Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([Sn](C)(C)C)=[CH:3][CH:2]=1.N#N.Br[C:15]1[C:19]([Br:20])=[CH:18][S:17][CH:16]=1.CCOC(C)=O>C1(C)C=CC=CC=1.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>[Br:20][C:19]1[C:15]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)=[CH:16][S:17][CH:18]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: Brc1cscc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cscc2Br)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Through a solution of p-tolyltrimethyltin (3.17 g, 12.4 mmol) in dry toluene (8 mL) was bubbled N2 for 5 min to degas the solution. To this was added 3,4-dibromothiophene (2.31 g, 9.56 mmol) and a catalytic amount of Pd(PPh3)4 (552 mg, 5 mol %). The reaction mixture was brought to reflux (120° C.) and left overnight. The reaction was cooled to rt and the toluene and replaced by EtOAc. The insoluable salts were removed by filtration through a plug of celite. The product was purified by flash chromatography on a silica column eluting with hexane to afford 1.09 g (45%) of the titled compound as a clear, colorless oil.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][CH2:12][NH:13]CC1C=CC(C#N)=CC=1)[CH3:9].C(C1C=CC(C=O)=CC=1)#N.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH:41]=O)=[CH:36][CH:35]=1>>[ClH:33].[ClH:1].[ClH:33].[NH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][CH2:12][NH:13][CH2:41][CH2:40][C:37]1[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=1)[CH3:9]
Reactant: O=CCc1ccc(Cl)cc1
Reactant: CN(CCCN)CCCNCc1ccc(C#N)cc1
Agent: Cl
Agent: N#Cc1ccc(C=O)cc1
Product: CN(CCCN)CCCNCCc1ccc(Cl)cc1
Yield: 51 %

Procedure:
In a similar manner to that described above, N-{3-[N-(3-aminopropyl)-N-methylamino]propyl}-p-cyanobenzylamine trihydrochloride (81% yeild) and N-{3-[N-(3-aminopropyl)-N-metylamino]propyl}-2-(p-chlorophenyl)ethylamine trihydrochloride (51% yield) were obtained from p-cyanobenzaldehyde and p-chlorophenylacetaldehyde, respectively. The physicohemical properties of these compounds were as shown in Table 8.
Reaction SMILES: [N:1]1([C:6]2[C:15]3[C:10](=[N:11][C:12](Cl)=[C:13]([Cl:16])[N:14]=3)[N:9]=[C:8](Cl)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C.[NH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>O1CCOCC1>[Cl:16][C:13]1[N:14]=[C:15]2[C:10](=[N:11][C:12]=1[N:23]1[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]1)[N:9]=[C:8]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[N:7]=[C:6]2[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1nc(N2CCCC2)c2nc(Cl)c(Cl)nc2n1
Reactant: OC1CCNCC1
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: OC1CCN(c2nc3nc(N4CCNCC4)nc(N4CCCC4)c3nc2Cl)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
a)+b) 80 mg (0.26 mmol) 4-pyrrolidin-1-yl-2,6,7-trichloro-pteridine are dissolved in 5 ml dioxane and combined with 29 mg (0.29 mmol) 4-hydroxypiperidin and 49 μl (0.37 mmol) diisopropylethylamine. The mixture is stirred for approx. 16 h at 40° C. The reaction mixture is then slowly added dropwise to a solution of 113 mg (1 mmol) piperazine in 15 ml dioxane at a temperature of 80° C. The mixture is stirred for approx. 16 h at 80° C., cooled to ambient temperature and then poured onto ice water. It is extracted with dichloromethane, the organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The residue is taken up in some dichloromethane and combined with petroleum ether, the precipitate formed is suction filtered. Yield 58 mg (53% of theoretical).
Reaction SMILES: C(OC([NH:8][CH:9]([C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O)(C)(C)C.C(#N)C.[NH2:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:45])[C:28]([C:42]([OH:44])=[O:43])=[CH:29][N:30]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]>C(N(CC)CC)C>[NH2:24][C:25]1[C:34]([F:35])=[C:33]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH:9]([NH2:8])[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH2:17]2)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:45])[C:28]([C:42]([OH:44])=[O:43])=[CH:29][N:30]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]
Reactant: CC(C)(C)OC(=O)NC(c1cccnc1)[C@@H]1CCNC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1c(F)c(N2CC[C@@H](C(N)c3cccnc3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 32.8 %

Procedure:
3-(R)-[1Tert-butoxycarbonylamino-1-(3-pyridyl)methyl)pyrrolidine [F2] (0.461 mmol) was added to an acetonitrile suspension (5 ml) of 5-amino-6,7,8-trifluoro-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (156 mg, 0.493 mmol) and the mixture was heated under reflux for 19 hours in the presence of triethylamine (0.5 ml). After cooling, the solvent of the reaction solution was evaporated under a reduced pressure. The resulting residue use dissolved in chloroform (50 ml) this was washed with 10% citric acid (40 ml) and saturated brine (40 ml) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was mixed with concentrated hydrochloric acid (5 ml) under ice-cooling, further mixed with 1 mol/l hydrochloric acid aqueous solution (5 ml) at room temperature and then washed with chloroform (50 ml×5). This hydrochloric acid aqueous solution was adjusted to an alkaline liquid property by adding 10 mol/l sodium hydroxide aqueous solution, further adjusted to a liquid property of pH 7.4 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then extracted with chloroform (150 ml×3). The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under a reduced pressure to obtain the crude title compound as light yellow crystals. This was purified by recrystallizing from ethanol to obtain 71.5 mg (32%) of the title compound.
Reaction SMILES: C([N:4]([C:6](=O)[CH2:7][O:8][CH2:9][C:10]1[NH:11][C:12]([CH3:33])=[C:13]([C:29]([O:31][CH3:32])=[O:30])[CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH2:5])(=O)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1.[C:57](#N)[CH3:58]>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[CH:14]1[C:13]([C:29]([O:31][CH3:32])=[O:30])=[C:12]([CH3:33])[NH:11][C:10]([CH2:9][O:8][CH2:7][C:6]2[S:44][C:57]([CH3:58])=[N:5][N:4]=2)=[C:15]1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C1=C(COCC(=O)N(N)C(C)=O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CC#N
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CCOC(=O)C1=C(COCc2nnc(C)s2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-acetyl-2-{[4-(2,3-dichlorophenyl)-3ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetylhydrazine (1.50 g) and Lawesson's reagent (1.18 g) in acetonitrile (50 ml) was stirred at room temperature for 24 hours and then evaporated. The residue was purified by chromatography on silica (t.l.c. grade, 20 g) using dichloromethane plus 40% v/v n-hexane followed by dichloromethane plus 0-1% v/v methanol as eluant. Appropriate fractions were combined and evaporated and residual oil triturated with diethyl ether. The resulting solid was collected, washed with diethyl ether and dried to give the title compound (0.82 g), m.p. 140°-144° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH:21](B1OC(C)(C)C(C)(C)O1)=[CH2:22]>>[CH2:21]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1)[CH3:22]
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Product: CCc1nc(Nc2cc(C)[nH]n2)cc2cc(OC)ccc12

Procedure:
Similar procedure as described in example 330 was used, starting (1-Chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and ethenylboronic acid pinacol ester to give (1-Ethyl-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 283(MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:5]([CH2:17][CH3:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[O:26])[CH:20]=1)[CH3:2].CO.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:17]([C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[CH:20]=1)[CH3:18]
Reactant: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(C=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(CO)c1
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A solution of 2′,6′-diethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde (2.86 g, 7.64 mmol) in a mixed solvent of methanol (8 mL) and tetrahydrofuran (16 mL) was ice-cooled, sodium borohydride (90%, 0.161 g, 3.82 mmol) was added, and the mixture was stirred for 2 hr under nitrogen atmosphere. The reaction mixture was treated with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:80-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (2.41 g, yield 84%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C@H:9]([CH2:10]I)[C@H:8]([NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]1=[O:22].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C)C=O>[N:29]([CH2:10][C@H:9]1[N:6]([CH2:5][C:4]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:3]=2[O:2][CH3:1])[C:7](=[O:22])[C@H:8]1[NH:12][C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N+:30]=[N-:31]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CI)c(OC)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CN=[N+]=[N-])c(OC)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 6 ml of N,N-dimethylformamide are added 740 mg of cis-1(2,4-dimethoxybenzyl)-4-iodomethyl-3-phenylacetamido-2-oxoazetidine and 146 mg of sodium azide and the mixture is stirred for 4 days at room temperature. The solvent is distilled off in vacuo, and ethyl acetate and water are added to the residue. The ethyl acetate layer is separated, washed with an aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off in vacuo. To the residue, ether is added and the precipitated crystals are collected by filtration to give cis-4-azidomethyl-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine, m.p. 110°-111° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]3)=[CH:4][CH:3]=1.Cl.Cl.Cl.[N:24]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH:36]([NH:39][C:16]([C:10]3[NH:11][C:12]4[C:8]([CH:9]=3)=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=3)[CH:15]=[CH:14][CH:13]=4)=[O:18])[CH2:37][CH2:38]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(O)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(4-fluoro-phenoxy)-1H-indole-2-carboxylic acid 145 (preparation see below) and amine 5.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1(B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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:8]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: Brc1cccnc1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C1=C(c2cccnc2)CCCC1
Yield: 90.9 %

Procedure:
A solution of 3-bromopyridine (0.38 g, 2.40 mmol), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.50 g, 2.40 mmol), tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12 mmol) and cesium carbonate (1.72 g, 5.29 mmol) in 1,4-dioxane (8.0 mL) and water (4.0 mL) was stirred at 90° C. for 4 hours. After allowing to cool, the reaction solution was subjected to extraction with ethyl acetate (50 mL), and the organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with column chromatography (hexane/ethyl acetate=2:1) to yield the title compound (347.3 mg, 99%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][Mg]Br>CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[CH3:11])[CH:9]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cc(Br)ccc1F
Solvent: CCOCC
Product: CC(O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde 101 (100 g, 0.492 mol) in ether (500 mL), cooled in an ice bath, was added a 3 M solution of methyl magnesium bromide in ether (173 mL, 0.516 mol) in a dropwise manner. The reaction mixture was stirred for 30 minutes in the ice bath. The reaction mixture was allowed to warm to room temperature and was stirred for 15 minutes. The reaction mixture was cooled in an ice bath and the reaction was quenched by addition of water in a dropwise manner. The reaction mixture was acidified with dilute hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with ether for two times. The combined organic layer was dried over magnesium sulfate and evaporated under reduced pressure to afford 1-(5-Bromo-2-fluoro-phenyl)-ethanol 102 (106 g, 0.484 mol) which was used in the next step without further purification.
Reaction SMILES: C[C:2]12[CH2:13][CH2:12][C:8]3([CH2:9][CH2:10][CH2:11]1)[C:3]2(C)[CH2:4][CH2:5][CH:6]=[C:7]3C.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C.C(OO)(=O)C>O.ClCCl>[CH3:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2][CH2:11][CH2:10][CH2:9][CH2:8][CH2:12][CH3:13]
Reactant: CC1=CCCC2(C)C3(C)CCCC12CC3
Agent: CC(=O)OO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CCCCC=CCCCCCC
Reaction time: 2 h

Procedure:
A mixture of 20.4 g (0.1 mole) of 1,2,6-trimethyltricyclo[5,3,2,02,7 ]dodeca-5-ene and 17 g of sodium carbonate was added to 100 ml of dichloromethane, and the materils were mixed and stirred while keeping the temperature at 0° to 5°C. Then, 20.8 g (0.11 mole) of an acetic acid solution containing 40% peracetic acid was added dropwise thereto over a period of 2 hours at that temperature. The materials were stirred at that temperature for 2 hours, and further stirred at room temperature for 3 additional hours. Subsequently, 200 ml of water was added thereto, and the resulting solution was extracted twice with dichloromethane. The extract was washed with an aqueous saturated sodium chloride solution until the solution became neutral, and then dried with anhydrous sodium sulfate. Dichloromethane was then recovered by distillation, and the residue was distilled in vacuum, whereby 21 g of the fraction of Compound (II) (85°-90°C/0.03 mmHg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15]Br)=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[OH2:21]>CS(C)=O.[Cu-]=O>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15][OH:21])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)cc2CBr)ccc1F
Reactant: O
Agent: O=[Cu-]
Solvent: CS(C)=O
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2CO)ccc1F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-bromomethyl pyrazole(2.5 g, 7.18 mmol) in DMSO (40 mL) was added copper(I) oxide(2.16 g, 15.08 mmol) and water (12 mL). The reaction mixture was stirred at 60° C. for 2 hours then cooled to RT and stirred at RT overnight. The next day, the mixture was filtered through celite, filter pad was washed with ethyl acetate(20 mL); the filtrate was partitioned between ethyl acetate(50 mL) and water(50 mL); organic phase was separated and washed with water(3×30 mL); dried over sodium sulfate; filtered, concentrated, flash chromatography (ethyl acetate : hexane, 1:6) to afford 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-hydroxymethyl pyrazole(1.7 g). CI mass spectrum m/z (rel. intensity) 286 (M+H, 100).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9](=[O:12])[CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[CH2:20][CH3:21])[CH3:2].[C:22]([O:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH2:40][O:41][C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:35]Br)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([O:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH2:40][O:41][C:42](=[O:49])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:35][O:19][C:17]1[CH:16]=[CH:15][C:14]([CH2:20][CH3:21])=[C:13]([C:4]2[CH:5]=[CH:6][C:7]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:8][C:3]=2[CH2:1][CH3:2])[CH:18]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: CCC(=O)c1ccc(-c2cc(O)ccc2CC)c(CC)c1
Product: CCC(=O)c1ccc(-c2cc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)ccc2CC)c(CC)c1

Procedure:
In a manner similar to that of Example 1(o), by reacting 1.67 g (5.9 mmol) of 1-(2,2′-diethyl-5′-hydroxybiphenyl-4-yl)-1-propanone with 2.73 g (6.2 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide, and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (95/5), 1.88 g (50%) of the expected product are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[CH3:23][N:24]([CH3:34])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:33])=[CH:27][CH:26]=1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: CN(C)c1ccc(N=C=O)cc1
Product: CN(C)c1ccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 4-dimethylaminophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].S(=O)(=O)(O)O.[CH3:21][C:22](=[CH2:24])[CH3:23].C(=O)=O>ClCCl.CC(C)=O>[C:22]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])([CH3:24])([CH3:23])[CH3:21]
Reactant: C=C(C)C
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 77 %

Procedure:
Dissolve 2-(3-hydroxypropyl)isoindole-1,3-dione (2 g, 9.74 mmol, 1 eq) in 40 mL of dichloromethane under N2. Add sulfuric acid (780 μL) and cool reaction mixture to −5° C. Condense isobutylene gas to a liquid using a −78° C. cold finger charged with dry ice and acetone. Add approximately 20 mL of the condensed liquid to the reaction mixture and slowly warm the solution to room temperature overnight while stirring. Add saturated, aqueous sodium hydrogencarbonate to the reaction mixture and extract product into the organics. Wash separated organic layer with water and dry over magnesium sulfate to give 1.969 g (77% yield) of 2-(3-tert-butoxypropyl)isoindole-1,3-dione as a colorless oil.
Reaction SMILES: Cl.[CH:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]3[CH2:11][CH2:12][CH:13]([CH2:14][CH2:15][NH2:16])[C:7]=3[C:6]=12.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25].O>O1CCCC1>[CH:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]3[CH2:11][CH2:12][CH:13]([CH2:14][CH2:15][NH:16][C:24](=[O:26])[CH3:25])[C:7]=3[C:6]=12
Reactant: CC(=O)OC(C)=O
Reactant: NCCC1CCc2ccn3nccc3c21
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCC1CCc2ccn3nccc3c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
To a mixture of 2-(8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridin-9-yl)ethanamine hydrochloride (45.5 mg, 0.191 mmol) and triethylamine (206 μL, 1.48 mmol) in tetrahydrofuran (1.5 mL) was added acetic anhydride (42.0 μL, 0.444 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 min. Water (50 μL) was added, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) and recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (22.4 mg, yield 48%).
Reaction SMILES: [OH-].[K+].[CH3:3][SH-:4][C:5](=[N:7][OH:8])[CH3:6].[CH3:9][N:10]([S:14][N:15]([CH3:17])[CH3:16])[C:11](F)=[O:12]>C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.C1C=CC=CC=1>[CH3:9][N:10]([S:14][N:15]([CH3:17])[CH3:16])[C:11]([O:8][N:7]=[C:5]([S:4][CH3:3])[CH3:6])=[O:12]
Reactant: C[SH-]C(C)=NO
Reactant: CN(C)SN(C)C(=O)F
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CSC(C)=NOC(=O)N(C)SN(C)C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
Powdered potassium hydroxide (3.3 g), 5.2 g of S-methyl-N-hydroxythioacetimidate, 0.1 g dicyclohexyl-18-crown-6, and 200 ml of benzene were stirred at room temperature for 0.5 hr. Then 8.0 g of N-methyl-N-(dimethylaminosulfenyl)carbamoyl fluoride was added slowly at 28° C. The reaction temperature was held at 28°-32° C. with external cooling. The mixture was stirred for 1 hr., and then was washed with water until neutral. After drying (MgSO4), the solution was concentrated in vacuo, and the residue was recrystallized from diisopropyl ether to give 9.0 g (76 percent yield) of S-methyl N-[N'-methyl-N'-(dimethylaminosulfenyl)carbamoyloxy]Thioacetimidate, m.p. 68°-70° C.