Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O.[CH2:19]=[C:20]([CH3:22])[CH3:21].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]2[CH2:19][C:20]([CH3:22])([CH3:21])[C:9]3[C:2](=[CH:3][CH:4]=[C:5]([C:6]#[N:7])[CH:8]=3)[NH:1]2)[CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: C=C(C)C
Reactant: O=Cc1cccc(Br)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(C#N)cc21
Temperature: 85 °C
Reaction time: 18 h
Yield: 40.1 %

Procedure:
To a stirred solution of 4-aminobenzonitrile (10.0 g, 84.7 mmol) and 3-bromobenzaldehyde (10 mL, 84.7 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 0-10% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (11.6 g, 40.0%) as a light yellow solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 341.0 & 343.0.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(O)(O)O.[S:12](=[O:16])(=O)(O)[OH:13]>O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([S:12]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)(=[O:16])=[O:13])=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccccc1
Agent: OB(O)O
Solvent: O
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 82 %

Procedure:
470.6 g (5.0 moles) of phenol and 6.2 g (0.1 mole) of boric acid were placed in a glass flask having a capacity of 2 liters. While the mixture was heated to 180°-186° C., 102.2 g (1.0 mole) of 96% sulfuric acid were added dropwise, after which the water of reaction was removed at 180°-186° C. The phenol was then distilled off over a period of 2 hours at a temperature of from 160° to 200° C. Analysis of the crude product revealed the following composition: 3% phenol, 1% isomeric sulfone and 97% bis(4-hydroxyphenyl) sulfone. Further purification was conducted as described in Example 1. There were obtained 205 g (0.82 mole; yield 82%) of bis(4-hydroxylphenyl) sulfone showing a purity of >99%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:25][C:26]([F:31])([F:30])[CH:27]1[O:29][CH2:28]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:23])([F:24])[CH:20]([F:21])[F:22])[CH:13]=2)[CH2:28][CH:27]([OH:29])[C:26]([F:31])([F:30])[F:25])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Reactant: FC(F)(F)C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 55 °C
Yield: 44.8 %

Procedure:
Ex-528B) N-(3-nitrophenyl)-3-(1,1,2,2-tetrafluoroethoxy)benzene-methanamine (3.25 g, 9.44 mmol) from EX-528A and 1,1,1-trifluoro-2,3-epoxypropane (0.895 mL, 10.4 mmol) were dissolved in 15 mL of acetonitrile. Ytterbium (III) trifluoromethane-sulfonate (0.77 g, 1.24 mmol) was added, and the stirred solution was warmed to 55° C. for 48 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10 to give 1.93 g (45%) of the desired 3-[(3-nitrophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a brown oil. HRMS calcd. for C18H16F7N2O4: 457.0998 [M+H]+, found: 457.1008. 1H NMR (CDCl3) δ3.7 (dd, 1H), 3.9 (dd, 1H), 4.4 (m, 1H), 4.8 (m, 2H), 5.9 (tt, 1H), 7.0-7.2 (m, 4H), 7.3-7.4 (m, 2H), 7.6 (m, 2H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:31]=[C:30](F)[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].C[N:34]([CH3:37])C=O>O>[Cl:22][C:23]1[CH:31]=[C:30]([N:34]2[CH:37]=[CH:9][C:8]([CH3:15])=[N:7]2)[CH:29]=[CH:28][C:24]=1[C:25]([N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11]1)=[O:26]
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: CN(C)C=O
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 62 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Step B (12.8 g, 65 mmol) in dimethylformamide (120 mL) under nitrogen was added potassium carbonate (19.76 g, 143 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-chloro-4-fluorobenzoyl chloride of Step C (78 mmol) in dimethylformamide (50 mL). After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate gradient from 95:5 to 80:20) to provide the pure title compound (14.25 g, 62%) along with some less pure material (2.7 g). The pure material is an off-white crystalline solid, which is used as such in the next step.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH:14]([CH3:16])[CH3:15])[C:10]([O:12]C)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].O1CCOCC1.[Li+].[OH-].[ClH:25]>O>[Cl-:25].[C:10]([C@@H:9]([NH2+:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[CH:14]([CH3:16])[CH3:15])([OH:12])=[O:11]
Reactant: Cl
Reactant: C=CCCCCCN[C@H](C(=O)OC)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCCCCC[NH2+][C@H](C(=O)O)C(C)C
Product: [Cl-]

Procedure:
To a solution (0.4M) of methyl (2S)-2-(hept-6-en-1-ylamino)-3-methylbutanoate 67 in a 1:1 mixture of dioxane and water, LiOH (4 eq.) was added, and the reaction mixture was stirred at reflux for 24 h. The reaction mixture was then cooled and brought to pH=2 by small additions of HCl(aq) 6N. The white precipitate was filtered and washed with H2O and dried overnight. The title compound (71%) as a white precipitate was used in the next step without any further purification. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 9.80 (bs, 1H), 8.95 (bs, 1H), 5.74 (ddt, J 17.0, 16.9, 6.7, 1H), 4.95 (d, J 17.0, 1H), 4.89 (d, J 10.2, 1H), 3.73-3.70 (m, 1H), 2.91-2.72 (m, 2H), 2.43-2.35 (m, 1H), 1.96 (q, J 6.7, 2H), 1.78-1.65 (m, 2H), 1.33-1.24 (m, 4H), 1.01 (d, J 7.1, 3H), 0.92 (d, J 6.8, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[OH:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][OH:22])[CH2:26][CH2:27]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: OCCN1CCNCC1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(CCO)CC4)cc3nc21
Yield: 52.7 %

Procedure:
The reaction is carried out under the conditions of Reference Example 1 but starting from 1.6 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 6.8 g of 1-(2-hydroxyethyl)-piperazine in 16 cm3 of pyridine. After concentrating the reaction mixture to dryness under reduced pressure, the residue is taken up in 50 cm3 of water. The mixture is brought to pH 6.9 by adding 0.4 cm3 of acetic acid. The precipitate obtained is drained, washed with twice 10 cm3 of water and recrystallized twice from 10 cm3 of dimethylformamide. 1.1 g of 7-fluoro-8-[4-(2-hydroxyethyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-di hydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 275°-276° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]\[C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.O1CCCC1.C(O)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1nc(/C=C\c2ccc([N+](=O)[O-])cc2)cs1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Yield: 29.9 %

Procedure:
A mixture of N-{4-[(Z)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (2 g) and 10% palladium carbon (400 mg) in methanol (25 ml), tetrahydrofuran (25 ml) and acetic acid (18 ml) was stirred under 4 atm hydrogen at ambient temperature for 5 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate. The organic solution was washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with n-hexane/ethyl acetate (1:2)→ethyl acetate as an eluent, and triturated with ethyl alcohol/ethyl ether to give N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (539.6 mg) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10]([CH2:12][CH:13]([CH3:15])[CH3:14])=[O:11].Cl[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20].[Cl-].[NH4+]>CO>[CH3:14][CH:13]([CH3:15])[CH2:12][C:10]([C:3]1[C:2]([OH:1])=[C:7]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:6]([OH:8])=[C:5]([CH2:7][CH:2]=[C:3]([CH3:10])[CH3:4])[C:4]=1[OH:9])=[O:11]
Reactant: CC(C)CC(=O)c1c(O)cc(O)cc1O
Reactant: CC(C)=CCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)=CCc1c(O)c(CC=C(C)C)c(O)c(C(=O)CC(C)C)c1O
Yield: 17.1 %

Procedure:
Under an atmosphere of nitrogen, 441 mg (11.1 mmol, 2.06 equivalents) of an oily 60% sodium hydride was washed with dry hexane to remove paraffin. To this was added 6.0 ml of dry methanol cooling with ice and stirred. Then, a methanol (6.0 ml) solution of 1.135 g (5.400 mmol) of (2-methylpropyl) (2,4,6-trihydroxyphenyl) ketone (5) was added dropwise to the solution. Further, a methanol (5.0 ml) solution of 1.205 g (11.52 mmol, 2.130 equivalents) of 1-chloro-3-methyl-2-butene was slowly added dropwise. The mixture was stirred cooling with ice for 1.5 hours, then added 50 ml of a saturated aqueous ammonium chloride solution, and extracted from ether. The ether layer was washed with saturated brine, dried over sodium sulfate, and distilled under a reduced pressure to remove the solvent and obtain 1.752 g of a crude product in the form of a red viscous oily substance. This crude product was subjected to silica gel column chromatography (40 g of Wako Gel C-300 and eluted sequentially with 200 ml each of petroleum ether:ether at varying ratios=19:1, 18:2, 17:3, and 16:4). From the eluate of the column, various fractions were sequentially obtained. As the first fraction, 160 mg of {3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (15) was obtained in the form of light yellow crystals shaped fine needles.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[N+:13]([CH:15](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:16])#[C-:14].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:16][C:15]1[N:13]=[CH:14][O:8][C:7]=1[C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(F)(F)F)cc1
Yield: 68.4 %

Procedure:
A mixture of 4-(trifluoromethyl)benzaldehyde (3.45 mL, 25.8 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (5.40 g, 25.8 mmol), and K2CO3 (4.28 g, 31.0 mmol) in methanol (125 mL) was heated to reflux. After 2.5 hours the volatiles were evaporated, and the residue was partitioned between diethyl ether and H2O. The aqueous phase was extracted with diethyl ether, and the combined organic extract was washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash chromatography (Analogix Intelliflash 280; 10% to 30% ethyl acetate/hexanes eluant; SF65-400 g column), which yielded 4.01 g (68% yield) of the title compound as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.85 (m, 4H), 2.42 (s, 3H). MS (DCI+) m/z 228 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=O.[BH4-].[Na+]>C(O)C>[NH:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=2[CH:6]=[N:7]1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
4-Nitro-1H-indazole (1.63 g, 10 mmol) in ethanol (100 mL) was treated with BiCl3 (3.46 g, 11 mmol) followed by a portionwise addition of NaBH4 The reaction mixture was stirred at ambient temperature for 20 minutes and filtered through Celite. The filtrate was evaporated under reduced pressure and the residue was partitioned between ethyl acetate/dilute NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure to provide the title compound as a tan solid (1.0 g). 1H NMR (300 MHz, DMSO-d6) δ 5.64 (s, 2H), 6.1 (d, 1H), 6.6 (d, 1H), 6.98 (t, 1H), 8.03 (s, 1H), 12.6 (s, 1H).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO.[H][H]>C(Cl)Cl.[Ru]>[OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCCC(=O)CC(=O)OC
Reactant: [H][H]
Agent: [Ru]
Solvent: CO
Solvent: ClCCl
Product: CCCCC[C@@H](O)CC(=O)OC
Yield: 94.9 %

Procedure:
Into a 100-ml autoclave (made of Hastelloy) were introduced 20 g of methyl 3-oxooctanoate (manufactured by Inoue Perfumery Mfg. Co., Ltd., Japan) and 40 ml of methanol. The atmosphere in the autoclave was replaced with nitrogen gas. Thereto was added a solution prepared by dissolving 150 mg of Ru2Cl4 ((+)-(T)BINAP)2Et3N as a ruthenium-optically active phosphine complex in 1.2 ml of methylene chloride. Asymmetric hydrogenation was conducted at a reaction temperature of 65° C. and a hydrogen pressure of 30 atm. After the reaction mixture was thus reacted for 6 hours, it was taken out of the autoclave. The methanol was distilled off, and the residue was subjected to vacuum distillation to obtain 19.2 g of methyl (R)-3-hydroxyoctanoate. Yield, 95%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[CH3:12]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([O:7][CH3:12])=[O:6]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: CO
Product: COC(=O)c1ccc(N)c(N)c1

Procedure:
To the stirred suspension of commercial 3,4-diaminobenzoic acid (10.3 g) in methanol (150 ml) conc. sulphuric acid (5 ml) was added cautiously. The mixture was stirred under reflux for 3 h. About half of the solvent is removed by distillation and dichloromethane (150 ml) is added. The organic layer was poured in ice water (300 ml) and with vigorous stirring the pH was adjusted to 11 with 10M NaOH. The organic layer was separated and the aqueous layer extracted with dichloromethane (150 ml). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by fractional crystallisation from dichloromethane to give methyl 3,4-diaminobenzoate (7.05 g) as beige coloured solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.[Cl:13][C:14]1[CH:15]=[C:16]([C@H:21]([CH2:33][CH:34]=O)[CH2:22][N:23]([CH3:32])[C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]>ClCCl.CO>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([C@H:21]([CH2:33][CH2:34][N:10]2[CH2:11][CH2:12][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9]2)[CH2:22][N:23]([CH3:32])[C:24](=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: c1cncc(C2CCNCC2)c1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CN(C[C@@H](CCN1CCC(c2cccnc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl

Procedure:
Using a procedure similar to that described in Example 1 (alternative procedure), 4-(3-pyridyl)piperidine was alkylated using (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide. Chromatography of the crude product, with dichloromethane:methanol (9:1) as the eluent, followed by conversion to the hydrochloride salt gave the title compound as a white solid (0.253 g); mp 70°-140° C. (dec); NMR: 1.8-2.4 (m, 6), 2.73 (s, 3), 2.8-3.2 (broad s, 5), 7.0-7.2 (m, 3), 7.4 (s, 4), 7.5-7.7 (m, 2), 7.9 (m, 1), 8.2 (broad s, 1), 8.7 (d, 2 J=5); MS: m/z=496(M+1). Analysis for C28H31ClN3O·2.2 HCl·3 H2O: Calculated: C, 53.94; H, 6.31; N, 6.74; Found: C, 53.53; H, 6.16; N, 6.65.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=2)[O:11][C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4]1.[C:21]([O-:24])(O)=[O:22].[Na+]>O1CCOCC1.O.CCOCC.[OH-].[Na+]>[C:18]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][C:5]1([CH2:6][CH2:7][N:8]([C:21]([O:24][C:5]([CH3:10])([CH3:6])[CH3:4])=[O:22])[CH2:9][CH2:10]1)[CH2:4][C:3]2=[O:2])([OH:20])=[O:19]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C(=O)O)ccc1O2
Temperature: 25 °C
Reaction time: 13 h

Procedure:
4-Oxospiro[chroman-2,4′-piperidine]-6-carboxylic acid hydrochloride (15.0 g, 50.3 mmol) was dissolved in 1,4-dioxane (150 ml) and H2O (150 ml), NaHCO3 (10.6 g, 126 mmol) and DIBOC (13.2 g, 60.4 mmol) were added thereto in this order. After stirred at room temperature for 13 h, the reaction mixture was diluted with Et2O and 5N NaOH aq. (12.1 ml). The aqueous layer was washed with Et2O and acidified with 6N HCl aq. (PH=ca. 3), then extracted with CHCl3. The organic layer was washed with brine and dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was triturated with MeOH—H2O and the insoluble solid was collected through filtration to obtain the intended compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[Br:13]Br.N#N.CC(C)=O.C(Cl)(Cl)(Cl)Cl>C(O)(=O)C>[Br:13][C:10]1[C:5]2[O:4][N:3]=[C:2]([Cl:1])[C:6]=2[CH:7]=[CH:8][C:9]=1[O:11][CH3:12]
Reactant: COc1ccc2c(Cl)noc2c1
Reactant: BrBr
Agent: N#N
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)noc2c1Br
Reaction time: 8 h

Procedure:
To a stirred solution of 3-chloro-6-methoxy-1,2-benzisoxazole (25 g) in acetic acid (200 ml) was added a solution of bromine (32.6 g) in acetic acid (100 ml) dropwise under N2 at ambient temperature. The mixture was allowed to stir overnight. TLC (silica gel, 5% acetone/CCl4) revealed the presence of starting material. Additional bromine (11 g) in acetic acid (50 ml) was added, and the reaction mixture was allowed to stir overnight. The reaction was filtered and washed with water. The precipitate was collected and recrystallized from methanol to yield the desired compound, m.p. 134°-135° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH:24][CH2:25][CH3:26])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(N([CH2:32][CH3:33])CC)C.C(OC(=O)C)(=[O:36])C.O>ClCCl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][N:24]([CH2:32][CH3:33])[C:25](=[O:36])[CH3:26])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCNCC1(c2ccc(OC3CCN(C(C)C)CC3)cc2)CCOCC1
Reactant: CCN(CC)CC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCN(CC1(c2ccc(OC3CCN(C(C)C)CC3)cc2)CCOCC1)C(C)=O
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To a stirred solution of N-[(4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]-N-ethylamine (102 mg, 0.283 mmol) and triethylamine (99 μl. 0.708 mmol) in dichloromethane (1 ml) was added dropwise acetic anhydride (29 μl, 0.312 mmol). Reaction left at ambient temperature for 4 hours until reaction complete. Water (1 ml) and dichloromethane (10 ml) added to the reaction, the extracted with saturated NaHCO3 (2×10 ml). Organic washings were dried over Na2SO4 and concentrated in vacuo to give the title compound as an oil (107 mg, 94%). 1H NMR (400 MHz, CD3OD) δ 7.20-7.31 (multiplet due to rotamers, 2H), 6.92-7.00 (multiplet due to rotamers, 2H), 4.36-4.46 (m, 1H), 3.70-3.88 (m, 2H), 3.20-3.55 (several peaks due to rotamers, 4H), 2.78-2.90 (m, 3H), 2.60, (q, 2H), 2.25-2.52 (multiple peaks due to rotamers, 2H), 1.70-2.10 (multiple peaks, 11H), 1.10 (d, 6H), 0.80-1.00 (two triplets due to rotamers, 3H).
Reaction SMILES: B.C1(C)C=CC=CC=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:28]=[C:29]([F:31])[CH:30]=1)[C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1)=[O:14]>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([C@H:13]([OH:14])[C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:16]2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cc(F)cc(Cl)c2)C1
Agent: B
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cc(F)cc(Cl)c2)C1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A mixture of 10 M H3B.S2Me in THF (47.7 mL, 0.477 mol) and 1 M R-CBS-oxazaborolidine in toluene (72 mL, 0.072 mol) were dissolved in 100 mL anhydrous THF and cooled to −15° C. (R)-tert-butyl 3-(3-chloro-5-fluorobenzoyl)piperidine-1-carboxylate in 400 mL anhydrous THF was added dropwise to the above solution and stirred at −15° C. for 2 hr. The reaction was quenched with methanol (500 mL). The solvent was removed under reduced pressure and the residue was purified by column chromatography. The product was re-crystallized three times with EtOAc/Hexanes to give (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (55 g, 0.156 mol). 1H NMR (CDCl3, 400 MHz) δ7.10 (s, 1H), 7.04-6.90 (dd, 2H), 4.46-4.30 (d, 1H), 4.05-2.40 (m, 5H), 1.74 (s, 1H), 1.60 (s, 1H), 1.53-1.31 (m, 11H), 1.30-1.14 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:18][C:11]3=[N:12][CH:13]=[C:14]([Cl:17])[C:15]([CH3:16])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[OH:19].[CH:20]([C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=O.C[Si](Cl)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[Cl:17][C:14]1[C:15]([CH3:16])=[C:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH2:20][C@H:22]4[CH2:26][CH2:25][CH2:24][N:23]4[C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])=[C:3]([OH:19])[CH:4]=3)[NH:18][C:11]2=[N:12][CH:13]=1
Reactant: Cc1c(Cl)cnc2[nH]c(-c3ccc(N)c(O)c3)nc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: Cc1c(Cl)cnc2[nH]c(-c3ccc(NC[C@H]4CCCN4C(=O)OC(C)(C)C)c(O)c3)nc12
Reaction time: 8 h

Procedure:
2-Amino-5-(6-chloro-7-methyl-3H-imidazo[4,5-b]pyridin-2-yl)phenol (Example 249) (0.050 g, 0.18 mmol) and tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate (0.036 g, 0.18 mmol) were dissolved in NMP (1.0 ml) and acetic acid (0.10 ml). TMSCl (0.046 ml, 0.36 mmol) and NaBH(OAc)3 (0.072 g, 0.36 mmol) were added and the mixture stirred overnight. The crude mixture was purified by HPLC-C18 giving the title compound (0.017 g, 21%).