Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.C1(C)C=CC=CC=1.[F:13][CH:14](F)[C:15](C(OC(C)(C)C)=O)([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:16](OCC)=[O:17]>O>[F:13]/[CH:14]=[C:15](\[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)/[CH2:16][OH:17]
Reactant: CCOC(=O)C(CCc1ccc(F)cc1)(C(=O)OC(C)(C)C)C(F)F
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: OC/C(=C/F)CCc1ccc(F)cc1
Reaction time: 4.5 h

Procedure:
Add methanesulfonic acid (47.7 kg, 496 mol) to a toluene solution of ethyl 2-(difluoromethyl)-2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate as prepared in Example 3.1 at a temperature of 40° C.-50° C. After 3 to 6 hours, cool the reaction to ambient temperature. Add toluene (91 kg) and water (421 kg) and stir for 30 minutes. Separate the aqueous layer. Add to the organic layer a 20% by weight solution of sodium chloride in water (420 kg) and stir for 30 minutes. Separate the layers to give the title compound as a solution in toluene.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:12])[CH3:11])=[N:2]1.C(N(CC)CC)C.[C:20](Cl)(=[O:23])[O:21][CH3:22]>C(Cl)(Cl)Cl>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([C:20]([O:21][CH3:22])=[O:23])[N:2]=1)(=[O:12])[CH3:11]
Reactant: COC(=O)Cl
Reactant: CC(=O)c1n[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)n1nc(C(C)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 1-(1H-indazol-3-yl)ethanone (5.0 g) and triethylamine (6.53 mL) in chloroform (80 mL) was added dropwise a solution of methyl chlorocarbonate (3.24 g) in chloroform (20 mL) under ice-cooling over 1 hour, and the mixture was stirred at room temperature for 14 hours. The reaction solution was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated tinder reduced pressure. The resulting residue was triturated with n-hexane to give methyl 3-acetyl-1H-indazole-1-carboxylate) [REx(101-1)] (6.67 g) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:34])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=4[CH3:33])=[CH:19][CH:18]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35](N1CCOCC1)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:35]=[CH:33][C:26]5[C:25](=[CH:30][CH:29]=[C:28]([O:31][CH3:32])[CH:27]=5)[C:24]4=[O:34])=[CH:21][CH:22]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Nc2ccc(N3CC[C@]4(CCN(C(=O)OC(C)(C)C)C4)C3)cc2)c(C)c1
Reactant: O=CN1CCOCC1
Product: COc1ccc2c(=O)n(-c3ccc(N4CC[C@]5(CCN(C(=O)OC(C)(C)C)C5)C4)cc3)ccc2c1

Procedure:
According to Method Q, (S)-7-[4-(4-methoxy-2-methyl-benzoylamino)-phenyl]-2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester was reacted with N-formylmorpholine. In this way the product was obtained with molecular weight 475.59 (C28H33N3O4); MS (ESI): 476 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].Br[CH2:12][C:13](=O)[C:14]([CH3:17])([CH3:16])[CH3:15].Cl.O>C(O)C>[C:14]([C:13]1[NH:6][C:5]2[C:7]([CH:12]=1)=[CH:8][C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=2)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)CBr
Reactant: COc1cc(N)ccc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc2[nH]c(C(C)(C)C)cc2cc1Cl

Procedure:
A solution of 4-chloro-3-methoxyaniline (4.68 g) in ethanol (4.5 mL) was heated under reflux while stirring. To the solution was added 1-bromo-3,3-dimethyl-2-butanone (0.243 mL×5) in five portions at an interval of 5 minutes, and this mixture was heated under reflux while stirring for 4 hours. The reaction mixture was left to be cooled. To the reaction mixture were added 2 mol/L hydrochloric acid and water successively, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (893 mg). 1H-NMR (CDCl3) δ ppm: 1.37 (9H, s), 3.89 (3H, s), 6.09-6.16 (1H, m), 6.88 (1H, s), 7.50 (1H, s), 7.72-8.12 (1H, br).
Reaction SMILES: [C:1]1([S:7]([CH:10]=[CH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O)(=O)=O.[H][H]>CC(C)=O.[Pd]>[C:1]1([S:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CS(=O)(=O)c3ccccc3)cc12
Reactant: [H][H]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(=O)(=O)c3ccccc3)cc12
Yield: 73.4 %

Procedure:
A stirred solution of (R)-5-(2-benzenesulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (34.0 g) in acetone (200 mL) was treated with methanesulfonic acid (8.5871 g) then 5% palladium on carbon (50% wet) (34.0 g) added and the mixture exposed to hydrogen (50 psi) at ambient temperature. When conversion was judged to be complete the mixture was filtered (washing with acetone-85 mL-and mixed acetone/water-81 mL/4 mL). The combined filtrate and washings were diluted with water (800 mL) and the pH adjusted (with stirring) to about 11 by addition of 40% aqueous sodium hydroxide. After granulation of the precipitate the solids were collected by filtration to give the title compound (25.08 g) as that produced in Example 32).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][SH:29])[CH2:22][CH2:21]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:1].[ClH:14].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[SH:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:31][CH:30]=3)[CH2:21][CH2:22]2)[OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OC(Nc1ccc(Cl)c(Cl)c1)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 52.2 %

Procedure:
The procedure described in Example 2 was followed, using 1.6 g of 3,4-dichlorophenyl isocyanate, 3.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.9 g of triethylamine and 50 ml of methylene chloride, to give 1.2 g (26% of theory) of N-(3,4-dichlorophenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 227°-230° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>CN(C1C=CN=CC=1)C.CCCCCC>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Nc1cccc2cccnc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)cc1
Yield: 64.5 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (200 mg, 1.38 mmol), p-toluenesulfonyl chloride (260 mg, 1.3 mmol) and DMAP (cat.) gave the title compound (250 mg, 60%) after trituration from n-hexane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCc1ccccc1
Product: Brc1ccc(OCc2ccccc2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and benzyl alcohol by the method of Example 10 (b).
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>C(O)C>[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:5][CH:4]=1
Reactant: Nc1ccc(S)cc1
Reactant: OCCCCCCCl
Agent: [Na]
Solvent: CCO
Product: Nc1ccc(SCCCCCCO)cc1
Reaction time: 1 h

Procedure:
Sodium metal (24 g, 1.05 mol) was added cautiously, in small portions, to 1 liter of stirred absolute ethanol under nitrogen. When the sodium has dissolved, 125 g (1.0 mol) of 4-aminothiophenol was added slowly. 6-Chlorohexanol (143 g, 1.05 mol) was added in small portions, and the resulting mixture was heated at reflux with stirring for one hour. The reaction mixture was cooled, filtered, and the ethanol was evaporated at reduced pressure. The residue was taken up in dichloromethane, and the solution was washed with water, with 5% NaHCO3 and again with water. The organic layer was dried (Na2SO4), concentrated, and the solid residue was recrystallized from ethanol. A pale yellow solid was obtained, mass 156 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][N:13]1[CH2:17][CH2:16][CH:15](O)[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH:15]1[CH2:16][CH2:17][N:13]([CH3:12])[CH2:14]1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: CN1CCC(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2Cl)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-chloro-4-nitrophenol (2.0 g) in tetrahydrofuran (60 mL) is added 1-methyl-3-pyrrolidinol (2.3 g), triphenyl phosphine (6.0 g), and diethylazodicarboxylate (3.6 mL) and the mixture is stirred at room temperature under an atmosphere of argon for 1.5 hours. The solution is then concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 10% aqueous sodium hydroxide, water, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is chromatographed over silica gel (ethyl acetate then 10% methanol in dichloromethane is used as the eluant). Pooled product fractions are then recrystallized from hexanes to provide the desired product as a yellow solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH3:10])=[N:6][S:7][C:8]=1N.[NH2:11][C:12]1[C:21]([C:22]([O:24]N2C3C=C(Cl)C=CC=3N=N2)=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1.O>CN1C(=O)CCC1>[NH2:11][C:12]1[C:21]([C:22]([O:24][C:8]2[S:7][N:6]=[C:5]([CH3:10])[C:4]=2[Br:3])=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccc(Cl)cc21
Reactant: Cc1nsc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nsc(OC(=O)c2c(N)nn3cc(F)cnc23)c1Br
Reaction time: 0.17 h

Procedure:
NaH (210.3 mg, 5.259 mmol) was added to a solution of 4-bromo-3-methyl-isothiazol-5-amine (533 mg, 2.761 mmol) in dry NMP (21.95 mL) at RT. The solution was stirred at RT for 5 min before (6-chlorobenzotriazol-1-yl) 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a* (914.4 mg, 2.630 mmol) was added. After 10 min, the reaction mixture was treated with water (120 mL) and stirred for 15 mins. The pale brown solid was filtered off and dried in vacuo to afford 4-bromo-3-methylisothiazol-5-yl 2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate. (801 mg, 82%). MS (ES+) 370.5.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][CH:27]1[CH2:31][CH2:30][CH:29]([CH3:32])[NH:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:28]1[CH:29]([CH3:32])[CH2:30][CH2:31][CH:27]1[CH3:26])=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC1CCC(C)N1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2C(C)CCC2C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 2,5-dimethylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.53 minutes; C23H24Cl2N4O2 (459.38); mass spectrum: (N−H)−=458/460/462 (chlorine isotope).
Reaction SMILES: C(O)(=O)C.CO[CH:7]1[CH2:11][CH2:10][CH:9](OC)O1.[NH2:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:30]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[O:31]([C:29]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N:14]3[CH:7]=[CH:11][CH:10]=[CH:9]3)=[CH:39][CH:38]=2)[CH:30]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(Nc1cc(Oc2ccccc2)ccc1C(=O)O)c1ccc(-n2cccc2)cc1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
0.25 mL of acetic acid and 4.1 μL of 2,5-dimethoxytetrahydrofuran were added sequentially to 10 mg of 2-(4-aminobenzamido)-4-phenoxybenzoic acid at room temperature and stirred at 90° C. for 5 minutes. After the reaction mixture was cooled so room temperature, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified wish silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; ethyl acetate] to obtain 3.8 mg of 4-phenoxy-2-(4-(1H-pyrrol-1-yl)benzamido)benzoic acid a brown solid.
Reaction SMILES: [C:1]1([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:19]1([Mg]Br)[CH2:21][CH2:20]1>>[CH:19]1([CH:15]([C:14]2[CH:13]=[N:12][C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[CH:18][CH:17]=2)[OH:16])[CH2:21][CH2:20]1
Reactant: O=Cc1ccc(-c2cccc3ccccc23)nc1
Reactant: Br[Mg]C1CC1
Product: OC(c1ccc(-c2cccc3ccccc23)nc1)C1CC1

Procedure:
Synthesized using compound 54b (253 mg, 1.09 mmol) and cyclopropylmagnesium bromide (4.34 mL, 2.17 mmol, 0.5 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Light yellow solid. Yield: 239 mg, 80%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.39-0.54 (m, 2H), 0.60-0.72 (m, 2H), 1.22-1.29 (m, 1H), 4.04-4.14 (m, 1H), 7.42-7.60 (m, 5H), 7.86-7.92 (m, 3H), 8.04-8.08 (m, 1H), 8.77 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=3.3, 3.9, 14.4, 60.6, 125.0, 125.5, 125.9, 126.1, 126.7, 127.7, 128.6, 129.1, 134.2, 137.8, 138.5, 147.8, 158.5, 171.4; MS (ESI): m/z=276.34 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)[CH:10]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:14])[CH:13]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C:8]1[N:9]([C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)[CH:10]=[C:11]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12](=[O:14])[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl[5-(benzyloxy)-1-(biphenyl-3-yl)-4-oxo-1,4-dihydropyridin-2-yl]carbamate (4.68 g, 10 mmol) was added TFA-DCM (1:1, 60 mL), and the resulting solution was stirred for 1 h at rt. The solution was then concentrated and treated with saturated aq. NaHCO3-EtOAc. The organic layer was separated, washed with brine, dried (Na2SO4), filtered, and concentrated to give 2-amino-5-(benzyloxy)-1-(biphenyl-3-yl)pyridin-4(1H)-one as a slightly yellow solid 1H NMR (500 MHz, DMSO): ä 7.82 (ddd, J=7.8, 1.8, 1.0 Hz, 1 H); 7.76-7.73 (m, 2 H); 7.67-7.61 (m, 2 H); 7.53-7.47 (m, 2 H); 7.43-7.34 (m, 6 H); 7.33-7.29 (m, 1 H); 7.04 (s, 1 H); 5.65 (s, 2 H); 5.49 (s, 1 H); 4.89 (s, 2 H).
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:23]=C)=[N:8]1.[O:27]1CCOCC1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[N:20]1[CH:21]=[CH:22][C:17]([C:15]2[S:16][C:12]([C:9]3[N:10]=[CH:11][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:26])([CH3:25])[CH3:1])[N:8]=3)=[C:13]([CH:23]=[O:27])[N:14]=2)=[CH:18][CH:19]=1
Reactant: C1COCCO1
Reactant: C=Cc1nc(-c2ccncc2)sc1-c1ncn(COCC[Si](C)(C)C)n1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: Cc1cccc(C)n1
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)nc2C=O)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution of 4-[5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-4-vinyl-1,3-thiazol-2-yl]pyridine (1.43 g, 2.60 mmol) in a 3:1 mixture of 1,4-dioxane (17.5 mL, 224.6 mmol) and water (5.8 mL, 324.25 mmol) was added 2,6-lutidine (1.50 mL, 12.98 mmol) and the mixture was cooled to 0° C. Sodium metaperiodate (2.80 g, 12.98 mmol) was added followed by the addition of 4% osmium tetroxide in water (0.50 mL, 0.080 mmol) and the reaction mixture was slowly warmed to ambient temperature and allowed to stir overnight. Water (10 mL) was added. The resulting yellow precipitate was collected by filtration, washed with water, ether and MeOH. The filtrate was concentrated under reduced pressure and dried on the high vac to give the title compound (1.0 g, yield 99%). LCMS: (FA) ES+, 388. 1H NMR (400 MHz, d6-DMSO) δ: 10.70 (s, 1H), δ:9.05 (s, 1H), 8.79-8.80 (dd, J=1.5 Hz, 2H), 7.98-8.0 (dd, J=1.5 Hz, J=1.7 Hz, 2H), 5.64-5.66 (s, br, 2H), 3.64-3.68 (m, 2H), 0.870-0.90 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([OH:7])=[O:6].[CH:13]1[CH:18]=CC=C[CH:14]=1>C(O)(C)C>[ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([O:7][CH:13]([CH3:18])[CH3:14])=[O:6]
Reactant: c1ccccc1
Reactant: CC(C)C[C@H](N)C(O)C(=O)O
Agent: Cl
Solvent: CC(C)O
Product: CC(C)C[C@H](N)C(O)C(=O)OC(C)C

Procedure:
Hydrogen chloride was passed into a solution of 4.0 g of (2RS,3S)-3-amino-2-hydroxy-5-methylhexanoic acid in 50 ml of isopropanol was stirring under ice-cooling, and to the reaction mixture was 100 ml of dry benzene. The mixture was heated under reflux for 10 minutes while removing water formed during the reaction. The reaction mixture was concentrated under reduced pressure to obtain 5.7 g of isopropyl (2RS,3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:18](O)=O)[C:5]([C:8]2[C:9](=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[C:10](O)=O)=[CH:6][CH:7]=1.[C:21]1([NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27].O>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:9]=2[C:10]2[NH:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:28]=2)=[C:4]([C:18]2[NH:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:28]=2)[CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1cc(Br)ccc1-c1ccc(Br)cc1C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Brc1ccc(-c2ccc(Br)cc2-c2nc3ccccc3[nH]2)c(-c2nc3ccccc3[nH]2)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a mixture containing 3.0 g of 4,4'-dibromodiphenic acid and 1.8 g of o-phenylene diamine was added 100 g of polyphosphoric acid (85%). The mixture was stirred and heated at 60° C. for 1 hour, 100° C. for 1 hour, and finally at 160° C. for 24 hours. The cooled heterogenous mixture was poured into 2L of distilled water. The procedure was not successful in that the product was identified as an anhydride (IR, MS and elemental analysis). This procedure was repeated using methanesulfonic acid/phosphorus pentoxide and polyphosphoric acid/sulfolane as solvents. The same result was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][C:16](=[O:18])[C:15]([OH:19])=[C:14]2[C:20]2[CH:25]=[CH:24][C:23]([CH:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:8][CH:9]=1)=[O:4].CS(C)=O.P([O-])([O-])([O-])=O>C(Cl)Cl>[OH:19][C:15]1[C:16](=[O:18])[CH2:17][C@H:13]([CH2:12][CH2:11][CH2:10][C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)[C:14]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=1
Reactant: CCCCCC(O)c1ccc(C2=C(O)C(=O)C[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCC(O)c1ccc(C2=C(O)C(=O)C[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
A mixture of 34 (5 mg, 0.011 mmol), rabbit liver esterase (3 mg, Aldrich), DMSO (50 μL) and pH 7.2 phosphate buffer (0.5 mL) was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 and washed with H2O and brine. The resulting organic solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (0%→30% methanol/dichloromethane) gave compound 35 (1 mg, 21%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].C(=O)(O)[O-].[Na+]>C(O)C.[Cl-].[Na+].O>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 83.6 %

Procedure:
To 600 mg of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 15 mL of absolute ethanol was added 500 mg of 3-chloro-4-fluoroaniline. After refluxing the reaction under an inert atmosphere for 2 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/hexanes. Drying in vacuo yielded 765 mg (83%) of 4-(3-chloro-4-fluoro-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile as yellow needles: melting point 108-111° C.; mass spectrum (m/e): M+H 316.8.
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[OH:18][C:19]12[CH2:29][C:23]3([OH:30])[CH2:24][C:25]([OH:28])([CH2:27][C:21]([OH:31])([CH2:22]3)[CH2:20]1)[CH2:26]2>>[OH:18][C:19]12[CH2:20][C:21]3([OH:31])[CH2:22][C:23]([O:30][C:1](=[O:4])[CH:2]=[CH2:3])([CH2:24][C:25]([OH:28])([CH2:27]3)[CH2:26]1)[CH2:29]2
Reactant: OC12CC3(O)CC(O)(C1)CC(O)(C2)C3
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3(O)CC(O)(CC(O)(C3)C1)C2
Yield: 83 %

Procedure:
The reaction was conducted in the same manner as the step of Example 36 (2) except that 1,3,5,7-tetrahydroxyadamantane was used instead of the 1,3-dicarboxy-5-adamantanol, and, as a result, a 1,3,5-trihydroxy-7-acryloyloxyadamantane (yield: 83%, white solid) was obtained.