Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[C:8]([CH:17]=1)[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([O-:3])=[O:2].[CH3:25][C:26]([CH3:28])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH:26]([N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][O:9][C:8]2[CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[C:18]([F:24])([F:23])[C:19]([F:20])([F:21])[F:22])[CH2:12][CH2:13]1)([CH3:28])[CH3:25]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCC2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)N1CCC(COc2cc([N+](=O)[O-])ccc2C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine (646 mg) in 1,2-dichloroethane (6.4 ml), then added acetone (136 ul), NaBH(OAc)3 (541 mg) and finally AcOH (105 ul). Stirred the cloudy yellow solution under N2 at RT overnight. Added another 130 uL acetone and stirred at RT over weekend. Quenched the reaction with 30 mL N NaOH/H2O and stirred 10 min. Extracted with Et2O and the organic layer was brine-washed, dried over Na2SO4, filtered and concentrated in vacuo. Dried under high vacuum for several h to obtain 1-isopropyl-4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine as a yellow orange solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1)(=O)=O.O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:36][CH:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:39][CH2:38]4)[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 1.20 g; 3.52 mmol) and Cs2CO3 (2.26 g; 6.94 mmol) in DMF (20 mL) was added tert-butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate (1.32 g; 4.50 mmol) under nitrogen. The reaction mixture was stirred at 90° C. for 2 hours, cooled to r.t., added to water (200 mL) with vigorous stirring. The resulting solid was collected by vacuum filtration to afford 1.60 g (84%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH2:7]([O:14][CH2:15][CH:16]1[CH:20]([CH2:21]I)[O:19][C:18](=[O:23])[NH:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[CH2:7]([O:14][CH2:15][CH:16]1[CH:20]([CH2:21][N:4]2[CH:3]=[C:2]([Br:1])[CH:6]=[N:5]2)[O:19][C:18](=[O:23])[NH:17]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Brc1cn[nH]c1
Reactant: O=C1NC(COCc2ccccc2)C(CI)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(COCc2ccccc2)C(Cn2cc(Br)cn2)O1
Temperature: 90 °C

Procedure:
A mixture of 4-bromo-1H-pyrazole (2.33 g, 15.9 mmol), 4-[(benzyloxy)methyl]-5-(iodomethyl)-1,3-oxazolidin-2-one (5.00 g, 14.4 mmol), and potassium phosphate tribasic (9.17 g, 43.3 mmol) in DMF (50 mL) was stirred and heated to 90° C. for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by reverse phase HPLC to afford 4-[(benzyloxy)methyl]-5-[(4-bromo-1H-pyrazol-1-yl)methyl]-1,3-oxazolidin-2-one. MS ESI calc'd. for C15H12BrN3O3 [M+H]+ 366 and 368. found 366 and 368. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 7.38-7.29 (m, 5H), 4.63-4.60 (m, 1H), 4.54 (s, 2H), 4.39 (d, J=5.6 Hz, 2H), 3.80-3.76 (m, 1H), 3.41 (d, J=4.8 Hz, 2H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]([NH:7][C:8]1[S:9][C:10]([CH2:13][CH3:14])=[N:11][N:12]=1)=[O:6].[H][H].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]#[N:34])=[CH:23][CH:22]=1>CN(C)C=O>[F:16][C:4]([F:15])([F:3])[C:5]([N:7]=[C:8]1[N:12]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:25][CH:26]=2)[N:11]=[C:10]([CH2:13][CH3:14])[S:9]1)=[O:6]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCc1nnc(NC(=O)C(F)(F)F)s1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccc(-c3ccccc3C#N)cc2)c(=NC(=O)C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
To a suspension of 124.1 g of sodium hydride (55% dispersion in oil) in 1.5 liters of N,N-dimethylformamide was added 533.7 g of 2-trifluoroacetamido-5-ethyl-1,3,4-thiadiazole on ice. After the evolution of hydrogen subsided, a solution of 643.6 g of 4'-bromomethyl-2-cyanobiphenyl in 3 liters of N,N-dimethylformamide was added dropwise. The resulting mixture was stirred at room temperature for one hour and then at 80° C. for 5 hours, followed by concentration under reduced pressure. Water and ethyl acetate were added to the concentrate. The organic layer was then washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a 3:1 mixture of hexane and ethyl acetate. Crude crystals were recrystallized from ethanol, whereby 490.8 g of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH:15]=[CH:14][C@@H:13]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[O:12][C@@H:10]1[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([CH2:16][OH:17])[O:12][C@@H:10]1[CH3:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)C=C[C@H]1NC(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H]1O[C@H](CO)CC[C@H]1NC(=O)OC(C)(C)C
Reaction time: 19 h
Yield: 79.7 %

Procedure:
The compound (960 mg, 2.68 mmol) obtained in Step 5 above was dissolved in ethyl acetate (5 ml) and ethanol (5 ml), platinum (IV) oxide (18 mg, 0.08 mmol) was added and the resulting mixture was stirred for 19 hours under hydrogen atmosphere. The catalyst was removed by filtration through celite, then the solvent in the filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=9:1→2:3 (v/v)] to give 524 mg (79%) of the title compound as a colorless solid.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18]O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][NH:41][CH2:40][CH2:39][NH:38]1)=[O:36])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][N:41]([CH2:18][CH2:17][CH2:16][N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:40][CH2:39][NH:38]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)C1CNCCN1
Reactant: OCCCN1c2ccccc2CCc2ccccc21
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1CN(CCCN2c3ccccc3CCc3ccccc32)CCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a stirred solution of 3-(10,11 -dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanol (1.17 g, 0.0046 mol, prepared similarly as described in example 2) and triethylamine (1.18 g, 0.012 mol) in toluene (30 ml) at 0° C., methanesulfonyl chloride (0.70 ml, 0.009 mol) was added dropwise over 10 minutes. The resulting mixture was stirred at 0° C. for 1 h. Toluene (50 ml) and water (100 ml) were added, and the phases were separated. The aqueous layer was extracted with toluene (50 ml), and the combined organic phases were washed with brine (2×100 ml), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile (10 ml) and the above 2-piperazine-carboxylic acid ethyl ester (1.40 g, 0.0089 mol), potassium carbonate (0.67 g, 0.0049 mol) and toluene (5 ml) were added. The resulting mixture was heated at reflux temperature for 18 h. Water (50 ml) was added, and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (2×20 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (27 g) using a gradient of methanol and ethyl acetate (5:100→20:100), affording 0.6 g (33%) of 4-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperazinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:27][N:28]=[C:29]=[O:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:29]([NH:28][CH3:27])=[O:30])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: NCCCN1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CN=C=O
Product: CNC(=O)NCCCN1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
The compound of Example 59 is reacted with methyl isocyanate in an aprotic solvent to obtain the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:22]([F:25])([F:24])[F:23])=[C:8]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[S:12](=[O:18])(=[O:17])[CH2:11][C:10]([CH3:20])([CH3:19])[C:9]2=[O:21])=[O:5])C.[OH-].[K+]>C(O)C.O>[C:4]([C:6]1[C:7]([C:22]([F:24])([F:25])[F:23])=[C:8]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[S:12](=[O:18])(=[O:17])[CH2:11][C:10]([CH3:20])([CH3:19])[C:9]2=[O:21])([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(C)c2c(c1C(F)(F)F)C(=O)C(C)(C)CS2(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)c(C(F)(F)F)c2c1S(=O)(=O)CC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
2.4 Grams (6.3 mmol) of 6-ethoxycarbonyl-5-trifluoromethyl-3,3,8-trimethylthiochroman-4-one-1,1-dioxide was dissolved in 25 ml of ethanol, and than a solution of 0.62 g (9.5 mmol) of potassium hydroxide in 3 ml of water was added. The mixture was stirred at room temperature for 2 hours, then diluted with water and washed with chloroform, and an aqueous layer was acidified with a 5 wt % hydrochloric acid aqueous solution. An organic precipitate was extracted with ethyl acetate, and an organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1.9 g (yield 86%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][C@H:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:31][C@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: C[C@H](N)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1c([N+](=O)[O-])c(Cl)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
The method described in Part A of Example 1 was used to treat 2,4-dichloro-3-nitroquinoline (19.4 g, 78.5 mmol) in DMF (100 mL) with triethylamine (32 mL, 0.235 mol) and (S)-(−)-α-methylbenzylamine (11.5 g, 94.2 mmol) with the modification that the reaction was allowed to warm to room temperature and stirred for two hours. After the isolated precipitate was washed with water, it was dried under high vacuum overnight to provide 25.1 g of 2-chloro-3-nitro-N-[(1S)-1-phenylethyl]quinolin-4-amine as an orange solid.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([O:17][CH3:18])[C:10]=1[F:19])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:20](OC(=O)C)(=O)C.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][CH:20]=[C:3]([C:2](=[O:1])[C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([O:17][CH3:18])[C:10]=1[F:19])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: NCC(F)(F)F
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC)c1F
Product: CCOC(=O)C(=CNCC(F)(F)F)C(=O)c1cc(F)c(F)c(OC)c1F
Temperature: 0 °C

Procedure:
2.00 g (5.79 mmol) of ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate are stirred in 3.8 ml (4.14 g, 40.55 mmol) of acetic anhydride and 4.82 ml (4.29 g, 28.96 mmol) of thriethylorthoformate for 2 h under reflux. The solvent is then completely removed on a rotary evaporator and the residue is dissolved in 10 ml of ethanol. 1.03 g (10.43 mmol) of 2,2,2-trifluoro-1-aminoethane are added dropwise to the ice cold solution, the mixture is brought to room temperature and stirred over night at this temperature. For the work-up the solvent is removed and the residue is reacted further as a crude product without purification steps.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][C:11](=[O:13])[NH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][C:18]1[CH:19]=[CH:20][C:21](S(O)(=O)=O)=[CH:22][CH:23]=1.[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30].CN1CCOCC1>CN(C)C=O>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@H:9]([C:14]([NH:28][C@H:29]([C:31]([O:33][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:32])[CH3:30])=[O:16])[CH2:10][C:11](=[O:13])[NH2:12]
Reactant: C[C@H](N)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 79 %

Procedure:
1.5 g (4.24 mmoles) of p-nitrophenyl ester of BOC-Asparagine are added to a solution cooled to 0° of 1.7 g (4.84 mmoles) of p-toluene sulfonate of the benzyl ester of alanine and of 0.53 ml (4.84 mmoles) of N-methylmorpholine, in 15 ml of dimethylformamide. After 24 hours at ambiant temperature, the product is purified as described above. In suspension in ether, 1.33 g (79%) of the product is obtained after filtration, having a melting point and a rotatory power (in dimethyl formamide) respectively of m.p. 138°-141°; αD25 = 17.5° (c = 1.02 DMF).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)#[N:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][CH:9]([C:7](=[O:8])[C:6]2[CH:14]=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COC(=O)CC(=O)c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(C#N)cc1)C(=O)c1ccc(C#N)cc1
Reaction time: 1.5 h

Procedure:
Methyl p-cyanobenzoylacetate 17.77 g, 0.087 mole) and p-cyanobenzyl bromide (17.16 g, 0.087 mole) were combined in 525 ml DMF under N2 . K2CO3 (12.1 g, 0.087 mole) was added, the slurry stirred 1.5 hours and finally poured into a mixture of 2.5 liters H2O and 0.5 liter ethyl acetate. The organic layer was separated, washed with fresh H2O and then brine, stripped to dryness, and the residue slurried in ether to yield title product: 14.83 g (53.6%); m.p. 154°-157°; tlc (4:1 toluene:ethyl acetate) Rf 0.44.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][C:15]([OH:17])=O.[CH2:36]([N:38]1CCOCC1)[CH3:37].ClC(OCC)=O.C(N)C>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)(=[O:19])=[O:20])[CH2:14][C:15]([NH:38][CH2:36][CH3:37])=[O:17]
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)c2c(Cc3c(F)cccc3F)cccc2OC)cc1OC
Reactant: CCN1CCOCC1
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)CN(c1c(Cc2c(F)cccc2F)cccc1OC)S(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 0.25 h

Procedure:
To 1.8 g of N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl]glycine dissolved in 30 ml of tetrahydrofuran at 0° C. are introduced 0.5 ml of N-ethylmorpholine and 0.38 ml of ethyl chloroformate. After 15 minutes at 10° C., 0.8 g of ethylamine dissolved in tetrahydrofuran is added and the mixture is left at room temperature for 30 minutes. The medium is taken up in ethyl acetate and washed with water, and the organic phase is dried over anhydrous sodium sulfate and concentrated to give 1.4 g of the expected product.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.Cl.[CH2:87]([O:89][C:90](=[O:93])[CH2:91][NH2:92])[CH3:88]>>[OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([NH:92][CH2:91][C:90]([O:89][CH2:87][CH3:88])=[O:93])=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CCOC(=O)CN
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Yield: 161.3 %

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (533 mg) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with glycine ethyl ester hydrochloride (242 mg) in a similar manner as described in Example 24-(i) to give the titled compound (600 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:24][C:25](O)=[O:26])[N:9]=2)=[CH:4][CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.N1C=CC=CC=1.[Cl-].ClC1N(C)C=C[N+]=1C>ClC(Cl)C>[N:30]1[CH:31]=[CH:32][CH:33]=[N:34][C:29]=1[NH:28][C:25](=[O:26])[CH2:24][CH:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:14]2[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]12
Reactant: Nc1ncccn1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(CC(=O)O)c1nnc(C)n1-2
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(CC(=O)Nc1ncccn1)c1nnc(C)n1-2
Yield: 65.4 %

Procedure:
(±)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (1.0 g), 2-aminopyrimidine (0.28 g) and pyridine (0.49 ml) are added to dichloroethane (15 ml), and the mixture is stirred in an ice bath. A solution of 2-chloro-1,3-dimethylimidazolium chloride (0.63 g) in dichloroethane (12 ml) is dropwise added to this mixture at a temperature of not more than 5° C. The mixture is stirred at room temperature overnight, and the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled away and the residue is purified by column chromatography (chloroform:methanol=20:1) and recrystallized from ethanol to give 0.78 g of (±)-N-(2-pyrimidinyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide, melting point 251°-253° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:45](=[O:55])[N:46]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:47][CH2:48][CH2:49][CH3:50])=[N:4][N:5]([C:8]2[CH:32]=[CH:31][C:11]([C:12]([NH:14][S:15]([C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25]4)=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[O:13])=[CH:10][C:9]=2[C:33]([N:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36]2)=[O:34])[C:6]=1[CH3:7].[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>>[CH2:47]([N:46]([CH2:51][CH2:52][CH2:53][CH3:54])[C:45]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:32]=[CH:31][C:11]([C:12](=[O:13])[NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]4[C:26](=[CH:25][C:24]([C:28]([N:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)=[O:29])=[CH:23][CH:22]=4)[CH:27]=3)(=[O:16])=[O:17])=[CH:10][C:9]=2[C:33]([N:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36]2)=[O:34])[N:4]=1)=[O:55])[CH2:48][CH2:49][CH3:50]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(C(=O)O)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Reactant: C1COCCN1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(C(=O)N5CCOCC5)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 23.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 12B of Example 12, 7-(N-(4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoyl)sulfamoyl)-2-naphthoic acid (Intermediate 46A 12 mg, 0.015 mmol) and morpholine (4 mg, 0.046 mmol) were converted to the title compound (3 mg, 20%). 1H NMR (1:1 CD3OD:CDCl3, 2:1 mixture of amide rotamers) δ 8.67 (s, 1H), 8.21 (d, J=8.3 Hz, 1H), 8.14 (dd, J=8.7, 1.5 Hz, 1H), 8.11 (d, J=1.7 Hz, 1H), 8.06 (s, 1H), 7.98 (t, J=7.6 Hz, 2H), 7.60 (d, J=8.3 Hz, 1H), 7.44-7.42 (m, 1H), 7.19-7.09 (m, 3.5H), 6.89 (d, J=7.2 Hz, 0.5H), 4.83 (br s, 1H), 4.50 (s, 1H), 4.36 (br s, 1H), 3.79 (br s, 4H), 3.68 (br s, 3H), 3.54 (br s, 3H), 3.45 (s, 1H), 3.00 (br s, 1.5H), 2.83 (br s, 1.5H), 2.29 (s, 2H), 2.24 (s, 1H), 1.50-1.44 (m, 1H), 1.40-1.35 (m, 2H), 1.32-1.16 (m, 4H), 1.12-0.99 (m, 2H), 0.92-0.86 (m, 3H), 0.75 (t, J=7.4 Hz, 2H), 0.68 (t, J=7.4 Hz, 1H); MS(ESI+) m/z 853.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:20]=[C:19]([C:21]3[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][CH2:30][CH:31]=O.N1C=CC=CC=1C.B.C(=O)([O-])O.[Na+]>C(O)(=O)C.CN(C)C=O>[NH2:28][C:22]1[N:23]=[C:24]([NH:27][CH2:31][CH2:30][OH:29])[CH:25]=[CH:26][C:21]=1[C:19]1[O:18][N:17]=[C:16]([CH2:15][C:12]2[CH:13]=[N:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH:20]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Reactant: O=CCO
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccn1
Solvent: CN(C)C=O
Product: Nc1nc(NCCO)ccc1-c1cc(Cc2ccc(OCc3ccccc3)nc2)no1
Reaction time: 1.67 h
Yield: 9.8 %

Procedure:
To a mixture of 3-(3-(6-benzyloxy-pyridin-3-ylmethyl)-isoxazol-5-yl)-pyridin-2,6-diamine (40 mg, 0.11 mmol) described in Example 25 and N,N-dimethylformamide (0.5 mL) were 2-hydroxyacetaldehyde (7.7 mg, 0.13 mmol), α-picoline-borane (14 mg, 0.13 mmol), and acetic acid (40 μL) at room temperature, which was stirred for 100 minutes at the same temperature. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, after which the organic layer was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain a crude product, and then purified by NH silica gel column chromatography (ethyl acetate:methanol=50:1) to obtain the title compound (4.5 mg, 10%).