Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[N:7]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28](=O)[CH2:29][CH3:30])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:32])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[OH:46][NH3+:47].C(=O)([O-])O.[Na+]>CO>[C:1]([O:5][C:6](=[O:44])[N:7]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28](=[N:47][OH:46])[CH2:29][CH3:30])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:32])[CH2:12][CH2:13]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: [NH3+]O
Reactant: CCC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCC(=NO)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 97.6 %

Procedure:
To 2 mL of a methanol solution containing 84 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxo-5-propionylquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 40 mg of hydroxylammonium chloride was added, and stirred at room temperature for 9.5 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=20:1], to give 84 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(1-(hydroxyimino)propyl)-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[NH:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9].OS(O)(=O)=O.O=S(=O)=O.[N+:26]([O-])([OH:28])=[O:27]>O>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[N+:26]([O-:28])=[O:27])[NH:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: CC(C)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Add portion-wise 57.5 g. of m-trifluoromethyl isobutyranilide to 260 ml. of 15-18% oleum while maintaining the internal temperature at about 5° C. To this mixture add drop-wise 20 g. of 90% nitric acid with stirring. Stir at about 5° C. for 2 hours and pour into about 11/2 liters of ice and water with stirring. Collect the 3'-trifluoromethyl-4'-nitro-isobutyranilide by filtration and wash with water until substantially free of excess acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([NH2:16])[C:3]=1[N+:17]([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([NH2:16])[C:3]=1[NH2:17]
Reactant: Nc1nc(SCc2ccccc2)nc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1nc(SCc2ccccc2)nc(Cl)c1N
Temperature: 85 °C
Yield: 78.3 %

Procedure:
A suspension of the product from example 2, step (d) (980 mg), NH4Cl (1.61 g) and iron powder (559 mg) in EtOH (100 ml) and H2O (15 ml) was heated at 85° C. for 1.5 h. The mixture was filtered through celite and washed with hot MeOH (100 ml) before concentrating the filtrate onto silica under reduced pressure. Column chromatography using 1:1 isohexane/ethyl acetate as eluent provided the subtitled product as a yellow solid (0.69 g, 78%)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[CH2:28]([CH:30]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([CH2:45][NH2:46])[CH:38]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:29]>ClCCl>[CH2:28]([CH:30]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([CH2:45][NH:46][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=2)[CH:38]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:29]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CN)c1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(CNC(=O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of 4-(trifluoromethyl)benzoic acid (114 mg, 0.600 mmol) and triethylamine (0.21 mL, 1.51 mmol) in dichloromethane (3 mL), ethyl chlorocarbonate (0.063 mL, 0.659 mmol) was added under stirring and cooling with ice, and the mixture was stirred for 20 minutes. Next, after ethyl 2-ethyl-3-[3-(aminomethyl)-4-methoxyphenyl]propanoate hydrochloride (200 mg, 0.663 mmol) was added, the mixture was stirred for 1 hour under cooling with ice and for 3 hours at room temperature. Dichloromethane (20 mL) was added to the reaction mixture, which was washed with 1 mol/L hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=4:1 v/v) to afford 245 mg (93%) of the title compound as colorless crystals.
Reaction SMILES: C(N(CC)CC)C.[N:8]([CH:11]1[CH:14]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[NH:13][C:12]1=[O:24])=[N+:9]=[N-:10].[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C)C=O>[Si:25]([N:13]1[CH:14]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:11]([N:8]=[N+:9]=[N-:10])[C:12]1=[O:24])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: [N-]=[N+]=NC1C(=O)NC1CCOC(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CCOC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (0.2 mol) is added dropwise to an ice-cold stirred solution of 3-azido-4-(2-trifluoroacetoxyethyl)-azetidin-2-one (0.2 mol) and t-butyldimethylsilyl chloride (0.2 mol) in dimethylformamide (100 ml). The resulting mixture is stirred for 10 min. in the cold and for 10 min at room temperature, and then evaporated under vacuum to remove DMF. The residue is taken up to methylene chloride, washed with water and brine, dried with magnesium sulfate, and evaporated under vacuum to provide N-(t-butyldimethylsilyl)-3-azido 4-(2-trifluoroacetoxyethyl)-azetidin-2-one.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[P:20]([O:25]C)([O:23][CH3:24])[O:21][CH3:22]>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22])[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: COP(OC)OC
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Product: COP(=O)(Cc1ccc2nc(Cl)nc(N3CCOCC3)c2n1)OC
Temperature: 120 °C

Procedure:
To 4-(6-(bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (2 g) was added Trimethyl Phosphite (30 eq) and the reaction was refluxed at 120° C. for 90 minutes. The reaction was cooled and concentrated to dryness under vacuum. To the dried crude was added water, upon which a yellow solid crashed out and was filtered and dried overnight under vacuum to afford 2 g of pure dimethyl (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylphosphonate.
Reaction SMILES: CON(C)[C:4](=[O:9])[CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][Mg]Cl>>[CH3:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH2:11][C:12]1[CH:13]=[C:14]([CH3:15])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccc(C[Mg]Cl)c1
Reactant: CON(C)C(=O)CC(C)C
Product: Cc1cccc(CC(=O)CC(C)C)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 36-b) using N-methoxy-N-methyl-3-methylbutanamide and 3-methylbenzyl magnesium chloride to obtain a title compound as a light yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([N:7]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:6].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([N:7]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:6])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc(F)cc2)c1
Product: CC(=O)Nc1cccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc(F)cc2)c1
Yield: 98.3 %

Procedure:
Using 3-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(4-fluorophenyl)benzamide (223.2 mg, 0.48 mmol) and acetic anhydride (0.055 ml, 0.58 mmol), the procedure of inventive Example 94 was repeated to obtain 238.6 mg (98.3%) of the title compound in a light yellow amorphous form.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][C:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH3:24])[CH:6]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][C:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[N:16]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[C:15]=2[CH3:24])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OC)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cn1cc(Br)cn1
Product: CCOC(=O)c1ccc(OC)c(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 40, Step 6, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-4-methoxy-benzoic acid ethyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:33])([O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[NH:30][N:29]=[N:28]2)=[CH:23][CH:22]=1)[CH:17]([F:19])[F:18]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:30]1[C:31](=[O:32])[N:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:16]([F:15])([F:33])[CH:17]([F:19])[F:18])=[CH:26][CH:25]=2)[N:28]=[N:29]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]nnn1-c1ccc(OC(F)(F)C(F)F)cc1
Product: C[C@@H](n1nnn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 66.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.049 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.17 g of 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]- 5(1H,4H)-tetrazolone, 1.28 g of 1-[(1R, 2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl ]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-5(1H,4H)-tetrazolone was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:25][C:26]#[N:27])=[N:6][C:7]([CH:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:8][CH:9]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:10][C:7]1[N:6]=[C:5]([CH2:25][C:26]#[N:27])[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(CC#N)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])c(CC#N)n1
Yield: 59.3 %

Procedure:
A mixture of (3-nitro-6-(dicarbo-t-butoxymethyl)-2-pyridyl)acetonitrile (6.85 g, 18.2 mmol), dioxane (150 mL), and 2M sulfuric acid (25 mL) was heated at reflux for 12 hours. The resulting solution was cooled, neutralized with sodium carbonate, and extracted with ethyl acetate (3×50 mL). These extracts were combined, dried (MgSO4), and evaporated under reduced pressure to yield an oil. This oil was passed through a silica gel filter (approximately 100 g) followed by methylene chloride. This filtrate was evaporated under reduced pressure to afford (6-methyl-3-nitro-2-pyridyl)acetonitrile (1.91 g, 10.8 mmol, 59%) as an off-white solid: mp, 70°-72° C.; IR (KBr)
Reaction SMILES: [Li]CCCC.[C:6](Br)([CH3:8])=[CH2:7].CON(C)[C:13](=[O:30])[C@@H:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15][CH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21].[NH4+].[Cl-]>C1COCC1>[CH3:8][C:6](=[CH2:7])[C:13](=[O:30])[C@@H:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:15][CH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21]
Reactant: C=C(C)Br
Reactant: CON(C)C(=O)[C@H](CC1CCNC1=O)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)[C@H](CC1CCNC1=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
n-BuLi (2.5 M, 3.17 mL, 7.9 mmol) was added dropwise to a solution of isopropenyl bromide (0.9 g, 8.3 mmol) in THF (15.0 mL) at −78° C. and the mixture was stirred at −78° C. for 30 min. A solution of tert-butyl ((2S)-1-(methoxy(methyl)amino)-1-oxo-3-(2-oxopyrrolidin-3-yl) propan-2-yl)carbamate (500 mg, 1.58 mmol) in THF (5.0 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 3 h and then allowed to warm to ambient temperature and stirred for 12 h. Saturated aqueous NH4Cl (50 mL) was added and the resulting mixture was extracted with EtOAc (50 mL×2). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=20:1) to afford tert-butyl ((2S)-4-methyl-3-oxo-1-(2-oxopyrrolidin-3-yl)pent-4-en-2-yl)carbamate (200 mg, 42% yield) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH2:25])(=[O:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:25][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[CH:8]=2)[N:3]=1)(=[O:24])=[O:23]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: Cc1cc2nc(Cl)c(Cl)nc2cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc2nc(Cl)c(NS(=O)(=O)c3ccccc3Cl)nc2cc1C
Yield: 71.3 %

Procedure:
According to Example 132, by use of 2,3-dichloro-6,7-dimethylquinoxaline (Compound HC) (300 mg, 1.32 mmol), dimethyl sulfoxide (5 mL), 2-chlorobenzenesulfonamide (253 mg, 1.32 mmol) and potassium carbonate (182 mg, 1.32 mmol), the mixture was stirred and reacted at 150° C. for 2 hours. Then, slurry purification was performed using diisopropyl ether, to give 2-chloro-N-(3-chloro-6,7-dimethylquinoxalin-2-yl)benzenesulfonamide (360 mg, yield: 71%).
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1C)C.C([Li])(C)(C)C.CCCCC.[N:27]1(C#N)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1COCC1>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([OH:14])=[N:3][C:15]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[CH:16]2
Reactant: N#CN1CCOCC1
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2c(O)nc(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (500 mg, 2.259 mmol) in THF (5 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (2658 μl, 4.52 mmol) and the solution was stirred for 0.5 h before addition of morpholine-4-carbonitrile (253 mg, 2.259 mmol) in THF (5 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected and washed with water to give 6-methoxy-3-morpholinoisoquinolin-1-ol (350 mg, 60% yield) as a solid after drying.
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[C:16]([O:25][CH3:26])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O>[ClH:1].[CH3:26][O:25][C:16]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[CH2:12][CH2:11]1)=[O:15])=[O:24]
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: COC(=O)c1ccccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccccc1NC(=O)[C@H]1CC[C@H](CNC(=N)N)CC1

Procedure:
Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (3 g, 0.013 mole) (which is prepared by the method as disclosed in Japanese Patent First Publication No. 19694/1977, C.A., 87, 53269x) and methyl anthranilate (2.3 g, 0.015 mole) are added to pyridine (20 ml), and the mixture is stirred for a while, and thereto is added dicyclohexylcarbodiimide (3.1 g, 0.015 mole), and the mixture is stirred at room temperature for 72 hours. After the completion of the reaction, water (10 ml) is added to the reaction mixture, and the mixture is stirred for 30 minutes, and the undissolved materials are filtered off. The filtrate is concentrated to dryness. The resulting residue is washed with ethyl acetate (100 ml) and recrystallized from water to give the title compound (2.23 g) as white crystals. m.p. 118.5°-120.5° C.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]([F:11])([F:10])[CH:6]([OH:9])[CH2:7][CH3:8])C.CO.[OH-].[Na+].Cl>O>[F:10][C:5]([F:11])([CH:6]([OH:9])[CH2:7][CH3:8])[C:4]([OH:12])=[O:3]
Reactant: CCOC(=O)C(F)(F)C(O)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(O)C(F)(F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
Into a 10-L glass flask with a dropping funnel, 784 g (purity: 98%, 4.30 mol) of 2,2-difluoro-3-hydroxy-pentanoic acid ethyl ester, 300 mL of methanol and 2400 mL of water were added. The glass flask was cooled with ice water, followed by dropping 515 g (6.18 mol/1.4 eq) of 48% aqueous sodium hydroxide solution into the glass flask over 2 hours. The resulting solution was heated to room temperature and stirred for 1 hour. The completion of the reaction was confirmed by gas chromatography. The solution was washed twice with 800 mL of diisopropyl ether. The glass flask was again cooled with ice water. Then, 717 g (6.88 mmol/1.6 eq) of concentrated hydrochloric acid was dropped into the glass flask. After confirming that the pH of the solution was 1, the solution was stirred for 1 hour at room temperature. Subsequently, the solution was separated into an organic layer and an aqueous layer with the addition of 1000 mL of a mixed solution of diisopropyl ether and ethyl acetate. The aqueous layer was extracted three times with 1000 mL of a mixed solution of diisopropyl ether and ethyl acetate. The thus-obtained organic layers were combined and concentrated under a reduced pressure. With this, 683 g of 2,2-difluoro-3-hydroxy-pentanoic acid was obtained (yield: 98%, purity: 95%).
Reaction SMILES: Cl[C:2]1[S:6](=[O:7])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]=1.[CH2:16]([O:18][C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)[CH3:17]>>[CH2:8]([N:5]1[C:4](=[O:15])[C:3]2[C:19]([O:18][CH2:16][CH3:17])=[CH:23][CH:22]=[C:21]([OH:20])[C:2]=2[S:6]1=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C=C(Cl)S(=O)N1Cc1ccccc1
Reactant: CCOc1ccco1
Product: CCOc1ccc(O)c2c1C(=O)N(Cc1ccccc1)S2=O
Yield: 40 %

Procedure:
Reaction of 5.8 g (0.024 mol) of 5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide with 3.76 g (0.0335 mol) of 2-ethoxyfuran afforded 3.05 g (40%) of 2-benzyl-4-ethoxy-7-hydroxybenzisothiazol-3-one-1-oxide, 5.7 g of which was reacted with 3.6 g (0.0197 mol) of 2-[2-methoxyethoxy]ethyl bromide in the presence of 4.95 g (0.0358 mol) of potassium carbonate in 125 ml of methyl ethyl ketone and 25 ml of DMF to give 7.0 g (93%) of 2-benzyl-4-ethoxy-7-[2-(2-methoxy-ethoxy)ethoxy]benzisothiazol-3-one-1-oxide, which was oxidized as before with 3-chloroperbenzoic acid in MDC to give 2-benzyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]-saccharin. Debenzylation of 6.6 g (0.015 mol) of the latter with 3.34 g (0.053 mol) of ammonium formate in the presence of 6.4 g of 10% palladium-on-charcoal catalyst in methanol afforded the ammonium salt of 4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin, which was reacted with 2.38 g (0.015 mol) of chloromethyl phenyl sulfide in 100 mL of DMF to give 1.46 g (21%) of 2-phenylthiomethyl-4-ethoxy-7-[2-(2-methoxyethoxy)-ethoxy]saccharin, mp 73°-75° C. (from isopropanol). Treatment of 1.4 g (0.0029 mol) of the product with 0.4 g (0.0029 mol) of sulfuryl chloride in MDC afforded 1.16 g (100%) of 2-chloromethyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]-saccharin.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)O>C(O)C>[C:11](=[N:10][NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: NNc1cccc(Br)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Brc1cccc(NN=C(c2ccccc2)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
(3-Bromophenyl)hydrazine hydrochloride (10 g, 44 mmol, 1 eq.), benzophenone (8.14 g, 44 mmol, 1 eq.) and ethanol (100 mL) are placed in a 250 mL round-bottomed flask. 2 mL of concentrated sulfuric acid are then added. The resulting suspension is heated at a temperature in the region of 80° C. After 30 minutes at this temperature, the suspension becomes a solution. The solution is stirred at this temperature for 18 hours, and is then concentrated to 95%. The residue is diluted with ethyl acetate and washed with sodium hydrogen carbonate solution. After drying over magnesium sulfate, the solution is concentrated and the residue is purified by chromatography on a column of silica gel, eluting with an ether/heptane mixture (3/97 by volume). 15 g (95%) of N-benzhydrylidene-N′-(3-bromophenyl)hydrazine are thus obtained.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl.CCOCC>[O:8]1[CH2:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCCCO
Solvent: CCOCC
Solvent: ClCCl
Product: OCCCCCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
A mixture of 3 (1.4 g, 12 mmol) and m-chloroperbenzoic acid (2.92 g, 14.4 mmol) in methylene chloride (40 mL) was stirred at room temperature overnight. It was then diluted with ether, washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, and dried over magnesium sulfate. Removal of the solvent afforded 1.64 g of the crude 6,7-epoxy-1-heptanol (5).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH:25]3[CH2:30][CH2:29][CH:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)=[O:14])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>C(#N)C>[C:31]([C@H:28]1[CH2:29][CH2:30][C@H:25]([O:24][C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:15]([C:13](=[O:14])[CH2:12][NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])[CH2:16][CH2:17]3)[CH2:26][CH2:27]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOP(=O)(CCNCC(=O)N1CCc2cc(OC3CCC(C(C)(C)C)CC3)ccc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CCN3C(=O)CNCCP(=O)(O)O)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To stirring solution of (2-{2-[5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-2-oxo-ethylamino}-ethyl)-phosphonic acid diethyl ester (16 mg, 0.03 mmol) in acetonitrile (0.5 mL) was added bromotrimethylsilane (0.5 mL, 4 mmol). The reaction mixture was stirred at 50° C. overnight. After the solvent was concentrated, the residue was purified by HPLC (acetonitrile-water) to give white precipitate product (7.5 mg, yield: 53%). ESI-MS: 439.2 (M+H)+