Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:21][CH2:22][CH2:23][CH2:24]I>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:24][CH2:23][CH2:22][Cl:21])[C:6]=2[CH:12]=1
Reactant: ClCCCI
Reactant: Cc1c(Cl)cc2c(c1Cl)OCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cc2c(c1Cl)OCC(=O)N2CCCCl
Yield: 79.1 %

Procedure:
6,8-Dichloro-7-methyl-4H-benzo[1,4]oxazin-3-one (81MF2225a) (2.33 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2225b) (2.44 g, 79%). 1H NMR (CDCl3) δ 7.02 (s, 1H), 4.67 (s, 2H), 4.06 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.2, 2H), 2.43 (s, 3H), 2.18-2.10 (m, 2H); 13C NMR (CDCl3) δ 163.7, 140.5, 130.3, 128.3, 127.6, 124.1, 113.5, 67.9, 42.2, 39.3, 30.0, 17.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([CH2:21]O)=[C:16]([CH3:23])[C:15]=3[CH:24]=2)=[O:9])=[N:6][CH:7]=1.CS([Cl:29])(=O)=O.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([CH2:21][Cl:29])=[C:16]([CH3:23])[C:15]=3[CH:24]=2)=[O:9])=[N:6][CH:7]=1
Reactant: CC1=C(CO)CCCc2ccc(NC(=O)c3ccc(Cl)cn3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(CCl)CCCc2ccc(NC(=O)c3ccc(Cl)cn3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.3 %

Procedure:
To a solution of 5-chloro-N-(8-(hydroxymethyl)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-2-yl)picolinamide from step 3B (52 mg, 0.15 mmol) in dichloromethane (1 mL) was added methanesulfonylchloride (0.015 mL, 0.20 mmol) and DIPEA (0.048 mL, 0.27 mmol). The mixture was stirred at rt for 20 h. The mixture was subjected to chromatography (hexanes-100% EtOAc) to give 5-chloro-N-(8-(chloromethyl)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-2-yl)picolinamide (30 mg, 0.083 mmol, 55% yield). LCMS (M+H)+=361.2. 1H NMR (500 MHz, chloroform-d) δ 9.81 (br. s., 1H), 8.58 (dd, J=2.3, 0.6 Hz, 1H), 8.27 (dd, J=8.4, 0.6 Hz, 1H), 7.90 (dd, J=8.4, 2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.57 (dd, J=8.1, 2.3 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 4.37 (s, 2H), 2.57 (t, J=7.0 Hz, 2H), 2.21 (s, 3H), 2.17 (quin, J=7.1 Hz, 2H), 2.05-1.98 (m, 2H)
Reaction SMILES: [S:1](=[O:13])(=[O:12])([O:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11])[NH2:2].[CH:14]1(N=C=NC2CCCCC2)CCCCC1.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])N=[C:33]([C:39]([OH:41])=O)[N:32]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:38][O:37][C:35]1[CH:36]=[C:31]([O:30][CH3:29])[N:32]=[C:33]([C:39]([NH:2][S:1](=[O:13])(=[O:12])[O:3][C:4]2[C:5]([Cl:11])=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:10])=[O:41])[CH:14]=1
Reactant: NS(=O)(=O)Oc1c(Cl)cccc1Cl
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1cc(OC)nc(C(=O)O)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(OC)nc(C(=O)NS(=O)(=O)Oc2c(Cl)cccc2Cl)c1
Reaction time: 3 h

Procedure:
2.4 g of 2,6-dichlorophenyl sulfamate are added in portions at 0° C. to 2° C. to a mixture of 2.3 g of dicyclohexylcarbodiimide, 120 mg of 4-dimethylaminopyridine and 2.2 g of 4,6-dimethoxypyrimidine-2-carboxylic acid in 80 ml of absolute dichloromethane, and stirring is continued for 0.5 hour at 0° C. and 3 hours at room temperature. The mixture is filtered off with suction, the organic phase is washed with 100 ml of 1N hydrochloric acid and then with water and dried over sodium sulfate. The solvent is distilled off, and the residue is recrystallized from diisopropyl ether. This gives 3.2 g of 2,6-dichlorophenyl N-[(4,6-dimethoxypyrimidin-2-yl)carbonyl]sulfamate of melting point 136°-139° C.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[N:20]=2)[CH2:6][C@H:5]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N+:2]=[N-:3].C.[C:44]([C:46]1[CH:50]=[CH:49][S:48][CH:47]=1)#[CH:45].C(N(CC)CC)C>O1CCOCC1.[Cu]>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[C:21]1[N:20]=[C:19]([C:18]([NH:17][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:11]=2[N:7]2[CH2:8][C@H:9]([CH3:10])[C@H:4]([N:1]3[CH:45]=[C:44]([C:46]4[CH:50]=[CH:49][S:48][CH:47]=4)[N:3]=[N:2]3)[C@H:5]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:6]2)=[O:34])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Reactant: C#Cc1ccsc1
Agent: [Cu]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1cc(-c2ccsc2)nn1
Temperature: 100 °C
Yield: 48 %

Procedure:
In a high pressure vial was added tert-butyl (3R,4S,5S)-4-azido-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate (1.0 equiv.), copper in charcoal (0.4 equiv.), 3-ethynyl thiophene (5.0 equiv.) and triethylamine (1.0 equiv.), in dioxane (0.09 M) to give a black suspension. The pressure tube was sealed and the mixture was stirred with heating to 100° C. overnight. The reaction was cooled to RT, filtered through celite, concentrated to yield tert-butyl (3R,4S,5S)-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methyl-4-(4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl)piperidin-3-ylcarbamate in 48% yield. LC/MS (m/z)=691.2 (MH+), Rt=0.98 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[C:10]3[C:11]=2[C:6](=[C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]2=[CH:9]3)[C:5]1=[O:22].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>N1C=CC=CC=1>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:1][CH2:2][CH2:3][N:4]2[C:13](=[O:14])[C:12]3[CH:15]=[CH:16][CH:17]=[C:10]4[C:11]=3[C:6](=[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]3=[CH:9]4)[C:5]2=[O:22])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCN2C(=O)c3cccc4cc5ccccc5c(c34)C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
A mixture of 1.01 g (3.5 mmol) of 2-(2-hydroxyethyl)-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione in 10 ml of pyridine is treated with 0.69 g (3.6 mmol) of p-toluenesulfonyl chloride. The mixture is stirred at room temperature for 24 hours and poured into 50 ml of cold water. The solid is collected, washed with water, dried in vacuo, and crystallized from dimethylformamide water to give 1.2 g (77%) of 2-[2-(p-toluenesulfonyloxy)ethyl]-1,2-dihydro-3H-dibenz-[de,h]isoquinoline-1,3-dione. M.p. 240° C.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C@H:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([CH:24]=[CH2:25])[NH:19]1.[CH:26]([CH2:28][C:29](O)=[O:30])=[CH2:27].Cl>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C@H:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([CH:24]=[CH2:25])[N:19]1[C:29](=[O:30])[CH2:28][CH:26]=[CH2:27]
Reactant: C=C[C@@H]1CCC[C@H](c2ccccc2F)N1
Reactant: C=CCC(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccccc1F
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Diethyl cyanophosphonate (1.23 mL) was added to a solution of (2R*,6S*)-2-(2-fluorophenyl)-6-vinylpiperidine (518 mg), vinylacetic acid (0.66 mL), and triethylamine (2.1 mL) in DMF (10 mL) at room temperature, and the reaction solution was stirred at room temperature for 21 hours. Ethyl acetate and 1 N hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was sequentially washed with saturated sodium bicarbonate water and brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 442 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1/[N:13]=[CH:14]/[C:15]1[N:20]=[C:19]([C:21]2[CH:41]=[CH:40][CH:39]=[CH:38][C:22]=2[CH2:23][N:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)C(=O)OC(C)(C)C)[CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].[BH3-]C#N.[Na+].FC(F)(F)C(O)=O.[OH-].[Na+]>C(O)=O.CO>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([C:21]2[CH:41]=[CH:40][CH:39]=[CH:38][C:22]=2[CH2:23][NH:24][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:20]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1/N=C/c1cccc(-c2ccccc2CN(C(=O)OC(C)(C)C)c2ccccc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O=CO
Product: CC(C)c1cccc(C(C)C)c1NCc1cccc(-c2ccccc2CNc2ccccc2)n1
Temperature: 25 °C

Procedure:
Methanol (40 mL) and (E)-tert-butyl 2-(6-((2,6-diisopropylphenylimino)methyl)pyridin-2-yl)benzyl(phenyl)carbamate (12) (2.56 g (4.67 mmol) were combined to form a yellow suspension. Then some NaBH3CN (0.293 g, 4.66 mmol) was added followed by four drops of 88% formic acid. Then additional NaBH3CN (0.878 g, 14.0 mmol) was added in small portions over 5 minutes. The mixture was heated to reflux for 3 hours then evaporated to near dryness. Water (20 mL) and Et2O (40 mL) were then added followed by a CH2Cl2 (6 mL). The organics were separated, dried over brine then magnesium sulfate, filtered, and evaporated to a thick oil. Chloroform (25 mL) was then added to form a solution. Trifluoroacetic acid (10 mL) was added and the mixture was heated to reflux to cause gas evolution. After 45 minutes the mixture was cooled to ambient temperature and 3 M NaOH (60 mL) was added. The biphasic mixture was rapidly stirred for several minutes. The organics were separated, washed with water (50 mL) and brine (5 mL). The organics were then separated and dried over magnesium sulfate. Filtration and evaporation afforded the product as a thick oil that was dried thoroughly under reduced pressure at 65° C. Yield: 2.0 g, 95%). 1H NMR (CD2Cl2, 500 MHz): 7.77 (t, 1H), 7.39-7.58 (m, 5H), 7.31 (d, 1H), 7.02-7.12 (m, 5H), 6.63 (t, 1H), 6.58 (d, 2H), 4.62 (br, 1H), 4.41 (br, 2H), 4.23 (br, 1H), 3.97 (br, 1H), 3.35 (sept, 2H), 1.20 (d, 12H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[S:2][CH3:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: CSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 64.2 %

Procedure:
To a stirred solution of 0.364 g of 2-(methylthio)benzoyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo(2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid which is crystallized from ethyl alcohol to give 0.480 g of the desired product as a white solid, m.p. 171°-174° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-])=O.[N+:14]([C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1)([O-])=O>NC1C=CC(S(N)(=O)=O)=CC=1>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:14])(=[O:12])=[O:11].[NH2:14][C:17]1[CH:18]=[C:19]([S:23]([NH2:1])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: Nc1ccc(S(N)(=O)=O)cc1
Product: Nc1cccc(S(N)(=O)=O)c1
Product: Nc1ccccc1S(N)(=O)=O

Procedure:
By using (a) 2-nitrobenzenesulfonyl chloride, (b) 3-nitrobenzenesulfonyl chloride instead of 4-nitrobenzenesulfonyl chloride in the above (A), (a') 2-aminobenzenesulfonamide (m.p. 184° C.-186° C.), (b') 3-aminobenzenesulfonamide (m.p. 139° C.-140° C.) were obtained respectively.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10](=[S:16])([NH2:15])[CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C.C(OCC)(=O)C>[CH3:10][CH2:11][CH2:12][CH:3]([CH3:2])[CH3:4].[CH2:11]([C:10]1[S:16][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:15]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCC(C)C
Product: CCCCc1nc(C(=O)OCC)cs1

Procedure:
Ethyl 3-bromo-2-oxopropanoate (6.76 mL) was added very carefully to a stirred solution of pentanethioamide (example 78, step e) (6.30 g) in ethanol (100 mL). The solution was then heated at reflux for 16 h. After cooling, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and evaporated in vacuo. Purification by silica gel chromatography eluting with 1:6 ethyl acetate: isohexane gave the subtitled compound as a yellow oil. Yield 6.5 g.
Reaction SMILES: C(N1C=CN=C1)(N1[CH:7]=[CH:6]N=C1)=O.[Cl:13][C:14]1[C:19]([CH:20]=[C:21]([C:23](O)=[O:24])[Cl:22])=[CH:18][C:17]([N:26]2[C:30](=[O:31])[C:29]3[CH2:32][CH2:33][CH2:34][CH2:35][C:28]=3[C:27]2=[O:36])=[C:16]([F:37])[CH:15]=1.Cl.C([N:41]([CH2:43][C:44]([OH:46])=[O:45])[CH3:42])C.C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[C:19]([CH:20]=[C:21]([C:23]([N:41]([CH2:43][C:44]([O:46][CH2:6][CH3:7])=[O:45])[CH3:42])=[O:24])[Cl:22])=[CH:18][C:17]([N:26]2[C:27](=[O:36])[C:28]3[CH2:35][CH2:34][CH2:33][CH2:32][C:29]=3[C:30]2=[O:31])=[C:16]([F:37])[CH:15]=1
Reactant: O=C(O)C(Cl)=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(C)CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN(C)C(=O)C(Cl)=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
6 mmol of carbonyldiimidazole were added dropwise to a solution of 5 mmol of N-[4-chloro-5-(2-hydroxycarbonyl-2-chloroethen-1-yl)-2-fluorophenyl]-3,4,5,6-tetrahydrophthalimide in 50 ml of absolute tetrahydrofuran, after which stirring was carried out for one hour at about 20° C. 5 mmol of ethyl sarcosine hydrochloride were then added to the reaction mixture. 5 mmol of triethylamine in 5 ml of tetrahydrofuran were then added dropwise. Stirring was carried out for 48 hours at about 20° C., after which the solvent was removed under reduced pressure from a water-jet pump. The residue was taken up in water, after which the product was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and then evaporated down. The crude product was purified by chromatography over silica gel (eluent: 1:2 petroleum ether/methyl tert-butyl ether). Yield: 0.97 g (40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([O:2][CH3:1])[CH:7]=5)=[O:10])[CH:45]=[CH:44][CH:43]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: COc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(C)n1
Yield: 91.7 %

Procedure:
In the same manner as in Example 18-4 and using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (201 mg, 1.29 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (265 mg, 92%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:59][C:60]1[CH:61]=[C:62](B(O)O)[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]>>[F:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:62]2[CH:63]=[CH:64][C:65]([O:66][CH3:67])=[C:60]([F:59])[CH:61]=2)[CH:12]=[C:13]([F:18])[CH:14]=1
Reactant: CS(=O)(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reactant: COc1ccc(B(O)O)cc1F
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCC4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1F
Yield: 67 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[1-(methylsulfonyl)piperidin-4-yl]ethoxy}-1H-inden-1-one obtained in Step 3 of Example 100 as a starting material instead of 6-(2-morpholino ethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3-fluoro-4-methoxyphenylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (67%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([NH:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=[N:4][NH:3]1.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[O:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl.FC(F)(F)C1C=CC=CC=1OC1CCNCC1>>[F:29][C:14]([F:13])([F:28])[C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[O:18][CH:19]1[CH2:20][CH2:21][N:22]([C:10](=[O:12])[CH2:9][NH:8][C:7]2[C:2](=[O:1])[NH:3][N:4]=[CH:5][CH:6]=2)[CH2:23][CH2:24]1
Reactant: O=C(O)CNc1ccn[nH]c1=O
Reactant: FC(F)(F)c1cccc(OC2CCNCC2)c1
Agent: Cl
Agent: FC(F)(F)c1ccccc1OC1CCNCC1
Product: O=C(CNc1ccn[nH]c1=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Yield: 36 %

Procedure:
Compound 44 is prepared from intermediate 7a and from 4-(3-trifluoromethyl-phenoxy)-piperidine (obtained following the method described for 1a) applying synthesis method 2 (yield: 36%).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:32](=[O:33])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[O:21])[C:16](=C)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=[O:36])C>>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:32](=[O:33])[N:14]2[C:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[O:21])=[C:16]([OH:36])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc(OC)cc1
Reactant: CCOC(C)=O
Product: COc1ccc(COC(=O)C2=C(O)CS[C@@H]3C(NC(=O)COc4ccccc4)C(=O)N23)cc1
Temperature: 0 °C

Procedure:
A solution of 2.5 g. of p-methoxybenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate in 350 ml. of ethyl acetate was cooled in an acetone-dry ice bath. Ozone was bubbled through the cold solution for 8 minutes and then oxygen was passed through the ozonized reaction mixture to expel excess ozone. The intermediate ozonide was decomposed by adding to the reaction mixture 25 g. of sodium bisulfite with stirring at a temperature of about 0° C. The reaction solution was decanted and was washed successively with water, 5% hydrochloric acid and a saturated solution of sodium chloride. The washed mixture was dried and evaporated to yield the reaction product, p-methoxybenzyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate as an amorphous solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl([O-])=[O:18].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:18])=[O:11])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: COc1ccc(C=O)cc1OC1C=CCC1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)O)cc1OC1C=CCC1
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A solution of 3-cyclopent-2-enyloxy-4-methoxybenzaldehyde (7.70 g) in t-butanol (160 mL) and 2-methyl-2-butene (40 mL) is treated dropwise with an aqueous solution (150 mL) containing sodium chlorite (80% technical grade; 4.39 g) and sodium dihydrogen phosphate (38.49 g), and left to stand overnight. The resulting mixture is extracted with dichloromethane (2×250 mL), and the combined organic layers are dried over sodium sulfate, the solvent is removed under reduced pressure, and the resulting residue is recrystallized fromethyl acetate, to give 3-cyclopent-2-enyloxy-4-methoxybenzoic acid (5.89 g), in the form of a colorless solid. m.p. 160°-163° C. [Elemental analysis: C,66.4; H,6.0%; calculated: C,66.7; H,6.0%].
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.[NH:22]1[CH2:27][CH2:26][CH:25]([O:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9]([N:22]2[CH2:27][CH2:26][CH:25]([O:28][N:29]3[C:30](=[O:39])[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:37]3=[O:38])[CH2:24][CH2:23]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCNCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1OC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.5 %

Procedure:
3-(Trifluoromethyl)benzenesulfonyl chloride (3.23 g, 13.2 mmol) was added to a solution of 2-(piperidin-4-yloxy)isoindoline-1,3-dione trifluoroacetic acid (3.56 g, 9.80 mmol) and N,N-diisopropylethylamine (7.10 g, 55.0 mmol) in CH2Cl2 (85 ml), and stirred at room temperature for 17 hours. The reaction mixture was washed with aqueous 1 N HCl solution (20 ml×3), aqueous NaHCO3 solution (20 ml×3), brine (20 ml×2), dried over Na2SO4, filtered and concentrated in vacuo to give 2-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)isoindoline-1,3-dione (4.12 g, 93%) as a white solid: LCMS: 454 [M+1]+.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([O:6][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCC(O)CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCC(O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-hydroxyhexadecanoic acid (1.90 g) and triethylamine (0.97 ml) in DMF (20 ml) was added benzyl bromide (0.83 ml) and the mixture was stirred at room temperature for 3 days. After the solvent was removed in vacuo, ethyl acetate and water were added to the residue. The separated ethyl acetate layer was washed twice with water and then dried over anhydrous sodium sulfate. After concentration, the residue was purified by a silica gel column chromatography (silica gel 15 g, chloroform: methanol=100:0-8) to afford 1.22 g of benzyl 3-hydroxyhexadecanoate.