Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:17])([CH3:16])[C:14](=O)[NH:13][C:12]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:16])([CH3:17])[CH2:14][NH:13][C:12]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCOCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CNC(=O)N1CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 9a (28 g) in THF (250 ml) was added to a suspension of LiAlH4 (8 g) in THF (250 ml) at 20°-25° C. After stirring at room temperature for 1 h, the mixture was cooled to 0° C., water (10 ml) and aqueous NaOH (10 ml) were added, the inorganic salts were filtered and the solvents were evaporated in vacuo. The remaining oil was purified by column chromatography on silica gel (ethyl acetate) yielding 9b as an oil: 10 g.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH2:7][C@:8]([NH:16][S@](C(C)(C)C)=O)([C:10]1[S:11][C:12]([CH3:15])=[CH:13][N:14]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1.C(N(CC)CC)C.O>O1CCCC1>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH2:7][C@@:8]([C:10]1[S:11][C:12]([CH3:15])=[CH:13][N:14]=1)([NH2:16])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc([C@](C)(CO[Si](C)(C)C(C)(C)C)N[S@@](=O)C(C)(C)C)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc([C@@](C)(N)CO[Si](C)(C)C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
To a solution of 254 mg of (S)—N-[(2S)-1-{[tert-butyl (dimethyl)silyl]oxy}-2-(5-methyl-1,3-thiazol-2-yl)propan-2-yl]-2-methylpropane-2-sulfinamide in 6.9 ml of tetrahydrofuran (THF) was added 1.1 ml of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 4 hours. To the reaction mixture was added 0.62 ml of triethylamine, and water was then added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. To the obtained residue was added ethyl acetate and the insoluble materials were separated by filtration. The filtrate was concentrated under reduced pressure to obtain 185 mg of (2S)-1-{[tert-butyl (dimethyl)silyl]oxy}-2-(5-methyl-1,3-thiazol-2-yl)propan-2-amine.
Reaction SMILES: S(=O)(=O)(O)O.[Br-].[Li+].[CH3:8][O:9][C:10]([C:12]1([CH2:39][CH:40]=[CH2:41])[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:17][C:16]2[CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=[CH:30][C:15]=2[N:14](COC)[C:13]1=[O:38])=[O:11].C(=O)(O)[O-].[Na+]>CO>[CH3:8][O:9][C:10]([C:12]1([CH2:39][CH:40]=[CH2:41])[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:17][C:16]2[CH:27]=[C:28]([C:31]([F:34])([F:32])[F:33])[CH:29]=[CH:30][C:15]=2[NH:14][C:13]1=[O:38])=[O:11]
Reactant: C=CCC1(C(=O)OC)C(=O)N(COC)c2ccc(C(F)(F)F)cc2CC1c1ccccc1OC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: CO
Product: C=CCC1(C(=O)OC)C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccccc1OC
Reaction time: 8 h
Yield: 104.2 %

Procedure:
Concentrated sulfuric acid (8 ml) and anhydrous lithium bromide (720 mg; 8 mmole) were added to a suspension of 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-1-(methoxymethyl)-4-(methoxyphenyl)-3-(2-propenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one (905 mg; 1.9 mmole) in methanol (40 ml) with stirring. The reaction mixture was heated under reflux (bath temperature=80°-85° C.) for nine hours, and then allowed to stand overnight at room temperature. The acid was carefully neutralized by the addition of saturated sodium bicarbonate solution and extracted with ethyl acetate (three times). The combined organic layers were dried (magnesium sulfate) and concentrated yielding 858 mg of the title compound as a solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[C@@H](O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C@@H:26]([OH:25])[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: O[C@@H]1CCNC1
Product: CC(C)(C)c1nc(N2CC[C@@H](O)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-pyrrolidin-3-ol and isolated as colorless gum (11.6 mg, 64%). MS(m/e): 387.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>CN(C)C1C=CN=CC=1>[C:15]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2)(=[O:17])[CH3:16]
Reactant: COC(=O)c1cc2c(O)cccc2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: COC(=O)c1cc2c(OC(C)=O)cccc2[nH]1
Temperature: 80 °C

Procedure:
Methyl 4-hydroxyindole-2-carboxylate (0.5 g) and 4-dimethylaminopyridine (50 mg) were dissolved in acetic anhydride (5 ml) and heated at 80° C. for 3 hours. The reaction was allowed to cool overnight to precipitate white crystals, which were filtered and dried in vacuo (0.44 g, 72%); NMR δ(CD3SOCD3) 2.34 (s, 3H), 3.85 (s, 3H), 6.80 (d, 1H) 7.06 (s, 1H), 7.23 (t, 1H), 7.29-7.35 (m, 1H), 12.1 (bs, 1H); M/z (−) 232 (M−H+).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH2:27][CH3:28])=[N:25][N:24]([C:29]3[CH:34]=[C:33]([N+:35]([O-])=O)[CH:32]=[CH:31][C:30]=3[C:38]([F:41])([F:40])[F:39])[C:23]2=[O:42])=[C:17]([F:43])[CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO.[H][H]>O=[Pt]=O.CCOC(C)=O>[NH2:35][C:33]1[CH:32]=[CH:31][C:30]([C:38]([F:39])([F:41])[F:40])=[C:29]([N:24]2[C:23](=[O:42])[N:22]([CH2:21][C:18]3[CH:19]=[CH:20][C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:6](=[O:7])(=[O:8])[NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:16][C:17]=3[F:43])[C:26]([CH2:27][CH3:28])=[N:25]2)[CH:34]=1
Reactant: [H][H]
Reactant: CCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F

Procedure:
A mixture of 388 mg (0.625 mmol) of 4-[[2'-(N-t -butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-5-ethyl-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step A), 6 mL of EtOH, 8 mL of EtOAc, and 30 mg of 5% PtO2 was shaken with hydrogen for 3.5 hours on a Parr hydrogenation apparatus. Removal of the catalyst followed by evaporation of volatiles gave 383 mg (quantitative) of a cream-colored solid [top >105° C. (gradual)] of sufficient purity to be used in the next step without further purification; mass spectrum (FAB) m/e 599 (M+Li)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:21]O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[O:13][C:14]=1[CH3:15].S(Cl)([Cl:25])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:21][Cl:25])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[O:13][C:14]=1[CH3:15]
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cc1Br
Reactant: O=S(Cl)Cl
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1Br
Reaction time: 2 h
Yield: 87 %

Procedure:
(3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}phenyl)methanol (4.20 g) was added to thionyl chloride (5 mL) at 0° C., and the mixture was stirred for 2 hrs. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-{[2-bromo-4-(chloromethyl)phenoxy]methyl}-2-(2-furyl)-5-methyloxazole as pale-yellow crystals (3.82 g, yield 87%). Recrystallization from ethyl acetate-hexane gave pale-yellow needle crystals. melting point: 125-126° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:20]([O-])=O)[C:10]([F:19])=[C:11]([F:18])[C:12]=3[O:14][CH:15]([CH3:17])[CH3:16])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.O>CC(O)=O.[Fe]>[NH2:20][C:9]1[C:10]([F:19])=[C:11]([F:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[C:13]2[C:8]=1[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(C)C)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(C)C)c(F)c(F)c(N)c2c1=O
Temperature: 90 °C
Reaction time: 5 h
Yield: 68.7 %

Procedure:
A suspension of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-5-nitro-4-oxoquinoline-3-carboxylate (222 mg, 0.560 mmol) and iron powder (188 mg, 3.36 mmol) in AcOH (6 mL) was stirred at 90° C. for 5 h. After water was added, the reaction mixture was stirred for 30 min. The crude product was extracted with EtOAc, washed with saturated aq. NaHCO3 and brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified by column chromatography (Hexane:EtOAc 5:1→1:1) to yield ethyl 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-4-oxoquinoline-3-carboxylate (141 mg, 69%) as a pale yellow solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl[CH:10]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18].O>C1(C)C=CC=CC=1>[C:1]1([O:7][CH:10]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccc(C(Cl)c2cccnc2)c(Cl)c1
Reactant: Oc1ccccc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(C(Oc2ccccc2)c2cccnc2)c(Cl)c1

Procedure:
1 gm of phenol is added to 100 ml of toluene in a 250 Erlenmeyer flask equipped with a refluxing condensor. 0.26 gm sodium is added and the system is heated at reflux until the sodium has dissolved. The system is then allowed to come to room temperature. At this time, 2.50 gm of alpha-chloro-2,4-dichloro-alpha-(3-pyridyl)toluene in 30 ml of toluene is added over 1 hour. The system is then heated at reflux for 6 hours. The system is added to water and the product extracted in the organic phase. The toluene is removed by stripping to give the 3-pyridyl-2,4-dichlorophenylcarbinol phenylether.
Reaction SMILES: [CH2:1]([C@H:8]([NH:22][C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28]([O-:30])=[O:29])=[O:24])[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH2:1]([C@H:8]([NH:22][C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28]([OH:30])=[O:29])=[O:24])[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cc(C(=O)[O-])ccc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cc(C(=O)O)ccc2C)c1
Reaction time: 8 h

Procedure:
3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino) carbonyl]4-methylbenzoate (200 mg, 0.42 mmol) is treated with lithium hydroxide (39 mg, 0.96 mmol) in tetrahydrofuran/methanol/water (2/1/1, 2 ml), and the mixture stirred overnight at 20–25 degrees C. The mixture is decanted and the supernatant concentrated to give 3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-4-methylbenzoic acid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([CH2:15][CH2:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:22]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:40].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:40][C:7]1[C:6]2[N:22]=[C:3]([CH2:1][CH3:2])[N:4]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[C:5]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:15][CH2:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:10][C:9]=2[N:8]=1
Reactant: [NH4+]
Reactant: CCc1nc2cnc3cc(CCC(=O)N(C)C)ccc3c2n1CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(CCC(=O)N(C)C)ccc3c2n1CC(C)(C)O
Reaction time: 0.17 h

Procedure:
To a stirring solution of crude 3-[2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylpropanamide, (1.2 g, 3.3 mmol) in dichloromethane (75 mL) was added 3-chloroperoxybenzoic acid (60% pure, 941 mg, 3.6 mmol). After 18 hours concentrated ammonium hydroxide (50 mL) was added and the reaction was vigorously stirred for 10 minutes. p-Toluenesulfonyl chloride (690 mg, 3.6 mmol) was then added in one portion and the reaction was stirred for one hour. The fractions were separated and the aqueous fraction was extracted with chloroform (3×50 mL). The combined organic fractions were concentrated under reduced pressure. Purification of the residue by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-6% gradient of methanol in dichloromethane) followed by recrystallization from acetonitrile provided 651 mg of 3-[4-amino-2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylpropanamide as an off-white solid, mp 234-237° C.
Reaction SMILES: [BH4-].[Li+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23](=[O:24])[CH2:22][CH:21]([C:25](OC)=[O:26])[CH2:20]2)=[CH:15][CH:14]=1.Cl.[OH-].[Na+]>O1CCCC1.CO>[OH:26][CH2:25][CH:21]1[CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:5]3[CH2:6][CH2:7][CH2:8][CH:4]3[CH3:3])=[CH:18][CH:17]=2)[C:23](=[O:24])[CH2:22]1
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCCCN3CCCC3C)cc2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCCN1CCCOc1ccc(N2CC(CO)CC2=O)cc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Lithium borohydride (0.1 g, 4.92 mmol, 1.8 eq) is added to a solution of methyl 1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-5-oxopyrrolidine-3-carboxylate a54 (0.99 g, 2.73 mmol, 1 eq) in tetrahydrofuran (20 ml) and methanol (0.35 ml). The mixture is stirred at 75° C. for 1 h, then cooled to 0° C. and a solution of 1 M hydrochloric acid is added. A solution of 2M sodium hydroxide is then added to reach a pH of 10. The aqueous layer is extracted twice with ethyl acetate, then the organic layers are dried over magnesium sulfate, and concentrated under vacuum to give 0.79 g of 4-(hydroxymethyl)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 72 as a colorless oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)OCc1cccc(C(=O)OC(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3.0 g of t-butyl 6-acetoxymethylpyridine-2-carboxylate were added 330 mg of potassium carbonate, 20 mL of methanol and 20 mL of water, and the mixture was stirred at room temperature for 3 hours. The methanol was removed under reduced pressure, then the residue was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by chromatography on silica gel (chloroform-ethanol 50:1) to give t-butyl 6-hydroxymethylpyridine-2-carboxylate as a yellow powder.
Reaction SMILES: BrC1C=CC(S(NC2C=CN=C(Cl)C=2)(=O)=O)=CC=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=2)[CH2:21]1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][C:36]=1[F:45]>>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:33][C:29]2[CH:30]=[N:31][CH:32]=[C:27]([N:22]3[CH2:23][C@H:24]([CH3:26])[NH:25][C@H:20]([CH3:19])[CH2:21]3)[CH:28]=2)(=[O:43])=[O:42])=[CH:37][C:36]=1[F:45]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: C[C@@H]1CN(c2cncc(N)c2)C[C@H](C)N1
Agent: O=S(=O)(Nc1ccnc(Cl)c1)c1ccc(Br)cc1
Product: C[C@@H]1CN(c2cncc(NS(=O)(=O)c3ccc(Br)c(F)c3)c2)C[C@H](C)N1

Procedure:
The title compound was prepared in a manner similar to 4-bromo-N-(2-chloro-4-pyridinyl)benzenesulfonamide (D3) using 5-[cis-3,5-dimethyl-1-piperazinyl]-3-pyridinamine (D36) and 4-bromo-3-fluorobenzenesulfonyl chloride as the starting materials.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C@:5]12[O:12][C@:9]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=4)[CH:14]=3)([O:10][CH2:11]1)[C@H:8]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:7]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:6]2[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[OH:4].[O:54]1CCC[CH2:55]1>>[CH2:47]([O:46][C@H:6]1[C@H:7]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@@H:8]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@:9]2([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=4)[CH:14]=3)[O:12][C@@:5]1([CH:3]1[O:4][C:55](=[O:54])[NH:1][CH2:2]1)[CH2:11][O:10]2)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CN)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Reactant: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C5CNC(=O)O5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
To a solution of 2-amino-1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 10b (50 mg, 0.07 mmol, obtained from the synthetic method described in step 2 of example 10) in tetrahydrofuran (10 mL) was added N,N′-carbonyldiimidazole (14.3 mg, 0.09 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (10 mL×2) and then saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 27a as a white solid (36 mg, 69.5%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.42 (m, 1H), 7.34 (m, 12H), 7.20 (m, 3H), 7.10 (m, 2H), 6.91 (m, 2H), 6.78 (m, 2H), 5.46 (s, 1H), 4.95 (t, 2H), 4.84 (t, 2H), 4.30 (dd, 2H), 4.22 (d, 1H), 4.11 (m, 1H), 4.02 (m, 5H), 3.85 (d, 1H), 3.70 (d, 1H), 3.54 (m, 2H), 3.36 (d, 1H), 1.45 (t, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.N1C=CC=CC=1>O1CCCC1>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:9][NH:8][C:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NNC(=O)c1ccc[nH]1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(NNC(=O)c1ccc[nH]1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.750 g of 1H-pyrrole-2-carbohydrazide (5.99 mmol) in 50 ml tetrahydrofuran was added 1.315 g 4-bromobenzoyl chloride (5.99 mmol) and 1 ml pyridine (11.99 mmol) at room temperature under nitrogen. After one hour of stirring at room temperature, the desired product precipitated. The precipitate was filtered, washed with minimum dichloromethane and methanol and dried to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 10.47 (s, 1H), 10.04 (s, 1H), 7.84-7.88 (m, 2H), 7.75 (d, J=8.8, 1H), 7.75 (q, J=4.2, 1H), 6.91-6.95 (m, 2H), 6.33-6.15 (m, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[CH:19]1(C2C=CC(F)=C(B(O)O)C=2)[CH2:21][CH2:20]1>>[CH:19]1([C:7]2[CH:6]=[CH:5][C:4]([F:10])=[C:3]([C:11]3[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=3)[CH:2]=2)[CH2:21][CH2:20]1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: OB(O)c1cc(C2CC2)ccc1F
Product: O=C(O)c1csc(-c2cc(C3CC3)ccc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (5-cyclopropyl-2-fluorophenyl)boronic acid gave the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH:19]1([C:24]2[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([C:24]2[CH:25]=[CH:26][C:27]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=3)=[CH:28][CH:29]=2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Oc1ccc(C2CCCC2)cc1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C3CCCC3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 4-cyclopentylphenol and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)(=[O:14])=[O:13])[C:9](=[O:24])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>C1(C)C=CC=CC=1>[C:1]1([CH:7]2[CH2:11][N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:28](=[O:29])[NH:27][CH2:25][CH3:26])[CH2:19][CH2:18]4)(=[O:14])=[O:13])[C:9](=[O:24])[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN=C=O
Reactant: O=C1NC(c2ccccc2)CN1S(=O)(=O)c1ccc2c(c1)CCN2
Solvent: Cc1ccccc1
Product: CCNC(=O)N1CCc2cc(S(=O)(=O)N3CC(c4ccccc4)NC3=O)ccc21
Temperature: 55 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
4-Phenyl-1-(indoline-5-sulfonyl)-4,5-dihydro-2-imidazolone (0.25 g, 0.73 mmol) prepared in Preparation 5 was dissolved in 10 ml of toluene and then ethylisocyanate (0.1 ml, 1.09 mmol) was added thereto. The reaction mixture was stirred at 50-60° C. for 18 hours. After the solvent was evaporated, the residue was dissolved in 50 ml of dichloromethane, washed twice with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography (eluent:dichloromethane/methanol=15/1, v/v) to afford 0.22 g of the title compound.