Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.[Br:38][C:39]1[CH:40]=[CH:41][C:42]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:43]([CH:46]=1)[CH:44]=O.Cl>C1COCC1>[CH2:48]([O:47][C:42]1[CH:41]=[CH:40][C:39]([Br:38])=[CH:46][C:43]=1[CH:44]=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: Brc1ccc(OCc2ccccc2)c(C=Cc2ccccc2)c1
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a stirred suspension of benzyl triphenylphosphonium bromide (7.44 g, 17.2 mmol) in freshly distilled THF (60 ml), under argon, was added a solution of LiN(SiMe3)2 (18.2 ml, 1N). The resulting red solution was allowed to stir for 30 minutes, then a solution of 5-bromo-2-benzyloxybenzaldehyde (5.0 g, 17.2 mmol) in freshly distilled THF (15 ml) added. The reaction was stirred at ambient temperature for 60 hours, treated with 1N aqueous HCl (60 ml) and extracted with ethyl ether (2×). The combined etherial extracts were washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant:hexane) to give β-(2-benzyloxy-5-bromophenyl)styrene as a white solid (5.5 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=3)[C:13]=2[CH2:17]Cl)[N:8]([CH2:30][C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[CH:7]=1)=[O:5])[CH3:2].[CH3:39][NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=3)[C:13]=2[CH2:17][N:40]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH3:39])[N:8]([CH2:30][C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2ccc(Oc3ccc(NC(C)=O)cc3)c(CCl)c2c1=O
Reactant: CNCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2ccc(Oc3ccc(NC(C)=O)cc3)c(CN(C)Cc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
78 mg of 6-(4-acetamidophenoxy)-5-(chloromethyl)-1-(2′,6′-difluorobenzyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid-ethyl ester, dissolved in 3 ml of dimethylformamide, was mixed with 84 μl of N-methylbenzylamine and 84 μl of N,N-diisopropyl-ethylamine at 0° C. and stirred at room temperature for 20 hours. After 20 ml of aqueous sodium bicarbonate solution was added, the precipitate was suctioned off, washed with water and then with n-hexane, and dried at room temperature in a vacuum. 70 mg of the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([Cl:15])=[O:8])[C:5]([Cl:11])=[N:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)cnc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)cnc1Cl
Yield: 99.4 %

Procedure:
To a slurry of 5-bromo-2-chloronicotinic acid (2.063 g, 8.725 mmol) in methylene chloride (20 mL) was slowly added oxalyl chloride (1.11 g, 8.725 mmol) followed by the addition of dimethylformamide (5 drops). After 4 H the mixture was concentrated in vacuo to provide 2.21 g of 5-bromo-2-chloropyridine-3-carbonyl chloride as a light brown solid, which was used as is in the next reaction.
Reaction SMILES: C(OC([NH:8][CH:9]([C:14]1([C:18]2[CH:30]=[CH:29][C:21]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15]1)[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH:9]([C:14]1([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=2)[CH2:15][CH2:16][CH2:17]1)[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(=O)COc1ccc(C2(C(CC(C)C)NC(=O)OC(C)(C)C)CCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc(C2(C(N)CC(C)C)CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 69 (0.25 g, 0.0005 mole) in 20 mL of 1:1 mixture of DCM and trifluoroacetic acid (TFA) was stirred at room temperature for 8 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (50 mL), washed with brine (25 mL), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by 0-100% gradient of ethyl acetate and hexane as eluent to give the pure amine 70 as colorless oil in 85% (0.13 g) yield. 1H NMR (400 MHz, CDCl3): δ 0.85 (3H, broad s); 0.83 (3H, broad s); 1.25 (3H, t, J=4.5 Hz); 1.59 (1H, m); 1.85 (2H, m); 1.93 (2H, m); 2.20 (2H, m); 2.42 (2H, m); 2.68 (2H, m); 3.21 (1H, m); 4.08 (2H, q, J=4.5 Hz); 5.09 (2H, s); (6.81 (2H, broad d); 7.13 (2H, broad d).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[O:21][CH2:22][CH3:23].[OH-].[NH4+:25].Cl>O>[NH2:25][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[O:21][CH2:22][CH3:23]
Reactant: [NH4+]
Reactant: CCOc1c(Cl)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)O
Agent: Cl
Agent: [OH-]
Solvent: O
Product: CCOc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)O
Temperature: 80 °C
Yield: 66.5 %

Procedure:
6-Chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-ethoxy-pyrimidine-4-carboxylic acid (380 mg, 1.1 mmol) was slurried in water (3.5 mL) and 28% aqueous ammonium hydroxide solution (720 μL, 10.6 mmol) was added. The reaction mixture was sealed and heated at 80° C. for 24 h. The reaction mixture was then acidified to pH 7 via dropwise addition of concentrated hydrochloric acid, and the crude product transferred into a 500 mL separatory funnel containing 100 mL 0.1M hydrochloric acid solution. The product was then extracted with dichloromethane five times. The combined organic layers were then dried, filtered and concentrated to yield the title compound (250 mg, 69% yield) as a tan solid: 1H NMR (DMSO-d6) δ 7.58 (dd, 1H, J=8, 9 Hz), 7.38 (dd, 1H, J=2, 9 Hz), 3.98 (q, 2H, J=7 Hz), 3.90 (d, 3H, J=1 Hz), 1.31 (t, 3H, J=7 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH:6]=[CH:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.Cl.[CH3:19][C:20]1[CH:29]=[C:28]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>O1CCOCC1.O>[CH3:19][C:20]1[CH:29]=[C:28]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([NH:1][C@@H:2]3[C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH:5]=[CH:6][CH2:7]3)(=[O:40])=[O:39])=[CH:34][CH:33]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: N[C@H]1CC=CC[C@H]1C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CC=CC[C@H]3C(=O)O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a stirred solution of 423.5 mg (3 mmol) of cis-2-amino-4-cyclohexene-1-carboxylic acid in 8 mL of dioxane and 8 mL of water was added 2.1 mL of triethylamine, followed by 1.13 g (3 mmol) of 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride in one portion as a solid. The solution was stirred at room temperature overnight. After removal of the volatile material, 10 mL of dichloromethane and 10 mL of water were added to the residue. The mixture was adjusted pH to 5 with 1N HCl solution. The solid was collected by filtration, washed with a small volume of water, followed by dichloromethane to provide 1.05 g of cis-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxylic acid in 77% yield. MS: 453.1 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:6](C=C)=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].[CH2:12]([OH:14])[CH3:13].[O-:15][Mn](=O)(=O)=O.[K+].[O-]S([O-])(=O)=O.[Mg+2]>O>[CH3:1][N:2]1[C:6]([CH:13]([OH:15])[CH2:12][OH:14])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: C=Cc1cnc([N+](=O)[O-])n1C
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCO
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Product: Cn1c(C(O)CO)cnc1[N+](=O)[O-]

Procedure:
To a solution of 6.2 g. of 1-methyl-2-nitro-5-vinylimidazole in 570 ml. of ethanol cooled to about -10° C., a solution of 5.46 g. of KMnO4 and 8.85 g. of MgSO4 .7H2O in 750 ml. of H2O is added with stirring. The reaction mixture is filtered through Celite and washed with ethanol. The filtrate is concentrated to dryness under vacuum at 50° C., and the residue is taken up with acetone. The resulting solution is filtered and concentrated to dryness under vacuum. The resulting solid is crystallized from methyl ethyl ketone. Yield 3.15 g. (41.6%), m.p. 119°-121° C.
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CS(N)(=O)=O.[C:64]([O:69][CH2:70][CH3:71])(=[O:68])/[CH:65]=[CH:66]/[CH3:67].S([O-])([O-])=O.[Na+].[Na+]>O.C(O)(C)(C)C>[O:22]1[C@H:66]([CH3:67])[C@H:65]1[C:64]([O:69][CH2:70][CH3:71])=[O:68]
Reactant: C/C=C/C(=O)OCC
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)[C@H]1O[C@@H]1C
Temperature: 3 °C
Reaction time: 25 h
Yield: 50.4 %

Procedure:
AD-mix-β [Produced by ALDRICH company] (213 g) was added to a mixture of tert-butanol (760 ml) and water (760 ml). To the mixture was added methanesulfonamide (14.5 g). Under ice cooling, ethyl crotonate (17.4 g) was added, and the mixture was stirred for 5 hours at 0 to 6° C. and 25 hours at room temperature. Sodium sulfite (225 g) was added and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate (1 litter)for 22 hours by using liquid-liquid extraction apparatus. The ethyl acetate layer was taken, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added diethyl ether (300 ml), and insolubles were filtered off. The filtrate was concentrated under reduced pressure. To the residue was added 30% a solution of hydrogen bromide in acetic acid (125 ml), and the mixture was stirred for 1 hour at 45° C. After the mixture was cooled to room temperature, ethanol (280 ml) was added. The mixture was stirred for 21 hours at 45° C. and poured into a mixture of sodium hydrogencarbonate (168 g) and water (500 ml) under ice cooling with cautiously. The mixture was extracted five times with diethylether (200 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 ml). To the solution was added DBU (23.4 g). The mixture was stirred for 1 hour at room temperature, diluted with dichloromethane (300 ml) and washed with water (100 ml) and 0.5 N hydrochloric acid (200 ml). The aqueous layer was extracted twice with dichloromethane (50 ml). The dichloromethane layers were combined, and to the layer was added triethylamine (1 ml). The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to distillation under reduced pressure to give ethyl (2S,3R)-2,3-epoxybutanoate (10.0 g) as colorless liquid (Yield: 50%). Optical purity based on the analysis of HPLC of the product was 95% ee.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([OH:16])([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])=[CH:5][N:6]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[S:3][C:4]([C:7]([OH:16])([C:8]([F:9])([F:10])[F:11])[C:12]([F:15])([F:13])[F:14])=[CH:5][N:6]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.9 %

Procedure:
To a solution of (2-amino-1,3-thiazol-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (79.8 mg 0.3 mmol) from step 1 of example 1-1-1 in pyridine (1 ml) was added 4-chlorobenzensulfonyl chloride 63.3 mg (0.3 mmol). The reaction mixture was stirred at r.t. for 24 h. Pyridine was removed under reduced pressure to yield the residue, which was washed with 1N HCl to give a light brown solid. The solid was washed by water, saturated NaHCO3, brine, and dried by vacuum. Further purification by preparative TLC(CHCl3:CH3OH, 90:10) afforded the title compound as a white solid (38.2 mg). 1H NMR (DMSO-d6) δ7.55 (s, 1H), 7.60 (d, 2H), 7.78 (d, 2H), 9.50 (s, 1H), 13.2 (brs, 1H); ESIMS: m/z 439 (M−H).
Reaction SMILES: N1C(=O)C2N(C)C=NC=2N(C)[C:2]1=O.CCN(C1C=CC=CC=1)CC.[Cl:25][C:26]1[N:34]=[C:33]2[C:29]([NH:30][CH:31]=[N:32]2)=[C:28]([Cl:35])[N:27]=1.[I:36][CH3:37].[H-].[Na+]>CN(C)C=O>[Cl:25][C:26]1[N:34]=[C:33]2[C:29]([N:30]([CH3:2])[CH:31]=[N:32]2)=[C:28]([Cl:35])[N:27]=1.[I:36][CH3:37]
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)c1ccccc1
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cnc2nc(Cl)nc(Cl)c21
Yield: 10 %

Procedure:
2,6 dichloro-7-methyl-7H-purine was prepared from theobromine (a-1) in 10% yield following the procedure of Uretskaya, G. Ya., Rybinka, E. I., and Men'shikov, G. P. Zh. Obshch. Ki., 1960, 30, 327 with the modification of N,N, diethylaniline disclosed by Stanovik, B. et at in the Australian Journal of Chemistry, 1981, 34, 1729. 1H NMR was identical in all respects to the material prepared by alkylation of commercially available 2,6 dichloropurine with base and iodomethane. For example, the procedure reported by Feng et al. (WO2004/087053) utilizes 60% NaH as base, dimethylformamide (DMF) as the solvent and iodomethane yielded a 1:1 mixture of the N-7/N-9 methylated products which were separated via silica chromatography. The procedure reported by Lewi et et al (WO2005/028479 A2) utilizes potassium carbonate as the base, acetonitrile as solvent (rt 70 h) and iodomethane and yielded a 2:1 isolated yield of methylated purines after silica chromatography (60% yield N9Me/30% yield N-7 Methylated). Similarly acetone can replace acetonitrile as the solvent and after refluxing with potassium carbonate and iodomethane for 24 h a 3:1 mixture of N9/N7 is obtained. The N-7 methylated product was isolated in 16.3% purified yield after silica chromatography. A report by Chi-Huey Wong et al. (see, Bioorg & Med Chem 13 (2005) 4622-4626) utilizes tetrabutylammonium fluoride as the base (1M solution THF) and iodomethane to give similarity a 3:1 ratio of the N-9/N-7 methylated purines which could be separated by silica chromatography. 1H NMR (400 MHz, DMSO d6) 8.79 (s, 1H, H8), 4.06 (s, 3H, N7Me).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[H-].[Na+].[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]Cl.[I-].[Na+].[CH3:22][N:23](C=O)[CH3:24]>C1(C)C=CC=CC=1>[CH3:14][N:15]([CH3:19])[CH:16]([N:23]([CH3:24])[CH3:22])[CH2:17][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1][CH2:2][C:3]1=[O:11]
Reactant: CN(C)C=O
Reactant: O=C1CSc2ccccc2N1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)C(CN1C(=O)CSc2ccccc21)N(C)C
Temperature: 0 °C

Procedure:
A mixture of 108 g of 1,4-benzothiazin-3(4H)-one in 650 ml of DMF is stirred and treated portionwise with 32.5 g of sodium hydride (50% dispersion) while maintaining the temperature below 50°. The solution is then heated to 70°, cooled to 25° and treated with 350 ml of 2.8 N toluene solution of 2-dimethylaminoethyl chloride and 6 g of sodium iodide. This mixture is heated at 100°-105° for 3 hours, cooled, poured into 2 liters of ice-water, and extracted with 500 ml of ether (three times). The organic phases are combined and extracted with a solution of 120 ml of concentrated HCl in 500 ml of water. The aqueous phase is cooled and treated portionwise with 240 g of K2CO3. The liberated base is extracted with 500 ml of ether (three times), the organic phases are combined, dried (MgSO4), filtered and the solvent evaporated. The residue is fractionated to give 103.5 g of colorless product; b.p. 146°-149° (0.2 mm).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][C:29]=2[CH3:30])=[N:8][C:7]=1[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CCc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CCc1ccc(C)c(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Yield: 88.4 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (350 mg) in acetonitrile (30 ml) were added ethyl 3-(3-hydroxy-4-methylphenyl)propanoate (191 mg) and cesium carbonate (597 mg), and the mixture was heated under reflux for 15 hr. The reaction mixture was concentrated, and water was added to the residue. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (400 mg) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:14]=1.C(NCC)C.CCCCCC.C([OH:35])C>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:10][CH2:11][NH:12][CH2:13][C@@H:14]1[OH:35]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2Cl)CC1
Reactant: CCO
Solvent: CCCCCC
Solvent: CCNCC
Product: O[C@H]1CNCC[C@@H]1c1ccc(F)cc1Cl

Procedure:
3.62 g of the entitled compound was obtained as a pale orange solid from the latter fraction (retention time: 14.8 min) in the same method as in Production Example 25-3, for which, however, tert-butyl 4-(2-chloro-4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate was used in place of tert-butyl 4-(2-chlorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate used in Production Example 25-3, and an optically-active column (Daicel's CHRALPAK AD column, 2 cm×25 cm; 0.1% diethylamine, hexane/ethanol=9/1; flow rate, 20 mL/min) was sued for the optical resolution.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].[OH:11][CH:12]1[CH2:15][NH:14][CH2:13]1.C(N(CC)C(C)C)(C)C.CN(C)C(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([N:14]2[CH2:15][CH:12]([OH:11])[CH2:13]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: OC1CNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)cn1
Temperature: 120 °C
Yield: 49 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 2-nitro-5-bromopyridine (3.00 g, 14.8 mmol), 3-hydroxyazetidine hrdrochloride (2.91 g, 26.56 mmol), N,N-diisopropylethyl amine (5.67 g, 43.91 mmol) and tetrabutylammonium iodide (8.17 g, 22.1 mmol) and N,N-dimethylacetamide (15 mL). This mixture was heated at 120° C. (bath temperature) for 14 h. After this time, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with brine (250 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using a silica gel column, eluting the desired product with 80% ethyl acetate in hexanes to afford a 49% yield (1.43 g) of 120a as a yellow semi-solid: 1H NMR (500 MHz, DMSO-d6) δ 8.13 (d, 1H, J=9.0 Hz), 7.70 (d, 1H, J=2.5 Hz), 6.91 (m, 1H), 5.83 (d, 1H, J=6.0 Hz), 4.65 (m, 1H), 4.31 (m, 2H), 3.83 (m, 2H); MS (ESI+) m/z 196.2 (M+H).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][CH:11]([CH2:13]O)[OH:12]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:2]1([CH:1]2[O:9][CH2:10][CH:11]([OH:12])[CH2:13][O:8]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(O)CO
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OC1COC(c2ccccc2)OC1
Temperature: 0 °C
Yield: 21.1 %

Procedure:
A mixture of about 184 g of glycerol, about 212.03 g of benzaldehyde and about 3.6 g of p-toluenesulfonic acid was refluxed for about 5 hours, using a Dean-Stark trap. The mixture was then cooled at about 0° C. for about 17 hours and the solid collected and dissolved in about 1200 ml of warm toluene containing about one gram of sodium methoxide. This solution was washed with about 600 ml of dilute (about 1%) dibasic sodium phosphate and dried. Dilution with petroleum ether gave a solid which was recrystallized from toluene-petroleum ether, giving about 76 g of the desired title compound as a white solid.
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[Na].C(NC1C=CC=CC=1)=O.[K].C(NC1C=CC=CC=1)=O.[N+:30]([C:33]1[CH:38]=[CH:37][C:36](Cl)=[CH:35][CH:34]=1)([O-:32])=[O:31]>>[CH:7]1[CH:8]=[CH:9][C:4]([NH:3][C:36]2[CH:37]=[CH:38][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=2)=[CH:5][CH:6]=1
Reactant: O=CNc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K]
Agent: [Na]
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Reaction time: 1.5 h
Yield: 93 %

Procedure:
Into a suitable reactor is charged 64.4 parts by weight (0.45 mole) of sodium formanilide and 8.0 parts by weight (0.05 mole) of potassium formanilide to give a 90/10 ratio of the salts. In addition, there is added 23.4 parts by weight (0.193 mole) of formanilide and 60.6 parts by weight (0.385) of p-nitrochlorobenzene. The mixture is heated and stirred for 1.5 hours at 152°-160° C. The product is isolated as described in Example 1 to obtain 75.1 parts by weight or 93% yield of 4-nitrodiphenylamine. Conversion of p-nitrochlorobenzene is 98.4%.