Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][N:11]([C:26]3[N:27]=[CH:28][C:29]4[C:34]([C:35]=3[CH3:36])=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:12]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=2)[CH:3]=[CH:2]1.[Cl:37]N1C(=O)CCC1=O>O1CCCC1>[Cl:37][C:3]1[C:4]2[C:9](=[CH:8][C:7]([CH2:10][N:11]([C:26]3[N:27]=[CH:28][C:29]4[C:34]([C:35]=3[CH3:36])=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)(=[O:14])=[O:13])=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3cc[nH]c3c2)c2ncc3ccccc3c2C)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(Cl)c[nH]c3c2)c2ncc3ccccc3c2C)cc1
Reaction time: 17 h
Yield: 64.5 %

Procedure:
To a solution of ethyl 4-{[(1H-indol-6-ylmethyl)(4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate (177 mg, 0.36 mmol) prepared in Example 116 in tetrahydrofuran (1.8 mL) was added N-chlorosuccinimide (57 mg, 0.43 mmol) at room temperature, and the mixture was stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→1:1) to give ethyl 4-{[[(3-chloro-1H-indol-6-yl)methyl] (4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate (124 mg, 65%) as a white solid.
Reaction SMILES: [CH2:1]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24](Cl)=[O:25])[CH:19]=1.C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([N:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][C:11]([F:12])([F:13])[F:14])=[O:25])[CH:19]=1
Reactant: FC(F)(F)CNCCc1ccccc1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: O=C(c1cc(Cl)ncn1)N(CCc1ccccc1)CC(F)(F)F
Reaction time: 2 h

Procedure:
0.80 g (3.94 mmol) phenethyl-(2,2,2-trifluoroethyl)-amine and 3.9 mL (3.9 mmol) of a 1M sodium hydroxide solution were added dropwise to 0.77 g (4.33 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 20 mL dichloromethane while cooling with a bath of ice and ethanol. The mixture was first stirred for 2 h with cooling and then for 1 h at RT. 50 mL of a saturated sodium hydrogen carbonate solution were added and the mixture was stirred for 10 min. The organic phase was separated off, washed with water and 1M hydrochloric acid, dried on sodium sulphate, filtered and concentrated by rotary evaporation i.vac.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14](P(OCC)(OCC)=O)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:27]([C:29]1[C:30]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:34]=1)=O>C1COCC1>[CH2:3]([O:10][C:11]([NH:13]/[C:14](=[CH:27]\[C:29]1[C:30]([NH:41][C:42]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:48])=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:34]=1)/[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(OCC)C(NC(=O)OCc1ccccc1)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cc(-c2ccccc2)cnc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44.3 %

Procedure:
To a slurry of 60% of sodium hydride (156 mg, 3.90 mmol) in THF (8 niL) at 0° C. was added 1A (1.2 g, 3.34 mmol) in several portions over 10 min. The reaction mixture was then brought to RT for 20 min, then cooled again at 0° C. A suspension of 1D (830 mg, 2.78 mmol) in THF (10 mL) was added over 10 min at 0° C., then the reaction was warmed up to RT. After stirring for 20 min, the reaction was quenched with water (30 mL). The aqueous layer was extracted with EtOAc (50 mL×2). The combined organics were dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with CH2Cl2-hexanes to give the title compound (620 mg). The mother liquid was concentrated and the resulting residue was purified by silica gel (110 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give additional 130 mg of the title compound (total 750 mg, 54%) as an off-white solid. LC/MS (method A): retention time=3.40 min, (M+H)+=504.
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][C:20](=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:9]=1>C(OCC)(=O)C>[CH3:36][Si:33]([CH3:34])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:38])([CH3:37])[CH3:1])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: CCOC(=O)C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1

Procedure:
To a 50 mL roundbottom flask is charged ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)-methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate (800 mg, 1.43 mmol) and ethyl acetate (15 mL). The flask is flushed with argon and 5% palladium on carbon (100 mg) is added. The flask is sealed and degassed under vacuum.
Reaction SMILES: Cl.[F:2][C:3]1([F:20])[CH2:8][CH2:7][CH:6]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>C(Cl)Cl>[F:20][C:3]1([F:2])[CH2:4][CH2:5][CH:6]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:30]([O:31][CH3:32])=[O:33])[CH2:7][CH2:8]1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(CC2CCC(F)(F)CC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(CC2CCC(F)(F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.5 %

Procedure:
Methyl 2-((4,4-difluorocyclohexyl)methyl)piperidine-4-carboxylate hydrochloride (5.1 g, 16.36 mmol) was dissolved in DCM (150 mL), then DIPEA (7.14 mL, 40.89 mmol) was added. Methyl carbonochloridate (1.803 mL, 22.90 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 2 h. The mixture was washed with 0.1 M HCl (100 mL) and satd NaHCO3 (100 mL), then dried through a phase separator and evaporated yielding crude dimethyl 2-((4,4-difluorocyclohexyl)methyl)piperidine-1,4-dicarboxylate (5.7 g, 105%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[C:28]3[F:50])[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:38]([O:37][C:36]([N:35]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:54])=[O:53])[NH:1][C:58](=[O:59])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][CH:33]=2)[C:28]([F:50])=[CH:29][N:30]=1)[C:43](=[O:44])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:42])([CH3:40])([CH3:39])[CH3:41]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c2)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)ccc1[C@@H](C)CO
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 34.5 %

Procedure:
To a solution of 19A (135 mg, 0.168 mmol) in acetonitrile (6 mL) and dichloromethane (3 mL) at 0° C., was added phosgene solution (20% in toluene, 0.106 mL, 0.201 mmol) dropwise. The mixture was stirred at 0° C. for 40 min, then at rt for 10 min. Extra phosgene was removed by bubbling Ar for 20 min. The crude was redissolved in acetonitrile (1.0 mL) and dichloromethane (1.0 mL), and was added dropwise via syringe pump into a solution of TEA (0.187 mL, 1.340 mmol) in dichloromethane (60 mL) at rt over 3.0 h. The solution was stirred at rt over night. The solvent was removed and the crude residue was purified using a prep HPLC equipped with a C18 PHENOMENEX® Luna Axia column (30 mm×75 cm, 5μ). The desired fractions were collected and concentrated to give a mixture of diastereoisomers (114 mg). The diastereoisomers were separated by a prep chiral HPLC [(R,R)-Whelk-01 250×21.1 mm column] to give 19B (48 mg, 0.058 mmol, 34.4% yield). MS (ESI) m/z: 832.6 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]2.[Br:16]Br.O>Br>[Br:16][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][C:2]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]1)[CH2:3]2
Reactant: O=C1NC(=O)C2(Cc3ccccc3C2)N1
Reactant: BrBr
Agent: Br
Solvent: O
Product: O=C1NC(=O)C2(Cc3ccc(Br)cc3C2)N1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of (±)-spiro[imidazolidine-4,2′-indane]-2,5-dione (1.0 g, 4.97 mmol) in 48% HBr (30 mL) was added Br2 (3.1 g, 19.9 mmol) and the reaction mixture was allowed to stir at ambient temperature for 4 days. The reaction was poured onto ice (30 g) and H2O (10 mL) and the solid precipitate filtered off, washed with H2O (4×20 mL), and dried in vacuo to give the title compound as a light brown solid. MS: m/z=282 (M+1).
Reaction SMILES: O=[C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17])[C:3]([OH:5])=[O:4].[CH3:18][NH2:19].C(O)(=O)C.[ClH:24]>C(O)C.[Pd]>[ClH:24].[CH3:18][NH:19][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17])[C:3]([OH:5])=[O:4]
Reactant: CN
Reactant: COc1cccc(C=CC(=O)C(=O)O)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CNC(CCc1cccc(OC)c1OC)C(=O)O
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
70.0 g of 2-keto-4-(2,3-dimethoxyphenyl)-3-butenoic acid (0,30 moles) dissolved in 700 ml of ethanol are placed into a hydrogenator, then 43.0 g of an 8.03M (0.34 mole) methylamine solution and glacial acetic acid under nitrogen atmosphere are added to pH from 8 to 9, keeping the temperature below 25° C. Stirring is continued for about 15 minutes, then 14.0 g of 5% Pd/C (about 50% humidity) are added, under hydrogen pressure (40 psi, room temperature) for 6 hours. The reaction mixture is then adjusted to markedly acid pH with concentrated HCl, filtered and the solution is evaporated to dryness. The resulting solid is taken up and triturated with heating (50° C.) with 300 ml of acetone, then it is left to cool under stirring, filtered and dried under vacuum at 40° C. Yield: 51 g, 60% (moles), 73%(weight); TLC: methylene chloride/methanol/acetic acid 75/20/10; Rf=0,5; Developer: ninhydrin. M.p.=165°-166° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cn2)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)cn2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 4-(5-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound 26.1, 1 g, 2.80 mmol, 1.00 equiv), zinc cyanide (400 mg, 3.42 mmol, 1.22 equiv), Pd(PPh3)4 (200 mg, 0.17 mmol, 0.06 equiv) in DMF (50 mL) was stirred under nitrogen for 2 h at 100° C. After cooling to room temperature, the reaction was then quenched by careful addition of 300 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×100 mL of ethyl acetate. The combined organic layers were washed with 1×100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:4) yield 0.5 g (58%) of the title compound as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:17])([C:10]1[N:14]([CH3:15])[C:13](=[O:16])[O:12][N:11]=1)[CH3:9])(C)(C)C.[ClH:19].O1CCOCC1>C(O)C>[ClH:19].[NH2:7][C:8]([C:10]1[N:14]([CH3:15])[C:13](=[O:16])[O:12][N:11]=1)([CH3:9])[CH3:17]
Reactant: Cn1c(C(C)(C)NC(=O)OC(C)(C)C)noc1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cn1c(C(C)(C)N)noc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of [1-methyl-1-(4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (1.45 g, 5.64 mmol) in ethanol (15 mL) was added 4M-HCl in dioxane (5.64 mL, 22.5 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The solution was concentrated in vacuo to a volume of 5 mL. With stirring diethyl ether (15 mL) was added drop by drop over a period of 30 minutes and stirring was continued for another 30 minutes. The precipitate was isolated by filtration, washed with diethyl ether (3×1 mL) and dried in vacuo, to give the title compound (1.0 g, 95%) as white solid; GC-MS (EI) 157.0 (M)+.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[NH:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[O:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[C:7]([NH2:9])=[NH:8].[CH3:26][S:27]([O:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:43])[NH2:42])[CH:37]=2)[CH:32]=1)(=[O:29])=[O:28].C1CCC(N=C=NC2CCCCC2)CC1>N1C=CC=CC=1>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:26][S:27]([OH:30])(=[O:29])=[O:28].[NH:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[O:22][C:21]([C:23]([O:25][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:42])[NH2:43])[CH:37]=4)[CH:32]=3)=[O:24])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[C:7]([NH2:9])=[NH:8]
Reactant: N=C(N)Nc1ccc(CCc2ccc(C(=O)O)o2)cc1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: N=C(N)Nc1ccc(CCc2ccc(C(=O)Oc3ccc4cc(C(=N)N)ccc4c3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To 2.9 g of 5-(p-guanidinophenylethyl)-furan-2-carboxylic acid methanesulfonate, 2.2 g of 6-amidino-2-naphthol methanesulfonate and 1.9 g of DCC was added 15 ml of anhydrous pyridine. The reaction mixture was stirred overnight at room temperature. The insolubles were filtered off and the filtrate was added to 100 ml of ethyl ether with stirring. Decantation is conducted to remove the ethyl ether. After repeating the procedure several times, the filtrate was dissolved in a small amount of methanol and the resulting solution was added to a saturated aqueous sodium hydrogencarbonate solution while stirring. The insolubles which were precipitated were collected by filtration and washed with water and acetone. The precipitate was suspended in a small amount of methanol and methanesulfonic acid was added to the resulting suspension. The insolubles were filtered off and the filtrate was added with stirring to 100 ml of ethyl ether. The ethyl ether was removed by decantation. After repeating the procedure several times, acetone was added to the filtrate. The mixture was stirred and decanted to remove the acetone. To the resulting mixture was added a small amount of ethanol and isopropanol and stirred. A pale yellow solid which was precipitated was collected by filtration to give 2.5 g of 6-amidino-2-naphthyl 5-(p-guanidinophenylethyl)-furan-2-carboxylate dimethanesulfonate.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[CH2:22]([N:24]=[C:25]=[S:26])[CH3:23]>>[CH2:22]([NH:24][C:25]([NH:21][NH:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:11]=[CH:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[CH:14]=1)=[O:19])=[S:26])[CH3:23]
Reactant: CSc1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Reactant: CCN=C=S
Product: CCNC(=S)NNC(=O)c1ccc2ncn(-c3ccc(SC)cc3)c2c1
Yield: 90 %

Procedure:
In the same manner as in Reference Example 115 and using 1-[4-(methylthio)phenyl]-1H-benzimidazole-6-carbohydrazide instead of 3-[4-(methylthio)phenyl]-1-benzofuran-5-carbohydrazide and ethyl isothiocyanate instead of methyl isothiocyanate, the title compound (yield 90%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32]>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:1]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:17])=[O:18])[CH:13]=[CH:12][C:11]=1[O:20][C:31](=[O:32])[N:30]([CH3:34])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(O)c(C(=O)OCc2ccccc2)c1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C(=O)Oc1ccc(S(C)(=O)=O)cc1C(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
A mixture of 1 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid benzyl ester, 1.5 mmol of N-methylmorpholine and 0.2 mmol of 4-dimethylaminopyridine in 4 ml of dimethylformamide was treated with 1.3 mmol of N,N-dimethyl-carbamoylchloride. The reaction mixture was stirred at 60° for 48 hours, concentrated in vacuo and the residue taken up in 5 ml of water. Acidification with diluted hydrochloric acid and extraction with ethyl acetate yielded a crude product which was purified by chromatography (SiO2; ethyl acetate/cyclohexane 1.1). MS (m/e): 378.3 (MH+, 100%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[C:15]([NH:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccccc1-c1ccc(F)cc1
Solvent: ClCCl
Product: O=C(NC(=S)Nc1ccccc1-c1ccc(F)cc1)c1ccccc1

Procedure:
A mixture of 2-amino-4'-fluorobiphenyl (1.5 g) and benzoylisothiocyanate (1.3 g) in dichloromethane (20 ml) was heated under reflux for 6 hours to yield N-benzoyl-N'-(4'-fluoro-2-biphenylyl)thiourea as a colourless solid (m.p. 123°-124° C.).
Reaction SMILES: CO[C:3]([C:5]1[N:9]=[C:8]([CH2:10][CH3:11])[O:7][N:6]=1)=[O:4].[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH2:10]([C:8]1[O:7][N:6]=[C:5]([C:3]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:19][CH:20]=2)=[O:4])[N:9]=1)[CH3:11]
Reactant: CCc1nc(C(=O)OC)no1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Product: CCc1nc(C(=O)NCCc2ccc(S(N)(=O)=O)cc2)no1

Procedure:
Following the procedure of Example 1A, 5-ethyl-1,2,4-oxadiazol-3-carboxylic acid methyl ester is reacted wth p-(β-aminoethyl)-benzenesulfonamide to yield p-[β-(5-ethyl-1,2,4-oxadiazole-3-carbonylamino)ethyl]-benzenesulfonamide in almost quantitative yield, M.P. 159°-160°C. The compound can be recrystallized from methanol.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(OCC)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([Cl:18])=[CH:20][CH:21]=2)[NH2:10])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: NN(C(=O)c1ccc(Cl)cc1)c1ccc(Br)cc1
Reaction time: 16 h

Procedure:
A mixture consisting of 44.7 g. (0.20 mole) p-bromophenylhydrazine hydrochloride, 250 ml. diethyl ether, 70 ml. (0.504 mole) triethylamine, and 35.0 g. (0.20 mole) p-chlorobenzoyl chloride in 50 ml. diethyl ether (mixed in that order at -5° to -15°C. during 20 minutes) was stirred continuously for about 16 hrs. at about 25° C. The reaction mixture was filtered, and the solids on the filter were washed with water and then recrystallized from 95% ethanol. There was thus obtained 15.5 g. p-chlorobenzoic acid (p-bromophenyl)hydrazide having a melting point of 185° C. (dec.). An analytical sample melting at 184.5°C. (dec.) was obtained after two recrystallizations from ethyl acetate.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[Br:14][CH2:15][CH2:16][CH2:17][OH:18].CCOC(C)=O>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][O:18][Si:10]([CH3:13])([CH3:12])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCBr
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 21.8 %

Procedure:
Imidazole (0.52 g, 7.6 mmol) and t-butyldimethylchlorosilane (5.80 g, 38 mmol) were added successively to a solution of 1-bromo-3-propanol (5.35 g, 38 mmol) in dry THF (10 mL) at room temperature. The resulting suspension was stirred at room temperature for 20 hours. EtOAc (25 mL) was added. The solution was washed with water, dried over Na2SO4, filtered and concentrated in vacuo at room temperature. The residue was chromatographed on silica gel eluting with 1:10 EtOAc:Hex to give the title compound 2.1 g (22%) as a colorless volatile liquid. 1H NMR (300 MHz, CDCl3) δ 3.74 (t, J=5.7 Hz, 2H), 3.52 (t, J=6.5 Hz, 2H), 2.02-2.06 (mult, 2H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 60.6, 35.7, 30.8, 26.1, −5.2.