Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1.I[CH2:15][CH2:16][CH3:17].CN(C)C=O>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:15][CH2:16][CH3:17])[C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1cccc(Br)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCN(C(C)=O)c1cccc(Br)c1

Procedure:
In a manner similar to that of Example (27b), by reaction of 820 mg (20.5 mmol, 1.1 eq) of 60% sodium hydride, 4.0 g (18.7 mmol, 1 eq) of N-(3-bromophenyl)acetamide (prepared in Example 27a) and 2.20 mL (22.4 mmol, 1.2 eq) of 1-iodopropane in 15 ml of tetrahydrofuran in the presence of 1.5 ml of dimethylformamide, N-(3-bromophenyl)-N-propylacetamide is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](O)[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[C:29]([O:32][C:33](=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:33][O:32][C:29](=[O:31])[CH3:30])[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(O)c2)c1=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cccc(-n2cc(-c3ccccn3)cc(-c3ccccc3C#N)c2=O)c1
Temperature: 25 °C

Procedure:
To 56 mg of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-hydroxyphenyl)-1,2-dihydropyridin-2-one were added 1 ml of acetic anhydride and 1 ml of pyridine and the mixture was stirred at room temperature for one night. The reaction solution was concentrated in vacuo and purified by an NH silica gel chromatography (hexane-ethyl acetate system) to give 30 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[Cl:24][C:25]1[CH:34]=[CH:33][C:28]([C:29](=[O:32])[CH2:30]Br)=[CH:27][C:26]=1[F:35]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:30]=1[C:29](=[O:32])[C:28]1[CH:33]=[CH:34][C:25]([Cl:24])=[C:26]([F:35])[CH:27]=1
Reactant: O=C(CBr)c1ccc(Cl)c(F)c1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ccc(Cl)c(F)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 4-chloro-3-fluorophenacyl bromide* .
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[N+:6]([O-:9])[C:5]([C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:14]O>>[Cl:1][C:2]1[C:7]([Cl:8])=[N+:6]([O-:9])[C:5]([C:10]([O:12][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)c(Cl)[n+]1[O-]
Agent: Cl
Product: COC(=O)c1ccc(Cl)c(Cl)[n+]1[O-]
Temperature: 45 °C

Procedure:
A suspension of 5,6-dichloropyridine-2-carboxylic acid-N-oxide (5.0 g, 24.0 mmol) in methanol (100 mL) was saturated with HCl gas and the reaction mixture heated at 40-50° C. for one hour. The solvent was removed and the residue dissolved in diethyl ether/ethyl acetate. The organic solution was washed with water, saturated sodium bicarbonate solution, brine, dried, and concentrated to give methyl 5,6-dichloropyridine-2-carboxylate-N-oxide (4.0 g, 18.1 mmol). 1H NMR (DMSO-d6): δ 7.75 (s, 2H), 3.88 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.O.[Br:16]Br>C(O)(=O)C>[Br:16][C:12]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:14])[N:9]2[CH3:13])=[N:4][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc2c(n1)CCC(=O)N2C
Solvent: O
Solvent: CC(=O)O
Product: COc1nc2c(cc1Br)N(C)C(=O)CC2
Temperature: 60 °C
Yield: 82.1 %

Procedure:
To a solution of 0.6 g (3.1 mmol) 6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one in 8 ml of acetic acid was added 8 ml of water. To this mixture was added 0.32 ml (6.2 mmol) of bromine. The reaction mixture was heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature and poured into 50 ml of water. The suspension was extracted with ethyl acetate. The ethyl acetate extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica using chloroform as the elutant. Appropriate fractions were combined and evaporated to yield 0.69 g of 7-bromo-6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one. TLC Rf=0.8 (10:1 ethyl acetate/chloroform). 1H NMR (CDCl3) δ 7.42 (s, 1H), 4.0 (s, 3H), 3.3 (s, 3H), 3.0 (m, 2H), 2.7 (m, 2H). Mass Spectrum: m/e=271.2, 273.2 (p+1,3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16](I)[N:11]3[N:10]=2)=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16]([C:22]4[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=4)[N:11]3[N:10]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Nc2nn3c(I)cnc3s2)cc1
Reactant: OB(O)c1ccc(O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(-c2cnc3sc(Nc4ccc(F)cc4)nn23)cc1
Temperature: 140 °C
Yield: 35.7 %

Procedure:
(4-Fluoro-phenyl)-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-amine (0.065 g, 0.18 mmol) was suspended in 1,4-dioxane (1 mL) at room temperature, and argon was bubbled into the mixture while tetrakis(triphenylphosphine)-palladium(0) (21 mg, 0.018 mmol), 4-hydroxyphenylboronic acid (21 mg, 0.21 mmol), cesium carbonate (118 mg, 0.36 mmol) and water (1 mL) were added. The mixture was deoxygenated for 10 minutes and heated under microwave irradiation at 140° C. for 30 minutes. On cooling, the mixture was diluted with dichloromethane (5 mL), adsorbed in silica and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.4:9.6 to 1:9) to give 4-[2-(4-fluoro-phenylamino)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-phenol as a beige solid (21 mg, 36% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([CH:17]([CH3:19])[CH3:18])[CH2:14][S:13]1.[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C@@H:15]([CH:17]([CH3:19])[CH3:18])[CH2:14][S:13]1
Reactant: BrC1CCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](C(C)C)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H](C(C)C)N1C1CCCC1

Procedure:
(1S)-1-Isopropyl-2-hydroxyethylamine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with cyclopentyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-3-cyclopentyl-1,3-thiazolidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([NH:18][CH3:19])[N:12]=1.[OH-].[Na+]>>[Cl:10][C:11]1[N:12]=[C:13]([NH:18][CH3:19])[N:14]=[C:15]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)[N:16]=1
Reactant: O=C(O)C1CCNCC1
Reactant: CNc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Product: CNc1nc(Cl)nc(N2CCC(C(=O)O)CC2)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
4-Piperidinecarboxylic acid (2.10 g, 16.3 mmol, 1.00 equiv) was added to the suspension prepared in step a. The resulting mixture was heated to 40° C. and treated with 1 N NaOH to maintain a pH of 9-10. The reaction mixture was stirred for 2 h at the same temperature and then used immediately in the next step without workup or purification. MS (ES+): m/e 428.9 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]S(C)(=O)=O)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:50]=[CH:49][C:31]([CH2:32][N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[C:34]2[C:42]2([OH:48])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:30][CH:29]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:45]2[CH2:46][CH2:47][C:42]([C:34]3[N:33]([CH2:32][C:31]4[CH:49]=[CH:50][C:28]([F:27])=[CH:29][CH:30]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]=3)([OH:48])[CH2:43][CH2:44]2)([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Reactant: CS(=O)(=O)CCC1(Cc2ccccc2)CCN(Cc2ccccc2)C1=O
Product: O=C1N(Cc2ccccc2)CCC1(CCN1CCC(O)(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1)Cc1ccccc1

Procedure:
Prepare by the method of Example 6.6.2 using 1-benzyl-3-(phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-pyrrolidine and 4-[1-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.31 (silica gel, 30% methanol/ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][C@H:27]2[CH2:30][C@H:29]([C:31]([O:33]C)=[O:32])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:26][C@H:27]2[CH2:30][C@H:29]([C:31]([OH:33])=[O:32])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: COC(=O)[C@H]1C[C@H](Nc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1C[C@H](Nc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl trans-3-((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)amino)cyclobutanecarboxylate (2.0 mg, 4.2 μmol) was dissolved in THF (0.422 ml) before 0.1 N sodium hydroxide (169 μl, 17 μmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was acidified with 2 N HCl, diluted with THF, separated, dried over sodium sulfate, and was concentrated to give the title compound. MS (ESI) m/z: Calculated: 459.1; Observed: 460.0 (M++H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[N:10]([CH2:12][CH2:13][CH2:14][C:15](=O)[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=1[NH2:25])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:27])[N:10]([CH2:12][CH2:13][CH2:14][C:15]1[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=2[N:25]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(NC(=O)CCCN(C)C(=O)OCc2ccccc2)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cccc2[nH]c(CCCN(C)C(=O)OCc3ccccc3)nc12
Temperature: 150 °C

Procedure:
To a mixture of crude [3-(2-amino-3-methoxy-phenylcarbamoyl)-propyl]methyl-carbamic acid benzyl ester acid in 7 mL toluene were added a few drops of DMF and 523 mg of TsOH and the reaction mixture was heated at 150° C. for 2.5 h in the microwave. Sat. aq. NaHCO3 solution was added, the phases were separated and the organic phase was washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. Purification by CC EtOAc/MeOH (10:1) yielded 0.74 g of the desired compound as brown foam.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:11][C:5]=2[O:4][CH2:3]1.[C:18]1([CH:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[OH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[OH:25][CH:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:26]1[CH2:27][CH2:28][N:29]([C:14](=[O:16])[C:13]([NH:12][C:10]2[CH:9]=[CH:8][C:6]3[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=3[CH:11]=2)=[O:17])[CH2:30][CH2:31]1
Reactant: OC(c1ccccc1)C1CCNCC1
Reactant: O=C1COc2cc(NC(=O)C(=O)O)ccc2N1
Solvent: CCOCC
Product: O=C1COc2cc(NC(=O)C(=O)N3CCC(C(O)c4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-oxalamic acid (Example 53b) and phenyl-piperidine-4-yl-methanol [J. Amer. Chem. Soc.,52, 4006. (1930)] according to the method described in Example 1c. Melting Point: 195-197° C. (diethylether)
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[C:16](Cl)(=[O:26])[C:17]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][O:20][C:19]=2[CH:18]=1>C1COCC1>[CH2:21]1[O:22][C:23]2[CH:24]=[CH:25][C:17]([C:16]([C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])=[O:26])=[CH:18][C:19]=2[O:20]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: O=C(O)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)c1ccc2c(c1)OCO2
Temperature: -100 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
To a solution of 2-bromobenzoic acid (12 g, 0.06 mol) in THF (200 ml) at -100° C. under an argon atmosphere was added dropwise n-butyl lithium (50 ml of 2.5M solution in hexanes, 0.125 mol), maintaining the temperature below -90° C. Upon completion of the addition, the resulting solution was stirred at -100° C. for 1 h, at which time was added slowly a solution of piperonylic acid chloride (11 g, 0.06 mol) in THF (50 ml), maintaining the temperature below -90° C. The resulting mixture was allowed to warm to -80° C. and stirred for 1 h, then was allowed to slowly warm to room temperature and left to stand for 48 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between Et2O and 1M HCl. The organic phase was extracted with 10% aqueous NaOH. The NaOH extract was acidified with concentrated HCl, and the combined aqueous material was extracted with Et2O. The Et2O extract was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a solvent gradient of 10-30% EtOAc/0.1% HOAc/hexanes to afford the title compound as an off-white solid (4.5 g, 28%).
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8](=[O:16])[NH:7][C:6]=2[N:5]=[C:4]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=2[F:26])[N:3]=1>N[C@@H](CO)C>[F:26][C:20]1[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:17][C:4]1[N:3]=[C:2]([NH:10][C@H:9]([CH3:12])[CH2:8][OH:16])[C:11]2[N:10]=[C:9]([C:12]([F:14])([F:15])[F:13])[C:8](=[O:16])[NH:7][C:6]=2[N:5]=1
Reactant: O=c1[nH]c2nc(SCc3cccc(F)c3F)nc(Br)c2nc1C(F)(F)F
Agent: C[C@@H](N)CO
Product: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)c(C(F)(F)F)nc12

Procedure:
The titled compound was prepared from the product of example 37, step (b) (150 mg) and D-alaninol (100 μl) using the method of Example 2, step (f).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)([CH3:12])[CH3:11]>CO.[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([O:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(Oc1ccc([N+](=O)[O-])cc1)c1nc2ccccc2s1
Agent: [Pd]
Solvent: CO
Product: CC(C)(Oc1ccc(N)cc1)c1nc2ccccc2s1
Reaction time: 4.5 h
Yield: 90.7 %

Procedure:
Hydrogenation of a solution of 55.2 mg of O-[1-(benzothiazol-2-yl)-1-methylethyl]-4-nitrophenol [prepared as described in step (b) above] in 1.1 ml of methanol was carried out in the presence of a 5% palladium-charcoal catalyst. After 4.5 hours, the reaction vessel was blown through with nitrogen gas to give a nitrogen gas atmosphere. The mixture was then filtered and the solvent was removed from the resulting filtrate by evaporation under reduced pressure to give 45.3 mg of the crude product as an oil.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[OH-].[Na+]>CO>[C:11]1([S:9]([CH2:8][CH:7]=[CH:6][CH:5]=[CH:4][C:3]([OH:17])=[O:2])=[O:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C=CC=CCS(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=CC=CCS(=O)c1ccccc1
Temperature: 20 °C
Yield: 89 %

Procedure:
To a solution of 6-benzenesulfinyl-hexa-2,4-dienoic acid methyl ester (0.243 g, 0.97 mmol) in methanol (2.0 mL) were added a solution of aqueous sodium hydroxide (1M. 4.0 mL, 4 mmol) and distilled water (10 mL). After stirring at reflux for one hour, the mixture was allowed to cool to 20° C. and was concentrated under reduced pressure. The solution was washed with diethyl ether (25 mL) and then poured onto a mixture of ethyl acetate (20 mL) and hydrochloric acid (2M, 5 mL) at 0° C. The mixture was shaken, and the organic layer separated and washed successively with saturated aqueous sodium hydrogen carbonate (10 mL), distilled water (10 mL), brine (10 mL), then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a pale yellow solid that was recrystallised from ether/hexanes to give the title compound (0.204 g, 89%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][CH2:33][C@H:34]1[N:38]([S:39]([C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=2)(=[O:41])=[O:40])[CH2:37][C@H:36](O)[CH2:35]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N(C([O-])=O)=NC([O-])=O>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:25]([O:32][CH2:33][C@H:34]1[N:38]([S:39]([C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=2)(=[O:41])=[O:40])[CH2:37][C@@H:36]([O:3][S:2]([CH3:1])(=[O:5])=[O:4])[CH2:35]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)O
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1C[C@H](O)C[C@H]1COCc1ccccc1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1C[C@@H](COCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Reaction time: 0.08 h
Yield: 80.9 %

Procedure:
To a suspension of methanesulphonic acid (0.96 g) in toluene (30 ml) was added triethylamine (1.40 ml) and triphenylphosphine (2.72 g) at 0–5° C. The suspension was stirred for 5 minutes, and (3R,5S)-5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-ol (3.46 g) dissolved in toluene (20 ml) was added dropwise in 5 minutes, followed by diisipropyl azodicarboxylate (2.0 ml). The reaction mixture was stirred for 3 h at 85° C., poured onto ice/water and extracted with ethy acetate. The organic phase was washed with 10% KHSO4— and NaCl solutions, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:2 and 1:1 as eluents to obtain (3S,5S)-methanesulfonic acid 5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl ester (3.35 g) as a slightly yellow syrup, MS: 476 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:36])=[N:4][O:5][C:6]=1[N:7]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20](O)[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:10])=[O:9].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:36])=[N:4][O:5][C:6]=1[N:7]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2ccc(C)cc2C)sc2ncccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2ccc(C)cc2C)sc2ncccc12
Yield: 52.4 %

Procedure:
The title compound was prepared by the method of Example 5(A) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[α-hydroxy-2,4-dimethylbenzyl]thieno [2,3-b]pyridine-3-sulfonamide (0.1 7 g, 0.31 mmoles), CH2Cl2 (5 ml), triethylsilane (0.5 ml, 3.1 mmoles) and boron trifluoride etherate (0.2 ml, 1.5 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 87 mg (53%) of the title compound.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@H:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:14]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:13]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:12]([CH2:40][O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:11]2)=[CH:6][C:5]=1[CH:49]([C:54]1[N:55]=[N:56][C:57]2[CH:63]=[C:62]([CH3:64])[CH:61]=[CH:60][C:58]=2[N:59]=1)C(OC)=O.C1COCC1.CO>C(Cl)Cl.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@H:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:14]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:13]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@@H:12]([CH2:40][O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:11]2)=[CH:6][C:5]=1[CH2:49][C:54]1[N:55]=[N:56][C:57]2[CH:63]=[C:62]([CH3:64])[CH:61]=[CH:60][C:58]=2[N:59]=1
Reactant: COC(=O)C(c1nnc2cc(C)ccc2n1)c1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2nc(Cc3cc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)ccc3Cl)nnc2c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 53.8 %

Procedure:
Sodium hydroxide (40 mg, 0.81 mmol) was added to methyl 2-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)-2-(7-methylbenzo[e][1,2,4]triazin-3-yl)acetate (compound 62, 228 mg, 0.27 mmol) in the mixture of THF, MeOH and water (9/1/1 ratio) at room temperature, and then the mixture was stirred at 70° C. for a 1 day until starting material was disappeared. After reaction complete, the solution was work-up with CH2Cl2. After evaporating the volatile solvent, silica gel column chromatography (Hx/EtOAc=⅓) gave the desired compound (115 mg, 73% yield) as light yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:20])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.[C-:21]#[N:22].[K+].C(Cl)Cl>CN(C)C=O>[Cl:19][C:14]1[CH:13]=[C:12]([S:11][C:5]2[N:4]([CH3:20])[C:3]([CH2:2][C:21]#[N:22])=[N:7][C:6]=2[CH:8]([CH3:10])[CH3:9])[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: CC(C)c1nc(CCl)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1nc(CC#N)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 72.5 °C
Yield: 52.5 %

Procedure:
In 13.6 ml of dry dimethylformamide was dissolved 4.75 g (13.6 mmol)of 2-chloromethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole (28a)and 1.0 g of potassium cyanide (97.5%), and the mixture was stirred with heating at 70 to 75° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and to the residue, water was added. The mixture was extracted with diethyl ether, and the organic layer was washed with water 3 times and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was fractionated by silica gel chromatography (ethyl acetate:methylene chloride=1:9 to 4)to obtain 2.43 g of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]acetonitrile (Compound I-80a)(yield 53%). mp 103-105° C.