Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[OH:23])[CH3:8].CI>CN(C)C=O>[CH2:7]([O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[O:23][CH3:1])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CCOCOc1ccc(O)c(OCOCC)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOCOc1ccc(OC)c(OCOCC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
Potassium carbonate (14.3 g, 103 mmol) was added to 3a (2.50 g, 10.3 mmol) in N,N-dimethylformamide (103 mL). After 10 minutes, methyl iodide (6.43 mL, 103 mmol) was added and the solution was heated to reflux for 12 hours. Upon cooling to room temperature, the solution was extracted with EtOAc (3×50 mL); combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (SiO2, 4:1 Hexane:EtOAc) to afford 4a as a yellow oil (2.40 g, 91%): 1H NMR (CDCl3, 500 MHz) δ 6.87 (d, J=2.8 Hz, 1H), 6.72 (d, J=8.9 Hz, 1H), 6.60 (dd, J=13.3, 1.7 Hz, 1H), 5.18 (s, 2H), 5.07 (s, 2H), 3.76 (s, 3H), 3.72-3.69 (m, 2H), 3.68-3.63 (m, 2H), 1.17-1.13 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 150.7, 146.2, 143.9, 111.2, 107.9, 105.8, 93.2, 93.0, 63.3, 63.0, 55.4, 14.1, 14.0; IR (film) νmax 2976, 2932, 2899, 2835, 1595, 1508, 1393, 1227, 1153, 1103, 1080, 1009, 847 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C13H20O5, 279.1208; found, 279.1181.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.C(OP([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(OCC)=O)C.[H-].[Na+]>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.80 g), ethyl diethylphosphonoacetate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.080 g) under ice-cooling. The mixture was stirred at room temperature for 3 hrs. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration to give ethyl (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoate as pale-brown crystals (0.85 g, yield 96%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 177-178° C.
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[C:10]1([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N:25]3[CH2:30][CH2:29][N:28](C)[CH2:27][CH2:26]3)=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CS(C)=O>[C:10]1([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N:25]3[CH2:30][CH2:29][N:28]([C:2]#[N:1])[CH2:27][CH2:26]3)=[N:17]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
To a stirred mixture of 1.5 g of cyanogen bromide 2.0 g of potassium carbonate and 30 ml of dimethylsulfoxide was added, dropwise, a solution of 2.8 g of 1-phenyl-3-(4-methyl-1-piperazinyl)-1H-indazole in 30 ml of dimethylsulfoxide. The reaction mixture was stirred at ambient temperature for 1.5 hours and then poured into water. The aqueous mixture was extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by flash chromatography on silica gel, utilizing ethyl acetate-hexane (1:1) as the eluent, followed by recrystallization from isopropyl alcohol-water to yield 2.3 g (59%) of 4-(1-phenyl-1H-indazol-3-yl)-1-piperazine carbonitrile, m.p. 118°-120°.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[BrH:13]>C1CCCCC1>[Br:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: Br
Reactant: OCCCCCCCCCCO
Solvent: C1CCCCC1
Product: OCCCCCCCCCCBr
Yield: 89 %

Procedure:
1,10-Decanediol (4 g) was dissolved in 100 ml of cyclohexane, and 57% aqueous hydrobromic acid solution (58 ml) was added to this solution. The reaction mixture was refluxed for six hours while stirring. After the reaction, the mixture was extracted three times with diethyl ether. The organic layer was neutralized with saturated sodium hydrogen carbonate solution, washed with saline solution, dried over magnesium sulfate, and filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel flash chromatography (hexane:ethyl acetate=7:3) gave 10-bromodecan-1-ol as white crystals at an 89% yield.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:32][C:33]([O:35]CC)=[O:34]>CN(C=O)C>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:32][C:33]([OH:35])=[O:34])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CBr
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
To a solution of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (203 mg, 0.535 mmol) in DMF (5 mL), NaH (43 mg, 1.07 mmol, 60% in mineral oil) is added at 0° C. The mixture is stirred at 0° C. and ethyl bromoacetate (98 mg, 0.588 mmol) is added. Stirring is continued at 0° C. for 30 min, then at rt for 72 h. The reaction is quenched by adding water (2 mL) and the mixture is concentrated. The residue is dissolved in THF (10 mL), methanol (10 mL) and 2 N aq. LiOH (10 mL). The mixture is stirred at 60° C. for 2 h before it is cooled to rt, acidified by adding 2 N aq. HCl and extracted three times with EA (3×20 mL). The combined org. extracts are concentrated and the crude product is purified by prep. HPLC to give the title compound (146 mg) as a white solid; LC-MS: tR=1.14 min, [M+H]+=438.07; 1H NMR (CDCl3): δ 7.90 (s, 1H), 7.88 (s, 1H), 7.79 (s br, 1H), 7.50 (s, 1H), 7.29 (s, 1H), 4.57 (s, 2H), 4.01 (s, 3H), 3.20-3.29 (m, 1H), 2.79 (q, J=7.5 Hz, 2H), 2.42 (s, 3H), 2.04-2.16 (m, 2H), 1.82-1.95 (m, 4H), 1.68-1.80 (m, 2H), 1.34 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:10][N:9]1[C:33]([CH:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:34])=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Product: CN1CCC(C(=O)N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)NCC#N)CC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K2 was coupled with 1-methylpiperidine-4-carboxylic acid in analogy to experiment A1 to give (2S,4R)-1-(1-methyl-piperidine-4-carbonyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide; salt with formic acid as a colorless oil. MS: 487.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[Al+3].[Cl-].[Cl-].[Cl-].[Cl-].C(C1NC=C[N+]=1C)C.Cl[C:26](=[O:31])[C:27]([O:29]C)=[O:28]>O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([F:1])=[C:3]2[C:11]([C:26](=[O:31])[C:27]([OH:29])=[O:28])=[CH:10][NH:9][C:4]=12
Reactant: Nc1ncc(F)c2cc[nH]c12
Reactant: COC(=O)C(=O)Cl
Agent: CCc1[nH]cc[n+]1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Nc1ncc(F)c2c(C(=O)C(=O)O)c[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-fluoro-1H-pyrrolo[2,3-c]pyridin-7-amine (2.26 g, 15 mmol) was added to a mixture of AlCl3 (12.0 g, 90.0 mmol) and ethylmethylimidazolium chloride (4.38 g, 30.0 mmol). Methyl chlorooxoacetate (3.6 mL, 30.0 mmol) was added slowly to the above solution and the mixture was stirred at rt for 3 h. Reaction flask was placed in an ice bath and water was slowly added until a white precipitate formed. The solid was collected by filtration and suspended in DMF. TEA (7 mL) was added and the mixture was stirred at rt for 1 h. Solvent was removed in vacuum. Chloroform (50 mL) was added and the solid was collected by filtration to afford 2-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid as a bright yellow solid (2.3g, 90% pure). LCMS: m/e 238 (M+H)+, ret time 0.96 min (method 3).
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:16]O>>[NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: Nc1c(O)cccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(O)c1N
Yield: 95 %

Procedure:
To a stirred solution of 2-amino-3-hydroxybenzoic acid (1.22 g, 8.0 mmol) in MeOH (80 mL) was added SOCl2 (9.52 g, 80.0 mmol) dropwise at 0° C. The mixture was then heated at reflux overnight. Most of the methanol was removed and the residue was partitioned between DCM and saturated aqueous NaHCO3. The organic phase was washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure to give methyl 2-amino-3-hydroxybenzoate (1.27 g, 95%). LC-MS (ES-API); rt 8.09 min; m/z calculated for C8H9NO3 [M+H]+ 168.1, found 168.1.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[S:22][C:21]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=4[C:19]=3[CH3:28])(=[O:17])=[O:16])[C:10]2=[O:29])[CH:4]=1)#[N:2].C(C1SC=C(CN2CC[C@H](NS([C:47]3[CH:56]=[CH:55][C:54]4[C:49](=[CH:50]C(OC)=CC=4)[CH:48]=3)(=O)=O)C2=O)C=1)#N.C(Br)C1C=CC=CC=1>>[C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([CH2:50][C:49]3[CH:54]=[CH:55][CH:56]=[CH:47][CH:48]=3)[S:15]([C:18]3[S:22][C:21]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=4[C:19]=3[CH3:28])(=[O:17])=[O:16])[C:10]2=[O:29])[CH:4]=1)#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Reactant: Cc1c(S(=O)(=O)N[C@H]2CCN(Cc3csc(C#N)c3)C2=O)sc2ccc(Cl)cc12
Agent: BrCc1ccccc1
Product: Cc1c(S(=O)(=O)N(Cc2ccccc2)[C@H]2CCN(Cc3csc(C#N)c3)C2=O)sc2ccc(Cl)cc12

Procedure:
The title compound is prepared as in EXAMPLE 126, Part A using 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as in EXAMPLE 129, Part A, in place of 7-methoxynaphthalene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide and benzyl bromide in place of MeI. The crude product is purified by column chromatography eluting with gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound as a white solid.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH2:8]([SH:13])[CH2:9][CH2:10][CH2:11][CH3:12].[NH2:14][C:15]1[N:23]=[C:22](Cl)[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cl-].[Na+].O>[NH2:14][C:15]1[N:23]=[C:22]([S:13][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCCCS
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 110 °C
Yield: 79.9 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (277 mg, 6.9 mmol, 60% in mineral oil) were added 1-pentanethiol (2 ml, 16 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred under heating at 110° C. for 4 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (102 mg, yield 81%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:20])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6]2)#[N:2].Cl.[NH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(O)C>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[C:4]([CH3:20])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:7][CH2:6]2
Reactant: NO
Reactant: Cc1c(C#N)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1c(C(=N)NO)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
1,1-Dimethylethyl 6-cyano-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 16; 404 mg; 1.48 mmol) was stirred overnight at 80° C. with hydroxylamine hydrochloride (619 mg; 8.90 mmol) and sodium bicarbonate (748 mg; 8.9 mmol) in ethanol (10 ml). Further sodium bicarbonate (400 mg) and hydroxylamine hydrochloride (300 mg) were added, and heating continued for ca. 8 h. The mixture was cooled to room temperature, and the resulting solid removed, washed with ethanol, and dried under high vacuum to give the title compound as a white solid (431 mg).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([C:31]([N:33]2[CH2:36][CH:35]([O:37]C3CCCCO3)[CH2:34]2)=[O:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:17]2[NH:21][C:20]([C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[CH:19][CH:18]=2)[CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(N(CC)CC)C>CO>[F:1][C:2]1[CH:30]=[C:29]([CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:17]2[NH:21][C:20]([C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[CH:19][CH:18]=2)[CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1)[C:31]([N:33]1[CH2:34][CH:35]([OH:37])[CH2:36]1)=[O:32]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CC(OC4CCCCO4)C3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CC(O)C3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
2-(5-{3-(2-Fluoro-4-{[3-(tetrahydro-2H-pyran-2-yloxy)azetidin-1-yl]carbonyl}phenoxy)-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole (110 mg, 0.181 mmol) synthesized in Example (42b) was dissolved in methanol (10 mL), and 10-camphorsulfonic acid (20 mg, 0.086 mmol) was added, followed by stirring at room temperature overnight under nitrogen atmosphere. To the reaction solution, triethylamine (0.1 mL) was added, and the solvent was distilled off under reduced pressure. The resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=90%-100%) to afford the desired compound (62 mg, yield 65%) as a yellow solid.
Reaction SMILES: [CH2:1]([Sn:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([CH:21]([CH2:24][CH3:25])[CH2:22][OH:23])[CH3:20]>>[CH2:1]([Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([O:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:19][CH3:20])[O:18][Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCC(CC)CO
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Product: CCCCCCCC[Sn](CCCCCCCC)(OCC(CC)CC)O[Sn](CCCCCCCC)(CCCCCCCC)OCC(CC)CC
Temperature: 25 °C
Yield: 99 %

Procedure:
893 g (2.48 mol) of di-n-octyl tin oxide (Sankyo Organic Chemicals Co., Ltd., Japan) and 2403 g (23.6 mol) of 2-ethyl-1-butanol were placed in a 5000 mL volumetric pear-shaped flask. The flask was connected to an evaporator to which was connected an oil bath equipped with a temperature controller, a vacuum pump and a vacuum controller. The purge valve outlet of this evaporator was connected to a line containing nitrogen gas flowing at normal pressure. After closing the purge valve of the evaporator to reduce pressure inside the system, the purge valve was opened gradually to allow nitrogen to flow into the system and return to normal pressure. The oil bath temperature was set to about 165° C., the flask was immersed in the oil bath and rotation of the evaporator was started. After heating for about 40 minutes in the presence of atmospheric pressure nitrogen with the purge valve of the evaporator left open, distillation of 2-ethyl-1-butanol containing water began. After maintaining in this state for 7 hours, the purge valve was closed, pressure inside the system was gradually reduced, and excess 2-ethyl-1-butanol was distilled with the pressure inside the system at from 74 to 25 kPa. After the fraction no longer appeared, the flask was taken out of the oil bath. After allowing the flask to cool to the vicinity of room temperature (25° C.), the purge valve was opened gradually and the pressure inside the system was returned to atmospheric pressure. 1114 g of reaction liquid were obtained in the flask. Based on the results of 119Sn-, 1H- and 13C-NMR analyses, 1,1,3,3-tetra-n-octyl-1,3-bis(2-ethylbutyloxy) distannoxane was confirmed to have been obtained at a yield of 99% based on di-n-octyl tin oxide. The same procedure was then repeated 12 times to obtain a total of 13380 g of 1,1,3,3-tetra-n-octyl-1,3-bis(2-ethylbutyloxy) distannoxane.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([OH:7])[NH:4][N:3]=1.[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.C(O)(=O)C>C1COCC1>[OH:7][C:5]1[NH:4][N:3]=[C:2]([N:1]2[C:11](=[O:12])[C:10]3[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:13])[CH:6]=1
Reactant: Nc1cc(O)[nH]n1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cc(O)[nH]n1
Temperature: 0 °C
Reaction time: 96 h

Procedure:
To a solution of 3-amino-1H-pyrazol-5-ol (10.00 g, 101 mmol) in THF (300 mL) at RT was added phthalic acid anhydride (14.9 g, 101 mmol) followed by acetic acid (69.3 ml, 1.21 mol). The mixture was heated to reflux. After 4 days, the mixture was concentrated in vacuo to afford a slurry that was cooled to 0° C. and filtered. The solid was rinsed with Et2O and dried in vacuo to afford 2-(5-hydroxy-1H-pyrazol-3-yl)isoindoline-1,3-dione as a yellow solid that was advanced without further purification. MS: Found M+H+=230.2.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN(C=O)C.O>[C:22]([O:21][C:19](=[O:20])[CH2:18][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[C:3]([O:9][CH3:10])[CH:4]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: COc1cc(O)ccc1I
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCC(=O)OC(C)(C)C)ccc1I
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Compound 1 (0.8 g, 3.19 mmol) was dissolved in dry DMF (30 ml). Dried potassium carbonate (1.32 g, 9.57 mmol) was added and the mixture was deaerated with argon. Tert-butyl bromoacetate (0.71 ml, 4.78 mmol) was added to the mixture and the reaction was stirred overnight at 70° C. The reaction mixture was cooled to room temperature and diluted with water (20 ml). The product was extracted with diethyl ether (3×50 ml) and dried over sodium sulphate. The product was purified by flash chromatography on silica gel using dichloromethane as an eluent. The yield was 1.1 g (96%). 1H NMR (CDCl3, 500 MHz): δ 7.66 (1H, d, J=8.5 Hz), 6.39 (1H, dd, J=8.5 Hz, 2.5 Hz), 6.34 (1H, d, J=2.5), 4.57 (2H, s), 3.79 (3H, s), 1.51 (9H, s).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Br[C:11]([F:18])([F:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.O.[Cu]>[Cl:8][C:7]1[C:2]([C:11]([F:18])([F:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Br)c(Cl)c1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(F)(F)c1ncc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 56 g (0.246 mol) of 2-bromo-3,5-dichloropyridine in 500 mL of dry dimethylsulfoxide, were added 53 g (0.261 mol) of ethyl bromodifluoroacetate followed by 94 g (0.518 mol) of copper bronze (200 mesh). The beige suspension was heated at 50° C. for 5 hours. After cooling of the reaction mixture, a solution of 44 g (0.328 mol) of potassium monophosphate in 280 mL of water was added and stirred for 1 hour. The black mixture was then filtered over a cake of Supercel™, and the cake was washed three times by 200 mL of ethyl acetate. The organic phases were collected, washed with brine and dried over magnesium sulfate. Evaporation of the solvent under vacuum gave 57.6 g of brown oil. After purification by column chromatography on silica gel (heptane/ethyl acetate 9/1) 40 g (57%) of ethyl (3,5-dichloropyridin-2-yl)(difluoro)acetate (Int-7) were obtained as a yellow oil, (M+1)=270, 19F-NMR (235 MHz, CDCl3) δ (ppm): −104.21 (CF2).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:44]1[N:45]=[C:46]([NH2:49])[S:47][CH:48]=1)[C:19]([NH:21][CH:22]1[C:42](=[O:43])[N:24]2[C:25]([C:39]([OH:41])=[O:40])=[C:26]([CH2:29][S:30][C:31]3[N:35]([CH2:36][CH:37]=[CH2:38])[N:34]=[N:33][N:32]=3)[CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C>C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:44]1[N:45]=[C:46]([NH2:49])[S:47][CH:48]=1)[C:19]([NH:21][CH:22]1[C:42](=[O:43])[N:24]2[C:25]([C:39]([OH:41])=[O:40])=[C:26]([CH2:29][S:30][C:31]3[N:35]([CH2:36][CH:37]=[CH2:38])[N:34]=[N:33][N:32]=3)[CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Yield: 42.8 %

Procedure:
Trifluoroacetic acid (20 ml) was added under ice-cooling to a stirred suspension of 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(2.05 g) in anisole (2 ml), and the resultant mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure and diethyl ether was added thereto. Precipitates were collected by filtration, washed with diethyl ether, dried and dissolved in an aqueous solution of sodium bicarbonate. An insoluble material was filtered off and the filtrate was adjusted to pH 3.2 with conc.hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.8 g).