Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:26][CH3:27]>CN(C=O)C>[CH2:26]([N:10]1[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]([C:1]#[N:2])=[C:11]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH3:27]
Reactant: CCI
Reactant: N#CCc1ccccc1NC(=O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1c(-c2cccnc2)c(C#N)c2ccccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of N-(2-cyanomethyl-phenyl)-nicotinamide (Example 83a, 400 mg, 1.69 mmol) in DMF (17 mL) is added Cs2CO3 (1.1 g, 3.37 mmol). The reaction is heated to 80° C., at which time a solution of iodoethane (0.14 mL, 1.75 mmol) in DMF (5 mL) is added over 75 min. The temperature is then increased to 100° C. After stirring for an additional 2 h, the reaction is cooled to room temperature and quenched with saturated aqueous NH4Cl, and diluted with ethyl acetate and water. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 3:10 to 1:0) to furnish 1-ethyl-2-pyridin-3-yl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 1.40 (t, J=7.2 Hz, 3H), 4.22 (q, J=7.2 Hz, 2H), 7.32-7.45 (m, 2H), 7.47-7.51 (m, 1H), 7.54 (dd, J=7.8, 5.6 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.91-7.98 (m, 1H), 8.78-8.85 (m, 2H). HRMS (ESI) m/z 248.1190 [(M+H)+ Calcd for C16H14N3: 248.1188].
Reaction SMILES: O[C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[N:8]3)[N:5]=[CH:4][C:3]=1C(O)=O.C1(C2C3C(N=CC=2)=C2C(C(O)=CC=N2)=CC=3)C=CC=CC=1.P(Br)(Br)([Br:48])=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:48][C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[N:8]3)[N:5]=[CH:4][CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=C(O)c1cnc2c(ccc3c(-c4ccccc4)ccnc32)c1O
Agent: O=C([O-])O
Agent: Oc1ccnc2c1ccc1c(-c3ccccc3)ccnc12
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccnc2c1ccc1c(-c3ccccc3)ccnc12
Temperature: 260 °C

Procedure:
4-Hydroxy-7-phenyl-1,10-phenanthroline-3-carboxylic acid is de-carboxylated in three gram amounts by heating at 250-270° C. in a Woods metal bath until effervescence ceases. A cake, principally comprising 7-phenyl-1,10-phenanthrolin-4-ol, cracks away from the sides of the beaker and is ground up in a mortar. This material is treated with excess phosphoryl bromide (15 mL) and the mixture is heated to 140° C. for 8 hrs. The reaction mixture is cooled to room temperature, and the remaining phosphoryl bromide is distilled off under reduced pressure to yield a semi-crystalline mass. This solid is stirred into a mixture of toluene and dilute sodium bicarbonate sufficient to make the mixture slightly basic. The mixture is stirred for several hours, after which time the toluene layer is separated and the aqueous layer is extracted with additional toluene. The toluene fractions are combined, treated with decolorizing charcoal, filtered, and evaporated to yield the desired product, which is collected by filtration and re-crystallized from toluene.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.I[CH2:34][CH3:35]>>[CH2:34]([N:21]([CH2:20][CH2:19][C:18]1[CH:29]=[CH:30][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:31])[F:32])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH3:35]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared as described in Example 102 using tert-butyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate (C50) and iodoethane and isolated as a yellow oil (0.175 g, 100%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.16-8.06 (m, 2H), 7.89-7.73 (m, 2H), 7.45-7.36 (m, 2H), 7.31 (s, 2H), 3.42 (s, 2H), 3.23 (t, J=35.4 Hz, 2H), 2.96-2.84 (m, 2H), 1.47 (s, 9H), 1.08 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 477 ([M+H]+).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:23])[CH:4]([S:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=1)=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:24](O)(=[O:35])[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>>[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([S:10]([CH:4]([C:3](=[O:23])[NH:2][OH:1])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:24]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)=[O:35])=[O:11])=[CH:17][CH:16]=1)[C:20]#[C:21][CH3:22]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC#CCOc1ccc(S(=O)C(CCCCN)C(=O)NO)cc1
Product: CC#CCOc1ccc(S(=O)C(CCCCNC(=O)c2ccc3ccccc3n2)C(=O)NO)cc1

Procedure:
6-Amino-2-(4-but-2-ynoxy-benzenesulfinyl)-hexanoic acid hydroxyamide resin (0.33 g, 1.1 meq/g) prepared in step B was acylated with quinaldic acid (1.2 g, 4.0 eq) according to the procedure in Example 13, Step E to give quinoline-2-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl]-amide resin.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:21]1CCOCC1.C(Cl)(=O)OCC(C)C.N>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:19])[NH2:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-benzyloxycarbonylpiperidine-4-carboxylic acid (10.5 g) in tetrahydrofuran (100 ml) were dropwise added N-methylmorpholine (4.6 ml) and isobutyl chlorocarbonate (5.4 ml) with ice-cooling and under an argon atmosphere, and the mixture was stirred at the same temperature for 10 min. Then, 28% aqueous ammonia (100 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated and water was added. The mixture was extracted with ethyl acetate and washed successively with aqueous sodium hydrogencarbonate solution, 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and dried under reduced pressure to give the title compound (8.3 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=1>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=2)=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Reactant: NC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(Br)c1OCc1ccc(C(N)=O)cc1
Temperature: 80 °C
Yield: 67 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (1.0 g, 3.71 mmol) in acetonitrile (10 mL) was added potassium carbonate (1.53 g, 11.08 mmol) and 4-(bromomethyl)benzamide (795 mg, 3.71 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 4-((6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)benzamide as a solid (1 g, 67%).
Reaction SMILES: [BH4-].[Na+].[Br-].[CH2:4]([N+:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CCO>[CH2:4]([N:11]1[CH2:12][CH:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[CH2:15][CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)c1cc[n+](Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)C1=CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
Add sodium tetrahydroborate (1.8 g, 47.4 mmol) in portions to a solution of 1-benzyl-4-isopropyl-pyridin-1-ium bromide (11.1 g, 36.5 mmol) in EtOH (55 mL) at 0° C. Allow the reaction mixture to reach ambient temperature slowly and stir overnight. Add 10 mL of water and remove the organic solvent under vacuum. Add water and then adjust the pH with HCl (5M) to a pH of 1-2. Stir the mixture for 15 min and then add NaOH (2M) until the pH is 8-9. Extract the aqueous layer with EtOAc, combine the organic layers; and sequentially wash with NaOH (2M) then brine. Dry the organic over anhydrous sodium sulphate; filter; and concentrate the filtrate. Purify the compound by chromatography on a silica gel cartridge eluting with hexane:ethyl acetate (9:1, 7:3, 5:5, and then 100% ethyl acetate) to obtain the title compound as a pale yellow oil (6.7 g, 83%). MS (m/z): 216 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:8]3[CH:9]=[C:10]([C:20]4[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=4)[N:11]([CH2:16][O:17][CH2:18][CH3:19])[C:12]=3[CH:13]=[CH:14][CH:15]=2)=[O:6])[CH2:3][CH2:2]1.Cl.[NH2:29][C@@H:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[OH:35].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:26][C:25]1[C:20]([C:10]2[N:11]([CH2:16][O:17][CH2:18][CH3:19])[C:12]3[CH:13]=[CH:14][CH:15]=[C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])[C:8]=3[CH:9]=2)=[N:21][C:22]([NH:29][C@@H:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[OH:35])=[N:23][CH:24]=1
Reactant: CCOCn1c(-c2nc(Cl)ncc2Cl)cc2c(C(=O)NC3CC3)cccc21
Reactant: N[C@@H]1CCC[C@@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CCOCn1c(-c2nc(N[C@@H]3CCC[C@@H]3O)ncc2Cl)cc2c(C(=O)NC3CC3)cccc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 59.6 %

Procedure:
A mixture of N-cyclopropyl-2-(2,5-dichloropyrimidin-4-yl)-1-(ethoxymethyl)-1H-indole-4-carboxamide (10 g, 25 mmol), (1S,2R)-2-aminocyclopentanol hydrochloride (4.1 g, 30 mmol) and DIPEA (5 mL, 30 mmol) in DMSO (70 mL) is stirred at 100° C. for 3 h, then poured into water and extracted with EA. The combined extracts are washed with aqueous saturated sodium chloride, dried over Na2SO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel to give 2-{5-chloro-2-[(1R,2S)-2-hydroxycyclopentylamino]pyrimidin-4-yl}-N-cyclopropyl-1-(ethoxymethyl)-1H-indole-4-carboxamide (7 g, 60.3%). MS (m/z): 470 (35Cl) and 472 (37Cl) (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[O:7][C:6]1=[O:25].[CH:35](=O)[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:24][C:21]([F:22])([F:23])[C:13]1[CH:12]=[C:11]([C@H:8]2[O:7][C:6](=[O:25])[N:5]([CH2:4][C:3]3[CH:26]=[C:27]([O:30][C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][C:2]=3[NH:1][CH2:35][CH3:36])[C@H:9]2[CH3:10])[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:14]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1N
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCNc1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C

Procedure:
To a solution of (4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (80 mg, 0.159 mmol) in dichloroethane (1.6 mL) was added acetaldehyde (9 μL, 0.159 mmol) and NaBH(OAc)3 (67 mg, 0.318 mmol). The reaction was stirred at room temperature, and after 30 minutes acetaldehyde (4.5 μL, 0.80 mmol) was added. After an hour, additional acetaldehyde (4.5 μL, 0.80 mmol) was added. After an additional hour, the reaction was diluted with EtOAc (20 ml) and washed with saturated NH4Cl solution and brine (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (10 to 20% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(ethylamino)-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.66 (25% EtOAc/hexanes). LCMS=531.2 (M+1)+. 1H NMR (CDCl3, 500 MHz), 7.88 (s, 1H), 7.73 (s, 2H), 7.10 (dd, J=2.1, 8.8 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.59 (d, J=8.9 Hz, 1H), 5.66 (d, J=8.4 Hz, 1H), 4.81 (s, 1H), 4.70 (d, J=15.4 Hz, 1H), 4.08 (d, J=15.4 Hz, 1H), 4.06-4.00 (m, 1H), 3.20-3.13 (m, 2H), 1.32 (t, J=7.1 Hz, 3H), 0.78 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:15])([F:14])[CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([F:14])([F:15])[CH2:11][CH2:12][O:13][S:23]([CH3:22])(=[O:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC(F)(F)COCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC(F)(F)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyloxy-2,2-difluoro-4-hydroxybutane (50 g, 0.231 moles) and dry pyridine (100 mL) in dichloromethane cooled in an ice bath, methanesulfonyl chloride (26.52 g, 0.232 moles) in dichloromethane (100 mL) is slowly added. After stirring at room temperature overnight, the mixture is washed with 2N HCl (2×1 L) and twice with water. Drying and subsequent evaporation of the solvent yields 1-benzyloxy-2,2-difluoro-4-methanesulfonyloxybutane as a yellow oil: 63.44 g (93%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.C([Li])CCC.[Cl-].[CH3:19][Ga+:20][CH3:21]>CCOCC.CCCCCC.CCCCCC>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Ga:20]([CH3:21])[CH3:19]
Reactant: C[Ga+]C
Reactant: FC(F)(F)c1ccccc1CBr
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Ga](C)Cc1ccccc1C(F)(F)F
Reaction time: 0.25 h

Procedure:
5.25 g (22 mmol) of o-trifluoromethylbenzyl bromide in 10 ml of ether/hexane are added at -50° to a mixture of 45 ml of ether/hexane (2:1) and 14.7 ml (1.5N =22 mmol) of n-butyllithium. After stirring for 15 minutes, 2.1 g (16 mmol) of dimethylgallium chloride in 20 ml of hexane are added. Then the reaction mixture is allowed to come to room temperature, it is stirred for 24 hours, and the LiCl is filtered off and the solvent removed. After sublimation in vacuo, o-trifluoromethylbenzyldimethylgallium is obtained with a Mp. 35°-38°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].Br[C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([Br:15])[N:14]=1>C1COCC1>[Br:15][C:13]1[N:14]=[C:9]([O:7][CH2:6][CH2:5][O:4][CH3:3])[C:10]([NH2:16])=[N:11][CH:12]=1
Reactant: COCCO
Reactant: Nc1ncc(Br)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1nc(Br)cnc1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A flame-dried round bottom flask was charged with a suspension of 95% NaH (1.3 eq) in anhydrous THF (0.2 M). The stirring mixture was cooled to 0° C. in an ice-water bath and 2-methoxyethanol (1.2 eq) was added drop wise via syringe. After 30 min 3,5-dibromopyrazin-2-amine (1 eq) was added, the reaction was warmed to rt and stirred for 3 h. The crude mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were washed once each with H2O and brine, then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 5-bromo-3-(2-methoxyethoxy)pyrazin-2-amine. LC/MS (m/z): 250.0 (MH+).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>ClCCl>[CH3:8][O:7][C:5](=[O:6])[CH:4]=[CH:3][CH2:2][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)/C=C/CBr
Reactant: C1CCNCC1
Solvent: ClCCl
Product: COC(=O)C=CCN1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl 4-bromocrotonate (2 g, 11.2 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0° C. Piperidine (1.11 mL, 11.2 mmol) was added slowly. The mixture was stirred at 0° C. for 1 hour. The solvent was removed in vacuo. The crude material was used as is. MS m/z 184 (M+1).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[C:30]([C@@H:31]([F:42])[C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)=[C:29]([CH:43]4[CH2:48][CH2:47][C:46]([F:50])([F:49])[CH2:45][CH2:44]4)[C:28]4[C@@H:27]([O:51][CH2:52][C:53]5[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=5)[CH2:26][C:25]([CH3:62])([CH3:61])[CH2:24][C:23]=4[N:22]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>O1CCCC1>[F:50][C:46]1([F:49])[CH2:47][CH2:48][CH:43]([C:29]2[C:28]3[C@@H:27]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=4)[CH2:26][C:25]([CH3:62])([CH3:61])[CH2:24][C:23]=3[N:22]=[C:21]([CH:18]3[CH2:17][CH2:16][N:15]([C:12]4[N:13]=[CH:14][C:9]([OH:8])=[CH:10][N:11]=4)[CH2:20][CH2:19]3)[C:30]=2[C@@H:31]([F:42])[C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:39])([F:41])[F:40])=[CH:36][CH:37]=2)[CH2:44][CH2:45]1
Reactant: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(O[Si](C)(C)C(C)(C)C)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(O)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 1.00 g (1.13 mmol) of (5S)-2-(1-{5-[(tert-Butyldimethylsilyl)oxy]pyrimidin-2-yl}piperidin-4-yl)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 13, in 2 ml of tetrahydrofuran, 1.5 ml of a solution of 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran was added, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, toluene and water were added to the reaction solution to separate an organic phase. Further, the reaction mixture was extracted with toluene from the aqueous phase. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=78/22-55/45 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 861 mg of the title compound as a white solid (yield: 99%).
Reaction SMILES: [Na:1].C([O:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][N:27]1[C:31](=[O:32])[CH2:30][CH:29]([S:33]([OH:36])(=[O:35])=[O:34])[C:28]1=[O:37])=[O:25])=[O:11])C1C=CC=CC=1>CN(C)C=O.[C].[Pd]>[Na:1].[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][N:27]1[C:31](=[O:32])[CH2:30][CH:29]([S:33]([OH:36])(=[O:35])=[O:34])[C:28]1=[O:37])=[O:25])([OH:11])=[O:9]
Reactant: O=C(CCCCCCCCCCCCC(=O)ON1C(=O)CC(S(=O)(=O)O)C1=O)OCc1ccccc1
Agent: [Pd]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCCCCCC(=O)ON1C(=O)CC(S(=O)(=O)O)C1=O
Reaction time: 20 h
Yield: 43.6 %

Procedure:
In 1 ml of dimethylformamide was dissolved N-(13-benzyloxycarbonyltridecanoyloxy)sulfosuccinimide sodium salt (50 mg, 0.11 mmole). To the obtained solution, was added 5 mg of 10% palladium carbon and the mixture was stirred for 20 hours under an atmosphere of hydrogen. The reaction mixture was filtered and to the filtrate 30 ml of ethyl acetate was added. The mixture was stirred for 30 minutes and the solid that formed was collected by filtration and dried under reduced pressure to give N-(13-carboxytridecanoyloxy)sulfosuccinimide sodium salt (22 mg, 63%) having the following properties.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=2)[CH2:30][CH2:29]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCCc1cc(CCC=O)n(Cc2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(Cc2ccccc2)n1

Procedure:
180 mg (84.2%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-benzyl-3-butyl-1H-pyrazol-5-yl)propanal (133 mg, 0.492 mmol), 1-(2-fluorophenyl)piperazine (155 mL, 0.984 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[C:17]([C:18](=[O:21])[C:19]=3[OH:20])=[CH:16][C:15]([O:22][CH3:23])=[CH:14][CH:13]=4)=[CH:9][C:4]=2[O:3]C1.B(Br)(Br)Br>>[OH:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:21])[C:19]=2[OH:20])=[CH:16][C:15]([O:22][CH3:23])=[CH:14][CH:13]=3)[CH:7]=[CH:6][C:5]=1[OH:1]
Reactant: COc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1
Agent: BrB(Br)Br
Product: COc1ccc2oc(-c3ccc(O)c(O)c3)c(O)c(=O)c2c1
Yield: 58648816 %

Procedure:
The reaction was conducted according to the same procedure as Example 57 except that 50 mg (159 pmol) of the compound obtained in Example 5 instead of the compound obtained in Example 12 and 1.5 molar equivalents of boron tribromide (BBr3) were used. Then the resulting product was separated by preparative TLC to give 28 mg of the title compound in a yield of 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[CH:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.I[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: OCCc1ccc(I)cc1
Product: OCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1

Procedure:
The product was prepared analogously to Example 48.1c from 1.74 g (8.06 mmol) of 5-(4-chlorophenyl)-2-ethynylpyridine and 2.00 g (8.06 mmol) of 2-(4-iodophenyl)ethanol (24 at RT, triethylamine as base and acetonitrile as solvent). Yield: 1.80 g (67% of theoretical); C21H16ClNO (M=333.811); calc.: molpeak (M+H)+:334/336 (Cl); found: molpeak (M+H)+:334/336 (Cl).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([NH2:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:20][C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24].O1CCOCC1.C1(C)C=CC=CC=1>O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][C:21]1[N:10]=[C:8]([C:7]2[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]([OH:14])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[O:9][CH:20]=1
Reactant: CC(C)(C)c1cc(C(N)=O)cc(C(C)(C)C)c1O
Reactant: COC(=O)CC(=O)CCl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)Cc1coc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Yield: 46.3 %

Procedure:
A mixture of 3,5-di-tert-butyl-4-hydroxybenzamide (5.0 g, 20.0 mmol), methyl 4-chloroacetoacetate (3.01 g, 20.0 mmol), dioxane (30 mL), and toluene (300 mL) was refluxed for 5 days, with continuous water removal (Dean Stark trap). The volatiles were removed in vacuo and the residue waspurified by flash chromatography on silica gel (eluting solvent: hexane/EtOAc 3/1) to give a brown viscous oil (3.2 g). Crystallization of the brown oil from ethyl ether (after cooling to 0° C.) gave a white solid (2.6 g, 38% yield), m.p. 126°-128° C.