Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[F:23][C:24]([F:30])([F:29])[S:25](Cl)(=[O:27])=[O:26].O>O1CCCC1>[CH3:12][C:11]1[C:2]([O:1][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])=[C:3]([CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Methyl 2-hydroxy-3-methyl-5-nitrobenzoate (Reference Compound No. 1-4-(2), 6.0 g, 28.4 mmol) was dissolved in tetrahydrofuran (200 mL), then triethylamine (16.7 mL, 120 mmol) and trifluorometanesulfonyl chloride (6.23 mL, 58.5 mmol) were added thereto, and then the reaction mixture was stirred at room temperature overnight. Water (500 mL) was added to the reaction mixture, then the whole was extracted with ethyl acetate (500 mL). The organic layer was washed with 0.2N aqueous NaOH solution (200 mL, twice) and saturated brine (200 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (9.32 g) as a pale yellow oil. (Yield 96%)
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.C(=O)([O-])[O-].[K+].[K+].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C)C=O>[F:1][CH:2]([F:5])[CH2:3][N:16]1[C:12](=[O:22])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]1=[O:17]
Reactant: FC(F)CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(F)F
Temperature: 120 °C
Reaction time: 12 h
Yield: 99.6 %

Procedure:
An amount of 54.25 g (0.529 mol) of 2,2-difluoro-1-chloroethane, 9.1 g (0.066 mol) of potassium carbonate and 50 g (0.264 mol) of potassium phthalimide are dissolved in 237 g of N,N-dimethylformamide. The reaction mixture is stirred in an autoclave under pressure at 120° C. for 12 h. After the end of the reaction, cooling is carried out to ambient temperature and the solvent is exhaustively removed under vacuum. The remaining residue is treated with 250 ml of water and the solid is filtered off. The filter residue is washed twice with water and the product is dried under vacuum. An amount of 55.5 g of 2-(2,2-difluoroethyl)-1H-isoindole-1,3(2H)-dione with a purity of 96.5% is obtained. This corresponds to a yield of 95.8% of theory.
Reaction SMILES: CN(C)C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].C([O:21][CH2:22][CH2:23][C:24]1[C:25](=[O:51])[O:26][C:27]2[C:32]([C:33]=1[NH:34][C:35]1[C:40]([Cl:41])=[CH:39][N:38]=[CH:37][C:36]=1[Cl:42])=[CH:31][CH:30]=[C:29]([O:43][CH3:44])[C:28]=2[O:45][CH:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)C1C=CC=CC=1>ClCCl>[CH:46]1([O:45][C:28]2[C:29]([O:43][CH3:44])=[CH:30][CH:31]=[C:32]3[C:27]=2[O:26][C:25](=[O:51])[C:24]([CH2:23][CH2:22][OH:21])=[C:33]3[NH:34][C:35]2[C:36]([Cl:42])=[CH:37][N:38]=[CH:39][C:40]=2[Cl:41])[CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)c(CCOCc3ccccc3)c(=O)oc2c1OC1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)c(CCO)c(=O)oc2c1OC1CCCC1
Temperature: 25 °C

Procedure:
N,N-Dimethylaniline (174 mg, 1.44 mmol) and aluminum trichloride (143 mg, 1.08 mmol) were sequentially added to a solution of 3-(2-(benzyloxy)ethyl)-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (100 mg, 0.18 mmol) and dichloromethane (10 mL). The reaction was refluxed for 8 h, allowed to cool to rt, quenched with cold water (1 mL), and then poured into ice water (20 mL). The mixture was extracted with dichloromethane (15 mL×3), and the combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate:petroleum ether) to give 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-3-(2-hydroxyethyl)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.26 (s, 1H), 8.47 (s, 2H), 6.94 (d, 1H), 6.85 (d, 1H), 5.58 (m, 1H), 4.83 (m, 1H), 3.81 (s, 3H), 3.60 (m, 2H), 2.68 (m, 2H), 1.90-1.50 (m, 8H); MS (ESI): 464.9.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH:19]([S:22](Cl)(=[O:24])=[O:23])([CH3:21])[CH3:20]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:22]([CH:19]([CH3:21])[CH3:20])(=[O:24])=[O:23])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: CC(C)S(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Yield: 39 %

Procedure:
According to the general procedure A, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with isopropylsulfonyl chloride to obtain the desired product. Yield: 39%. 1H-NMR (500 MHz, CDCl3): δ=7.50-7.43 (m, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H), 7.15-7.09 (q, 1H, J=1.6 Hz), 6.62 (s, 1H, br), 6.22-6.18 (q, 1H, J=1.5 Hz), 5.65 (s, 1H, br), 3.30-3.28 (m, 1H), 1.38-1.37 (d, 6H, J=1.2 Hz); m/z=469 [M−I]−.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[C:3]#[N:4].[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C(OCCCC)CCC.C1COCC1.CO>[CH3:5][C:2]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:1])[CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:4]
Reactant: CC(C)(C#N)N1CCCCC1
Reactant: [Li]c1ccccc1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Product: CC(C)(C(N)c1ccccc1)N1CCCCC1
Yield: 56 %

Procedure:
The title compound (1.16 g, 56%) was prepared from 2-methyl-2-(1-piperidinyl)propanenitrile D7 (1.30 g, 8.6 mmol), and phenyllithium in dibutylether (5.2 ml of a 1.8M solution; 9.4 mmol) in THF (15 ml), followed by reaction with sodium borohydride (0.975 g, 25.7 mmol) in methanol (20 ml) in a similar manner to that described in D2. 1H NMR (CDCl3) δ: 0.76 (3H, s), 0.91 (3H, s), 1.44 (2H, m), 1.54-1.65 (4H, m), 1.95 (2H, m), 2.57 (4H, m), 4.19 (1H, s), 7.20-7.31 (3H, m), 7.40 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7]([O:28][CH2:29][CH3:30])=[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=12)[CH3:2].Cl>C(O)(=O)C>[CH2:29]([O:28][C:7]1[C:8]2[C:9](=[O:27])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=3[F:26])[C:11](=[O:13])[C:12]=2[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[CH:34]=[CH:33][CH:32]=[CH:31][C:6]=12)[CH3:30]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)c(F)c1
Agent: Cl
Solvent: CC(=O)O
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1F)C2=O
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
Ethyl {4-[4,9-bis(ethyloxy)-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate (0.050 g, 0.11 mmol) was dissolved in glacial acetic acid (2 ml) and 2N hydrochloric acid (2 ml) added which caused precipitation. The reaction mixture was heated to 100° C. under argon (the precipitate went back into solution) for 2 hours. The reaction mixture was cooled to room temperature and water added with stirring for 5 minutes. A solid precipitate formed which was filtered, washed with water, and collected to give the title compound as a yellow solid. The product was dried overnight in a vacuum oven (0.024 g, 0.05 mmol).
Reaction SMILES: C([N:8]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH:12]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:13]2)=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COc1ccc(C2=CCCN(Cc3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C2CCCNC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of 1-benzyl-5-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (1.5 g, 5.4 mmol) in 50 mL of methanol was added 10% Pd/C (1.14 g). Hydrogen gas was introduced via balloon and the reaction mixture was stirred overnight at rt. The reaction mixture was then filtered through Celite, and the filter pad was washed with additional methanol (100 mL). The filtrates were combined, and the methanol was evaporated under reduced pressure to give 3-(4-methoxyphenyl)piperidine (950 mg, 3.73 mmol, 69.4% yield). LCMS (Method 107): (ES-API), m/z 192.2 (M+H) RT=1.497 min; 1H NMR (300 MHz, DMSO-d6) δ 7.13 (dt, J=8.5, 2.0 Hz, 2H), 6.84 (dt, J=8.5, 2.2 Hz, 2H), 3.72 (s, 3H), 3.17 (s, 2H), 2.93 (d, J=10.6 Hz, 2H), 2.49-2.39 (m, 1H), 1.81 (d, J=1.9 Hz, 1H), 1.74-1.57 (m, 1H), 1.57-1.40 (m, 2H).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.C[Li].[CH2:17](OCC)C.[Cl-].[NH4+]>O1CCCC1>[C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[CH:10][N:11]=1)(=[O:5])[CH3:17]
Reactant: CCOC(=O)c1cc2ccoc2cn1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cc2ccoc2cn1
Temperature: -30 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
5-Ethoxycarbonylfuro[2,3-c]pyridine obtained in Example 2(3.82 g, 20.0 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −30° C. To the cooled solution, 22.0 mL (22.0 mol) of 1.0 M solution of methyllithium/diethyl ether was added, and the solution was stirred for 2 hours at the same temperature, the reaction mixture was then poured into 100 mL of 5% ammonium chloride aqueous solution which had been cooled on ice, and the product was extracted twice with 100 mL of ethyl acetate. After washing with 100 mL of saturated sodium bicarbonate aqueous solution and 100 mL of saturated saline water, the extract was concentrated to give 3.12 g of crude product. This product was purified by column chromatography on silica gel, giving 2.48 g (77.0% yield) of 5-acetylfuro[2,3-c]pyridine.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:7])(O)=[O:2]>C(O)(=O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH:6]2[C:5]3[C:4](=[CH:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=3)[C:1](=[O:2])[O:7]2)=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccc(F)cc2)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)C(=O)OC2c1ccc(F)cc1
Temperature: 60 °C

Procedure:
Zink (38 g, 0.58 mol) was suspended in acetic acid (400 mL). The mixture was heated to 60° C. 2,4-dicarboxy-4′-fluoro-benzophenone (21 g, 0.075 mol) was added in portions of 5 grams. After addition, the reaction mixture was heated at reflux temperature for two hours. The suspension was filtered while it was still hot. The filtrate was added to ice-water (1 kg) and the title compound was isolated by filtration. Yield 17.8 g (90%). 1H NMR (d6-DMSO): δ 6.84 (s, 1H), 7.17 (t, 2H), 7.43 (dd, 2H), 7.59 (d, 1H), 8.31 (d, 1H), 8.35 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[CH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[O:22][CH3:23])[NH:7][C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]>[Pd].C(O)(=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[O:22][CH3:23])[NH:7][C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)NC(=Cc2cc(OC)c(OC)cc2OC)C1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCN1C(=O)NC(Cc2cc(OC)c(OC)cc2OC)C1=O

Procedure:
3-n-Butyl-5-(2,4,5-trimethoxybenzylidene) hydantoin (10.0 g; 0.03 mole) was mixed with glacial acetic acid (150 ml.) and hydrogenated in a Parr apparatus in the presence of 5% Pd/C (2 g). After 2 hours the catalyst was filtered off, washed with warm acetic acid and the colourless filtrate evaporated in vacuo to give a white crystalline solid. Recrystallisation from ethyl acetate gave the title compound, yield 9.2 g (91%), m.p. 122° C.
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH:5]3[CH:6]2[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]1[CH2:4]3>P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>[O:1]=[C:2]1[CH:7]2[CH:5]3[CH:6]2[C@@H:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@H:3]1[CH2:4]3
Reactant: CCOC(=O)C1C2CC3C(C2=O)C31
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(=O)[C@@H]1C2C3C[C@H]1C(=O)C32
Yield: 45.5 %

Procedure:
2.0 g (0.011 mol) of ethyl rac-2-oxotricyclo[2.2.1.03,5 ]heptane-7-carboxylate (compound of the formula I where R1 =Et) are stirred in 25 ml of 0.1M potassium phosphate buffer, pH=7, at 50° C. with 300 mg of lipase SP 526 from Candida antarctica (Novo Nordisk) using a magnetic stirrer. The pH is kept constant with the aid of an autotitrator. After metering in approximately 12.0 ml of 0.5M NaOH, the reaction mixture is extracted with tert-butyl methyl ether. After drying with Na2SO4 and concentrating the organic phase, 0.89 g (0.005 mol, 90%) of ethyl (1R,7R)-(+)-2-oxotricyclo[2.2.1.03,5 ]heptane-7-carboxylate (HPLC [Chiracel OD, n-hexane+EtOH:100+1.1 ml/min, 210 nm]; 98% ee) is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH:17]=[CH:18][C:19]([OH:21])=O)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(OCC)(OCC)=O.[Cl-].[CH3:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH3+:41])[CH2:37][CH2:36]1.CN(C1C=CC=CN=1)C>C(Cl)Cl.C(N(CC)CC)C>[CH3:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:19]([CH:18]=[CH:17][CH:16]=[CH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([O:22][CH3:23])[CH:11]=2)=[O:21])[CH2:37][CH2:36]1
Reactant: C[C@H]1CC[C@H]([NH3+])CC1
Reactant: COc1cc(C=CC=CC(=O)O)ccc1OCc1ccccc1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C=CC=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCc1ccccc1

Procedure:
Using 4g of 4-(4-benzyloxy-3-methoxyphenyl)-l,3-butadiene-1-carboxylic acid, 3 ml of diethyl chlorophosphate, 3.5 ml of triethylamine, 150 ml of methylene chloride, 2.2 g of trans-4-methylcyclohexylammonium chloride, and 0.5 g of -dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 3.62 g of N-(trans-4-methylcyclohexyl)-4-(4-benzyloxy-3-methoxyphenyl)-1,3-butadiene-l-carboxamide (a compound of the present invention) was obtained as a pale yellowhish brown oil, which had the following physiochemical properties:
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.N1C=CC=CC=1.C([O:26][CH2:27][C:28](Cl)=[O:29])(=O)C.C1CCN2C(=NCCC2)CC1>CC#N.CCOC(C)=O.O.[Cl-].[Na+].O.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:15][C:2]1([CH3:16])[O:1][C:27](=[O:26])[C:28]([OH:29])=[C:3]1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: CC(=O)OCC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(O)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a 0° C. solution of the alcohol of Example 1, Step 3 (14.0 g, 57.8 mmol) in CH3CN (180 mL) were added pyridine (10.0 mL) and acetoxyacetyl chloride (12.7 g, 93.0 mmol) after a period of 7 h at r.t., DBU (15.0 mL) was added to the reaction mixture. After a period of 1 h at 80° C., a second portion of DBU (20.0 mL) was added. The reaction mixture was kept at 80° C. for 18 h. The reaction mixture allowed to cool to r.t. The mixture was diluted with EtOAc (500 mL) and H2O (500 mL) and acidified with 6NHCl. After the addition of brine (100 mL), the aqueous phase was extracted 2 times with EtOAc. The organic phase was evaporated to provide a brown residue. To the solid was added a 2:1 mixture of CH2Cl2 -toluene (150 mL). The solid was filtered and washed with CH2Cl2 -toluene to provide 7.0 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:34]([CH2:35]OS(C)(=O)=O)=[CH:33][N:32]=[CH:31]1.CN1C(CO)=CN=C1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:34]2[N:30]([CH3:29])[CH:31]=[N:32][CH:33]=2)=[CH:4][CH:3]=1
Reactant: Cn1cncc1COS(C)(=O)=O
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Agent: Cn1cncc1CO
Product: Cn1cncc1Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(F)ccc23)c2ccc(Cl)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid 3-methyl-3H-imidazol-4-ylmethyl ester (prepared by mesylation of the commercially available (3-methyl-3H-imidazol-4-yl)-methanol) gave the title compound. ES-MS m/e (%): 493.1(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)nc1
Product: O=C(Cl)c1ccc(Cl)nc1

Procedure:
6-Chloronicotinic acid (67 g) was treated with thionyl chloride (130 ml) and the resulting mixture heated under reflux for 2 hours. After evaporation to dryness, 60°-80° petroleum ether (60 ml) was added, and the solution again evaporated to dryness. The resulting residue was taken up in petroleum ether (60°-80°) and the solution filtered. Partial evaporation of the filtrate, followed by cooling, gave the desired product, 6-chloronicotinoyl chloride, as a white precipitate, m.p. 45°-47° (73). The product was characterized by infra-red spectroscopy, and was used directly in the next stage without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.[CH2:18]([NH:22][CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH2:37][CH3:38])[CH:25]=1)[CH2:19][CH2:20][CH3:21].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:18]([N:22]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH2:37][CH3:38])[CH:25]=1)[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(CC)c1
Reactant: FC(F)(F)c1ccc(-c2cncc(Cl)n2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(CC)c1)c1cncc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 17.3 %

Procedure:
A mixture of 2-chloro-6-[4-(trifluoromethyl)phenyl]pyrazine (0.172 g, 0.56 mmol), ethyl {4-[(butylamino)methyl]-2-ethylphenoxy}acetate (0.25 g, 0.85 mmol) and N,N-diisopropylethylamine (0.099 mL, 0.56 mmol) were heated together in a reactivial at 100° C. for 18 h. The vial was then allowed to cool to room temperature and the residue dissolved in CH2Cl2 (50 mL) and the organic solution washed with water (15 mL) and brine (10 mL). The solution was then passed through a hydrophobic frit and evaporated. Purification by Biotage™ chromatography (Silica, 40 g) eluting 9:1cyclohexane:EtOAc, afforded the title compound as a pale yellow oil (50 mg).
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.[CH2:9]([O:11][C:12]([CH3:24])([CH3:23])[CH2:13][NH:14][C:15]1[N:16]=[CH:17][NH:18][C:19]=1C(N)=O)[CH3:10]>C(Cl)Cl>[CH2:9]([O:11][C:12]([CH3:23])([CH3:24])[CH2:13][N:14]1[C:15]2[N:16]=[CH:17][NH:18][C:19]=2[C:4](=[O:5])[NH:6][C:7]1=[S:8])[CH3:10]
Reactant: CCOC(C)(C)CNc1nc[nH]c1C(N)=O
Reactant: CCOC(=O)N=C=S
Solvent: ClCCl
Product: CCOC(C)(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.171 g, 1.30 mmol) was added to a stirred solution of 4-[(2-Ethoxy-2-methylpropyl)amino]-1H-imidazole-5-carboxamide (0.246 g, 1.09 mmol), which had been obtained from Example 1(c), in CH2Cl2 (1.1 mL) at r.t. for 0.5 h, then the reaction was left unstirred at 4° C. for 16 h. The reaction mixture was heated to r.t. for 1 h and the solvent was evaporated, the residue was dissolved in 2% sodium hydroxide (aq.) (27 mL) and the reaction was heated at 50° C. for 5.5 h. The pH was adjusted to neutral with conc. HCl and 1M HCl. The precipitate was collected by filtration, washed with water and purified by flash silica gel chromatography (CHCl3/MeOH; 20:1), to give the title compound in 47% yield (96 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:24][OH:25])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([N:21]([CH3:23])[CH3:22])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:28]([N:30]=C=O)=[O:29].O>C(Cl)Cl>[C:28]([O:25][CH2:24][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([N:21]([CH3:22])[CH3:23])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)(=[O:29])[NH2:30]
Reactant: CN(C)c1ccc2onc(OCC(CO)NC(=O)OC(C)(C)C)c2c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CN(C)c1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1

Procedure:
To a solution of 0.58 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-dimethylamino-1,2-benzoisoxazole in 12 ml of methylene chloride is added 0.26 g of trichloroacetyl isocyanate at -35° to -30° C., and the temperature is elevated to 0° C., after which they are subjected to reaction at the same temperature for one hour. To the reaction mixture is added 10 ml of water, and they are subjected to reaction at 20°-25° C. for one hour, after which the organic layer is separated. The separated organic layer is dried over anhydrous magnesium sulfate and thereafter the solvent is removed by distillation under reduced pressure, to obtain 0.94 g of brown, oily 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-dimethylamino-1,2-benzoisoxazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([CH3:25])[C:19]3[CH2:20][NH:21][CH2:22][CH2:23][C:18]=3[C:17](=[O:24])[O:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:26]([NH:33][C:34]([N:21]1[CH2:22][CH2:23][C:18]2[C:17](=[O:24])[O:16][C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)([CH3:25])[C:19]=2[CH2:20]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1(c2cccc(OCc3ccccc3)c2)OC(=O)C2=C1CNCC2
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: CC1(c2cccc(OCc3ccccc3)c2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
A mixture of 3-(3-benzyloxyphenyl)-3-methyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.15 mmol) and benzyl isocyanate (27 μL, 0.22 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (43 mg, 61.6%). 1H NMR (300 Hz, CDCl3) δ 1.84 (s, 3H), 2.38 (br s, 2H), 3.26-3.32 (m, 1H), 3.51-3.58 (m, 1H), 3.79 (d, J=18.0, 1H), 4.37-4.30 (m, 3H), 4.94 (t, J=6.0, 1H), 5.04 (s, 2H), 6.87-6.94 (m, 3H), 7.24-7.39 (m, 11H).