Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][C:10]3[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][C:15]=3[N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([CH2:7][C:8]2[S:9][C:10]3[CH2:11][NH:12][CH2:13][CH2:14][C:15]=3[N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(CN3CCCCC3)sc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CCN(Cc2nc3c(s2)CNCC3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of tert-butyl 2-(piperidin-1-ylmethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (0.534 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (1 ml) and reaction mixture was stirred at room temperature for 2 h. Solvent was evaporated under reduced pressure and residue was azeotroped twice with dichloromethane and used in the next step.
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5]([C:7]1[N:16]=[C:15]2[N:9]([CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:14]=32)[CH:8]=1)=O.Cl.[CH:24]1([NH:30]N)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:21][C:19]1[N:18]=[CH:17][C:14]2[C:15]3[N:9]([CH2:10][CH2:11][O:12][C:13]=2[CH:20]=1)[CH:8]=[C:7]([C:5]1[N:30]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:2]=[CH:3][N:4]=1)[N:16]=3
Reactant: CN(C)C=NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: NNC1CCCCC1
Agent: Cl
Product: Clc1cc2c(cn1)-c1nc(-c3ncnn3C3CCCCC3)cn1CCO2

Procedure:
Following the procedures of Example 378, 8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-methylideneamide was reacted with cyclohexylhydrazine hydrochloride to give 8-Chloro-2-(2-cyclohexyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (MS (ESI+) 371.2/373.2) which was reacted with L-prolineamide to give 409. MS (ESI+) 449.2.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([CH:10]=[N:11]O)=[CH:8][C:7]2[O:13][CH2:14][O:15][C:6]=2[CH:5]=1)[CH2:2][CH3:3].C(OC(=O)C)(=O)C>O>[CH2:1]([C:4]1[C:9]([C:10]#[N:11])=[CH:8][C:7]2[O:13][CH2:14][O:15][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc2c(cc1C=NO)OCO2
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCc1cc2c(cc1C#N)OCO2
Reaction time: 2 h

Procedure:
62.2 g (0.3 mol) of 6-n-propyl-3,4-methylenedioxybenzaldoxime were stirred with 400 ml of acetic anhydride for 3 hours under reflux, and the reaction solution was cooled and poured into water. It was left to stand for 2 hours and then extracted with toluene, and the organic phase was washed first with water, then with sodium bicarbonate solution and again with water until neutral. After drying over sodium sulphate, the organic phase was concentrated and distilled. 38 g (67% of theory) of boiling point 116° C./3 mm Hg were obtained.
Reaction SMILES: IC.[NH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14](=[O:16])[CH3:15].[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:10][C:8]1[C:7]([O:12][CH3:13])=[CH:6][C:5]([C:14](=[O:16])[CH3:15])=[C:4]([NH:3][CH3:17])[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1cc(OC)c(OC)cc1C(C)=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Iodomethane (14 ml) was added to a stirred mixture of 2'-amino-4',5'-dimethoxyacetophenone (40 g), potassium carbonate (31.2 g) and dry dimethylformamide (200 ml) and the mixture stirred at ambient temperature for 40 hours. The solvent was evaporated under reduced pressure and the residue triturated with dichloromethane (250 ml). The mixture was filtered and the filter bed washed with dichloromethane (50 ml). The combined filtrate and washing were evaporated and the residue purified by flash chromatography on a silica gel column eluted with dichloromethane:industrial methylated spirit (99:1then 49:1) followed by trituration with diethyl ether (400 ml then 100 ml) to give the novel compound 4',5'-dimethoxy-2'-(methylamino)acetophenone, m.p. 121°-123.5°.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:26])[N:9]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][SH:32]>>[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][S:32][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[O:26])=[N:4][CH:3]=1
Reactant: COC(=O)CCS
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCC(C(F)(F)F)CC1
Product: COC(=O)CCSc1cnc(NC(=O)N(C2CCCCC2)C2CCC(C(F)(F)F)CC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(4-trifluoromethyl-cyclohexyl)-urea (Example 204) and 3-mercaptopropionic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH:3]1[NH:7][CH2:6][CH2:5][O:4]1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16](=[S:18])=[S:17].C([O-])(=O)C.[Zn+2:23].C([O-])(=O)C>O>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:1][C:2]([Cl:9])([Cl:8])[CH:3]1[N:7]([C:16]([S-:18])=[S:17])[CH2:6][CH2:5][O:4]1.[Cl:1][C:2]([Cl:9])([Cl:8])[CH:3]1[N:7]([C:16]([S-:18])=[S:17])[CH2:6][CH2:5][O:4]1.[Zn+2:23]
Reactant: S=C=S
Reactant: ClC(Cl)(Cl)C1NCCO1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: c1ccncc1
Product: S=C([S-])N1CCOC1C(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
Thirty and four-tenth grams (0.160 mole) of 2-trichloromethyloxazolidine (preparation described by W. Ruske and I. Hartmann, J. Prakt. Chem. 18, 146 (1962) was dissolved in 480 g. of pyridine. With rapid stirring at room temperature, 14.4 g. (0.184 mole) of carbon disulfide was added dropwise followed by 15.2 g. (0.083 mole) of anhydrous zinc acetate. The reaction mixture was heated 3 hours at 45°- 50°C, cooled to room temperature, and then diluted with 1 liter water; the precipitated product was filtered and dried in vacuo at room temperature to obtain 33.4 g. of the desired pyridine adduct melting at 205°- 207°C (decomp.). A small analytical sample, recrystallized in methanol, sintered at 209°C and melted with decomposition at 212°-214°C. It had the following anaylsis: Found: C, 26.70; H, 2.74; N, 6.30; S, 19.60; Cl, 31.37; Zn, 9.55%. Calcd for C10H10Cl6N2O2S4Zn . C5H5N: C, 26.65; H, 2.22; N, 6.23; S, 18.95 Cl, 31.54; Zn, 9.68%.
Reaction SMILES: [CH:1]12[NH:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[P:18](Cl)(=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl>[CH2:20]([O:19][P:18]([N:7]1[CH:1]2[CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: O=C(OCc1ccccc1)N1CCC2NC2C1
Reactant: CCOP(=O)(Cl)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Reaction time: 24 h
Yield: 21 %

Procedure:
To a solution of benzyl 3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (1.0 equiv.) in DCM (0.26M) was added diethyl phosphorochloridate (1.3 equiv.) and triethyl amine (1.5 equiv.). The reaction was stirred for 24 h, then concentrated to dryness. Added water and ethyl acetate, the organics were extracted, dried with Na2SO4, and concentrated. The crude was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (50% to 100% ethyl acetate) to yield benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate as a clear oil in 21% yield. LCMS (m/z): 369.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([N:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCCCCCCBr
Reactant: COc1cc(NS(=O)(=O)c2ccc(C)cc2)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCN(c1cc(OC)cc(OC)c1)S(=O)(=O)c1ccc(C)cc1
Temperature: 120 °C
Yield: 96.3 %

Procedure:
A mixture of N-(3,5-Dimethoxy-phenyl)-4-methyl-benzenesulfonamide (15.0 g, 48.9 mmol), 1-bromoheptane (9.63 g, 53.8 mmol) and potassium carbonate (17.1 g, 124.2 mmol) in anhydrous DMF (100 mL) was stirred and heated at 120 ° C. for 4 h, and then cooled to room temperature and poured into ice-cold water (400 mL). Diethyl ether (400 mL) was added to extract the product. The ethereal solution was separated and washed with water, brine and dried with Na2SO4. Removal of solvent and drying reagent provided 19.50 g of light yellow liquid, which was treated with small amount of diethyl ether to give 19.10 g (96.4%) of the title compound as a white solid upon cooling.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH2:3]1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCC(N2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3-Dimethyl-6-nitroindoline (0.8 g) was dissolved in CH2Cl2 (50 mL), N-methyl-4-piperidone (1 g) was added to the mixture, followed by 2.5 g NaBH(OAc)3 and glacial AcOH (1 mL). The mixture was stirred at RT overnight. Saturated NaHCO3 solution (50 ml) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCO3 solution and once with brine, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 9:1 EtOAc:MeOH to afford the title compound as an orange oil. MS:290 (M+1). Calc'd. for C16H23N3O2—289.37.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:13]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[N:4]([CH3:13])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccc2c(I)n[nH]c2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-iodo-1H-indazole-6-carbonitrile (2.0 g, 7.43 mmol), t-BuOK (1.2 g, 10.4 mmol) in THF (50 mL), iodomethane (1.2 g, 10.4 mmol) in THF (5 mL) was added dropwise at 0° C. under ice-water bath. The resulting mixture was stirred overnight at room temperature. Two isomers, which are methylated at N-1 and N-2 position respectively, were formed. The excess solvent was removed under reduced pressure, the residue was dissolved in EtOAc (100 mL), washed with brine (2×10 mL), the combined organics were dried over Na2SO4. After removal of drying agent and concentration, the crude mixture (1.6 g) was used in the next step without further purification. MS: (M+H)+=411;
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([CH2:12][NH2:13])[OH:11]>>[OH:11][CH2:10][CH2:12][NH:13][CH2:1][CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:9]
Reactant: c1ccc(C2CO2)cc1
Reactant: NCCO
Product: OCCNCC(O)c1ccccc1
Temperature: 125 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A mixture of styrene oxide (2.40 g, 0.020 mole) and ethanolamine (1.22 g, 0.020 mole) was heated at 125° C. in an oil bath for 2 hr. An NMR analysis showed no styrene oxide remaining. On standing at ambient temperature for 16 hrs, partial solidification occurred. The material was triturated with ethyl acetate, giving a white solid which was collected by filtration and washed with isopropyl ether. A small amount of second crop was obtained from the filtrate for a total of 0.82 g (23%). Recrystallization from ethyl acetate-isopropyl ether gave 0.69 g of a white solid, m.p. 96°-98° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[C:14]([F:22])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[C:14]([F:22])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2c(C)c(Cl)cc(C(C)=O)c2OC)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylate (1.2 g, 3.4 mmol) and 3.75 M sodium hydroxide in water (10 mL, 38 mmol) in methanol (10 mL) was stirred at room temperature overnight. The mixture was neutralized with HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was used directly in next step (704 mg, 61%). LCMS calculated for C17H15ClFO4 (M+H)+: m/z=337.1. found: 337.1.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][NH:18][C:15]=4[N:16]=[CH:17][C:12]3=[CH:11][N:10]=2)[C@H:6]([CH2:21][CH3:22])[CH2:5]1)=[N+]=[N-].[F:23][C:24]([F:32])([F:31])[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28]>CCO.[OH-].[OH-].[Pd+2]>[CH2:21]([C@H:6]1[N:7]([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][NH:18][C:15]=4[N:16]=[CH:17][C:12]3=[CH:11][N:10]=2)[CH2:8][C@@H:4]([NH:1][S:27]([CH2:26][CH2:25][C:24]([F:32])([F:31])[F:23])(=[O:29])=[O:28])[CH2:5]1)[CH3:22]
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: CC[C@@H]1C[C@H](N=[N+]=[N-])CN1c1ncc2cnc3[nH]ccc3n12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC[C@@H]1C[C@H](NS(=O)(=O)CCC(F)(F)F)CN1c1ncc2cnc3[nH]ccc3n12
Yield: 15.7 %

Procedure:
To slurry of palladium hydroxide on carbon (20 mol %, 0.013 g, 0.019 mmol) in EtOH (5 mL) was added a solution of 1-((2R,4S)-4-azido-2-ethylpyrrolidin-1-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.110 g, 0.371 mmol, prepared using E from (2R,4S)-tert-butyl-4-azido-2-ethylpyrrolidine-1-carboxylate (synthesized as described in. J. Med. Chem. 1988, 31, 1598-1611) with HCl, J with Example #5, Step C, OO, D with NaOH) in EtOH (2 mL). The reaction mixture was sparged with hydrogen and an atmosphere of hydrogen was maintained via balloon. After about 2 h the reaction mixture was filtered and concd under reduced pressure The residue was dissolved in DCM (5 mL) and 3,3,3-trifluoropropane-1-sulfonyl chloride (0.080 g, 0.41 mmol, Matrix) was added. After about 15 h additional 3,3,3-trifluoropropane-1-sulfonyl chloride (80 mg, 0.408 mmol, Matrix) was added. After about 2 days the reaction mixture was partitioned between EtOAc (10 mL) and brine (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concd under reduced pressure. The crude product was purified by chromatography on silica gel eluting with EtOAc to provide N-((3S,5R)-5-ethyl-1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)-3,3,3-trifluoropropane-1-sulfonamide (0.025 g, 16%) as a brown solid: LC/MS (Table 1, Method a) Rt=1.81 min; MS m/z: 431 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.S([O-])([O-])(=O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([N:1]2[C:9]3=[N:8][CH:7]=[CH:6][CH:5]=[C:4]3[CH:3]=[CH:2]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cnc2[nH]ccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 7-azaindole (25 g), para-toluenesulfonyl chloride (44.5 g) and a catalytic amount of tetrabutylammoniun sulfate in dry toluene (300 mL) was added sodium hydroxide (160 g in 500 mL of water). The biphasic solution was stirred at ambient temperature for 3 hours then extracted twice with toluene (100 mL). The combined extracts were dried over magnesium sulfate then concentrated under vacuo. The resultant solid was triturated with diethyl ether then dried at 60° C. under vacuo to yield the title compound (39.74 g) as a pale yellow solid, m.p. 136-138° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH2:32][C:33]([N:35]([CH3:43])[C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)=[O:34])[CH3:31]>>[CH3:31][N:30]([CH2:32][C:33]([N:35]([C:36]1[CH:37]=[CH:38][C:39]([NH:42]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:40][CH:41]=1)[CH3:43])=[O:34])[CH3:29]
Reactant: CN(C)CC(=O)N(C)c1ccc(N)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and N-dimethylaminomethylcarbonyl-N-methyl-p-phenylenediamine Rf value: 0.1 (silica gel, methylene chloride/ethanol=10:1) C29H30N4O4
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].C(Cl)Cl.[C:33]1([CH2:39]C=O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Na]>C([O-])([O-])=O.[K+].[K+]>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: O=CCc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)CC1)O2
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (2.0 g, 5.9 mmol, Intermediate 1, hydrochloride salt) in 1 M K2CO3 solution (30 ml) was stirred for 10 minutes, then DCM (3×30 ml) was added to extract the corresponding free base. The organic phase was dried and concentrated to 50 ml, then phenylacetaldehyde (0.79 ml, 7.10 mmol) and sodium triacethoxyborohydride (1.88 g, 8.88 mmol) were subsequently added. The mixture was stirred for 3 h, washed with water, and the pH value was adjusted to 8 with aqueous ammonia. The product was extracted with DCM and the organic solution was dried and concentrated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 99:1 to 97:3) to give (E)-3-{1′-(2-phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (1.72 g) as a light yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH3:10][Mg]Cl>O1CCCC1>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([CH3:10])([OH:9])[CH2:5][CH2:4]1
Reactant: C[Mg]Cl
Reactant: O=C1CCC(CO)CC1
Solvent: C1CCOC1
Product: CC1(O)CCC(CO)CC1
Temperature: 25 °C

Procedure:
4-(Hydroxymethyl)cyclohexanone (800 mg) in tetrahydrofuran (15 mL) was treated with 3 M methylmagnesium chloride in tetrahydrofuran (6.24 mL) at 0° C. The reaction was warmed to room temperature over 2 hours and was quenched with methanol and water. The resulting mixture was concentrated and the residue was suspended in ethyl acetate. The precipitates were filtered off and the filtrate was concentrated. The residue was purified by chromatography, eluting with 0-100% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:27])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:12]=1)[C:5]#[N:6].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>O>[Cl:27][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:12]=1)[C:5]#[N:6]
Reactant: COc1ccc(Oc2c(Cl)cc(C#N)cc2Cl)cc1C(=O)N1CCCCC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#Cc1cc(Cl)c(Oc2ccc(O)c(C(=O)N3CCCCC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,5-Dichloro-4-[4-hydroxy-3-(piperidine-1-carbonyl)-phenoxy]-benzonitrile was prepared from 3,5-dichloro-4-[4-methoxy-3-(piperidine-1-carbonyl)-phenoxy]-benzonitrile according to a procedure analogous to that described in EXAMPLE 2, Step B. Boron tribromide (1M in dichloromethane, 2.0 equiv) was used. After water addition, the mixture was stirred for 30 minutes at RT, then basified with aqueous saturated sodium bicarbonate solution, and extracted with dichloromethane (3×10 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The title product of Step E was used in the next step without purification.) MS (APCI+) Calc.: 390.0, Found: 391.1 (M+1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[OH-].[Na+].O>C(O)C>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:2]2[C:3](=[O:9])[CH:4]3[CH2:7][CH2:8][N:1]2[CH2:6][CH2:5]3)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1CN2CCC1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1C(=Cc2ccc(Cl)cc2)N2CCC1CC2
Reaction time: 48 h
Yield: 79.9 %

Procedure:
A solution of 3-quinuclidinone (54.5 g), 4-chlorobenzaldehyde (84.0 g) and sodium hydroxide (3.50 g) in absolute ethanol (400 cm3) was heated at reflux for 2.5 hours. The mixture was cooled and addition of water (100 cm3) caused the product to precipitate as an orange solid. The precipitate was collected and washed with 1:1 ethanol-water (400 cm3). The mother-liquors were stood for 2 days, after which time further precipitated material was collected. The orange solid was redissolved in dichloromethane (800 cm3) and washed with water (200 cm3). The organic phase was dried (MgSO4), filtered and evaporated to dryness to give the title compound as a bright yellow powder (86.2 g, 76%), mp. 108°-110° C.; δH (360 MHz; CDCl3) 1.99-2.05 (4H, m, 2×NCH2CH2), 2.63 [(1H, quintet, J=2.9, (CH2)2CH], 2.92-3.01 (2H, m, 2×NCH), 3.11-3.19 (2H, m, 2×NCH), 6.95 (1H, s, C=CH), 7.33 (2H, d, J=8.6, 2×ArH o to Cl) and 7.98 (2H, d, J=8.6, 2×ArH m to Cl); m/z (CI+ ; NH3) 248 (M+ +H, 100%).
Reaction SMILES: [C:1]1([S:7]([CH:10]([NH:15][C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[C:11](Cl)(Cl)Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[C:1]1([S:7]([C:10]2[N:15]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[O:17][C:11]=2[NH:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1ccccc1
Reactant: O=C(NC(C(Cl)(Cl)Cl)S(=O)(=O)c1ccccc1)c1cccs1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1nc(-c2cccs2)oc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N(1-Phenylsulfonyl-2,2,2-trichloroethyl)thiophene-2-carboxamide (0.4 g, 1.003 mmol) is dissolved in tetrahydrofuran, mixed with benzylamine (0.428 g, 4.012 mmol) and stirred overnight at room temperature. The resulting precipitate was filtered off with suction and discarded, the mother liquor was concentrated in a rotary evaporator and the residue was crystallized in 15 ml of petroleum ether, filtered off with suction and dried in air.