Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][C:10]([O:12]CC)=[O:11]>C(OCC)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH2:3]1
Reactant: CCOC(=O)CBr
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCOCC
Product: CN1CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Dissolve N-methylpiperazine (5.0 mL, 45.09 mmol) in diethyl ether in a stoppered flask and treat with neat ethyl bromoacetate (3.012 g, 18.036 mmol). Stir the reaction mixture at room temperature overnight, filter and wash the filter cake with diethyl ether. Combine the organic filtrates and evaporate the solvent in vacuo to give a light yellow oil. Take up in water (60 mL) and heat at 95° C. for 4 hours, allow to cool to room temperature and stir overnight. Evaporate the solvent in vacuo and dissolve the residue in acetonitrile and evaporate the solvent in vacuo (twice) to azeotrope residual water. Dissolve in a minimal amount of methanol, dilute with diethyl ether and place in the freezer. Isolate the crystals which form by decanting the supernatant and wash with diethyl ether. Obtain two more crops of crystals from the mother liquor to give 4-methylpiperazine-1-acetic acid (2.345 g, 82%); mp 158°-160° C. (lit 159.5°-161° C.), 1H NMR (D2O) δ3.98 (s, 2), 3.81-3.32 (m, 8), 2.89 (s, 3).
Reaction SMILES: Cl.[C:2]12([CH2:12][CH2:13][NH2:14])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18](O)=[O:19]>>[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([NH:14][CH2:13][CH2:12][C:2]12[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2)=[O:19]
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: Cl
Product: Nc1cccc(Cl)c1C(=O)NCCC12CC3CC(CC(C3)C1)C2

Procedure:
Prepared according to the method of Example 14 from 1-adamantaneethylamine hydrochloride (CN 26482-53-1) (0.105 g) and 2-amino-6-chlorobenzoic acid (0.132 g) and purified by supercritical fluid chromatography eluting with CO2 in ethanol to give the title compound, contaminated with 0.35 mol equivalents of imidazole, as a white solid (0.046 g).
Reaction SMILES: [S:1]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:12])[NH:5][C:4]=2[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24].O>CN(C)C=O>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][N:5]1[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[S:1][CH:2]=[CH:3][C:4]1=2
Reactant: ClCCCCBr
Reactant: O=C1CCCCc2sccc2N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCCc2sccc2N1CCCCCl
Yield: 93.4 %

Procedure:
To a solution of 2.0 g of 6,7,8,9-tetrahydrothieno[3,2-b]azocin-5(4H)-one in 20 ml of dimethylformamide was added 1.3 g of potassium t-butoxide under ice-cooling and stirred at the same temperature. To the mixture was added 2.0 g of 1-bromo-4-chlorobutane and stirred at room temperature for 5 hours. The mixture was poured into water and extracted ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel using a chloroform as an eluent to give 2.8 g of 4-(4-chlorobutyl)-6,7,8,9-tetrahydrothieno[3,2-b]azocin-5(4H)-one as a pale yellow oil.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)=[C:16]([C:27](OCC)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1ccc(Cl)c(Cl)c1
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3ccc(Cl)c(Cl)c3)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 21.3 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(3,4-dichlorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (1.40 g, 2.88 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (0.48 g, 2.65 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.35 g, 32%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22]([Cl:29])[N:21]=1>CO>[Cl:29][C:22]1[N:21]=[C:20]([NH:11][CH:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[CH2:6][CH2:7]2)[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NC1CCc2ccc(F)cc21
Solvent: CO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CCc2ccc(F)cc21
Yield: 52 %

Procedure:
Dissolve 6-fluoroindan-1-ylamine (8.50 g, 56.22 mmol) in methanol (200 mL) and triethylamine (8.62 mL, 61.84 mmol). Add 2,6-dichloro-3-nitropyridine (10.85 g, 56.22 mmol) and stir under nitrogen for 14 hours. Filter the reaction mixture and wash the solids with methanol and hexanes to give the title compound as a yellow solid (9.00 g, 52%). MS (ES) m/z=308 [M+1].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.C[Al](C)C.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:51])([CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[C@H:26]([S:28][C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:44]=[CH:43][C:38]([C:39](OC)=[O:40])=[CH:37][CH:36]=2)[O:31][CH2:30]1)[CH3:27]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:51])([CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[C@H:26]([S:28][C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:36]=[CH:37][C:38]([C:39]([NH:8][C:7]3[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=3)=[O:40])=[CH:43][CH:44]=2)[O:31][CH2:30]1)[CH3:27]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 4-(trifluoromethoxy)aniline (123 mg, 0.69 mmol), trimethylaluminium (0.64 ml, 1.07M n-hexane solution, 0.69 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (100 mg, 0.20 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (122 mg, yield 95%) as white solid which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[CH2:16]([OH:20])[CH2:17][CH2:18][CH3:19].C(P(CCCC)CCCC)CCC>O>[CH2:16]([O:20][C:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:1]=1)[CH2:17][CH2:18][CH3:19]
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Reactant: CCCCO
Agent: CCCCP(CCCC)CCCC
Solvent: O
Product: CCCCOC1=NC=CC(c2ccccc2)=CC1
Temperature: -40 °C
Yield: 44.1 %

Procedure:
A 22 Liter reaction flask is equipped with a heating mantle, overhead stirring apparatus, condenser, addition funnel, thermometer probe, and nitrogen inlet/outlet. The flask is purged thoroughly with nitrogen and maintained under nitrogen throughout the reaction. The flask is charged with 4-nitrobiphenyl (1700 g, 8.53 moles) and 1-butanol (3793 g, 51.2 moles). The resulting mixture is heated to reflux to form a clear solution. Tributylphosphine (3500 g, 17.3 moles) is charged to the addition funnel and added dropwise to the hot 4-nitrobiphenyl solution. The temperature is gradually increased as needed to maintain reflux. The reaction is monitored by gas chromatography analysis for completion. The reaction is cooled and water is added (500 mL). The reaction is concentrated to an oil, followed by the addition of petroleum ether (8.0 L). The resulting mixture is cooled to −40° C. and filtered to remove undesired tributylphosphine oxide. The filtrate is concentrated again and petroleum ether (8.0 L) is added. The mixture is cooled and filtered. The resulting filtrate is concentrated to an oil and purified by silica gel chromatography to give the title compound (908 g, 44%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=O.[NH2:14][CH2:15][C:16]([N:18]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH2:19][CH3:20])=[O:17]>>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][N:18]([CH2:19][CH3:20])[C:16]([CH2:15][NH:14][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=[O:17]
Reactant: CCOC(=O)c1ccnc(C=O)c1
Reactant: CCN(CCN(C)C)C(=O)CN
Product: CCOC(=O)c1ccnc(CNCC(=O)N(CC)CCN(C)C)c1

Procedure:
By General Procedure A from ethyl 2-formylpyridine-4-carboxylate and 2-amino-N-[2-(dimethylamino)ethyl]-N-ethylacetamide. 1H NMR (300 MHz, CDCl3), δ ppm: 3.47-3.32 (m, 4H), 3.27-3.20 (m, 2H), 2.44-2.35 (m, 2H), 2.22 (s, 6H), 1.53 (s, 2H), 1.15-1.06 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][Si:15]([CH3:18])([CH3:17])Cl>CCOCC.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Si:15]([CH3:18])([CH3:17])[CH3:14])=[CH:4][CH:3]=1
Reactant: Brc1ccc(Br)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 94.4 g of p-dibromobenzene is cooled to -20° C. in 400 ml of absolute ether. To the solution is added dropwise 255 ml of 15% butyllithium in hexane so that the temperature does not rise above -10° C. Then the mixture is agitated for one hour at room temperature. After a negative Gilman test (H. Gilman, J. Swiss, J. Amer. Chem. Soc. 62: 1847 [1940]), the mixture is again cooled to -20° C. and 46 ml of trimethylchlorosilane in 200 ml of absolute ether is added dropwise thereto so that the temperature does not exceed -10° C. After the addition step is finished, the mixture is stirred for 16 hours at room temperature and another hour under reflux. The thus-formed precipitate is suctioned off and thoroughly washed with ether. The resultant filtrate is concentrated and then distilled with a water-jet aspirator, thus producing 65.52 g of p-bromotrimethylsilylbenzene, bp (16 torr) 103°-110° C.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]2=[O:17])=[C:5]1[C:27]([O:29]C)=[O:28])[CH:2]=[CH2:3].C[N+]1([O-])CC[O:35]CC1.O>CC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[CH2:18][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13](=[O:14])[N:4]3[CH2:1][CH:2]([CH2:3][OH:35])[O:29][C:27](=[O:28])[C:5]3=2)[C:10]1=[O:17]
Reactant: C=CCn1c(C(=O)OC)c2c(c(OC)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: O
Product: COc1c2c(c3n(c1=O)CC(CO)OC3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.20 g, 0.46 mmol), N-methylmorpholine N-oxide (67 mg, 0.58 mmol), water (0.2 mL), and osmium tetroxide (0.75 mL, 0.08 M in t-butanol) in acetone (1 mL) was stirred at room temperature overnight. The product mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel. Collection and concentration of appropriate fractions provided the title compound. (ES MS M+1=437.2)
Reaction SMILES: [C-]#[N:2].[K+].[C:4]([C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[NH:14][C:15](=O)C(Cl)Cl)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.C(O)C.C>[NH2:2][C:15]1[C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)([OH:11])[C:12]2[C:13](=[CH:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)[N:14]=1
Reactant: [C-]#N
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC1=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
Potassium cyanide (18 g) in water (150 ml) was added to a suspension of 2'-benzoyl-2,2,4'-trichloro-acetanilide (30 g) in ethanol (400 ml). The reaction was stirred overnight and after treatment with charcoal diluted with water, 2-Amino-5-chloro-3-phenyl-3H-indol-3-ol (19.57 g) was obtained as off white crystals m.p. 205°-208°C after recrystallization from acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].FC(F)(F)C(O[C:29]1[C:34]([F:35])=[C:33]([F:36])[C:32]([F:37])=[C:31]([F:38])[C:30]=1[F:39])=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23][C:29]2[C:30]([F:39])=[C:31]([F:38])[C:32]([F:37])=[C:33]([F:36])[C:34]=2[F:35])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a stirred mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.30 g, 4.136 mmol), Et3 N (0.63 mL, 4.549 mmol) in DMF (20 mL) was added pentafluorophenyl trifluoroacetate at 0° C. The resulting mixture was stirred at room temp for 1 hr. The mixture was poured into water (60 mL) and precipitate was collected with suction. The crude solid was washed with 0.1 N HCl, H2O, n-hexane, and dried at 40° C. to afford 1.91 g (96%) pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl) ureido]phenylacetate as a pale brownish crystalline powder. IR (KBr) 1785, 1224, 1216 cm−1; 1H-NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 3.76 (s, 3H), 3.90 (s, 2H), 6.49 (s, 1H), 6.81 (d, J=1.5 Hz, 1H), 6.91 (dd, J=1.5, 8.3 Hz, 1H), 7.15 (t, J=7.3 Hz, 3H), 7.24 (m, 1H), 7.50 (d, J=7.8 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H); MS (FAB) m/z 481 (M++1); Anal. Calcd for C30H33N3O5S.1/4H2O: C, 57.51; H, 3.57; N, 5.83. Found: C, 57.40; H, 3.75; N, 5:68.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.[CH3:37][C:38]1([CH2:42][NH2:43])[CH2:41][O:40][CH2:39]1>>[CH3:22][NH:21][C:19](=[O:20])[C@:18]([CH3:33])([N:17]([CH3:34])[C:15](=[O:16])[C:14]1[CH:35]=[CH:36][C:11]([C:10]#[C:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][NH:43][CH2:42][C:38]3([CH3:37])[CH2:41][O:40][CH2:39]3)=[CH:4][CH:5]=2)=[CH:12][CH:13]=1)[C:23]([NH:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)=[O:24]
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: CC1(CN)COC1
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CNCC3(C)COC3)cc2)cc1

Procedure:
From (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.15 g) as obtained in Example 16-(1) and [(3-methyloxetan-3-yl)methyl]amine (63 mg), (2S)-N,2-dimethyl-2-[methyl(4-{[4-({[(3-methyloxetan-3-yl)methyl]amino}methyl)phenyl]ethynyl}benzoyl)amino]-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow solid) was obtained (0.13 g, 73%) in the same manner as in Example 16-(2).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH:4]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.O>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH:4]=1
Reactant: CC(=O)c1cc(CO)on1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc(COC2CCCCO2)on1

Procedure:
A solution of 1-[5-(hydroxymethyl)-1,2-oxazol-3-yl]ethanone (252 mg, 1.79 mmol), 3,4-dihydro-2H-pyran (0.24 ml, 2.68 mmol) and pyridinium 4-methylbenzenesulfonate (44.69 mg, 0.18 mmol) in DCM (10 mL) was stirred at RT for 16 hr and then for a further 0.5 hr at 40° C. after the addition of more 3,4-dihydro-2H-pyran (0.24 ml, 2.68 mmol) and pyridinium 4-methylbenzenesulfonate (44.69 mg, 0.18 mmol). The reaction mixture was diluted with water (5 ml) and the solution extracted with DCM (2×20 ml). The combined organic layers were washed with brine (5 ml), dried (Na2SO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography (Isolute, 9:1 heptane:EtOAc) to give the title intermediate: 1H NMR (500 MHz, CDCl3) delta 1.56-1.53 (2H, m), 1.68-1.60 (2H, m), 1.89-1.69 (2H, m), 2.65 (3H, s), 3.62-3.51 (1H, m), 3.93-3.78 (1H, m), 4.68 (1H, d, J=13.9 Hz), 4.75 (1H, t, J=3.3 Hz), 4.86-4.80 (1 H, m), 6.63 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9]2)[C:3]=1[C:12](OC)=O.C([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22])(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:12]1([C:3]2[C:4]3[C:10]([CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:11][C:2]=2[C:27]2[CH:26]=[CH:25][C:24]([S:21]([NH2:20])(=[O:22])=[O:23])=[CH:29][CH:28]=2)[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(Cl)cc2cccccc1-2
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: Cc1ccccc1
Product: NS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Temperature: 0 °C
Yield: 277.5 %

Procedure:
Methyl 2-(4-t -butylaminosulfonylphenyl) azulene-1-carboxylate: To a solution of methyl 2-chloroazulene-1-carboxylate (0.50 g) in toluene (20.0 ml) was added 4-t-butylaminosulfonyl-phenylboronic acid (0.87 g), tetrakis(triphenylphosphine)palladium (0) (0.12 g), and 2M aqueous Na2CO3 (4.5 ml), and the reaction mixture was heated under reflux for 16 hr. The mixture was poured into ice-water, followed by extracted with EtOAc. The combined EtOAc extracts were washed with water and brine, dried over Na2SO4, and concentrated. The crude product was purified by SiO2 column chromatography (CHCl3 /EtOAc, 100:1) to give the title compound (1.13 g) as violet crystals; mp 169°-170° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3([C:26]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Reactant: COC(=O)CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)CCCNC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), methyl 4-aminobutanoate hydrochloride (6.71 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC to give the title compound. LCMS m/z=477.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[CH3:12][S-:13].[Na+]>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[S:13][CH3:12])[CH:5]=[O:6]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSc1c(F)cc(C=O)cc1F
Temperature: 125 °C

Procedure:
A solution of 3,4,5-trifluorobenzaldehyde (1.0 g, 6.3 mmol) in DMSO (7.8 mL) was treated with a slurry of sodium methanethiolate (0.438 g, 6.25 mmol) in DMSO (0.3 mL). The solution was warmed at 125° C. for 17 min in a microwave. Upon completion, the reaction was diluted with EtOAc and washed with H2O (1×) and saturated aqueous NaCl (1×). The combined aqueous was back-extracted with EtOAc (3×), and the combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to yield a crude oil that was purified by silica gel column chromatography (0-30%, EtOAc-hexanes) to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 9.88 (s, 1H), 7.39 (d, J 7.0 Hz, 2H), 2.58 (s, 3H).
Reaction SMILES: [C:1]([C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][NH:11][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:19]SC1C(C2C=NC=CC=2)=NNC=1>>[C:1]([C:8]1[C:9]([C:13]2[CH2:14][N:15]([CH3:19])[CH2:16][CH2:17][CH:18]=2)=[N:10][NH:11][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC#Cc1c[nH]nc1-c1cccnc1
Reactant: CSc1c[nH]nc1-c1cccnc1
Product: CCCCCC#Cc1c[nH]nc1C1=CCCN(C)C1
Yield: 44 %

Procedure:
Compound 44B was converted to compound 45B, using the methodology described for the conversion of 21A to 22A (see Scheme 3). Yield: 44% (amorphous). LCMS (method A); Rt: 1.84 min, ([M+H]+=258). 1H-NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 6.78-6.66 (bs, 1H), 3.42-3.38 (m, 2H), 2.59 (bt, J=7 Hz, 2H), 2.45 (s, 3H), 2.44-2.37 (m, 2H), 1.62-1.43 (m, 4H), 0.94 (t, J=7 Hz, 3H).
Reaction SMILES: [ClH:1].Cl.[CH:3]1(NC(C2C3C=C(C4C(C)=CN=C(NCCC5CCN(C)CC5)N=4)SC=3C=CC=2)=O)CC1.[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[CH:55]=[CH:54][N:53]=[C:52]([NH:56][CH2:57][CH2:58][CH2:59][CH:60]5[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]5)[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:37][CH2:36]1>>[ClH:1].[ClH:1].[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[CH:55]=[CH:54][N:53]=[C:52]([NH:56][CH2:57][CH2:58][CH2:59][CH:60]5[CH2:61][CH2:62][N:63]([CH3:3])[CH2:64][CH2:65]5)[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:36][CH2:37]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3ccnc(NCCCC4CCNCC4)n3)cc12
Reactant: Cc1cnc(NCCC2CCN(C)CC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Agent: Cl
Product: CN1CCC(CCCNc2nccc(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1

Procedure:
Using the method of 2-{5-methyl-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 450 [M(free base)+H].