Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.B.C(O)C>C1COCC1>[CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Agent: B
Solvent: C1CCOC1
Solvent: CCO
Product: c1ccc2c(c1)CNc1ccccc1O2
Temperature: 25 °C
Yield: 101.9 %

Procedure:
Dibenzo[b,f][1,4]oxazepin-11(10H)-one (1.001 g, 4.7 mmol) was dissolved in THF (20 mL) and the borane (2M in THF, 20 mL, 40.0 mmol) was added. The reaction mixture was refluxed for 3 hours. The mixture was cooled down to room temperature and an excess of ethanol was added to quench the reaction. The resulting mixture was refluxed for 2 hours. The mixture was cooled down and concentrated in vacuo. The residue was dissolved in ethyl acetate and the organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated to afford title compound 398 (0.945 g, quantitative). MS (m/z): 198.1 (M+H). 1H NMR (CD3OD) δ (ppm): 7.29-7.19 (m, 2H), 7.16-7.04 (m, 2H), 7.01-6.99 (m, 1H), 6.82-6.78 (m, 1H), 6.63-6.59 (m, 2H), 4.88 (s, 1H), 4.39 (s, 2H). MS (m/z): 198.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.Br[C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:25])[CH3:24])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(N)n1
Temperature: 42.5 °C

Procedure:
Ethyl (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate (32.25 g) of Formula (I) is dissolved in N,N-dimethylformamide (258 ml) at room temperature. Tert.-butyl 2-bromoisobutyrate (38.47 g) and anhydrous potassium carbonate (47.61 g) are added and the resulting suspension is heated to 40-45° C. for 20-25 hrs. The reaction mass is cooled to 30-32° C. and it is added slowly to water. The resulting slurry is stirred at 25-30° C. for about one and a half hours. The product is filtered, washed with water and dried under reduced pressure. Yield: 50 g (93.37%), water content <1.0% w/w; Chromatographic purity (HPLC) >98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[CH3:26][CH:27]=[CH:28][CH2:29][NH2:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:30][CH2:29][CH2:28][CH:27]=[CH2:26])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Yield: 78.7 %

Procedure:
A stirred mixture of 8-chloro-1-(chloromethyl)-6-phenyl-4-H-s-triazolo[4,3-a][1,4]benzodiazepine (1.37 g., 0.004 mole), potassium iodide (0.67 g., 0.004 mole), methylallylamine (0.84 g., 0.012 mole) and tetrahydrofuran (100 ml.) is kept at ambient temperature (25° C.) for 18 hours and concentrated in vacuo. The residue is mixed with water and extracted with methylene chloride. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is crystallized from ethyl acetate-Skellysolve B hexanes to give 1.19 g of 8-chloro-1-[(allylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 157°-160° C. The analytical sample has a melting point of 158° -164° C. Anal. calcd. for C21H20ClN5 : C, 66.75; H, 5.33; Cl, 9.38; N, 18.53. Found: C, 66.87; H, 5.46; Cl, 9.42; N, 18.67. Preparation 40 8-Chloro-1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:14][C:13](=[O:15])[CH:12]=[CH:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[O:1]([CH2:8][CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=COC(COc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCOC(COc2ccccc2)C1
Yield: 58.4 %

Procedure:
2-Phenoxymethyl-2,3-dihydropyran-4-one (2.30 g, 11.3 mmol) was dissolved in ethyl acetate (150 ml). 10% Palladium on charcoal (400 mg) was added. The reaction mixture was hydrogenated until the reaction stopped. The catalyst was removed by filtration through a glas-filter. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (200 g), using ethyl acetate/heptane 1:1 as eluent, to give 1.36 g of 2-phenoxymethyltetrahydropyran-4-one.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[O:3].[CH2:12](OC(=O)C)C>>[CH3:12][N:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[O:3]
Reactant: CCOC(C)=O
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Product: Cn1c(=O)[nH]c2nc[nH]c2c1=O

Procedure:
The first step in the synthesis involves blocking the 7 position in 1-methyl xanthine. The procedure of Hu, Singh and Ullman, J. Am. Chem. Soc., 45: 1711-1713 (1980) was followed. To 700 ml of dry DMF in a 1-liter conical flask was added 3.2 g (18.9 mmoles) of 98% 1-methylxanthine (Aldrich Chemical Co., cat. #28,098-4), the mixture was stirred magnetically and warmed until dissolution occurred and then cooled to room temperature. To the stirred solution was added 2.0 g (18.9 mmoles) of anhydrous sodium carbonate followed by the dropwise addition, over a period of 1 hour, of 3.0 g (19.3 mmoles) of 97% chloromethyl pivalate (Aldrich Chemical Co., cat. #14,118-6) dissolved in 50 ml of DMF. The reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue treated with 50 ml of methylene chloride. The insoluble material was collected by filtration and washed with 1N HCl to give 1.24 g of 1-methylxanthine. The methylene chloride solution was evaporated to dryness to yield a mixture of mono- and bis- protected xanthine. The mono-protected 1-methyl-7-}pivaloyloxy)methyl1 xanthine was separated from the bis protected xanthine by crystallization from ethyl acetate. By this method there was obtained 1.5 g of the monoprotected xanthine (m.p. 204°-206°). The ethylacetate filtrate from the isolation of the monoprotected xanthine, containing the bis-protected xanthine, was evaporated to dryness and refluxed with 20 ml of 2N sodium hydroxide for 18 hours. The reaction mixture was cooled and acidified with concentrated HCl and extracted with chloroform. Evaporation of the aqueous layer yielded 0.5 g of 1-methylxanthine.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH:7]=[CH:8][CH:9]=1)=[O:4].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3](=[O:4])[CH2:2][N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1
Reactant: O=C(CCl)c1cccn1Cc1ccccc1F
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Product: CN1CCN(CC(=O)c2cccn2Cc2ccccc2F)CC1

Procedure:
A mixture of 2-chloroacetyl-1-(2-fluorobenzyl)pyrrole Example 1a, N-methylpiperazine and triethylamine in methaol is treated by the procedure described in Example 1b to produce 1-(2-fluorobenzyl)-2-[α-(4-methylpiperazino)-acetyl]pyrrole.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:25])[NH:4][C:5]([C:11]2[CH:16]=[C:15]([C:17](=[O:20])[CH2:18]Br)[CH:14]=[CH:13][C:12]=2[O:21][CH2:22][CH2:23][CH3:24])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9].C(N(CC)CC)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[Br:1][C:2]1[C:3](=[O:25])[NH:4][C:5]([C:11]2[CH:16]=[C:15]([C:17](=[O:20])[CH2:18][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:14]=[CH:13][C:12]=2[O:21][CH2:22][CH2:23][CH3:24])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CCCOc1ccc(C(=O)CBr)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1ccc(C(=O)CN2CCOCC2)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Reaction time: 12 h
Yield: 39.2 %

Procedure:
The compound (150 mg, 0.32 mmol) of example 71 was dissolved in dichloromethane (20 ml), added with triethylamine (0.5 ml) and morpholine (40 mg, 0.46 mmol), followed by stirring for 12 h. The reaction mixture was washed orderly with water (10 ml) and saturated saline. The organic phase was dried with anhydrous Na2SO4, and concentrated under reduced pressure to give an oil, which was passed through a silica gel column to obtain the title compound (60 mg, yield: 39%). 1H NMR (CDCl3) δ: 11.20 (1H, br), 9.21 (1H, d), 8.17 (1H, dd), 7.15 (1H, d), 4.30 (2H, t), 3.75-3.64 (10H, br), 3.52 (1H, m), 2.03 (2H, m), 1.30 (6H, d), 1.16 (3H, t).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:12]1[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1.[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:12]1[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:17]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1cccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c1
Yield: 93.7 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 3-dimethylaminophenol (0.82 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (1.72 g), sodium hydride (55 wt. %, 0.26 g) and anhydrous N,N-dimethylformamide (50 ml) and the reaction mixture was purified to give the title compound (2.17 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]3[CH:33]=[CH:32][C:31]4[NH:30][C:29](=[O:34])[C:28]5[NH:35][CH:36]=[CH:37][C:27]=5[C:26]=4[CH:25]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=O)(C)(C)C.[CH2:38]([C:40]([O-:42])=[O:41])[CH3:39]>ClC(Cl)C>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]3[CH:33]=[CH:32][C:31]4[NH:30][C:29](=[O:34])[C:28]5[NH:35][CH:36]=[CH:37][C:27]=5[C:26]=4[CH:25]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.[CH2:38]([C:40]([O-:42])=[O:41])[CH3:39]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(-c3ccc4[nH]c(=O)c5[nH]ccc5c4c3)ccc21
Agent: CCC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=c1[nH]c2ccc(-c3ccc4[nH]ccc4c3)cc2c2cc[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
1 mL of trifluoroacetic acid is added to a solution of 70 mg (0.15 mmol) 8-(1-tert-butoxycarbonyl-1H-indol-5-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate dissolved in 4 mL of dichloroethane. The solution is stirred for 2 hours at room temperature then the precipitate that forms is filtered and washed with diethyl ether to give 26 mg (45%) of 8-(1H -indol-5-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a brown solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].C[O-].[Na+].[CH2:28](Br)[CH:29]=[CH2:30]>O>[CH2:30]([O:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:17])=[O:13])=[CH:9][CH:10]=1)[CH3:4])[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: CC(=NO)c1ccc(NC(=O)NCC(=O)Oc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCON=C(C)c1ccc(NC(=O)NCC(=O)Oc2ccccc2)cc1

Procedure:
A solution of the N-[4-(1-hydroxyiminoethyl)phenyl]-N'-phenoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the product N-[4-(1-allyloxyiminoethyl)phenyl]-N'-phenoxycarbonylmethylurea.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[CH:27]=[C:26](Br)[CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[CH:27]=[C:26]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH3:29])[CH:36]=4)[CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2s1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)c1
Temperature: 80 °C

Procedure:
0.3 ml of 2 M aqueous sodium carbonate solution and 4.1 mg (0.005 mmol) of PdCl2(dppf) are added to a mixture of 40 mg (0.10 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A) and 15.1 mg (0.10 mmol) of 3-methoxyphenylboronic acid in 1 ml of DMF. The reaction mixture is heated at 80° C. for 14 h, filtered through kieselguhr and evaporated to dryness. Purification of the crude product by preparative HPLC, subsequent addition of 1N hydrochloric acid and drying under high vacuum result in 25.5 mg (57% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[F:15].Cl[C:17](OC(Cl)(Cl)Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:14][C:5]1[C:6]2[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[O:10][C:11]=2[C:2]([N:1]=[C:17]=[O:18])=[C:3]([F:15])[CH:4]=1
Reactant: CC1(C)CCc2c(Cl)cc(F)c(N)c2O1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)CCc2c(Cl)cc(F)c(N=C=O)c2O1
Yield: 97.8 %

Procedure:
By the method of Example 1, Step F, 3.6 grams (0.016 mole) of 8-amino-5-chloro-3,4-dihydro-2,2-dimethyl-7-fluoro-2H-1-benzopyran and 3.1 grams (0.016 mole) of trichloromethyl chloroformate were reacted in 100 mL of toluene, yielding about 4.0 grams of 5-chloro-3,4-dihydro-2,2-dimethyl-7-fluoro-2H-1-benzopyran-8-yl isocyanate. The product was taken to the next step without further characterization.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:9]2[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:8]=2[N:7]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.C(NC(C)C)(C)C.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[OH:44]>O1CCCC1.CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:9]2[CH:17]=[CH:18][C:19]([C:21]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[OH:44])=[O:23])=[CH:20][C:8]=2[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Reactant: Nc1ccccc1O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(=O)OCc1nc2cc(C(=O)Nc3ccccc3O)ccc2n1C1CCOCC1
Temperature: 50 °C
Reaction time: 14 h
Yield: 124.5 %

Procedure:
A 4-neck flask (200 mL) equipped with a reflux condenser was charged with 2-acetoxymethyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid (see Working Example 7-1) (1.50 g, 4.71 mmol), anhydrous tetrahydrofuran (40 mL), and oxalyl chloride (0.657 g, 5.18 mmol), and anhydrous N,N-dimethylformamide (0.4 mL) was then added dropwise at room temperature, after which the reaction mixture was stirred at 50° C. for 14 hours. After being allowed to cool to room temperature, the solvent was distilled off under reduced pressure to give a pale yellow residue which was cooled to 0 to 5° C., which was taken up in anhydrous tetrahydrofuran (40 mL) and diisopropylamine (0.79 mL, 5.65 mmol), followed by 2-aminophenol (0.57 g, 5.81 mmol), and this was stirred for 24 hours at room temperature. The precipitated crystals were filtered off, these were washed with tetrahydrofuran and dried under reduced pressure with heating to yield the title compound (2.40 g, quant.) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:34])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[CH:20][C:19]=1[O:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:34])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][C:19]=1[O:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of tert-butyl 4-[N′-(2-benzyloxyphenyl)ureido]-3-methoxyphenylacetate (2.35 g, 5.08 mmol) in CH2Cl2 (25 mL) was added TFA (25 mL) at 0° C. After being stirred at room temperature. for 3 hr, the mixture was concentrated. The residue was dissolved in 1N NaOH and washed with Et2O. The basic water layer was poured into ice-1N HCl and the resulting mixture was extracted with CHCl3—MeOH (4:1, v/v). The extracts were washed with brine, dried over Na2SO4, and concentrated to dryness. The residue was dissolved in isopropyl ether and hexane was added to this solution until the crystallization was completed. The solid was collected to give 4-[N′-(2-benzyloxyphenyl)ureido]-3-methoxyphenylacetic acid (1.59 g, 77%) as a brownish solid. 1H-NMR (DMSO-d6) δ3.50 (s, 2H), 3.85 (s, 3H), 5.26 (s, 2H), 6.76 (d, J=8.3 Hz, 1H), 6.83-6.89 (m, 2H), 6.91 (s, 1H), 7.01 (dd, J=8.3, 2.3 Hz, 1H), 7.31 (t, J=7.3 Hz, 1H), 7.39 (t, J=7.3 Hz, 2H), 7.49 (d, J=7.3 Hz, 2H), 7.97 (d, J=8.3 Hz, 1H), 8.04 (d, J=8.3 H, 1H), 8.80 (s, 1H), 8.86 (s, 1H), 12.24 (broad s, 1H); FAB-MS m/z 407 (M++1).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:15][CH2:16][CH3:17])(=O)=O)=CC=1.[OH:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.[H-].[Na+]>CN(C)C=O>[F:19][C:18]([F:20])([F:21])[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH2:11][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(CCOc1ccc(C(=O)OCC)cc1)C(F)(F)F
Reaction time: 8 h
Yield: 87.5 %

Procedure:
In a round-bottomed flask, 0.88 g of the 3-trifluoromethylheptyl p-toluenesulfonate ◯2 , 0.4 g of ethyl p-hydroxybenzoate and 1 ml of dimethylformamide were placed, and 50 mg of sodium hydride was added thereto, followed by 8 hours of heat-refluxing and 15 hours of standing at room temperature. After the reaction, dimethylformamide was distilled off, and dilute hydrochloric acid was added to the product, which was then extracted with methylene chloride. The resultant organic layer was washed with water and dried with magnesium sulfate, followed by distilling-off of the solvent and purification by thin layer chromatography (developer: methylene chloride/hexane=1/1) to obtain 0.7 g of ethyl p-(3-trifluoromethylheptyloxy)benzoate ◯3 . (Yield: 80%).
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[BH4-].[Na+]>O>[OH:17][CH:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:12]=2[CH:11]=[CH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]1=2
Reactant: Cc1cccc2c(=O)c3ccccc3ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc2c1C=Cc1ccccc1C2O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
26 g. of 1-Methyl-5H-dibenzo[a,d]cyclohepten-5-one are dissolved in 200 ml. of dioxane, a solution of 9 g. of sodium borohydride in 35 ml. of water is added thereto and the mixture is stirred at room temperature for 4 hours. The mixture is subsequently evaporated under reduced pressure. The residue is shaken with ether and water. The ethereal phase is washed with water, dried over sodium sulfate, filtered and evaporated. The 5-hydroxy-1-methyl-5H-dibenzo[a,d]cycloheptene obtained is recrystallized from petroleum ether and melts at 114°-116°C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH2:28][S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][CH:36]([CH2:38][C:39](O)=[S:40])[F:37].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.Cl>ClCCl.O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:39](=[S:40])[CH2:38][CH:36]([F:37])[F:35])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH2:28][S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(=S)CC(F)F
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCSc3c[nH]nn3)CS[C@H]12
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SCSc2c[nH]nn2)CS[C@@H]2[C@H](NC(=S)CC(F)F)C(=O)N12
Temperature: -30 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 7β-amino-3-(1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester (550 mg : 1.08 mMol.) and difluoromethylthioacetic acid (160 mg : 1.13 mMol.) in dichloromethane (8 ml) cooling at -30° C. are added N-methylmorpholine (0.27 ml : 2.46 mMol.) and phenyl dichlorophosphate (0.19 ml : 1.27 mMol.), and the mixture is stirred at -30° C. for 1 hour. The reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with aqueous saline, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (toluene : ethyl acetate=1:1) to give 7β-difluoromethylthioacetamido-3-(1,2,3-triazol-4-ylthiomethyl- thio) -3-cephem-4-carboxylic acid diphenylmethyl ester (475 mg) as pale yellow foam. Yield : 69%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:8][C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH2:17][CH2:18][N:19]=2)[CH:12]=[C:11]([Cl:20])[C:10]=1[OH:21].C(=O)=O.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[O:35][N:34]=[C:33]([CH3:36])[CH:32]=1>CN(C)C=O>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH2:17][CH2:18][N:19]=2)[CH:12]=[C:11]([Cl:20])[C:10]=1[O:21][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[O:35][N:34]=[C:33]([CH3:36])[CH:32]=1
Reactant: Oc1c(Cl)cc(C2=NCCO2)cc1Cl
Reactant: Cc1cc(CCCCCBr)on1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CN(C)C=O
Product: Cc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)on1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a stirred suspension of milled potassium carbonate (172.5 gm, 1.25 moles) in 1.35 L dimethylformamide (DMF) was added 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol hydrochloride (133.5 gm, 0.5 moles). Heavy gas evolution (CO2) occurred and the reaction was warmed on the stream bath to 70° c. After stirring for about 5 minutes, 5-(5-bromopentyl)-3-methylisoxazole (121.8 gm, 0.525 moles) was added in one portion. The mixture was heated to 90°-95° C. for 1 hr, allowed to cool to room temperature and then filtered. The filter cake was rinsed with DMF and the filtrate was concentrated under water vacuum to a viscous brown oil (260 gm). This residue was dissolved in 300 ml isopropyl acetate and washed with water and then with brine. The organic layer was dried over MgSO4, charcoaled, filtered and evaporated to dryness. The crude product (220 gm oil) was diluted with 287 ml acetone (1.5 volumes based on theoretical yield) and was cooled and stirred in a Dry Ice/acetone bath to -25° C. The product was collected and air dried to give 115 gm (60% yield) of 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole, m.p. 38°-40° C. A sample when recrystallized from triethylamine had the m.p. 42°-43° C.