Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]1COC[CH2:12]1.C([Mg]Cl)=C.[Cl-].[NH4+]>O>[OH:5][CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:2]=1[OH:1])[CH:11]=[CH2:12]
Reactant: C1CCOC1
Reactant: Cc1cccc(C=O)c1O
Agent: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: C=CC(O)c1cccc(C)c1O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A 1 L four-necked round-bottomed flask was equipped with a magnetic stirrer bar, a thermometer and a pressure-equalizing dropping funnel. A 2-hydroxy-3-methylbenzaldehyde (30.0 g, 0.22 mol) and THF (300 ml) were added to it under a nitrogen atmosphere. After the mixture was cooled to 0° C., a solution of vinyl magnesium chloride in THF (1.9 M, 237 ml, 0.45 mol) was added thereto over 45 minutes while maintaining the mixture temperature of 15° C. or less. The mixture was gradually warmed to room temperature and stirred at room temperature for 18 hours. The mixture was cooled to 0° C. and a 20% aqueous ammonium chloride solution (600 ml) was added thereto at 0° C. After the mixture was stirred at room temperature for 30 minutes, the mixture was poured into water (500 ml). The mixture was extracted with ethyl acetate (3×500 ml). The organic layer was combined and successively washed with a 20% aqueous ammonium chloride solution (300 ml), water (2×300 ml) and a saturated aqueous NaCl solution (300 ml), followed by drying with anhydrous sodium sulfate (150 g). The solid was removed by filtration and the filtrate was concentrated to obtain 34.3 g of 2-(1-hydroxy-2-propenyl)-6-methylphenol as a brown gum.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH:23]([C:25]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:26]=1[Cl:32])[OH:24].O>CN(C)C=O>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH:23]([C:25]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:26]=1[Cl:32])[O:24][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC(c1cc2ccccc2s1)c1cc(Br)ccc1Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(c1cc2ccccc2s1)c1cc(Br)ccc1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Benzo[b]thiophene (1.12 g) was dissolved in tetrahydrofuran (50 ml). This solution was cooled to −78° C., and a solution of 1.58 M hexane (10.5 ml) of n-butyllithium was added dropwise to the solution, and the mixture was stirred for 15 minutes at −78° C. Then, 5-chloro-2-bromobenzaldehyde (3.15 g) dissolved in tetrahydrofuran (50 ml) was added dropwise to the reaction mixture, and the mixture was stirred for two hours at room temperature. Aqueous solution of saturated ammonium chloride was added to the reaction mixture, and then the solvent was evaporated from the filtrate under reduced pressure to give the residue. Ethyl acetate and water were added to the residue obtained, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 1-benzothiene-2-yl(5-bromo-2-chlorophenyl) methanol (4.75 g). Imidazole (1.08 g) and tert-butyl dimethylchlorosilane (2.99 g) were added to a solution of 1-benzothiene-2-yl(5-bromo-2-chlorophenyl) methanol in dimethylformamide (100 ml), and the mixture was stirred for three hours at 70° C. Water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, the solvent was evaporated therefrom under reduced pressure to give the residue, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain [1-benzothiene-2-yl(5-bromo-2-chloro phenyl)methoxy](tert-butyl) dimethylsilane (3.34 g).
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.F[C:14]1[C:15]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:16]([CH3:33])[C:17](C#N)=[C:18]2[C:22]=1[O:21][C:20]([C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])=[N:19]2.[CH2:40]([N:42](CC)CC)C>[Cl-].[Na+].O>[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][N:9]([C:14]2[C:22]3[O:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])([C:40]#[N:42])[NH:19][C:18]=3[CH:17]=[C:16]([CH3:33])[C:15]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:8]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N3CCCCC3)nc2c1C#N
Reactant: CCN(CC)CC
Reactant: CN(C)[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(c(N3CC[C@H](N(C)C)C3)c1-c1ccccc1)OC(C#N)(C(=O)N1CCCCC1)N2
Reaction time: 1.25 h

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (700 μl) solution of (3S)-3-(dimethylamino)pyrrolidine (24 μl, 192 μmol) was added at 150° C. to a dimethyl sulfoxide (2.5 ml) solution of 7-fluoro-5-methyl-6-phenyl-2-(piperidin-1-ylcarbonyl)-1,3-benzoxazole-4-carbonitrile (I-117) (58 mg, 160 μmol) and triethylamine (29 μl, 208 μmol), followed by stirring at the same temperature for 75 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the obtained organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (20:1, v/v) gave a crude product of the entitled compound as a solid, and the solid was recrystallized from diisopropyl ether/n-hexane to obtain the entitled compound (23 mg, 31%) as a pale yellow solid.
Reaction SMILES: [CH2:1]=[CH:2]C1C=CC=CC=1.[Br:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].C([Mg]Br)C>CCOCC>[Br:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]([OH:13])[CH2:1][CH3:2]
Reactant: O=Cc1ccccc1Br
Reactant: C=Cc1ccccc1
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CCC(O)c1ccccc1Br

Procedure:
With the exception of three compounds, the styrene compounds herein utilized for preparing the α-chloro oximes are known and their preparations are published in the prior art. The compounds not previously known are synthesized following well-known published procedures. Thus, 2-bromobenzaldehyde is allowed to react with a Grignard reagent, ethyl magnesium bromide in anhydrous ether, to yield 1-(2-bromophenyl)propanol. This propanol derivative is then dehydrated by refluxing it in toluene in the presence of p-toluenesulfonic acid catalyst to yield the desired 1-bromo-2-(1-propenyl)benzene. Another previously unknown substituted styrene, namely, 1,2-dichloro-4-(1-propenyl)benzene is prepared by the same general procedure from 3,4-dichlorobenzaldehyde and ethyl magnesium bromide, followed by dehydration of the intermediate substituted propanol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH:34]1([NH:37][CH3:38])[CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH:34]1([N:37]([CH3:38])[S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=2)(=[O:22])=[O:21])[CH2:36][CH2:35]1
Reactant: CNC1CC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N(C)C4CC4)c3)n2)n1
Yield: 51.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available N-cyclopropyl-N-methylamine [CAS-no. 5163-20-2] (0.16 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 51%) as a white solid. MS (ISP) 524.3 [(M+H)+]; mp 157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.[CH2:23](O)[C:24]#[CH:25].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.ClCCl>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:25][C:24]#[CH:23])[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reactant: C#CCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CCOc1cc(OC)cc2oc(-c3cn4nc(OC)sc4n3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
A solution of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 205 mgs, 0.646 mmol) in THF (10 mL) was treated at r.t. and under a nitrogen atmosphere, with propargyl alcohol (0.096 mL, 1.615 mmol), tri-n-butylphosphine (0.398 mL, 1.615 mmol) and dropwise, over a 25 min period with a solution of 1,1′-(azodicarbonyl)dipiperidine (408 mgs, 1.615 mmol) in THF (10 mL). The mixture was sonicated in a bath for 30 min and stirred at r.t. for another 30 min. The mixture was then dissolved in dichloromethane (50 mL) and washed with sat. aqueous NaHCO3, brine and dried (MgSO4). Evaporation of the solvent gave a solid that was purified by silica gel column chromatography ISCO to give the title material (180 mg, 0.507 mmol, 78% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.38 (s, 1H), 6.92 (s, 1H), 6.86 (dd, J=1.8, 1.0 Hz, 1H), 6.53 (d, J=1.6 Hz, 1H), 4.94 (d, J=2.7 Hz, 2H), 4.21 (s, 3H), 3.77-3.84 (m, 3H), 3.60-3.66 (m, 1H).
Reaction SMILES: [CH2:1]([PH2:7])[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH:8]([CH:10]=[O:11])=[O:9]>O1CCCC1>[CH2:1]([P:7]1[CH:8]([OH:9])[CH:10]([OH:11])[P:7]([CH2:1][CH2:2][C:3]([CH3:4])([CH3:6])[CH3:5])[CH:8]([OH:9])[CH:10]1[OH:11])[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: O=CC=O
Reactant: CC(C)(C)CCP
Solvent: C1CCOC1
Product: CC(C)(C)CCP1C(O)C(O)P(CCC(C)(C)C)C(O)C1O
Yield: 90 %

Procedure:
Following the procedure of Example 2, mononeohexyl phosphine (200 parts) in tetrahydrofuran, is reacted with 250 parts of glyoxal and 256 parts (90% yield) of 1,4-dineohexyl-2,3,5,6-tetrahydroxy-1,4diphosphorinane, m.p. 186°-210° C., are isolated.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[Cl:14][C:15]1[CH:16]=[C:17]([C:25](=O)[CH3:26])[CH:18]=[CH:19][C:20]=1[O:21][CH:22]([F:24])[F:23]>O1CCCC1>[Br:13][C:9]1[CH:8]=[C:7]([C:25]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH:22]([F:23])[F:24])=[C:15]([Cl:14])[CH:16]=2)=[CH2:26])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(OC(F)F)c(Cl)c1
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1)c1ccc(OC(F)F)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 16.4 mL, 26.2 mmol, 1.16 eq.) was added dropwise over 20 min to a solution of 1,3-dibromobenzene (3.00 mL, 24.8 mmol, 1.1 eq) in 25 mL of dry tetrahydrofuran at −78° C. and under an inert atmosphere. The white suspension formed was stirred at −78° C. for 30 min. A solution of 1-(3-chloro-4-difluoromethoxy-phenyl)-ethanone (7 g, 31.7 mmol, 1.0 eq.) in 25 mL of tetrahydrofuran was then added dropwise and the reaction stirred for 1 h. The reaction mixture was examined by LC-MS which showed the complete formation of tertiary alcohol. The solution was quenched with a saturated solution of ammonium chloride and water. 2 N HCl was then added to reach pH=5. The two phases were separated; the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude (tertiary alcohol) and a catalytic amount of p-toluenesulfonic acid were dissolved in 70 mL toluene (Dean-Stark apparatus) and the mixture was heated to reflux for 3 h. The solution was examined by TLC (cyclohexane) which showed consumption of starting material but many side products formed. Solvent was evaporated under reduced pressure and the crude residue was purified by flash chromatography eluting with cyclohexane. The desired product was obtained as yellow oil (2.2 g, Yield: 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH2:22])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])C>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:22][S:28]([CH3:26])(=[O:30])=[O:29])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
2-(3-Chlorophenoxy)-3-[3-(3-aminopyridin-4-yl)propoxy]pyridine (0.15 g, 0.42 mmol) obtained in Example 25 is dissolved in methylene chloride (5 ml) and pyridine (0.34 ml), and thereto is added ethylsulfonyl chloride (0.04 ml, 0.50 mmol) under ice-cooling, and the mixture is stirred for 3 hours. To the mixture is added ice-water (20 ml), and the mixture is extracted with ethyl acetate (50 ml×2). The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution (20 ml×2) and a saturated brine (20 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by basic silica gel column chromatography (eluent: chloroform/methanol), and further recrystallized from diethyl ether to give the title compound (0.07 g) as colorless crystals, m.p. 131-133° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:39]=[CH:38][C:11]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:37])[C:30]4[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=4)[CH2:25][CH2:24]3)[CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1.[CH:40]([O:43][C:44]1[C:49]([O:50][CH3:51])=[CH:48][C:47](B(O)O)=[CH:46][C:45]=1[O:55][CH3:56])([CH3:42])[CH3:41]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:40]([O:43][C:44]1[C:45]([O:55][CH3:56])=[CH:46][C:47]([C:33]2[CH:32]=[CH:31][C:30]([C:29]([N:26]3[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][N:17]4[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C:11]5[CH:10]=[CH:9][C:8]([C:47]6[CH:48]=[C:49]([O:50][CH3:51])[C:44]([O:43][CH:40]([CH3:42])[CH3:41])=[C:45]([O:55][CH3:56])[CH:46]=6)=[CH:39][CH:38]=5)[CH2:15][CH2:16]4)[CH2:28][CH2:27]3)=[O:37])=[CH:35][CH:34]=2)=[CH:48][C:49]=1[O:4][CH3:1])([CH3:42])[CH3:41]
Reactant: O=C(c1ccc(Br)cc1)N1CCN(CCCN2CCN(C(=O)c3ccc(Br)cc3)CC2)CC1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(B(O)O)cc(OC)c1OC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: COc1cc(-c2ccc(C(=O)N3CCN(CCCN4CCN(C(=O)c5ccc(-c6cc(OC)c(OC(C)C)c(OC)c6)cc5)CC4)CC3)cc2)cc(OC)c1OC(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Under nitrogen were added 2.40 mL (48 mmol) of a 2 mol/L aqueous sodium carbonate solution and 729.9 mg (0.632 mmol) of tetrakis(triphenylphosphine)palladium (0) to a solution of 4.50 g (7.79 mmol) of 1,3-bis[4-(4-bromobenzoyl)-1-piperazinyl]propane and 4.50 g (18.7 mmol) of 4-isopropoxy-3,5-dimethoxyphenylboronic acid in ethanol-toluene (15 mL -60 mL), and the mixture was stirred for 3 hours at 80° C. The reaction mixture was concentrated under reduced pressure to remove the organic solvents. Water (15 mL) was added to the residue and the mixture was extracted with chloroform (100 mL, 3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give 5.93 g of 1,3-bis[4-[4-(4-isopropoxy-3,5-dimethoxyphenyl)benzoyl]-1-piperazinyl]propane as a colorless oil (yield 94%).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][C:13]([O-:16])(C)[CH3:14].[K+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[C:3]([O:16][CH:13]([CH3:14])[CH3:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(C(=O)O)cc1Cl
Temperature: 80 °C

Procedure:
5,6-Dichloronicotinic acid (1.95 g, 10 mmol) is added to a solution of KOtBu (2.28 g, 20 mmol) in isopropanol (20 mL). The mixture is heated at 80° C. for 15 h. The mixture is diluted with water (60 mL) and acidified with 1M aq. HCl. The aq. solution is extracted with ether (5×50 mL) and the combined org. extracts are dried (Na2SO4), filtered and evaporated to provide 5-chloro-6-isopropoxy-nicotinic acid; 1H NMR (d6-DMSO) δ 1.38 (d, J=6.2 Hz, 7H), 5.44 (hept, J=6.2 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H)
Reaction SMILES: [N:1]1([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11]C(C#N)=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-:19].[Na+].[CH3:21][CH2:22][OH:23]>>[F:14][C:13]([F:16])([F:15])[C:12]1[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:8][CH:9]=[C:21]([CH:11]=1)[C:22]([OH:19])=[O:23]
Reactant: CCO
Reactant: [OH-]
Reactant: N#Cc1cnc(N2CCOCC2)c(C(F)(F)F)c1
Agent: [Na+]
Product: O=C(O)c1cnc(N2CCOCC2)c(C(F)(F)F)c1

Procedure:
A solution of 249 mg (0.97 mmol) of 2-(morpholin-4-yl)-3-trifluoromethyl-5-cyanopyridine (from Step D) in 5 mL 1:1 v/v 5 N NaOH/EtOH was heated at reflux for 1 h. The mixture was cooled and partitioned between 20 mL of ether and 20 mL of water. The aqueous layer was separated and adjusted to pH=4 with conc. HCl. The precipitated solid was filtered, rinsed with water and dried to afford 138 mg of the title compound: 1H NMR (500 MHz, CD3OD) δ 3.52 (app t, J=5.0, 4H), 3.78 (app t, J=5.0, 4H), 8.40 (d, J=2.0, 1H), 8.90 (d, J=2.0, 1H); ESI-MS (m/z) 277.3; HPLC A: 2.71 min.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Mg]Br)=[CH:34][CH:33]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=3)([C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[OH:19])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(CN2CCC(C(=O)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCOc1ccc(CN2CCC(C(O)(c3ccc(Cl)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 65 °C
Reaction time: 3.5 h

Procedure:
A solution of 0.6 gram (0.0014 mole) of N-(4-propoxyphenylmethyl)-4-(4-trifluoromethoxyphenylcarbonyl)piperidine in 15 mL of tetrahydrofuran was stirred, and to the stirred solution was slowly added 1.8 mL of 4-chlorophenylmagnesium bromide (0.0018 mole-1M in diethyl ether). Upon completion of the addition, the reaction mixture was warmed to 65° C., where it was stirred for 3.5 hours. After this time the reaction mixture was allowed to cool to ambient temperature, where it stirred for about 18 hours. The reaction mixture was then poured into a mixture of 50 mL of ice and 75 mL of an aqueous solution saturated with ammonium chloride. The mixture was stirred until the ice melted and then extracted with ethyl acetate. The extract was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was dissolved in boiling petroleum ether and treated with decolorizing carbon. Diatomaceous earth was stirred in, and the mixture was filtered through a pad of activated magnesium silicate. The magnesium silicate pad was washed with 30% acetone in methylene chloride. The filtrate and wash were combined and concentrated under reduced pressure, yielding 0.4 gram of N-(4-propoxyphenylmethyl)-4-[(4-trifluoromethoxyphenyl)(4-chlorophenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:16][OH:17])[C:13]([OH:15])=O)=O)C1C=CC=CC=1.C[N:19]1[CH2:24][CH2:23]O[CH2:21][CH2:20]1.Cl[C:26](OCC(C)C)=O.N1CCCC1>O1CCCC1>[NH2:11][C@H:12]([CH2:16][OH:17])[C:13]([N:19]1[CH2:20][CH2:21][CH2:26][CH2:23][CH2:24]1)=[O:15]
Reactant: O=C(N[C@H](CO)C(=O)O)OCc1ccccc1
Reactant: CN1CCOCC1
Reactant: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: N[C@H](CO)C(=O)N1CCCCC1
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
(2R)-2-Benzyloxycarbonylamino-3-hydroxypropionic acid (1.91 g, 8.00 mmol) and N-methylmorpholine (809 mg, 8.00 mmol) were dissolved in tetrahydrofuran (20 ml). After isobutyl chloroformate (1.09 g, 8.00 mmol) was added dropwise at −15° C. or below, the reaction mixture was stirred for 30 minutes. Then, pyrrolidine (1.13 g, 16.0 mmol) was added at −15° C. or below, and the reaction mixture was further stirred at 0° C. for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1N hydrochloric acid, 1N aqueous solution of sodium hydroxide, a saturated aqueous solution of sodium hydrogencarbonate, and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was dissolved in a solvent mixture of methanol (15 ml)-tetrahydrofuran (15 ml). Then, 10% palladium on carbon (wet) (300 mg) was added, and the reaction mixture was stirred at room temperature under the stream of hydrogen for 90 minutes. After the catalyst was removed by filtration, the solvent of the filtrate was distilled off under reduced pressure to yield (2R)-2-amino-3-hydroxy-1-(piperidin-1-yl)propan-1-one (684 mg, 3.97 mmol, 50%) as a colorless oil. Similarly to Example 5, the title compound (107 mg, 0.223 mmol, 74%) was obtained as white crystals from phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (157 mg, 0.300 mmol) synthesized in Production example 5-2 and previously obtained (2R)-2-amino-3-hydroxy-1-(piperidin-1-yl)propan-1-one (228 mg, 1.32 mmol).
Reaction SMILES: O1CCC[CH2:2]1.[OH:6][C:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9](=[O:17])[C:8]=1[C:18](=[O:33])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:32])[CH2:29][O:30][CH3:31])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.CO.ClCCl>[CH3:2][O:6][C:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9](=[O:17])[C:8]=1[C:18](=[O:33])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:32])[CH2:29][O:30][CH3:31])[CH:22]=1
Reactant: C1CCOC1
Reactant: COCC(=O)Nc1cccc(C=CC(=O)c2c(O)c3ccccc3oc2=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COCC(=O)Nc1cccc(C=CC(=O)c2c(OC)c3ccccc3oc2=O)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 5 ml of tetrahydrofuran and 6 ml of dichloromethane were added 0.59 g of 4-hydroxy-3-[3-[3-(methoxyacetylamino)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one, 0.45 g of triphenylphosphine and 55 mg of methanol, and to the mixture was added dropwise 0.74 g of a 40% toluene solution of diethyl azodicarboxylate. The mixture was stirred at room temperature for 40 minutes, and the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.18 g of 4-methoxy-3-[3-[3-(methoxyacetylamino)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (22d)].