Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1.[NH3:13]>C(Cl)Cl>[NH2:13][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1.[NH2:13][C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[N:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Reactant: N
Solvent: ClCCl
Product: Nc1ccc(C(F)(F)F)c(Cl)n1
Product: Nc1nc(Cl)ccc1C(F)(F)F

Procedure:
6.48 g of 2,6-dichloro-3-trifluoromethylpyridine and 18 ml of 28% aqueous ammonia were placed in a 50 ml autoclave, and the mixture was reacted for 24 hours at 90° C. (inner pressure: about 2 atms.). After completion of the reaction, the reaction product was allowed to cool, and methylene chloride was added thereto to thereby extract the desired product and the unreacted starting material. The methylene chloride in the extract was evaporated off, and the separation was carried out by silica gel column chromatography using firstly n-hexane and then methylene chloride as eluents. Thus, 1.12 g of 2-amino-3-trifluoromethyl-6-chloropyridine having a melting point of 99° to 101° C. and 1.37 g of 2-amino-5-trifluoromethyl-6-chloropyridine having a melting point of 111° to 113° C. were obtained.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:44]=[C:43]([F:45])[C:16]([CH2:17][S:18][C:19]2[N:20]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C:21]([C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([O:34][CH3:35])[CH:28]=3)([CH3:26])[CH3:25])=[CH:22][N:23]=2)=[C:15]([Cl:46])[CH:14]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:46][C:15]1[CH:14]=[C:13]([CH:44]=[C:43]([F:45])[C:16]=1[CH2:17][S:18][C:19]1[N:20]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[C:21]([C:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([O:34][CH3:35])[CH:28]=2)([CH3:26])[CH3:25])=[CH:22][N:23]=1)[O:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCO[Si](C)(C)C(C)(C)C)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCO)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Yield: 95 %

Procedure:
To a solution of 2-(4-(3-(tert-Butyldimethylsilyloxy)propoxy)-2-chloro-6-fluorobenzylthio)-5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (750 mg, 1.08 mmol) in THF (10 mL) was added dropwise TBAF (1.0M in THF, 0.54 mL, 0.54 mmol). After the reaction was complete, it was quenched by addition of AcOH (0.5 mL). The mixture was evaporated in vacuo and the residue was purified by flash chromatography (EtOAc/Hex=1:2) to give the title compound (592 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 7.29-7.26 (m, 1H), 7.21 (d, J=0.96 Hz, 1H), 6.91-6.84 (m, 1H), 6.76 (dt, J=8.18, 0.81 Hz, 3H), 6.70-6.65 (m, 1H), 6.58 (d, J=8.03 Hz, 1H), 6.52-6.43 (m, 2H), 6.38-6.30 (m, 2H), 4.15 (s, 3H), 4.06 (t, J=5.98 Hz, 3H), 3.84 (t, J=5.89 Hz, 2H), 3.79 (t, J=10.73 Hz, 4H), 2.13-1.97 (m, 4H), 1.48 (s, 8H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.CN([CH:17]=[O:18])C>C1COCC1>[CH3:8][C:3]1[N:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Cc1ncccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 3-bromo-2-methylpyridine (148; 10 g, 58.1 mmol) in THF (150 mL) was added n-BuLi (2.5 M, 25.6 mL) at −78° C. The reaction mixture was stirred at this temperature for 1 h. DMF (1.30 mL) was then added and the resulting reaction mixture was stirred for 1 h at −78° C. The reaction was quenched by the addition of aq. NH4Cl. Upon warming to room temperature, the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 2-methylnicotinaldehyde 149 (2.18 g, 31%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][C:12]([N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13].O1CCC[CH2:29]1>>[Cl:27][C:23]1[CH:22]=[C:21]([N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12](=[O:13])[CH2:11][NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[C:3]([CH3:29])[CH:2]=2)=[O:9])[CH:26]=[CH:25][CH:24]=1
Reactant: C1CCOC1
Reactant: NCC(=O)N(c1ccccc1)c1cccc(Cl)c1
Reactant: O=C=Nc1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)c2cccc(Cl)c2)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Phenyl isocyanate (1.06 g) is added at a temperature in the region of 20° C. to a solution of 2-amino-N-(3-chlorophenyl)-N-phenylacetamide (2 g) in anhydrous tetrahydrofuran (30 cc). The suspension obtained is stirred for 3 hours at a temperature in the region of 20° C. and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization of the residue in acetonitrile, N-(3-chlorophenyl)-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide (2.3 g), m.p. 184° C., is thereby obtained.
Reaction SMILES: Cl[CH:2]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1>>[CH:15]1([CH:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COc1ccc2oc(C(Cl)C3CCCCC3)c(C)c2c1
Product: COc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)c2c1

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-5-methoxy-3-methyl-1-benzofuran (395 mg) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (338 mg) synthesized in Example 2(2) and in the same manner as in Example A22(4), the title object compound (305 mg, 47%) was obtained as a white solid.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:33][CH2:32][CH2:31][C@@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:28]([OH:30])=[O:29])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:27])[NH:23][N+]([O-])=O)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].O.Cl>Cl.CC(O)=O.CO.[Pd]>[NH:1]1[CH2:33][CH2:32][CH2:31][C@@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:28]([OH:30])=[O:29])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:27])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CCCN1)C(=O)O
Reaction time: 6 h
Yield: 95.3 %

Procedure:
0.90 Gram (1.28 m mole) of BOC-D-Pro-Phe-Arg(NO2)-CHA was dissolved in 3.8 ml of 2N-HCl/AcOH with a small amount of MeOH and reacted at room temperature for 2 hours. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, the residue thus obtained was suspended in 113 ml of MeOH, 37 ml of H2O and 2.2 ml of 1N-HCl. Next, 1 g of palladium black was added thereto and reduced by hydrogenation at 30° C. for 6 hours. After the hydrogenation was completed, the catalyst was removed by filtration and the solvent was also removed by evaporation under reduced pressure. The residue thus obtained was purified by using a gel filtration using TOYOPEARL HW 40F column with MeOH as the developing solvent to obtain 0.66 g (95.3%) of H-D-Pro-Phe-Arg-CHA.2HCl.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:11]1[CH:16]=[N:15][C:14]([NH:17][C:18](=[O:37])[C@@H:19]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[C:28]([Cl:36])[CH:27]=2)[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][N:12]=1)[C:6](OCC)=[O:7])C.[H-].C([Al+]CC(C)C)C(C)C.O.C(OCC)(=O)C>O1CCCC1>[Cl:36][C:28]1[CH:27]=[C:26]([C@@H:19]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:18]([NH:17][C:14]2[CH:13]=[N:12][C:11]([CH:5]([CH2:6][OH:7])[CH2:4][OH:3])=[CH:16][N:15]=2)=[O:37])[CH:31]=[CH:30][C:29]=1[S:32]([CH3:35])(=[O:34])=[O:33]
Reactant: CCOC(=O)C(C(=O)OCC)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C(CO)CO)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 11.3 %

Procedure:
A solution of 2(R)-{5-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazin-2-yl}-malonic acid diethyl ester (189 mg, 0.33 mmol) in tetrahydrofuran (5.0 mL) cooled to 0° C. was treated with a 1.0M solution of diisobutylaluminum hydride in hexanes (1.84 mL, 1.84 mmol). The reaction mixture was stirred at 0° C. for 1.25 h and then at 25° C. for 2 h. At this time, the reaction was re-cooled to 0° C. and was treated with an additional amount of a 1.0M solution of diisobutylaluminum hydride in hexanes (0.92 mL, 0.92 mmol). The reaction was stirred at 0° C. for 15 min and then at 25° C. for 1 h. At this time, the reaction mixture was poured onto a mixture of ice, water, and ethyl acetate. The aqueous layer was extracted with ethyl acetate and diethyl ether. The combined organic layers were washed with a 1N aqueous citric acid solution, a cold saturated aqueous sodium bicarbonate solution, a saturated aqueous sodium chloride solution, dried over magnesium sulfate and sodium sulfate, treated with charcoal, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 9/1 ethyl acetate/acetonitrile) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxy-1-hydroxymethyl-ethyl)-pyrazin-2-yl]-propionamide (17.9 mg, 11%) as a pale yellow foam: mp 110–120° C.; (ES)+-HRMS m/e calcd for C22H28N3O5 (M+H)+ 482.1511, found 482.1512.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.Cl.[N:10]#[C:11][NH2:12].[OH-].[K+]>>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11]([NH2:12])=[NH:10]
Reactant: N#CN
Reactant: Cc1ccccc1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1ccccc1NC(=N)N
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To 150 g of o-toluidine (product of Tokyo Chemical Industry) was added 109 g of a 35 to 37% aqueous solution of hydrochloric acid (product of Wako Pure Chemical Industries) and, after heating to 85° C., 128 g of a 50% aqueous solution of cyanamide (product of Sigma-Aldrich Corp.) was added dropwise. After completion of the dropping of the aqueous cyanamide solution, a further 26.8-g portion of the aqueous hydrochloric acid was immediately added, and the mixture was stirred at 85° C. for 2 hours. The reaction mixture was cooled to room temperature and then neutralized with 236 g of a 50% aqueous solution of potassium hydroxide (product of Wako Pure Chemical Industries) to give 1-(o-tolyl)guanidine.
Reaction SMILES: C([Si](C)(C)[C:6]1[N:10]([CH3:11])[C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[Cl:21])[CH:13]=2)=[CH:8][N:7]=1)(C)(C)C.Cl>CO.O>[Cl:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:9]3[N:10]([CH3:11])[CH:6]=[N:7][CH:8]=3)[S:20][C:19]=12
Reactant: Cn1c(-c2cc3nccc(Cl)c3s2)cnc1[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: Cn1cncc1-c1cc2nccc(Cl)c2s1
Yield: 84.6 %

Procedure:
2-[2-(tert-Butyl-dimethyl-silanyl)-3-methyl-3H-imidazol-4-yl]-7-chloro-thieno[3,2-b]pyridine (912 mg, 2.50 mmol) was dissolved in 15 mL of methanol and 10 mL of 1N aqueous hydrochloric acid and heated to 35° C. overnight. The solution was cooled, diluted with water, and extracted with ethyl acetate (3×30 mL). The aqueous layer was made basic (pH 9) with 1N aqueous sodium hydroxide and extracted with chloroform (3×30 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated to afford 528 mg (84%) of 7-chloro-2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridine. 1H NMR (400 MHz, CD3OD) δ8.58 (d, 1H), 7.84 (s, 1H), 7.68 (s, 1H), 7.47 (d, 1H), 7.42 (s, 1H), 3.93 (s, 3H). LC-MS: 250.1, 252 (MH+); HPLC RT: 4.40 min.
Reaction SMILES: CN1CCCN(C)C1=O.[CH2:10]([N:17]1[CH2:20][C:19](C(OCC)=O)([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.O.O.O.C([O-])(=O)C.C([N+](CC)(CC)CC)C.O>[CH2:10]([N:17]1[CH2:20][CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CN(Cc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: CCOC(=O)C1CN(Cc2ccccc2)C1
Temperature: 130 °C
Reaction time: 12 h

Procedure:
Tetraethylammonium acetate tetrahydrate (9.42 g) was added to a 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 40 mL) solution of diethyl 1-benzylazetidine-3,3-dicarboxylate (7.00 g, which was prepared according to the method described in Synthetic Communications, volume 33, No. 19, page 3347, 2003), followed by stirring at 130° C. for 12 hours. The reaction solution was added with water, and extracted with an ethyl acetate-hexane (1:1) mixed solvent. The organic layer was washed with water, hexane was added, and extracted with 0.5 mol/L hydrochloric acid. The aqueous layer was washed with tert-butyl methyl ether, and the pH was adjusted to 8 using a 5 mol/L aqueous sodium hydroxide solution, followed by further extraction with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated, to thereby obtain the title compound (3.21 g) having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1)CCC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[N:13]3)=[CH:6][C:7]=1[C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1
Reactant: O=S(=O)(Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1cnccn1
Yield: 33.4 %

Procedure:
Trifluoromethanesulfonic acid 2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenyl ester (30.0 mg, 0.068 mmol) was coupled to 2-tributylstannylpyrazine (50.2 mg, 0.14 mmol) as described in Example 42, affording 5-(4-fluoro-3-pyrazin-2-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (8.4 mg, 33%). δH (360 MHz, CDCl3) 7.46 (1H, dd, J 10.5 and 8.4), 7.56-7.61 (1H, m), 7.63 (1H, d, J 4.2), 7.85 (1H, d, J 8.4), 8.24 (1H, dd, J 2.3 and 7.2), 8.55 (1H, d, J 8.8), 8.60 (1H, d, J 2.5), 8.68-8.69 (1H, m), 9.23 (1H, t, J 1.9), 9.30 (1H, d, J 4.6). m/z (ES+) 371 [MH]+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([NH2:21])[C:18]([O:22][CH3:23])=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH3:29][N:30]([CH3:36])[CH2:31][CH2:32][C:33](Cl)=[O:34]>N1C=CC=CC=1>[CH3:29][N:30]([CH3:36])[CH2:31][CH2:32][C:33]([NH:21][C:19]1[C:18]([O:22][CH3:23])=[C:17]2[C:13]([C:14]3[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=3[NH:16]2)=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=2)[CH:20]=1)=[O:34]
Reactant: CN(C)CCC(=O)Cl
Reactant: CCS(=O)(=O)c1cccc(-c2cc(N)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Solvent: c1ccncc1
Product: CCS(=O)(=O)c1cccc(-c2cc(NC(=O)CCN(C)C)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 105 °C
Yield: 54.8 %

Procedure:
To a suspension of Compound 239 (150 mg, 0.38 mmol) in pyridine (2.0 mL) was added 3-(dimethylamino)propanoyl chloride (71 mg, 0.38 mmol) and the reaction mixture was heated at 105° C. for 5 h. and quenched with aqueous NH4Cl solution. Organic matter was extracted with CH2Cl2 (with 10% EtOH) and washed with brine. The organic extracts were dried (Na2SO4) and concentrated and purified by preparative HPLC to yield the title compound (103 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.33 Hz, 3 H) 2.24 (s, 3 H) 2.33 (s, 6 H) 2.56 (t, J=5.81 Hz, 2 H) 2.62 (t, J=5.31 Hz, 2 H) 3.41 (d, J=7.33 Hz, 2 H) 3.93 (s, 3 H) 7.41 (d, J=1.26 Hz, 1 H) 7.87 (t, J=7.71 Hz, 1 H) 7.93-7.97 (m, 1 H) 8.03 (d, J=8.84 Hz, 1 H) 8.06 (s, 2 H) 8.22 (d, J=2.02 Hz, 1 H) 10.99 (br. s., 1 H) 12.07 (s, 1 H); [M+H] calc'd for C26H31N4O—4S, 495.2; found, 495.4.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH3:4].[CH3:5]C=CC.C[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1>>[C:14]1([CH3:5])[CH:15]=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:16][CH:2]([CH3:1])[CH2:3][CH3:4]
Reactant: Cc1ccc(C)cc1
Reactant: CC=CC
Reactant: C=CCC
Product: CCC(C)Cc1ccccc1C

Procedure:
Particular preference is given to the reaction of toluene with ethene or propene to give propylbenzene or isobutylbenzene, the reaction of cumene with ethene to give tert-amylbenzene and the reaction of xylenes with butadiene to give 5-tolylpentenes, and the reaction of p-xylene with 1-butene or 2-butene to give 1-tolyl-2-methylbutane.
Reaction SMILES: [CH3:1][S:2]([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1)=[O:3].[CH3:24][C:25]1[CH:26]=[C:27]2[N:32]([C:33]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[N:31]=[C:30]([S:45]([CH3:47])=[O:46])[N:29]=[CH:28]2>>[CH3:47][S:45]([C:30]1[N:29]=[CH:28][C:27]2=[CH:26][C:25]([CH3:24])=[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N:40]([CH3:1])[S:41]([CH3:44])(=[O:42])=[O:43])[N:32]2[N:31]=1)=[O:46].[CH3:24][C:11]1[CH:10]=[C:7]2[N:6]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:5]=[C:4]([S:2]([CH3:1])=[O:3])[N:9]=[CH:8]2
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3NS(C)(=O)=O)n2n1
Agent: Cc1cc2cnc(S(C)=O)nn2c1-c1ccccc1NS(C)(=O)=O
Product: Cc1cc2cnc(S(C)=O)nn2c1-c1ccccc1N(C)S(C)(=O)=O

Procedure:
N-[2-(2-Methanesulfinyl-6-methyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide was prepared in an analogous fashion to Example 1220 replacing N-[2-(2-methylsulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide with N-[2-(6-Methyl-2-methylsulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide to give N-[2-(6-Methyl-2-methylsulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide as an orange residue, which was used without further manipulation (0.13 g, 96%). LC/MS (E/I+) 379.05 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]#[CH:9].[C:10](=[O:13])([O-])[O-].[Na+].[Na+].BrBr.[CH3:18][OH:19]>>[CH3:18][O:19][C:2]1([CH2:6][CH2:7][C:8]#[CH:9])[CH:3]=[CH:4][CH:5]([O:13][CH3:10])[O:1]1
Reactant: C#CCCc1ccco1
Reactant: CO
Reactant: O=C([O-])[O-]
Agent: BrBr
Agent: [Na+]
Product: C#CCCC1(OC)C=CC(OC)O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred mixture of 6.01 g of 4-(2-furyl)-1-butyne [Perfumery Essent. Oil Record., 57, 364 (1966)], 10.6 g of sodium carbonate and 150 ml of methanol at -25° C., was added dropwise a solution of 8.0 g of bromine in 50 ml of methanol during a period of 3 hours. The mixture was then stirred at 25° C. for 45 minutes and concentrated in vacuo. The residue was partitioned with ether and brine. The ether layer was separated, washed with brine, dried and concentrated. Distillation of the residue at 0.5mm gave 6.62 g of the desired compound as a light yellow liquid, bp 57°-61° C. (0.5 mm).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:31][CH2:30][C:29]1=[O:32]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:28]3[CH2:31][CH2:30][C:29]3=[O:32])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1CCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 17.9 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 110 and azetidin-2-one (142 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (158 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([O:26]S(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]([F:40])([F:39])[CH:36](O)[CH3:37]>>[C:1]([O:5][C:6]([C:8]1[C:9]([O:26][CH:36]([CH3:37])[C:35]([F:40])([F:39])[F:34])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Product: CC(Oc1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)OC(C)(C)C)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 92 step A from 6-chloro-4-(3-chloro-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 91 step C, 150 mg, 0.29 mmol) and 1,1,1-trifluoro-propan-2-ol (0.052 ml, 0.58 mmol). Sticky pale yellow liquid (70 mg, 50%). LC-MS (ESI): 486 (M+H)+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[NH:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1>O.Cl>[F:13][C:12]([F:15])([F:14])[C:10]1[CH:9]=[CH:8][C:7]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:29][CH:30]=3)[N:1]=[N:5][C:6]=2[CH:11]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(-n2nnc3cc(C(F)(F)F)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2.1 g of sodium nitrite in 25 ml of water was added drop-by-drop over a 5-minute period to a stirred solution of 7.4 g of 1C in 150 ml of 12% hydrochloric acid, at 0° C. The mixture then was allowed to warm to room temperature and was stirred for 24 hours. It then was diluted with 200 ml of water and extracted with ether. The ether extract was dried (MgSO4), filtered and concentrated to dryness. The residue was absorbed on silica gel and chromatographed, using as eluent a 2:15:33 v/v/v mixture of tetrahydrofuran, ethyl acetate and hexane (hereinafter, Solvent A), to give 1, as an amber syrup.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.C(O)(=O)C.[BH3-]C#[N:24].[Na+]>CO.ClCCl>[CH3:8][CH:7]([NH:24][CH:14]1[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [BH3-]C#N
Reactant: NCCc1ccccc1
Reactant: CN1CCC(=O)CC1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(NC1CCN(C)CC1)c1ccccc1

Procedure:
DL-Phenylethylamine (606 mg, 5.0 mmol) was dissolved in 10 ml methanol and 1-Methyl-4-piperidone (566 mg, 5.0 mmol) in 10 ml methanol was added. Mixture was stirred and Acetic acid (˜0.75 ml) was added until pH˜5. NaCNBH3 (628 g, 10 mmol) was slowly added. Gas evolution observed. After magnetic stirring for 20 hrs methanol was partly removed on Rotavapor (40° C.). Ethylacetate, 2M NaOH and water were added until pH˜10. Phases were separated and aq. phase was then re-extracted with ethylacetate and dichloromethane. Combined organic phases were dried over MgSO4. Concentration on Rotavapor (40° C.) yielded 838 mg crude 47AKU-36. TLC (10% methanol in dichloromethane): Rf=0.3. HPLC-MS (Method A): M+=219.1 (UV/MS (%)=100/94).