Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([C:17]([OH:19])=O)=[N:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([Cl:16])[CH:9]=2)([O:3][CH3:4])=[O:2].S(Cl)([Cl:22])=O>>[C:1]([C:5]1[C:6]([C:17]([Cl:22])=[O:19])=[N:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([Cl:16])[CH:9]=2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1c(C(=O)O)nc2cc(Cl)ccc2c1O
Reactant: O=S(Cl)Cl
Product: COC(=O)c1c(C(=O)Cl)nc2cc(Cl)ccc2c1O

Procedure:
Concurrently, 3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carbonyl chloride was prepared from 3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carboxylic acid (121 mg, 0.43 mM) by heating to 60° C. in thionyl chloride (4 mL). After 3 hours the crude acid chloride was isolated by distilling away the excess thionyl chloride. The crude 3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carbonyl chloride (130 mg, 0.43 mM) was then placed in anhydrous tetrahydrofuran (3 mL) at ambient temperature and added via cannula to the 4-(trifluoromethoxy)phenylhydrazine solution. After 30 minutes the reaction mixture was poured into 1.0N hydrochloric acid producing a precipitate. The solid was isolated to yield the title compound (185 mg, 95%) as an off-white solid, mp 346-350° C.; MS 456 (M+H). 1H NMR 12.67 (s, 1H, exchangeable), 10.79 (s, 1H, exchangeable), 8.37 (br s, 1H, exchangeable), 8.13 (d, J=8.61 Hz, 1H), 7.83 (d, J=1.76 Hz, 1H), 7.48 (dd, J=8.61, 1.76 Hz, 1H), 7.21 (d, J=8.50 Hz, 2H), 6.94 (d, J=8.50 Hz, 2H), 3.70 (s, 3H).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[I:10]Cl.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[OH:4][C:3]1[CH:5]=[CH:6][C:7]([I:10])=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: ClI
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1cc(I)ccc1O
Reaction time: 14 h

Procedure:
To a solution of salicylaldehyde (10 g, 82 mmol) in 50 mL of CH2Cl2 is added 22 mL of a 1 M ICl solution in CH2Cl2. The solution is stirred for 14 hours. After this time, a saturated solution of sodium sulfite is added until the color is discharged. The solution is diluted with CH2Cl2. The layers are separated. The organic layer is washed with water. The organic layer is dried over MgSO4, filtered and concentrated. The resulting crude material is recrystallized from cyclohexane to give the title compound (7.2 g, 32 mmol) as white solid.
Reaction SMILES: O1CCCCC1[O:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.O1CCCCC1OCCCC(OC(=O)C)COC1C=CC(F)=CC=1>>[C:22]([O:21][CH:11]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)/[CH:10]=[CH:9]/[CH2:8][OH:7])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(/C=C/COC1CCCCO1)COc1ccc(F)cc1
Agent: CC(=O)OC(CCCOC1CCCCO1)COc1ccc(F)cc1
Product: CC(=O)OC(/C=C/CO)COc1ccc(F)cc1

Procedure:
The synthesis of this compound is carried out by the procedure of Example 2, Step E except that an equivalent quantity of 1-(2-tetrahydropyranyloxy)-4-acetoxy-5-(4-fluorophenoxy)-trans-2-pentene is substituted for the 1-(2-tetrahydropyranyloxy)-4-acetoxy-5-(4-fluorophenoxy)-pentane of Example 2, Step E. The product is obtained as a viscous oil.
Reaction SMILES: [C:1]([O:6][OH:7])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].[OH-].[Na+].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>O>[C:12]([O:7][O:6][C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CCC(C)(C)OO
Reactant: CC(C)(C)C(=O)Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)(C)OOC(=O)C(C)(C)C

Procedure:
The reaction is effected in a reactor arrangement of a first reactor of type D with two reactors of type B connected downstream in series. 0.26 kg/l·h of an 88% by weight solution of tert-amyl hydroperoxide in water, 0.47 kg/l·h of a 25% by weight solution of potassium hydroxide in water, 0.50 kg/l·h of a 25% by weight solution of sodium hydroxide in water and 0.26 kg/l·h of pivaloyl chloride are fed to the first reactor. The metering rates are based on the total volume of the reactor arrangement in litres. Cooling with cooling water keeps the internal temperature in the first reactor at 25° C. and in the two downstream reactors at 15° C. The reaction mixture withdrawn from the third reactor is mixed with 0.79 kg/l·h of demineralized water and 0.08 kg/l·h of isododecane, and the organic phase is removed. The organic phase is washed successively with an 8% by weight solution of sodium hydroxide in water, with a solution of 10% by weight of sodium sulphite in water comprising acetic acid and with demineralized, water, and then dried with calcium chloride. 0.42 kg/l·h of a 75% by weight solution of tert-amyl peroxypivalate in isododecane is obtained (80.6% based on pivaloyl chloride).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([OH:14])=[O:13].[OH-].[Na+].O.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>CC(C)=O>[CH2:34]([O:33][C:31]([N:18]1[CH2:17][CH2:16][C:15]([C:12]([OH:14])=[O:13])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(C(=O)O)(c2ccccc2)CC1
Temperature: 5 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A mixture of 37.7 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate, 53.3 g of 30% aqueous NaOH solution and 250 ml of water is cooled to 5° C. A solution of 18 g of benzyl chloroformate in 60 ml of acetone is added rapidly at 5° C. and the reaction mixture is stirred overnight while the temperature is allowed to rise to RT. It is washed twice with ether and, after decantation, the aqueous phase is acidified to pH 1 by the addition of concentrated HCl and then 2N HCl. The precipitate formed is wrung, dried, taken up with ether and wrung again to give 30.6 g of the expected product. M.p.=142°-144° C.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:3]([O:5]C)=[O:4].C1(C(CCC)(CCC)C(OC)=O)C=CC=CC=1>>[CH3:7][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)c1ccccc1
Agent: CCCC(CCC)(C(=O)OC)c1ccccc1
Product: CC(C)(C(=O)O)c1ccccc1

Procedure:
The title compound was prepared according to the procedure of Example 1C, substituting the product of Example 9A for the product of Example 1B. 1H NMR (300 MHz, CDCl3): δ 7.33 (m, 5 H), 1.60 (s, 6 H).
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])C.[C:12](#[N:14])[CH3:13]>C1CCCCC1.O>[CH3:10][C:7]([CH3:8])([CH3:9])[C:6](=[O:11])[CH2:13][C:12]#[N:14]
Reactant: CCOC(=O)C(C)(C)C
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: CC(C)(C)C(=O)CC#N
Temperature: 80 °C

Procedure:
To a refluxed solution of sodium hydride (33.18 g, 553.03 mmol) in 275 mL of cyclohexane is added a mixture of 2,2-dimethyl-propionic acid ethyl ester (30 g, 230.43 mmol) in 79 mL acetonitrile (553.03 mmol) in 25 mL of cyclohexane. The mixture is maintained at 80° C. overnight. The mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organics are washed with water, dried over sodium sulfate, filtered and concentrated to afford title compound which was used crude in subsequent reaction. ESI m/z 124=MH−
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[C:12]1([S:18]([N:21]2[C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[CH3:9][O:8][C:6]1[N:5]=[C:4]([S:10][CH3:11])[N:3]=[C:2]([C:23]2[C:24]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:21]([S:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)(=[O:20])=[O:19])[CH:22]=2)[CH:7]=1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Reactant: COc1cc(Cl)nc(SC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(SC)n1

Procedure:
A mixture of 4-chloro-6-methoxy-2-(methylthio)pyrimidine (10.2 g, 53.7 mmol), 1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (18.8 g, 48.8 mmol), 2M aqueous K2CO3 (48.8 mL, 98.0 mmol), 1,2-dimethoxyethane/dimethylfomamide (9/1, 200 mL) and
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:16][CH3:17])=[C:8]([C:10]#[C:11][Si](C)(C)C)[CH:9]=1>O.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:16][CH3:17])=[C:8]([C:10]#[CH:11])[CH:9]=1
Reactant: COc1ccc(Cl)cc1C#C[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#Cc1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 135.9 %

Procedure:
Add a solution of potassium hydroxide (3.28 g, 58.5 mmol) in water (30 mL) dropwise over 25 minutes to a stirred solution of (5-chloro-2-methoxy-phenylethynyl)-trimethylsilane (13.7 g, 57.4 mmol) in methanol (275 mL) and stir at room temperature for 2 hours. Concentrate, add brine to residue, and extract with EtOAc (×2). Dry organic layer over MgSO4 and concentrate to get 13 g of a black oil. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-5% EtOAc/hexanes to afford the title compound (8.98 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[N:31]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:34]1[CH2:33][CH2:32][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 g (19 mmol) of 2,4-difluorobenzoic acid and 4 mL of DIEA (1.2 equiv.) in 40 mL of dry DCM is added 3.08 g (1.2 equiv) of HOBt and 4.2 g (22.55 mmol) of t-butyl piperazine-1-carboxylate, and the mixture was stirred at RT for 30 min. 4.4 g (11 equiv.) of EDCl are added and the reaction mixture is stirred overnight at RT. Water is added and the resulting mixture is extracted with DCM. The organic layer is dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain t-butyl 4-(2,4-difluorobenzoyi)piperazine-1-carboxylate as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 1.47 (s, 9H), 3.30 (m, 2H), 3.41 (m, 2H), 3.53 (m, 2H), 3.76 (m, 2H), 6.86 (dt, 1H, J=8.8 Hz and 0.8 Hz), 6.97 (dt, 1H, J=8.8 Hz and 0.8 Hz), 7.41 (dd, 1H, J=14.4 Hz and 7.2 Hz).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:14]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:15][N:16]=1)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:14]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:25])=[CH:15][N:16]=1
Reactant: Cc1ccccc1C(=O)c1cnc(NCCCNC(=O)OC(C)(C)C)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccccc1C(=O)c1cnc(NCCCN)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
339 mg {3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-propyl}-carbamic acid tert-butyl ester was added to a solution of 25% aqueous hydrochloric acid in dioxane. The mixture was stirred 1 h at room temperature and maintained overnight in the refrigerator. The mixture was poured into saturated aqueous sodium bicarbonate solution (50 ml). The organics were extracted with dichloromethane (3×50 ml), dried over magnesium sulfate and evaporated under reduced pressure to afford the title compound as yellow foam (254 mg) which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:13]1[CH:18]=[C:17](C=O)[C:16]([CH:21]=O)=[CH:15][CH:14]=1.C(Cl)Cl>CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:21][C:16]3[C:15](=[CH:14][CH:13]=[CH:18][CH:17]=3)[C:11]2=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: O=Cc1ccccc1C=O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 42.6 %

Procedure:
A mixture of 4-acetylphenylisocyanate (27.5 g, 0.17 mol) and o-phthalicdicarboxaldehyde (25.0 g, 0.186 mol) is heated in an oil bath at 170°-175° C. for 4.0 hours under nitrogen atmosphere. On cooling the melt solidified which is pulverized and refluxed with CH2Cl2 and CH3OH and filtered to give 18.2 g (41.4%) of the desired 2-(4-acetylphenyl)-2,3-dihydro-1H-isoindole-1-one, mp 235°-237° C. The residue is recrystallized from DMF (1800 ml). Yield 13.0 g (29.6%), mp 236-239° C. (Jap. patent J5 7050-960; mp 243°-244° C. for the nonsolvated compound, prepared by a different route).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:15][NH2:16]>>[CH:1]1[C:13]2[C:12](=[N:15][NH2:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: NN
Product: NN=C1c2ccccc2-c2ccccc21

Procedure:
Symmetrical charge transport materials can be prepared by the following procedure. In the first step a 9-fluorenone or a derivative compound reacts with an excess of hydrazine at 50-70° C. for 1-6 hours to produce a 9-fluorenone hydrazone compound or derivative thereof. Then, the 9-fluorenone hydrazone compound can be isolated and purified. In the next step, the 9-fluorenone hydrazone reacts with a linking compound having 2 aldehyde groups or ketone groups, such as OCH—CHO, a quinone derivative, or a diphenoquinone derivative, in a mole ratio of 2:1 (2 mole of hydrazine derivative with 1 mole of the linking compound). The desired product can be isolated and purified by recrystalization or/and column chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
14 g of 3-Bromobenzyl alcohol was dissolved in 200 ml of N,N-dimethylformamide, and 15 g of t-butylchlorodimethyl silane and 10 g of imidazole were added. After stirring was continued at room temperature overnight, the solution was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography, and 21 g of [(3-bromobenzyl)oxy] (t-butyl)dimethylsilane was obtained in the 4:1 hexane-ethyl acetate fraction. Then, the obtained 21 g of [(3-bromobenzyl)oxy] (t-butyl)dimethylsilane was dissolved in 300 ml of tetrahydrofuran, and the mixture was cooled to −78° C. under nitrogen atmosphere. 55 ml of butyl lithium (1.52 M solution in hexane) was added thereto, and the mixture was stirred for 30 minutes. A solution of 11.5 g of 4-formylmorpholine solution in 20 ml of tetrahydrofuran was added. After stirring was continued at −78° C. for 1 hour, 1N-hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 14.7 g of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH:13]=[O:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1onc(-c2ccc(F)cn2)c1C=O
Temperature: 0 °C
Yield: 90.3 %

Procedure:
To a solution of [3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-methanol (1.9 g, 9.13 mmol) in DCM (38 mL) was added a suspension of DMP (4.65 g, 10.96 mmol) in DCM (30 mL) portionwise and under argon at room temperature and then the mixture was cooled to 0° C. and the resulting mixture warmed up to room temperature overnight. The mixture was then poured carefully into stirred saturated sodium hydrogen carbonate solution and the aqueous layer extracted with DCM. The combined organic layers were then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) gave the title compound (1.7 g, 90%) as a white solid. MS: m/e=207.0 [M+H]+. Alternatively
Reaction SMILES: COS(O)(=O)=O.B(OC)(OC)OC.C[C:15]([O:17][CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O.N>C(=O)(OC)OC>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][O:17][CH3:15])[CH2:28][S:27][C@H:22]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COS(=O)(=O)O
Agent: N
Solvent: COC(=O)OC
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 113.9 %

Procedure:
22.0 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 3) and 2.10 g of trimethyl borate were added to 30 ml of dimethyl carbonate. The mixture was cooled to 10° C. Next, 2.74 g of 7-ACA were added and the mixture was stirred at 10° C. for 1.5 hours. After completion of the reaction, the reaction mixture was poured over crushed ice, and aqueous ammonia was added thereto to adjust the pH to 3.5. The crystals precipitated were filtered off, washed with water and dried to afford 2.80 g of crude 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. Water was added to the crude crystals, and then aqueous ammonia was added to adjust the pH to 8. The mixture was then decolored using activated carbon. The activated carbon was filtered off and the filtrate was adjusted to pH 3.5 with hydrochloric acid. The crystals precipitated were filtered off, washed with water and dried to give 2.11 g (yield 86%) of the desired compound in a highly pure form.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.B(F)(F)F.CCOCC.CS(O)(=O)=O.B(OC)(OC)OC>S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: CS(=O)(=O)O
Agent: FB(F)F
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 10 ml of sulfolane were added 1.41 g of 7-ACA, 2.4 ml of boron trifluoride ethyl ether, 0.34 ml of methanesulfonic acid and 3.13 ml of trimethyl borate. The mixture was heated at 30° C. for 5 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.49 g. The yield of the desired product was 39%.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.CS(O)(=O)=O.B(OC)(OC)OC>[Cl-].[Zn+2].[Cl-].S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: CS(=O)(=O)O
Agent: [Cl-]
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 10 ml of sulfolane were added 1.41 g of 7-ACA, 6.0 g of zinc chloride, 0.34 ml of methanesulfonic acid and 3.06 ml of trimethyl borate. The mixture was heated at 30° C. for 23 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.95 g. The yield of the desired product was 75%.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:11](=[O:12])[C:10]([CH3:15])([CH3:14])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 6-bromopyridin-2-amine (10 g, 57.79 mmol, 1 eq.) in 150 ml of DCM were added TEA (17.54 g, 173.3 mmol, 3 eq.) and 2,2-dimethylpropionyl chloride (10.45 g, 86.69 mmol, 1.5 eq.) dropwise. The temperature rose slowly. The reaction was stirred overnight at r.t. The white solid was removed by filtration and the solvent was evaporated. The crude was dissolved in with EtOAc and washed with 0.1N aq. HCl, sat. aqueous NaHCO3. The organics were dried over MgSO4 and concentrated. The resulting solid was recrystallized in EtOAc to give N-(6-bromopyridin-2-yl)-2,2-dimethylpropanamide (13.52 g, 91% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>C(O)(=O)C.[Pd]>[CH3:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cccc(N)c1C
Reaction time: 1.5 h
Yield: 101.6 %

Procedure:
Methyl 2-methyl-3-nitrobenzoate (10.0 g) is dissolved in acetic acid (50 ml) and thereto 5% Pd-C (1 g) is added to carry out catalytic reduction at room temperature under 1 atm. After 1.5 hours, the catalyst is filtered off. The reaction mixture is concentrated, and thereto is added water, and the mixture is made alkaline with potassium carbonate, followed by extraction with dichloromethane. The solvent is concentrated to give methyl 2-methyl-3-aminobenzoate (8.6 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[ClH:15]>>[ClH:15].[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: Cl
Product: COC(=O)c1cccc(N)c1C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of 185.6 g of stannous chloride dihydrate in concentrated hydrochloric acid (450 ml) at 15° was added 48.8 g of 2-methyl-3-nitrobenzoic acid, methyl ester. The temperature of the reaction mixture rose steadily to 63° before a cooling bath was applied. After the addition was complete, the solution was stirred at 40° to room temperature for 1.5 hours. The desired product was obtained by filtration of the reaction mixture at 7°, washing with ethyl acetate and n-butyl chloride, and drying. The yield of 3-amino-2-methylbenzoic acid, methyl ester, hydrochloride m.p. 220°-228° (dec.), was 60.8 g as a white solid.