
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
2-(3,4-dimethoxy-5-iodophenyl)-1,3-dioxane (42) (FIG. 22) (1.7 g, 4.86 mmole) was dissolved in 40 ml dry THF and cooled to -78° C. under an argon atmosphere. n-butyllithium (4.3 ml of a 1.25M soln.) was added and the reaction was warmed to 0° C. and was stirred at that temperature for an additional 45 minutes. The aryl lithium solution was then poured onto solid carbon dioxide covered with anhydrous diethyl ether. A white precipitate formed immediately. Water was added and the organic solvent subsequently removed in vacuo. The remaining aqueous solution was extracted with ethyl acetate. The organic layer was washed with 5% sodium thiosulfate, water, and then stirred vigorously over an equivolume of 10% HCl overnight. The organic layer was separated and the product extracted into 10% K2CO3. The basic solution was acidified with 10% HCl and the product extracted into chloroform. The organic layer was dried over MgSO4, and concentrated in vacuo to a white solid (0.412 g, 40%). The solid can be recrystallized from hexane/ethyl acetate.
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[CH2:7]([NH:14][CH2:15][C:16]([OH:18])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:19].[CH:20](=O)[CH3:21].CCO>C(Cl)Cl>[ClH:19].[CH2:7]([N:14]([CH:20]([C:5]#[N:6])[CH3:21])[CH2:15][C:16]([OH:18])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: C[Si](C)(C)C#N
Reactant: CC=O
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CC(C#N)N(CC(=O)O)Cc1ccccc1

Procedure:
TMSCN (18.8 mL, 141 mmol) was added cautiosly to a stirred solution of benzylglycine free base (23.3 g 141 mmol—from the HCl salt by partition between EtOAc and brine basified with saturated Na2CO3 solution) and acetaldehyde (7.88 mL, 141 mmol) in CH2Cl2 (50 mL). After 4 h the volatiles were removed in vacuo and the residue was taken up in EtOAc and washed with brine, dried (Na2SO4) and evaporated in vacuo to an oil. The oil was redissolved in EtOAc and 9.9 M HCl in EtOH (15.25 mL, 151 mmol) was added to give a crystalline precipitate which was isolated by filtration, washing with EtOAc and Et2O to give the title compound (18-2):
Reaction SMILES: [C:1]([Cl:5])(=[O:4])[CH2:2][CH3:3].[CH:6](=[O:10])[CH:7](C)[CH3:8].[CH:11](Cl)(Cl)Cl>[Cl-].[Zn+2].[Cl-]>[C:6]([O:4][CH:1]([Cl:5])[CH:2]([CH3:11])[CH3:3])(=[O:10])[CH2:7][CH3:8]
Reactant: CCC(=O)Cl
Reactant: ClC(Cl)Cl
Reactant: CC(C)C=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CCC(=O)OC(Cl)C(C)C
Temperature: 25 °C

Procedure:
To a vigorously stirred, ice-cooled solution of propionyl chloride (1407 g, 14.8 moles) in 3A sieve-dried chloroform (3000 ml) was added zinc chloride (7.4 g) followed by the dropwise addition (exotherm) of isobutyraldehyde (1132 g, 14.8 moles) at such a rate that the temperature was maintained at 25° C. (three hours).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH2:18][C:17]1([C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22]1)[CH2:16][CH2:15]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH2:18][C:17]1([C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22]1)[CH2:16][CH2:15]2)=[O:7]
Reactant: Nc1ccc2c(c1)CCC1(C2)NC(=O)NC1=O
Reactant: O=C(O)c1cccc(Cl)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C1NC(=O)C2(CCc3cc(NC(=O)c4cccc(Cl)c4)ccc3C2)N1

Procedure:
A mixture of 3-chlorobenzoic acid (11 mg, 0.067 mmol), (±)-6′-amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione (described in Intermediate 2) (13 mg, 0.056 mmol), EDC (13 mg, 0.067 mmol), HOBT (10 mg, 0.067 mmol), and N,N-diisopropylethylamine (0.012 mL, 0.067 mmol) was stirred in DMF (0.3 mL) at ambient temperature for 18 h. The crude mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a white solid. MS: m/z=370 (M+1). HRMS: m/z=370.0957; calculated m/z=370.0953 for C19H17ClN3O3.
Reaction SMILES: Br[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[NH2:22][C:23](N)=[S:24].[OH2:26]>CS(C)=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:2]3[S:24][C:23](=[O:26])[NH:22][C:3]3=[O:5])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1
Reactant: O
Reactant: O=C(O)C(Br)Cc1ccc(OCc2ccc(Cl)cc2)cc1
Reactant: NC(N)=S
Solvent: CS(C)=O
Product: O=C1NC(=O)C(Cc2ccc(OCc3ccc(Cl)cc3)cc2)S1
Temperature: 110 °C

Procedure:
In 2 ml of dimethylsulfoxide are dissolved 200 mg of 2-bromo-3-[4-(4-chlorobenzyloxy)phenyl]propionic acid and 100 mg of thiourea and the solution is heated at 110° C. for 3 hours. Then, after 0.5 ml of water is added, the solution is further heated for 5 hours. Then, 10 ml of water is added and the resulting crystals are recovered by filtration and recrystallized from benzene-n-hexane (1:1). By the above procedure is obtained 170 mg of 5-[4-(4-chlorobenzyloxy)benzyl]thiazolidine-2,4-dione.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[CH3:11][CH2:12]O>>[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2[NH:3][C:4]3[C:12]([CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=3[C:5]=2[CH2:4]1
Reactant: CN1CCC(=O)CC1
Reactant: CCO
Agent: Cl
Product: Cc1cccc2c3c([nH]c12)CCN(C)C3
Temperature: 80 °C
Reaction time: 5 h

Procedure:
O-Tolyl hydrazine hydrochloride (1 equiv.) is taken in EtOH. 1-Methylpiperidin-4-one hydrochloride (0.76-1.4 equiv.) and ethanolic HCl is added (pH acidic) and the contents are stirred at 80° C. for 5 h. The reaction is monitored by TLC. After completion of the reaction, the reaction mixture is concentrated. The residue is dissolved in aq NaHCO3 solution and extracted with EtOAc. The organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 2,6-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [C:1]1([P:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[NH:17][CH:16]([CH3:19])[CH2:15][CH2:14]3)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.Cl[SiH](Cl)Cl.[OH-].[Na+]>C(Cl)Cl>[C:20]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[NH:17][CH:16]([CH3:19])[CH2:15][CH2:14]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1CCc2cccc(P(=O)(c3ccccc3)c3ccccc3)c2N1
Agent: Cl[SiH](Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCc2cccc(P(c3ccccc3)c3ccccc3)c2N1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of 8-diphenylphosphinoyl-2-methyl-1,2,3,4-tetrahydroquinoline (6) (1.5 g, 4.5 mmol) in dry degassed toluene (40 mL) was added degassed Et3N (3.15 mL, 22.5 mmol) followed by trichlorosilane (2.25 mL, 22.5 mmol). The mixture was stirred at 80° C. for 30 minutes before cautiously adding 2N NaOH (150 mL) and cooling down to room temperature. Products were then extracted with EtOAc, washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated to give a yellow oil. This oil was taken up in CH2Cl2 (100 mL), and filtered over silica gel (˜25 mL) eluting with further portions of CH2Cl2 (4×100 mL). The combined filtrates were then evaporated to give compound 7 (1.2 g) as a light yellow oil in 80% yield. 1H NMR (400.13 MHz, CDCl3) δ 7.4-7.3 (m, 10H, Ph-H), 6.99 (d, 1H, J=7.2 Hz, C5—H), 6.62 (ddd, 1H, J=7.2, 6.0, 1.2 Hz, C7—H), 6.52 (t, 1H, J=7.6 Hz, C6—H), 4.65 (bs, 1H, N1—H), 3.4-3.3 (m, 1H, C2—H), 2.9-2.7 (m, 2H, C4a/b—H), 2.0-1.9 (m, 1H, C3a—H), 1.6-1.5 (m, 1H, C3b—H), 1.11 (d, 3H, J=6.4 Hz, C1′—CH3) ppm; 13C NMR (100.61 MHz, CDCl3) δ 147.9 (d, J=18.2 Hz), 147.7 (d, J=18.2 Hz), 136.1 (d, J=12.1 Hz), 136.0 (d, J=13.1 Hz), 135.8 (d, J=13.1 Hz), 135.7 (d, J=13.1 Hz), 134.1-133.5 (m), 132.5 (d, J=12.1 Hz), 132.4 (d, J=12.1 Hz), 130.5, (d, J=13.1 Hz), 128.7-128.4 (m), 120.7 (d, J=12.1 Hz), 117.0, (d, J=12.1 Hz), 116.3 (d, J=12.1 Hz), 47.4, 39.6, 26.8, 22.4 ppm; 31P NMR (161.97 MHz, CDCl3) δ −21.9 ppm.
Reaction SMILES: [H][H].[C:3]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4]1>>[C:3]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4]1.[CH:3]([OH:8])([OH:7])[CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Solvent: O=C1CCCO1
Product: CCCC(O)O
Temperature: 160 °C
Reaction time: 6 h

Procedure:
A stainless steel tubular reaction with an O.D. of 1 inch and I.D. 0.93 inches was packed with 70 ml (27 g.) of the catalyst from Example 1 to provide a 7 inch bed length. The catalyst was reduced over a six hour period at 150°-300° C. using hydrogen in nitrogen in increasing concentration of from about 3% to about 10% H2. The hydrogen mixture was introduced intermittently until there was little exotherm, after which the hydrogen concentration was increased to 100%. A feed of γ-Butyrolactone was pumped to a vaporizer from which the vapor was carried by a hydrogen stream to the reaction. The ratio of hydrogen to butyrolactone feed (99% pure) was 150:1. The reactor was maintained at 160° C. temperature, 600 psig. pressure and an LHSV of 0.05 (g. of feed/hour/volume of catalyst). The product vapors were collected and condensed. A conversion of 90% butyrolactone with 95% selectivity to butanediol was obtained.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][NH2:26])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl:27][CH2:28][C:29](Cl)=[O:30].O>C(OCC)(=O)C>[N:8]1([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][NH:26][C:29](=[O:30])[CH2:28][Cl:27])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
0.54 ml of triethylamine was added to a solution of 1.00 g of 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine in 20 ml of ethyl acetate, and the resulting mixture was cooled. 0.31 ml of 2-chloroacetyl chloride were then added to the mixture. The reaction mixture was then stirred at room temperature for 1 hour, after which it was mixed with water, and the aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.94 g (yield 73%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1F)[CH3:2].[CH3:16][S:17]([CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1[N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:23][CH2:24]1)[CH3:2]
Reactant: CS(=O)(=O)CCC1CCNCC1
Reactant: CCOc1cc(F)c(CC)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(CC)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 64 %

Procedure:
To 1-ethyl-4-(ethyloxy)-2-fluoro-5-nitrobenzene (0.19 g, 0.89 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine (Example 101, Step D) (0.20 g, 1.1 mmol), and K2CO3 (0.43 g, 3.1 mmol) was added DMSO (12 mL). The reaction was heated to 100° C. for two days. Reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step B (0.22 g, 0.57 mmol, 65% yield). 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 6.57 (s, 1H), 4.13 (q, J=6.9 Hz, 2H), 3.20 (d, J=11.6 Hz, 2H), 3.00-3.13 (m, 2H), 2.92 (s, 3H), 2.67 (t, J=11.7 Hz, 2H), 2.57 (q, J=7.4 Hz, 2H), 1.77-1.97 (m, 4H), 1.36-1.68 (m, 6H), 1.24 (t, 3H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C([O:9][C:10]1[CH2:13][C:12](=[O:14])[CH:11]=1)(=O)C>C(OCC)(=O)C>[CH2:1]([NH2+:3][CH2:4][CH3:5])[CH3:2].[OH:14][C:12]1[CH2:13][C:10](=[O:9])[CH:11]=1
Reactant: CCNCC
Reactant: CC(=O)OC1=CC(=O)C1
Solvent: CCOC(C)=O
Product: CC[NH2+]CC
Product: O=C1C=C(O)C1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A solution of 3.67 g of diethylamine (99.5 percent; 50.0 mmol) in 10 g of ethyl acetate was instilled in a solution of 3.25 g of 3-acetoxy-2-cyclobuten-1-one (triketene, content, 97 percent; 25.0 mmol) in 40 g of ethyl acetate at 20° C. within 18 minutes. The reaction mixture was stirred for another hour at room temperature, then filtered and dried under vacuum. 3.75 g of the title product with a purity of 94.1 percent (according to HPLC), corresponding to a yield of 89.8 percent, relative to the 3-acetoxy-2-cyclobuten-1-one, was obtained. Data for the title compound was:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]C(C)(C)C)=[O:36].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(Cl)cc5)n4)cc3)c(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(-c2ccc(Cl)cc2)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
Enantiomer 2 of tert-butyl 6-chloro-7-(4-(6-(4-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (10 mg, 0.017 mmol) was diluted with dichloromethane (100 μL) followed by the addition of trifluoroacetic acid (100 μL). After stirring for 2 hours, the reaction was concentrated to yield Enantiomer 2 of 6-chloro-7-(4-(6-(4-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (9.0 mg, 0.017 mmol, 99% yield). MS (apci, positive) m/z=535.1. 1H NMR (400 MHz, CDCl3) δ 9.03 (br s, 1H), 8.35 (d, 1H), 7.96 (d, 2H), 7.90-7.85 (m, 4H), 7.48-7.42 (m, 4H), 7.05 (d, 2H), 6.60 (s, 1H), 4.29-4.23 (m, 2H), 3.82 (t, 1H), 2.36 (dd, 1H), 2.19-2.10 (m, 1H).