Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:8]([CH3:17])=[C:9]([N+:14]([O-:16])=[O:15])[C:10](=[O:13])[NH:11][CH:12]=1)(C)C.[F-]>C1COCC1.C(OCC)(=O)C>[C:6]([C:7]1[C:8]([CH3:17])=[C:9]([N+:14]([O-:16])=[O:15])[C:10](=[O:13])[NH:11][CH:12]=1)#[CH:5]
Reactant: Cc1c(C#C[Si](C)(C)C)c[nH]c(=O)c1[N+](=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1c[nH]c(=O)c([N+](=O)[O-])c1C
Yield: 37.4 %

Procedure:
To a stirred solution of 5-trimethylsilylethynyl-4-methyl-3-nitro-2-pyridone (1.0 g, 2.7 mmol) in THF (10 mL) was added tetrabutylammoniun fluoride (1M in THF, 2 mL). After 30 minutes the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel (40% ethyl acetate/hexane) gave 5-ethynyl-4-methyl-3-nitro-2-pyridone (0.18 g, 22%).
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])#[N:7].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[CH3:12][O:11][C:9](=[O:10])[C:8]([C:6]#[N:7])=[CH:1][CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CC#N
Reactant: CC(C)C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C#N)=CC(C)C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of isobutyraldehyde (18.2 mL, 200 mmol) in dry benzene (20 mL) was added methyl cyanoacetate (18 mL, 200 mmol), ammonium acetate (2 g) and glacial acetic acid (4 mL). The reaction mixture was' stirred at 60° C. for 30 minutes and allowed to cool to room temperature. Excess of solvents was removed in vacuo and the residue was dissolved in EtOAc (200 mL). The organic layer was washed with water, dried over sodium sulfate and evaporated to give 2-cyano-4-methyl-pent-2-enoic acid methyl ester as pale yellow oil. Further purification of the pale yellow oil by distillation (7 mm Hg) gave product 2 (27.4 g, 56%) as colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.16 (d, J=6.6 Hz, 6H), 2.96-3.04 (m, 1H), 3.87 (s, 3H), 7.47 (d, J=10.5 Hz, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[Br:16]Br>C(Cl)(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>[Br:16][C:5]1[S:1][C:2]([C:6]2([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)=[N:3][CH:4]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)C1(c2nccs2)CC1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C1(c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.9 %

Procedure:
The product from Step 2 (860 mg, 3.82 mmol) was taken up in CHCl3 (19 mL) and placed in a cool water bath. NaHCO3 (353 mg, 4.20 mmol) was added, followed by bromine (1.22 g, 7.63 mmol). After stirring for 90 min at room temperature, the reaction was diluted with 10% Na2S2O3 and saturated NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-10% ether in hexanes) afforded tert-butyl 1-(5-bromo-1,3-thiazol-2-yl)cyclopropane-carboxylate (545 mg, 47%) as a colorless oil. MS ESI: [M-t-Bu]+ m/z 247.9/249.9.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[C:3]#[CH:4].[CH3:7][O:8][CH2:9][CH2:10]Br>>[CH3:7][O:8][CH2:9][CH2:10][O:6][C:2]([CH3:5])([CH3:1])[C:3]#[CH:4]
Reactant: C#CC(C)(C)O
Reactant: COCCBr
Product: C#CC(C)(C)OCCOC
Yield: 61.6 %

Procedure:
In accordance with the procedure of the step 1 of Example 10, and using 21.7 g of 3-methyl-1-butyn-3-ol and 39.4 g of 2-bromoethyl methyl ether, 22.6 g of 3-(2-methoxyethoxy)-3-methyl-1-butyne was obtained.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[N:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[C:22]2[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=O.O>CN(C)C=O>[C:38]([O:37][C:36]([NH:35][CH2:34][C:23]1[N:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:25](=[O:29])[C:26]2[C:21]([C:22]=1[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[CH:20][C:19](/[CH:17]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:28][CH:27]=2)=[O:42])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C=O)ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (1.0 mL, 5 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (0.20 g, 5 mmol) (60% in oil), and the mixture was stirred at room temperature for 10 min. To the obtained mixture was added a solution of tert-butyl (6-formyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (2.17 g, 5 mmol) in N,N-dimethylformamide (20 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give ethyl (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenate (2.03 g, 71.7%) as an amorphous.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH2:10]([N:17]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: NCc1ccccc1
Solvent: O
Product: Cc1cc(O)cc(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-hydroxy-6-methyl-2-pyrone (0.2 mol, 25.2 g) and benzylamine (0.2 mol, 21.4 g) were added to water (800 mL) and heated to reflux with stirring for 2 hours. After cooling to room temperature, a light brown solid was collected by filtration. (33.4 g, 77%): 1H NMR (DMSO-d6/300 MHz) δ: 10.5 (s, 1H), 7.4-7.1 (m, 5H), 5.8-5.6 (m, 2H), 5.2 (s, 2H), 5.1 (s, 2H), 2.2 (s, 3H). ESHRMS m/z 216.100 (M+H, C12H13NO2 requires 216.102).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[CH2:19]([N:21]1[C:33]2[CH:32]=[CH:31][C:30]([NH2:34])=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20]>>[C:14]([CH:13]=[C:11]1[CH2:12][NH:8][C@H:9]([C:16]([NH:34][C:30]2[CH:31]=[CH:32][C:33]3[N:21]([CH2:19][CH3:20])[C:22]4[C:27]([C:28]=3[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:18])[CH2:10]1)#[N:15]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=CC#N)CN3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 36% purity by LC/MS. MS(ESI+): m/z=345.2.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[C:27]([CH3:28])[C:22]2=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=1)([CH3:3])[CH3:2].Br[CH2:43][C:44]([NH2:46])=[O:45].C(N(CC)CC)C>>[CH:1]([O:4][C:5]1[C:6]([NH:18][C:19]2[N:24]=[C:23]3[NH:25][N:26]=[C:27]([CH3:28])[C:22]3=[C:21]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=2)=[CH:7][C:8]([CH3:17])=[C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:43][C:44]([NH2:46])=[O:45])[CH2:13][CH2:12]2)[CH:10]=1)([CH3:3])[CH3:2]
Reactant: NC(=O)CBr
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCN(CC(N)=O)CC1
Temperature: 100 °C

Procedure:
The mixture of N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (20 mg, 0.035 mmol), 2-bromoacetamide (0.1 N in DMF, 0.035 mmol, 0.35 mL) and triethylamine (0.1 N in DMF, 0.105 mmol, 1.05 mL) was heated at 100° C. for 10 min. The resulting reaction mixture was purified by RP-HPLC to afford 2-(4-(5-isopropoxy-4-(4-(2-(isopropylsulfonyl)phenylamino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylphenyl)piperidin-1-yl)acetamide. MS (ES+): 635.3 (MH+).
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]12.[CH3:8][S:9]([NH2:12])(=[O:11])=[O:10].C(O[K])(C)(C)C.Cl>O1CCCC1>[CH3:8][S:9]([NH:12][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[OH:1])(=[O:11])=[O:10]
Reactant: C1CCC2OC2C1
Reactant: CS(N)(=O)=O
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)NC1CCCCC1O

Procedure:
In a nitrogen atmosphere, a mixture of 108 g of 1,2-epoxycyclohexane, 95.1 g of methanesulfonamide, 11.2 g of t-butoxypotassium, and 1,000 g of tetrahydrofuran was heated under reflux for 100 hours. The reaction solution was neutralized with hydrochloric acid and then subjected to conventional aqueous work-up. Purification by column chromatography yielded an alcohol compound, 2-[(methylsulfonyl)amino]cyclohexanol. In a nitrogen atmosphere, the alcohol compound was combined with 111 g of triethylamine and 2,000 g of acetonitrile, to which 105 g of methacryloyl chloride was added dropwise at −20° C. The mixture was gradually warmed to room temperature and then stirred for 10 hours. The reaction mixture was subjected to conventional aqueous work-up and purified by column chromatography, obtaining 165 g of 2-[(methylsulfonyl)amino]-cyclohexyl methacrylate. The yield was 63% based on the methanesulfonamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:33])[F:32])[CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:16][C:15]=2[O:34][C:35]([F:38])([F:37])[F:36])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>ClCCl.C(O)(C)C>[F:33][CH:31]([F:32])[O:30][C:26]1[CH:25]=[C:24]([S:21]([NH:20][C:18]2[CH:17]=[CH:16][C:15]([O:34][C:35]([F:38])([F:36])[F:37])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)(=[O:22])=[O:23])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(NS(=O)(=O)c3cccc(OC(F)F)c3)ccc2OC(F)(F)F)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(OC(F)(F)F)c(N2CCNCC2)c1)c1cccc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.2 %

Procedure:
0.22 g 4-[5-(3-Difluoromethoxy-benzenesulfonylamino)-2-trifluoromethoxy-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.388 mmol) were dissolved in 5 ml dichloromethane. 1.5 mL 6 N hydrochlorid acid in isopropanol were added and the reaction mixture was stirred at room temperature for 2.5 h. The solvents were evaporated, the residue was dissolved in water and the pH was adjusted to 8-9 with 1 N aqueous solution of sodium hydroxide. Thereby a white suspension formed, which was extracted once with a mixture of ethyl acetate and dichloromethane. The still existent suspensions were filtered, and the combined organic filtrates were dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 0.140 g of the desired product.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.[Si:14]([O:21][C@H:22]([CH2:27][O:28][CH3:29])[C:23](OC)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1COCC1.CCOC(C)=O>[Si:14]([O:21][C@H:22]([CH2:27][O:28][CH3:29])[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][N:11]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: Cc1ccc(N)nc1
Reactant: COC[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium (2.5M in hexanes) (2.04 mL, 3.26 mmol) was added dropwise to a stirred solution of 5-methylpyridin-2-amine (CAS 1603-41-4) (353 mg, 3.26 mmol) in THF (10 mL) cooled to 10° C. under nitrogen. The resulting solution was stirred at ambient temperature for 10 minutes and then added to a solution of (R)-methyl 2-(tert-butyldimethylsilyloxy)-3-methoxypropanoate C5b (810 mg, 3.26 mmol) in THF (10 mL) at 10° C. The resulting solution was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with saturated ammonium chloride (50 mL), water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. Purification by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane provided (R)-2-(tert-butyldimethylsilyloxy)-3-methoxy-N-(5-methylpyridin-2-yl)propanamide (300 mg). 1H NMR (400 MHz, CDCl3) δ 0.15 (3H, s), 0.16 (3H, s), 0.88 (9H, s), 2.12 (3H, s), 3.46 (3H, s), 3.61-3.65 (2H, m), 4.35-4.42 (1H, m), 7.47 (1H, d), 8.19 (1H, d), 8.20 (1H, s), 8.97 (1H, s), m/z (ESI+) (M+H)+=325; HPLC tR=3.08 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC.C([O-])(O)=O.[Na+]>[O:1]=[C:2]1[CH2:3][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:5]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(O)C4)c3)ncnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(=O)C4)c3)ncnc21
Reaction time: 2 h

Procedure:
To a solution of {3-hydroxy-1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile (1.62 g, 3.82 mmol) in DCM (50 mL) at 0° C. was added Dess-Martin periodinane (2.1 g, 5.0 mmol). After stirring for 2 hours, the reaction solution was diluted with ether and saturated NaHCO3 solution. The aqueous layer was extracted with ethyl acetate three times. The combined extracts were washed with brine, dried over sodium sulfate, decanted and evaporated. The crude was used in the next step without purification. LCMS (M+H)+: 423.2.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([NH:19]C(OC(C)(C)C)=O)[CH2:13]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:27].O1CCOCC1>C(O)(=O)C>[ClH:27].[C:1]([O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([NH2:19])[CH2:13]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(OC(=O)c3ccccc3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NC1Cc2ccc(OC(=O)c3ccccc3)cc2C1

Procedure:
Using 5-benzoyloxy-2-(tert-butoxycarbonylamino)indan (130 mg, 0.37 mmol), 4N hydrochloric acid-dioxane (2 ml) and acetic acid (6 ml), a similar procedure to Example 24 was carried out to obtain 5-benzoyloxy-2-aminoindan hydrochloride (67 mg, 0.35 mmol) having the following physical properties:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:5](COCC[Si](C)(C)C)[C:6]=1[Cl:7].Cl.C(OCC)(=O)C>C(O)C>[Cl:7][C:6]1[N:5]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:3][C:2]=1[Cl:1]
Reactant: CCOC(=O)c1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(Cl)c(Cl)[nH]1
Yield: 64.1 %

Procedure:
Ethyl 4,5-dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-carboxylate obtained in Example (7b) (0.61 g, 1.79 mmol) was dissolved in ethanol (3 mL). A 4 N hydrochloric acid/ethyl acetate solution (15 mL) was added, and the mixture was heated under reflux for one hour. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 1/1) to obtain 0.24 g of the title compound as a pale yellow oily substance (65%).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][CH:15]1[CH2:20][CH:19]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18][CH:17]([CH3:26])[CH:16]1[OH:27].C(O)(C)C>CC(C)=O>[CH3:14][CH:15]1[CH2:20][CH:19]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18][CH:17]([CH3:26])[C:16]1=[O:27]
Reactant: CC(C)CCC1CC(C)C(O)C(C)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(C)CCC1CC(C)C(=O)C(C)C1
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Jones reagent (150 mL) was added dropwise at room temperature to a solution of 2,6-dimethyl-4-(3-methylbutyl)cyclohexanol (100 g, 0.5 mol, produced according to Example 4) in acetone (3,000 mL). The reaction mixture was stirred for 1 h and isopropanol added to decompose excess Jones reagent. The salts were removed by filtration and the solution concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with water (400 mL), 5% sodium bicarbonate (200 mL) and brine (200 mL). The organic layer was dried, the solvent evaporated, and the residue fractionated to yield 71 g of the ketone, bp 96°-100° C. (3 mm). NMR (CDCl3) δ0.8-1.1 (12H, m), 1.1-3.2 (12H, m). IR (film) 1725, 1140, 990 cm-1. MS (m/e) 196 (M+), 69, 82, 97, 41.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH3:8])=[N:5][N:6]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13](OCC)=[O:14]>>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[S:3][C:4]([S:7][CH3:8])=[N:5][N:6]2[C:13](=[O:14])[CH:12]=1
Reactant: CSc1nnc(N)s1
Reactant: CCOC(=O)CC(=O)CCl
Product: CSc1nn2c(=O)cc(CCl)nc2s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-amino-5-methylthio-1,3,4-thiadiazole (9.4 g) was reacted with ethyl 4-chloro-acetoacetate (15.8 g) in polyphosphoric acid (50 g) under stirring at 100° C. for 1 hour. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water until neutral to give 7-chloromethyl-2-methylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 168°-169° C. (12.4 g), which was reacted with triphenylphosphine (14.4 g) in acetonitrile (250 ml) under stirring at reflux temperature for 24 hours. After cooling the precipitate was filtered and washed with isopropyl ether to give (2-methylthio-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-7-yl)-methyl-triphenylphosphonium chloride (24 g), which was suspended in dimethylsulphoxide (100 ml) and treated dropwise with potassium terbutoxide (5 g) dissolved in dimethylsulphoxide (80 ml) at a temperature of about 20° C. The solution of the ylide so obtained was then reacted with benzaldehyde (4.65 g) at room temperature for 60 minutes. After dilution with ice water the precipitate was extracted with ethyl acetate and the organic solution was evaporated in vacuo to dryness: after purification over SiO2 column with CHCl3 -hexane, crystallization from CH2Cl2 -methanol gave 3.8 g of 2-methylthio-7-trans-(2-phenyl-ethenyl)-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 180°-182° C., N.M.R. (CDCl3) δp.p.m.: 2.82 (s) (3H, --SCH3), 6.35 (s) (1H, C-6 proton), 6.70 (d) (1H, β-ethenyl proton), 7.2-7.7 (m) (5H, phenyl protons), 7.70 (d) (1H, α-ethenyl proton); JHαHβ =16 Hz.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13].[N+:25]([C:28]1[CH:38]=[CH:37][C:31]([CH2:32][O:33][C:34](Cl)=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26].[OH-].[Na+]>O.O1CCCC1>[OH:11][C@H:9]1[CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:13])[C@H:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:34]([O:33][CH2:32][C:31]2[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:38][CH:37]=2)=[O:35])[CH2:10]1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: NCCOC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCOC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Yield: 51.4 %

Procedure:
To a solution of (2S,4R)-2-(2-aminoethyloxymethyl)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.12 g) in a mixture of water (20 ml) and tetrahydrofuran (40 ml) was added a solution of 4-nitrobenzyloxycarbonyl chloride (0.85 g) in tetrahydrofuran (4 ml) under ice-cooling with stirring, keeping the pH between 8.5-9.5 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for 2 hours. The reaction mixture was evaporated under reduced pressure and then ethyl acetate (50 ml) was added thereto. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.88 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1>CO.[Pd]>[NH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(O)c(N)c1

Procedure:
The mixture containing 4-methoxy-2-nitrophenol in methanol with catalytic amount of 10% Pd/C was hydrogenated until disappearance of yellow color to yield 2-amino-4-methoxyphenol. MS: MH+=140.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[C:10](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CCOCC1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)C1CCOCC1
Yield: 99.3 %

Procedure:
Tetrahydro-2H-pyran-4-carboxylic acid (1.00 g, 7.68 mmol) was slowly added to a stirred suspension of anhydrous potassium carbonate (1.17 g, 8.45 mmol) in acetone (40 mL), followed by dimethyl sulfate (0.8 mL, 8.45 mmol). The mixture was stirred and heated for 3 h. The inorganic salts were then removed by filtration and washed with acetone, and the filtrate was dried and concentrated to give methyl tetrahydro-2H-pyran-4-carboxylate (1.1 g, 99%), which was used in the next step without further purification. GC-MS m/z 145 (MH+); 1H NMR (300 MHz, CDCl3) δ 11.70-1.80 (m, 4H), 2.47-2.52 (m, 1H), 3.34-3.43 (m, 2H), 3.65 (s, 3H), 3.88-3.95 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[OH:11])[CH3:18]
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(F)cc1O
Temperature: 120 °C
Yield: 85 %

Procedure:
To a solution of 4-fluoro-2-hydroxybenzoic acid compound 3 (20.0 g, 128.11 mmol) in ethanol (100 mL) was added conc. sulfuric acid (10 mL). The resulting mixture was heated in a 120° C. oil bath O/N. The solvent was removed under reduced pressure to give crude product, which was purified by column chromatography (silica gel, 10% EtOAc in hexane) to afford the title compound 4 (19.9 g, 85%) as a colorless solid. 1H NMR 400 MHz (CDCl3) δ: 11.15 (s, 1H), 7.83 (d, J=6.6 Hz, 1H), 7.81 (d, J=6.6 Hz, 1H), 6.62 (dd, J=10.1, 2.3 Hz, 1H), 6.61 (dd, J=7.0, 2.0 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H); MS (ES) m/z: 185 (M+1)+.