Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:35][C:36]([O:38]CC)=[O:37])[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])=[O:16]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Ethyl 2-(2-methyl-4,5-diphenyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (0.300 g, 0.546 mmol) was dissolved in a 3:1:1 mixture of THF/MeOH/water (10 ml) and charged with lithium hydroxide (0.065 g, 2.73 mmol). The reaction was stirred at rt for 1 h, at which time LC/MS suggested the reaction was complete. The reaction was acidified with 3 N HCl, and the resulting mixture concentrated to almost dryness (water left), diluted with 3 mL brine solution and extracted 3 times with DCM. The organic layers were combined, dried, filtered, and concentrated under vacuum to yield 2-(2-methyl-4,5-diphenyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid (285 mg, 0.546 mmol, 100% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH:9]=2)[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[C:42]1(=[O:52])[N:46]([CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH:9]=3)[CH:4]=2)[C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12
Reactant: CCCN(CCC)CCCc1ccc2cc(CO)ccc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCN(CCC)CCCc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
The compound (453 mg) obtained in Example 121-9 was added with triphenylphosphine (516 mg) and phthalimide (245 mg), and then dissolved in anhydrous THF (10 ml). The solution was added with a 40% diethylazodicarboxylate/toluene solution (0.892 ml) in an ice bath and stirred at room temperature for 2 hours under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the residue was then purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (439 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])=[C:11]([CH3:29])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]([CH3:34])[CH:32]=[O:33].C(N(CC)CC)C.ClC(OC1C=CC=CC=1)=O>O1CCCC1.C(O)C.C(OCC)C>[CH3:30][N:31]([CH3:34])[C:32](=[O:33])[NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])=[C:11]([CH3:29])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Oc2ccnc(N)c2)ccc1NC(=O)CC(=O)Nc1ccc(F)cc1
Agent: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(Oc2ccnc(NC(=O)N(C)C)c2)ccc1NC(=O)CC(=O)Nc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 75 %

Procedure:
To a solution of N-[4-(2-aminopyridin-4-yloxy)-2-methylphenyl]-N′-(4-fluorophenyl)malonamide (60 mg) in tetrahydrofuran (6 ml)-N,N-dimethylformamide (0.090 ml) was added triethylamine (0.042 ml), and then phenyl chloroformate (0.038 ml) was added thereto while cooling in an ice water bath, followed by stirring for 20 min. The reaction mixture was concentrated under a reduced pressure. To a suspension of the residue in N,N-dimethylformamide (2.4 ml) were added diethylamine hydrochloride (61 mg) and triethylamine (0.106 ml), followed by stirring at room temperature for 7 hrs and 20 min. The reaction mixture was partitioned between ethyl acetate (50 ml) and a 1 N aqueous solution of sodium hydroxide (30 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then suspended in ethanol (0.5 ml)-diethyl ether (5 ml), filtered off, washed with diethyl ether and dried under aeration to provide the titled compound (52.7 mg, 75%) as colorless powder.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[NH:3])[CH3:2].Br[CH2:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1)=O.C(N(CC)C(C)C)(C)C>COCCOC>[C:9]([O:8][C:6](=[O:7])[NH:5][N:4]1[CH:14]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[N:3]=[C:1]1[CH3:2])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(=N)NNC(=O)OC(C)(C)C
Reactant: Cn1cc(C(=O)CBr)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: Cc1nc(-c2cnn(C)c2)cn1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 2-ethanimidoylhydrazinecarboxylate (17.3 g, 99.9 mmol), 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethanone (16.89 g, 83.18 mmol) and N,N-diisopropylethylamine (31.9 mL, 183 mmol) were combined in ice-cold 2-methyltetrahydrofuran (400 mL) and 1,2-dimethoxyethane (100 mL), and the reaction mixture was heated to reflux. After 2.5 hours, the reaction was cooled and washed with 50% saturated aqueous sodium chloride solution (75 mL). The aqueous layer was extracted with 2-methyltetrahydrofuran (100 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in warm ethyl acetate (60 mL), allowed to cool to room temperature, then cooled to 5° C. for 30 minutes. The resulting solid was collected by filtration and washed with a small quantity of cold ethyl acetate, then washed with diethyl ether, to provide the product as a very pale yellow solid. Yield: 16.0 g, 57.7 mmol, 69%. LCMS m/z 278.5 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.49 (br s, 9H), 2.23 (s, 3H), 3.84 (s, 3H), 6.87 (s, 1H), 7.51 (s, 1H), 7.60 (s, 1H), 8.67 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C([O-])(=O)C.[Na+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[Cl:26])N.Cl.N([O-])=O.[Na+]>O.CC(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([C:3]2[C:4](=[O:12])[O:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CC(C)=O
Product: O=c1oc2ccccc2c(O)c1-c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 16 %

Procedure:
33.8 g. (0.21 mol) of 4-hydroxy-coumarin, 140 ml. of acetone, 40 g. of sodium acetate and 6.6 g. of cuprous chloride are placed in a one-liter reactor. The mixture is brought to a temperature lower than 5° C. There are then added dropwise a solution of the diazonium chloride of 3,4-dichloro-aniline, prepared from 32.4 g. (0.2 mol) of 3,4-dichloro-aniline, 80 ml. of concentrated hydrochloric acid, 120 ml. of water and 20 g. (0.33 mol) of sodium nitrite. A slight liberation of nitrogen is found. The substance is left for one hour between -8° C. and -5° C. and it is then brought for one hour to 50° C. The acetone is then evaporated under vacuum. A pH value of 1 is adjusted. The chestnut-coloured precipitate is taken up under heat in 2 liters of a 5% solution of sodium bicarbonate, followed by filtration and then the filtrate is acidified with HCl. The product obtained is recovered, washed with water, dried and recrystallised from a mixture of ethanol and water (70-30). A chestnut-coloured product is obtained. Weight 9.8 g.; yield 16% (theoretical yield 51.4 g.); M.P. 262° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:4]([C:5]([O:7]C)=[O:6])[C:3]=1[C:13]([O:15]C)=[O:14].[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1ccc(O)c(N)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1c(O)ccc(C(=O)O)c1C(=O)O

Procedure:
A solution of dimethyl 3-amino-4-hydroxyphthalate C1-4 (11.25 g, 50 mmol) and NaOH (14.0 g, 350 mmol) in ethanol (140 mL) and H2O (50 mL) was stirred at 70° C. overnight. LCMS indicated that the reaction was complete. The reaction mixture was concentrated in vacuo, neutralized to pH<3, and filtered to yield 3-amino-4-hydroxyphthalic acid C1-5 as a white solid (9.6 g, yield: 97%), which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9](Cl)([CH3:11])[CH3:10].[SH-:16].[Na+]>CO>[CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9]([SH:16])([CH3:11])[CH3:10]
Reactant: COC(CC(C)CCCC(C)(C)Cl)OC
Reactant: [SH-]
Agent: [Na+]
Solvent: CO
Product: COC(CC(C)CCCC(C)(C)S)OC

Procedure:
A solution of 10 g. of 1,1-dimethoxy-7-chloro-3,7-dimethyloctane, 1.1 equivalents of sodium hydrosulfide and 100 ml. of methanol is refluxed for 24 hours. After cooling, solvent is evaporated under reduced pressure and the concentrate taken up in ether. The ether solution is washed with water, dried over magnesium sulfate and then evaporated to give 1,1-dimethoxy-7-mercapto-3,7-dimethyloctane.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:24]=O)=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH3:23])[N:18]=[CH:17]4)[N:8]=2)[CH:6]=1.Cl.[NH:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:1][C:2]1[C:3]([CH2:24][N:27]2[CH2:30][CH:29]([OH:31])[CH2:28]2)=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH3:23])[N:18]=[CH:17]4)[N:8]=2)[CH:6]=1
Reactant: Cc1cn(-c2ccnc(Nc3ccc4c(cnn4C)c3)n2)cc1C=O
Reactant: OC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cn(-c2ccnc(Nc3ccc4c(cnn4C)c3)n2)cc1CN1CC(O)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of intermediate 13 (0.45 g, 1.3 mmol), 3-azetidinol hydrochloride (0.3 g, 2.7 mmol) and triethylamine (0.76 mL) in 50 mL of dichloromethane, was added NaBH(OAc)3 (0.86 g, 4.5 mmol) at room temperature. The reaction was stirred for 12 hour at room temperature and then quenched with 1N—NaOH. It was extracted with dichloromethane (×2) and washed with brine. The collected organic layers were dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by column chromatography to afford desired Compound No. 143 as a pale yellow solid (0.27 g, 51%); MS (ESI) m/z 391 [M+H]+.]+; 1H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.48 (d, 1H, J=5.4 Hz), 8.30 (s, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.62 (m, 2H), 7.12 (d, 1H, J=5.4 Hz), 5.34 (m, 1H), 4.19 (m, 1H), 4.04 (s, 3H), 3.49 (m, 2H), 3044 (s, 2H), 2.77 (m, 2H), 2.29 (m, 3H).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:18])[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)(C)C>[NH2:10][C:11]1([CH3:18])[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCC(O)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CC1(N)CCC(O)CC1

Procedure:
A mixture of example 45E (169 mg, 0.64 mmol), ammonium formate (105 mg, 1.67 mmol) and 10% palladium on carbon (7 mg) in isopropanol (5 mL) was heated at 80° C. for 1 hour. The reaction mixture was cooled and filtered through a plug of Celite. The filter pad was washed with ethyl acetate (50 mL), and the filtrate was concentrated in vacuo to afford the titled compound as an inseparable mixture of diastereomers. MS (CI) m/z 130 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 3.77-3.71 (m, 2H), 3.65-3.61 (m, 2H), 1.87-1.61 (m, 4H), 1.63-1.33 (m, 10H), 1.15 (s, 3H), 1.11 (s, 3H).
Reaction SMILES: CO[C:3](OC)([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:4][NH:5][C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1)=[S:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:15][C:14]1[C:9]([NH:8][C:6]2[S:7][C:3]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[CH:4][N:5]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(CNC(=S)Nc1ncccc1C)(OC)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1cccnc1Nc1ncc(-c2ccncc2)s1
Temperature: 140 °C

Procedure:
1-(2,2-Dimethoxy-2-pyridin-4-yl-ethyl)-3-(3-methyl-pyridin-2-yl)-thiourea (19-2, 0.050 g, 0. 16 mmol) and p-toluenesulfonic acid monohydrate (0.003 g, 0.02 mmol) were combined and heated to 140° C. The reaction was terminated at partial conversion and was purified by reverse phase HPLC to provide the titled compound. 1H NMR (CD3OD) δ8.61 (d, 2H, J=7.1 Hz), 8.48 (s, 1H), 8.30 (dd, 1H, J=1.0, 4.8 Hz), 8.15 (d, 2H, J=7.3 Hz), 7.74 (dd, 1H, J=0.7, 7.3 Hz), 7.10 (dd, 1H, J=5.1, 7.3 Hz), 2.43 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:63][C:64]([F:68])([F:67])[CH2:65][NH2:66]>C(Cl)Cl>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:66][CH2:65][C:64]([F:68])([F:67])[F:63])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: NCC(F)(F)F
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCC(F)(F)F)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) were added HBTU (30 mg, 0.079 mmol) and (2,2,2-trifluoroethyl)amine (0.031 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (37 mg, 80%). LC-MS m/z 603 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:23][CH:24]=3)[OH:29])[CH2:11][CH2:10]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)c1ccc(C(=O)CCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ccc(C(O)CCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 80.6 %

Procedure:
To a solution of 4-diphenylmethoxy-1[3-(4-tert-butylbenzoyl)propyl]-piperidine (4.7 g; 0.01 mol) in ethanol (80 ml), sodium borohydride (0.4 g; 0.0105 moles) was added, and the mixture was boiled under reflux for 1.5 hours. Then the solvent was removed in vacuo and the residue dissolved in methylene chloride. The resulting solution was washed with water, dried (Na2SO4) and the solvent removed in vacuo to give an oil, which was crystallized on treatment with petroleum ether (b.p. 50°-70° C.). 4-Diphenylmethoxy-α(-4-tert-butylphenyl)-1-piperidinebutanol (3.8 g; yield 80.6%) was obtained, m.p. 129°-131° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1.OCCC1CCN(C(OC(C)(C)C)=O)CC1>>[O:26]1[CH2:31][CH2:30][CH:29]([O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:28][CH2:27]1
Reactant: OC1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Agent: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OC4CCOCC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 2 of EXAMPLE 7 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, step 2) and tetrahydro-2H-pyran-4-ol instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate.
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[OH-].[Na+].[CH3:9][N:10]1[C:18]([S:19]([O-:21])=[O:20])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]2)=[N:11]1.[Li+]>O>[CH3:9][N:10]1[C:18]([S:19]([NH2:1])(=[O:21])=[O:20])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]2)=[N:11]1
Reactant: Cn1nc2ccccc2c1S(=O)[O-]
Reactant: NOS(=O)(=O)O
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nc2ccccc2c1S(N)(=O)=O
Temperature: 10 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
A solution containing 9.5 g (72 mmol) of 2-methyl-2H-indazole in 200 ml of ethyl ether, was cooled to -30° C., and 61.4 g (144 mmol) of n-butyl lithium (a 15% hexane solution) was dropwise added thereto. The mixture was stirred for one hour at the same temperature, and then an excess amount of sulfurous acid gas was blown thereinto for 3 hours at a temperature of not higher than -20° C. After completion of the reaction, the mixture was returned to room temperature, stirred for 12 hours and then diluted with ethyl ether. The product was subjected to filtration. The crystals were dried to obtain crude lithium 2-methyl-2H-indazole-3-sulfinate. This product was used for the subsequent reaction without purification. 48.8 g (430 mmol) of hydroxylamine-O-sulfonic acid was gradually added to a solution containing 17.2 g (430 mmol) of sodium hydroxide in water 300 ml) under cooling with ice (not higher than 10° C.). This solution was added all at once to a solution containing the crude lithium 2-methyl-2H-indazole-3-sulfinate previously prepared in water (100 ml), and then the mixture was stirred for 12 hours at room temperature. Formed crystals were collected by filtration to obtain 8.8 g (yield: 58%) of 2-methyl-2H-indazole-3-sulfonamide (slightly yellow granular crystals). Melting point: 181°-183° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:19][O:20][CH3:21]>CC#N>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:19][O:20][CH3:21])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cc(O)cc1F
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCOc1cc(O)c(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Fluoro-4,6-dihydroxybenzaldehyde (12 g) was dissolved in MeCN (250 mL), and cesium carbonate (25.1 g) and chloromethylmethylether (6.95 mL) were added thereto, followed by stirring at room temperature for 1 hour. The insoluble materials were removed by filtration through celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 94:6) to obtain 2-fluoro-6-hydroxy-4-(methoxymethoxy)benzaldehyde (11.89 g) as a white powder.
Reaction SMILES: [NH2:1][CH:2]([CH:10]([OH:20])[CH:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([NH:1][CH:2]([CH:10]([OH:20])[CH:11]([NH:19][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NS(C)(=O)=O
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
A solution of the resultant compound of Example 12 (0.049 mmol) and 0.032 ml (0.29 mmol) of 4-methylmorpholine in 1 ml of dichloromethane Was cooled to 0° C. and treated with 0.008 ml (0.10 mmol) of methanesulfonyl chloride. After 0.5 h, the solution was washed with 10% aqueous citric acid, dried over Na2SO4, and concentrated. Flash chromatography using 5% methanol in chloroform gave 2.6 mg (13%) of the desired compound. 1H NMR (CDCl3) δ2.16 (s, 3H), 2.34 (s, 3H), 2.93 (m, 4H), 3.41 (d, J=4 Hz, 1H), 3.7-3.8 (m, 2H), 3.92 (m, 1H), 5.06 (d, J=9 Hz, 1H), 5.42 (d, J=9 Hz, 1H), 7.2-7.4 (m, 10H). Mass spectrum (M+NH4)+ =444.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:23])=[C:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=3[O:21]C)[CH:16]=[O:17])[CH:11]=2)[C:6]([CH3:25])([CH3:24])[CH2:5][C:4]1=[O:26])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:23])=[C:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=3[OH:21])[CH:16]=[O:17])[CH:11]=2)[C:6]([CH3:25])([CH3:24])[CH2:5][C:4]1=[O:26])[CH3:2]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
A solution of 7.05 g of Compound 1B (20.1 mmol) in 6 mL of dry dichloromethane was treated with 4 mL of 1M BBr3 in dichloromethane. The reaction flask was then equipped with a reflux condenser, nitrogen inlet and heated to reflux. After 2 hours another 20 mL of BBr3 was added and refluxing continued for an additional 2 hours. The reaction mixture was allowed to cool to room temperature. The crude reaction mixture was diluted with dichloromethane and washed with water (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and excess solvent removed on the rotary evaporator. The crude product Compound 1C was purified by flash chromatography (EtOAc/Hexanes; gradient 15% to 30%) to give 3.6 g (53%) of product as a white solid. MS (electrospray): mass calculated for C21H23NO3, 337.17; m/z found 338.3, [M+H]+. 1HNMR (400 MHz, CDCl3): 9.91 (s, 1H), 7.85 (dd, J=2.0, 8.5 Hz, 1H), 7.70 (d, J=1.98 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.89 (s, 1H), 6.20 (s, 1H), 4.01 (q, J=7.1 Hz, 2H), 2.52 (s, 2H), 2.15 (s, 3H), 1.33 (s, 6H), 1.22 (t, J=7.09 Hz, 3H).