Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:14]([O:16]CC)=[O:15])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].[OH-].[K+]>C(O)C>[C:10]([O:9][C:7](=[O:8])[CH2:6][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:19])[C:14]([OH:16])=[O:15])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)O
Yield: 60 %

Procedure:
To the tri-ester of example 21 (38 g, 0.14 mol) in ethanol (456 mL) was added 77.6 mL of a 10% aqueous solution of potassium hydroxide. The resulting mixture was refluxed for 3 hours. The isolated product was purified by flash chromatography (SiO2, 90% dichloromethane-10% methanol) to afford 20.68 g (60.6% yield) of the title compound: 1H NMR (CDCl3, 400 MHz) 4.16 (q, 2H), 3.72 (t, 1H), 2.80 (d, 2H), 1.35 (s, 9H), 1.20 (t, 3H); 13C NMR (CDCl3, 400 MHz) 170.0, 168.9, 81.6, 62.4, 47.7, 34.5, 28.2, 14.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][O:11][N:12]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][CH:3]=1.C(CN)O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][O:11][NH2:12])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1OCC=Cc1ccc(Br)cc1
Solvent: ClCCl
Solvent: NCCO
Product: NOCC=Cc1ccc(Br)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
33.4 g (0.093 mol) of N-[3-(4-bromophenyl)-prop-2-enyloxy]-phthalimide wereintroduced a little at a time into 50 ml of ethanolamine and the temperature increased to 30° C. during this procedure. The mixture was stirred for two hours at 60° C. and then allowed to cool, and 200 ml of dichloromethane were added. The mixture was extracted by shakingwith ice water. After drying was evaporating down the organic phase, the residue was recrystallized from petroleum ether. Yield: 95.3%; mp.: 35°-38° C.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].N1C=CC=C(C2C=C3C=CNC3=NC=2)C=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([C:37]2[CH:38]=[C:39]3[CH:45]=[CH:44][NH:43][C:40]3=[N:41][CH:42]=2)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>>[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([C:37]2[CH:38]=[C:39]3[C:45]([C:4]([C:3]4[C:6]([F:11])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=4[F:1])=[O:5])=[CH:44][NH:43][C:40]3=[N:41][CH:42]=2)[CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30]
Reactant: O=Cc1c(F)ccc(F)c1F
Reactant: CS(=O)(=O)c1cccc(-c2cnc3[nH]ccc3c2)c1
Agent: c1cncc(-c2cnc3[nH]ccc3c2)c1
Product: CS(=O)(=O)c1cccc(-c2cnc3[nH]cc(C(=O)c4c(F)ccc(F)c4F)c3c2)c1

Procedure:
was prepared using the protocol of Steps 3 and 4 of Scheme 17, substituting propane-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide with 2,3,6-Trifluoro-benzaldehyde and 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with 5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine in Step 3. MS(ESI) [M−H+]−=429.0.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH:19]=[C:18]([Br:34])[CH:17]=2)=[CH:8][C:7]=1[CH3:35]>C(O)C.[OH-].[Na+]>[Br:34][C:18]1[CH:17]=[C:16]([C:15]#[C:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]([CH3:35])[CH:8]=2)[CH:21]=[C:20]([C:22]#[C:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=2)[CH:19]=1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC#Cc2cc(Br)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O

Procedure:
A solution of (4-{3-[3-bromo-5-(4-trifluoromethyl-phenylethynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (94 mg, 0.169 mmol) in ethanol (5 ml) and 1N NaOH (0.5 ml) was stirred at 75° C. for 30 min. The reaction mixture was evaporated and the residue dissolved in water (2 ml). Aqueous 1N HCl (0.6 ml) was added and the mixture was extracted with methylene chloride (3×15 ml). The combined organic phases were dried and evaporated to give the title compound in 79 mg (86%) yield.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([C:60]([N:62]2[CH2:66][CH2:65][C@@H:64]([CH:67]([C:72]([O:74][CH2:75][C:76]3[CH:81]=[CH:80][C:79]([N+:82]([O-:84])=[O:83])=[CH:78][CH:77]=3)=[O:73])[NH:68][C:69]([NH2:71])=[NH:70])[CH2:63]2)=[O:61])[CH2:43]1.C(OCC)(=O)C>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=4)=[O:48])[C@H:44]([C:60]([N:62]4[CH2:66][CH2:65][C@@H:64]([CH:67]([C:72]([O:74][CH2:75][C:76]5[CH:77]=[CH:78][C:79]([N+:82]([O-:84])=[O:83])=[CH:80][CH:81]=5)=[O:73])[NH:68][C:69]([NH2:71])=[NH:70])[CH2:63]4)=[O:61])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: N=C(N)NC(C(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@@H](C(NC(=N)N)C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 80 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (0.70 g) in anhydrous acetonitrile (10 ml), N,N-diisopropylethylamine (0.21 ml) and a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3R)-3-(4-nitrobenzyloxycarbonylguanidinomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (1.28 g) in anhydrous acetonitrile (10 ml) were added while stirring in an ice bath. The resulting mixture was allowed to react overnight at 0° C. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate/methanol=95/5-9/1-6/4), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3R)-3-(4-nitrobenzyloxycarbonylguanidinomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (0.97 g) was obtained.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[F:12][C:13]([F:28])([F:27])[O:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]([OH:26])=[O:25])=[N:20][NH:21]2)=[CH:17][CH:16]=1.[N:29]12[CH2:36][CH2:35][CH:32]([CH2:33][CH2:34]1)[C@H:31](O)[CH2:30]2>N1C=CC=CC=1>[F:28][C:13]([F:12])([F:27])[O:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]([O:26][C@H:31]3[CH:32]4[CH2:35][CH2:36][N:29]([CH2:34][CH2:33]4)[CH2:30]3)=[O:25])=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1n[nH]c2cc(OC(F)(F)F)ccc12
Reactant: O[C@@H]1CN2CCC1CC2
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: O=C(O[C@@H]1CN2CCC1CC2)c1n[nH]c2cc(OC(F)(F)F)ccc12
Temperature: 25 °C
Yield: 16 %

Procedure:
p-Toluenesulfonyl chloride (0.16 mmol) was added to a 0° C. solution of 6-(trifluoromethoxy)-1H-indazole-3-carboxylic acid (0.81 mmol) in pyridine. (5.00 mL). (3S)-Quinuclidin-3-ol (0.81 mmol) was added and the reaction mixture was allowed to warm to rt. The reaction mixture was maintained for 16 h and was filtered and concentrated. The residue was redissolved in methanol and loaded on a 5 g SCX column. The column was washed with methanol and the product was eluted with methanol/dimethylethylamine (9/1) and concentrated. The residue was purified by preparative HPLC to produce the desired product in 16% yield. Note: this procedure works equally well when p-toluenesulfonyl chloride is replaced with oxalyl chloride. 1H NMR (CDCl3) δ 8.52 (s, 1 H), 7.96 (d, J=8.9, 1H), 7.49 (s, 1 H), 7.09 (d, J=8.9, 1H), 5.31 (m, 1 H), 3.72-3.29 (m, 6 H), 2.56 (m, 1 H), 2.32 (m, 1 H), 2.06-1.88 (m, 3 H); LC/MS (EI) tR 4.9 min, m/z 356 (M++1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)[CH:4]=[N:3]1>Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccccc2[N+](=O)[O-])cn1
Agent: Cl
Product: Cn1cc(-c2ccccc2N)cn1
Yield: 84.5 %

Procedure:
By the procedure of Example 3, 25 g of 1-methyl-4-(2-nitrophenyl)-1H-pyrazole prepared in Example 17 was reacted with 81.2 g of stannous chloride dihydrate in 200 ml concentrated HCl at reflux for 1 hour to yield, after similar work up, 18 g of the title compound as an oil.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.[Si](Cl)(Cl)(Cl)Cl.Cl.[CH:17]1C=CC=CC=1>>[CH3:17][C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=1[C:7]([OH:9])=[O:8]
Reactant: c1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: Cl[Si](Cl)(Cl)Cl
Product: Cc1ccccc1C(=O)O
Temperature: 25 °C

Procedure:
To a reaction vessel was added 5 grams (0.037 moles) of para toluic acid suspended in about 100 ml of benzene. Then, 3.14 grams (0.0185 moles) of silicon tetrachloride were added and the reaction mixture stirred at room temperature. A small amount of HCl gas evolved during this stirring. Even though a small amount of material remained undissolved, the reaction mixture was distilled at 80° C. and atmospheric pressure. The overhead condensate contained only benzene and silicon tetrachloride. The pot residue was further heated until p-toluic acid sublimed. Analysis of the liquid remaining in the pot showed it to contain what is probably a silicon chloro toluate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=3)[CH2:11][CH2:10][N:9]=2)=[CH:4][C:3]=1[O:19][CH3:20].C(=O)([O-])[O-].[Na+].[Na+].[F:27][C:28]([F:41])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>O1CCOCC1>[F:41][C:28]([F:27])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=4)[CH2:11][CH2:10][N:9]=3)=[CH:4][C:3]=2[O:19][CH3:20])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(C2=NCCc3ccc(Cl)cc32)ccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C2=NCCc3ccc(Cl)cc32)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
28.7 mg of 1-(4-amino-3-methoxyphenyl)-7-chloro-3,4-dihydroisoquinoline are dissolved in 400 μl of dioxane, and 300 μl of a 0.33 molar solution of sodium carbonate are then added. 480 μl of a 0.25 molar solution of 4-trifluoromethoxybenzenesulfonyl chloride in dioxane are added to this mixture. The whole is stirred at RT for 16 h and the reaction mixture is loaded, at neutral pH, onto a cartridge containing 400 mg of diatomaceous earth and 300 mg of alumina. The product is eluted with 12 ml of dichloromethane. The eluate is concentrated and the residue is purified by flash chromatography on silica gel. 34 mg of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:4]1([C:7]([OH:9])=O)[CH2:6][CH2:5]1)[CH3:2].CCOC(OC(OCC)=O)=O.[F:31][C:32]([F:49])([F:48])[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[C:44]([CH2:46][NH2:47])[CH:43]=[CH:42][N:41]=2)=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:4]1([C:7]([NH:47][CH2:46][C:44]2[CH:43]=[CH:42][N:41]=[C:40]([C:37]3[CH:36]=[CH:35][C:34]([O:33][C:32]([F:49])([F:31])[F:48])=[CH:39][CH:38]=3)[CH:45]=2)=[O:9])[CH2:5][CH2:6]1)[CH3:2]
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2ccnc(-c3ccc(OC(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.7 %

Procedure:
A solution of acid 15A (0.5 g, 1.7 mmol) in THF (30 mL) was added with DEPC (0.34 mL, 1.3 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.51 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (40 mL) and washed with water (50 mL) and brine. The separated organic phase was dried over Na2SO4 and evaporated under reduced pressure and the residue was purified by flash chromatography (7:3 EtOAc:Petroleum ether) to afford a white solid (0.18 g) after crystallization from diethyl ether. Yield=30%, 1HNMR (DMSO, 200 MHz) δ 1.09 (bs, 2H), 1.22 (t, 3H, J=8), 1.26 (bs, 2H), 3.41 (bs, 2H), 4.43 (d, 2H, J=6); 7.27 (d, 1H, J=4), 7.46-7.42 (m, 4H), 7.90 (m, 3H), 8.23 (m, 3H), 8.61 (d, 1H, J=5.2). [M+1] 537.53 (C25H23F4N3O4S requires 537.13).
Reaction SMILES: [H-].[Na+].[C:3]([NH2:12])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH3:26])[CH:22]=2)[N:17]=[C:16]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:15]=1.O>CN(C=O)C>[CH2:25]([O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[N:15]=[C:14]2[O:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[C:3]([NH2:12])=[O:11])[CH3:26]
Reactant: NC(=O)c1ccccc1O
Reactant: CCOc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2nc(-c3cccnc3)nc(Oc3ccccc3C(N)=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.3 %

Procedure:
(The method G8 is representative of method G6, G7, G9, G10 and G11. These six methods can be implemented in a similar way except for substitution of the appropriate base, solvent and temperature) To a 2.5 dram reaction vial was first added sodium hydride 60% (0.028 g, 0.700 mmol) and salicylamide (0.072 g, 0.525 mmol) in DMF (2 mL). The mixture was allowed to stir at room temperature for 1 h. Then, 4-chloro-6-ethoxy-2-(pyridin-3-yl)quinazoline (0.100 g, 0.350 mmol) was added to the mixture, and the reaction was allowed to proceed at room temperature overnight. LC-MS analysis of the crude mixture showed about 85% of product formed and 10% remaining starting material. Water (30 mL) was added to the mixture, and the product was extracted with chloroform (3×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified via ISCO (silica gel, 97.5:2.5 CH2Cl2/MeOH; 12 g column) to afford 13.9 mg of the desired product as a white solid (10.3%) LCMS m/z=387 (M+1) (Method C) (retention time=2.05 min). 1H NMR (300 MHz, DMSO) δ 11.47 (s, 2H), 9.39 (s, 1H), 8.66 (d, J=2.8 Hz, 1H), 8.56-8.47 (m, 1H), 8.01-7.90 (m, 2H), 7.69-7.55 (m, 2H), 7.55-7.40 (m, 2H), 7.05 (t, J=7.5 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 4.23 (q, J=6.9 Hz, 2H), 1.44 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:40][C:41](OC2C=CC=CC=2)=[O:42])[C:27](=[CH:38][CH:39]=1)[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH:22][C:41]([NH:40][C:26]2[CH:25]=[C:24]([Cl:23])[CH:39]=[CH:38][C:27]=2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[O:42])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(Cl)c(NC(=O)OCc2ccccc2)c1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Product: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Cl)c(NC(=O)OCc2ccccc2)c1
Yield: 77.7 %

Procedure:
1.0 g (2.93 mmol) of 3-benzyloxycarbonylamino-4-chlorobenzenesulfonamide and 1.18 g (2.93 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as Preparation Example 1 to obtain 1.43 g (yield 78%) of benzyl 2-{[(3-benzyloxycarbonylamino-4-chlorobenzene sulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 5.19 (2H, s), 5.36 (2H, s), 7.21 (1H, dd), 7.34-7.48 (10H, m), 7.72-7.76 (2H, m), 7.97 (1H, d), 8.25 (1H, d), 8.30 (1H, d), 9.53 (1H, s), 10.30 (1H, s). 1.38 g (2.20 mmol) thereof was dissolved in 50 ml of THF, then 200 mg of palladium-carbon (10%) was added and the mixture was stirred under a hydrogen flow for 2 hours. The reaction mixture was filtered with Celite to remove the palladium-carbon, then the filtrate was concentrated in vacuo to obtain a carboxylic acid. The product obtained was suspended in 50 ml of THF, then 356 mg (2.20 mmol) of CDI was added under ice cooling and the resultant mixture was treated in the same way as Preparation Example 1 to obtain 560 mg (yield 66%: 2 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 6.00 (2H, s), 7.12 (1H, s), 7.26 (2H, t), 7.48 (1H, d), 7.66 (1H, s), 7.86 (1H, d), 11.76 (1H, br).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][NH:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[N:4]([CH3:23])[C:3]1=[O:24].[CH2:25](N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[N:13][NH:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[N:4]([CH3:23])[C:3]1=[O:24].[C:32]([N:14]1[C:15]([CH3:16])=[C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:24])[N:4]([CH3:23])[C:5]=3[CH:10]=2)[C:12]([C:17]2[CH:18]=[C:19]([CH3:25])[CH:20]=[CH:21][CH:22]=2)=[N:13]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Agent: Cc1[nH]nc(-c2ccccc2)c1-c1ccc2c(c1)n(C)c(=O)n2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)n1nc(-c2cccc(C)c2)c(-c2ccc3c(c2)n(C)c(=O)n3C)c1C
Reaction time: 0.33 h

Procedure:
1,3-Dimethyl-5-(5-methyl-3-phenyl-1H-pyrazol-4-yl)-1,3-dihydro-benzoimidazol-2-one is prepared according to the procedures outlined in Example 337. 1,3-Dimethyl-5-(5-methyl-3-phenyl-1H-pyrazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (70.9 mg) is diluted with dichloromethane and is treated with triethylamine (0.1 mL) and acetyl chloride (0.05 mL). The mixture is allowed to stir for 20 minutes then is diluted with saturated sodium bicarbonate and extracted into dichloromethane. The organic layer is dried over sodium sulfate and concentrated to give 8 mg 5-(1-Acetyl-5-methyl-3-m-tolyl-1H-pyrazol-4-yl)-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:16][CH2:17][O:18]C2CCCCO2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:16][CH2:17][OH:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#CCCOC2CCCCO2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C#CCCO)CC1
Yield: 96 %

Procedure:
A solution of 4.5 g (13.4 mmol) of 4-[4-(Tetrahydro-pyran-2-yloxy)-but-1-ynyl]-piperidine-1-carboxylic acid tert-butyl ester and 1 g (4mmol) of pyrimidium toluene-4-sulfonate in 45 ml MeOH was stirred at 55° C. for 1 h. The reaction was partitioned between aqueous solution of 10% KHSO4 /ether (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl, dried over Na2SO4 and evaporated to give 3.26 g (97%) of 4-(4-Hydroxy-but-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester, MS: 254 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[O:8])[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:27][C:28]([Si](C)(C)C)([F:30])[F:29]>O1CCCC1>[F:27][C:28]([F:30])([F:29])[CH:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[OH:8]
Reactant: O=CC1CCOCC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(C1CCOCC1)C(F)(F)F
Yield: 47.1 %

Procedure:
According to Reference Example 8-12, by use of tetrahydro-2H-pyran-4-carbaldehyde (300 mg, 2.63 mmol) dissolved in tetrahydrofuran (6 mL), a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (0.526 mL, 0.526 mmol) and (trifluoromethyl)trimethylsilane (0.466 mL, 3.16 mmol), the mixture was stirred and reacted at room temperature for 1.7 hours. Then, purification by preparative thin-layer chromatography (hexane/ethyl acetate=4/1) was performed to give 2,2,2-trifluoro-1-(tetrahydro-2H-pyran-4-yl)ethanol (Compound EA) (228 mg, yield: 47%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[CH:10][N:11]=[C:5]2[N:4]=1.C([O-])(=O)C.[Na+].[Br:19]Br>C(O)(=O)C>[Br:19][C:9]1[N:6]2[N:7]=[CH:8][C:3]([C:2]([F:1])([F:12])[F:13])=[N:4][C:5]2=[N:11][CH:10]=1
Reactant: BrBr
Reactant: FC(F)(F)c1cnn2ccnc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1cnn2c(Br)cnc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.8 %

Procedure:
To a solution of 3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.2211 g, 1.18 mmol) in acetic acid (6 ml) was added sodium acetate (0.1470 g, 1.79 mmol), then bromine (90.8 μl, 1.76 mmol). The solution was stirred at room temperature for 6 h, then partitioned between saturated aqueous NaHCO3 (100 ml) and ethyl acetate (100 ml). The aqueous layer (pH 9) was further extracted with ethyl acetate (100 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 25% EtOAc/isohexane) to afford 0.2073 g (66%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 8.30 (1H, s), 8.83 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:7][N:6]1[C:2]([NH:1][C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:3]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]=[N:5]1
Reactant: CCOC(=O)CC(=O)Nc1cnn(C)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)Nc1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The crude residue containing ethyl 3-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-3-oxopropanoate was dissolved in N,N-dimethylformamide (20 ml), and trityl chloride (5.52 g) and triethylamine (4.14 ml) were added with stirring. The mixture was stirred overnight and quenched with water (10 ml). The whole mixture was extracted with ethyl acetate, and the extract was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residual oil, which was chromatographed on silica gel eluting with dichloromethane-ethyl acetate (2:3) to give ethyl 3-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropanoate (1.23 g).