Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH2:28][CH2:29][C:30]#[CH:31]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:8]1([C:5]2[N:6]=[CH:7][C:2]([C:31]#[C:30][CH2:29][CH2:28][CH2:27][O:26][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)=[N:3][C:4]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CCCCOC1CCCCO1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C(#Cc1cnc(-c2ccccc2)c(-c2ccccc2)n1)CCCOC1CCCCO1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of 1.58 g of 2-chloro-5,6-diphenylpyrazine in 10 ml of triethylamine, 1.20 g of 5-(2-tetrahydropyranyloxy)-1-pentyne, 208 mg of dichlorobis(triphenylphosphine)palladium (II) and 56 mg of copper (I) iodide were added, followed by stirring under an argon atmosphere at 80° C. for 8 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in diethyl ether, and then the insoluble matter was removed by filtration through celite. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain 1.79 g of the desired compound as a brown oily substance.
Reaction SMILES: N1([O:10][C:11]2[CH:12]=[N:13][N:14]([CH:18]([CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[C:19]([NH:21][C:22]3[CH:26]=[CH:25][N:24]([CH2:27][C@@H:28]4[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]4)[N:23]=3)=[O:20])[C:15](=[O:17])[CH:16]=2)C2C=CC=CC=2N=N1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1O>>[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[O:10][C:11]1[CH:12]=[N:13][N:14]([CH:18]([CH2:35][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40]2)[C:19]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH2:27][C@@H:28]3[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]3)[N:23]=2)=[O:20])[C:15](=[O:17])[CH:16]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(On4nnc5ccccc54)cc3=O)n2)O1
Reactant: Oc1ccccc1Cl
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4ccccc4Cl)cc3=O)n2)O1

Procedure:
Using the method described in Example 126, Step 1, 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide (Example 114, Step 1) and 2-chloro-phenol afforded 2-[4-(2-chloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as a white solid as a mixture of diastereomers (99.4 mg, 80%); ES+-HRMS m/e calcd for C27H32N5O5Cl [M+H+] 542.2165 found 542.2167. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.09 (br. s., 1H), 1.28 (br. s., 1H), 1.24 (s, 3H), 1.30 (d, J=1.8 Hz, 3H), 1.37-1.76 (m, 7H), 1.85-2.00 (m, 1H), 2.18-2.33 (m, 1H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.3, 6.5 Hz, 1H), 4.04-4.19 (m, 2H), 4.27-4.41 (m, 1H), 5.45 (dd, J=10.6, 4.2 Hz, 1H), 5.69 (d, J=3.0 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.35-7.47 (m, 1H), 7.51 (m, 2H), 7.59 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 8.20 (d, J=3.0 Hz, 1H), 10.85 (br. s., 1H).
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:26][CH2:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[CH:15]1[C:27]1[CH:32]=[CH:31][C:30]2[O:33][CH2:34][O:35][C:29]=2[CH:28]=1)/[CH:3]=[CH:4]/[C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN(CC)CC.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH2:36]([NH:43][C:9](=[O:10])[C:8]1[CH:7]=[CH:6][C:5](/[CH:4]=[CH:3]/[C:2](=[O:1])[N:14]2[CH2:26][CH2:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]=3[CH:15]2[C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)=[CH:13][CH:12]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)c1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Yield: 13 %

Procedure:
This product was prepared by stirring a solution of Example 31 (0.2 g, 0.43 mmol) in 50 mL of THF with benzylamine (0.5 mL, 9 equiv.), Et3N (1 mL) and diphenylphosphoryl azide (0.5 mL). After two days the reaction mixture was concentrated in vacuo. The residue was taken up in 100 mL of DCM and washed with 3×50 mL of water. Drying over Na2SO4 and evaporation of the solvent gave a residue which was purified via flash chromatography with cyclohexane and Et2O. Evaporation in vacuo and recrystallization from EtOH gave the title compound (0.03 g, 13%) as white crystals.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([O:21]C)=O)[C:12]=3[N:11]=2)[CH:7]=[CH:8][CH:9]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:1])=[O:21])[C:12]=3[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N
Reactant: COC(=O)c1cccc2[nH]c(-c3cccc(OC)c3)nc12
Product: COc1cccc(-c2nc3c(C(N)=O)cccc3[nH]2)c1
Yield: 46 %

Procedure:
Following standard procedure C, a liquid ammonia solution of methyl 2-(3'-methoxyphenyl)-1-H-benzimidazole-4-carboxylate (203 mg, 0.596 mmol) was heated under constant volume. The solid residue was recrystallised from methanol to give the pure product (73.5 mg, 46%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[Cl:17])=[O:5])C>[OH-].[Na+].C(O)C>[Cl:17][C:7]1[S:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2)sc1Cl
Temperature: 100 °C
Yield: 43.2 %

Procedure:
2-Chloro-5-phenyl-thiophene-3-carboxylic acid ethyl ester (0.44 g, 1.65 mmol) was dissolved in a solution of 1 M NaOH (3 mL) and ethanol (2 mL). The reaction mixture was heated to 100° C. using microwave irradiation for 10 minutes. After cooling, the reaction mixture was partitioned between diethyl ether and water. The aqueous solution was acidified with 1 M HCl and further extracted with diethyl ether. The combined organic solutions were dried over magnesium sulfate, filtered and the solvent evaporated. The residue was triturated in diethyl ether and filtered to give the title compound (0.17 g). 1H NMR (400 MHz, CHCl3-d): δ 7.6 (s, 1H), 7.55 (d, 2H), 7.4-7.3 (m, 3H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([OH:28])[C@H:7]1[O:12][C@H:11]([O:13][C@:14]2([CH2:23][OH:24])[O:18][C@H:17]([CH2:19]O)[C@@H:16]([OH:21])[C@@H:15]2[OH:22])[C@H:10]([OH:25])[C@@H:9]([OH:26])[C@@H:8]1[OH:27]>N1C=CC=CC=1>[CH2:6]([OH:28])[C@H:7]1[O:12][C@H:11]([O:13][C@@:14]2([CH2:23][OH:24])[O:18][C@H:17]([CH2:19][Cl:4])[C@@H:16]([OH:21])[C@@H:15]2[OH:22])[C@H:10]([OH:25])[C@@H:9]([OH:26])[C@@H:8]1[OH:27]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: OC[C@H]1O[C@H](O[C@@]2(CO)O[C@H](CCl)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Attempts to synthesize cyclic sulfates of unprotected sugars with sulfuryl chloride and pyridine have been reported. Bragg P. D. et al, Can. J. Chem. 1959, 37, 1412. However, this reaction is not clean, and several side products are isolated. For example, reaction of sucrose with sulfuryl chloride at -78° C. afforded the 6,6'-dichloro-6,6'-deoxysucrose and 6'-chloro-6'-deoxysucrose in 43 and 29% yields, respectively. At room temperature, a complex mixture was formed from which 3',4'-anhydro-1',6'-dichloro-1',6'-dideoxy-β-D-ribo-hexulofuranoside. 2,3-cyclic sulfate was isolated in 17% yield, showing that chlorination occurred as well as inversion of configuration during cyclic sulfate formation. Ballard J. M, et al., J. Chem. Soc., Perkin Trans. 1, (1973) 1524-1528.
Reaction SMILES: C(OC(Cl)=O)C.[C:7]([NH:17][CH2:18][C:19]([OH:21])=O)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].CN1CCOCC1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]([N:39]([CH3:41])[CH3:40])[CH3:38])=[CH:32][CH:31]=1>O1CCCC1>[C:7]([NH:17][CH2:18][C:19]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]=[C:37]([N:39]([CH3:40])[CH3:41])[CH3:38])=[CH:34][CH:35]=1)=[O:21])([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(=Nc1ccc(N)cc1)N(C)C
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=Nc1ccc(NC(=O)CNC(=O)OCc2ccccc2)cc1)N(C)C
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
22.8 g (0.21 mol) of chloroformic acid ethyl ester were added dropwise at -15° C to a solution of 41.8 g (0.2 mol) of N-(carbobenzoxy)-glycine and 21.3 g (0.21 mol) of N-methylmorpholine in 250 ml of absolute tetrahydrofuran. The mixture was stirred for 10 minutes at -10° C and was then filtered. A solution of 33.7 g (0.19 mol) of N'-(4-aminophenyl)-N,N-dimethylacetamidine in 100 ml of absolute tetrahydrofuran was added dropwise to the filtrate at -10° C. The mixture was then stirred for 30 minutes at -10° C, 1 hour at 0° C and 2 hours at room temperature. Thereafter, the mixture was concentrated on a rotary evaporator, suspended in sodium hydroxide solution and repeatedly extracted with chloroform. The chloroform phase was dried with Na2SO4 and concentrated. The residue was recrystallized from benzene-ligroin. 39.2 g of N'-[4-(carbobenzoxyglycylamino)-phenyl]-N,N-dimethylacetamidine of melting point 133° C were thus obtained and were slowly introduced into 800 ml of HBr/glacial acetic acid, with cooling. The mixture was stirred for 2 hours at room temperature and was then stirred into 2 liters of dry ether. A crystalline precipitate formed and this was filtered off, washed with ether and then dissolved in water. The aqueous solution was rendered alkaline, with cooling, and was repeatedly extracted with chloroform. The organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from toluene to afford 22.9 g (51% of theory) of N,N-dimethyl-N'-(4-glycylaminophenyl)acetamidine, melting point 142°-145° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27]C)=[C:16]([CH2:19][NH:20][CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:27])=[C:16]([CH2:19][NH:20][CH2:21][C:22]([N:24]([CH3:25])[CH3:26])=[O:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNCC(=O)N(C)C
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: CN(C)C(=O)CNCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (0.21 g, 0.60 mmol) was added to a stirred solution of N1,N1,N2-trimethylglycinamide (Me2N-Gly-Nme) (0.348 g, 1.81 mmol) and DIPEA (0.234 g, 1.81 mmol) in dimethylformamide (1 ml) at 140° C., over a period of 5 minutes. The reaction mixture was stirred for 5 minutes, cooled to room temperature and purified by preparative LCMS (standard acidic system) to give N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N1,N1-dimethylglycinamide (0.193 g, 74.2%) as a white solid. 1H NMR Spectrum: (DMSO-d6) 2.27 (s, 3H), 2.80 (s, 3H), 2.98 (s, 3H), 3.71 (s, 2H), 3.94 (s, 3H), 7.19 (s, 1H), 7.27 (t, 1H), 7.47-7.52 (m, 2H), 8.30 (s, 1H), 8.43 (s, 1H), 9.85 (s, 1H); Mass Spectrum: (M+H)+ 432. Solid N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N1,N1-dimethylglycinamide (0.150 g, 0.348 mmol) was added over a period of 1 minute to a stirred solution of anhydrous lithium iodide (0.232 g, 1.74 mmol) in 2,4,6-collidine (0.5 ml) at 130° C., previously stirred for 30 minutes at 130° C. The reaction mixture was allowed to stir for 5 hours, cooled, concentrated and purified by preparative LCMS (standard acidic system) to afford N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-hydroxyquinazolin-6-yl}methyl)-N1,N1-dimethylglycinamide (0.080 g, 55.2%) as an orange foam; Mass Spectrum: (M+H)+ 418.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[N:5][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1.[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=O)[CH3:15].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]1[N:2]([CH3:1])[C:3]2[C:4]([N:13]=1)=[N:5][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:7][CH:8]=2)[CH3:15]
Reactant: CNc1ccc(C(F)(F)F)nc1N
Reactant: CCSc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCSc1ccccc1-c1nc2nc(C(F)(F)F)ccc2n1C
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A mixture of N3-methyl-6-trifluoromethylpyridin-2,3-diamine (0.38 g), 2-ethylsulfanylbenzoic acid (0.40 g), WSC (0.42 g), and pyridine (3 ml) was stirred under reflux for hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. To the resulting residue, tripotassium phosphate (1.06 g) and 1-propanol (4 ml) were added, and stirred under reflux for 4 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.33 g of 2-(2-ethylsulfanylphenyl)-1-methyl-5-trifluoromethyl-1H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 166).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]([CH2:19][CH2:20][CH2:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH2:6][CH:7]([OH:18])[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)[CH3:4].[C:30](Cl)(=[O:32])[CH3:31]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[C:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([S:22][CH2:21][CH2:20][CH2:19][N:5]([CH2:3][CH3:4])[CH2:6][CH:7]([OH:18])[CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:28][CH:27]=1)(=[O:32])[CH3:31]
Reactant: CCN(CCCSc1ccc(O)cc1)CC(O)COc1ccc(C#N)cc1
Reactant: CC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN(CCCSc1ccc(OC(C)=O)cc1)CC(O)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sodium hydroxide (0.9 g in 25 ml dioxan) was added 4-[3-[ethyl[3-[(4-hydroxyphenyl)thio]propyl]amino]-2-hydroxypropoxy]-benzonitrile (3.4 g, 8.8 mmol) and tetrabutylammonium hydrogen sulphate. To the solution was added dropwise acetylchloride (0.78 g, 10 mmol) dissolved in dioxan (10 ml). The solution was stirred at room temperature for 2 h. After filtration and evaporation the residue was dissolved in methylene chloride, treated with charcoal and filtered through Celite. The solvent was evaporated. The yield of the title compound was 3.8 g.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][N:17]=[C:18]2[C:21]2([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[N:26]=3)[CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:12]=1)(C)(C)C.Cl>>[Cl:31][C:27]1[N:26]=[C:25]([C:21]2([C:18]3[C:19]4[C:14](=[CH:13][CH:12]=[C:11]([O:10][CH2:9][CH2:8][NH2:7])[CH:20]=4)[CH2:15][CH2:16][N:17]=3)[CH2:24][CH2:23][CH2:22]2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Agent: Cl
Product: NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl[2-({1-[1-(6-chloropyridin-2-yl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethyl]carbamate (300 mg, 0.658 mmol) were dissolved in isopropanole (4 ml). 5N isopropanolic hydrochloric acid (2 ml) was added and the reaction mixture stirred at room temperature for 4 hours. The solvent was evaporated in vacuo and dichloromethane (20 mL) was added. 1N aqueous sodium hydroxide solution was added dropwise until pH 10 was reached. The phases were separated and the aqueous layer was extracted twice with dichloromethane. The combined organich layers were dried (MgSO4) and concentrated in vacuo. The crude product was used for the next step without further purification. Yield: 150 mg (0.422 mmol, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 89.2 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.39 g).
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.Cl[CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:12]=[C:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:4][CH:3]=[C:2]1[O:1][CH2:14][C:15]#[N:16]
Reactant: O=c1c(O)coc2ccccc12
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1coc2ccccc2c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
A mixture of 3-hydroxychromone (4.86 g, 0.03 mole), chloroacetonitrile (2.26 g, 0.03 mole) and potassium carbonate (3.0 g, 0.02 mole) in dimethylformamide (40 ml) is stirred at 100° C. under nitrogen for 4 hrs. The reaction mixture is cooled, poured into water (200 ml), filtered, washed with water and sucked dry. Recrystallization from methanol gives white crystals (4.7 g, 94%), mp 145°-146° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][OH:19])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:19][CH2:18][C@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COS(C)(=O)=O
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.06 mL, 0.77 mmol) was added to a solution of (R)-N-Boc-pyrrolidine-2-methanol (125.3 mg, 0.62 mmol) and triethylamine (0.22 mL, 1.6 mmol) in dichloromethane at 0° C. under argon. After stirring for 1 h, the reaction mixture was partitioned between dichloromethane (50 mL) and sodium hydrogen sulfate (15 mL). The organic layer was sequentially washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and the solvent was removed in vacuo to yield (R)-N-Boc-pyrrolidine-2-methanol methanesulfonate, which was used crude.
Reaction SMILES: FC(F)(F)C(O)=[O:4].O=S1(=O)CCNCC1.Cl[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:49]=[CH:48][C:24]([C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:47])=[C:32]([NH:34][C:35](=[O:46])[C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=3)[CH:33]=2)=[O:26])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CC(N(C)C)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[OH:4][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:49]=[CH:48][C:24]([C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:47])=[C:32]([NH:34][C:35](=[O:46])[C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=3)[CH:33]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(OCCCCl)cc3)ccc2C)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S1(=O)CCNCC1
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(OCCCO)cc3)ccc2C)cc1OC
Temperature: 100 °C

Procedure:
S,S-Dioxothiamorpholine trifluoroacetic acid salt (0.22 g) was added to a stirred mixture of N-{5-[4-(3-chloropropoxy)benzamido]-2-methylphenyl}-3,4-dimethoxybenzamide (0.5 g), tetra-n-butylammonium iodide (0.096 g), di-isopropylethylamine (0.29 g) and DMA (4 ml) and the mixture was stirred and heated to 100° C. for 1 week. The reaction mixture was allowed to cool to ambient temperature and poured into water (100 ml). The resultant precipitate was isolated and washed with water and with diethyl ether. The solid so obtained was purified by column chromatography on silica gel using increasingly polar mixtures of methylene chloride and methanol as eluent. There were thus obtained in turn:
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([S:27]([CH2:30][CH2:31][CH2:32][OH:33])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:21]=[C:22]([S:27]([CH2:30][CH2:31][CH2:32][OH:33])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=2[CH3:26])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)CCCO)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)CCCO)cc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 3-[(3-bromo-4-methylphenyl)sulfonyl]propan-1-ol (Intermediate 68), the title compound was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C(O)(=O)C.[NH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.O.Cl.[NH4+].[OH-]>C(O)C>[NH:21]1[CH2:26][CH2:25][C:24]2([C:16]3=[C:15]4[C:10](=[N:9][C:8]3=[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH2:4]3)[NH:1]2)[CH:11]=[CH:12][CH:13]=[CH:14]4)[CH2:23][CH2:22]1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: C1=CCC2=C3N=c4ccccc4=C3C3(CCNCC3)NC2=C1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a mixture prepared from 8 g of 2-(2-aminophenyl)indole, 2.5 ml of acetic acid and 100 ml of ethanol was added 6.5 g of 4-piperidone·H2O·HCl. The mixture was refluxed for 6 hours and thereafter cooled to room temperature. The resultant mixture was treated with dilute NH4OH and the resultant solid was collected, washed with water and dried. The crude product (9.15 g) was flash chromatographed using CH3OH as an eluent, and thereafter converted to the HCl salt. This salt was converted back to the free base using CH2Cl2 /dilute NH4OH to give 5.96 g of solid, m.p. 257°-259° dec.