Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:22]1([CH2:21][CH2:20][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2
Temperature: 70 °C
Yield: 77.8 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (3.9 g) and 2-bromoethylbenzene (2.9 g) were dissolved in DMF, and potassium carbonate was added. The mixture was stirred under heating at 70° C. for 5 hours, and after the completion of the reaction, the solvent was evaporated under reduced pressure. Ethyl acetate was added to the obtained residue and the mixture was washed with saturated brine. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:methanol=30:1). The obtained eluate was concentrated and IPE was added. The precipitated crystals were collected by filtration to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (4.3 g), melting point 119-121° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=[CH2:32])=[CH:27][N:26]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:32][CH2:31][C:28]3[CH:27]=[N:26][C:25]([CH3:24])=[CH:30][CH:29]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc([N+](=O)[O-])cc1)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-8-methyl-2-(4-nitrophenyl)-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[O:18][CH3:19])/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C:22]([NH2:24])=[S:23].CN(C)C1C=CC=CC=1>>[NH2:24][C:22]1[S:23][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[O:18][CH3:19])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:21]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@H]1OC)C(=O)CBr
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@H]1OC)c1csc(N)n1

Procedure:
Ethyl 4-bromo-(Z)-2-(trans-2-methoxycyclohexyloxyimino)-3-oxobutyrate was treated with thiourea (0.79 g) and N,N-dimethylaniline (1.318 ml) as described in Example 4d to give the title compound as an orange gum (1.78 g) after silica gel chromatography. νmax (CH2Cl2) 3460, 3370, 3250, 3100, 1730, 1605, and 1530 cm-1 ; δH (CDCl3) inter alia 1.10-1.20 (11H, m), 3.32 (1H, m), 3.43 (3H, s), 4.00-4.50 (3H, m), 6.55 (2H, br. s), and 6.66 (1H, s). [Mass spectrum: EI M+ (327)].
Reaction SMILES: [C:1](OCC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O-].[Na+].Cl.[N:17]1([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29](=[O:34])[CH2:28]3)=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)C>[C:1]([N:20]1[CH2:21][CH2:22][N:17]([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29](=[O:34])[CH2:28]3)=[O:24])[CH2:18][CH2:19]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Cc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: CCOC(=O)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1Cc2cc(C(=O)N3CCN(C(=O)c4ccccc4)CC3)ccc2N1
Yield: 6.8 %

Procedure:
To 100 ml of ethanol were added 1.36 g of ethyl benzoate, 0.5 g of sodium ethylate and 2.6 g of 5-(piperazinylcarbonyl)oxindol hydrochloride and the mixture was reacted in an autocrave at 140° to 150° C. under 110 atm for 6 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 200 ml of chloroform. After washing, in turn, with 1% aqueous potassium carbonate solution, dilute hydrochloric acid, and water, the chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The resultant residue was purified by silica-gel column chromatography [silica-gel: WAKO C-200, eluent: chloroform:methanol (V/V)=20:1], and the crude crystal was recrystallized from methanol to give 215 mg of 5-(4-benzoyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[CH2:19]([NH:26][C:27]1[C:36]([CH2:37][Cl:38])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:38].[ClH:18].[CH2:19]([NH:26][C:27]1[C:36]([CH2:37][C:6]2[C:7]3[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=3)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=2[OH:17])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc2nc(NCc3ccccc3)c(CCl)cc2c1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCc2ccccc2)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 9 %

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (70 mg, 0.30 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-benzyl-3-(chloromethyl)-6-methoxyquinolin-2-amine hydrochloride SLA 41008 (105 mg, 0.30 mmol) followed by a 2 N aq. LiOH (0.30 mL, 0.60 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided, after evaporation, 17.3 mg of 4-((2-(benzylamino)-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.28 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-(benzylamino)-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 44 as a yellow solid (16 mg, 9% yield).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[CH:13]1([NH:19][OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N+:19]([O-:20])=[CH:1][C:3]2[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: ONC1CCCCC1
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Agent: [Na]
Product: O=S(=O)(O)c1ccc(C=[N+]([O-])C2CCCCC2)o1
Yield: 84.3 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-cyclohexylhydroxylamine, the title compound was prepared in 84.3% yield as the sodium salt, m.p. 236.1° C. (dec.).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([C@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:35])[CH2:21][C@@H:22]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:23]1[CH:27]=[CH:26][O:25][N:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46]Cl)=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])([CH3:39])([CH3:38])[CH3:37].O>CN(C=O)C>[C:36]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][O:34][C:31]2[CH:32]=[CH:33][C:28]([C@@H:22]([C:23]3[CH:27]=[CH:26][O:25][N:24]=3)[CH2:21][C:20]([N:15]3[C@@H:14]([CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:18][O:17][C:16]3=[O:19])=[O:35])=[CH:29][CH:30]=2)=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)c1cc(CCl)ccc1C(C)(C)C
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 31 %

Procedure:
Cesium carbonate (360 mg, 1.1 mmol) was added to a mixture of 7.5 (40.0 mg, 0.10 mmol) and 26.5 (27.0 mg, 0.12 mmol) in DMF (2.0 mL). The resulting mixture was stirred at room temperature for 19 hours. The mixture was then treated with water (5 mL) and extracted with EtOAc (15 mL). The organic layer was separated, washed twice with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-30% EtOAc/hexane) to give (S)-3-((S)-3-(4-(4-tert-butyl-3-isopropylbenzyloxy)phenyl)-3-(isoxazol-3-yl)propanoyl)-4-benzyloxazolidin-2-one (18.0 mg, 30%) as a clear oil. The ester (18.0 mg, 0.031 mmol) was treated with THF/H2O (3/1, v/v, 2.0 mL) and hydrogen peroxide (30%, 0.021 mL, 0.19 mmol) and cooled to 0° C. LiOH (2.60 mg, 0.062 mmol) was added. The resulting mixture was stirred at 0° C. for 1 hour. A saturated solution of Na2SO3 was added to the mixture, and the reaction was stirred for 1 hour. The mixture was extracted with EtOAc (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-30% EtOAc/hexane) to give 26 (5.80 mg, 44%) as a colorless film. MS ESI (neg.) m/e: 420 (M−H). 1H NMR (500 MHz) (CDCl3) δ 8.28 (1H, s); 7.37-7.34 (2H, m); 7.20-7.17 (3H, m); 6.96-6.94 (2H, d, J=8.2 Hz); 6.07 (1H, s); 4.98 (2H, s); 4.56 (1H, dd, J=7.8, 7.4 Hz); 3.64 (1H, m), 2.36 (1H, dd, J=16.8, 7.8 Hz), 2.99 (1H, dd, J=16.8, 7.4 Hz), 1.43 (9H, s), 1.26 (6H, d, J=7.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C1C[O:15][CH2:14]C1.Cl.C(Cl)(Cl)=O>O>[Br:1][C:2]1[CH:10]=[C:6]2[C:7]([O:9][C:14](=[O:15])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: C1CCOC1
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: O
Product: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a stirred solution of 5-bromo-2-amino-benzoic acid (25 g, 0.115 mmol) in a mixed solvent of THF:H2O:conc. HCl (4:2:1, 350 mL), was added a solution of phosgene (0.23 mmol, 20% in toluene) dropwise. The reaction mixture was allowed to stir at room temperature for 4 h. The resulting precipitate was filtered, washed with water and dried under reduced pressure to give the title compound (22.5 g, 78%) as a gray solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:13]Br>C(O)(=O)C.O>[Br:13][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:3]=[C:2]([Cl:1])[C:7]=1[OH:8]
Reactant: BrBr
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1cc(Cl)c(O)c(Br)c1

Procedure:
To a solution of 3-chloro-4-hydroxyphenylacetic acid (2.5 g) in glacial acetic acid (35 mL) was added 0.8 mL of neat bromine carefully while stirring. The mixture was stirred in dark at ambient temperature for 51 h. The resulting mixture was diluted with water, extracted with ethyl acetate, dried and concentrated in vacuo to afford 3-bromo-5-chloro-4-hydrox-yphenylacetic acid. This crude product was dissolved in methanol (15 mL), treated with concentrated sulfuric acid (1 mL) carefully, stirred at reflux for 18 h. Cooled reaction mixture was concentrated under reduced pressure, diluted with water carefully, extracted with dichloromethane. The combined organic layers were dried and concentrated. Flash column chromatography on silica gel with ethyl acetate/hexane (0-50% gradient elution) afforded 3-bromo-5-chloro-4-hydroxyphenylacetic acid methyl ester (2.5 g, 68%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH:8]([CH3:10])[CH3:9]>C(OCC)C>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:17][CH:16]=1)=[O:6]
Reactant: O=C=NCCCl
Reactant: CC(C)COc1ccc(N)cc1
Solvent: CCOCC
Product: CC(C)COc1ccc(NC(=O)NCCCl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-chloroethyl isocyanate (15 g, 142 mmols) is added dropwise to a solution of 4-isobutoxy phenylamine (20 g, 121 mmols) in diethyl ether (100 mL) and stirred at RT for 1 h. The solid formed is collected by filtration and recrystallisation from ethanol affords the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[C:15](=O)[C:14]3[C:13]([C:17]([O:19]CC)=O)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][CH:7]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:2]1.O.[NH2:29][NH2:30]>CO>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[C:15]3=[N:29][NH:30][C:17](=[O:19])[C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([C:14]=43)[NH:8][CH:7]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:2]1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccoc1)C(c1ccccc1)N2
Solvent: O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1ccoc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
A mixture of ethyl 3-(furan-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (80 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) was stirred at 45° C. overnight. Methanol was removed under reduced pressure. The crude product was purified by prep-HPLC to give 9-(furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (5 mg, yield 7%). 1H-NMR (400 MHz, CD3O) δ (ppm): 4.19 (d, J=8.0 Hz, 1H), 4.67 (d, J=8.0 Hz, 1H), 6.26 (s, 1H), 7.07-7.21 (m, 7H), 7.30 (s, 1H), 7.27 (m, 1H), 7.41 (d, 1H), 7.51 (m, 1H); LC-MS (ESI) m/z: 330 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:18]=1[F:27].[CH3:28][C:29]1(C)[C:33](C)(C)OB(C(C)=C)O1>COCCOC>[F:16][C:4]1[CH:5]=[C:6]([C:29]([CH3:33])=[CH2:28])[CH:7]=[C:2]([F:1])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:18]=1[F:27]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(OS(=O)(=O)C(F)(F)F)cc2F)n1
Solvent: COCCOC
Product: C=C(C)c1cc(F)c(-c2nc(C(=O)OC)ccc2F)c(F)c1
Temperature: 90 °C

Procedure:
To a degassed solution of methyl 6-(2,6-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)-5-fluoropicolinate (1.0 equiv.) in DME/2M Na2CO3 (3/1, 0.09 M) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.5 equiv.) and PdCl2(dppf)-CH2Cl2Adduct (0.1 equiv.). The reaction was heated to 90° C. in an oil bath for 15 min. The mixture was cooled to rt and partitioned between water and ethyl acetate. The organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography (Analogix, eluting with 0-100% ethyl acetate). The pure fractions were concentrated to yield methyl 6-(2,6-difluoro-4-(prop-1-en-2-yl)phenyl)-5-fluoropicolinate. LC/MS=308.2 (M+H), Rt=0.99 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 2.15 (s, 3H), 4.01 (s, 3H), 5.23 (s, 1H), 5.47 (s, 1H), 7.11 (d, J=9.39 Hz, 2H), 7.65 (t, J=8.41 Hz, 1H), 8.26 (dd, J=8.61, 3.91 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([N+:20]([O-])=O)=[C:4]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1>[Pt].C1(C)C=CC=CC=1.CO>[NH2:20][C:5]1[C:4]([O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:3][C:2]([CH3:1])=[C:7]([CH3:8])[C:6]=1[NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)c1C
Agent: [Pt]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCNC(=O)OC(C)(C)C)c1C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Catalyst (5 g of 5% platinum on carbon) was added to a warm solution of tert-butyl 2-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]ethylcarbamate (50.4 g) in a mixture of toluene (500 mL) and methanol (40 mL). The mixture was placed under hydrogen pressure (50 psi, 3.4×105 Pa). After 2 hours more catalyst (4 g) was added and the hydrogenation continued overnight. The reaction mixture was filtered through a layer of Celite® filter aid and the filter cake was washed with hot toluene (1 L). The filtrate was concentrated under reduced pressure to provide 45.1 g of tert-butyl 2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]ethylcarbamate as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:3]([OH:5])=[O:4].CI.[C:13](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][CH:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:3]([O:5][CH3:13])=[O:4]
Reactant: O=C(O)C(O)c1ccsc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C(O)c1ccsc1
Yield: 65.3 %

Procedure:
A mixture of (RS) 2-hydroxy-2-(thien-3-yl)acetic acid (prepared as described in Akiv. Kemi., 58, 519, 1957) (6.32 g), methyl iodide (17 g) and potassium carbonate (6 g) in acetone was refluxed for 2 hours, evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic extracts, after drying over magnesium sulphate, were evaported to leave the title compound as a yellow oil (4.49 g, 67%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:36])[CH3:35])[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])[CH3:36])[C:27]([OH:29])=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
A mixture of 1.2 g of the product of Step A, 2 ml of methanolic 1N potassium hydroxide solution and 4 ml of methanol was refluxed for 2 hours and was then cooled during which 390 mg of the starting material crystallized which meant 810 mg of the starting product was saponified. The mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in 1 ml of dimethylformamide and 2 ml of N hydrochloric acid solution (pH=2). The mixture was stirred and 10 ml of water were added thereto. The mixture was extracted with methylene chloride and the organic phase was washed with water. The wash waters were extracted with methylene chloride and the combined organic phases were dried and vacuum filtered. The filtrate was evaporated and the oil residue was taken up in 4 ml of chloroform. The solution was diluted with 30 ml of ether and crystallization was effected. After 30 minutes with stirring, the mixture was vacuum filtered and the product was rinsed with ether and dried to obtain 472 mg of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(1-tert.-butoxycarbonyl-1-methylethyloxyimino)-acetic acid melting at 190° C.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][NH:32][CH2:33][CH3:34]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:32]([CH2:33][CH3:34])[CH3:31])=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Reactant: CCNC
Agent: Cl
Product: CCN(C)C(=O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 13.9 mg (0.23 mmol) of methylethylamine are reacted together by general method E. 50.1 mg (91.4% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][CH2:18][CH:19]=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])=[O:34])[CH:27]=[CH:26]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][CH2:18][CH2:19][N:39]3[CH2:38][CH2:37][N:36]([S:33]([C:28]4[CH:27]=[CH:26][C:25]5[C:30](=[CH:31][CH:32]=[C:23]([Cl:22])[CH:24]=5)[CH:29]=4)(=[O:35])=[O:34])[CH2:41][CH2:40]3)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CCC=O)cc2C1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCc2sc(CCCN3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1

Procedure:
In a similar manner to Referential Example 47 except for the use of 3-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propanal, 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11]([CH:13](P(OC)(OC)=O)[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:12].[CH3:31][Si:32]([CH3:50])([CH3:49])[CH2:33][CH2:34][S:35]([N:38]1[C:46]2[C:41](=[CH:42][C:43]([CH:47]=O)=[CH:44][CH:45]=2)[CH:40]=[CH:39]1)(=[O:37])=[O:36]>O1CCCC1>[CH3:9][O:10][C:11](=[O:12])[C:13]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[CH:47][C:43]1[CH:42]=[C:41]2[C:46](=[CH:45][CH:44]=1)[N:38]([S:35]([CH2:34][CH2:33][Si:32]([CH3:31])([CH3:50])[CH3:49])(=[O:36])=[O:37])[CH:39]=[CH:40]2
Reactant: C[Si](C)(C)CCS(=O)(=O)n1ccc2cc(C=O)ccc21
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,1,3,3-Tetramethylguanidine (0.68 mL, 5.43 mmol) was added at room temperature to a solution of N-(benzyloxycarbonyl)-α-phophonoglycine trimethyl ester (1.88 g, 5.69 mmol) in tetrahydrofuran (40 mL). The mixture was stirred at room temperature for 15 min and cooled to −78° C., and a solution of 1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indole-5-carbaldehyde (1.6 g, 5.17 mmol) in tetrahydrofuran (15 mL) was added slowly. The resulting reaction mixture was stirred at −78° C. for 2 h and then warmed to room temperature in 3 h. Solvents were removed in vacuo and the residue was subjected to flash chromatography on silica gel using methylene chloride/hexanes (1:1.5) with 1% triethylamine as eluent to afford the title compound as a 92:8 Z/E mixture (determined by integration of CO2CH3, for Z isomer at 3.79 ppm, and E isomer at 3.65 ppm). For the Z isomer: 1H-NMR (CD3CN, 500 MHz) δ 7.96 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.56 (d, J=3.7 Hz, 1H), 7.51 (s, 1H), 7.43-7.35 (m, 5H), 7.67 (d, J=3.7 Hz, 1H), 5.16 (s, 2H), 3.79 (s, 3H), 3.42-3.38 (m, 2H), 0.87-0.83 (m, 2H), −0.04 (s, 9H). Mass spec. 515.20 (MH)+.