Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[CH3:3][NH:4][CH3:5].[C:6]([C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)#[N:7]>>[NH2:7][CH2:6][C:8]1[CH:9]=[C:10]([S:14]([N:4]([CH3:5])[CH3:3])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: CNC
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CO
Product: CN(C)S(=O)(=O)c1cccc(CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Step 1) To a 2M dimethylamine methanol solution (3.7 ml) was added 3-cyanobenzenesulfonyl chloride (1.5 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, saturated brine was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure. 10% Palladium carbon powder (0.79 g) was added to a solution (10 ml) of the residue in ethanol, and the mixture was stirred overnight under a hydrogen atmosphere (1 atm). The solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) to give 3-(aminomethyl)-N,N-dimethylbenzenesulfonamide (1.0 g) as a colorless oil.
Reaction SMILES: C(N[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)C.CC1N=C([O:37][CH2:38][CH2:39][CH3:40])N=C(C(O)=O)C=1>>[CH3:28][C:17]1[CH:16]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[C:6]([CH3:29])[N:5]=[C:4]([O:37][CH2:38][CH2:39][CH3:40])[N:9]=3)[O:14][N:13]=2)[CH:26]=[C:25]([CH3:27])[C:18]=1[O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]
Reactant: CCCOc1nc(C)cc(C(=O)O)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Product: CCCOc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1

Procedure:
rac-3-{2,6-Dimethyl-4-[5-(6-methyl-2-propoxy-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 6-methyl-2-propoxy-pyrimidine-4-carboxylic acid; LC-MS: tR=0.87 min*; [M+H]+=415.08.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([OH:28])[CH2:3][N:4]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[O:15]COC>C1COCC1.Cl.C(OCC)(=O)C>[CH3:1][C:2]([CH3:29])([OH:28])[CH2:3][N:4]([S:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:20])=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:12])[F:13])=[CH:7][C:6]=1[OH:15]
Reactant: COCOc1cc(C(F)(F)F)ccc1N(CC(C)(C)O)S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)CN(c1ccc(C(F)(F)F)cc1O)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.2 %

Procedure:
To a solution of 1,1-dimethyl-2-[N-(2-methoxymethoxy-4-trifluoromethylphenyl)-phenylsulfonylamino]ethanol (380 mg; prepared in Reference Example 22.) in THF (4.0 ml), 6N HCl (0.8 ml) was added. The mixture was stirred for 2 days at room temperature. The reaction mixture was diluted with ethyl acetate, washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=2:1) to give the title compound (291 mg) having the following physical data.
Reaction SMILES: P([O-])(OC)[O:2]C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.CC1C=CC2C(=CC=CC=2)C=1.[CH3:40][C:41]1[CH:50]=[C:49]2[C:44]([CH:45]=[CH:46][CH:47]=[C:48]2[C:51](=[O:53])C)=[CH:43][CH:42]=1.BrBr.COP(OC)(OC)=S>C1C=CC=CC=1>[CH3:40][C:41]1[CH:50]=[C:49]2[C:44]([CH:45]=[CH:46][CH:47]=[C:48]2[C:51]([OH:53])=[O:2])=[CH:43][CH:42]=1
Reactant: CC(=O)c1cccc2ccc(C)cc12
Reactant: COP([O-])OC
Agent: BrBr
Agent: COP(=S)(OC)OC
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: Cc1ccc2cccc(C(=O)O)c2c1

Procedure:
1-Iodopropane and benzyl chloride were commercial products. 6-Bromohexanoic acid tert-butyl ester was synthesized by passing isobutylene through solution of 6-bromohexanoic acid in dichlomethane in presence of concentrated sulfuric acid (See, Lecher, H. Z., Greenwood, R. A., Whitehouse, K. C. and Chao, T. H. “The Phosphonation of Aromatic Compounds with Phosphorus Pentasulfide.” J. Am. Chem. Soc. 78, (1956) 5018-5022.) and used directly without purification in the next step of the synthetic process. Dimethyl thiophosphite was produced by refluxing dimethyl phosphite (Sigma-Aldrich, St. Louis, Mo.) with Lawesson's reagent in benzene. (Snatzke, G. and Kunde, K. “Perhydrodibenz[a.j]anthracen-14-one, I. Synthese 2-substituierter Dibenz[a.j]anthracen-Derivate.” Chem. Ber. 106, (1973) 1341-1362) 7-Methylnaphthalene-1-carboxylic acid was prepared by acetylation of 2-methylnaphthalene to 1-(7-methyl-naphthalen-1-yl)-ethanone followed by oxidation with bromine. (See, Hilgetag, G. and Teichmann, H. “Uber einige Methylierungsreactionen der beiden isomeren Trimethylthiophosphate.” J. Prakt. Chem. 8, (1959) 90-96.)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]#[N:10])[NH2:5].[F-].[Cs+].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1C(=O)CCC1.CCOC(C)=O.Cl[Pd](Cl)(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)P(C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:9]([C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:10]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([PH](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[PH](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)cc1-c1ccccc1
Temperature: 100 °C
Yield: 95.5 %

Procedure:
Commercially available 3-chloro-4-cyanoaniline (305 mg, 2.0 mmol) was dissolved in NMP (8 mL), and CsF (608 mg, 4.0 mmol), phenyl boronic acid (268 mg, 2.2 mmol) and dichlorobis(tricyclohexylphosphino)palladium (73 mg, 0.1 mmol) were added. The reaction was then heated to 100° C. for 16 h. After cooling to rt, the reaction mixture was taken up in EtOAc, washed with water (2×), dried (Na2SO4), concentrated under reduced pressure, and purified by silica gel flash chromatography eluting with EtOAc/hexanes (1:1) to give compound 47A (371 mg, 96%) as a yellow solid. LC/MS m/z 195 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.C(OCC)(=O)C.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>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:7]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)=[CH:34][CH:35]=1
Reactant: COC(=O)[C@@H]1C=C(OS(=O)(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2ccc(N)nc2)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: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C=C(c2ccc(N)nc2)CN1C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 72.4 %

Procedure:
A mixture of (S)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (1.55 g, 4.13 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.00 g, 4.54 mmol), Pd(PPh3)4 (0.239 g, 0.21 mmol) and Cs2CO3 (3.36 g, 10.32 mmol) in THF (10 mL) and water (2 mL) was microwave heated to 100° C. for 10 min. The reaction was then diluted with ethyl acetate (50 mL) and water (25 mL). The layers were separated and the organics were washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate and concentrated, then purified by flash chromatography [0-8% methanol/DCM eluent] to provide (S)-1-tert-butyl 2-methyl 4-(6-aminopyridin-3-yl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (0.955 g, 72% yield). LCMS (m/z): 320.4 (MH+), 0.50 min.
Reaction SMILES: C([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:54]/[O:55][CH2:56][F:57])/[C:27]([NH:29][C@@H:30]2[C:52](=[O:53])[N:32]3[C:33]([C:49]([O-:51])=[O:50])=[C:34](/[CH:37]=[CH:38]/[CH2:39][N+:40]([C@@H:43]([C:46](=[O:48])[NH2:47])[CH2:44][OH:45])([CH3:42])[CH3:41])[CH2:35][S:36][C@H:31]23)=[O:28])[N:22]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C(OCC)C>C1(OC)C=CC=CC=1>[NH2:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:54]/[O:55][CH2:56][F:57])/[C:27]([NH:29][C@@H:30]2[C:52](=[O:53])[N:32]3[C:33]([C:49]([O-:51])=[O:50])=[C:34](/[CH:37]=[CH:38]/[CH2:39][N+:40]([C@@H:43]([C:46](=[O:48])[NH2:47])[CH2:44][OH:45])([CH3:42])[CH3:41])[CH2:35][S:36][C@H:31]23)=[O:28])[N:22]=1
Reactant: C[N+](C)(C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OCF)c3nsc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1)[C@H](CO)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: COc1ccccc1
Product: C[N+](C)(C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OCF)c3nsc(N)n3)[C@H]2SC1)[C@H](CO)C(N)=O
Reaction time: 1 h
Yield: 99.6 %

Procedure:
The compound (500 mg) of Example 38 was suspended in anisole (3 ml), followed by an addition of trifluoroacetic acid (3.5 ml) under ice cooling. The resulting mixture was stirred for 1 hour at the same temperature, followed by a further addition of trifluoroacetic acid (1.5 ml). The resulting mixture was stirred for 1 hour. Ethyl ether was added, and a precipitate thus formed was collected by filtration to obtain the target product (350 mg). Its infrared spectrum and NMR spectrum were consistent with those of Example 10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:16]=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(Oc2ccnc(Cl)c2)cc1
Yield: 99.7 %

Procedure:
Using the method of Example 3, Step A, 4-methoxyphenol (2.35 g, 18.9 mmol), 60% sodium hydride in mineral oil (0.757 g, 18.9 mmol), and 2-chloro-4-nitropyridine (3.00 g, 18.9 mmol) were reacted to provide 2-chloro-4-(4-methoxyphenoxy)pyridine (4.44 g, 99% yield) as an oil. 1H NMR (CDCl3) δ 8.20 (d, 1H), 7.01 (d, 2H), 6.95 (d, 2H), 6.75-6.77 (m, 2H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][OH:12])[C:9]=1[Cl:10])=[O:4].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[C:9]=1[Cl:10])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1scc(CO)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1scc(COS(C)(=O)=O)c1Cl
Reaction time: 6 h

Procedure:
To a solution of 2-methoxycarbonyl-3-chloro-4-hydroxymethylthiophene (6 g, 29 mmol) in methylene chloride (100 mL) were added triethylamine (8.1 mL, 58 mmol) and methanesulfonyl chloride (2.5 mL, 32 mmol) at ambient temperature. After stirring for 6 hours, the react ion mixture was concentrated to afford 2-methoxycarbonyl-3-chloro-4-(methylsulfonyloxy)methylthiophene. The crude product was dissolved in DMF (150 mL) and excess potassium cyanide was added to the solution. The reaction mixture was stirred at ambient temperature for 16 hours, then poured into water, and extrated with methylene chloride. The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford 2-methoxycarbonyl-3-chloro-4-cyanomethylthiophene.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH:16]1[CH3:27])=O)(C)(C)C>ClCCl>[CH3:27][CH:16]1[NH:15][CH2:20][CH2:19][N:18]([C:21]2[N:22]=[CH:23][CH:24]=[CH:25][N:26]=2)[CH2:17]1
Reactant: CC1CN(c2ncccn2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CN(c2ncccn2)CCN1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.6 %

Procedure:
5 mL trifluoro acetic acid was added to 240 mg of 2-methyl-4-pyrimidin-2-yl-piperazine-1-carboxylic acid tert-butyl ester in 10 mL dichlormethane. The mixture was stirred for 24 h at RT. The solvent of the mixture was evaporated and the residue was dissolved in dichlormethane and extracted with 10% aqueous potassium hydrogencarbonate. The organic layer was evaporated to yield 150 mg of the desired product. Rt: 0.50 min (method B), (M+H)+: 179
Reaction SMILES: [B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:18].[CH3:19][O:20][C:21]1[CH:33]=[CH:32][C:24]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:18][C:33]1[CH:32]=[C:24]([CH:23]=[CH:22][C:21]=1[O:20][CH3:19])[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: [IH2+]
Reactant: COc1ccc(Cc2cccnc2)cc1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cc2cccnc2)cc1I
Reaction time: 2 h

Procedure:
Bis(pyridine)iodonium tetrafluoroborate (1.35 g, 3.64 mmol) was added to a solution of 3-(4-methoxybenzyl)pyridine (720 mg, 3.64 mmol) in 9:1 TFA:DCM (20 mL) and the mixture was stirred for 1 h at 0° C. The ice bath was removed and the reaction was stirred for 2 h. EtOAc was added and the mixture was washed with water twice, satd. sodium thiosulfate twice, dried over MgSO4, concentrated in vacuo, and purified by column chromatography to give 3-(3-iodo-4-methoxybenzyl)pyridine as a yellow oil. MS (ESI) m/z: Calculated: 325.0; Observed: 326.3 (M++1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]1([C@H:19]([N:21]2[CH:25]=[CH:24][N:23]=[N:22]2)[CH3:20])[CH2:18][O:17]1.O>CN(C)C=O.C(OCC)(=O)C>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:17])([C@H:19]([N:21]1[CH:25]=[CH:24][N:23]=[N:22]1)[CH3:20])[CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: C[C@@H](n1ccnn1)[C@@]1(c2ccc(F)cc2F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](n1ccnn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.6 %

Procedure:
1H-1,2,4-Triazole (63 mg) was added under ice-cooling to a dispersion of 60% sodium hydride in oil (36 mg) in dimethylformamide (1.5 ml) and the resulting mixture was stirred for 10 minutes at room temperature. To the mixture was added a solution of (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(1H-1,2,3-triazol-1-yl)ethyl]oxirane (116 mg) in dimethylformamide (0.8 ml), followed by heating for 5 hours at 50° C. and cooling. Cold water (10 ml) and ethyl acetate (20 ml) were added to the reaction mixture. The separated aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated saline, dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (acetone/dichlormethane=1:2→1:1). The obtained crystals were recrystallized from diisopropyl ether to give the title compound (Compound 6, 66 mg, 45%) as colorless crystals.
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][N:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:19](=[O:32])[N:18]=3)[CH2:13][CH:12]=2)=[CH:7][CH:6]=1.B(Br)(Br)Br>O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][N:20]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:24]5[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=5)=[CH:28][CH:29]=4)[C:19](=[O:32])[N:18]=3)[CH2:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(Cn2cnc(N3CC=C(c4ccc(F)cc4)CC3)nc2=O)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)ncn1Cc1ccc(OCc2ccc(O)cc2)cc1
Yield: 28.3 %

Procedure:
To a dichloromethane solution (8.0 mL) of 4-[4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl]-1-(4-methoxybenzyl)-1,3,5-triazin-2(1H)-one (200 mg, 0.510 mmol) synthesized in Reference Synthesis Example 352, boron tribromide (1.53 mL, 1.53 mmol) was added at 0° C. and the resultant mixture was stirred at room temperature for 1 day. After the completion of the reaction, to the reaction solution, water was added and extraction with chloroform from the reaction solution was performed. The organic layer was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (chloroform/ethyl acetate→methanol/ethyl acetate) to obtain the title compound (35.0 mg, yield: 18%) of Synthesis Example 483a and the title compound (7.15 mg, yield: 3%) of Synthesis Example 483b.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].[H-].[Na+].C1(N(C2C=CC=CC=2)[C:18]([NH:20][S:21]([CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])=[O:19])C=CC=CC=1.C1(C=CS(N)(=O)=O)C=CC=CC=1>CCOCC.CN(C)C=O>[CH3:2][O:3][C:4]([CH:5]([NH:6][C:18]([NH:20][S:21]([CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])=[O:22])=[O:19])[CH3:7])=[O:8]
Reactant: COC(=O)C(C)N
Reactant: O=C(NS(=O)(=O)C=Cc1ccccc1)N(c1ccccc1)c1ccccc1
Agent: Cl
Agent: NS(=O)(=O)C=Cc1ccccc1
Agent: [H-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C(C)NC(=O)NS(=O)(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3.5 g. of DL-alanine methyl ester hydrochloride in 20 ml. of N,N-dimethylformamide is added 1.05 g. of a 56.6% suspension of sodium hydride in mineral oil. The mixture is stirred at ambient temperature for 15 minutes, and then 3.8 g. of N-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide is added. The whole reaction mixture is then maintained at ca. 90° C. for 40 minutes. After being allowed to cool to room temperature, it is diluted with an excess of ether and then it is extracted with water. Acidification of the water extract with dilute hydrochloric acid causes precipitation of the crude product, which is then filtered off. The ether phase is washed with dilute hydrochloric acid, which causes a further crop of product to precipitate. It is filtered off and the two crops of product are combined. This yields 1.55 g. of material having a melting point of 135°-139° C. The crude product is recrystallized from a mixture of acetone and hexane, giving 0.70 g. of N-[N-1-methoxycarbonylethyl)carbamoyl]-2-phenylethenesulfonamide, m.p. 138°-140° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([NH:32][CH:33]=[O:34])[CH:31]=1)[NH:28][C:27](=[O:35])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([NH:32][CH:33]=[O:34])[CH:31]=1)[NH:28][C:27](=[O:35])/[C:26]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Reactant: O=CNc1cc(F)cc2c1NC(=O)C2
Product: Cc1c(/C=C2\C(=O)Nc3c(NC=O)cc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 95 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-formamide 20c obtained from step 3 of Example 20 as starting materials to obtain (Z)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-7-yl}-formamide 29 (59 mg, yield 95%) as a yellow solid.
Reaction SMILES: B.C1COCC1.[Cl:7][C:8]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11].Cl>C1COCC1>[Cl:7][C:8]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][NH2:11]
Reactant: N#Cc1cccc(F)c1Cl
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NCc1cccc(F)c1Cl
Temperature: 70 °C

Procedure:
BH3.THF in THF (1.0 M, 50.0 ml) was carefully added into the THF (40.0 ml) solution of 2-chloro-3-fluorobenzonitrile (662 mg, 4.17 mmol) at rt. The resulting mixture was heated at 70° C. under an atmosphere of nitrogen for 16 h. After cooling to ambient temperature, conc. HCl (5.18 ml, 62.5 mmol) was added slowly. The combined mixture was heated at 70° C. for 30 min. After that time, the mixture was concentrated in vacuo to remove most of solvent, water (20 ml) was added, and the mixture was extracted with Et2O (3×30 ml). The extracts were washed with water (20 ml). The combined aqueous layers were basified by saturated Na2CO3 until pH=9 and extracted with EtOAc (3×50 ml). These EtOAc extracts were washed with brine (50 ml) dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as colorless oil. 1H NMR (400 MHz, CDCl3): δ=1.67 (brs, 2H), 3.97 (s, 2H), 7.03-7.09 (m, 1H), 7.17-7.26 (m, 2H). MS(ES+): m/z=160.14/162.09 (64/32) [MH+]. HPLC: tR=0.40 & 0.70 min (polar—5 min, ZQ3; peak splitting).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[Si:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33]O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[Si:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17])([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Product: CC(C)(C)[Si](C)(C)OCCCCOc1cccc(OCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Mitsunobu reaction of phenol 24 with 4-(tert-butyldimethylsilanyloxy)butan-1-ol gave 2-(2-(3-(4-(tert-butyldimethylsilyloxy)butoxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil. Yield (1.3 g, 78%): 1H NMR (400 MHz, CDCl3) δ 7.84-7.87 (m, 2H), 7.70-7.74 (m, 2H), 7.10-7.14 (m, 1H), 6.42-6.49 (m, 3H), 4.20 (t, J=5.6 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.92 (t, J=6.6 Hz, 2H), 3.66 (t, J=5.6 Hz, 2H), 1.78-1.86 (m, 2H), 1.61-1.69 (m, 2H), 0.89 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [CH2:1]1[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH3:6].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1CO1
Reactant: NCCCCCCN
Product: CCCCC(O)CNCCCCCCNCC(O)CCCC

Procedure:
Condensation of 1-hexene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxyhexylamine] (I: R = CH3 (CH2)3, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11](=O)[C:12]1[C:17]([O:18][CH2:19][CH3:20])=[CH:16][C:15]([C:21]2[C:26]([CH2:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:29][CH3:30])=[N:14][CH:13]=1)C.[Cl-].[NH4+]>CCOCC>[CH:1]1([CH:11]([C:12]2[CH:13]=[N:14][C:15]([C:21]3[C:26]([CH2:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:29][CH3:30])=[CH:16][C:17]=2[O:18][CH2:19][CH3:20])[OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Reactant: Cl[Mg]C1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOc1cc(-c2c(CC)cccc2CC)ncc1C(O)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclopentyl magnesium chloride solution (2 M in THF, 2 mL, 4 mmol) is slowly added to a solution of 6-(2,6-diethyl-phenyl)-4-ethoxy-nicotinic acid ethyl ester (prepared by a route analogous to that given in Example 2) (163 mg, 0.5 mmol) in ether (5 mL) at 0° C. The mixture is stirred at room temperature for 30 minutes. Saturated ammonium chloride solution (2 mL) is added and the organic solution is separated. The organic layer is separated and dried over anhydrous Na2SO4. The solvents are removed in vacuo and the crude is purified with PTLC (hexanes/EtOAc 3:1) to give cyclopentyl-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-methanol. 1H NMR: (CDCl3) 8.44 (s, 1H), 7.28 (t, 1H), 7.12 (d, 2H), 6.74 (S, 1H), 4.61 (t, 1H), 4.06 (q, 2H), 2.29 (m, 4H), 1.92 (m, 1H), 1.47 (m, 10H), 1.21 (m, 1H), 1.02 (m, 6H).