Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].[NH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[NH:13][C:14]2=[O:17])=[CH:9][CH:8]=1>C(O)C>[OH:3][C@H:2]([CH2:4][OH:5])[CH2:1][NH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])[NH:13][C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: OC[C@@H]1CO1
Solvent: CCO
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NC[C@H](O)CO)cc12
Yield: 63 %

Procedure:
(R)-Glycidol (78.3 μl, 1.18 mmol) was added to an ethanol solution (4 ml) that contained the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in step C of Example 1-1, and the obtained mixture was stirred under heating to reflux for 3 days. Thereafter, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain 7-((S)-2,3-dihydroxypropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (281.9 mg; yield: 63%) in the form of a pale yellow amorphous substance.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13]([CH2:15][CH2:16][N:17]([CH2:25][CH2:26][CH3:27])[CH:18]([CH2:23][CH3:24])[C:19](OC)=O)=[O:14].[O:28]1CCCC1>C1(C)C=CC=CC=1>[C:13]([C@@H:15]1[CH2:16][N:17]([CH2:25][CH2:26][CH3:27])[C@@H:18]([CH3:19])[CH2:23][C:24]1=[O:28])([O:12][CH3:11])=[O:14]
Reactant: C1CCOC1
Reactant: CCCN(CCC(=O)OC)C(CC)C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCN1C[C@@H](C(=O)OC)C(=O)C[C@@H]1C
Temperature: -20 °C

Procedure:
To a stirred solution of 162 mL of 0.5M potassium bistrimethylsilylamide in toluene and 600 mL of anhydrous tetrahydrofuran cooled to -78° C. under nitrogen atmosphere was added dropwise a solution of 7.5 g of (±)-methyl 2-(2-methoxycarbonylethyl(1-propyl)amino)butyrate in 50 mL of dry (tetrahydrofuran over 20 min, keeping the internal temperature under -70° C. The mixture was allowed to warm to -20° C. for 2 h, then quenched with 100 mL of saturated aqueous sodium bicarbonate and extracted into 3×200 mL portions of ethyl acetate. The combined extracts were dried over MgSO4 and concentrated under reduced pressure. There was obtained 6.6 g of predominantly (±)-trans-5-carbomethoxy-2-methyl-4-oxo-1-propyl piperidine as an oil: TLC (EtOAc); 1H NMR (400 MHz, CDCl3) 3.76 (s, 3H), 3.2 (m, 1H), 2.9 (m, 1H), 2.62-2.0 (complex m, 6H), 1.5 (m, 2H), 1.25 (d, 3H), 0.5 (dd, 3H).
Reaction SMILES: C(O)C.O1C[CH2:7][CH2:6][CH2:5]1.[C:9]1([O:15]C)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Li]>N.Cl>[CH2:5]([C:10]1[C:9](=[O:15])[CH2:14][CH2:13][CH2:12][CH:11]=1)[CH2:6][CH3:7]
Reactant: COc1ccccc1
Reactant: C1CCOC1
Agent: Cl
Agent: N
Agent: [Li]
Solvent: CCO
Product: CCCC1=CCCCC1=O
Temperature: -78 °C

Procedure:
Absolute ethanol (200 mL) followed by tetrahydrofuran (50 mL) was added at −78° C. to a solution of methyl phenyl ether from step 1 (10.0 g, 66.58 mmol) suspended in anhydrous ammonia (700 mL). Lithium metal (2.3 g, 330 mmol) was added at −78° C. in small portions over 0.5 h to yield a deep blue solution. The reaction was stirred at −78° C. until a white solution resulted. The cooling bath was taken away, the flask exposed to the atmosphere, and the ammonia was removed under a stream of nitrogen. The solid residue remaining was dissolved in a minimum amount of water and acidified to pH 3 with 10% hydrochloric acid, and then extracted several times with diethyl ether. The combined ether phase was washed with saturated sodium chloride, dried (sodium sulfate), filtered, and carefully concentrated under reduced pressure at 0° C. to provide an oil. The oil was dissolved in 10% hydrochloric acid (200 mL) and refluxed for 3 h. The reaction mixture was then cooled to room temperature and extracted several times with diethyl ether. The combined ether extracts were washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield an oil. Purification by flash column chromatography (silica, 89:11 hexanes/ethyl acetate) gave 2-propylcyclohexenone (4.43 g): 1H NMR (300 MHz, CDCl3) δ 6.95–6.89 (m, 1H), 5.97 (app dt, J=10, 2 Hz, 1H), 2.39–2.36 (m, 3H), 2.20–2.04 (m, 1H), 1.88–1.63 (m, 2H), 1.50–1.25 (m, 4H), 0.93 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12](=O)[C:13]([CH3:16])([CH3:15])[CH3:14].C(OC(=O)C)(=O)C>[Cl-].[Cl-].[Zn+2].C1(C)C=CC=CC=1>[CH3:12][C:13]([CH3:16])([CH3:15])[CH:14]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(C)(C)C=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CC(C)(C)C)C(=O)OCC
Temperature: 105 °C

Procedure:
In 1-liter flask, to a mixture of 320 g (2.0 mol) of diethyl malonate, 172 g (2.0 mol) of pivalaldehyde, and 256 g (2.51 mol) of acetic anhydride 38.4 g (0.28 mol) of ZnCl2 was added in one portion by vigorous stirring. This mixture was spontaneously warmed to ca. 105° C. The formed red mixture was refluxed for 36 h, then cooled to ambient temperature, and 800 ml of toluene was added. This solution was washed by 3×500 ml of water. The combined aqueous solution was extracted with 2×350 ml of toluene. The combined toluene extract and solution was dried over K2CO3, passed through ca. 7 cm layer of silica gel 60 (40-63 um) on glass frit, and then evaporated to dryness. Fractional rectification of the residue gave yellowish oil of the title product, b.p. 132-135° C./20 mm Hg. Yield 254 g (56%).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([N:11]=[C:12]=[O:13])([CH3:10])[CH3:9].[CH3:14][C:15]1[NH:19][N:18]=[C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH:16]=1.Cl>C(OCC)(=O)C>[CH:8]([NH:11][C:12]([N:19]1[C:15]([CH3:14])=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[N:18]1)=[O:13])([CH3:10])[CH3:9]
Reactant: CC(C)N=C=O
Reactant: Cc1cc(Oc2cccc(C(F)(F)F)c2)n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)nn1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.6 %

Procedure:
Triethylamine (0.17 g, 1.7 mmol) and isopropyl isocyanate (0.14 g, 1.7 mmol) were added to a solution of 5-methyl-3-(3-trifluoromethylphenyloxy)pyrazole (0.36 g, 1.5 mmol) in ethyl acetate (5 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a colorless viscous substance of N-isopropyl-5-methyl-3-(3-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.15 g, yield: 30.6%). 1H-NMR (CDCl3, TMS, ppm): δ 1.25 (d, J=6.6 Hz, 6H), 2.60 (d, J=0.6 Hz, 3H), 4.05 (sep, J=6.6 and 6.6 Hz, 1H), 5.71 (q, J=0.6 Hz, 1H), 6.81 (br d, J=6.6 Hz, 1H), 7.30-7.35 (m, 1H), 7.40-7.52 (m, 3H).
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:11]>O>[Cl:11][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH3:9]
Reactant: CCC(O)c1ccccc1
Reactant: Cl
Solvent: O
Product: CCC(Cl)c1ccccc1

Procedure:
13.6 g (0.1 mole) of 1-phenylpropan-1-ol are taken up in petroleum ether and are reacted at -20° C. with hydrochloric acid until the precipitation of water is terminated. Subsequently, the organic phase is washed neutral with water, dried (sodium sulfate) and the petroleum ether removed in a vacuum. The bright yellow, thermolabile oil is used without further purification. The oil has an Rf of 0.8 (CH2Cl2) and is attained in a yield of 13.1 g (85%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][NH:14][CH2:13]1.Cl[CH2:27][CH:28]1[CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][N:14]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[CH2:13]1
Reactant: ClCC1CC1
Reactant: Clc1cccc(OC2CNCCc3ccccc32)c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(OC2CN(CC3CC3)CCc3ccccc32)c1

Procedure:
A mixture of 1-(m-chlorophenoxy)-2,3,4,5-tetrahydro-3-benzazepine of Example 4, (7.0 g. 0.026 mole), chloromethylcyclopropane (4.6 g, 0.051 mole) and sodium bicarbonate (8.4 g, 0.10 mole) in DMF (85 ml) was warmed at 80°-90° C. for four hours. The reaction mixture was cooled, then concentrated under high vacuum to an oil which was stirred with water and extracted with ether. The ether extracts were twice washed with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered, then concentrated to an oil which was dissolved in ether and then converted to the oxalate salt (7 g, mp 80°-95° C.) using the procedure of Example 1. This material was rebasified, then passed through a silica gel dry column with ethyl acetate as eluent. The desired product was extracted with ethyl acetate then concentrated to an oil (3.3 g). This oil was converted to the oxalate salt using the procedure of Example 1 and then immediately recrystallized from a 20:1 solution of ethyl acetate/methanol to yield 1-(m-chlorophenoxy)-3-cyclopropylmethyl-2,3,4,5-tetrahydro-3-benzazepine oxalate, (3.1 g, d 100°-101° C.)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:38]=[CH:37][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([NH:30][CH2:31][C:32](O)=[O:33])=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:39]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:40]=[CH2:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:38]=[CH:37][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])[N:14]=[C:13]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([NH:30][CH2:31][C:32]([NH:45][S:42]([CH2:39][CH:40]=[CH2:41])(=[O:44])=[O:43])=[O:33])=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCS(N)(=O)=O
Reactant: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(=O)NS(=O)(=O)CC=C)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a solution of 2-(4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetic acid (50 mg, 0.09 mmol) in DMF (2 mL) was added prop-2-ene-1-sulfonamide (17 mg, 0.14 mmol), HATU (71 mg, 0.19 mol) and iPr2NEt (66 uL, 0.38 mmol). The mixture was stirred at r.t. for 16 hours before all the solvents were removed under vacuum. All solvents were removed nuder vacuum and the residue was purified by silica gel column (MeOH/DCM=5% to 10%) to give 4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(2-(allylsulfonamido)-2-oxoethyl)benzamide (53 mg, 89%) as a white solid.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[S:8][C:7]2=[CH:9][N:10]=[CH:11][N:6]2[CH:5]=1.S(Cl)([Cl:14])=O>C1COCC1>[ClH:14].[Cl:1][CH2:3][C:4]1[S:8][C:7]2=[CH:9][N:10]=[CH:11][N:6]2[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cn2cncc2s1
Agent: Cl
Solvent: C1CCOC1
Product: ClCc1cn2cncc2s1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
2-Hydroxymethylimidazo[5,1-b]thiazole hydrochloride (1.40 g) is suspended in 15 ml of THF, 0.8 ml of thionyl chloride is added thereto, and the mixture is stirred at 60° C. for 1.5 hr. The solvent is removed by evaporation to give 2-chloromethylimidazo[5,1-b]thiazole hydrochloride. This compound is dissolved in 7 ml of DMF, 1.78 g of triphenylphosphine is added thereto, and the mixture is stirred at 100° C. for 12 hr. The resultant precipitate is collected by filtration to give 2.14 g of (imidazo[5,1-b]thiazol-2-yl)methyltriphenylphosphonium chloride hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:57]=[CH:56][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:48][C:49]([O:51]C(C)(C)C)=[O:50])[C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[C:42]([F:45])([F:44])[F:43])=[CH:27][N:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:48][C:49]([OH:51])=[O:50])[C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[C:42]([F:43])([F:44])[F:45])=[CH:27][N:26]=3)=[CH:20][CH:21]=2)=[O:14])=[CH:56][CH:57]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cn3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cn3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
Prepared using General Procedure 8: To a stirred solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-5-(2-(4-methoxy-2 (trifluoromethyl)phenyl)acetamido)picolinamido)methyl)phenyl 4-(heptyloxy)benzoate INT-16 (18 mg, 0.02 mmol) in DCM (1 mL) was added a solution of TFA (0.1 mL) and DCM (0.2 mL). The reaction mixture was stirred at room temperature for 12 h. The solvent was evaporated under high vacuum to give 12 mg (75%) of 2-(N-(4-((4-(heptyloxy)benzoyl)oxy)benzyl)-5-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)picolinamido)acetic acid 298 as a white solid. LCMS-ESI (m/z) calculated for C39H40F3N3O8: 736; no m/z observed, tR=11.36 min (Method 2). 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.60 (s, 1H), 8.72 (dd, J=11.1, 2.1 Hz, 1H), 8.19-8.09 (m, 1H), 8.09-7.97 (m, 2H), 7.71 (dd, J=28.2, 8.7 Hz, 1H), 7.43 (dd, J=16.8, 8.3 Hz, 3H), 7.27-7.15 (m, 4H), 7.10 (d, J=8.9 Hz, 2H), 4.75 (d, J=23.0 Hz, 2H), 4.30 (s, 1H), 4.08 (t, J=6.5 Hz, 2H), 3.97 (s, 1H), 3.89 (s, 2H), 3.82 (d, J=2.0 Hz, 3H), 1.73 (dd, J=14.5, 6.6 Hz, 2H), 1.50-1.15 (m, 8H), 0.87 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N#N.Cl[C:18](Cl)(Cl)[C:19](Cl)=[O:20].[NH4+].[Cl-]>COCCOC.C(OC)(C)(C)C>[O:20]=[C:19]1[CH2:18][C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:1]1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2
Temperature: 15 °C
Yield: 15 %

Procedure:
To a flame-dried RB flask with tert-butyl 4-methylenepiperidine-1-carboxylate (2.96 g, 15 mmol, 1.0 equiv) and Zn/Cu couple (6.54 g, 172.5 mmol, 11.5 equiv) under vacuum, t-BuOMe (60 mL) was charged and refilled the flask with N2 balloon. To the mixture thus obtained stirred at 15° C., a solution of 2,2,2-trichloroacetyl chloride in DME (20 mL) was added dropwise. The mixture was stirred at room temperature overnight after addition. To the reaction mixture stirred in an external ice-bath, a saturated solution of NH4Cl (60 mL) was added slowly and carefully (especially the first few drops). After addition, the mixture was stirred at room temperature for 4 h, filtered to remove the solid. The phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated to give the residue which was purified by CombiFlash (40 g silica gel column, EtOAc/Hexane: 0-40%) to afford 619 mg (15%) of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[C:24]1([O:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:12])=[CH:19][CH:18]=2)(=[O:21])=[O:22])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1
Product: O=C1Nc2ccccc2C1=CNc1ccc(S(=O)(=O)Oc2ccccc2)cc1
Yield: 23 %

Procedure:
The title compound was prepared in 23% yield from 3-hydroxymethylene-1,3-dihydro-indol-2-one and phenyl 4-aminobenzenesulfonate according to
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]1[N:19]([CH:20]([CH2:22][CH3:23])[CH3:21])[C:18](=[O:24])[CH:17]=[C:16]([C:25]([F:28])([F:27])[F:26])[N:15]=1.[Cl:31]N1C(=O)CCC1=O>ClCCl>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:11])([F:10])[F:12])=[CH:5][C:4]=1[NH:13][C:14]1[N:19]([CH:20]([CH2:22][CH3:23])[CH3:21])[C:18](=[O:24])[C:17]([Cl:31])=[C:16]([C:25]([F:26])([F:27])[F:28])[N:15]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(C)n1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Solvent: ClCCl
Product: CCC(C)n1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)c(Cl)c1=O
Yield: 28 %

Procedure:
A dichloromethane (10 ml) solution of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-sec-butyl-6-trifluoromethyl-4(3H)-pyrimidinone (430 mg, 0.96 mmol) and N-chlorosuccinimide (141 mg, 1.06 mmol) was heated under reflux for 4 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure, the resulting residue was suspended in ether (20 ml) and then the solid deposited was filtered. The resulting filtrate was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure. By purifying the thus obtained residue by a silica gel column chromatography (toluene), 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-sec-butyl-5-chloro-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 59] was obtained as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][O:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.O.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]=[C:2]1[C:10]2[C:9]([C:11]([O:13][CH3:15])=[O:12])=[CH:8][O:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1coc2c1C(=O)CCC2
Temperature: 25 °C
Yield: 848.6 %

Procedure:
To a solution of 2.11 g of 4-oxo-4,5,6,7tetrahydrobenzo[b]furan-3-carboxylic acid in 100 ml of methanol is added 202 mg of p-toluenesulfonic acid hydrate and the mixture heated at reflux for 24 hours. The reaction mixture is cooled to room temperature and the methanol concentrated in vacuo to a residue. The residue is dissolved in 100 ml of ethyl acetate and washed with 30 ml of saturated sodium bicarbonate and 30 ml of brine. The organic layer is dried with Na2SO4, filtered and the filtrate concentrated in vacuo to a residue which is crystallized from ethyl acetate-hexane to give 1.75 g of the desired product as a white crystalline solid, m.p. 100°-102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][C:7]=1[Br:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C2CCC(=O)CC2)cc1
Solvent: ClCCl
Product: Nc1ccc(C2CCC(=O)CC2)cc1Br

Procedure:
The title compound was prepared from 4-(4-amino-phenyl)-cyclohexanone (as prepared in the previous step) by bromination with NBS according to the procedure in Example 4, step (b), replacing CH3CN with CH2Cl2. Mass spectrum (ESI, m/z): Calcd. for C12H14NOBr, 268.0/270.0 (M+H). found 268.3/270.2.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[N:18]1([C:1]([N:3]2[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]3[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]2=3)=[CH2:2])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: c1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: C=C(n1ccnc1)n1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 25 °C
Yield: 23.1 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300 mg, 1.33 mmol), 1H-imidazole (182 mg, 2.66 mmol), TBAF.3H2O (1.2 g, 3.80 mmol) and dichloro bis(triphenylphosphine) palladium (II) (47 mg, 0.06 mmol) was heated at 85° C. for 30 min. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh) eluting with 4% MeOH-DCM to yield 90 mg of 5-(1-imidazol-1-yl-vinyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. The free base was converted into the di-HCl salt by treatment with ethanolic HCl. 1H NMR (CD3OD, D1-HCl salt) δ (ppm): 9.21 (s, 1H), 7.78 (d, 2H), 7.38 (s, 1H), 7.1 (d, 1H), 6.92 (d, 1H), 6.21 (d, 1H), 5.75 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.83 (m, 1H), 3.6 (m, 1H), 3.18 (m, 5H), 2.4 (s, 3H).
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.[Cl:29]C1SC2C(Cl)=CC=CC=2N=1>>[Cl:29][C:3]1[C:4]2[S:8][C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)=[N:6][C:5]=2[CH:27]=[CH:28][CH:2]=1
Reactant: Clc1nc2cccc(Cl)c2s1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccc(Cl)c2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2,7-dichloro-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.22 (m, 2H), 2.23-2.31 (m, 2H), 3.12 (q, J=11.1 Hz, 2H), 3.42 (d, J=12.4 Hz, 2H), 4.46-4.56 (m, 1H), 7.60-7.66 (m, 2H), 8.09 (s, 1H), 8.12 (dd, J=6.2, 2.9 Hz, 1H), 8.44 (s, 2H), 8.56 (d, J=1.8 Hz, 1H). MS (ES+): m/z=411.09/413.06 (3:1) [MH+]. HPLC: tR=2.16 min (ZQ2, polar—5 min).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[CH3:8].[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:7][C:5]1[S:6][C:2]([NH:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([CH3:18])=[CH:10][CH:11]=2)=[C:3]([CH3:8])[N:4]=1
Reactant: Cc1nc(C)c(Br)s1
Reactant: Cc1ccc(CCN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(CCNc2sc(C)nc2C)cc1
Temperature: 160 °C
Reaction time: 48 h
Yield: 13.2 %

Procedure:
To a solution of 5-bromo-2,4-dimethyl-1,3thiazole (1.00 g, 5.21 mmol) in DMSO (5 mL) was added 2-(p-tolyl)ethylamine (1.06 g, 7.81 mmol) and potassium carbonate (1.1 g, 7.9 mmol). The reaction mixture was stirred for 6 d at ambient temperature and for 2 d at 160° C. under a nitrogen atmosphere. After cooling to ambient temperature it was diluted with ethyl acetate (20 mL) and washed with aqueous sodium carbonate (saturated, 20 mL) and water (20 mL). Drying over sodium sulfate, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=70:30 to 0:100) afforded the title compound (170 mg, 13%) as a light brown solid. MS m/e: 247.0 [M+H]+.