Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[N:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[C:11]=S.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:33][NH2:34]>C1COCC1.O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]3[NH:33][N:34]=[C:11]([NH:10][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[C:7]=3[CH2:8][C:2]1=2
Reactant: O=C1CCc2sccc21
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Reactant: NN
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc(Nc2n[nH]c3c2Cc2sccc2-3)cc1
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Isothiocyanato-4-trifluoromethyl-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(4-trifluoromethyl-phenyl)-amine as brown solid in 30% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14](N(OC)C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Mg]Br>C1COCC1>[CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14](=[O:15])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1sccc1OCc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1sccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a cold (0° C.) solution of 3-(benzyloxy)-N-methoxy-N-methyl-2-thiophenecarboxamide (3.47 g, 12.50 mmol) in THF (50 mL) was added a solution of methylmagnesium bromide in THF (1 M, 35 mL). After being stirred at 0° C. for 1 hr, the reaction mixture was quenched with saturated aqueous NH4Cl solution, diluted with water, and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate/CH2Cl2=3/1/1) followed by recrystallization from n-hexane/ethyl acetate to give 1-[3-(benzyloxy)-2-thienyl]ethanone as a white solid (2.592 g, yield; 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](/[CH:18]=[N:19]/[S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1.[CH3:26][Mg]Br.[NH4+].[Cl-]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH:18]([NH:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH3:26])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)S(=O)/N=C/c1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(NS(=O)C(C)(C)C)c1cc2nccn2cc1-c1ccc(Cl)cc1Cl

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid 1-[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-meth-(E)-ylideneamide (20 mg, 0.045 mmol) in anhydrous THF (0.5 mL) was added methylmagnesium bromide (3 M solution in Et2O, 0.045 mL, 0.14 mmol) at RT. The reaction mixture was stirred for 3 h30 then poured into a saturated solution of NH4Cl in water and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and evaporated to dryness to give the crude 2-methyl-propane-2-sulfinic acid {1-[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-ethyl}-amide intermediate.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](OS(C1C(C)=CC=CC=1)(=O)=O)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].Cl.[CH3:34][N:35]([CH2:37][CH2:38][SH:39])[CH3:36].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:39][CH2:38][CH2:37][N:35]([CH3:36])[CH3:34])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH3:3]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Reactant: CN(C)CCS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(SCCN(C)C)CC12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl 6-(1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (46 mg), 2-(N,N-dimethylamino)ethyl mercaptan hydrochloride (14.2 mg), and triethylamine (14 μl) in anhydrous DMF (2 ml) is stirred at room temperature (25° C.) for 2 hrs. The mixture is added to ethyl acetate (20 ml), washed with 5% sodium bicarbonate (10 ml), water (4×10 ml) and brine, dried over MgSO4, filtered, concentrated in vacuo. Purification of the residue by chromatography on silica gel gives benzyl 6-(1-hydroxyethyl)-3-(2-dimethylaminoethylthio)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31](C)([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.[CH2:35](N(CC)CC)C>>[CH:16]([N:8]([CH:7]([CH3:2])[CH3:35])[CH2:9][CH3:10])([CH3:15])[CH3:11].[CH3:1][C:2]1[C:3]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: Cc1c(OC2CCN(C(=O)OC(C)(C)C)CC2)ncnc1N1CCc2cc(S(C)(=O)=O)ccc21
Reactant: CCN(CC)CC
Product: CCN(C(C)C)C(C)C
Product: Cc1c(OC2CCN(C(=O)OC(C)C)CC2)ncnc1N1CCc2cc(S(C)(=O)=O)ccc21
Yield: 88 %

Procedure:
The same reaction as in the method described in Example 2 was performed using the tert-butyl 4-({5-methyl-6-[5-(methylsulfonyl)indolin-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate (208 mg, 0.426 mmol) produced in Example 26 and, instead of triethylamine, diisopropylethylamine (380 μL, 2.13 mmol) to obtain the title compound as white foam (177 mg, yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[C:9]([O:25][CH2:26][CH3:27])=[C:10]([CH:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[C:9]([O:25][CH2:26][CH3:27])=[C:10]([C:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOc1c(OCc2ccc(Cl)cc2)cccc1C(O)c1c[nH]c2ncccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CCOc1c(OCc2ccc(Cl)cc2)cccc1C(=O)c1c[nH]c2ncccc12
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 73.7 %

Procedure:
To a solution of [3-(4-chloro-benzyloxy)-2-ethoxy-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl) methanol (630, 20 mg, 0.05 mmol) in tetrahydrofuran (8 mL) was added Dess-Martin periodinane (52 mg, 0.12 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 50 minutes. The reaction was quenched with a saturated solution of sodium thiosulfate, extracted with ethyl acetate, washed with sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was washed with a mixture of ethyl ether and hexanes (1:1) to provide the compound as a yellow solid (P-1892, 15 mg, 75%). MS (ESI) [M+H+]+=407.38.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:59](Br)[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70]>CN(C=O)C>[CH2:70]([O:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1)[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH3:59]
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
5,10,15,20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (200 mg, 0.294 mmol) is dissolved and potassium carbonate (487 mg, 3.53 mmol, 12 eqv.) in suspended under argon in absolute DMF (50 mL) and the mixture is heated to 55° C. A solution of dodecyl bromide (49.4 μl, 0.206 mmol, 0.7 eqv.) in absolute DMF (10 mL) is added dropwise during 30 min. The mixture is stirred at 55° C. for 2 h. The solvent is removed in vacuo at 50° C., water (80 mL) is added and the mixture extracted with ethyl acetate (3×40 mL). The combined organic fractions are dried (Na2SO4) and the solvent evaporated. The product is isolated by chromatography on a column (300 g) of silica. Tetra-alkylated and tri-alkylated compounds are eluted with toluene:ethyl acetate (30:1 by vol.), di-substituted compound (trans-isomer) with toluene:ethyl acetate (15:1 by vol.), di-substituted compound (cis-isomer) with toluene:ethyl acetate (10:1 by vol.) and the desired product (mono-alkylated compound) with toluene:ethyl acetate (5:1 by vol). Solvent is removed in vacuo and the residue dried at high vacuum to give product as a violet solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[O-].[Na+].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25%) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10% HCl was added and the mixture extracted with 4×75 mL ethyl acetate. The extracts were dried over MgSO4, filtered and concentrated to afford 8.47 g (94%) of a brown oil which was carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][NH:11]/[C:10]/2=[CH:15]\[N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.[CH:19](=[O:24])[CH2:20][CH2:21][CH:22]=O>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:10]3=[C:15]([N+:16]([O-:18])=[O:17])[CH:22]4[O:24][CH:19]([N:11]3[CH2:12][CH2:13][CH2:14]2)[CH2:20][CH2:21]4)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])/C=C1\NCCCN1Cc1ccc(Cl)nc1
Reactant: O=CCCC=O
Solvent: CC#N
Product: O=[N+]([O-])C1=C2N(Cc3ccc(Cl)nc3)CCCN2C2CCC1O2
Temperature: 25 °C
Yield: 38 %

Procedure:
To a 50 ml round bottom flask was added 1.34 g (0.005 mol) (E)-1-((6-chloropyridin-3-yl)methyl)-2-(nitromethylene)-hexahydropyrimidine, 30 ml dry acetonitrile and 0.860 g (0.01 mol) succinaldehyde and catalytic concentrated Hl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as faint yellow powder with 38% yield.
Reaction SMILES: [CH3:1][N:2]1[C:19](=O)[C:18](=O)[N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1.B#B.C(O)(=O)C.O>O1CCCC1>[CH3:1][N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1
Reactant: CN1CC2c3cccn3Cc3ccccc3N2C(=O)C1=O
Agent: B#B
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN2c3ccccc3Cn3cccc3C2C1

Procedure:
348 g of 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine are added portionwise over 1 hour to 4,500 ml of tetrahydrofuran and 7,410 ml of 1-molar diborane in tetrahydrofuran while cooling with ice to 18° and stirring under nitrogen. The mixture is refluxed for 24 hours, again cooled to 5° and combined with 1,200 ml of glacial acetic acid followed by 900 ml of water. The solution is refluxed for 24 hours, evaporated and the residue taken up in 10,500 ml of methanol. The solution is again refluxed for 2 hours, evaporated, the residue dissolved in 3,000 ml of water and the pH of the solution adjusted to 14 with 1,200 ml of 10% aqueous sodium hydroxide. The mixture is extracted with diethyl ether, the extract dried, filtered and evaporated to yield the 2-methyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][ 1,4]benzodiazepine melting at 98°-100°.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[S:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[O:22])=[CH:15][C:14]=2[Cl:32])[CH:5]=[CH:4]1)C.[NH:33]1C2C(=CC=CC=2)C=[CH:34]1.[C:42](O)(C(F)(F)F)=O>CO>[CH3:1][N:3]([CH2:4][C:5]1[C:6]2[C:7](=[CH:8][CH:9]=[C:10]([S:12][C:13]3[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]4[CH2:24][CH2:25][N:26]([C:29](=[O:31])[CH3:30])[CH2:27][CH2:28]4)=[O:22])=[CH:15][C:14]=3[Cl:32])[CH:11]=2)[NH:33][CH:34]=1)[CH3:42]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCn1ccc2cccc(Sc3ccc(/C=C/C(=O)N4CCN(C(C)=O)CC4)cc3Cl)c21
Reactant: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc4[nH]cc(CN(C)C)c4c3)c(Cl)c2)CC1

Procedure:
The title compound was prepared by the procedures described in Example 217, substituting the indole from Example 186 with the indole from Example 85, resulting in a white solid. 1H NMR (CDCl3, 300 MHz) δ 2.15 (s, 3H), 2.54 (s, 6H), 3.47-3.85 (m, 8H), 4.05 (s, 2H), 6.56 (d, J=8.7 Hz, 1H), 6.77 (d, J=15.6 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 7.36 (dd, J=1.5, 8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.52 (s, 2H), 7.56 (d, J=15.6 Hz, 1H), 7.88 (s, 1H), 9.27 (s, 1H). MS (ESI+) (M+H)+ at m/z 497, 499. Anal. Calcd for C26H29ClN4O2S.0.46 TFA.1.72 MeOH: C, 56.89; H, 6.06; N, 9.27. Found: C, 56.83; H, 6.15; N, 9.46.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:52][CH3:53])([C:31]2[NH:32][N:33]=[C:34](/[CH:36]=[CH:37]/[C:38]3[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=3)[N:35]=2)[CH2:28][CH2:29]O)=[CH:23][CH:22]=1>C(Cl)(Cl)(Cl)Cl.C1COCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([O:52][CH3:53])[C:31]3[N:32]([N:33]=[C:34](/[CH:36]=[CH:37]/[C:38]4[CH:43]=[CH:42][C:41]([N:44]5[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]5)=[C:40]([O:50][CH3:51])[CH:39]=4)[N:35]=3)[CH2:29][CH2:28]2)=[CH:23][CH:22]=1
Reactant: COc1cc(/C=C/c2n[nH]c(C(CCO)(OC)c3ccc(F)cc3)n2)ccc1-n1cnc(C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(/C=C/c2nc3n(n2)CCC3(OC)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 1.9 %

Procedure:
Triphenylphosphine (22 mg) was added to a suspension of 3-(4-fluorophenyl)-3-methoxy-3-(5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-2H-[1,2,4]triazol-3-yl)propan-1-ol (38 mg) in carbon tetrachloride (2 mL) and THF (2 mL), and the reaction solution was heated under reflux for seven hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and a saturated sodium bicarbonate solution were added to the resulting residue, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system), again purified with silica gel column chromatography (elution solvent: ethyl acetate-methanol system) and then purified by LC-MS. After concentrating the target fraction, ethyl acetate and a saturated sodium bicarbonate solution were added to the residue, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 0.69 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([O:27][CH3:28])[C:6]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[CH3:13].I[CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44].CCN(CC)CC>CCOCC>[CH3:28][O:27][C:5]1[C:6]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]2[C:12](=[C:3]([NH:2][CH:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]3[C:38](=[O:39])[C:37]4=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]4[C:35]3=[O:44])[CH:4]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH3:13]
Reactant: CC(I)CCCN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(N)c2nccc(C)c2c1OCCCCCCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1OCCCCCCc1ccccc1
Reaction time: 4 h

Procedure:
A stirred mixture of 8-amino-6-methoxy-4-methyl-5-(6-phenylhexoxy) quinoline hydrochloride (2.7 g, 0.007 mol), and 4-iodo-1-phthalimido-pentane (IPP) (3.0 g, 0.009 mol) was maintained at 100° C. while 1 ml of Et3N was added dropwise. After an additional 3 h of IPP and 1 ml of Et3N were added, heating was continued for 4 h and the mixture was allowed to cool, diluted with Et2O (100 ml), filtered, washed with saturated NaCl and dried (Na2SO4). Solvent removal provided a quantitative yield of 6-methoxy-4-methyl-8-(1-methyl-4-phthalimidobutylamino)-5-(6-phenylhexoxy) quinoline as a brown syrup which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(OCC)C.O.C([O-])([O-])=O.[K+].[K+]>[CH3:18][S:19]([O:10][CH2:9][CH2:8][C:7]#[C:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20]
Reactant: OCCC#Cc1cccs1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC#Cc1cccs1
Reaction time: 0.5 h

Procedure:
To a solution of 750 mg of 1a and 1 ml of triethyl amine in 15 ml of diethyl ether, was added dropwise at 0° C. 400 μl of methanesulfonyl chloride in 5 ml of diethyl ether. The reaction mixture was stirred for ½ hr and then diluted with 30 ml of water and 5 ml of 1M K2CO3. The product was extracted with diethyl ether and the combined extracts were once washed with water, dried and concentrated, to provide 1.2 g of mesylate 1b; Rf 0.50 (heptane/ethyl acetate 1/1), MS-ESI: [M+1] 231.07.
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:31])[C:9]1[S:10][C:11]([S:29][CH3:30])=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:18]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:30][S:29][C:11]1[S:10][C:9]([C:8]([NH2:31])=[NH:7])=[CH:13][C:12]=1[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:18]=1)(=[O:16])=[O:15]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(N2CCCCC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(N2CCCCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a solution of 5-methylsulfanyl-4-(3-piperidin-1-yl-benzenesulfonyl)-thiophene-2-carboxamidine (10 mg, 0.020 mmol, Example 286: step h) in 1 mL of CH2Cl2 under Ar at 0° C. was added 5 drops (˜200 ul) of TFA. The mixture was stirred at 0° C. for 1 h. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5% MeOH/CH2Cl2) gave 7.5 mg (77%) of product as colorless oil: 1H-NMR (CD3OD, 400 MHz) δ 8.25 (s, 1H), 7.76 (dd, 1H, J=1.6, 1.6 Hz), 7.62 (ddd, 1H, J=7.5, 1.6, 1.6 Hz), 7.56 (ddd, 1H, J=7.5, 1.6, 1.6 Hz), 7.51 (dd, 1H, J=7.5, 7.5), 3.31–3.30 (m, 4H), 2.54 (s, 3H), 1.57–1.56 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C17H21N3O2S3, 396.1 (M+H), found 396.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.CCCCCC>[CH2:18]([N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCNCc1ccccc1
Reactant: O=C(Nc1cccc(Cl)c1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCN(Cc1ccccc1)C(=O)Nc1cccc(Cl)c1

Procedure:
A solution of 1.46 g of phenyl N-(3-chlorophenyl)carbamate in 15 ml of tetrahydrofuran was added to a solution of 1.92 g of N-benzyl-n-butylamine in 20 ml of tetrahydrofuran and the mixture stirred under reflux for hours. The mixture was diluted with hexane and the precipitate collected by filtration. Recrystallization from pentane afforded 1-benzyl-1-(n-butyl)-3-(3-chlorophenyl)urea, m.p. 69°-70° C.
Reaction SMILES: CO[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].C[O-].[Na+]>C1(C)C(C)=CC=CC=1.CO>[C:11]([CH2:12][C:3](=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
Methylbenzoate (136.0 grams; 1.0 mol), acetophenone (30.0 grams; 0.25 mol), sodium methoxide (17.3 grams; 0.3 mol) and xylene (300 ml) were placed into a four-necked, round bottom, one liter flask equipped with stirrer, nitrogen addition adapter, thermometer and Oldershaw column connected with distillation head and a trap. The mixture was heated with stirring to 135°-140° C. and maintained there for 6 hours while under a blanket of nitrogen. At 110°-120° C. methanol started to evolve and the reaction mixture became semi-solid. After two hours of heating the contents of the flask somewhat liquified. Towards the end of the reaction, nearly 25 ml of liquid consisting of methanol and xylene had been collected in the trap. The reaction mixture was cooled to room temperature and acidified with hydrochloric acid (500 ml of 6N). Stirring was continued for about 30 minutes until all the solid was dissolved. The xylene layer was separated and washed twice with water, then twice with aqueous sodium carbonate and then twice again with water. The xylene layer was removed by evaporation from the dibenzoylmethane (53.1 grams; 95% yield). Analysis by GLC showed the product to be 95% pure. This product after recrystallized from methanol had a melting point of 77°-78° C. The distillate (347.0 grams) containing xylene, methylbenzoate and water was subjected to azeotropic distillation.