Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10]N.CS[C:14]1[NH:15][S:16](=[O:21])(=[O:20])[CH2:17][CH2:18][N:19]=1>>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][C:14]1[NH:15][S:16](=[O:21])(=[O:20])[CH2:17][CH2:18][N:19]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC1=NCCS(=O)(=O)N1
Product: Cc1nc[nH]c1CSCCC1=NCCS(=O)(=O)N1
Yield: 32.7 %

Procedure:
A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (4.0 g.) and 3-methylthio-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide (4.2 g.) was heated in an oil bath at 140° for 4 hours. The product was chromatographed on a column of silica gel with ethyl acetate-ethanol (3:2) as eluant and finally recrystallised from ethanol-ether to give 3-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide (2.2 g.) m.p. 146°-147°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17]OS(C)(=O)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][N:23]=[N+:24]=[N-:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Dissolved 1-benzyloxycarbonyl-3-methanesulfonyloxymethyl-piperidine (5.24 mmol, 1 eq) in DMF (50 mL). Added sodium azide (1.7 g, 26.2 mmol, 5 eq). Warmed the mixture to 60° C. and let stir overnight. Removed the DMF under reduced pressure. Diluted the residue with ethyl acetate and washed with water and then brine. Dried the organic layer over anhydrous Na2SO4, filtered and concentrated giving 1.27 g. crude product.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1Br
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ncccc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.8 %

Procedure:
To a solution of 3-bromo-2-pyridinecarboxylic acid (available from Fluorochem Ltd, 0.81 g, 4.03 mmol) in DMF (10 ml) was added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.53 g, 4.03 mmol) and DIPEA (2.11 ml). The mixture was stirred at room temperature for 10 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (0.5 g, 2.01 mmol) was added and the mixture stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to 5 ml which was added to 2×50 g aminopropyl cartridges that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 2 h before being eluted with MeOH. The solvent was removed in vacuo to give a brown oil that was placed in the vacuum oven overnight. DCM was added to the oil and a precipitate occurred, which was collected by filtration to give the title compound (0.58 g) as a cream solid.
Reaction SMILES: CN(C(ON1N=N[C:11]2[CH:12]=[CH:13][CH:14]=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C.C(O)(=O)C[C:50](CC(O)=O)(C(O)=O)[OH:51]>ClCCl>[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][CH2:36][N:35]([C:50]([C:11]2([CH3:10])[CH2:12][CH2:13][CH2:14]2)=[O:51])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)C2(C)CCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (1.71 g), [1,4]diazepane-1-carboxylic acid tert-butyl ester (0.813 ml) and DIPEA (3.58 ml) were added to a solution of the product of example 104b (470 mg) in dichloromethane (20 ml). After stirring for 2 h at room temperature, the reaction mixture was poured in an aqueous citric acid solution (10%) and extracted with ethyl acetate. The organic layer was washed with a sat. aqueous NaHCO3 solution, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica in toluene/acetone [100/0→3/1 (v/v)] as eluent.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[CH3:19]O>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:19])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1
Reactant: Cc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Reactant: CO
Product: COc1ccc(C(=O)Cc2ccc(C)cc2)c(O)c1
Yield: 92.9 %

Procedure:
Using the previous procedure and starling from 1-(2,4-dihydroxyphenyl)-2-(4-methylphenyl)ethanone (7.51 g, 31.0 mmol) and methanol (1.32 mL, 32.55 mmol), 7.38 g (93%) of the title compound was obtained as a white solid: mp (EtOAc/hexane) 71-72° C.; IR (KBr) 1639, 1623, 1590, 1516, 1508, 1439, 1388, 1355, 1268, 1231, 1205, 1131, 10.33, 1010, 957, 800, 780, 571, 504, 491 cm−1; 1H NMR (400 MHz, CDCl3) δ 12.72 (br s, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.24-7.14 (m, 4H), 6.43-6.40 (m, 2H), 4.1.5 (s, 2H), 3.81 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDC3) δ 202.63, 166.56, 166.28, 137.14, 132.47, 131.71, 129.87, 129.61, 113.60, 108.20, 101.43, 55.98, 44.89, 21.48; HRMS calculated for C16H16NaO1(M+Na)+ 279.0997; found 279.0989.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][N:20]2[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:33])[C:3]1=[O:34].[CH2:36](Br)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C([O-])(=O)/C=C/C([O-])=O>>[CH3:32][C:28]1([CH3:31])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:33])[N:20]([CH2:19][CH2:18][CH2:17][N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:15][CH2:14][CH2:13][N:4]2[C:3](=[O:34])[C:2]([CH3:35])([CH3:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:12])[C:29]1=[O:30]
Reactant: CCCCCCBr
Reactant: CC1(C)C(=O)N(CCCNCCCN2C(=O)c3ccccc3C(C)(C)C2=O)C(=O)c2ccccc21
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: CCCCCCN(CCCN1C(=O)c2ccccc2C(C)(C)C1=O)CCCN1C(=O)c2ccccc2C(C)(C)C1=O

Procedure:
N,N-Bis-[3-(3,4-dihydro-4,4-dimethyl-1,3-dioxo-2(1H)-isoquinolyl)-propyl]-n-hexylamine was prepared analogous to Example 27 from 2.6 gm of N,N-bis-[3-(3,4-dihydro-4,4-dimethyl-1,3-dioxo-2(1H)-isoquinolyl)-propyl]-amine and 1 gm of n-hexyl bromide. M.p. of the fumarate: 137°-138° C; yield: 1.7 gm (50% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:11])[C:9]=1[Cl:10])=[O:4].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][Br:12])[C:9]=1[Cl:10])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1scc(C)c1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1scc(CBr)c1Cl
Yield: 54.2 %

Procedure:
3-Chloro-4-methyl-2-thiophenecarboxylic acid methyl ester (3.81 g) was dissolved in carbon tetrachloride (40 mL). To the solution, N-bromosuccinimide (3.56 g) and α,α′-azobisisobutyronitrile (200 mg) were added, and the mixture was heated under reflux for 2.5 hours. The insoluble material was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate hexane=1:19→1:9), to thereby give the title compound (2.92 g) as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[CH:11]([N-]C(C)C)(C)C.[Li+].CI.O>C1COCC1>[CH3:11][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: COC(=O)C1CCOCC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Methyl tetrahydropyran-4-carboxylate (2.88 g, 20.0 mmol) was dissolved in THF (100 mL), and a 2.0 mol/L solution of lithium diisopropylamide in THF (22.0 ml, 44.0 mmol) was added thereto at 0° C., followed by stirring at room temperature for 30 minutes. Methyl iodide (4.98 ml, 40.0 mmol) was added dropwise to the reaction mixture, followed by stirring for 1 hour. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford methyl 4-methyltetrahydropyran-4-carboxylate (1.93 g, 61%).
Reaction SMILES: O(Cl)Cl.[Ti:4].[C:5]([OH:10])(=[O:9])[C:6]([OH:8])=[O:7].[OH-].[NH4+:12]>>[C:5]([O-:10])(=[O:9])[C:6]([O-:8])=[O:7].[NH2:12][Ti+3:4].[C:5]([O-:10])(=[O:9])[C:6]([O-:8])=[O:7].[C:5]([O-:10])(=[O:9])[C:6]([O-:8])=[O:7].[NH2:12][Ti+3:4]
Reactant: [Ti]
Reactant: [NH4+]
Reactant: O=C(O)C(=O)O
Agent: ClOCl
Agent: [OH-]
Product: N[Ti+3]
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
A titanium oxychloride solution (about 383.2 g, 12.5% by weight titanium 1.0 mole), was prepared and was added rapidly to the oxalic acid slurry with stirring at a temperature of from about 40 to about 60 degrees C. The resulting clear solution was cooled to about 25 degrees C. Concentrated ammonium hydroxide solution was added dropwise over a period of about 40 minutes at a temperature of from 25 to 30 degrees C. to provide a white slurry with a pH of about 9. The slurry was stirred for 30 minutes while the pH was maintained at about 9.0 by the addition of small increments of ammonium hydroxide. The total amount of concentrated ammonium hydroxide (29.5% NH3) consumed was about 410.9 g (7.12 moles). The white slurry was filtered and the filter cake washed with six 400 ml displacement washes of 2% ammonium hydroxide. The wet cake was dried at about 120 degrees C. in a vacuum oven to provide approximately 156.5 g of amino titanium oxalate.
Reaction SMILES: F[C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([F:21])[CH:14]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH3:38])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29]CCCCCN(C)C.[K]>CN(C)C=O>[CH3:22][N:23]([CH3:38])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([F:21])[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(F)cc(-c2nc(-c3ncccc3F)no2)c1
Reactant: CN(C)CCCCCOCCCCCN(C)C
Agent: [K]
Solvent: CN(C)C=O
Product: CN(C)CCCCCOc1cccnc1-c1noc(-c2cc(F)cc(C#N)c2)n1

Procedure:
Alternatively, treatment of 3-(3-fluoropyrid-2-yl)-5-(3-fluoro-5-cyanophenyl)-1,2,4-oxadiazole with potassium 5-dimethylaminopentyloxide in N.N-dimethylformamide with a catalytic amount of 1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane (18-crown-6) and heating at 110° C. affords crude product. Standard work up and purification by one or more methods, including silica gel chromatography, recystallization, trituration, and reversed-phase high-performance liquid chromatography (RP-HPLC) affords purified 3-(3-(5-dimethylaminopentyloxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]2)=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([N:25]([CH:35]2[CH2:37][CH2:36]2)CC2C=CC(OC)=CC=2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.FC(F)(F)C([O-])=O>ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]2)=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([NH:25][CH:35]2[CH2:36][CH2:37]2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(CO)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCOC(CO)C2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.5 %

Procedure:
To a round bottom flask charged with (+/−)-2-((2-chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (35.2 mg, 0.06 mmol) in dichloromethane (200 μl) was added anisole (32.8 μl, 0.300 mmol), followed by trifluoroacetic acid (185 μl, 2.400 mmol). The reaction mixture was stirred at room temperature ON. LCMS indicated primarily the trifluoroacetate product was present. Excess TFA was removed in vacuo. The residue was treated with toluene and concentrated in vacuo (2×). The crude solid was treated with 2 N NH3/MeOH (˜1.5 mL)—a solid immediately precipitated out. After 20 min, the solid was isolated by vacuum filtration. LCMS indicated the solid was the desired alcohol product. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 15-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. (+/−)-2-((2-Chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.5 mg) was isolated.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:10][OH:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH:1]([C:4]1[C:5]([CH:10]=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccnc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)c1cccnc1C=O
Reaction time: 18 h
Yield: 61.7 %

Procedure:
To a vigorously stirred solution of (3-isopropyl-pyridin-2-yl)-methanol (26 g, 170 mmol) in CH2Cl2 (575 mL) was added MnO2 (105 g, 1.20 mol) under N2. The mixture was stirred for 18 h then filtered through a celite pad and concentrated in vacuo. Purification by column chromatography on silica gel (EtOAc/hexanes, 1:3) afforded 3 -isopropyl-pyridine-2-carbaldehyde (15.65 g, 61%) as an orange oil. 1H NMR(CDCl3) δ 1.26 (d, 6H, J=7.0 Hz), 4.17 (sep, 1H, J=6.6 Hz) 7.45 (dd, 1H, J=7.9, 4.4 Hz), 7.84 (d, 1H, J=7.9 Hz), 8.56 (dd, 1H, J=4.4, 1.3 Hz), 10.2 (s, 1H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:23]=[C:22]([S:24][NH2:25])[S:21][N:20]=1.C(=O)(O)[O-].[Na+]>COCCOC>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:23]=[C:22]([S:24]([NH2:25])=[O:6])[S:21][N:20]=1
Reactant: NSc1nc(-c2ccccc2Cl)ns1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: NS(=O)c1nc(-c2ccccc2Cl)ns1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
A solution of 3.45 g of 85% m-chloroperoxybenzoic acid in 100 ml of DME was added to a solution of 4 g of 3-(2-chlorophenyl)-1,2,4-thiadiazole-5-sulfenamide in 150 ml of DME at -70° C. over an hour. The resulting solution was stirred for 2 hours at -70° and thereafter warmed to room temperature. Concentration gave a solid which was stirred with 100 ml of sodium bicarbonate solution overnight. The solid was collected and the filtrate was extracted with ethyl acetate/dichloromethane. Concentration gave 0.7 g of solid which was recrystallized in benzene to give 0.52 g of solid, m.p. 130°-131°.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([NH:15][C:16](=[O:22])OC(C)(C)C)[CH:9]=[CH:8]2)[CH3:3].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31](C(O)=O)=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1.CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C>FC(F)(F)C(O)=O.CN(C)C=O.C(OCC)(=O)C>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:16]([NH:15][C:10]3[CH:9]=[CH:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH:6]=4)[CH:11]=3)=[O:22])=[CH:34][CH:35]=2)=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccccc1-c1ccc(Cl)cc1
Reactant: CN(C)Cc1ccc2cc(NC(=O)OC(C)(C)C)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1ccc2cc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
The tert-butyl 6-[(N,N-dimethylamino)methyl]-2-naphthylcarbamate (237 mg, 0.789 mmol) obtained in Reference Example 1 was dissolved in trifluoroacetic acid (4 ml), the solution was stirred at room temperature for 1 hour, and the solvent was concentrated under reduced pressure. To the residue were added ethyl acetate and an aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue, 4′-chlorobiphenylcarboxylic acid (184 mg, 0.789 mmol) and dimethylaminopyridine (96.4 mg, 0.789 mmol) were dissolved in N,N-dimethylformamide (4 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.789 mmol) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction solution were added ethyl acetate and an aqueous potassium carbonate solution, the mixture was extracted, the organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by alumina column chromatography (developing solvent: ethyl acetate), and the insolubles were crystallized from a mixed solution of ethyl acetate and diisopropyl ether (1:5) to obtain the titled compound (207 mg) as a white powder.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40](O)=[O:41])=[CH:33][C:32]=2[Cl:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=O)C.[NH2:47][C:48]([CH3:68])([CH3:67])[C:49]([N:51]1[CH2:56][CH2:55][N:54](C(OCC2C=CC=CC=2)=O)[CH2:53][CH2:52]1)=[O:50].C(N1CCNCC1)C1C=CC=CC=1>>[Cl:43][C:32]1[CH:33]=[C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:41])[NH:47][C:48]([C:49]([N:51]2[CH2:52][CH2:53][NH:54][CH2:55][CH2:56]2)=[O:50])([CH3:68])[CH3:67])[CH:35]=[CH:36][C:31]=1[CH2:30][C:29]1[C:25]([O:24][C@@H:6]2[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]2[OH:4])=[N:26][NH:27][C:28]=1[CH:44]([CH3:46])[CH3:45]
Reactant: CC(C)(N)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: c1ccc(CN2CCNCC2)cc1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)N2CCNCC2)cc1Cl

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-2-chlorophenyl}methyl)-5-isopropyl-1H-pyrazole and 1-(2-amino-2-methylpropionyl)-4-(benzyloxycarbonyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzyl-piperazine, respectively.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([S:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH:6]=1)[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].[OH-].[K+]>N1C=CC=CC=1.CO>[CH2:1]([NH:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:23]([CH3:22])(=[O:25])=[O:24])=[C:7]([S:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Reactant: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Product: CCNC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A mixture of N-ethyl-4-amino-3-(2,4-difluorophenylthio)benzamide (0.84 g) and methanesulfonyl chloride (0.57 g) in pyridine (5 ml) was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid, dried and evaporated. The residue obtained was dissolved in methanol and treated with potassium hydroxide (0.4 g). The solution was concentrated and the residue was dissolved in water. The aqueous solution was acidified with dilute hydrochloric acid and extracted with chloroform. The extract was washed with water, dried, and evaporated. The residual solid was recrystallized from ethanol to give N-ethyl-3-(2,4-difluorophenylthio)-4-(methanesulfonamido)benzamide (0.67 g).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.[CH2:8]1[O:10][CH2:9]1>[Cr].CC(CC(C)C)=O>[OH:10][CH2:9][CH2:8][N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7]
Reactant: C1CO1
Reactant: O=C1CCC(=O)N1
Agent: [Cr]
Solvent: CC(=O)CC(C)C
Product: O=C1CCC(=O)N1CCO

Procedure:
N-2-Hydroxyethyl succinimide was prepared by reacting 49.5g (0.5 mole) of succinimide with 26.5g (0.60 mole) of ethylene oxide in the presence of 0.49g (1%) of active chromium III tri-2-ethylhexanoate and 400 ml of methylisobutyl ketone for 2 hours at 160° to 165°C in an autoclave. N-2-Hydroxyethyl succinimide was obtained by filtration in 87.5% yield. The reaction did not proceed in the absence of COT.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Br:9]Br>ClCCCC>[Br:9][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: BrBr
Reactant: COC(=O)CC(C)=O
Solvent: CCCCCl
Product: COC(=O)CC(=O)CBr
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
In 2613 g of 1-chlorobutane was dissolved 523 g of methyl acetoacetate and cooled to 0° C. To this mixture was dropwise added 719 g of bromine at 5±5° C. over a period of one hour, and the mixture was thereafter kept at that temperature for four hours. The reaction mixture was washed with 1161 g of a 10% saline solution. After separating the mixture into an aqueous and organic layers, concentration of the organic layer in vacuous at a temperature of 40° C. or less gave 782.9 g of crude methyl 4-bromoacetoacetate. The gas chromatography analysis indicated that the content of methyl 4-bromoacetoacetate in the crude product was 72% (564 g, 64% yield).