Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[C@H:21]([S@:22](=[O:27])[CH2:23][C:24]=1[CH2:25]Cl)[C@H:20]([NH:28][C:29](=[O:68])/[C:30](=[N:45]\[O:46][C@@H:47]([CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)=[O:49])/[C:31]1[N:32]=[C:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[S:34][C:35]=1[Cl:36])[C:19]2=[O:69])=[O:16])([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.[I-:70].[Na+]>C(#N)C>[CH:1]([O:14][C:15]([C:17]1[N:18]2[C@H:21]([S@:22](=[O:27])[CH2:23][C:24]=1[CH2:25][I:70])[C@H:20]([NH:28][C:29](=[O:68])/[C:30](=[N:45]\[O:46][C@@H:47]([CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)=[O:49])/[C:31]1[N:32]=[C:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[S:34][C:35]=1[Cl:36])[C:19]2=[O:69])=[O:16])([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
Reactant: [I-]
Reactant: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)C[S@@](=O)[C@H]23)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CI)C[S@@](=O)[C@H]23)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.9 %

Procedure:
To a solution of (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(2-(((5R,6R,7R)-2-((benzhydryloxy)carbonyl)-3-(chloromethyl)-5-oxido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoethylidene)amino)oxy)succinate (27 g, 24.98 mmol) in Acetonitrile (300 mL) was added sodium iodide (5.62 g, 37.5 mmol). The mixture was stirred at room temperature over 1.5 h. LCMS indicated completion of the reaction. The solid was filtered off, the filtrate was concentrated under vacuum, and the residue was purified by CombiFlash Rf automated silica gel chromatography (330 g column), eluting with EtOAc/Hexanes (0-50%) to afford (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(2-(((5R,6R,7R)-2-((benzhydryloxy)carbonyl)-3-(iodomethyl)-5-oxido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoethylidene)amino)oxy)succinate (18 g, 14.97 mmol, 59.9% yield) as a red-brown solid. LCMS: (M+H)+: 1118.1
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11]OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:25]([NH:32][CH2:33][C@@H:34]([C:43]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[C:49]2[C:44]=1[CH:45]=[CH:46][C:47](=[O:61])[NH:48]2)[O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.CCOC(C)=O>C(#N)C>[CH2:25]([N:32]([CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:33][C@@H:34]([C:43]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[C:49]2[C:44]=1[CH:45]=[CH:46][C:47](=[O:61])[NH:48]2)[O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: O=[N+]([O-])c1ccc(CCOS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1ccc([N+](=O)[O-])cc1)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A stirred solution of 4-nitrobenzenesulfonic acid 2-(4-nitrophenyl)ethyl ester (3.78 g, 10.7 mmol); 5-[(R)-2-benzylamino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-benzyloxy-1H-quinolin-2-one (4.620 g, 8.975 mmol) and N,N-diisopropylethylamine (3.59 mL, 20.6 mmol) in acetonitrile (39.2 mL) was heated at 65° C. overnight. After cooling the reaction mixture to room temperature, EtOAc (20 mL) was added and this mixture was washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound (3.0 g, 50% yield) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([OH:35])=O)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:9]/[C:10](=[N:19]\[OH:20])/[C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[CH:12]=2)=[C:4]([CH3:36])[CH:3]=1.[NH2:37][CH2:38][C:39]1[NH:43][N:42]=[N:41][N:40]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH:40]1[C:39]([CH2:38][NH:37][C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:24]3[CH:25]=[CH:26][C:21]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[CH3:36])[CH2:9]/[C:10](=[N:19]\[OH:20])/[C:11]4[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[CH:12]=4)=[CH:22][CH:23]=3)=[CH:28][CH:29]=2)=[O:35])=[N:43][N:42]=[N:41]1
Reactant: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: NCc1nnn[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)NCc3nnn[nH]3)cc2)cc1

Procedure:
In analogy to example 228, (E)-4′-(1-(4-chloro-2-methylphenyl)-3-(hydroxyimino)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)propyl)biphenyl-4-carboxylic acid (example 227) was reacted with 5-aminomethyltetrazole in the presence of HATU to give the title compound as a light yellow foam, MS (ESI+): m/z=582.2 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]([CH3:25])[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=O>O1CCCC1>[OH:8][CH2:9][C:11]1([CH2:26][CH2:27][N:28]([CH3:29])[CH3:30])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]([CH3:25])[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: COC(=O)C1(CCN(C)C)c2ccccc2N(C)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCC1(CO)c2ccccc2N(C)c2ccccc21
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
20 gm of lithium aluminum hydride were added over 15 minutes to iced 400 cc of tetrahydrofuran and then a solution of 36 gm of 9-methoxycarbonyl-9-(β-dimethylaminoethyl)-10-methyl-acridane in 400 cc of tetrahydrofuran was added thereto over 30 minutes. The mixture was refluxed for 2 hours, then refrigerated and 200 cc of tetrahydrofuran containing 20% water were added thereto at a temperature below 0°C. The mixture was filtered and the filtrate was washed with methylene chloride and distilled to dryness in vacuo. The residue was dissolved in methylene chloride and the organic phase was washed with water, dried over magnesium sulfate and concentrated while adding ethyl acetate to replace the methylene chloride. Crystallization started and after icing for one hour the mixture was filtered. The precipitate was washed with water and was dried to obtain 24.5 gm of 9-hydroxymethyl-9-(β-dimethylaminoethyl)-10-methyl-acridane melting at 150°C. Concentration of the mother liquor gave a second cup of 1.6 gm of the product for a total yield of 79%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:3][CH:2]=1
Reactant: N#CCCCc1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCCCc1ccncc1
Temperature: 10 °C
Yield: 6.7 %

Procedure:
The title product of Example 22 (5.0 g, 34.0 mmol) in 40 mL of tetrahydrofuran was added dropwise to a stirred suspension of lithium aluminum hydride (LiAlH4, 3.2 g, 85.0 mmol) in 100 mL of THF over 20 minutes. The reaction was brought to reflux for 2 hours, cooled to 10° C., and treated with water (33.2 mL), 15% NaOH (3.2 mL), and then water (9.6 mL) again. The mixture was filtered and the solid was washed With Et2O. The filtrate was dried (Na2SO4), filtered, and stripped of solvent to yield 4.0 g of crude product that was distilled to produce the title compound (340 mg).
Reaction SMILES: CN(C=O)C.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=1[NH2:10].[CH3:21][N:22]1[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=[C:23]1S(C)(=O)=O.[Cl-].[NH4+]>CCOCC.[H-].[Na+]>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:9]=1[NH:10][C:23]1[N:22]([CH3:21])[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[N:24]=1
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: Cn1c(S(C)(=O)=O)nc(C(F)(F)F)cc1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
Sodium hydride (60% in oil, 468 mg, 17.6 mmol) was added to DMF (30 ml) solution of 2,5-bis(trifluoromethyl)aniline (3.8 g, 16.4 mmol), followed by stirring at room temperature for 30 minutes. Then, 3-methyl-2-methylsulfonyl-6-trifluoromethyl-4(3H)-pyrimidinone (3.0 g, 11.7 mmol) was added, followed by stirring for additional 4 hours. After completion of the reaction, the reaction solution was diluted with ether (20 ml), excess sodium hydride was neutralized with saturated ammonium chloride aqueous solution and then the aqueous layer was separated. After extraction of the aqueous layer with ether (20 ml×2), the organic layers were combined, washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=20:1˜8:1) to obtain light yellow crystals of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-methyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 46].
Reaction SMILES: P([O-])(O)(O)=O.[K+].[C:7]([NH:14][CH2:15][C:16](=[O:39])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC(Cl)(Cl)Cl)=[O:32])=[O:20])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>O1CCCC1.[Zn]>[C:7]([NH:14][CH2:15][C:16](=[O:39])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:20])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCCCCCCCC(=O)OCC(Cl)(Cl)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
One molar potassium dihydrogen phosphate (KH2PO4) solution (4.0 mL; 4.0 mmol) followed by zinc powder (2.0 g; 30 mmol) was added to a stirred solution of the product from 12b (1.50 g; 2.8 mmol) in tetrahydrofuran (25 mL). After stirring 18 h at ambient temperature, a new portion of 1 M KH2PO4 solution (5 mL) and zinc (2.0 g; 30 mmol) was added. Additional 1 M KH2PO4 solution (25 mL) was added after 5 h and the mixture was stirred overnight at ambient temperature. The mixture was vacuum filtered and the residue was washed with ethyl acetate. Ethyl acetate in the filtrate was evaporated off and the aqueous solution was extracted with dichloromethane (4×5 mL). The combined extracts were dried (Na2SO4), filtered, and evaporated. 1.04 g (93%) product was obtained (pale yellow waxy solid).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:20](=[CH:21][CH:22]=2)[O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][C:11]3=[O:23])[NH:4]1.[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([O:42][CH2:43][CH3:44])[C:35]=1[C:36]1[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=1)[C:30](O)=[O:31])[CH3:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(N(CC)CC)C>[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([C:30]([N:16]2[CH2:17][CH2:18][C:13]3([CH2:12][C:11](=[O:23])[C:10]4[C:20](=[CH:21][CH:22]=[C:8]([C:5]5[NH:4][C:3](=[O:2])[NH:7][N:6]=5)[CH:9]=4)[O:19]3)[CH2:14][CH2:15]2)=[O:31])[CH:33]=[C:34]([O:42][CH2:43][CH3:44])[C:35]=1[C:36]1[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=1)[CH3:25]
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3n[nH]c(=O)[nH]3)cc21
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnn(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4n[nH]c(=O)[nH]4)ccc2O3)cc(OCC)c1-c1cnn(C)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
6-(5-Oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (202 mg), 3,5-diethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (145 mg), EDCI (115 mg), HOBT (91.2 mg) and triethylamine (0.209 mL) were suspended in DMF (3 mL), and stirred at 50° C. for 16 hours. Water was added to it, the formed solid was taken out through filtration, and the resulting solid was recrystallized from methanol to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.08-8.04 (2.0H, m), 8.00 (1.0H, dd, J=8.8, 2.2 Hz), 7.93-7.91 (1.0H, m), 7.25 (1.0H, d, J=8.5 Hz), 7.22 (2.0H, br s), 6.68 (2.0H, s), 4.37-4.13 (1.0H, m), 4.08 (4.0H, q, J=6.8 Hz), 3.86 (3.0H, s), 3.66-3.13 (3.0H, m), 2.95 (2.0H, s), 2.14-1.69 (4.0H, m), 1.37 (6.0H, t, J=7.0 Hz). MS [M+H]+=573.
Reaction SMILES: [Br:1][C:2]1[C:7](O)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([C:7]1[C:2]([Br:1])=[N:3][C:4]([N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(O)c(Br)n1
Product: CC(=O)c1ccc([N+](=O)[O-])nc1Br

Procedure:
Starting materials 3-acetyl-6-amino-2-bromopyridine and 2-(2-chloro-3-ethoxy-6-fluorophenyl)-cyclopropylisocyanaze, were prepared in following manner: 5 g of 2-Bromo-3-pyridine (Aldrich) was added to a mixture of 25 ml of conc. H2SO4 and 25 ml of fuming HNO3 at 0° C. The mixture was stirred one hour at that temperature, then added to 350 ml of crushed ice and extracted with CH2C12. The extract was dried with Na2SO4 and evaporated in vacuo to yield 4.1 g of a crude product as a mixture of 2-bromo-6-nitro-3-pyridinol and 2-bromo-4,6-dinitro-3-pyridinol. The mixture (0.5 g) was treated with an excess of acetic anhydride at room temperature at 24 hours, then separated on a silica-gel column eluated with mixtures of hexane and ethylacetate to yield 0.28 g of 2-bromo-6- nitro-3-pyridinol as a yellowish solid. 2-Bromo-6-nitro-3-pyridinol was then treated with acetic anhydride at 80° C. at 14 hours under an atmosphere of nitrogen to yield 0.34 g of 3-acetyl-2-bromo-6-nitropyridine as a yellow solid. Hydrogenation of 3-acetyl-2-bromo-6-nitropyridine in ethanol ( Pt on C, 1 atm) gave 3-acetyl-6-amino-2-bromopyridine as a reddish oil. The cis/trans mixture of 2-(2-chloro-3-ethoxy-6-fluorophenyl)cyclopropyliso-cyanates were prepared from 2-chloro-4-fluorophenol (Aldrich) in manner analogous to Examples 362, 375 and 348 of WO 93/03022. This product was then condensed with 3-acetyl-6-amino-2-bromopyridine in a manner analogous to the method in Example 7 to provide cis/trans mixture of N-2-(2-Chloro-3-ethoxy-6-fluorophenyl)-cyclopropyl-N′-(6-bromo-5-hydroxypyrid-2-yl)-ureas. The two products were separated on a silica-gel column eluated with mixtures of hexane and ethylacetate to yield the titled compound as a white solid: 1H NMR (250 MHz, CDCl3) δ0 7.85 (d, 1H), 7.55 (br s, 1H), 6.98-6.72 (m, 2H), 4.04 (q, 2H), 3.27-3.04 (m, 1H), 2.18 (q, 1H), 1.74-1.65 H, (m, 1H), 1.43 (t, 3H), 0.92-0.80 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc2ncsc2c1
Yield: 75.1 %

Procedure:
A solution of benzothiazole-6-carboxylic acid (4.48 g, 25.0 mmol), tert-butyl carbazate (3.63 g, 27.5 mmol), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (5.75 g, 30.0 mmol) and 1-hydroxybenzotriazole (4.05 g, 30.0 mmol) in N,N-dimethylformamide (50 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/tetrahydrofuran=2/1), and crystallized from hexane/acetone to give the title compound (5.51 g, yield 75%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25]Cl.O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[O:12][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25]
Reactant: COCCOCCl
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COCCOCOc1ccc(C(C)(C)C)cc1Br
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (5.0 g, 21.8 mmol) and triethylamine (4.4 g, 43.5 mmol) in anhydrous dichloromethane (20 mL) at room temperature under nitrogen was added dropwise 2-methoxyethoxymethyl chloride (2.5 mL, 21.9 mmol) and the reaction mixture stirred overnight. The reaction mixture was poured into water (100 mL), the organic phase separated, dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)-1-((2-methoxyethoxy)methoxy)benzene (5.0 g, 72% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([NH:18][C:19](=[O:41])[CH2:20][C:21](=[O:40])[NH:22][C@@H:23]([CH2:29][NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=2[CH3:39])[C@@H:24]([OH:28])[CH2:25][CH2:26][CH3:27])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]([NH:18][C:19](=[O:41])[CH2:20][C:21]([NH:22][C@@H:23]([CH2:29][NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=2[CH3:39])[C@@H:24]([OH:28])[CH2:25][CH2:26][CH3:27])=[O:40])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1
Reactant: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)CC(=O)Nc1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)CC(=O)Nc1cc(N)cc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
The compound [3-(2-{(1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentylcarbamoyl}-acetylamino)-5-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (45 mg, 0.08 mmol, see procedure 8b above) was dissolved in CH2Cl2 (1.5 mL) and treated with TFA (0.5 mL). The solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in benzene and concentrated in vacuo; this procedure was repeated. The residue was purified by reverse-phase HPLC to afford the title compound as a white powder after lyopholization. MS found: (M+H)+=495.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.Cl.[CH3:27][O:28][C:29]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH2:36][NH:35][CH2:34]2)=[O:30].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:27][O:28][C:29]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH2:36][N:35]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:34]2)=[O:30]
Reactant: COC(=O)c1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c1F)C2
Yield: 20 %

Procedure:
180 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 52 mg of the target compound.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Si:19]([O:26][C@H:27]([CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([CH3:57])=[C:53]([F:58])[CH:52]=1)[CH2:28][O:29][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH3:31])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].CI>O1CCCC1.O>[Si:19]([O:26][C@H:27]([CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([CH3:57])=[C:53]([F:58])[CH:52]=1)[CH2:28][O:29][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH:39]([CH3:1])[C:40]([O:42][CH3:43])=[O:41])[CH3:31])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)CCc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)Cc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To diisopropylamine (0.45 mL, 3.23 mmol), a 2.69 M solution of n-butyl lithium in hexane (1.20 mL, 3.23 mmol) was added at −78° C. followed by stirring for 15 minutes. After adding anhydrous tetrahydrofuran (2 mL), the mixture was further stirred for 15 minutes at −78° C. Subsequently, a solution of methyl 3-{2-[(1R)-1-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]propyl}oxy)ethyl]phenyl}propanoate (615 mg, 1.08 mmol), which had been obtained in Example 179 (179a), in tetrahydrofuran (1 mL) was added thereto and stirred at −78° C. for 0.5 hours. After adding methyl iodide (0.6 mL, 6.46 mmol), the mixture was stirred at room temperature for 17 hours. Upon the completion of the reaction, water was added. After extracting the mixture with ethyl acetate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=85/15) to give the title compound as a colorless oily substance (446 mg, yield 70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[C:4]([CH3:18])[CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH2:29]([O:31][NH2:32])[CH3:30]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:32][O:31][CH2:29][CH3:30])=[O:13])=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(Br)ccc1Nc1cnccc1C(=O)O
Reactant: CCON
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCONC(=O)c1ccncc1Nc1ccc(Br)cc1C
Reaction time: 2 h
Yield: 77 %

Procedure:
3-[(4-Bromo-2-methylphenyl)amino]isonicotinic acid 2b (320 mg, 1.04 mmol) was dissolved in 15 ml dry DMF followed by the addition of DIPEA (2.08 mmol, 373 μl), ByBOP (1.25 mmol, 651 mg) and O-ethylhydroxylamine hydrochloride (2.08 mmol, 203 mg). The mixture was stirred for 2 h and the volatiles were removed in vacuo. The crude material was purified by flash chromatography using silica gel and a gradient of 0-5% methanol in DCM as eluent to give 280 mg (800 μmol; 77% yield) of pure desired product.