Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:14]([CH2:17][S:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[C:30]([OH:32])=O)=[CH:21][CH:20]=1)([OH:16])=[O:15]>ClC(Cl)C>[O:32]=[C:30]1[C:33]2[CH:34]=[C:19]([S:18][CH2:17][C:14]([OH:16])=[O:15])[CH:20]=[CH:21][C:22]=2[O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][C:26]1=2
Reactant: O=C(O)CSc1ccc(OCc2ccsc2C(=O)O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C(O)CSc1ccc2c(c1)C(=O)c1sccc1CO2
Temperature: 60 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
Trifluoroacetic acid anhydride (28.0 mL, 201 mmol) was added to a dichloroethane (300 mL) solution of the compound obtained in Example 20 (29.0 g, 89 mmol), and the mixture was stirred overnight at 60° C. The solvents were distilled off under a reduced pressure, and water was added to the residue. The precipitated crystals were separated by filtration and dried, to give 26.7 g (98%) of the captioned compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5](N)[CH2:4][CH2:3]1.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:9][CH2:8][C:7]2=[C:6]3[C:13](=[CH:12][CH:11]=[CH:10]2)[C:16]2[CH2:17][CH2:18][CH2:19][C:15]=2[N:5]3[CH2:4][CH2:3]1
Reactant: O=C1CCCC1
Reactant: CN1CCc2ccccc2N(N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCc2cccc3c4c(n(c23)CC1)CCC4
Temperature: 25 °C
Yield: 25.7 %

Procedure:
To a solution of 4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (1.55 g, 8.1 mmole) in 1-propanol (100 mL) was added cyclopentanone (5.23 g, 62.3 mmole), followed by p-toluenesulfonic acid monohydrate (3.2 g, 16.8 mmole), and the resulting reaction mixture was refluxed for 40 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate (150 mL), saturated aqueous sodium chloride (150 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 0.50 g of the title compound as a white solid, mp 128-130° C. MS (ESI) m/z 241 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C:11]([OH:25])([CH3:24])[CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:26][C:27]([F:42])([F:41])[C:28]1[CH:40]=[CH:39][C:31]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:30][CH:29]=1.[I-].[Na+].C(N(CC)CC)C>CN(C=O)C.O>[Cl:1][C:2]1[N:3]([CH2:10][C:11]([CH3:24])([OH:25])[CH2:12][N:36]2[CH2:35][CH2:34][CH:33]([O:32][C:31]3[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:41])[F:42])=[CH:40][CH:39]=3)[CH2:38][CH2:37]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(O)Cn2cc([N+](=O)[O-])nc2Cl)cc1
Reactant: FC(F)(F)c1ccc(OC2CCNCC2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)(CN1CCC(Oc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 80 °C
Reaction time: 7 h
Yield: 64.5 %

Procedure:
To a solution of 2-chloro-1-[2-hydroxy-2-methyl-3-(4-methylbenzenesulfonyloxy)propyl]-4-nitroimidazole prepared in Example 5 (0.30 g, 0.77 mmol) and 4-(4-trifluoromethylphenoxy)piperidine (0.21 g, 0.85 mmol) in DMF (6 ml), sodium iodide (0.13 g, 0.77 mmol) and triethylamine (0.12 ml, 0.77 mmol) were added followed by stirring at 80° C. for 7 hours. To the reaction mixture, water was added, and the resulting solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford 1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylphenoxy)piperidin-1-yl]propan-2-ol (0.23 g, yield 63%) as a yellow oil.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:21]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=1)N>>[CH3:29][C:25]1[CH:24]=[C:23]([N:21]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:28]=[CH:27][N:26]=1
Reactant: Cc1cc(NN)ccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: Cc1cc(-n2nccc2-c2nn(-c3ccccc3)ccc2=O)ccn1
Yield: 37 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 4-hydrazino-2-methylpyridine according to the method described for Example 1 in 37% yield. MS: M=330.1 (M+H)+
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][C:12](=[O:20])[C:11]=2[CH:21]=1)[CH3:6])C.C(=O)(O)[O-].[Na+].O>C(O)C>[CH3:19][C:16]([CH:14]1[CH2:13][C:12](=[O:20])[C:11]2[CH:21]=[C:7]([CH:5]([CH3:6])[C:4]([OH:22])=[O:3])[CH:8]=[CH:9][C:10]=2[O:15]1)([CH3:17])[CH3:18]
Reactant: CCOC(=O)C(C)c1ccc2c(c1)C(=O)CC(C(C)(C)C)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)CC(C(C)(C)C)O2

Procedure:
Ethyl-2-[2,3-dihydro-2-(1,1-dimethylethyl)-4-oxo-4H-1-benzopyran-6-yl]propionate (6 g) was dissolved in ethanol (200 ml) and heated to reflux with dilute aqueous sodium bicarbonate solution (50 ml) for eight hours. The reaction mixture was poured into water, acidified and extracted with ether. The combined ethereal extracts were washed with water and dried (MgSO4) and concentrated in vacuo affording a mixture of the desired product and starting material which were separated by chromatography on silica gel using dichloromethane/ether mixtures as eluant. The title compound was recrystallised from petroleum ether (bp 40°-60° C.) as a white solid: 1.4 g, mp 117°-8° C.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>N1C=CC=CC=1>[C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1/[CH:1]=[CH:12]/[C:13]([OH:15])=[O:14])#[N:6]
Reactant: O=C(O)CC(=O)O
Reactant: N#Cc1ccccc1C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: N#Cc1ccccc1/C=C/C(=O)O
Temperature: 0 °C
Yield: 69.9 %

Procedure:
A solution of 2-formylbenzonitrile (4.17 g, 31.8 mmol), malonic acid (7.61 g, 73.1 mmol), and piperidine (0.314 mL, 3.18 mmol) in pyridine (40 mL) was heated to reflux for 2 hr. The solution was cooled and poured into crushed ice (150 mL) and 12N HCl (30 mL). The white precipitate was filtered, washed with water, and air dried to give a tan powder (3.85 g, 70%). 1H NMR (500 MHz, DMSO-d6) δ 12.81 (br. s., 1H), 8.09 (d, J=7.9 Hz, 1H), 7.93 (dd, J=7.8, 0.9 Hz, 1H), 7.80-7.74 (m, 2H), 7.62 (td, J=7.6, 0.9 Hz, 1H), 6.80 (d, J=15.9 Hz, 1H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[CH2:13][CH:12]1[C:27](=[O:30])[NH:28][CH3:29])=O)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:29][NH:28][C:27]([CH:12]1[CH2:13][NH:14][CH2:15][CH2:16][NH:11]1)=[O:30]
Reactant: CNC(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)C1CNCCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 2-methylcarbamoyl-piperazine-1,4-dicarboxylic acid dibenzyl ester from step (b) above (1.64 g, 4.0 mmol) and 10% Pd/C (42 mg, 0.04 mmol, Aldrich) in ethanol (10 mL) was vigorously stirred under hydrogen atmosphere for 4 h at room temperature. The catalyst was filtered through Celite® pad and the filter cake was washed with EtOH. The filtrate was evaporated in vacuo to give the title compound, which was used in the next step without additional purification. MS (ESI, pos. ion) m/e: 144 (M+1).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH3:16])[C:5]1[N:30]([CH2:31][CH:32]([OH:34])[CH3:33])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: CC(O)CN
Reactant: COc1cc2c(cc1OC)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)-c1c(ccn1CC(C)O)C2
Reaction time: 0.5 h
Yield: 39 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-5,6-dimethoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.56 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 0.91 g (40%) of (RS)-1-(1,4-dihydro-6,7-dimethoxy-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol was obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:21]=1
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)COc4ccccc4)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3ccc(NCCOc4ccccc4)cc3)c2cc1OC
Temperature: 0 °C
Yield: 80.1 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenyl}-2-phenoxyacetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-])=O>[Fe]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1Cl
Agent: [Fe]
Product: Nc1cc(Cl)cc(Cl)c1Cl
Yield: 68 %

Procedure:
2,3,5-Trichloro nitrobenzene (D12) was reduced with iron powder as described in Description 7 to give the title compound (D13) (68%), MH+ 196/198.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:12]1([CH2:18][CH2:19][C:20]([N:9]2[CH2:10][CH2:11][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.2 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-phenyl-propionyl chloride (421.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing 3-phenyl-1-(3-phenylpyrrolidin-1-yl)propan-1-one are collected and the solvent is removed in vacuo to give 521 mg of colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (1 g, 5.02 mmol) and tetrahydropyran-4-one (2.5 g, 25 mmol) in methanol (10 mL), acetic acid (0.3 g, 5.02 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.63 g, 10.05 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford methyl 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (0.5 g, 35.5%).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[C:10]1([S:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH2:7]([N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:17])=[CH:19]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(c1ccccc1)c1c[nH]c2ccccc12
Reactant: Cc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=S(c1ccccc1)c1cn(Cc2ccccc2)c2ccccc12

Procedure:
A mixture of toluene (100 ml), 50% sodium hydroxide (20 ml), 3-phenylsulfinylindole (4.27 g, 17.7 mmol) and benzyltrimethylammonium chloride (6.01 g, 26.5 mmol) was vigorously stirred at reflux temperature for 4 hours. The organic phase was separated and combined with an ether extract of the aqueous phase. The extract was dried and evaporated in vacuo giving a solid which on crystallization from dichloromethane-hexane gave the solid product. Chromatography of the mother liquor on silica gel using hexane-ethyl acetate (3:2) as the eluant gave a further quantity of the title compound, m.p. 148°-149° C. identical to the material prepared in Example 8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][CH:6]=[CH:5]2.ClS([N:16]=[C:17]=O)(=O)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][CH:6]=[C:5]2[C:17]#[N:16]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1cc2[nH]ccc2cc1F
Solvent: CN(C)C=O
Product: Cc1cc2[nH]cc(C#N)c2cc1F
Temperature: 25 °C
Yield: 98.7 %

Procedure:
Into a solution of 5-fluoro-6-methyl-1H-indole (1.9 g, 12.8 mmol) in DMF (13 mL) at −78° C. was added chlorosulfonyl isocyanate (1.33 mL, 15.3 mmol). After addition the cooling bath was removed and the mixture was allowed to warm to room temperature. The mixture was then poured into ice water, filtered and washed with water and brine. The cake was then dissolved in acetonitrile and concentrated to give 5-fluoro-6-methyl-1H-indole-3-carbonitrile (2.2 g, 100%).
Reaction SMILES: [CH2:1]([C@@H:7]1[O:11][C:10](C)(C)[O:9][C:8]1=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>CO>[OH:11][C@@H:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([O:9][CH3:10])=[O:14]
Reactant: CCCCCC[C@@H]1OC(C)(C)OC1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCCCCC[C@H](O)C(=O)OC
Yield: 95.7 %

Procedure:
In a 250 mL round bottom flask fitted with a reflux condenser was placed 2.4 g (12 mmol) of (S)-5-hexyl-2,2-dimethyl-1,3-dioxolan-4-one in 150 mL of methanol containing 2 drops of concentrated sulfuric acid. Following heating at reflux for, 6 hours, the reaction mixture was cooled, and 0.5 g of sodium bicarbonate was added. The solvent was evaporated under reduced pressure and the residue dissolved in 200 mL of CH2Cl2. The solution was washed with 2×75 mL of water, 2×100 mL of saturated sodium bicarbonate solution, and 2×75 mL of brine, and dried (Na2SO4). The CH2Cl2 solvent was evaporated under reduced pressure to provide 2.07 g of crude product which was purified over silica gel using ethyl acetate:hexanes (1:5) to furnish 2.0 g (96%) of the title compound as a pale yellow oil: [α]D25 2.9° (C=0.8, CH3OH); IR (neat, cm-1) 3475 (br), 2925, 2857, 1739; 1H NMR (CDCl3) δ 4.19 (m, 1H), 3.79 (s, 3H), 2.73 (d, J=4.8 Hz, 1H), 1.89-1.75 (m, 1H), 1.72-1.56 (m, 1H), 1.55-1.39 (m, 2H), 1.39-1.28 (m,6H), 0.88 (t, J=6.6 Hz, 3H); HRMS calculated for C19H18O3 (M+), 174.1255, found 174.1255.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:5]([C:4]1[CH:8]=[CH:9][C:10]([N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]2[S:27][C:17]3[C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[O:20][CH2:21][CH2:22][C:16]=3[CH:15]=2)=[O:13])=[C:2]([Cl:1])[CH:3]=1)(=[O:6])[NH2:32]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a solution of 3-chloro-4-(N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid, from Example 227, (0.08 g, 0.20 mmol) in 72 mL of THF was added as a whole HATU (0.082 g, 0.22 mmol) and DIEA (0.12 mL, 0.72 mmol). This reaction mixture was allowed to stir at room temperature for 30 minutes. Next, ammonium chloride (0.12 g, 0.22 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was taken into a large volume of ethyl acetate, washed with water, then saline and dried (Na2SO4). The organic was then concentrated in vacuo to give 322 as a solid residue, purified by RP-HPLC. Yield=25% of theoretical. MS: (ESI+)=442.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]2[CH:7]=[C:8]([C:10]3[O:14][N:13]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]5[O:22][C:21]([C:23]6([NH:31]C(=O)OC(C)(C)C)[CH2:28][O:27]C(C)(C)[O:25][CH2:24]6)=[CH:20][C:19]=5[CH:39]=4)[N:11]=3)[O:9][C:5]=2[CH:4]=1.ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC>>[NH2:31][C:23]([C:21]1[O:22][C:18]2[CH:17]=[CH:16][C:15]([C:12]3[N:11]=[C:10]([C:8]4[O:9][C:5]5[CH:4]=[C:3]([O:2][CH3:1])[CH:41]=[CH:40][C:6]=5[CH:7]=4)[O:14][N:13]=3)=[CH:39][C:19]=2[CH:20]=1)([CH2:28][OH:27])[CH2:24][OH:25]
Reactant: COc1ccc2cc(-c3nc(-c4ccc5oc(C6(NC(=O)OC(C)(C)C)COC(C)(C)OC6)cc5c4)no3)oc2c1
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: COc1ccc2cc(-c3nc(-c4ccc5oc(C(N)(CO)CO)cc5c4)no3)oc2c1
Yield: 26 %

Procedure:
When the product of Step F was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 26% yield, as creamy green solid. 1H-NMR (CD3OD) 8.39 (d, 1H, J=1.74 Hz); 8.08 (dd, 1H, J=8.73, 1.89 Hz); 7.68 (b, 1H); 7.63 (d, 1H, J=8.73 Hz); 7.58 (d, 1H, J=8.7 Hz); 7.14 (d, 1H, J=1.8 Hz); 7.03 (s, 1H); 6.92 (dd, 1H, J=8.7, 2.22 Hz); 3.98 (d, 2H, J=11.00 Hz); 3.88 (d, 2H, J=11.01 Hz); 3.85 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].[C:9]([O:13][C:14]([N:16]1C(C2C=CC(C#N)=CC=2)O1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([NH:16][C:14](=[O:15])[O:13][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=1
Reactant: Brc1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nn1cnc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56.8 %

Procedure:
4-Bromo-1H-imidazole (3.2 g, 21.8 mmol) was weighed into a 500 mL round bottomed flask equipped with a magnetic stir bar under a nitrogen atmosphere. Anhydrous N,N-dimethylformamide (DMF, 12 mL) was added and the mixture was placed on ice. After 10 minutes the mixture was treated with sodium hydride (0.840 g, 21.0 mmol 60% dispersion in oil). After 5 minutes, the ice bath was removed and the reaction warmed to room temperature. After 15 minutes of vigorous stirring the ice bath was re-inserted and 3-(4-cyano-phenyl)-oxaziridine-2-carboxylic acid tert-butyl ester (1.92 g, 7.80 mmol) was added. The reaction was vigorously stirred for 5 minutes and the ice bath was removed. After 5 minutes the mixture was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organics were washed with dilute sodium carbonate, dried over sodium sulfate, and concentrated. The residue was purified using silica gel chromatography (0-5% methanol/dichloromethane) to afford the title compound (1.16 g, 4.43 mmol, 57%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 7.36 (d, J=1.5 Hz, 1H), 6.97 (d, J=1.5 Hz, 1H), 1.48 (s, 9H); ESIMS m/z 262 ([M]+), 260 ([M−2]−).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[C:22](=[O:28])[CH:21]=[CH:20]3)[CH:10]=1.[CH3:29]I>>[CH3:29][O:8][CH:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[C:22](=[O:28])[CH:21]=[CH:20]4)[CH:10]=2)[CH2:4]1
Reactant: CC1CCC(O)CC1c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Reactant: CI
Product: COC1CCC(C)C(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)C1
Yield: 60 %

Procedure:
Using an analogous procedure to that described in Example 2, (1RS,3RS,4SR)-4-methyl-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]cyclohexan-1-ol was reacted with methyl iodide to give (1RS,3RS,4SR)-1-methoxy-4-methyl-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]cyclohexane as a foam in 60% yield.