Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[CH2:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH3:10]>>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:9]([NH+:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH3:10]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(O)C(F)(F)F
Product: CC[NH+](CC)CC
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
Equimolar amounts of triethylamine and trifluoromethanesulfonic acid were weighed in a glove box under argon atmosphere. The weighed triethylamine and trifluoromethanesulfonic acid were mixed and stirred while being cooled by liquid nitrogen, thus obtaining a target ionic conductor.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15])([O-:3])=[O:2].[Cl:18][C:19]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][C:19]1[CH:28]=[CH:27][C:26]([NH:29][S:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:16])=[O:15])=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 45.3 %

Procedure:
In a similar fashion using route 14 general procedure 27, 2-nitro-4-trifluoromethylbenzenesulfonyl chloride (Intermediate 461) (1.24 g, 4.29 mmol), 5-chloro-quinolin-8-ylamine (Intermediate 27) (0.64 g, 3.58 mmol), DMAP (cat.), pyridine (0.86 ml, 10.7 mmol) and DCM (5 ml) gave the title compound (700 mg, 45%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: C(N)C=CC#CCC.[S:9]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16](/[CH:20]=[CH:21]/[CH2:22][O:23][CH2:24][CH2:25]O)[CH:17]=[CH:18][CH:19]=2)=[CH:10]1.[ClH:27].[CH2:28]([NH:30][CH2:31]/[CH:32]=[CH:33]/[C:34]#[C:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:29]>>[ClH:27].[CH2:28]([N:30]([CH2:25][CH2:24][O:23][CH2:22]/[CH:21]=[CH:20]/[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)[CH:15]=1)[CH2:31]/[CH:32]=[CH:33]/[C:34]#[C:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH3:29]
Reactant: CCNC/C=C/C#CC(C)(C)C
Reactant: OCCOC/C=C/c1cccc(-c2ccsc2)c1
Agent: CCC#CC=CCN
Agent: Cl
Product: CCN(C/C=C/C#CC(C)(C)C)CCOC/C=C/c1cccc(-c2ccsc2)c1

Procedure:
Compounds of Examples 26 to 29 were obtained by performing the same reaction as in Example 25 except that the corresponding alcohol derivatives and/or 2-hepten-4-ynylamine derivatives were used instead of the starting compounds, (E)-2-[3-[3-(3-thienyl)phenyl]-2propenyloxy]ethanol and/or (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, which were used in the above-mentioned reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11](=[O:20])[CH2:12][C@@H:13]([OH:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(B(CC)OC)C.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C@@H:11]([OH:20])[CH2:12][C@@H:13]([OH:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C[C@H](O)CC(=O)/C=C/c1ccc(Cl)cc1Cl
Agent: CCB(CC)OC
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)C[C@H](O)C[C@H](O)/C=C/c1ccc(Cl)cc1Cl

Procedure:
For instance, methyl (3R,6E)-3-[(tert-butyldimethylsilyl)oxy]-7-(2,4-dichlorophenyl)-5-oxo-6-heptenoate (which is one of the compounds of the formula (1)) is subjected to the tert-butyldimethylsilyl removing step using hydrogen fluoride in the manner as described in Japanese Patent Provisional Publication H5 (1993)-178841, to give methyl (3R,6E)-7-(2,4-dichlorophenyl)-3-hydroxy-5-oxo-6-heptenoate. The obtained ester is then subjected to Syn reduction using diethylmethoxyborane and sodium borohydride (NaBH4), to give methyl (3R,5S,6E)-7-(2,4-dichlorophenyl)-3,5-dihydroxy-6-heptenoate. Subsequently, thus obtained ester is treated with sodium hydroxide and hydrochloric acid in the manner as described in Journal of Medicinal Chemistry, 1985, vol. 28, No. 3, pp. 347-358, to give (+)-trans-(E)-6-[2-(2,4-dichlorophenyl)ethenyl]3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-on which has the 3-hydroxy-3-methylglutaryl Coenzyme A reductase preventive action.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:24])OCC2C=CC=CC=2)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:25]1([NH2:35])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)CCC1.[CH2:36]([N:39]([CH2:53][CH2:54][CH3:55])[C:40]([C:42]1[CH:43]=[C:44](C=C(CC)C=1)[C:45](O)=[O:46])=[O:41])[CH2:37][CH3:38]>>[CH2:25]([NH:35][CH2:13][C@@H:11]([OH:12])[C@@H:10]([NH:14][C:15]([C:45]1[O:46][C:42]([C:40]([N:39]([CH2:53][CH2:54][CH3:55])[CH2:36][CH2:37][CH3:38])=[O:41])=[CH:43][CH:44]=1)=[O:24])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[C:34]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Reactant: NC1CCCc2ccccc21
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Product: CCCN(CCC)C(=O)c1ccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2ccccc2)o1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V), H2N—CH2-phenyl (VI) and (CH3—CH2—CH2—)2N—CO—(2,5-furanyl)—CO— (IX), the title compound is obtained, MH+=528.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[O:15])[CH:5]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:3]1=2.[C:23]([Mg]Br)#[CH:24]>C1COCC1>[CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([OH:15])[C:23]#[CH:24])[CH:5]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:3]1=2
Reactant: CCOCCOc1cc(C=O)cc2c1C(C)(C)CCC2(C)C
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)c1cc(OCCOCC)c2c(c1)C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 97 %

Procedure:
40 g (131 mmol) of 5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde are dissolved in 400 mL of THF. 290 mL (145 mmol) of 0.5N ethynylmagnesium bromide solution are added and the reaction medium is then stirred for 1 hour. After treatment with 1N hydrochloric acid solution and extraction with ethyl acetate, followed by evaporation, the residue is purified by chromatography on a column of silica (eluent: 8/2 heptane/EtOAC). A yellow oil is obtained (m=42 g; yield=97%).
Reaction SMILES: [Na].[CH3:2][C:3]([C@@H:5]1[C@@:9]2([CH3:24])[CH2:10][CH2:11][C@@H:12]3[C@@:17]4([CH3:23])[CH2:18][CH2:19][C@@H:20]([NH2:22])[CH2:21][C:16]4=[CH:15][CH2:14][C@H:13]3[C@@H:8]2[CH2:7][CH2:6]1)=[O:4].C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)CC.O>[NH2:22][C@@H:20]1[CH2:19][CH2:18][C@@:17]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:12]2[CH2:11][CH2:10][C@@:9]2([CH3:24])[C@H:8]3[CH2:7][CH2:6][C@@H:5]2[CH:3]([OH:4])[CH3:2])[CH2:21]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCCO
Solvent: O
Solvent: CC(=O)O
Product: CC(O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a refluxing 100 ml of propanol were simultaneously added, over a period of 20 minutes, in small portions 5 g of sodium and a solution of 5 g of holamine in 5 ml of propanol while continuing reflux. After 1 hour and 25 minutes, the temperature was returned to ambient, the mixture chilled and acidified with acetic acid to pH 6. The pH raised to pH 8 with potassium carbonate and the mixture was diluted with 500 ml of water, partially evaporated, 300 ml of water were added and the mixture was allowed to crystallize for 24 hours in the refrigerator. The filtered crystals were washed in water and dissolved in 10 ml of methylene chloride to which was added 50 ml of ethyl acetate and 30 ml of isopropyl ether. The methylene chloride was evaporated and the product allowed to crystallize during 16 hours in the refrigerator. 3 g of 3α-amino pregn-5-ene- 20-ol was obtained melting at 160°.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])[NH:5][C:6](=[O:9])[C:7]=1[NH2:8].C([O-])(=O)C.[K+].N[C:26](N)=[S:27]>>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]2[C:7](=[N:8][C:26]([SH:27])=[N:1]2)[C:6](=[O:9])[N:5]=1)[CH2:18][CH3:19]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [K+]
Product: CCCOc1ccccc1C1=NC(=O)C2=NC(S)=NC2=N1
Temperature: 175 °C

Procedure:
A mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one (1.3 g), anhydrous potassium acetate (0.34 g) and thiourea (0.96 g) was heated at 170-180° C. for 2 hours. After digestion with water the mixture was filtered and the solid was dissolved in 1 Normal sodium hydroxide solution then re-precipitated by the addition of acetic acid. The dried solid was digested with chloroform and with ethanol to leave 1.12 g of a crude product. Repeated recrystallisations from dimethylformamide, 2-methoxyethanol, and acetic acid yielded the title compound, 0.32 g, m.p. 305-307° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16]N(C3C=CC(OC(C)C)=CC=3)CN(C3C=CC(OC(C)C)=CC=3)[CH2:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].ClC(OC(Cl)(Cl)Cl)=[O:39].[CH:45]([NH:48][C:49]([NH:51][CH:52]([CH3:54])[CH3:53])=[S:50])([CH3:47])[CH3:46].[OH-].[Na+]>>[CH:45]([N:48]=[C:49]1[N:51]([CH:52]([CH3:54])[CH3:53])[C:16](=[O:39])[N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=2)[CH2:12][S:50]1)([CH3:47])[CH3:46]
Reactant: CC(C)Oc1ccc(N2CN(c3ccc(OC(C)C)cc3)CN(c3ccc(OC(C)C)cc3)C2)cc1
Reactant: CC(C)NC(=S)NC(C)C
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)N=C1SCN(c2ccc(OC(C)C)cc2)C(=O)N1C(C)C
Yield: 66.8 %

Procedure:
In a similar manner, 2.8 g (0.006 mole) of 1,3,5-tris(p-isopropoxyphenyl)-hexahydro-s-triazine, 1.8 g (0.009 mole) of trichloromethyl chloroformate, 2.6 g (0.016 mole) of 1,3-diisopropylthiourea, and 15 g of a 10% aqueous sodium hydroxide solution were used to obtain 1.4 g (24% yield) of 2-isopropylimino-3-isopropyl-5-(p-isopropoxyphenyl)-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 372) of the formula, ##STR172## as white crystals melting at 60°-61° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([CH:8]1[C:17]2[CH:16]=[C:15]3[N:18]([CH3:25])[C:19](=[O:24])[CH:20]=[C:21](OC)[C:14]3=[CH:13][C:12]=2[NH:11][CH2:10][CH2:9]1)[CH3:7].O.CN(C)[CH:29]=[O:30]>>[Cl:3][C:21]1[C:14]2[C:15](=[CH:16][C:17]3[CH:8]([CH2:6][CH3:7])[CH2:9][CH2:10][NH:11][C:12]=3[CH:13]=2)[N:18]([CH3:25])[C:19](=[O:24])[C:20]=1[CH:29]=[O:30]
Reactant: CCC1CCNc2cc3c(OC)cc(=O)n(C)c3cc21
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Solvent: O
Product: CCC1CCNc2cc3c(Cl)c(C=O)c(=O)n(C)c3cc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
0.4 g of phosphorus oxychloride is added dropwise at 50-55° C. to 3 ml of dimethylformamide. The solution is stirred for a further 1 h at 50° C. 0.5 g (1.8 mmol) of 9-ethyl-4-methoxy-1-methyl-6,7,8,9-tetrahydropyrido-[2,3-g]quinol-2-one dissolved in 6 ml of dimethylformamide is then added at the same temperature with stirring. The mixture is stirred at 80-90° C. for a further 5 h. The intensively yellow-colored solution is discharged onto 50 ml of water and 10 g of ice and stirred at room temperature for 12 h. The pale-yellow precipitate is filtered off and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][S:6]([CH3:9])(=O)=O.[Br:19][C:20]1[CH:25]=[CH:24]C(S)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][S:6][C:9]1[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=1
Reactant: COC(=O)C(CS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: Sc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(CSc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Solution of 2-tert-Butoxycarbonylamino-3-methylsulfonylpropanoic acid methyl ester (0.86 g, 2.89 mmol) and 4-bromobenzenthiol (0.56 g, 2.89 mmol) in DMF (10 mL) was cooled to at 0° C. and treated with Cs2CO3 (1.1 g, 3.2 mmol). After stirring at room temperature for 2 h, the reaction was acidified with 5% HCl (15 mL) and diluted with ethyl acetate (25 mL). After separation, the aqueous layer was extracted with ethyl acetate (3×15 mL) and the combined organic layers were washed with sat. aq NaCl, dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography (5% ethyl acetate in heptane) gave the desired product (857 mg, 76%) as a white solid. 1H NMR (CDCl3), δ 7.40 (d, J=9 Hz, 2H), 7.27 (d, J=9, 2H), 5.30 (d, J=7 Hz, 1H), 4.56 (m, 1H), 3.59 (s, 3H), 3.35 (ddd, J=7, 7, 12 Hz, 2H), 1.47 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[C:11]([O:14][CH:15]=[CH2:16])(=[O:13])[CH3:12]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[C:11]([O:14][C@@H:15]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:16])(=[O:13])[CH3:12]
Reactant: CC(O)c1cncc(Br)c1
Reactant: C=COC(C)=O
Solvent: CCOCC
Product: CC(=O)O[C@H](C)c1cncc(Br)c1
Product: C[C@H](O)c1cncc(Br)c1
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(5-bromopyridin-3-yl)ethanol (2.0 g) in anhydrous Et2O (50 mL) at 0° C., was vinyl acetate (2 mL), 4A° molecular sieves (2.0 g), Lipase immobilized from Candida Antarctica (200 mg) and the reaction was stirred for 16 h. The catalyst and molecular sieves were filtered off and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc in hexanes) to provide 1.0 g of (S)-1-(5-bromopyridin-3-yl)ethanol and 1.18 g of (R)-1-(5-bromopyridin-3-yl)ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:10]([CH2:13][S:14]([C:17]2[CH:22]=C[C:20](F)=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].BrC1C(OC)=C(C(CSC2C=CC=CC=2)=CC=1)C(OCC)=O.[N:48]1C=CC=C(S([O-])(=O)=O)C=1.[Na+]>>[Br:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:10]([CH2:13][S:14]([C:17]2[CH:22]=[N:48][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC
Reactant: O=S(=O)([O-])c1cccnc1
Agent: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Agent: [Na+]
Product: CCOC(=O)c1c(CS(=O)(=O)c2cccnc2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 85, starting from ethyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 87) and sodium 3-pyridinesulphonate (prepared according to Crowell et al, J. med. Chem., 1989, 32, 2436).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[C:25]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]([CH3:25])[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (0.25 g, 0.00078 mole) in DMF (5 mL) was added K2CO3 (0.225 g, 0.00163 mole) followed by methyl iodide (0.116 g, 0.00081 mole) and at the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was then quenched with iced water and the resulting precipitate was isolated by filtration. The solid was recrystallized from ethyl acetate to afford 0.251 g (96%) of 5-(2-benzyloxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 337.15 (M+1)+, 90.13%. To a stirred solution of 5-(2-benzyloxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.251 g, 0.00075 mole) in methanol (40 mL) was added 10% Pd/C (0.05 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 1 hour. The mixture was then filtered through celite and the celite was washed with methanol. The combined filtrate was concentrated under reduced pressure to afford 0.169 g (92%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 247.1 (M+1)+, 99%. To a stirred solution of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.169 g, 0.00069 mol) in a mixture of THF (10 mL), methanol (5 mL) and H2O (5 mL), was added LiOH.H2O (0.087 g, 0.00206 mol) at ambient temperature and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and acidified with 10% HCl. The product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 0.13 g (87%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid. LCMS: 219.07 (M+1)+, 81.5%
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[CH3:7])(=[O:3])[CH3:2].C(OCCBr)(=O)C.[OH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)Br
Reactant: Oc1cccc2cccnc12
Agent: CC(=O)OCCBr
Product: CC(=O)OCCCOc1cccc2cccnc12

Procedure:
3-(Quinolin-8-yloxy)propyl acetate (44A) was prepared following a similar procedure as that described in example 39, except 2-bromopropyl acetate for 2-bromoethyl acetate and 8-hydroxyquinoline was used instead of 3-(dimethylamino)phenol in step 1 of example 39.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][S:12]([C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.B(Br)(Br)Br.O.C(=O)(O)[O-]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][S:12]([C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:21])=[O:22])=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCS(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(S(=O)(=O)CCCc2ccc(O)cc2)s1
Temperature: -78 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a suspension of product from Step B, (3.0 g, 8.0 mmol) in CH2Cl2 (132 ml), cooled to -78° C., was added boron tribromide (25.9 ml, 1.0M in CH2Cl2, 25.9 mmol) dropwise and the resulting mixture was stirred at room temperature overnight. The reaction was cooled to 0° C., water and saturated bicarbonate solution added and extracted with ethyl acetate. Drying and solvent evaporation gave a solid (2.9 g); recrystallization from CHCl3 gave the title compound (1.5 g, 52%); m.p. 112°-115° C.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)S(C(F)(F)F)(=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]([O:41][CH:42]=[CH2:43])(=[O:40])[CH3:39]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:38]([O:41][CH:42]=[CH:43][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)(=[O:40])[CH3:39]
Reactant: C=COC(C)=O
Reactant: O=S(=O)(Oc1ccc2ccccc2c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)OC=Cc1ccc2ccccc2c1
Yield: 50.6 %

Procedure:
To a solution of 2-naphthyl triflate (90 g, 326 mmol) in DMF (240 ml), add triphenylphosphine (9.6 g, 36.6 mmol), vinyl acetate (149 g, 1862 mmol) and palladium acetate (3.8 g, 17 mmol). Reflux the reaction mixture for 1 h, then quench by addition of sat'd NaHCO3 solution. Extract the mixture with Et2O, dry and concentrate. Purify the residue by chromatography on silica gel (5% EtOAc in hexane) to obtain 35 g (165 mmol, 51%) 2-(2-naphthyl)vinyl acetate.
Reaction SMILES: [NH2:1][C:2]1[C:23](I)=[CH:22][C:5]([CH2:6][NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[O:9])=[CH:4][C:3]=1[F:25].[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC>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.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:23]([CH:26]=[CH2:27])=[CH:22][C:5]([CH2:6][NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[O:9])=[CH:4][C:3]=1[F:25]
Reactant: CC(C)(C)c1ccc(CNC(=O)NCc2cc(F)c(N)c(I)c2)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(CNC(=O)NCc2ccc(C(C)(C)C)cc2)cc(F)c1N

Procedure:
To the 50 ml round bottom flask were put 1-(4-amino-3-fluoro-5-iodo-benzyl)-3-(4-t-butyl-benzyl)-urea (0.17 g, 0.37 mmol) and Pd(PPh3)4 (0.05 eq, 21.3 mg). And to this reaction mixture was added 20 ml toluene and tributyl(vinyl)tin (1.1 eq, 0.13 g) by syringe and refluxed for 2 hours. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, washed with 1M KF solution. And the combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (n-hexane/ethyl acetate=2/1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[C:21](I)=[CH:20][N:19]=2)[CH2:8][C@@:7]1([NH2:42])[CH2:40][CH3:41])=[O:5])[CH3:2].[SH:43][CH2:44][CH2:45][OH:46].C(O)CO.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.[Cu](I)I.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[C:21]([S:43][CH2:44][CH2:45][OH:46])=[CH:20][N:19]=2)[CH2:8][C@@:7]1([NH2:42])[CH2:40][CH3:41])=[O:5])[CH3:2]
Reactant: OCCS
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](c2ncc(I)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@@]1(N)CC
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCO
Solvent: CC(C)O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](c2ncc(SCCO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@@]1(N)CC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-iodopyrimidin-2-yl)}-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (400 mg) is dissolved in isopropyl alcohol (2 ml), then thereto are added 2-mercaptoethanol (96 μl), copper iodide (20 mg), ethylene glycol (62 μl) and potassium carbonate (156 mg), and the mixture is stirred at 80° C. under nitrogen flow overnight. After cooling to room temperature, water is added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer is washed with a saturated brine twice, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=2:1→1:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethylsulfanyl)pyrimidin-2-yl]}-amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (110 mg). MS (m/z): 660 [M+H]+