Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11](C(OCC1C=CC=CC=1)=O)[C:12]1[C:21]2[N:22]=[C:23]([CH2:30][O:31][CH2:32][CH3:33])[N:24]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[C:20]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][C:14]=2[N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:51]([N:58]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[CH2:59][C:60](O)=[O:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][O:31][CH2:32][CH3:33])[N:24]([CH2:25][C:26]([O:29][C:60](=[O:61])[CH2:59][N:58]([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)([CH3:28])[CH3:27])[C:20]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][C:14]=2[N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1nc2c(N(C(=O)OCc3ccccc3)C(=O)OCc3ccccc3)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)O
Reactant: O=C(O)CN(Cc1ccccc1)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOCc1nc2c(NC(=O)OCc3ccccc3)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)OC(=O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a suspension of ethyl 3-(4-(bis(benzyloxycarbonyl)amino)-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate (300 mg, 439 μmol), 2-(dibenzylamino)acetic acid (337 mg, 1.32 mmol) and DMAP (107 mg, 879 μmol) in dichloromethane (4 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (253 mg, 1.32 mmol) and molecular sieves (300 mg). After 1 h stirring at room temperature starting materials had dissolved, stirring at room temperature continued for 6 h and the mixture was left standing over the weekend. The residue was diluted with dichloromethane (50 mL) and washed with HCl (1 M, 20 mL) and water (20 mL). The aqueous phase was extracted with dichloromethane (50 mL), organic phases were combined, dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give the title compound (182 mg, 52%) as light yellow oil; LC-MS (UV peak area, ESI) 98%, 784.6 (MH+).
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:2][N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:15]([O:19][C:20](ON=C(C1C=CC=CC=1)C#N)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCOCC1.O>[C:15]([O:19][C:20]([N:6]1[CH2:7][CH2:8][N:3]([CH2:2][CH2:1][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH2:4][CH2:5]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: C1CN(CCN2CCNCC2)CCN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCN2CCNCC2)CC1

Procedure:
1,1'-ethylenedipiperazine (1.98 g, 10 mmol) is dissolved in 20 mL of dioxane:water (1:1) mixture and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10 mmol) is added. The mixture is then stirred until no starting material is detected on thin layer chromatography. The obtained mixture is fractionally separated by silica gel chromatography, followed by RP-HPLC to obtain N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine. Following the procedure of Example 6, but replacing 1-benzylpiperazine with N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine (1.817 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, followed by a carefully deprotection of N-tert-butoxycarbonyl group with 10% trifluoroacetic acid to obtain the pure title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2[N:14]([CH3:30])[C:15](=[O:29])[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[CH2:27][OH:28])[C:21]([OH:23])=O)=[CH:17][C:12]=2[CH:11]=[N:10]1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:31]1([NH:34][C:21](=[O:23])[C:20]2[CH:24]=[CH:25][C:26]([CH2:27][OH:28])=[C:18]([C:16]3[C:15](=[O:29])[N:14]([CH3:30])[C:13]4[N:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:10]=[CH:11][C:12]=4[CH:17]=3)[CH:19]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: Cn1c(=O)c(-c2cc(C(=O)O)ccc2CO)cc2cnn(-c3c(F)cccc3F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1c(=O)c(-c2cc(C(=O)NC3CC3)ccc2CO)cc2cnn(-c3c(F)cccc3F)c21
Temperature: 25 °C

Procedure:
3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(hydroxymethyl)benzoic acid (310 mg, 754 μmol) was treated with cyclopropanamine (0.21 mL, 3014 μmol) and HATU (430 mg, 1130 μmol) in THF (5.00 mL) under nitrogen and allowed to stir at RT. After 2 h the reaction was quenched by the addition of 1N NaOH (10 mL). The reaction mixture was extracted with EtOAc (2×25 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO 12 g column (70-100% EtOAc in hexanes) affording the title compound as an amorphous white solid. MS (ESI, pos.ion) m/z: 451.1 (M+1).
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-:3])=[O:2].[N-:14]=[N+:15]=[N-:16].[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:14]=[N+:15]=[N-:16])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 15.0 g (0.069 mole) of o-nitrobenzenesulfonyl chloride dissolved in 150 ml ethanol was added 5.89 g (0.090 mole) of sodium azide dissolved in a minimum amount of water. The solution was stirred for 30 minutes and then poured into a 2 liter Erlenmeyer flask containing 500 ml of ice water. The resultant white solid was filtered, dried and recrystallized from ethanol. The purified product had a melting point 73°-74° C. (lit. 73°-74° C.) and was isolated in 92% yield (14.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:16][CH2:17][CH:18]=[C:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]=2[CH2:23][O:22][C:21]2[CH:30]=[CH:31][C:32]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:33][C:20]1=2.[I-].[K+]>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:14])[CH2:9][CH2:10][N:11]([CH2:16][CH2:17][CH:18]=[C:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[N:29][C:24]=3[CH2:23][O:22][C:21]3[CH:30]=[CH:31][C:32]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:33][C:20]2=3)[CH2:12][CH2:13]1
Reactant: CC1(c2ccccc2Cl)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(C)(c3ccccc3Cl)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 12 h
Yield: 24.6 %

Procedure:
A solution of 4-(2-Chloro-phenyl)-4-methyl-piperidine (0.29 g, 1.38 mmol) in isopropanol (5 mL) was treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.19 g, 0.50 mmol) and catalytic potassium iodide. The solution was stirred at 80° C. for 12 hr, and evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate→87:10:3 ethyl acetate/methanol/triethylamine) to yield 0.062 g (25%) of the title compound, 1H-NMR (CDCl3) ∂: 1.10 (3H, s), 1.58 (6H, s), 1.78 (2H, m), 1.90 (1H, m), 2.10 (2H, m), 2.40 (8H, m), 5.30 (2H, brs), 6.18 (1H, t), 6.79(1H, m), 6.92 (1H, m), 7.19–7.39 (6H, m), 7.42 (1H, m), 7.55 (1H, m), 8.55 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.[CH3:18][N:19]([CH3:27])[CH:20]([CH2:25][CH3:26])[CH2:21][C:22](=O)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:23]3[CH2:26][CH2:25][CH:20]([N:19]([CH3:27])[CH3:18])[CH2:21][CH2:22]3)[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2
Reactant: Nc1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Reactant: CCC(CC(C)=O)N(C)C
Product: CN(C)C1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1

Procedure:
7-Amino-5-chloro-2-phenyl-1H-indole prepared in Example 3 and 4-dimethylaminohexanone were reacted according to the same procedure as Step B of Example 1 to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:5]=2[O:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH3:1]
Reactant: CC1=COc2cc(C)ccc2C(=O)N1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1=COc2cc(C)ccc2C(=O)N1CCCCBr
Yield: 68 %

Procedure:
2.84 g of 4,5-dihydro-3,8-dimethyl-1,4-benzoxazepin-5-one was dissolved in 75 ml of acetone, 12.9 g (4 equivalents) of 1,4-dibromobutane and 6.22 g (3 equivalents) of potassium carbonate were added, then the resultant mixture was heated and refluxed for 12 hours. This was allowed to cool, then was filtered, the filtrate was concentrated, and the residue was refined by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the above-referenced compound in an amount of 3.3 g (yield of 68%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[CH3:15]C(C)([O-])C.[K+].IC.O>CN(C=O)C.CO.ClCCl>[CH3:10][O:9][C:7]([C:5]1[N:6]=[C:2]([CH3:1])[N:3]([CH3:15])[C:4]=1[C:11]([O:13][CH3:14])=[O:12])=[O:8]
Reactant: COC(=O)c1nc(C)[nH]c1C(=O)OC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C)n(C)c1C(=O)OC
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
To a suspension of dimethyl 2-methyl-1H-imidazole-4,5-dicarboxylate (2 g, 10.1 mmol, prepared according to J. Med. Chem. 1989, 32, 119) in DMF (20 mL) was added under a nitrogen atmosphere potassium tert-butoxide (1.25 g, 11.1 mmol) at room temperature. The mixture was stirred for 15 min and iodomethane (694 μL, 11.1 mmol) was added. The reaction mixture was stirred for 2 h at the same temperature. The reaction mixture was poured into water (75 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was washed water (3×50 mL) and brine (20 mL), dried and concentrated in vacuo to give 720 mg of crude product. The combined aqueous phases were back-extracted dichloromethane (4×50 mL), dried over MgSO4 and concentrated in vacuo to give another 1.4 g of crude product. The combined crude material was purified by flash chromatography (using silica gel and a MeOH/dichloromethane gradient) to give the product as colorless oil (1.89 g, 8.91 mmol, 88.3%). MS: M=213.1 (M+H)+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[CH:10]([C:13]1[S:17][CH:16]=[C:15]([C:18]([N:20]2[CH2:25][C:24]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[O:23][CH2:22][CH2:21]2)=[O:19])[CH:14]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>C(#N)C>[OH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][C:24]2([O:23][CH2:22][CH2:21][N:20]([C:18]([C:15]3[CH:14]=[C:13]([CH:10]([CH3:11])[CH3:12])[S:17][CH:16]=3)=[O:19])[CH2:25]2)[CH2:26][CH2:27]1
Reactant: OCCCCCCCBr
Reactant: CC(C)c1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(CCCCCCCO)CC3)C2)cs1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 7-bromo-1-heptanol (380 mg) in acetonitrile (3.9 mL) was added to a solution of (5-isopropylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (Example 275, step i) (400 mg) and triethylamine (0.361 mL) in acetonitrile (8.6 mL). The resulting mixture was stirred at 60° C. for 16 hours. The solvent was removed under vacuum and the residue taken up in DCM (25 mL) and washed with brine (25 mL) and water (20 mL), then dried over sodium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0 to 10% methanol in DCM to afford the subtitled compound as a pale brown solid. Yield 0.305 g.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].[P:12](OCCCCCCOC(=O)C(C)=C)([OH:15])([OH:14])=[O:13]>>[P:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([OH:15])([OH:14])=[O:13]
Reactant: C=C(C)C(=O)OCCCCCCOP(=O)(O)O
Reactant: C=C(C)C(=O)OCCCCO
Product: C=C(C)C(=O)OCCCCOP(=O)(O)O

Procedure:
The same procedures as in Example 4-1 were carried out except for using 4-methacryloyloxybutan-1-ol (47.4 g, 0.30 mole) as a starting material (ester compound) for First Dropping Step of Amine of item (2) of Example 4-1, and the reactions were carried out with the same molar ratios and procedures on and after item (2) of Example 4-1, to give 4-methacryloyloxybutyl dihydrogenphosphate (Compound 1e). The light transmittance and the electric conductivity of the resulting phosphate monomer, and the number of days for gelation of the dental adhesive were evaluated in the same manner as in Example 4-1. The results are summarized in Table 11.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]([N:15]1[CH2:23][C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16]1)=[O:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25]O>>[CH2:1]([CH:8]([CH2:12][C:13]([N:15]1[CH2:16][C@H:17]2[C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:23]1)=[O:14])[C:9]([O:11][CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1
Agent: Cl
Product: COC(=O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid (100 mg) was added a 3% solution of hydrogen chloride in methanol (2 ml) and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed successively with saturated sodium bicarbonate solution and brine, treated with activated charcoal, and dried over MgSO4. The solvent was evaporated under reduced pressure to give 91 mg of methyl 2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate as a colorless viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].O[CH2:18][C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20]>>[NH2:21][C@@H:19]([CH3:20])[CH2:18][N:15]1[CH:14]=[CH:13][C:12]([C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=2)=[N:16]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1[N+](=O)[O-]
Product: C[C@H](N)Cn1ccc(-c2ccc(C#N)c([N+](=O)[O-])c2)n1
Yield: 71 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile was prepared using the method of Example 34(c) starting from 2-nitro-4-(1H-pyrazol-5-yl)benzonitrile (2.0 g, 9.34 mmol) and (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (1.6 g, 9.13 mmol). Yield 71.0%. H-NMR (400 MHz; DMSO-d6): 0.98 (d, 3H), 3.23-3.33 (m, 1H), 4.01-4.12 (m, 2H), 7.08 (d, 1H), 7.90 (d, 1H), 8.19 (d, 1H), 8.34 (dd, 1H), 8.69 (d, HA).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][N:5]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[C:6](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)SC>C(O)C>[CH3:1][N:2]([CH3:3])[C:6]([N:5]([CH3:4])[N:16]1[C:24](=[O:25])[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:18]2[C:17]1=[O:26])=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CSC(=Nc1ccccc1)N(C)N1C(=O)c2ccccc2C1=O
Reactant: CNC
Solvent: CCO
Product: CN(C)C(=Nc1ccccc1)N(C)N1C(=O)c2ccccc2C1=O

Procedure:
To a saturated solution of anhydrous dimethylamine in 80 ml. of ethanol was added 4.53 g. (0.01 mol) of 2-(1,2-dimethyl-3-phenylisothioureido)-1H-isoindole-1,3-(2H)-dione, and the resulting solution was heated to 50° C. for 30 minutes. Evaporation and treatment with heptane gave 3.5 g. of crystalline product, m.p. 146°-8° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]3)[CH2:12][CH2:11]1)[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH:24]=[CH:23]3)[CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOc1ccccc1N1CCN(CCC=Cc2ccc3c(c2)CCC(=O)N3)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: CCOc1ccccc1N1CCN(CCC=Cc2ccc3[nH]c(=O)ccc3c2)CC1

Procedure:
2.0 Grams of 6-{4-[4-(2-ethoxyphenyl)-1-piperazinyl]-1-butenyl}-3,4-dihydrocarbostyril and 3.5 g of DDQ were mixed in 20 ml of benzene and the mixture was refluxed by heating for 5 hours. The reaction mixture was then concentrated under a reduced pressure and the residue thus obtained was extracted with chloroform. The chloroform layer was washed with 5%-NaHCO3 aqueous solution three times then washed with water twice and dried. Chloroform was removed by distillation and the residue obtained was purified by a silica-gel column chromatography and recrystallized from methanol to obtain 0.12 g of 6-{4-[4-(2-ethoxyphenyl)-1-piperazinyl]-1-butenyl}carbostyril in colorless needle-like crystals. Melting point: 225°-228° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][C:29](I)=[CH:28][C:27]=2[F:33])=[C:4]([CH:12]=[C:13]([CH:16]=[N:17][O:18][CH2:19][CH2:20][C:21](=[O:24])[NH:22][CH3:23])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[C:34](C1C=CC(NC2C(F)=C(F)C(C=NOCCO)=CC=2C(NOCCO)=O)=C(F)C=1)#[CH:35].C(C1C=CC(NC2C(F)=C(F)C(/C=N/OCCO)=CC=2C(NOCCO)=O)=C(F)C=1)#C>>[C:34]([C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:3]2[C:2]([F:1])=[C:14]([F:15])[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][C:21](=[O:24])[NH:22][CH3:23])=[CH:12][C:4]=2[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6])=[C:27]([F:33])[CH:28]=1)#[CH:35]
Reactant: C#Cc1ccc(Nc2c(C(=O)NOCCO)cc(C=NOCCO)c(F)c2F)c(F)c1
Reactant: CNC(=O)CCON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: C#Cc1ccc(Nc2c(C(=O)NOCCO)cc(/C=N/OCCO)c(F)c2F)c(F)c1
Product: C#Cc1ccc(Nc2c(C(=O)NOCCO)cc(/C=N/OCCC(=O)NC)c(F)c2F)c(F)c1

Procedure:
This compound was synthesized from 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-ethoxyimino)-methyl]-benzamide (Example 14, Compound 14), and the actual reaction was carried out according to the method for manufacturing 2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyimino)-methyl]-benzamide (Example 2, Compound 2).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[C:4]([CH2:12][O:13][CH3:14])[C:3]=1[O:15][CH2:16][O:17][CH3:18].C1([Li])C=CC=CC=1.[CH3:26][O:27][C:28]([C:30]1[CH2:34][CH2:33][CH2:32][C:31]=1OS(C(F)(F)F)(=O)=O)=[O:29].[O-]S(C(F)(F)F)(=O)=O>C1COCC1.C(OCCCC)CCC.CCOCC.[Cl-].[Cl-].[Zn+2].[O-]S([O-])(=O)=O.[Zn+2].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>[CH3:26][O:27][C:28]([C:30]1[CH2:34][CH2:33][CH2:32][C:31]=1[C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[C:4]([CH2:12][O:13][CH3:14])[C:3]=1[O:15][CH2:16][O:17][CH3:18])=[O:29]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC1
Reactant: COCOc1cc(Br)c(OCOC)c(COC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCOCCCC
Product: COCOc1cc(COC)c(OCOC)c(C2=C(C(=O)OC)CCC2)c1
Temperature: -70 °C
Reaction time: 0.58 h
Yield: 55.9 %

Procedure:
Purge a solution of 1-bromo-2,5-bis-methoxymethoxy-3-methoxymethyl-benzene (2.76 g, 8.59 mmol) in THF (17 mL) with nitrogen and cool to −70° C. Clowly add a solution of phenyllithium (4.3 mL of a 2.0 M solution in dibutyl ether, 8.59 mmol) to the cooled solution, keeping the temperature below −60° C. After 35 minutes, add a solution of ZnCl2 (8.6 mL of a 1.0 M solution in Et2O, 8.59 mmol) and warm the reaction to 0° C. Purge a solution of 2-trifluoromethanesulfonyloxy-cyclopent-1-enecarboxylic acid methyl ester (2.36 g, 8.59 mmol) in THF (17 mL) with nitrogen. To the cooled zincate solution, add Pd(PPh3)4 (0.496 g, 0.430 mmol) followed by the triflate solution. Heat this mixture to 50° C. overnight then cool to room temperature. Quench the reaction with H2O and extract with EtOAc (3×50 mL). Combine the organic extracts, dry (Na2SO4), filter and concentrate. Purify the crude material using silica gel chromatography eluting with Hex:EtOAc (75:25, then 50:50) to afford the subtitled product (1.76 g, 56%) as an oil. 1H NMR (CDCl3) δ 1.95-2.05 (m, 2H), 2.78-2.85 (m, 4H), 3.42 (s, 3H), 3.47 (s, 6H), 3.57 (s, 3H), 4.51 (s, 2H), 4.80 (s, 2H), 5.12 (s, 2H), 6.74 (d, J=3.1 Hz, 1H), 7.04 (d, J=3.1 Hz, 1H).
Reaction SMILES: FS([O-])(=O)=O.[C:6]([C@@H:9]1[CH2:13][C@H:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[CH2:11][N+:10]1([CH2:25][CH2:26][OH:27])[CH3:24])(=[O:8])[NH2:7].O[C@@H]([C@H]1[C:52](=[O:53])[N:33]2[CH:34]([C:39]([O:41]C([N+]([O-])=O)C3C=CC=CC=3)=[O:40])C(=O)[C@H](C)[C@H]12)C>>[C:6]([C@@H:9]1[CH2:13][C@H:12]([S:14][C:15]2[C@H:16]([CH3:17])[C@@H:21]3[C@@H:20]([C@H:19]([OH:22])[CH3:18])[C:52](=[O:53])[N:33]3[C:34]=2[C:39]([O-:41])=[O:40])[CH2:11][N+:10]1([CH2:25][CH2:26][OH:27])[CH3:24])(=[O:8])[NH2:7]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)[N+](C)(CCO)C2)cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OC(c3ccccc3)[N+](=O)[O-])C(=O)[C@H](C)[C@H]12
Agent: O=S(=O)([O-])F
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3C[C@@H](C(N)=O)[N+](C)(CCO)C3)[C@H](C)[C@H]12

Procedure:
Following a procedure similar to that described in Example 7, but using 0.37 g of (2S, 4S)-2-carbamoyl-1-(2-hydroxyethyl)-4-(4-methoxybenzylthio)-1-methylpyrrolidinium fluorosulfonate (prepared as described in preparation 16) [in step (1)] and 260 mg of -nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate [in step (2)], 17 mg of the title compound were obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:23]1[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=[C:25]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([Cl:37])[C:32]=2[Cl:38])[N:24]=1>O1CCCC1>[Cl:37][C:33]1[C:32]([Cl:38])=[C:31]([C:25]2[N:24]=[C:23]([N:11]3[CH2:12][CH2:13][O:14][C@@H:9]([C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=4)[CH2:10]3)[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=2)[CH:36]=[CH:35][N:34]=1
Reactant: Fc1ccc([C@H]2CNCCO2)cc1
Reactant: Cn1c(Cl)nc(-c2ccnc(Cl)c2Cl)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCO[C@@H](c3ccc(F)cc3)C2)nc(-c2ccnc(Cl)c2Cl)cc1=O
Reaction time: 12 h
Yield: 68.8 %

Procedure:
To a solution of (2S)-2-(4-fluorophenyl)morpholine hydrochloride (0.8 g, 3.68 mmol) and triethylamine (2.1 g, 20.8 mmol) in tetrahydrofuran (20 ml) was added 2-chloro-6-(2,3-dichloropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (2.0 g, 6.88 mmol) portionwise and the mixture was stirred for 12 hours. The resulting suspension was partitioned between chloroform and 1N sodium hydroxide and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 6-(2,3-dichloropyridin-4-yl)-2-((2S)-2-(4-fluorophenyl)morpholin-4-yl)-3-methyl-3H-pyrimidin-4-one (1.1 g, 2.53 mmol, 69%) as white crystals.