Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][O:17][CH3:18]>C1C=CC=CC=1.S([O-])(O)(=O)=O.[K+].CCOCC.O>[CH3:18][O:17][CH2:16][CH2:15][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]1=[O:13]
Reactant: COCCBr
Reactant: O=C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: COCCC1CCCCC1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
Example 241 A) To a mechanically stirred mixture of KOt-Bu (87 g, 0.9 mol) in benzene (700 mL) cooled to 0° C. under an N2 atmosphere was added cyclohexanone (67 g, 0.75 mol) dropwise over 15 minutes. Ten minutes after the addition was complete, bromoethyl methylether (90 g, 0.78 mol) was added dropwise over 20 minutes. The reaction mixture was warmed to room temperature, refluxed for 7 hours, stirred at room temperature for 18 hours, and diluted with 0.5N potassium hydrogen sulfate (300 mL). The mixture was further diluted with Et2O (600 mL), 0.5N potassium hydrogen sulfate (200 mL), and water (200 mL) before the organic phase was separated. The organic layer was washed with water (200 mL) and brine (200 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was distilled to afford 41 g (25% yield) of 2-(2-methoxyethyl)cyclohexanone.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:8])C=CC=CC=1.[CH:18]12[CH2:24][CH:21]([CH:22]=[CH:23]1)[CH2:20][CH:19]2[CH:25]=[CH:26]C(O)=O.[N:30]1[CH:35]=CC=CC=1>>[CH:18]12[CH2:24][CH:21]([CH:22]=[CH:23]1)[CH2:20][CH:19]2[CH:25]=[CH:26][N:30]=[C:35]=[O:8]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C=CC1CC2C=CC1C2
Reactant: c1ccncc1
Product: O=C=NC=CC1CC2C=CC1C2
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Diphenylphosphoryl azide (12.1 g.) was added dropwise to a solution of 3-(5-norbornen-2-yl)acrylic acid (6.57 g.) in dry pyridine (30 ml.) and stirred at 80° C. for 30 minutes to give 2-(5-norbornen-2-yl)ethenyl isocyanate (I.R.: 2260 cm-1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:8])[NH:6][CH:7]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]2=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1c[nH]c(=O)c(-c2ccccc2)c1
Reactant: Ic1ccccc1
Product: Cc1cc(-c2ccccc2)c(=O)n(-c2ccccc2)c1
Yield: 77 %

Procedure:
5-Methyl-3-phenyl-2-(1H)-pyridone (B. E. Witzel, et al. Brit. Pat. 1,238,959) is reacted with iodobenzene as in Example 1 to give 1,3-Diphenyl-5-methyl-2-(1H)-pyridone in 77% yield.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:22]1[CH2:27][CH:26]=[C:25]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][CH:29]=2)[CH2:24][CH2:23]1>>[CH:13]1([N:10]2[CH2:9][C:8]([F:19])([F:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:37][C:34]4[CH:35]=[C:36]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[C:28]5[C:25]4[CH2:26][CH2:27][NH:22][CH2:23][CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc4[nH]cc(C5=CCNCC5)c4c3)ncc21

Procedure:
The title compound was prepared using Buchwald reaction from 2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one and 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.31 (m, 4H) 1.65 (m, 8H) 2.02 (m, 3H) 2.98 (br. s., 2H) 3.46 (s, 3H) 4.02-4.25 (m, 2H) 4.88 (br. s., 2H) 6.26 (s, 1H), 6.65 (d, J=8 Hz, 1H), 7.10 (s, 1H), 7.98 (s, 1H) 8.34 (d, J=8.0 Hz, 1H) 8.45 (s, 1H). [M+H] calc'd for C26H29F2N7O, 494. found 494.
Reaction SMILES: C([O:5][C:6](=[O:25])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:24])[CH:13]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:14][S:15][C:16](=[O:18])[CH3:17])(C)(C)C.C(O)(=O)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:16]([S:15][CH2:14][CH:13]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:25])=[O:5])=[O:24])(=[O:18])[CH3:17]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: COc1ccccc1
Product: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
2.9 g. of the product from Example 80 is dissolved in a mixture of trifluoroacetic acid (17.5 ml.) and anisole (8.4 ml.). After one hour storage at room temperature, the excess trifluoroacetic acid is removed in vacuo and the residue is precipitated twice from ether-hexane to yield 2.1 g. of the named product. Rf : 0.4 (silica gel-benzene:acetic acid, 75.25).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH:22]2[CH2:24][CH2:23]2)[CH2:20][CH3:21])[C:13]=1[NH2:25].[C:26](OC)(=[O:30])[C:27]([CH3:29])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]2[N:25]=[C:27]([CH3:29])[C:26](=[O:30])[N:18]([CH:19]([CH:22]3[CH2:24][CH2:23]3)[CH2:20][CH3:21])[C:14]=2[N:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C(C)=O
Reactant: CCC(Nc1nccc(-c2ccc(OC(F)F)cc2Cl)c1N)C1CC1
Solvent: CCO
Product: CCC(C1CC1)n1c(=O)c(C)nc2c(-c3ccc(OC(F)F)cc3Cl)ccnc21

Procedure:
4-(2-chloro-4-difluoromethoxy-phenyl)-N2-(1-cyclopropyl-propyl)-pyridine-2,3-diamine (0.088 g, 0.24 mmol) and methyl pyruvate (140 μL, 1.54 mmol) were treated as in Part F of Example 113 with the exception that ethanol was used as the solvent, gave 8-(2-Chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-propyl)2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 115a): 1H NMR (300 MHz, CDCl3) δ 8.48–8.46 (2d, 1H, J=4.7 Hz), 7.37–7.33 (m, 2H), 7.19–7.14 (m, 2H), 6.86–6.37 (t,1H, J=73.3 Hz), 5.16–4.92, 4.90–4.41 (2m, 1H), 2.57 (s, 3H), 2.49–2.38 (m, 1H), 2.29–2.19 (m, 1H), 2.10–1.93 (m, 1H), 0.90–0.85 (t, 3H, J=7.3), 0.80–0.71 (m, 1H), 0.59–0.50 (m, 1H), 0.49–0.48 (m, 1H), 0.23–0.18 (m, 1H). MS (AP) m/z 420.1 [(M+H)+, 100].
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]([CH3:16])=[C:6]([C:9]2[C:10]([OH:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1O.C1([OH:27])C(C)=CC=CC=1C.C(N(CC)CC)C.[CH3:35][Si:36]([CH3:39])(Cl)Cl>C(O)(C)C.ClC1C=CC=CC=1Cl>[CH3:35][SiH:36]([CH3:39])[O:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:6]1[C:5]([CH3:16])=[C:4]([CH3:17])[C:3]3([CH3:18])[O:27][C:2]3([CH3:1])[C:7]=12
Reactant: Cc1cccc(C)c1O
Reactant: C[Si](C)(Cl)Cl
Reactant: Cc1c(C)c(C)c(-c2ccccc2O)c(O)c1C
Solvent: CCN(CC)CC
Solvent: Clc1ccccc1Cl
Solvent: CC(C)O
Product: CC1=C(C)C2(C)OC2(C)C2=C1c1c(O[SiH](C)C)cccc12
Temperature: 80 °C
Yield: 92.6 %

Procedure:
A mixture of 300ml of ortho-dichlorobenzene, 24.2 grams (0.100 mole) of tetramethylbiphenol, 0.061 gram (0.0005 mole) of 2,6-xylenol and 21.8 grams (0.215 mole) of triethylamine was heated under a nitrogen atmosphere at 80° C. and 12.89 grams (0.100 mole) of dimethyldichlorosilane was added over a 10 minute period. The reaction mixture was then cooled and poured into 2,000 ml. of isopropanol to effect precipitation of product. There was obtained a white fibrous solid which was reslurried with 2,000 ml. of isopropanol. The product was then collected and pressed free of solvent with a dental dam. The product was then dried in a vacuum oven at 130° C. for 3 days. There was obtained 27.6 grams (92.6% yield) of a poly (dimethylsilyloxytetramethylbiphenyleneoxide) having a molecular weight of M(W)43,000. The polymer was molded in accordance with the method of Example 1. There was obtained a transparent tough film useful as a flame retardant dielectric material.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[CH2:14][CH:15]([OH:36])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.CC([O-])(C)C.[K+]>>[C:30]1([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH:15]([OH:36])[CH2:14][O:1][C:2]3[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[N:7]4)[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccc(O)c2cccnc12
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1ccc(OCC(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2cccnc12

Procedure:
Following the same procedure as in Example 23-(c), reaction and treatment were carried out using 360 mg of the above synthesized 5-hydroxy-8-methylquinoline, 1.39 g of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine and mg of t-BuOK in order to obtain 120 mg of 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]-8-methylquinoline.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].C1C(=O)N([Cl:18])C(=O)C1>CN(C=O)C.CCOCC>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([Cl:18])[C:3]=1[F:10]
Reactant: Nc1cc(F)c(Br)c(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nc1cc(F)c(Br)c(F)c1Cl
Reaction time: 48 h

Procedure:
4-Bromo-3,5-difluoroaniline (10.5 g, 50.5 mmol) is dissolved in DMF (100 mL). NCS (28.6 g, 50.5 mmol) is added portionwise at room temperature. After 48 hours, the reaction is diluted with Et2O and washed with brine. The separated organic phase is dried (Na2SO4) and concentrated to give an oil. The residue is purified by column chromatography (EtOAc/hexanes) to give 4-bromo-2-chloro-3,5-difluoroaniline.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N+:3]=1[O-:12].[NH2:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.CCN(C(C)C)C(C)C.O>CCCCO.CN(C1C=CN=CC=1)C>[O-:12][N+:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[NH:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: [O-][n+]1ccc2ccccc2c1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2c3ccccc3cc[n+]2[O-])C1
Temperature: 120 °C
Reaction time: 16 h
Yield: 34.9 %

Procedure:
To a solution of the compound from Step 2 1-chloroisoquinoline 2-oxide (1.2 g, 6.68 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (2.0 g, 10.02 mmol) in n-BuOH (20 mL) was added DIPEA (0.95 g, 7.35 mmol) and DMAP (81 mg, 0.668 mmol). The mixture was stirred at 120° C. for 16 h. The mixture was then poured into water (20 mL) and extracted with EtOAc (3×10 mL). The combined layers organic were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash column chromatography eluting with a gradient of petroleum ether: EtOAc (1:1 to 0:1) to afford the title compound (0.8 g, 35%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:11](Br)[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([O:8][C:9]1[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:11]([CH:27]=[CH2:28])[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1Br)C(C)CN(C)C2=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: C=Cc1c(C(=O)OCC)c(OCc2ccccc2)c2n1C(C)CN(C)C2=O
Temperature: 100 °C

Procedure:
A mixture of ethyl 8-(benzyloxy)-6-bromo-2,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (0.5 g, 1.19 mmol), tri-n-butyl vinyltin (0.46 mL, 1.42 mmol), and bis(tri-tert-butylphosphine)palladium(0) (0.12 g, 0.24 mmol) in toluene (6 mL) was purged with nitrogen for 2 minutes and sealed. The mixture was heated in a microwave oven at 100° C. for 10 minutes. The reaction mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with a hexanes and ethyl acetate gradient to provide titled product.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH3:4].[C:7]1([C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:14]2[CH:18]=[C:17]([CH:19]=[O:20])[N:16]=[CH:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+].O>O1CCCC1>[CH2:1]([CH:19]([C:17]1[N:16]=[CH:15][N:14]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=1)[OH:20])[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 20 °C
Yield: 57.8 %

Procedure:
A solution of 0.22 mole of n-butyl magnesium bromide in 75 ml of tetrahydrofuran is slowly added, under an atmosphere of argon, to 67.6 g (0.2 mole) of 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde (obtained as described in 1.b. above) in 500 ml of tetrahydrofuran. The temperature of the mixture is maintained at about 20° C. by cooling on an ice-bath. When the addition is complete, stirring is maintained for 30 minutes at ambient temperature and then 11 g of ammonium chloride and 100 ml of water are successively added. The mixture is extracted with dichloromethane. The organic phases are dried over anhydrous sodium sulfate, then evaporated under reduced pressure. The residue is recrystallized from a 2:1 v/v ethyl acetate-diethyl ether mixture. 45.8 g of alpha-n-butyl-1-triphenylmethyl-1H-imidazole-4-methanol are obtained. Yield: 58% of theory; M.P.: 119°-120° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[ClH:15].[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[N:8]=1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: Oc1ccc2nc(Cl)ccc2c1
Temperature: 0 °C

Procedure:
6-Hydroxycarbostyril (100 g) is added into phosphorus oxychloride (500 ml), and the mixture is refluxed for 5 hours. The mixture is concentrated under reduced pressure to remove the phosphorus oxychloride, and the residue thus obtained is dissolved in a small amount of chloroform, and then the mixture is poured into ice-water. The precipitated crystals are collected by filtration, washed successively with water, acetone and n-hexane, and dried to give 2-chloro-6-hydroxyquinoline hydrochloride (127 g).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:34])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([Cl:24])=[CH:18][N:17]=2)=O)C>C1(C)C(C)=CC=CC=1>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:34])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([Cl:24])=[CH:18][N:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2cc(Cl)cnc2n(Cc2ccc(OC)cc2)c1=O
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1C
Product: COc1ccc(Cn2c(=O)c(C(=O)NC3CCCCC3)c(O)c3cc(Cl)cnc32)cc1
Temperature: 140 °C
Yield: 89.3 %

Procedure:
Cyclohexylamine (6.15 mL, 53.70 mmol) was added to a stirred solution of 6-chloro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (75) (10.44 g, 26.85 mmol) in xylene and heated at 140° C. for 3 h. The solution was cooled and the solvent was evaporated under vacuum. The residue was suspended in water and extracted by dichloromethane. The combined organic phase was washed by water and brine, then dried over Na2SO4 and evaporated to yield 10.6 g (89%) of 6-chloro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid cyclohexylamide (93) as white solids. MP: 193° C.; 1H-NMR (CDCl3): δ 1.24-1.99 (m, 10H), 3.47 (s, 3H), 3.93 (m, 1H), 5.59 (s, 2H), 6.78 (m, 2H), 7.37 (m, 2H), 8.39 (d, J=2.4 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H), 10.15 (s, 1H); EIMS m/z 442 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30]O)([CH3:7])[CH3:6])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:53].CCOC(C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][Br:53])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A 100 mL round bottomed flask was charged with 2-{2-hydroxymethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester (1.0 g, 2.25 mmol), dissolved in anhydrous THF (75 mL), and then of triphenylphosphine (1.18 g, 4.50 mmol) and CBr4 (1.49 g, 4.50 mmol). The mixture was stirred at ambient temperature under a nitrogen atmosphere for 1 h and was poured into EtOAc (135 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated. The crude product was purified using radial chromatography (EtOAc:hexanes 15:85) to give a the title compound as a colorless oil (0.95 g, 76%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:31][C:32]2[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)[C:35]#[N:36])[CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:47][CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51].O>CN(C)C=O>[C:35]([C:34]1[CH:33]=[C:32]([CH:39]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:37]=1)[CH2:31][N:8]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])[C:5]1[N:6]=[CH:7][C:2]([O:1][CH2:47][CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[CH:3][CH:4]=1)#[N:36]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ccc(OCCCC(=O)OC(C)(C)C)cn1
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
3-{[(5-Hydroxy-pyridin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (150 mg) is dissolved in N,N-dimethylformamide (2.5 ml), and thereto is added 60% sodium hydride (12 mg) under ice-cooling and the mixture is stirred for 30 minutes and thereto is added tert-butyl 4-bromobutyrate (85 mg), and the mixture is stirred at room temperature for 6 hours. To the reaction solution is added water under ice-cooling, and the mixture is extracted with methylene chloride, and the organic layer is washed with a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to give tert-butyl 4-{6-[(3-cyano-5-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloxy}-butyrate (169 mg). MS (m/z): 742 [M+H]+
Reaction SMILES: O[CH2:2][C:3]1([CH2:14][OH:15])[O:10][C@@H:7]([O:8]C)[C@H:6]([OH:11])[C@@H:5]([OH:12])[C@H:4]1[OH:13]>S(=O)(=O)(O)O>[OH:15][CH2:14][C@@:3]12[CH2:2][O:8][C@@H:7]([O:10]1)[C@H:6]([OH:11])[C@@H:5]([OH:12])[C@H:4]2[OH:13]
Reactant: CO[C@@H]1OC(CO)(CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=S(=O)(O)O
Product: OC[C@@]12CO[C@@H](O1)[C@H](O)[C@@H](O)[C@H]2O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 39.6 %

Procedure:
Methyl 5-C-hydroxymethyl-α-L-arabino-hexopyranoside (3) (59.0 g, 0.263 moles) is dissolved in 0.70M sulfuric acid (260 ml), and stirred at 100° C. for 90 minutes. The solution is cooled to room temperature and neutralized using an ion exchange resin (Amberlite IRA-400 (OH-), 250 ml). The filtrate is removed from the resin, and the filtrate is refluxed for 15 minutes with activated carbon (4.0 g). Carbon is removed with a glass fiber filter, and the filtrate is evaporated to dryness with ethanol. The white waxy residue is refluxed for 15 minutes with methanol (50 ml). The solution is stored overnight at 0° C. The product crystal are filtered to yield 20.0 g (39.6%) of 5-C-hydroxymethyl 1,6-anhydro-β-L-altropyranose (4). M.P.=166.5° C.-168.5° C. [α]D23 =+145.1 (7.2 c. in water)
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34]C)[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:30])[CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20]2)=[CH:15][CH:14]=1.B(Br)(Br)[Br:37].O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(O)(=O)C>[BrH:37].[OH:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[OH:34])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:30])[CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CCNCC(O)COc2ccc3c(=O)cc(-c4ccccc4)oc3c2)cc1OC
Reactant: BrB(Br)Br
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Br
Product: O=c1cc(-c2ccccc2)oc2cc(OCC(O)CNCCc3ccc(O)c(O)c3)ccc12
Reaction time: 1 h

Procedure:
To a suspension of 7-[3-[(3,4-dimethoxyphenethyl)amino]-2-hydroxypropoxy]flavone, Example 3, (5.3 g, 11.1 mmol) in dry methylene chloride (100 ml) under nitrogen at -78° C. was slowly added boron tribromide (6.3 ml, 16.7 g, 66.9 mmol) via a syringe. The cooling bath was then removed and the suspension was stirred for 1 hour. The reaction mixture was carefully decomposed by addition of a sufficient amount of water to precipitate out a brown gum leaving a clear supernatant. The liquid was decanted and the residue was washed with three portions of water. The gum was dissolved in hot isopropanol, filtered, and left to precipitate overnight. The brown solid obtained was heated in acetic acid (50 ml) and water (10 ml) to give a dark brown solution which was then treated with a few crystals of sodium dithionite to give a light tan solution. In the presence of nitrogen, the product was crystallized from the solution; 1.9 g (33%), mp 207°-210° C. (decomp).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].[OH-].[K+]>O>[C:2]([O-:3])(=[O:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O-:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:1]
Reactant: CCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCC(=O)[O-]
Product: CCCCCCCCCC(=O)[O-]
Temperature: 25 °C

Procedure:
While introducing nitrogen, 144 g of polyglycerol (hydroxyl number 32 1113 mg KOH/g) and 36.0 g caprylic/capric acid (acid number=355 mg KOH/g) was stirred at 210° C. until an acid number of 1.0 mg KOH/g was reached. The water formed in the course of the reaction was distilled off continuously. After cooling to room temperature, the reaction product was in the form of a clear liquid.