Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.O.[Cu]I>[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:13])[CH2:16][CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C#C[Si](C)(C)C)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (25) (200 mg, 0.58 mmol), PdCl2(Ph3P)2 (16 mg, 0.03 mol %) and CuI (6 mg, 0.05 mol %) in triethylamine (1.2 mL) was heated to reflux. (Trimethylsilyl)acetylene (100 μL, 0.7 mmol) was added, and the bright yellow solution quickly turned orange then went brown within a minute. The reaction mixture was stirred for 3 h, cooled to room temperature, diluted with H2O (20 mL), and extracted with CHCl3 (3×15 mL). The combined organics were washed with saturated NaCl (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-[(trimethylsilyl)ethynyl]benzoate 26 (185.5 mg): 1H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H), 7.75 (s, 1H), 7.43 (s, 1H), 3.74 (s, 3H), 3.25 (br s, 2H), 2.95 (br s, 2H), 1.49 (br s, 2H), 1.34 (br s, 2H), 0.79 (br s, 3H), 0.56 (br s, 3H), 0.06 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].Cl.[C:11](Cl)(Cl)=[S:12]>O>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([N:7]=[C:11]=[S:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Solvent: O
Product: N#Cc1ccc(N=C=S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A solution of 6 g (0.051 mol) of 4-cyanoaniline in 50 cm3 of N hydrochloric acid is poured drop by drop into a suspension of 6.5 g (0.056 mol) of thiophosgene in 100 cm3 of water. The reaction medium is vigorously stirred for two hours at room temperature. The precipitate formed is filtered, washed with three fractions of 10 cm3 of water, then dried in vacuo in the presence of phosphorus pentoxide. The substance is recrystallized from a mixture of hexane and carbon tetrachloride. 7.2 g of 4-cyanophenyl isothiocyanate are obtained (yield 85%) of which the melting point is 117°-118° C.
Reaction SMILES: [O:1]1[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH:12]=[CH:13][CH:14]=1>>[OH:1][C:3]1([CH2:2][NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])[CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C1CCC2(C1)CO2
Reactant: Nc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(NCC2(O)CCCC2)c1

Procedure:
Reaction between 1-oxaspiro[2.4]heptane and 2-(3-(3-aminophenyl)propyl)isoindoline-1,3-dione gives 2-(3-(3-(((1-hydroxycyclopentyl)methyl)amino)phenyl)propyl)isoindoline-1,3-dione.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=C(C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)C[CH2:12][O:11][CH2:10]1)C1C=CC=CC=1.[NH2:47]CC1(N(CC2C=CC=CC=2)CC2C=CC=CC=2)COC1>>[NH2:8][C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[N:47][CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:10][O:11][CH2:12]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Product: NC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccncc23)COC1

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-1,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6-naphthyridine) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 9.15 (s, 1 H), 8.28-8.80 (d, J=6.4 Hz, 1 H), 8.00-7.95 (d, J=1.2 Hz, 1 H), 7.95-7.90 (d, J=7.2 Hz, 1 H), 7.62-7.58 (t, J=0.8 Hz, 1 H), 7.50-7.40 (m, 2 H), 6.31 (s, 1 H), 5.35 (s, 2 H), 4.65-4.58 (m, 6 H), 3.80 (s, 2 H), 3.60-3.50 (t, J=2.8 Hz, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:14][S:15]([NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CON(C)C(=O)c1ccnc(N)c1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccnc(NS(C)(=O)=O)c1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
2-Amino-N-methoxy-N-methyl-isonicotinamide (575 mg, 3.16 mmol) was dissolved in pyridine (4 mL), followed by the addition of methanesulfonyl chloride (0.73 mL, 9.48 mmol). The reaction was subsequently warmed to 40° C. and stirred 5h. The resultant mixture was quenched with 10% HCl, diluted with EtOAc, and the organic layer washed with 10% HCl and saturated sodium bicarbonate. The combined organics were dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to produce the desired sulfonamide.
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH:5]1[OH:13])([OH:3])=[O:2].[N:14]([O-])=[O:15].[Na+]>Cl>[C:1]([CH:4]1[N:9]([N:14]=[O:15])[CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH:5]1[OH:13])([OH:3])=[O:2]
Reactant: O=N[O-]
Reactant: O=C(O)C1NCc2sccc2C1O
Agent: Cl
Agent: [Na+]
Product: O=NN1Cc2sccc2C(O)C1C(=O)O
Temperature: 10 °C
Reaction time: 3 h

Procedure:
To a magnetically stirred suspension of 20 g (0.1 mole) 5-carboxy-4-hydroxy-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine in 200 cc 3 N hydrochloric acid maintained at 10° C. is added dropwise a 10% aqueous sodium nitrite solution (200 cc; 2.9 equivalents) and the resulting mixture is stirred at room temperature for 3 hours. The reaction medium remains heterogeneous throughout this step and nitrous fumes are evolved. The resulting precipitate is filtered off, washed with water and dried in vacuo, to give beige crystals (paste melting from 100° C.) in a yield of 21.3 g (93%).
Reaction SMILES: C(ON=O)(C)(C)C.N[C:9]1[C:21]([Br:22])=[CH:20][C:12]2[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:11]=2[C:10]=1[Br:23].CCOCC>CN(C=O)C>[Br:23][C:10]1[C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[CH:20]=[C:21]([Br:22])[CH:9]=1
Reactant: Nc1c(Br)cc2oc3ccccc3c2c1Br
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Brc1cc(Br)c2c(c1)oc1ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 116.4 %

Procedure:
To a solution of t-butylnitrite (0.89 ml, 7.2 mmol) dissolved in 10 ml of DMF at 50° C. was added dropwise a solution of 2-amino-1,3-dibromodibenzofuran 10 (1.0 g, 2.9 mmol) in 10 ml of DMF with nitrogen evolution. After stirring at 50° C. for 1 hour the reaction was diluted into ether and washed successively with H2O and saturated NaCl. Drying over MgSO4 and evaporation gave 1.1 g of a red solid which was purified by flash chromatography through 100 g of silica gel (20% methylene chloride:hexane) yielding 650 mg (68%) of the title compound as a pale orange solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][N:29]=1.BrBr>ClC1C=CC=CC=1>[Br:1][CH2:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: Cc1ncccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1cccnc1CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
51 g (290 mmol) of N-bromosuccinimide and 0.5 g of benzoyl peroxide were added, a little at a time, to a mixture of 40 g (290 mmol) of 2-methyl-3-nitropyridine (Example 3.b) and 400 ml of chlorobenzene, at the boiling point (liberation of bromine). After approximately 2 hours, the reaction mixture was cooled to room temperature (approximately 25° C.) and filtered, and the resulting solution was freed from solvent under reduced pressure. The resulting residue was chromatographed twice (cyclohexane/methylene chloride; cyclohexane/ethyl acetate). This gave 10.4 g (17%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[C:10]([O:9][C:7]([N:5]1[CH2:6][C@H:2]([NH:1][S:32]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:3][C@H:4]1[C:14]([O:16][CH3:17])=[O:15])=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of (2S,4R)-4-amino-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (6.04 g) in dichloromethane (60 ml) were added triethylamine (3.44 ml) and p-chlorobenzenesulfonyl chloride (6.26 g) in an ice bath. After being stirred at room temperature overnight, the solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from n-hexane to give (2S,4R)-1-t-butoxycarbonyl-4-(4-chlorophenylsulfonylamino)-2-methoxycarbonylpyrrolidine (9.13 g) as a pale yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].O>CN(C=O)C.N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 94.2 %

Procedure:
A solution of 4-aminobenzoic acid (1.40 g, 10 mmol) in DMF (10 mL) and pyridine (0.5 ml) was cooled to 0° C. To this solution was added of acryloyl chloride (0.94 g, 10 mmol) and the resulting mixture was stirred for 3 hours. The mixture was poured into 200 ml of water and the white solid obtained was filtered, washed with water and ether. Drying under high vacuum provided 1.8 g of the desired product which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[C:16](=[CH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14][C:13]=2[C:26]([OH:28])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:37][NH2:38].Cl>ClCCl>[OH:37][NH:38][C:26]([C:13]1[CH2:14][CH2:15][C:16](=[CH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]=1[S:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:28]
Reactant: C[Si](C)(C)ON
Reactant: COc1ccc(SC2=C(C(=O)O)CCC2=CCCc2ccccc2)cc1OC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(SC2=C(C(=O)NO)CCC2=CCCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-[(3,4-dimethoxyphenyl)thio]-3-(3-phenylpropyl-1-yl)-1-cyclopentenecarboxylic acid (0.6 g, 1.5 mmol) in dichloromethane (20 mL) is added 2 M oxalyl chloride (1.5 mL, 3 mmol). The mixture is stirred at room temperature for 15 minutes. The solvent is removed in vacuo and the residue is dissolved in dichloromethane and O-(trimethylsilyl)hydroxylamine (0.3 mL, 3 mmol) is added. The mixture is stirred at room temperature for 30 minutes. The mixture is poured into 5% HCl and is extracted with dichloromethane. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (100% ethyl acetate). The product is dissolved in the minimum amount of ethyl acetate and the solution is diluted to the cloudy point with hexane to precipitate N-hydroxy-2-[(3,4-dimethoxyphenyl)thio]-3-(3-phenylpropyl-1-yl)-1-cyclopentenecarboxamide on standing at room temperature overnight (0.1 g, 16%): m.p. 44-6° C. Anal. (C23H27NO4S.1/4H2O) C,H,N: 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.42-1.78 (m, 5H), 1.90-2.08 (m, 1H), 2.38-2.50 (m, 2H), 2.59-2.78 (m, 3H), 3.82 (s, 3H), 3.90 (s, 3H), 6.72-6.79 (d, 1H), 6.88-6.98 (m, 2H), 6.98-7.10 (d, 2H), 7.10-7.30 (m, 3H), 9.02 (s, 1H); MS (Ion Spray) m/e 413 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C(N(CC)CC)C.C([CH:23]([C:27](Cl)=[O:28])[C:24](Cl)=[O:25])C.[C:30](OCC)(=[O:32])[CH3:31]>>[CH2:30]([O:32][C:27](=[O:28])[CH2:23][C:24]([NH:6][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:11]([CH3:13])[CH3:12])=[O:25])[CH3:31]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 0 °C

Procedure:
A 5 L 4-necked flask was fitted with a mechanical stirrer and temperature probe and then purged with nitrogen. The flask was charged with 200 mL (188 g, 1.06 mol) of 2,6-diisopropyl aniline, 163 mL (118 g, 1.17 mol) of triethylamine and 2.5 L of ethyl acetate. The clear, yellow solution was cooled to 0° C. with stirring and 143 mL (168 g, 95% pure, 1.06 mol) of ethyl malonyl chloride was added over 15 min. The internal temperature rose as high as 22° C. during the addition. The cold bath was removed and the yellow suspension was stirred for 100 min (HPLC indicated reaction completion). The suspension was filtered and the filtrate was evaporated at the Rotavap giving yellowish solids. The crude ester were then recrystallized from 3.0 L of heptane yielding 240.24 g (78%) of N-(2,6-Diisopropyl-phenyl)-malonamic acid ethyl ester as slightly yellow solids. HPLC analysis indicated >99% (a/a) purity. The materials 1H-NMR spectrum was consistent with structure
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:9]=[C:10]([N:15]2[N:19]=[CH:18][CH:17]=[N:16]2)[C:11](O)=[N:12][CH:13]=1)([O-:7])=[O:6].[N+:20]([C:23]1[CH:24]=[C:25]([N:30]2[CH:34]=[CH:33][N:32]=[N:31]2)[C:26](O)=[N:27][CH:28]=1)([O-:22])=[O:21]>CN(C=O)C>[Cl:3][C:11]1[C:10]([N:15]2[N:19]=[CH:18][CH:17]=[N:16]2)=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][N:12]=1.[Cl:3][C:26]1[C:25]([N:30]2[CH:34]=[CH:33][N:32]=[N:31]2)=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][N:27]=1
Reactant: O=[N+]([O-])c1cnc(O)c(-n2nccn2)c1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(-n2ccnn2)c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Cl)c(-n2ccnn2)c1
Product: O=[N+]([O-])c1cnc(Cl)c(-n2nccn2)c1
Temperature: 0 °C

Procedure:
Thionyl chloride (19 ml) and DMF (4 ml) were added to a mixture (5.32 g) of 5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-ol and 5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridin-2-ol, followed by reflux for 1 hour. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 10:1). A light yellow solid of 2-chloro-5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridine (0.72 g) and a yellow solid of 2-chloro-5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridine (0.63 g) were thus obtained.
Reaction SMILES: C1(N[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)CCCCC1.[CH:14](=[N:22][CH:23]1[C:35](=[O:36])[N:25]2[C:26]([C:32]([OH:34])=[O:33])=[C:27]([CH2:30][OH:31])[CH2:28][S:29][C@H:24]12)[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17].[C:37]1([CH3:47])[CH:42]=[CH:41][C:40](S(O)(=O)=O)=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH:14](=[N:22][CH:23]1[C:35](=[O:36])[N:25]2[C:26]([C:32]([O:34][CH:47]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:33])=[C:27]([CH2:30][OH:31])[CH2:28][S:29][C@H:24]12)[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17]
Reactant: O=C(O)C1=C(CO)CS[C@@H]2C(N=Cc3ccccc3O)C(=O)N12
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CO)CS[C@@H]2C(N=Cc3ccccc3O)C(=O)N12
Yield: 91.3 %

Procedure:
To a suspension of 7-salicylideneamino-3-hydroxymethyl-3-cephem-4-carboxylic acid dicyclohexylamine salt (3 g) in ethyl acetate (60 ml) was added dropwise an ethyl acetate solution of p-toluenesulfonic acid (1.1 g) with stirring, and the reaction mixture was stirred for an hour at ambient temperature. After the precipitate was filtered off, the filtrate was treated with a solution of excess diphenyldiazomethane in ethyl acetate for an hour. The solvent was distilled off, and the residue was pulverized with diisopropyl ether, collected by filtration and dried to give benzhydryl 7-salicylideneamino-3-hydroxymethyl-3-cephem-4-carboxylate (2.66 g).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](O)=[O:14])[CH:9]=[CH:10][CH:11]=1.F[P-](F)(F)(F)(F)F.[N:28]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.N>CN(C=O)C>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([NH2:28])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1cccc(C)c1COc1cccc(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cccc(CC(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(2,6-Dimethylbenzyloxy)phenylacetic acid (3.08 g, 11.4 mmol) and Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (5.05 g, 11.4 mmol) in DMF (75 ml) was added triethylamine (2.30 g, 22.8 mmol), and the reaction mixture was stirred for 1 h at room temperature. To this reaction mixture was added liquid ammonia (100 ml) at −40 0° C., the resulting mixture was allowed to warm to ambient temperature over 10-12 hours and concentrated. The residue was taken into ethyl acetate and washed with water (2×), dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (ethyl acetate:hexane, 2.5:1 spiked with acetic acid) to give the title compound.
Reaction SMILES: C1(C[C:8]([O:10][CH:11]2CCCCO2)=[O:9])C=CC=CC=1.[C:17]1([C:23]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:11][O:10][C:8]([C:20]1[CH:21]=[CH:22][C:17]([C:23]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1)=[O:9].[CH3:11][O:10][C:8]([C:20]1[CH:19]=[CH:18][C:17]([CH2:23][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=1)=[O:9]
Reactant: O=C(Cc1ccccc1)OC1CCCCO1
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Product: COC(=O)c1ccc(C2(C(=O)O)CCCCC2)cc1
Product: COC(=O)c1ccc(CC(=O)O)cc1

Procedure:
The title compound was obtained from 2-[4-(methoxycarbonyl)phenyl]acetic acid (8a) by the method described above for tetrahydro-2H-pyran-2-yl 2-phenylacetate (5a) and 1-phenylcyclohexanecarboxylic acid (1/3). The crude product 1/4 was chromatographed on silica gel with toluene-ethyl acetate-acetic acid (8:2:0.1) as eluent to give 1-[4-(methoxycarbonyl)phenyl]-cyclohexanecarboxylic acid (1/4) in 68% yield (on 8a) as a white solid. 1H NMR (CDCl3, HMDSO) δ: 0.94-2.09 (8H, m); 2.25-2.65 (2H, m); 3.88 (3H, s); 7.49 (2H, d, J=8.6 Hz); 7.96 (2H, d, J=8.6 Hz); 10.07 (1H, br s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:22])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2cc(OCc3ccccc3)ccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccnc2cc(OCc3ccccc3)ccc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a suspension of 7-(benzyloxy)quinolin-4-ol (72 g, 287 mmol) in toluene (134 mL) was added phosphoryl trichloride (44 g, 287 mmol, Tianjin FuChen Chem. Co. Ltd.). The suspension was heated to 120° C. for 1 hour. The reaction mixture was then cooled to 70° C. and diluted with EtOAc (600 mL). The resulted mixture was stirred for 30 minutes while cooling down to 15° C. using an ice bath. The mixture was neutralized with 3 M NaOH aqueous solution to pH 7˜8 while maintaining the temperature of the solution under 20° C. The aqueous layer was separated and extracted with EtOAc (200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a pale yellow solid (70.8 g, 91.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27][C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH:36]1(CO)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:27][CH2:25][CH:36]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: OCC1CCCCCC1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCC4CCCCCC4)c(Cl)c3)c2cc1OC
Yield: 72.4 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cycloheptylmethanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (53 mg, yield 63%).