Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][CH:39]=1)[O:13][C:14]1[CH:19]=[C:18]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]([CH3:31])[C:21]2=[O:32])[C:17]([F:33])=[CH:16][C:15]=1[N+:34]([O-])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.[Fe]>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][CH:39]=1)[O:13][C:14]1[CH:19]=[C:18]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[N:22]([CH3:31])[C:21]2=[O:32])[C:17]([F:33])=[CH:16][C:15]=1[NH2:34])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)c3)c([N+](=O)[O-])cc2F)c1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)c3)c(N)cc2F)c1=O
Temperature: 35 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a mixture of 2.5 g of an iron powder, 8 ml of acetic acid and 0.8 ml of water was added dropwise a solution of 2.4 g of 2-(3-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene in 6.0 ml of acetic acid, while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture was stirred for 2 hours, then, the reaction solution was filtrated through Celite and diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium bicarbonate, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, then, the resulted residue was subjected to silica gel column chromatography to obtain 1.5 g of 2-(3-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[F:31]C1C(F)=CC=CC=1C=O>>[F:31][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=2)[O:9]1
Reactant: O=Cc1cccc(F)c1F
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2cccc(F)c2F)Oc2ccc(O)cc21

Procedure:
2-(2,3-Difluorophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 2.6 ml of 2,3-difluorobenzaldehyde. 1H NMR (400 MHz, d6-DMSO) δ: 9.51 (s, 1H), 7.53-7.46 (m, 2H), 7.31 (m, 1H), 7.14 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, 3 8.8, 3.0 Hz), 6.96 (d, 1H, J 8.8 Hz), 5.82 (dd, 1H, J 13.4, 2.8 Hz), 3.26 (dd, 1H, J −16.9, 13.4 Hz), 2.79 (dd, 1H, J −16.9, 2.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH2:12])=[N:7][CH:6]=[CH:5]2.[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22](O)=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:16]([O:15][C:13]([N:20]1[CH2:27][CH2:26][CH2:25][CH:21]1[C:22](=[O:23])[NH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1nccc2cc(Br)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1nccc2cc(Br)ccc12
Reaction time: 6 h
Yield: 115.4 %

Procedure:
To a mixture of 6-Bromo-isoquinolin-1-ylamine (0.80 g), Boc-L-proline (0.803 g), and 4-methylmorpholine (0.83 mL) in DMF (10 mL) was added HATU (1.39 g). Reaction mixture was stirred for 6 hours. Additional Boc-L-proline (0.803 g), 4-methylmorpholine (0.83 mL) and HATU (1.39 g) were added and reaction stirred overnight at ambient temperature and then concentrated. The residue was dissolved in ethyl acetate and washed with 10:1 H2O/saturated sodium bicarbonate solution, 5% lithium chloride solution, brine and dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 70% ethyl acetate/hexanes) to give 2-(6-Bromo-isoquinolin-1-yl carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.74 g): LCMS-ESI+: calc'd for C19H23BrN3O3: 421.31 (M+H+); Found: 419.8, 421.8 (M+H+).
Reaction SMILES: [Si:1]([N:8]1[CH:11]([C:12](C)([CH3:15])[CH:13]=C)[CH:10]([CH:17]([OH:19])[CH3:18])[C:9]1=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21](=[O:23])=[O:22].CC(C)=O.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[Si:1]([N:8]1[CH:11]([C:12]([C:21]([OH:23])=[O:22])([CH3:13])[CH3:15])[CH:10]([CH:17]([OH:19])[CH3:18])[C:9]1=[O:20])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=CC(C)(C)C1C(C(C)O)C(=O)N1[Si](C)(C)C(C)(C)C
Reactant: O=C=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(O)C1C(=O)N([Si](C)(C)C(C)(C)C)C1C(C)(C)C(=O)O

Procedure:
A solution of 1-(t-butyldimethylsilyl)-3-(1-hydroxyethyl)-4-(1,1-dimethyl-prop-2-enyl)-azetidin-2-one (3.0 mmol) in dry methylene chloride (30 ml) is cooled to -78° C. (dry ice-acetone) and a stream of ozone is bubbled through until the reaction mixture becomes blue. The ozone flow is then stopped and the reaction is purged by bubbling through nitrogen until the blue color disappears. Solid m-chloroperbenzoic acid (3.0 mmol) is added and the cold bath is removed. When the reaction mixture reaches room temperature, the flask is fitted with a reflux condenser and the mixture is heated at reflux for three days. Removal of solvents in vacuo gives a crude product which is chromatographed on silica gel (2% glacial acetic acid in methylene chloride) to yield 6.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Mg]Br.[Cl-].[NH4+]>C1COCC1.CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-benzyl-4-piperidone (26.5 mmol, 5 g) in THF (50 mL) was cooled to −15° C. and a solution of methyl magnesium bromide in ether (3 M, 22 mL) was added. The mixture was stirred for 0.5 hours then allowed to warm to room temperature. Saturated aqueous ammonium chloride (50 mL) was added and the products were extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as a pale yellow solid (5.0 g) that was used directly without further purification.
Reaction SMILES: OC1C2CN(C(OCC3C=CC=CC=3)=O)CCC=2N=C(C)N=1.ClC(F)(F)C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[F:37][CH:38]([F:61])[O:39][C:40]1[C:41]2[CH2:50][N:49](C(OCC3C=CC=CC=3)=O)[CH2:48][CH2:47][C:42]=2[N:43]=[C:44]([CH3:46])[N:45]=1>>[F:61][CH:38]([F:37])[O:39][C:40]1[C:41]2[CH2:50][NH:49][CH2:48][CH2:47][C:42]=2[N:43]=[C:44]([CH3:46])[N:45]=1
Reactant: Cc1nc2c(c(OC(F)F)n1)CN(C(=O)OCc1ccccc1)CC2
Agent: Cc1nc(O)c2c(n1)CCN(C(=O)OCc1ccccc1)C2
Agent: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Product: Cc1nc2c(c(OC(F)F)n1)CNCC2

Procedure:
Benzyl 4-hydroxy-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (see footnote 8) was reacted with sodium chloro(difluoro)acetate and cesium carbonate to generate benzyl 4-(difluoromethoxy)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate; hydrogenolytic removal of the protecting group provided the requisite 4-(difluoromethoxy)-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine.
Reaction SMILES: [CH2:1]([C:3]1O[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]=1)[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>CN(C)C=O>[CH2:1]([C:3]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:7](=[O:9])[C:6]2[C:5](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1)[CH3:2]
Reactant: Nc1ccc(O)cc1
Reactant: CCc1nc2ccccc2c(=O)o1
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2c(=O)n1-c1ccc(O)cc1
Temperature: 140 °C
Reaction time: 10 h
Yield: 66 %

Procedure:
2-ethyl-4H-3,1-benzoxazin-4-one (6.5 g, 37.1 mmol) and 4-aminophenol (4.05 g, 37.1 mmol) were dissolved in dimethylformamide (18 mL) and stirred at 140° C. for 10 hours. After leaving to cool to room temperature, distilled water (94 mL) was added, and the solid precipitate was filtered off. The product was recrystallized (ethanol) and the target compound (6.52 g, 66%) was obtained as light brown crystals.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[I:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=1)[C:28]([C:41](O)=[O:42])=[CH:27]2.[NH2:44][C:45]1[CH:46]=[N:47][C:48]([N:51]2[CH2:54][CH2:53][CH2:52]2)=[CH:49][CH:50]=1>CN(C=O)C.C(OCC)(=O)C.O>[N:51]1([C:48]2[N:47]=[CH:46][C:45]([NH:44][C:41]([C:28]3[N:29]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=4)[C:30]4[C:26]([CH:27]=3)=[CH:25][C:24]([I:23])=[CH:32][CH:31]=4)=[O:42])=[CH:50][CH:49]=2)[CH2:54][CH2:53][CH2:52]1
Reactant: Nc1ccc(N2CCC2)nc1
Reactant: O=C(O)c1cc2cc(I)ccc2n1Cc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc(I)ccc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
0.29 g (1.52 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and 0.2 g (1.52 mmol) of 1-hydroxybenzotriazole (HOBT) are added to a solution, stirred at 20° C. under an inert atmosphere, of 0.6 g (1.52 mmol) of 5-iodo-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared in stage 8.2, in 15 ml of DMF. The reaction mixture is stirred at ambient temperature for 20 minutes. 0.25 g (1.67 mmol) of 3-amino-6-(azetidin-1-yl)pyridine, prepared according to the protocol described in stage 1.6, is subsequently added to the reaction mixture. After stirring at 20° C. for 18 hours, the reaction mixture is poured into a mixture of 50 ml of water and 50 ml of ethyl acetate. The resulting mixture is separated by settling out and the aqueous phase is extracted with 20 ml of ethyl acetate. The combined organic phases are washed three times with 30 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The isolated product is subsequently precipitated, then washed with isopropyl ether at reflux, filtered under hot conditions, and then dried under reduced pressure. 0.47 g of the expected product is thus isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29][CH:28]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:9](=[O:11])[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:29][CH:28]=1
Reactant: O=C(O)C(CC1CCCC1)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(N)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
A solution of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (504 mg, 2.0 mmol) in methylene chloride (20 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (1.1 mL, 2.2 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 2 h. The reaction mixture was then treated with 6-amino-nicotinic acid methyl ester (532 mg, 3.5 mmol) and N,N-diisopropylethylamine (0.84 mL, 4.8 mmol). This solution was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate) afforded 6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (151.9 mg, 19.7%) as a colorless oil: EI-HRMS m/e calcd for C21H23ClN2O3 (M+) 386.1397, found 386.1398.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[CH:5]2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[C:6]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[CH:5]2
Reactant: COc1ccc(CN)cc1
Reactant: Clc1nc2ccc(Br)cc2cc1C1CCOCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2C2CCOCC2)cc1
Temperature: 130 °C

Procedure:
A glass microwave reaction vessel was charged with 6-bromo-2-chloro-3-(tetrahydro-2H-pyran-4-yl)quinoline (1.46 g, 4.47 mmol) and (4-methoxyphenyl)methanamine (5.80 mL, 44.7 mmol) in N-methyl-2-pyrrolidinone (5.80 mL). The reaction mixture was stirred and heated in a microwave reactor at 130° C. for 180 min. The reaction mixture was poured into water and extracted with EtOAc and DCM. The combined organic extracts were washed with saturated ammonium chloride, water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude material was purified by silica gel chromatography by eluting with 1:4 to 1:1 EtOAc in hexane, to provide 6-bromo-N-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)quinolin-2-amine as yellow solid.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[C:17](C(=CNC1C=CC(C)=CN=1)C(OCC)=O)#N>>[CH3:17][C:14]1[CH:15]=[CH:16][C:9]2[N:10]([CH:13]=1)[C:11](=[O:12])[C:6]([C:5]1[NH:1][N:2]=[N:3][N:4]=1)=[CH:7][N:8]=2
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Reactant: CCOC(=O)C(C#N)=CNc1ccc(C)cn1
Product: Cc1ccc2ncc(-c3nnn[nH]3)c(=O)n2c1

Procedure:
In a manner similar to that described for the preparation of 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one in Example 2, the title compound was prepared from ethyl 2-cyano-3-(5-methyl-2-pyridylamino)acrylate. The product (42.8% yield) had m.p. 321°-322° (decomp) after recrystallization from glacial acetic acid.
Reaction SMILES: [CH2:1]([C:4]1[O:8][C:7]([NH2:9])=[N:6][CH:5]=1)[CH2:2][CH3:3].[CH:10]1[C:23]2[CH:22]([C:24](Cl)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>>[CH2:1]([C:4]1[O:8][C:7]([NH:9][C:24]([CH:22]2[C:23]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:25])=[N:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: CCCc1cnc(N)o1
Product: CCCc1cnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1

Procedure:
The title compound, white solid, m.p. 203-205° C. and MS: m/e=334.1 (M+) was prepared in accordance with the general method of example 44a from 5-propyl-oxazol-2-ylamine [Ber. 95, 2419(1962)] and 9-xanthene-carboxylic acid chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][O:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:19](C#N)#[N:20].N1C=CC=CC=1.Cl>CN1CCCC1=O>[C:19]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][O:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:4][CH:3]=1)#[N:20]
Reactant: N#CC#N
Reactant: CCCCC[C@@H]1CO[C@@H](c2ccc(Br)cc2)CO1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CCCCC[C@@H]1CO[C@@H](c2ccc(C#N)cc2)CO1

Procedure:
A mixture of 31.3 g. trans-2-p-bromophenyl-5-pentyl-1,4-dioxane, 10 g. Cu2 (CN)2, 120 ml. pyridine and 60 ml. N-methylpyrrolidone is heated for 2 hours to 150°. One cools, adds thereto a solution of 120 g. FeCl3.6H2O in 600 ml. 20% hydrochloric acid, heats to 70° for 1.5 hours, while stirring. Works up as usu 1 and obtains trans-2-p-cyanophenyl-5-pentyl-1,4-dioxane.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[C:18]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[C:4]([O:6]C)=O.[CH3:34][Mg]Br.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[C:4]([C:3]1[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=1[O:12][C:13]1[C:18]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:6])[CH3:34]
Reactant: C[Mg]Br
Reactant: COC(=O)c1c(F)cccc1Oc1ncccc1NC(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1c(F)cccc1Oc1ncccc1NC(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 18 h
Yield: 8.2 %

Procedure:
Methyl 2-fluoro-6-(3-(3-(4-(trifluoromethoxy)phenyl)ureido)pyridin-2-yloxy)benzoate (250 mg, 0.54 mmol) was diluted in THF (10 mL) and cooled to −78° C. Methylmagnesiumbromide (3.0 M in Et2O, 1.07 mL, 3.22 mmol) was added and mixture was warmed to rt and stirred for 18 h. Sodium sulfate decahydrate was added and stirring was continued for 30 min. The solution was filtered over a pad of Celite® and washed using ethyl acetate. The organic phase was evaporated and crude material was purified using preparative HPLC to yield the desired material (20 mg) (M+H)+=450. 1H NMR (400 MHz, Acetone) δ ppm 2.33-2.40 (m, J=1.77 Hz, 3H), 7.07-7.18 (m, 3 H), 7.27 (d, J=8.84 Hz, 2 H), 7.56 (td, J=8.34, 6.57 Hz, 1 H), 7.63-7.70 (m, 3 H), 8.20 (s, 1 H), 8.67 (dd, J=7.96, 1.64 Hz, 1 H), 8.91 (s, 1 H).
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[F:16][C:17]([F:26])([CH2:23][CH:24]=[CH2:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl>[CH:24]1([CH2:23][C:17]([F:26])([F:16])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:1][CH2:25]1
Reactant: C=CCC(F)(F)C(=O)OCC
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)CC1CC1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A solution of diethyl zinc (500 mL, 1.0 M in hexanes) in methylene chloride (700 mL) was chilled to −10° C. under nitrogen in a cooling bath. A solution of trifluoroacetic acid (57 g, 0.5 mol) in methylene chloride (50 mL) was added dropwise over 1 hour 45 minutes. The mixture was stirred for 30 minutes at −5° C. A solution of diiodomethane (133.9 g, 0.5 mol) in methylene chloride (50 mL) was added to the mixture over a period of 20 minutes. The mixture became homogenous upon stirring for 30 minutes at 0° C. A solution of ethyl 2,2-difluoropent-4-enoate (40 g, 0.244 mol) in methylene chloride (50 mL) was added dropwise over a period of 25 minutes and the cooling bath was removed. The mixture was stirred for 1 hour at room temperature and then for 15 hours at reflux. The reaction was quenched by addition of saturated aqueous ammonium chloride (500 mL) and stirring for 30 minutes. The biphasic mixture was poured into 500 mL of saturated aqueous ammonium chloride and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3×300 mL) and the combined organic extracts were dried over magnesium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure to afford ethyl 3-cyclopropyl-2,2-difluoropropanoate (43.5 g, quant), as light yellow oil, which was used in the Example 4 without further purification. 1H-NMR (400 MHz, CDCl3): δ=0.12-0.22 (m, 2H), 0.49-0.59 (m, 2H), 0.75-0.91 (m, 1H), 1.37 (t, J=8 Hz, 3H), 1.95-2.05 (m, 2H), 4.34 (q, J=8 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([OH:24])[CH2:20][CH2:21][C:22]#[CH:23]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:23]#[C:22][CH2:21][CH2:20][CH2:19][OH:24])[CH:3]=1)=[O:17]
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C#CCCCO
Product: O=C(NCCC(O)c1cccc(C#CCCCO)c1)C(F)(F)F

Procedure:
Sonogashira reaction of 25 with pent-4-yn-1-ol gave 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(5-hydroxypent-1-ynyl)phenyl)propyl)acetamide as brown oil. Yield (1.46 g, 69%): 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.22-7.34 (m, 3H), 4.86 (d, J=8.0 Hz, 1H), 3.83 (t, J=5.2 Hz, 2H), 3.65-3.69 (m, 1H), 3.38-3.42 (m, 1H), 2.56 (t, J=7.2 Hz, 2H), 2.38 (bs, 1H) 1.93-1.99 (m, 2H), 1.83-1.88 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17]4[N:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:16]=4[CH2:15][N:14]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:13]=3[CH:41]=2)=[O:8])[CH:3]=1.CC1NN=C(C(C2C=CC3NC4N=C(C(F)(F)F)C=CC=4CN(S(C4C=CC(OC(F)(F)F)=CC=4)(=O)=O)C=3C=2)(O)C)C=1>>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([CH:7]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17]4[N:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:16]=4[CH2:15][N:14]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:39])([F:40])[F:38])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:13]=3[CH:41]=2)[OH:8])[CH:3]=1
Reactant: Cc1cc(C(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)Cc2ccc(C(F)(F)F)nc2N3)n[nH]1
Agent: Cc1cc(C(C)(O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)Cc2ccc(C(F)(F)F)nc2N3)n[nH]1
Product: Cc1cc(C(O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)Cc2ccc(C(F)(F)F)nc2N3)n[nH]1

Procedure:
The title compound was prepared from (5-methyl-1H-pyrazol-3-yl)[6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]methanone (the product of Example 527, Step B) using the procedure described in Example 511; Mass Spectrum: m/e=600 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([CH:20]([F:22])[F:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7](OCC2C=CC=CC=2)[CH:6]=1>CO>[F:1][C:2]([F:23])([CH:20]([F:21])[F:22])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: Oc1ccc(OCC(F)(F)C(F)F)cc1OCc1ccccc1
Solvent: CO
Product: Oc1ccc(OCC(F)(F)C(F)F)cc1
Reaction time: 1.5 h

Procedure:
4-(2,2,3,3-tetrafluoro-propoxy)-benzyloxy-phenol (0.09 mmol, 28 mg) (Step A) was dissolved in MeOH (2 mL) and Pd(C) (40% weight, 10 mg) was added. The mixture was stirred for 90 minutes under H2 atmosphere (1 atm), and filtered through a celite pad (EtOH). The filtrate was concentrated to give the title compound. 1H-NMR (CDCl3, 200.15 MHz): δ 6.85–6.75 (m, 4H), 6.05 (dt, J=53.2, 4.8), 4.28 (dt, 2H, J=12.1, 1.6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:24][C@H:13]23)=[O:7])[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(O)c(Cl)c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 32 %

Procedure:
The title compound is prepared from 3-chloro-4-hydroxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 32% of theory; LC (method 4): tR=1.96 min; Mass spectrum (ESI+): m/z=328/330 (Cl) [M+H]+.