Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[CH:11]=[C:10]([S:12][CH:13]([CH3:15])[CH3:14])[C:9]([Cl:16])=[CH:8][C:6]=1[NH2:7])(=[O:4])(=[O:3])[NH2:2].[Cl:17][CH2:18][C:19](Cl)=O.C([O-])(=O)C.[K+].O>O1CCOCC1>[Cl:17][CH2:18][C:19]1[NH:2][S:1](=[O:3])(=[O:4])[C:5]2[CH:11]=[C:10]([S:12][CH:13]([CH3:14])[CH3:15])[C:9]([Cl:16])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)Sc1cc(S(N)(=O)=O)c(N)cc1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Sc1cc2c(cc1Cl)N=C(CCl)NS2(=O)=O

Procedure:
A mixture of 2-sulfamoyl-4-isopropylthio-5-chloroaniline (0.02 mole) and chloroacetyl chloride (0.022 mole) in dioxane (75 ml.) is heated under reflux for 24 hours. The solution then is concentrated to dryness in vacuo, the residue dissolved in ethanol (60 ml.) and heated under reflux with potassium acetate (0.022 mole) and water (10 ml.) for 2 hours. The alcohol is removed in vacuo and the solution then acidified with hydrochloric acid. The precipitated product is recrystallized from a mixture of methanol and water to provide 3-chloromethyl-6-chloro-7-isopropylthio-1,2,4-benzothiadiazine-1,1-dioxide, m.p. 248°-250° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[F:7][C:8]1[C:9]([C:18]([F:21])([F:20])[F:19])=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[C:13]2[NH2:17]>N1C=CC=CC=1>[F:7][C:8]1[C:9]([C:18]([F:21])([F:19])[F:20])=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[C:13]2[NH:17][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: Nc1n[nH]c2c(F)c(C(F)(F)F)ccc12
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2c(F)c(C(F)(F)F)ccc12
Temperature: 3 °C
Reaction time: 76 h

Procedure:
1.0 cm3 of butyryl chloride is added to 2.1 g of 7-fluoro-6-(trifluoromethyl)-1H-indazole-3-amine, prepared as in patent application WO 02/22608, in 20 cm3 of pyridine, after cooling to about 3° C., and the mixture is then left at room temperature for 76 hours. The reaction medium is concentrated under reduced pressure (2 kPa; 40° C.) and the residue is taken up in 50 cm3 of ethyl acetate and 20 cm3 of water. The organic phase is washed with 2×20 cm3 of distilled water and then with 20 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulphate, filtration and concentration under reduced pressure (2 kPa; 40° C.), the residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40° C.); after drying (90 Pa; 40° C.), 875 mg of N-[7-fluoro-6-(trifluoromethyl)-1H-indazol-3-yl)butanamide are obtained in the form of a pink solid melting at 220°-222° C.
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)#[CH:7].[CH2:25]=[O:26].Cl>CCCCCC.O1CCCC1>[OH:26][CH2:25][C:7]#[C:6][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: C=O
Reactant: C#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(C#CCO)cc2)CC1
Reaction time: 1 h

Procedure:
6.75 ml (10.80 mmol) of 1.6 molar n-butyllithium solution in n-hexane are added dropwise at 0° C. to 2.48 g of 1-ethynyl-4-(trans-4-pentylcyclohexyl)benzene in 25 ml of tetrahydrofuran. After 1 hour, this solution is saturated with formaldehyde, acidified by means of aqueous hydrochloric acid and partitioned between ether and water, and the organic phase is dried and evaporated. Chromatography on silica gel using n-hexane/dichloromethane (1:2) gives 1.80 g of 1-(hydroxymethylethynyl)-4-(trans-4-pentylcyclohexyl)benzene, ##STR7## which is stirred for 2 hours at room temperature with 1.05 g (6.49 mmol) of diethylaminosulfur trifluoride in 10 ml of dichloromethane. After partitioning between water and dichloromethane, the organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel using n-heptane, giving 0.94 g of 1-(fluoromethylethynyl)-4-(trans-4-pentylcyclohexyl)benzene. ##STR8##
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[N:16]2[N:17]=[CH:18][C:19]([C:20]3[CH:21]=[N:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][CH:25]=3)=[C:15]2[N:14]=[C:13]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:12]=1[C:38](=[O:40])[CH3:39].[N:41]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C=O)C>[NH2:10][C:11]1[N:16]2[N:17]=[CH:18][C:19]([C:20]3[CH:21]=[N:22][C:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][CH:25]=3)=[C:15]2[N:14]=[C:13]([CH:32]2[CH2:33][CH2:34][N:35]([S:47]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)(=[O:49])=[O:48])[CH2:36][CH2:37]2)[C:12]=1[C:38](=[O:40])[CH3:39]
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1c(C2CCN(S(=O)(=O)N3CCOCC3)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
DIEA (121 mg, 0.94 mmoL) was added to at 0° C. a mixture of 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (64.3 mg, 0.15 mmoL) and morpholine-4-sulfonyl chloride (28.9 mg, 0.15 mmol) in DMF (3 mL). After stirring at 0° C. for 0.5 h and then room temperature for 2 h, the mixture was purified by prep-LC to afford 1-(7-amino-5-(1-(morpholinosulfonyl)piperidin-4-yl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone, LCMS tR=3.83 Min (5 min run, UV254nm). Mass calculated for, M+ 561.66, observed LC/MS m/z 567.66 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C:10]([C:18]#[N:19])=[C:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([CH3:24])([O-])=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:8][C:9]([C:10]1([C:18]#[N:19])[CH2:24][C:11]1([CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH3:17])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(CCC)=C(C#N)C(=O)OCc1ccccc1
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC1(CCC)CC1(C#N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
To a solution of 2-cyano-3-propyl-hex-2-enoic acid benzyl ester (0.91 g, 3.35 mmol) in 50 mL acetonitrile was added nitromethane (0.91 mL, 16.77 mmol), followed by DBU (0.50 mL, 3.35 mmol) resulting in an orange solution. The reaction was stirred at room temperature for 16 hours, then partitioned between Et2O and 1N HCl (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography of the residue (5→10% EtOAc/hexanes) afforded 0.71 g (81%) of 1-cyano-2,2-dipropyl-cyclopropanecarboxylic acid benzyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.21 (dd, J=18.3, 12.4 Hz, 2H), 1.79 (d, J=5.1 Hz, 1H), 1.74 (m, 1H), 1.52 (m, 3H), 1.43 (d, J=5.1 Hz, 1H), 1.36 (m, 3H), 1.04 (m, 1H), 0.95 (t, J=7.1 Hz, 3H), 0.73 (t, J=7.1 Hz, 3H). 13C NMR δ 166.40, 135.22, 128.81, 128.69, 128.48, 118.60, 68.23, 41.26, 36.45, 30.27, 29.76, 24.91, 19.74, 19.65, 14.22, 14.10. IR (neat) 2240, 1734 cm−1. Anal. Calcd for C18H23NO2: C, 75.76; H, 8.12; N, 4.91. Found: C, 75.38; H, 8.02; N, 4.97.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH2:14][CH2:15][CH:16]1[CH2:20][CH2:19][CH:18]([CH3:21])[N:17]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:17]1[CH:18]([CH3:21])[CH2:19][CH2:20][CH:16]1[CH2:15][NH:14][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=1[O:12][CH3:13])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC1CCC(CN)N1Cc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCC(C)N1Cc1ccccc1

Procedure:
By following general method B using 1.01 g. of 4-amino-5-chloro-2-methoxybenzoic acid and 1.0 g. of 2-aminomethyl-1-benzyl-5-methylpyrrolidine, 1.5 g. of N-(1-benzyl-5-methyl-2-pyrrolidinyl-methyl)-4-amino-5-chloro-2-methoxybenzamide was obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].I[CH2:6][C:7]12[CH2:14][CH2:13][C:10]([CH3:15])([CH2:11][CH2:12]1)[C:9](=[O:16])[O:8]2.[Cl-].[Na+]>CN(C=O)C>[N:1]([CH2:6][C:7]12[CH2:14][CH2:13][C:10]([CH3:15])([CH2:11][CH2:12]1)[C:9](=[O:16])[O:8]2)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC12CCC(CI)(CC1)OC2=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC12CCC(CN=[N+]=[N-])(CC1)OC2=O
Temperature: 100 °C
Yield: 78.3 %

Procedure:
2.6 g of sodium azide was added to a solution of 1.1 g of 1-iodomethyl-4-methyl-2-oxabicyclo[2.2.2]-octan-3-one (Example 28) in 10 ml of DMF. The solution was reacted for 15 hours, while being heated to 100° C. After reaction, 50 ml of an aqueous sodium chloride solution was added to the reaction solution. The solution was then extracted three times with 30 ml of ethyl acetate. The organic layer obtained was washed twice with an aqueous sodium chloride solution and dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance formed was subjected to column chromatography using 5 g of silica gel. From the fraction eluted with hexane and ethyl acetate=1:1, the solvent was removed in vacuo, yielding 0.6 g of 1-azidomethyl-4-methyl-2-oxabicyclo[2.2.2]octan-3-one as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[I:20]I>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[NH:4][CH:14]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH:13]1[I:20]
Reactant: II
Reactant: Nc1c(Br)cccc1C1C=CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1cccc2c1NC1C(I)CCCC21
Reaction time: 3 h

Procedure:
To the 2-bromo-6-cyclohex-2-en-1-ylaniline mixture (0.85 g, 3.4 mmol) above in dichloromethane (50 mL) was added sodium bicarbonate (2.3 g, 27 mmol) followed by iodine (3.5 g, 14 mmol). The reaction was stirred for 3 hours and then diluted with dichloromethane (100 mL). The organic phase was washed with a 10% w/w aqueous solution of sodium thiosulfate, washed with brine, and was dried by passing through a hydrophobic frit. The organic solution was concentrated to leave crude 8-bromo-1-iodo-2,3,4,4a,9,9a-hexahydro-1H-carbazole. MS m/z 378, 380 (M+1).
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[CH3:18])=[O:9])=O.B(F)(F)F.CCOCC>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[CH3:18])[C:8](=[O:9])[C:7]2[C:6](=[CH:22][CH:21]=[C:20]([N+:23]([O-:25])=[O:24])[CH:19]=2)[N:5]=1
Reactant: Cc1cc(Br)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cc(Br)ccc1-n1c(CF)nc2ccc([N+](=O)[O-])cc2c1=O
Yield: 94.1 %

Procedure:
4.0 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-bromoaniline, 3.0 g of boron trifluoride etherate and 30 ml of acetic acid are treated in the same manner as described in Example 1-(2), whereby 3.6 g of 2-fluoromethyl-3-(2-methyl-4-bromophenyl)-6-nitro-4(3H)-quinazolinone are obtained as pale yellow prisms.
Reaction SMILES: C([O:8][C:9](=[O:40])[C@H:10]([CH:37]([CH3:39])[CH3:38])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:21][C:20]=1[Br:36])[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pd]>[Br:36][C:20]1[CH:21]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][N:11]([C@H:10]([C:9]([OH:40])=[O:8])[CH:37]([CH3:38])[CH3:39])[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [H][H]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1Br)[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1Br)[C@H](C(=O)O)C(C)C

Procedure:
A solution of 2.4 g (4 mmol) of N-[(3-bromo-2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester in 90 ml of dioxane is hydrogenated at 5 bar and at room temperature with the addition of 1.2 g of Pd/C (10%) until the calculated amount of hydrogen has been absorbed. After evaporation of the filtered solution, the evaporation residue is dissolved in 2N sodium hydroxide solution and extracted with ether, and the aqueous phase is rendered acidic with 2N hydrochloric acid. The title compound is obtained by extracting with ethyl acetate, drying and evaporating as a colourless foam (Rf 0.40, system A2), FAB-MS: m/e=514 (M+H)+.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16]>CCOCC>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=1
Reactant: Cc1ccccn1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc(C=Cc2ccccn2)cc1
Yield: 45.6 %

Procedure:
A mixture of 20.4 g (0.2 mol) acetic acid anhydride, 18.6 g (0.2 mol) 2-methylpyridine and 26.2 g (0.2 mol) 4-cyanobenzaldehyde is heated to reflux for 24 h. One allows to cool, mixes with excess ether and filters. One isolates 18.8 g of title compound (46% of theory) of the m.p. 98°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[N:7]=[C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)[NH:9][C:5]=2[C:4]=1[S:24]([C:27]1[C:38]([CH3:39])=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:28]=1[CH3:40])(=[O:26])=[O:25].ClC1C=C(C=CC=1)C(OO)=[O:46]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[N:7]=[C:8]([S:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[O:46])[NH:9][C:5]=2[C:4]=1[S:24]([C:27]1[C:28]([CH3:40])=[CH:29][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:37][C:38]=1[CH3:39])(=[O:26])=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)COc1cc(C)c(S(=O)(=O)c2c(OC)ccc3nc(SCc4ncc(C)c(OC)c4C)[nH]c23)c(C)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(C)c(S(=O)(=O)c2c(OC)ccc3nc(S(=O)Cc4ncc(C)c(OC)c4C)[nH]c23)c(C)c1
Reaction time: 16 h

Procedure:
Solutions of methyl {4-[(5-methoxy-2{[4-methoxy,3,5-dimethyl(2-pyridyl)methyl]thio}benzimidazolyl)sulfonyl]-3,5-dimethylphenoxy}acetate (Intermediate A5, 7.1 g, 0.12 mol) in 100 mL of tetrahydrofuran and 3-chloroperoxybenzoic acid (2.6 g, 0.15 mol) in 20 mL of the same solvent were cooled in a freezer for 1 hr and then mixed. The solution was left in the freezer for about 16 hr, diluted with ethyl acetate, and washed with several portions each of 5% sodium metabisulfite, 5% sodium bicarbonate, and saturated sodium chloride. The organic phase was concentrated and then purified on flash silica gel (hexanes→ethyl acetate→1% methanol in ethyl acetate). The title compound recovered weighed 3.3 g (46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH3:16].C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25](=[O:47])[C@@H:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH:27]([CH3:29])[CH3:28].N1C=CC=CC=1>ClCCl>[CH3:23][O:24][C:25](=[O:47])[C@@H:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[CH:42][C:43]([NH:46][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[C:14]([O:15][CH3:16])[C:6]=4[C:7]=3[CH3:13])=[O:12])=[CH:44][CH:45]=2)=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH:27]([CH3:29])[CH3:28]
Reactant: COc1c(Cl)ccc2oc(C(=O)O)c(C)c12
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(Cl)c(OC)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To 80 mg (0.33 mmol) of 5-chloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 2 mL of oxalyl chloride and the mixture refluxed for 2 h, then stirred room temperature overnight. The excess oxalyl chloride was removed under vacuum. The residue was dissolved in 2 mL of dichloromethane and was added to a mixture of 181 mg (0.5 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester and 1 mL of pyridine in an ice/water bath. The mixture was stirred at 0° C. overnight. The reaction mixture was diluted with dichloromethane and was washed with 2N HCl, and water. Removal of the solvent in vacuo gave the crude product which was purified by column chromatography to give 168 mg (86% yield) of (S)-2-{4′-[(5-chloro-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as a white solid.
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C[Si](Br)(C)C.[P:18]([CH2:22][CH2:23][O:24][N:25]=[C:26]([C:53]1[N:54]=[C:55]([NH:58]C=O)[S:56][CH:57]=1)[C:27]([NH:29][CH:30]1[C:51](=[O:52])[N:32]2[C:33]([C:48]([OH:50])=[O:49])=[C:34]([CH2:37][S:38][C:39]3[S:40][C:41]4[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=4[N:43]=3)[CH2:35][S:36][C@H:31]12)=[O:28])([OH:21])([OH:20])=[O:19]>C(Cl)Cl>[P:18]([CH2:22][CH2:23][O:24][N:25]=[C:26]([C:53]1[N:54]=[C:55]([NH2:58])[S:56][CH:57]=1)[C:27]([NH:29][CH:30]1[C:51](=[O:52])[N:32]2[C:33]([C:48]([OH:50])=[O:49])=[C:34]([CH2:37][S:38][C:39]3[S:40][C:41]4[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=4[N:43]=3)[CH2:35][S:36][C@H:31]12)=[O:28])([OH:21])([OH:20])=[O:19]
Reactant: O=CNc1nc(C(=NOCCP(=O)(O)O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nc5ccccc5s4)CS[C@H]23)cs1
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: Nc1nc(C(=NOCCP(=O)(O)O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nc5ccccc5s4)CS[C@H]23)cs1
Reaction time: 0.5 h

Procedure:
A mixture of 7-[2-{2-(O,O-diethylphosphono)ethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-benzothiazolyl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.59 g.), methylene chloride (30 ml.) and bis(trimethylsilyl)acetamide (2.14 g.) was stirred for 30 minutes at 18° to 20° C. and thereto was added trimethylsilyl bromide (2.68 g.) followed by stirring for 5 hours and 45 minutes at 19° to 21° C. The reaction mixture containing 7-[2-(2-phosphonoethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-benzothiazolyl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was concentrated and to the residue were added methanol (30 ml.) and conc. hydrochloric acid (3 ml.). The mixture was stirred for 1.5 hours at room temperature and then evaporated. The residue was dissolved in an aqueous solution of sodium bicarbonate and the isolation was washed with ethyl acetate and then adjusted to pH about 2 with 10% hydrochloric acid. The precipitates were collected by filtration under cooling, washed with water, dried under reduced pressure and then suspended in methanol (20 ml.). After conc. hydrochloric acid was added to the suspension to dissolve the precipitates, the resulting solution was treated with activated charcoal and then thereto was added dropwise a mixture of conc. ammonia water and methanol (1:5) whereby the pH was adjusted to 3 to 4. The precipitates were collected by filtration under cooling to give a powder of the title compound (0.85 g.), mp. 170° to 210° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].Cl.[NH:23]1[C:27]([C:28]2[CH:29]=[C:30]3[C:40](=[CH:41][CH:42]=2)[O:39][C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][C:31]3=[O:43])=[N:26][N:25]=[N:24]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>O.CN(C=O)C>[CH3:3][CH:2]([N:4]1[C:8]2=[N:9][C:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][C:12]([C:13]([N:36]3[CH2:37][CH2:38][C:33]4([CH2:32][C:31](=[O:43])[C:30]5[C:40](=[CH:41][CH:42]=[C:28]([C:27]6[NH:26][N:25]=[N:24][N:23]=6)[CH:29]=5)[O:39]4)[CH2:34][CH2:35]3)=[O:15])=[C:7]2[CH:6]=[N:5]1)[CH3:1]
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccccc3)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncc2c(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5nnn[nH]5)ccc3O4)cc(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TEA (0.2 mL) was added to a DMF suspension (2 mL) of 1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid, 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride, EDCI and HOBT.H2O, heated at 80° C. and stirred for 2 hours. This was cooled to room temperature, iced water was added thereto, and its pH was adjusted to 2.5 with 1 N HCl solution added thereto. The resulting crystal was taken out through filtration, washed with water, washed with Et2O, and dried in vacuum at 70° C. to obtain the title compound as a pale brown powder. 1H-NMR (400 MHz, DMSO-d6) δ: 8.34 (1H, d, J=2.2 Hz), 8.26-8.21 (2H, m), 8.19 (1H, s), 8.19 (1H, dd, J=8.4, 2.6 Hz), 7.82 (1H, s), 7.58-7.47 (3H, m), 7.20 (1H, d, J=8.4 Hz), 5.33 (1H, sept, J=6.8 Hz), 4.45-4.30 (1H, m), 3.70-3.00 (3H, m), 2.95 (2H, s), 2.20-1.70 (4H, m), 1.55 (6H, d, J=6.8 Hz). MS [M+H]+=549.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([CH:24]=1)[C:17]([NH:19][CH2:20][CH2:21][NH:22][OH:23])=[O:18]>N1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([CH:24]=1)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH:8]=[O:10])[OH:23])=[O:18]
Reactant: O=CO
Reactant: O=C(NCCNO)c1cc(Br)ccc1Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)CCNC(=O)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A mixture of acetic anhydride (2 mL) and formic acid (1 mL) was allowed to stand at 55° C. for 2.5 h. After cooling to 0° C., the resulting mixed anhydride (0.5 mL) was added to a solution of 5-bromo-2-chloro-N-(2-hydroxyamino-ethyl)-benzamide (0.7 g, 2.4 mmol) in pyridine (6 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred for 1 h and the pyridine removed in vacuo. The residue was chased twice with water and twice with MeOH. The resulting solid was washed with ether/acetonitrile (9:1) to provide the title compound (0.42 g, 55%) as a white solid. 1H NMR* (400 MHz, CD3OD): δ 8.35 (s, 0.5H); 7.95 (s, 0.5H); 7.58 (m, 2H); 7.38 (m, 1H); 3.78 (m, 1H); 3.73 (m, 1H); 3.62 (m, 2H). * 1:1 mixture of rotamers. ESMS: M+H=321.