Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=1.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)(=O)C>[NH2:15][S:12]([C:4]1[CH:3]=[C:2]([N:1]2[CH:18]=[CH:22][CH:21]=[CH:20]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=[O:13])=[O:14]
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1ccc(N)cc1S(N)(=O)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-n2cccc2)cc1S(N)(=O)=O
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
In 3 ml of acetic acid, 300 mg (1.3 mmol) of methyl 4-amino2-(aminosulfonyl)benzoate and 0.23 ml of 2,5-dimethoxytetrahydrofuran were dissolved, followed by stirring at 110° C. for 1.5 hours. Acetic acid was then distilled off, followe by the addition of 30 ml of ice water. After the mixture thus obtained wa stirred for 20 minutes, the resulting precipitate was collected by filtration and dried in air. The brown solid thus obtained was purified b column chromatography, using silica gel ("Wako Gel C300", trade name; product of Wako Pure Chemical Industries, Ltd.) and dichloromethane, thereby obtaining the title compound as a white solid. Yield: 175.7 mg (48%). Its physicochemical properties are shown in Table 7.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:24])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH:16]([CH2:20][NH:21]C=O)[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2].[ClH:29].O>CO>[ClH:29].[NH2:21][CH2:20][CH:16]1[CH2:15][N:14]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:24])[CH2:19][CH2:18][O:17]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CNC=O)C3)c(F)c21
Agent: Cl
Solvent: CO
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CN)C3)c(F)c21

Procedure:
A solution of 500 mg of 1-ethyl-6,8-difluoro-7-[2-(formylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1 ml of concentrated hydrochloric acid, 2 ml of water and 10 ml of methanol is refluxed for 1.5 hours. The reaction mixture is concentrated under reduced pressure. The obtained crystals are washed with acetone, collected by filtration and recrystallized from dimethylformamide to give 7-[2-(aminomethyl)morpholino]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride, melting at 276°-278° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(N)cn2)C1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 66.2 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (239 mg, 0.8 mmol) was reacted with tert-butyl 3-(5-aminopyridin-2-ylamino)piperidine-1-carboxylate (337 mg, 1.1 mmol) to afford the desired product (300 mg, 69%) as a yellow solid: ESI MS m/z 566 [C28H32BrN5O3+H]+.
Reaction SMILES: Cl.N1([CH2:7][C:8](O)=O)C=NC=N1.[N:11]1([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](OCC3C=CC=CC=3)=O)[CH2:21][C@H:20]2[C:35](=[O:51])[NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[CH:39][CH:38]=2)=[O:18])[CH:15]=[N:14][CH:13]=[N:12]1>>[N:11]1([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:8]3[CH:7]=[CH:39][CH:38]=[CH:37][CH:42]=3)[CH2:21][C@H:20]2[C:35]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[CH:39][CH:38]=2)=[O:51])=[O:18])[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(Cc2ccccc2)CCN1C(=O)Cn1cncn1
Yield: 19 %

Procedure:
Proceeding as in Examples 11 and 12, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (S)-benzyl 4-(2-(1H-1,2,4-triazol-1-yl)acetyl)-3-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1-carboxylate, respectively, gave Compound 261, (S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)piperazine-2-carboxamide (67.9 mg, 19%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.83 (s, 1H), 8.45 (s, 1H), 7.96 (s, 1H), 7.51 (d, 2H), 7.28-7.13 (m, 7H), 7.06-6.98 (m, 4H), 5.49 (d, 1H), 5.28 (d, 1H), 4.91-4.89 (m, 1H), 3.68-3.38 (m, 5H), 2.92-2.85 (m, 1H), 2.25-2.17 (m, 2H). MS (EI) for C28H27FN6O3. found 515.3 (MH+).
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:19][NH:20][C:21]([NH2:23])=[O:22].C[O-].[Mg+2].C[O-].CO>>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:23][C:21]([NH:20][CH3:19])=[O:22])=[O:18])=[CH:16][CH:15]=1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 12.3 %

Procedure:
2-(4-Bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (420.0 mg, 1.35 mmol) and methyl urea (299.9 mg, 4.05 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 7.7 mL, 5.40 mmol). The resulting reaction mixture was then heated under reflux for 48 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The celite was thoroughly washed with ethyl acetate, and the filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 1-[2-(4-bromo-phenyl)-3-cyclopentyl-propionyl]-3-methyl urea (58.7 mg, 12%) as a white solid: mp 184-186° C.; EI-HRMS m/e calcd for C16H21BrN2O2 (M+) 352.0786, found 352.0791.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:2].C1(OC(=O)CC)CCCCC1.[H][H]>[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2]
Reactant: [H][H]
Reactant: CCOC1CCCCC1=O
Agent: [Pd]
Agent: CCC(=O)OC1CCCCC1
Product: CCOc1ccccc1O

Procedure:
A solution of 10 gm. 2-ethoxycyclohexanone in 100 ml. cyclohexylpropionate was refluxed over 400 mg. of palladium on carbon until approximately 75% hydrogen had evolved. The catalyst was removed by filtration. o-Ethoxyphenol was obtained in high yield.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1.S(Cl)([Cl:21])=O.[Cl-].[Li+].O>CN(C)C=O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][Cl:21])=[CH:4][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(CO)cc1-c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCl)cc1-c1ccccc1

Procedure:
To a solution of 10.5 g (43.3 mmol) of methyl 4-hydroxymethyl-2-phenylbenzoate in 50 mL of N,N-dimethylformamide was added 4.5 mL (62 mmol) of thionyl chloride, and 2.0 g (47 mmol) of lithium chloride. The reaction was complete upon dissolution of the lithium chloride. The solution was poured into 350 mL of water, then extracted with diethyl ether (3×100 mL). The combined diethyl ether layers were back extracted with water (2×100 mL), saturated aqueous sodium bicarbonate solution (1×100 mL), and brine (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to 11.1 g (98%) of 4-chloromethyl-2-phenylbenzoic acid methyl ester as a pale yellow oil.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH2:2]([OH:1])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
The fermentations were carried out in the manner described in Example 1 in a shaking flask using an aqueous solution of xylose as a source of xylose. Glucose was added as an energy and carbon source to the fermentation broth. The flasks were stirred and effectively aerated.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:22]([NH:24][C@H:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:26]([CH3:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6]CC1C=CC=CC=1>[Pd].CO>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:22]([NH:24][C@H:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:26]([CH3:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])[CH2:3][CH2:4][C:5](=[O:6])[OH:14]
Reactant: CC(C)[C@H](NC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)OC(C)(C)C)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@@H](N)CCC(=O)O)C(=O)N[C@H](C(=O)OC(C)(C)C)[C@@H](C)OC(C)(C)C

Procedure:
The compound obtained in accordance with (B) is subjected to catalytic hydrogenation over Pd in 80 percent strength methanol. The catalyst is filtered off and the solution is evaporated to dryness in vacuo. Triturating the residue with ether leads to a compound which is pure according to chromatography.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH3:12])[N:3]=1.CCO.[CH2:16]([NH2:18])[CH3:17]>C(Cl)Cl.O>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([CH2:17][CH2:16][NH2:18])[N:4]([CH2:11][CH3:12])[N:3]=1
Reactant: CCN
Reactant: CCn1nc(Br)c([N+](=O)[O-])c1Br
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCn1nc(Br)c([N+](=O)[O-])c1CCN
Yield: 45.6 %

Procedure:
A mixture of 3,5-dibromo-1-ethyl-4-nitro-1H-pyrazole (28.4 g; 95 mmol), EtOH (470 ml) and ethylamine (45.0 g, 700 mmol) was refluxed for 3 hours. The reaction medium was concentrated to the maximum under reduced pressure (rotary evaporator, water bath at 40° C.). The brown oil obtained was suspended in DCM (250 ml) and water (250 ml). The aqueous phase was washed with DCM (50 ml). The combined aqueous phases were extracted with DCM (50 ml) and the combined organic phases were then dried over NaSO4. After evaporating off the solvent, a solid was obtained (24.6 g), which was purified by chromatography on silica gel (eluent: EtOAc/hexane) to give (5-bromo-2-ethyl-4-nitro-2H-pyrazol-3-yl)ethylamine (11.4 g, 45%) in the form of a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].BrC[C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])N.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C([O-])(O)=O.[Na+]>CO.[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:30]3[CH:39]=[CH:38][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: NC(=O)[O-]
Agent: O=C([O-])O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)cc3)c2CC1
Temperature: 57.5 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0 g, 2.6 mmol) in methanol (15 mL) under nitrogen, add with stirring potassium hydroxide (4.5 g, 80.3 mmol) at ambient temperature. Heat at 55-60° C. for 2 h, cool to ambient temperature, and add methyl 4-bromomethylbenzoate (1.2 g, 5.2 mmol). TLC after 20 min shows formation of product; however, after 4 h at ambient temperature both TLC and LC/MS indicate complete hydrolysis of the ester and the carbamate. Dilute with saturated aqueous NH4Cl, extract three times with EtOAc, dry over anhydrous MgSO4, and concentrate in vacuo. Dissolve the crude material in THF (10 mL), treat with di-tert-butyl-dicarbonate (2 equiv) and saturated aqueous NaHCO3 (10 mL), and stir overnight. Extract three times with EtOAc, dry over anhydrous MgSO4 and concentrate in vacuo to give the desired intermediate as an oil that was used without purification [2.32 g, 50% purity with (Boc)2O]. MS (ES+) m/z 348 (M+H−Boc)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH:10]([N:20]=[N+]=[N-])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24].[H][H]>C(O)C.[Re+5]=S>[ClH:24].[CH2:1]([O:8][C:9](=[O:23])[CH:10]([CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC(COCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: S=[Re+5]
Agent: Cl
Solvent: CCO
Product: NC(COCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 20 h
Yield: 88 %

Procedure:
1.56 grams (0.005 mole) of 2-azido-3-benzyloxypropionic acid benzyl ester were dissolved in 10 ml of ethanol, 1.50 grams (0.041 mole) of dry hydrogen chloride gas led in and 0.03 grams of rhenium (VII) sulfide added. This reaction mixture was hydrogenated in an autoclave for 20 hours at 25° C. and a hydrogen pressure of 20 bar. After filtering off the catalyst the solvent was vaporized. The oil obtained (1.42 grams=88% of crude O-benzyl-D,L-serine benzyl ester hydrochloride) was dissolved in chloroform and treated with diethyl ether. The precipitated crystals were recrystallized three times from ethanol/diethyl ether. There was obtained 0.78 grams (48% of theory) of O-benzyl-D,L-serine benzyl ester hydrochloride having a melting point of 144.5°-145.5° C. (literature: 147.5°-148.5° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH2:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[F:12][C:13]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:14]=1[CH2:15][O:16][C:17]1[C:18]2[N:19]([C:23]([C:27](O)=[O:28])=[C:24]([CH3:26])[N:25]=2)[CH:20]=[CH:21][CH:22]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[F:12][C:13]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:14]=1[CH2:15][O:16][C:17]1[C:18]2[N:19]([C:23]([C:27]([NH:8][CH:6]3[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]3)=[O:28])=[C:24]([CH3:26])[N:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.8 mg (0.12 mmol) of 2,2,6,6-tetramethylpiperidine-4-amine were initially charged, and 32 mg (0.10 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid in 0.4 ml of DMF and 42 mg (0.13 mmol) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) in 0.2 ml of DMF were added. 20 mg (0.20 mmol) of 4-methylmorpholine were then added, and the reaction was stirred at RT overnight. The mixture was then filtered off and the filtrate was purified by preparative LC-MS (Method 12). The product-containing fractions were concentrated under reduced pressure. This gave 27 mg (59% of theory) of the target product.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[S:28][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][N:33]([C:9]([NH:8][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH3:7])=[O:16])[CH2:32][CH2:31]2)[S:28][CH:29]=1
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1F
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccc(F)c4F)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 15 h
Yield: 39.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (225 mg, 0.782 mmol), 1-[4-(2,3-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 117 mg (39.1%) of the desired product as a solid.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1.B(O)(O)[C:14]1[S:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[S:22]1[C:14]([C:2]2[C:10]3[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH3:12])[CH:3]=2)=[CH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]1=2
Reactant: Cn1cc(I)c2c(N)ncnc21
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3ccccc3s2)c2c(N)ncnc21

Procedure:
A solution of 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5 mg, 0.018 mmol), benzo[b]thiophen-2-yl-2-boronic acid (16 mg, 0.091 mmol), K3PO4 (19.3 mg, 0.091 mmol) and Pd(PPh3)4 (12.5 mg, 0.011 mmol) in DMF (3 mL) was heated to 60° C. under an argon atmosphere. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 281.1, found 281.3.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38]CC3C=CC([N+]([O-])=O)=CC=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].Cl.[OH:52][N:53]=[C:54]1[CH2:59][CH2:58][N:57]([C:60](=[NH:63])[CH2:61][SH:62])[CH2:56][CH2:55]1>C(#N)C.CS(C)=O.O1CCCC1.P([O-])([O-])([O-])=O.[C].[Pd].CCOCC>[OH:52][N:53]=[C:54]1[CH2:55][CH2:56][N:57]([C:60](=[NH:63])[CH2:61][S:62][C:32]2[C@H:33]([CH3:34])[C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]3[C:31]=2[C:36]([OH:38])=[O:37])[CH2:58][CH2:59]1
Reactant: N=C(CS)N1CCC(=NO)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: [Pd]
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCC(=N)N3CCC(=NO)CC3)[C@H](C)[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
0.28 ml of diisopropylethylamine and 0.29 ml of diphenylphosphoryl chloride were added dropwise to an ice-cooled solution of 500 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 6 ml of anhydrous acetonitrile, and then the mixture was stirred for one hour with ice-cooling. 0.2 ml of diisopropylethylamine and 426 mg of 2-(4-hydroxyiminopiperidin-1-yl)-2-iminoethylmercaptan hydrochloride in 3.6 ml of dimethylsulfoxide were added to the reaction mixture, and then the whole mixture was stirred for a further 30 minutes with ice-cooling. The reaction mixture was poured into 200 ml of anhydrous ether and the solvent was decanted off from the gummy material which formed. This material was dissolved in a mixture of 40 ml of tetrahydrofuran and 46 ml of 0.1M phosphate buffer (pH 7.0), and the solution was subjected to hydrogenation for 2 hours at room temperature in the presence of 0.6 g of 10% palladium-carbon. The hydrogenation mixture was filtered over "Celite" (Trade Mark) filter aid, and the filtrate was extracted with 80 ml of ether. The aqueous layer was concentrated under reduced pressure and the concentrate was subjected to chromatography through a 160 ml column of "Dowex 50W" (Trade Mark) cation exchange resin (Na+ type), giving 68 mg of the title product from the fraction eluted with water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17]([F:24])[C:16]=3F)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28][OH:29].O>CN(C=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17]([F:24])[C:16]=3[O:29][CH3:28])=[O:11])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)c(F)c(F)cc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: COc1c(F)c(F)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 140 °C

Procedure:
N-((4-Chlorophenyl)methyl)-4-hydroxy-6,7,8-trifluoro-3-quinolinecarboxamide (366 mg) from Example No. 15 and sodium hydride (60% dispersion, 40 mg) are dissolved in DMF (10 mL) and to the mixture is added methanol (200 μL). Additional sodium hydride (40 mg) is added, and the mixture is heated at 140° C. for 1 h. The reaction mixture is allowed to cool to rt, poured into water (50 mL), acidified with acetic acid (10 mL), and is filtered. The crude product is purified by column chromatography (hexane/2-propanol, 95/5) to afford 68 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=4[O:39][CH3:40])[CH2:28][CH2:27][C:26]([C:41]([OH:43])=O)=[CH:25][C:24]=3[CH:44]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=4[O:39][CH3:40])[CH2:28][CH2:27][C:26]([C:41]([NH:29][C:23]4[CH:24]=[CH:44][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:43])=[CH:25][C:24]=3[CH:44]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cc(OC)ccc2OC)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cc(OC)ccc2OC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (134 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (100 mg) and triethylamine (455 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 65) (210 mg) as yellow crystals.