Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[N:19]=[C:18]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=[CH:16][CH:15]=2)=[N:13]1
Reactant: CC(C)(C)OC(=O)CCOCCCc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCOCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 72.5 %

Procedure:
Methyl thiosalicylate (1.0 g, 6.1 mmol) and tert-butyl 3-[3-(6-cyano-2-pyridyl)propoxy]propanoate (1.6 g, 5.5 mmol) were dissolved in toluene (5.0 ml). Triethylamine (1.35 ml, 9.7 mmol) was added to the mixture and the mixture was refluxed for 14 hrs. The reaction mixture was subjected to a silica gel (110 g) column chromatography and eluted with hexane-ethyl acetate (3:2, v/v) to give the titled compound (1.7 g, 67%) as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][C:4]#[CH:5].[Br:7][C:8]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:9]=1[O:10][C:11]1[C:20]2[C:15](=[CH:16][C:17](OS(C(F)(F)F)(=O)=O)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1>>[Br:7][C:8]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:9]=1[O:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:5]#[C:4][CH2:3][N:2]([CH3:6])[CH3:1])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1OS(=O)(=O)C(F)(F)F
Reactant: C#CCN(C)C
Product: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1C#CCN(C)C

Procedure:
Using an analogous procedure to that described in the second last paragraph of Note [115] above, 3-dimethylamino-1-propyne was reacted with 4-(2-bromo-4-fluorophenoxy)-6-methoxy-7-trifluoromethanesulphonyloxyquinazoline to give 4-(2-bromo-4-fluorophenoxy)-6-methoxy-7-(3-dimethylamino-1-propynyl)quinazoline; NMR Spectrum: (DMSOd6) 2.29 (s, 6H), 3.55 (s, 2H), 4.0 (s, 3H), 7.38-7.83 (m, 3H), 7.67 (s, 1H), 8.05 (s, 1H), 8.63 (s, 1H); Mass Spectrum: M+H+ 430 and 432.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:18])[O:19][CH2:20][CH3:21])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(N)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Using a method analogous to that disclosed in Example 1, Step A, of U.S. Pat. No. 4,552,585, a solution of 10.0 grams (0.071 mole) of 3-chloro-4-methylaniline in 100 mL of chloroform was stirred, and 16.7 grams (0.212 mole) of pyridine was added. Ethyl chloroformate, 9.2 grams (0.085 mole), was then added dropwise during a 20 minute period. During the addition the reaction mixture temperature was held between 25°-30° C. with external cooling. Upon completion of addition the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was washed into a separatory funnel with 50 mL of chloroform, and the solution was washed with two 100 mL portions of water and 100 mL of aqueous 5% hydrochloric acid. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a waxy solid residue. The residue was recrystallized from hexane to yield 12.2 grams of ethyl (3-chloro-4-methylphenyl)carbamate; m.p. 51°-52° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:19])[CH2:15][CH:16](O)[CH3:17]>>[C:1]([O:12][CH:16]([CH3:17])[CH2:15][N:14]([CH3:19])[CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(O)CN(C)C
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)OC(C)CN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1-dimethylamino-2-propanol as starting materials to give the aimed compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7](O)=[C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:5]([CH3:17])=[N:4]1)[CH3:2].C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:17])[C:6]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: CCn1nc(C)c(C(=O)c2ccccc2)c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCn1nc(C)c(C(=O)c2ccccc2)c1Cl

Procedure:
A solution of 2.6 g of (1-ethyl-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-phenyl-methanone in 4 ml of phosphorus oxychloride was stirred at 80° C. for 1.5 h. The mixture was poured into 300 ml of saturated sodium hydrogen carbonate and extracted three times with 70 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40-60° C.) (1:4) for the elution to give 1.74 g of (5-chloro-1-ethyl-3-methyl-1H-pyrazol-4-yl)-phenyl-methanone as a pale yellow liquid. Mass spectrum (ES) m/z 249 [M+H]+, 290 [M+H+CH3CN]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[O:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=O.[OH:21][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[CH2:23][NH2:24].O.Cl>C1C=CC=CC=1>[ClH:31].[Cl:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH:22]([OH:21])[CH2:23][NH:24][CH:2]([CH3:4])[CH2:1][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[O:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(Oc2ccc(CC(C)=O)cc2)o1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 5-[4-acetonylphenoxy]furan-2-carboxylate (1.04 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (0.65 ) in dry benzene (100 ml) was heated under reflux, with azeotropic removal of water, for 1 hr. the solvent was evaporated and the residue dissolved in methanol (100 ml), cooled, and treated with sodium borohydride (0.4 g), in portions. The reaction mixture was stirred at ambient temperature for 2 hr. The solvent was evaporated and the residue partitioned between water and chloroform. The organic layer was dried (MgSO4) and evaporated to an oil which was purified by column chromatography on silica gel. Elution with 4% methanol:chloroform gave a colourless oil. An ethereal solution of the free base was treated with hydrogen chloride gas to give methyl 5-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxy]furan-2-carboxylate, hydrochloride as a 65:35 mixture of diastereoisomers, m.p. 148°-150° C. (ethylacetate-ether).
Reaction SMILES: C([C:5]1[C:13]([CH2:14][N:15]([C:17](=[O:30])[CH:18]([OH:29])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH3:16])=[C:12]([NH2:31])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(C)(C)C.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[NH2:31][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:13]=1[CH2:14][N:15]([C:17](=[O:30])[CH:18]([OH:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[CH3:16]
Reactant: CN(Cc1c(N)ccc(C(=O)O)c1C(C)(C)C)C(=O)C(O)Cc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cc(C(=O)O)ccc1N)C(=O)C(O)Cc1c[nH]c2ccccc12
Reaction time: 12 h

Procedure:
To a stirred solution of t-butyl-4-amino-3-[(2-hydroxy-3-indol-3-yl-N-methylpropanoylamino)methyl]benzoic acid (0.99 g, 2.34 mmole) in CH2Cl2 (20 mL) at RT was added TFA (20 mL). After 12 hr, the reaction contents were evaporated, washed with Et2O and dried under high vacuum overnight affording the title compound (0.86 g, 2.34 mmol) as a pink solid. This product was used without further purification: MS (ES) m/e 369 (M+H-TFA)+.
Reaction SMILES: [CH2:1]([C:9]1[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[C:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:11]2[S:12][CH:13]=[CH:14][C:10]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.[CH3:34][Sn:35](Cl)([CH3:37])[CH3:36].O>O1CCCC1>[CH2:1]([C:9]1[C:17]2[S:18][C:19]([Sn:35]([CH3:37])([CH3:36])[CH3:34])=[CH:20][C:16]=2[C:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:11]2[S:12][C:13]([Sn:35]([CH3:37])([CH3:36])[CH3:34])=[CH:14][C:10]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1c2ccsc2c(CCCCCCCC)c2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCc1c2cc([Sn](C)(C)C)sc2c(CCCCCCCC)c2cc([Sn](C)(C)C)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 4,8-dioctylbenzo[1,2-b:4,5-b′]dithiophene (782 mg, 1.89 mmol) in dry tetrahydrofuran (36 mL) was added n-butyllithium (2.5 M in hexane, 1.66 mL, 4.15 mmol) at −78° C. After 1 hour, trimethyltin chloride (877 mg, 4.40 mmol) was added in one portion. The mixture was stirred at room temperature for 2 hours, poured into water and extracted with ether three times. The organic layer was washed with brine and dried over anhydrous MgSO4. Upon evaporating the solvent, a pale yellow oil was obtained (1.03 g, yield 74%). Upon standing for one week, yellow crystals emerged and were collected (413 mg, yield 29%). 1H NMR (CDCl3, 500 MHz) δ=7.51 (s, 2H), 3.22 (t, J=8.0 Hz, 4H), 1.76-1.89 (m, 4H), 1.45-1.54 (m, 4H), 1.22-1.45 (bs, 16H), 0.90 (t, J=7.0 Hz, 6H), 0.47 (s, 18H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1.O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:23]([CH:20]2[CH2:22][CH2:21]2)=[O:24])[S:13][C:9]=1[C:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)C1CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
Compound 454 (1.67 g, 6.00 mmol) and DMAP (36.7 mg, 0.300 mmol) were suspended in pyridine (24 mL), and cyclopropanecarbonyl chloride (1.09 mL, 12.0 mmol) was added thereto, followed by stirring at 60° C. for 90 minutes. The reaction mixture was poured into water, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (chloroform:methanol=99:1), followed by recrystallizing from ethanol to afford the entitled Compound 456 (1.35 g, 65%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.Br.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:29]=[C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][NH:20][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)[CH:28]=[CH:27][NH:26]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: NCCc1cc[nH]c(=O)c1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2ccc(C(=O)NCCc3cc[nH]c(=O)c3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (100 mg, 0.4 mmol), 4-(2-aminoethyl)pyridin-2(1H)-one hydrobromide (96 mg, 0.44 mmol), HATU (182 mg, 0.48 mmol) and DIEA (155 mg, 1.20 mmol) in 30 mL of DCM was stirred at room temperature overnight. The solution was washed with sat NaHCO3 (2×30 mL), brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduce pressure to give crude N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (160 mg) and used without further purification. LC-MS: 369 [M+H]+, tR=1.35 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[O:34]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[N-]=C=O>CN(C=O)C.C(O)(=O)C>[O:34]1[CH:38]=[CH:37][C:36]([CH2:39][N:11]2[CH2:12][CH2:13][CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:9]([CH2:8][N:7]([C@@H:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH3:22])[C:6](=[O:33])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]2)=[CH:35]1
Reactant: O=Cc1ccoc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [N-]=C=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(Cc2ccoc2)CCC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a mixture of 13.3 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate, 3.4 mg of 3-furaldehyde, 0.050 mL of acetic acid, and 0.5 mL of DMF was added 75 mg of MP-Triacetoxyborohydride (Argonaut Technologies, USA) at room temperature, followed by stirring overnight. To the reaction mixture was added 50 mg of PS-Isocyanate (Argonaut Technologies, USA) at room temperature, followed by stirring for 2 hours, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl {[1-(3-furylmethyl)-4-phenylpiperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a crude product. To 0.5 mL of a methanol solution of the obtained crude product was added 0.5 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: registered trademark SunFire, Waters, particle diameter of 5 μm, inner diameter of 19 mm, and length of 100 mm), flow rate: 25 ml/min., column temperature: 20° C., methanol—a 0.1% aqueous formic acid solution) to obtain 4.9 mg of (1R)—N-{[1-(3-furylmethyl)-4-phenylpiperidin-3-yl]methyl}-1-(1-naphthyl)ethaneamine.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH2:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=1.Cl>O.CO>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])=[CH:26][CH:27]=2)=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(Nc1ccccc1)c1ccc(CCl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccccc1)c1ccc(CSc2ccc(O)cc2)cc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
In a 200 ml four-necked flask equipped with a stirrer and a thermometer, 1.34 g (10.6 mmol) of 4-mercaptophenol, 0.7 g (10.6 mmol) of potassium hydroxide and 50 ml of methanol were added at room temperature. After confirming that potassium hydroxide has been dissolved, the inner temperature was cooled to 10° C. and 2.6 g (10.6 mmol) of 4-chloromethyl-N-phenylbenzamide was added, followed by stirring at room temperature for 3 hours. After the completion of the reaction, the reaction solution was acidified with hydrochloric acid and 50 ml of water was added, and then the deposited crystal was collected by filtration to obtain 3.0 g of 4-(4-hydroxyphenylthiomethyl)-N-phenylbenzamide. The yield was 84%. The melting point was 220–222° C.
Reaction SMILES: C[O-].[Na+].[NH:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[C:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=[CH:13][C:12]([C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:18])[CH2:16]Cl)=[CH:11][CH:10]=1>CO.CN(C)C=O>[C:9]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:10]=[CH:11][C:12]([C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:18])[CH2:16][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:13][CH:14]=1
Reactant: OC(CCl)(c1ccccc1)c1ccc(-c2ccccc2)cc1
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: OC(Cn1ccnc1)(c1ccccc1)c1ccc(-c2ccccc2)cc1
Yield: 12.2 %

Procedure:
2.45 g (0.045 mol) of sodium methylate are dissolved in 20 ml of methanol, and 5.25 g (0.077 mol) of imidazole are added. A solution of 11.1 g (0.077 mol) of 1-(4-biphenylyl)-2-chloro-1-phenyl-ethanol in 50 ml of dimethylformamide is added dropwise to this mixture and the reaction mixture is heated under reflux for 16 hours. Thereafter, it is poured onto water and the crystals which form are extracted with hot acetonitrile. 3.2 g (21% of theory) of 1-(4-biphenylyl)-2-(imidazol-1-yl)-1-phenyl-ethanol of melting point 224° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[C:14]1[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=1.C(=O)(O)[O-].[Na+].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.O1CCOCC1>[CH3:19][C:17]1[N:18]=[C:14]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[S:15][C:16]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1sc(Br)nc1C
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(-c2ccc([N+](=O)[O-])cc2)nc1C
Yield: 83 %

Procedure:
The same operation as in Example (91a) was performed using 4-nitrophenylboronic acid (1 g, 6 mmol), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (1 g, 4 mmol), sodium bicarbonate (1.34 g, 16 mmol), tetrakis(triphenylphosphine)palladium (460 mg, 0.4 mmol), water (5 mL) and 1,4-dioxane (10 mL), to obtain 0.97 g of the title compound as a light yellow solid (83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][OH:14])=[C:11]([C:15]([N:17]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@@H:18]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][C@H:20]([C:31](OC)=[O:32])[CH2:19]2)=[O:16])[N:10]=[N:9]1.[CH3:39][OH:40]>C1COCC1.O.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][OH:14])=[C:11]([C:15]([N:17]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:18]2[CH2:19][C@@H:20]([C:31]([N:8]3[CH2:3][CH2:2][O:40][CH2:39][CH2:12]3)=[O:32])[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:23]2)=[O:16])[N:10]=[N:9]1
Reactant: CO
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nnn(-c3ccccc3F)c2CO)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (1.05 g) was dissolved in THF (10 ml)-methanol (8 ml)-water (8 ml), 8M aqueous sodium hydroxide solution (600 μl) was added and the mixture was stirred at 70° C. for 1.5 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water, neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue, morpholine, 1-hydroxybenzotriazole (150 mg) and triethylamine (700 μl) were dissolved in acetonitrile (20 ml), WSC.HCL (555 mg) was added and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed with water. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (764 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[S:12][CH2:13][CH2:14][OH:15].O=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([NH:1][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[C:3]([S:12][CH2:13][CH2:14][OH:15])[CH:4]=1
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1SCCO
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])c(F)cc2SCCO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a stirred solution of 2-(2-amino-5-fluoro-4-nitrophenylthio)ethanol (434 mg, 1.869 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (372 mg, 1.869 mmol) in dichloroethane (10 mL) and acetic acid (0.321 mL, 5.61 mmol) was added sodium triacetoxyborohydride (594 mg, 2.80 mmol). The resulting mixture was stirred at room temperature. After 1 hour, additional tert-butyl 4-oxopiperidine-1-carboxylate (372 mg, 1.869 mmol) was added, followed by additional sodium triacetoxyborohydride (594 mg, 2.80 mmol). After a further 3 hours, more tert-butyl 4-oxopiperidine-1-carboxylate (372 mg, 1.869 mmol) was added followed by more sodium triacetoxyborohydride (594 mg, 2.80 mmol). The reaction mixture was stirred overnight. The mixture was then quenched with 1 N NaOH (10 mL), water (20 mL), and saturated sodium carbonate (20 mL). The organic products were then extracted with dichloromethane (3×20 mL). The combined organics were dried, filtered, concentrated, and then chromatographed using 1:3 ethyl acetate:hexanes on silica gel to give the desired product (710 mg, 91%). 1H NMR (DMSO-d6) δ 7.45 (d, J=12.0 Hz, 1H), 7.23 (d, J=6.6 Hz, 1H), 5.08 (t, J=5.4 Hz, 1H), 5.02 (d, J=8.1 Hz, 1H), 3.96-3.84 (m, 2H), 3.69-3.55 (m, 5H), 2.99-2.83 (m, 2H), 1.92-1.83 (m, 2H), 1.45-1.18 (m, 11H); ESI-MS (m/z, %): 360 (100), 128 (30).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7].[CH2:42](I)[CH3:43]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][C:19]([CH2:42][CH3:43])=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7]
Reactant: CCI
Reactant: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1
Product: CCc1cc2ccn3c(=O)c(-c4ccc(OCc5ccccc5)cc4)cc(C(=O)N(CCOC)c4ccccc4)c3c2s1

Procedure:
By lithiation of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide and reaction with ethyl iodide.