Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)=[O:19])=[CH:12][C:11]=12.[N+]([C:32]1[CH:40]=CC(C(O)=O)=C[CH:33]=1)([O-])=O>>[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:19])[C:20]3[CH:28]=[CH:27][C:23]([C:24]([N:5]4[CH2:4][CH2:3][CH2:2][CH:6]4[CH:32]([CH3:40])[CH3:33])=[O:25])=[CH:22][CH:21]=3)=[CH:12][C:11]=12
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccc(C(=O)NCc2ccn3ccnc3c2)cc1
Reactant: CC(C)CCN
Product: CC(C)C1CCCN1C(=O)c1ccc(C(=O)NCc2ccn3ccnc3c2)cc1

Procedure:
The title compound was prepared as described in Example 1A, substituting (propan-2-yl)pyrrolidine for 3-methylbutan-1-amine and 4-(imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)benzoic acid for 4-nitrobenzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.44-9.36 (m, 1H), 8.86 (d, J=6.9 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H), 8.01-7.95 (m, 2H), 7.80 (s, 1H), 7.65-7.59 (m, 2H), 7.49 (d, J=7.6 Hz, 1H), 4.69 (d, J=5.8 Hz, 2H), 4.15-4.05 (m, 1H), 3.47-3.19 (m, 2H), 2.39-2.26 (m, 1H), 1.96-1.57 (m, 4H), 0.93-0.85 (m, 6H); MS (ESI(+)) m/e 391 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:35]2[CH:40]=[CH:39][C:38](I)=[CH:37][CH:36]=2)=[CH:19]/[CH2:20][O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=2)=[CH:14][CH:13]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:11][C:12]1[CH:13]=[CH:14][C:15](/[C:18](/[C:35]2[CH:36]=[CH:37][C:38]([C:10]#[C:9][CH2:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:39][CH:40]=2)=[CH:19]/[CH2:20][O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=2)=[CH:16][CH:17]=1
Reactant: C#CCN1CCN(C)CC1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCN(C)CC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under nitrogen atmosphere, 1-methyl-4-propargylpiperazine (380 mg, 2.75 mmol) was added to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (450 mg, 0.82 mmol; prepared as described in example 7) in a mixture of tetrahydrofuran (10 mL) and triethylamine (8 mL) The solution was cooled, tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol) and copper(I) iodide (22 mg, 0.115 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h, diluted with benzene (100 mL) and washed with water (2×50 mL). The organic solution was dried with anhydrous potassium carbonate and subsequently evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethanol 1:0-1:2) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(4-methylpiperazin-1-yl)propynyl]phenyl]-allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([OH:11])=O)[CH2:2]2.S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[ClH:14].[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([Cl:14])=[O:11])[CH2:2]2
Reactant: O=C(O)C1CN2CCC1CC2
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(Cl)C1CN2CCC1CC2

Procedure:
500 mg (2.61 mmol) of 3-quinuclidinecarboxylic acid are heated together with 1.9 ml (26.09 mmol) of thionyl chloride under reflux for 2 h. The reaction mixture is freed of excess thionyl chloride under reduced pressure. 20 ml portions of toluene are added twice and evaporated to dryness each time. The product obtained in this way is reacted immediately without further purification.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][CH2:8][O:9][CH2:10][CH2:11][CH:12]1[CH2:14][O:13]1.[Cl:15][C:16]1[NH:17][CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[N:20]=1>C(O)C>[Cl:15][C:16]1[N:17]([CH2:14][CH:12]([OH:13])[CH2:11][CH2:10][O:9][CH2:8][O:7][CH3:6])[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[N:20]=1
Reactant: COCOCCC1CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COCOCCC(O)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 78.2 %

Procedure:
Sodium acetate (3.51 g, 42.82 mmol) and 2-(2-methoxymethoxyethyl)oxirane (10.3 g, 77.86 mmol) were added to 2-chloro-4-nitro-1H-imidazole (5.74 g, 38.93 mmol) in ethanol (60 ml), and the resulting mixture was stirred under reflux for 13.5 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and then crystallized from methylene chloride-diisopropyl ether to afford 2-chloro-1-(2-hydroxy-4-methoxymethoxybutyl)-4-nitroimidazole (8.51 g, yield 78%) as a light yellow powder.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)(C)C>[NH2:18][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[N:15]=1
Reactant: NC(N)=S
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc(-c2csc(N)n2)cc1

Procedure:
At room temperature, methyl 4-bromoacetylbenzoate (1.00 g) and thiourea (296 mg) were dissolved in isopropanol (100 ml), followed by heating under reflux for 15 minutes. Under stirring at the same temperature, anhydrous sodium carbonate (206 mg) was added to the reaction mixture. The resulting mixture was heated under reflux for 20 minutes. After completion of the reaction, water (50 ml) was added under ice cooling and the solid so precipitated was collected by filtration. The solid was dissolved in water and dichloromethane. The organic layer so separated was dried over anhydrous sodium sulfate. The solvent was then distilled off. The pale yellow solid so precipitated was washed with ether, whereby the title compound (634 mg, 70%) was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6]CC)=O.[C:13]1(=[O:25])[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][CH2:16][CH:15]3[CH2:14]1.Cl>O1CCOCC1>[C:4]([CH:14]1[CH:15]2[C:24]3[C:19]([CH2:18][CH2:17][CH2:16]2)=[CH:20][CH:21]=[CH:22][C:23]=3[C:13]1=[O:25])([C:3]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: O=C1CC2CCCc3cccc1c32
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)C1C(=O)c2cccc3c2C1CCC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
To a suspension of 50% sodium hydride (7.4 g) in anhydrous dioxane (50 ml), under nitrogen, a solution of diethyl oxalate (34.5 g) in anhydrous dioxane (20 ml) and then a solution of 2a,3,4,5-tetrahydro-acenaphthen-1-one (20.4 g) in anhydrous dioxane (130 ml) are added under stirring at room temperature. The reaction mixture is kept under stirring at a temperature varying between about 25° C. and about 45° C. for 4 hours, then it is diluted with ice water (1500 ml) and acidified to pH 4 with 2N HCl. The precipitate is filtered, washed with water and then purified by treatment with methanol to give 2-ethoxalyl-2a,3,4,5-tetrahydro-acenaphthen-1-one (30.8 g), m.p. 92°-94° C., wich is reacted with methylhydrazine (5.7 g) in acetic acid (300 ml) at 50° C. for 1 hour.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Br[CH:56]([CH3:58])[CH3:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([CH:56]([CH3:58])[CH3:57])[CH2:49][CH2:48]1
Reactant: CC(C)Br
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 28 %

Procedure:
The desired compound was prepared according to the procedure of Example A111, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-bromopropane as starting materials in 28% yield. LCMS for C27H33ClN7O (M+H)+: m/z=506.2.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C@H:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:14]=[CH:13]2.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([CH:37]([CH3:41])[C:38]([OH:40])=[O:39])[CH:31]=[CH:30]2.[OH-].[Na+:43]>O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:14]=[CH:13]2.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C@H:37]([CH3:41])[C:38]([O-:40])=[O:39])[CH:31]=[CH:30]2.[Na+:43]
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2cc([C@H](C)C(=O)[O-])ccc2c1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
Using the apparatus of the above Comparative Example, a toluene solution of 2-(6-methoxy-2-naphthyl)propionic acid (580.68 grams, 18.11 wt % solids, 91.64% S-enantiomer) was prepared from a sample of high chiral purity (S)-2-(6-methoxy-2-naphthyl)propionic acid, and racemic 2-(6-methoxy-2-naphthyl)propionic acid. The solution was heated to 85° C. Totals of 27.59 grams of 49.22 wt % NaOH and 7.822 grams of water were added. Two clear liquid phases were obtained. Water was stripped to 94.0° C. in 285 minutes. The total amount of water collected during the strip was 21.36 grams and the amount of toluene removed was 1.83 grams. The batch was agitated at 93.6°-94.0° C. for 15 minutes and cooled to 75° C. in 82 minutes and agitated at 75° C. for 60 minutes. Solids in the slurry settled well at the end of the 60-minute 75° C. ride. The centrifuge cake (sodium (S)-2-(6-methoxy-2-naphthyl)propionate monohydrate) was washed with 149.94 grams of hot (75° C.) toluene. Totals of 483.77 and 127.61 grams of mother liquor and wash liquor were recovered, respectively. The wet centrifuge cake weighed 75.02 grams which after drying for 8 hours at 80°-90° C. and under full vacuum yielded 67.29 grams of anhydrous sodium (S)-2-(6-methoxy-2-naphthyl)propionate. Chiral purities for the product and the mother liquor were found by analysis to be 99.03% S-enantiomer and 80.28% S-enantiomer, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].Cl[C:13](OC(Cl)(Cl)Cl)=[O:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[N:4]=[C:13]=[O:14]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(N)c(Cl)cc1F
Solvent: Cc1ccccc1
Product: COc1cc(N=C=O)c(Cl)cc1F
Yield: 175.1 %

Procedure:
In the manner of Example 2, Step D, the reaction of 3.0 g (0.017 mole) of 2-chloro-4-fluoro-5-methoxyaniline with 1.68 g (0.0085 mole) of trichloromethyl chloroformate in 20 mL of toluene produced 3.0 g of 2-chloro-4-fluoro-5-methoxyphenyl isocyanate.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:15][C:14]=2[Cl:24])[CH:6]=1.CO.[Si](C=[N+]=[N-])(C)(C)[CH3:29]>C1(C)C=CC=CC=1>[Cl:24][C:14]1[CH:15]=[C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=1[O:12][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:25])[CH:10]=[C:9]([O:11][CH3:29])[CH:8]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(O)cc(CC(=O)OC)c2)c(Cl)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from step (i) was taken up in toluene (3 ml) and methanol (1 ml) and TMS-diazomethane (0.6 ml, 2M in diethylether) added, the mixture stirred at RT for 3 h then evaporated under reduced pressure. The residue was taken up in THF (2 ml) and methanol (1 ml) then 3M NaOH (2 ml) added and the mixture stirred at RT for 2 h. The mixture was then acidified to pH 2 and extracted with ethyl acetate. The organics were dried (MgSO4), evaporated under reduced pressure and then passed onto a Varian NH2 resin (eluting with ethyl acetate, acetonitrile, methanol, DCM then 20% acetic acid in DCM). The acidic fraction was evaporated under reduced pressure and then purified by RPHPLC to give a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].CI.[C:15]([O-:20])(=[O:19])[C:16]([O-:18])=[O:17]>CN(C)C=O>[C:15]([OH:20])(=[O:19])[C:16]([OH:18])=[O:17].[C:15]([OH:20])(=[O:19])[C:16]([OH:18])=[O:17].[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])C(=O)[O-]
Agent: CC(=O)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 Grams of o-methoxycarbonyl- -[4-3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide was suspended in 50 ml of dimethylformamide, then 621 mg of 50% oily sodium hydride was added to the suspension and stirred at a room temperature for 1 hour. Next, under ice-cooled condition, 2.5 g of methyl iodide was added dropwise to the suspention and stirred at a room temperature for 4 hours. The solvent was removed by distillation under a reduced pressure, the residue obtained was extracted with chloroform and 1N-sodium hydroxide aqueous solution. The chloroform layer was washed with water, dried and then chloroform was removed by distillation. The residue obtained was purified by a silica gel column chromatography, and the product obtained was converted into an oxalate, recrystallized from methanol-ether to obtain 3.11 g of o-methoxy-carbonyl-N-methyl-α-[4-dimethoxy-benzoyl)-1-piperazinyl]-acetanilide dioxalate in the form of colorless powdery crystals. Melting point: 181.0°-182.0° C. (decomposed).
Reaction SMILES: [F:1][C:2]([S:5][CH2:6][C:7]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([OH:27])=[O:26])=[C:14]([CH:17]([S:19][C:20]3[NH:24][N:23]=[N:22][N:21]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8])([F:4])[F:3].[CH2:30]1[C:38]2[C:33](=[CH:34][C:35](O)=[CH:36][CH:37]=2)[CH2:32][CH2:31]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[F:1][C:2]([S:5][CH2:6][C:7]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([O:27][C:35]3[CH:34]=[C:33]4[C:38](=[CH:37][CH:36]=3)[CH2:30][CH2:31][CH2:32]4)=[O:26])=[C:14]([CH:17]([S:19][C:20]3[NH:21][N:22]=[N:23][N:24]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8])([F:4])[F:3]
Reactant: Oc1ccc2c(c1)CCC2
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CSC(F)(F)F)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)Oc2ccc3c(c2)CCC3)N2C(=O)C(NC(=O)CSC(F)(F)F)[C@H]2SC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (4.70 g, 0.01 mol) and 5-indanol (1.34 g, 0.01 mol) in tetrahydrofuran is added dicyclohexylcarbodiimide (2.06 g, 0.01 mol) and the reaction is stirred for 4 hours at room temperature. The solid urea is collected and washed with tetrahydrofuran and the filtrate is evaporated to give 5-indanyl 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([NH2:18])=[CH:13][C:12]=2[O:19][C@@H:20]([CH3:24])[C:21]#[C:22][CH3:23])[CH2:7][CH2:6][NH:5][CH2:4]1.[F:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][CH2:33][CH2:34]Br)=[CH:29][CH:28]=1.C(N(CC)CC)C.CN(C=O)C>C(OCC)(=O)C>[F:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][CH2:33][CH2:34][N:5]2[CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:25])[C:11]3[CH:16]=[C:15]([Cl:17])[C:14]([NH2:18])=[CH:13][C:12]=3[O:19][C@@H:20]([CH3:24])[C:21]#[C:22][CH3:23])[C@H:3]([O:2][CH3:1])[CH2:4]2)=[CH:29][CH:28]=1
Reactant: CC#C[C@H](C)Oc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: Fc1ccc(OCCCBr)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC#C[C@H](C)Oc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A mixture comprising 0.10 g of the cis-N-(3-methoxy-4-piperidinyl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide, 0.07 g of 3-(4-fluorophenoxy)propyl bromide, 0.20 g of triethylamine and 10 ml of DMF was stirred at 50° C. for 2 hours and cooled. Ethyl acetate was poured into the resulting mixture. The obtained mixture was washed with water thrice, dried over magnesium sulfate, and freed from the solvent. The residue was purified by silica gel column chromatography (5% methanol/dichloromethane) to give 0.13 g of the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)(=[O:5])[CH3:4].Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH2:22][CH2:21]1.C>CS(C)=O.C(O)(C)C>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[CH2:22][CH2:21]2)=[C:9]([O:14][CH3:15])[CH:8]=1)(=[O:5])[CH3:4]
Reactant: Fc1ccccc1N1CCN(CCCCl)CC1
Reactant: COc1cc(NC(C)=O)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: COc1cc(NC(C)=O)ccc1OCCCN1CCN(c2ccccc2F)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
1.13 g of powdery sodium hydroxide are added under nitrogen atmosphere to a solution of 5.08 g of 4-acetamido-2-methoxyphenol in 70 ml of anhydrous dimethylsulfoxide. The mixture is stirred at 50° C. for 2 hours. A solution of 6 g of 1-(3-chloro-n-propyl)-4-(2-fluorophenyl)-piperazine in 20 ml of anhydrous dimethylsulfoxide is added dropwise at 20° C. to the mixture, and said mixture is stirred at 100° C. for 1.5 hours. After cooling, the reaction mixture is poured into ice-water. The crystalline precipitates are collected by filtration, whereby a crude product is obtained. The mother liquor obtained after isolating the crude product is extracted with chloroform. The extract is washed with water, dried and then evaporated under reduced pressure to remove the solvent, whereby another crude product is obtained. Both crude products obtained above are dissolved in hot isopropyl alcohol and then treated with activated charcoal. 6.95 of 1-[3-(4-acetamido-2-methoxyphenoxy)-n-propyl]-4-(2-fluorophenyl)-piperazine are thereby obtained as colorless needles. Yield: 74%
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]2[S:8][C:9]([C:11](OC)=O)=[CH:10][C:5]2=[N:4]1)[CH3:2].[ClH:15].S1C2C=C[N:21]=CC=2C=C1CN>>[Cl-:15].[CH2:1]([N:3]1[CH:7]=[C:6]2[S:8][C:9]([CH2:11][NH3+:21])=[CH:10][C:5]2=[N:4]1)[CH3:2]
Reactant: NCc1cc2cnccc2s1
Reactant: CCn1cc2sc(C(=O)OC)cc2n1
Reactant: Cl
Product: CCn1cc2sc(C[NH3+])cc2n1
Product: [Cl-]

Procedure:
Intermediate G was prepared from methyl 2-ethyl-2H-thieno[3,2-c]pyrazole-5-carboxylate (G-3) following similar procedures for synthesizing intermediate D from D-2, as described above. MS (m/z): 182 (M+1)+.
Reaction SMILES: O[CH2:2][CH:3]1[CH:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][CH:6]2[CH:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:16]=3[N:15]=[N:14]2)[O:4]1.C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1.[CH2:52]([O:54][P:55]([CH:60]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:59])[O:56][CH2:57][CH3:58])[CH3:53]>CS(C)=O.C(Cl)Cl>[CH2:52]([O:54][P:55]([CH:60]=[CH:2][CH:3]1[CH:7]2[CH:6]([O:10][C:9]([CH3:11])([CH3:12])[O:8]2)[CH:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:16]=3[N:15]=[N:14]2)[O:4]1)(=[O:59])[O:56][CH2:57][CH3:58])[CH3:53]
Reactant: CCOP(=O)(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCC
Reactant: CC1(C)OC2C(CO)OC(n3nnc4c(NC(=O)c5ccccc5)ncnc43)C2O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CCOP(=O)(C=CC1OC(n2nnc3c(NC(=O)c4ccccc4)ncnc32)C2OC(C)(C)OC12)OCC
Reaction time: 2 h
Yield: 29.6 %

Procedure:
Compound 6.3 (1.2 g, 2.91 mmol) was dissolved in 23 mL DMSO, and treated with DCC (3.6 g, 17.5 mmol) and DCA (0.24 mL, 2.91 mmol). The mixture was stirred for 2 h and then treated with 0.3 mL pyridine. Diethyl(triphenylphosphoranylidene)methylphosphonate (2.9 g, 6.98 mmol) was dissolved in 5 mL CH2Cl2 and it was added to the mixture dropwise and the mixture was stirred for 3 h. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with H2O three times, dried over MgSO4, filtered and concentrated down under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 100% EtOAc to 5% MeOH in EtOAc to give compound 6.4 (469 mg, 30% yield). 1HNMR (300 MHz, CD3OD) δ 1.17-1.35 (m, 6H), 1.46 (s, 3H), 1.64 (s, 3H), 3.85-3.97 (m, 4H), 4.04-4.12 (m, 1H), 5.01 (m, 1H), 5.33-5.45 (m, 2H), 5.81 (d, 1H, J=5.7), 6.63-6.77 (m. 1H), 7.57-8.12 (m, 5H), 8.87 (s, 1H). LRMS (ESI) MH+ C24H29N6O7P requires 545.2, Found 545.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[H][H]>[Pd].O1CCOCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C(O)C(O)Cc1ccc(O)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
10 g of 3-(4-hydroxyphenyl)pyruvic acid and 50 ml of dioxane were charged to a pressure reactor to form a solution, and 0.5 g of 5% palladium on charcoal was added thereto. The atmosphere was displaced with hydrogen, and the mixture was stirred at 70° C. under a hydrogen pressure of 5 kg/cm2 for 6 hours. After completion of the reaction, the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to give 10.0 g of 3-(4-hydroxyphenyl)lactic acid as colorless crystals.