Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].C(N(C(C)C)CC)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH:30][S:42]([CH3:41])(=[O:44])=[O:43])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1nc(NCCNS(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 0.25 h

Procedure:
A solution of the product of Example 157 (250 mg, 0.58 mmol), di-isopropylethylamine (111 uL, 0.64 mmol) and CH2Cl2 (10 mL) was cooled to −5° and methanesulfonyl chloride (50 uL, 0.64 mmol) was added and the resulting soln was warmed to 23°, stirred 15 min, diluted with CH2Cl2 (75 mL) and washed with 10% aq NaOH (2×20 mL) and satd aq NaCl, dried (Na2SO4), and concentrated to afford a brown solid. Chromatotron chromatography (CH2Cl2/CH3OH) and crystallization from Et2O afforded a pink solid. mp=105-115° (dec); LC MS (m/e)=504.2 (MH+). Rt=1.94 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2(O)[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[C:14]3[C:13](=[O:25])[O:12]2)[N:4]=1.B.[Na]>C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[C:14]3[C:13](=[O:25])[O:12]2)[N:6]=1
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(-c4cccs4)ccnc32)n1
Agent: B
Agent: [Na]
Solvent: CCO
Product: COc1cc(OC)nc(C2OC(=O)c3c(-c4cccs4)ccnc32)n1
Yield: 52.3 %

Procedure:
0.7 g of 7-(4,6-dimethoxypyrimidin-2-yl)-7-hydroxy-4-(2-thienyl)furo[3,4-b]pyridin-5(7H)one was dissolved in 30 ml of ethyl alcohol, and while this solution was stirred under cooling with ice, 0.07 g of sodium boron hydride was added thereto. The mixture was stirred at room temperature for 30 minutes, and then the ethyl alcohol was removed by distillation in vacuo. The residue was acidified with 10% hydrochloric acid and extracted with 200 ml of ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/2) to obtain 0.35 g (yield 52.0%) of the desired compound. m.p.: 120°-123° C.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][CH2:13][C@:14]4([CH3:20])[C:18](=O)[CH2:17][CH2:16][C@H:15]4[C@@H:10]3[C@H:9](O)C[C@H:7]1[CH2:6][C@H:5]([OH:22])[CH2:4][CH2:3]2.C[C:24]([CH3:27])([O-:26])[CH3:25].[K+].O>O1CCCC1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH3:9]/[CH:10]=[C:15]1/[CH2:16][CH2:17][C@@H:18]2[C@:14]/1([CH3:20])[CH2:13][CH2:12][C@H:11]1[C@H:25]2[C@H:24]([OH:26])[CH2:27][C@H:7]2[C@:2]1([CH3:1])[CH2:3][CH2:4][C@@H:5]([OH:22])[CH2:6]2
Reactant: CC(C)(C)[O-]
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1C[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C/C=C1/CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 72 h
Yield: 82 %

Procedure:
A solution of 1.282 g (ca. 0.0034 mol) of 3α,5β,7α-3,7-dihydroxyandrostan-17-one in 5 ml of tetrahydrofuran was added to a room temperature solution of 113 ml of tetrahydrofuran, 1.875 g (0.0167 mol) of potassium t-butoxide and 6.215 g (0.0167 mol) of ethyltriphenylphosphonium bromide. The mixture was stirred under argon for 72 hr. and then was poured into 750 ml of water containing 250 g of ice. After 30 min., the mixture was collected by suction filtration and washed with water. The dried, crude material (3.0 g) was chromatographed on 200 g of silica gel to afford, on elution with ethyl acetate--hexane (2:1), 0.888 g of material (82%). Trace amounts of impurities were removed by dissolving in a mixture of hexane and methylene chloride. The methylene chloride was distilled, the mixture was cooled, and the solid product, (Z)-3α,5β,7α-pregn-17(20)-ene-3,7-diol, was collected by filtration. The analytical sample was recrystallized from ethyl acetate then acetonitrile, mp 160°-161° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.ClC1[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]2[C:36]3[N:37]=[C:38]([NH:40][C:41](=[O:43])[CH3:42])[S:39][C:35]=3[CH:34]=[CH:33][CH:32]=2)[CH:25]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C@H:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]3[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]4[C:36]5[N:37]=[C:38]([NH:40][C:41](=[O:43])[CH3:42])[S:39][C:35]=5[CH:34]=[CH:33][CH:32]=4)[CH:25]=3)[CH2:13][CH2:12]2)[CH3:15])=[CH:21][CH:20]=1
Reactant: CC(=O)Nc1nc2c(Oc3cc(Cl)ncn3)cccc2s1
Reactant: C[C@H](c1ccc(F)cc1)N1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(=O)Nc1nc2c(Oc3cc(N4CCN([C@H](C)c5ccc(F)cc5)CC4)ncn3)cccc2s1

Procedure:
According to the procedures described in Example 21(b), 4-[(1R)-1-(4-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester, Example 21(a), (0.48 g, 1.6 mmol) and N-[4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide, Example 1(b), (0.512 g, 1.6 mmol) provided the title compound as a white solid. M.p.: 243.8-245.9° C. MS (ESI, pos. ion.) m/z: 493 (M+1).
Reaction SMILES: S([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][CH:7]=1)(O)(=O)=O.C(=O)([O-])[O-].[Ca+2]>O>[CH3:13][NH:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: CNc1ccc(O)cc1
Yield: 75 %

Procedure:
A mixture of p-(N-methylamino)phenol sulfate (13.6 g, 80 mmol), calcium carbonate (15 g, 160 mmol and water (30 mL) was triturated with mortar and pestil, and repeatedly extracted with ether (8×60 mL). The combined ether extracts were washed with water, and dried with anhydrous sodium sulfate. The solution was then evaporated to dryness, and the solid residue dried in vacuum over phosphorus pentoxide at ambient temperature to provide 7.32 g (60 mmol) of p-(N-methylamino)phenol. To anhydrous ether (240 mL) was added pyridine (4.8 mL, 60 mmol) and p-(N-methylamino)phenol 7.32 g (60 mmol). The resulting solution was added dropwise to a cooled solution (0° C.) of phosphorous oxychloride (5.4 mL, 60 mmol) in ether (100 mL) with stirring under nitrogen. The reaction mixture was stirred at room temperature for 60 minutes, filtered, and the filtrate added dropwise to a saturated solution of anhydrous ammonia in ether (450 mL, 0° C.). The reaction mixture was allowed to warm to room temperature with stirring (60 minutes). A white precipitate formed which was isolated by filtration, rinsed with ether and dried in vacuum over phosphorous pentoxide at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:8]([CH3:29])[C:7]=2[CH:30]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:8]([CH3:29])[C:7]=2[CH:30]=1
Reactant: COC(=O)c1ccc(NC(c2ccccc2)c2oc3ccc(OC)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2oc(C(Nc3ccc(C(=O)O)cc3)c3ccccc3)c(C)c2c1
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a mixture of methyl 4-{[(5-methoxy-3-methyl-1-benzofuran-2-yl)(phenyl)methyl]amino}benzoate (2.36 g) synthesized above, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (20.0 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1N hydrochloric acid (20.0 mL) was added at 0° C. The resulting precipitate was collected by filtration and the obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (1.09 g, 48%) as a pale-red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:3]=1[C:4](C1C=CC=CC=1F)=[O:5].OO.FC1C=CC=CC=1[OH:28]>ClCCl.[N+](C1C=CC=CC=1C(=[Se])O)([O-])=O>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:3]=1[C:4]([OH:5])=[O:28]
Reactant: Oc1ccccc1F
Reactant: O=C(c1ccccc1F)c1cc(Cl)c(Cl)cc1Cl
Agent: O=[N+]([O-])c1ccccc1C(O)=[Se]
Agent: OO
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)c(Cl)cc1Cl
Yield: 152.2 %

Procedure:
7.6 g (25mmol) of 2,4,5-trichloro-2'-fluorobenzophenone, 4.3 g (0.115 mol) of 90% hydrogen peroxide and 0.25 g of 2-nitrobenzoselenic acid were stirred for 24 h in 50 ml of dichloromethane. The insoluble constituents were then filtered off, water was added and the organic phase was separated off. After removal of the solvent, the residue was heated with 120 g of 60% sulfuric acid for 8 h to hydrolyze the ester present. 1.55 g (13.8 mmol, 55%) of 2-fluorophenol could then be separated off by steam distillation. 4.8 g (21 mmol, 85%) of 2,4,5-trichlorobenzoic acid (crude (GC) ca. 95%) were isolated from the mother liquor.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[CH:12]=[CH:13][C:14](O)=[O:15].[K+].[Br-]>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[CH:12]=[CH:13][CH2:14][OH:15]
Reactant: COc1cccc(C=CC(=O)O)c1
Agent: [Al+3]
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cccc(C=CCO)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Lithium aluminium hydride (213 mg; 5.5 mmol) was added portionwise to anhydrous THF (10 ml) at 0° C. To this a solution of 3-methoxycinnamic acid (2 g; 11 mmol) in THF (5 ml) was added. The reaction was left to stir at 0° C. for 10 min and then allowed to reach ambient temperature. The reaction mixture was quenched with 2M aqueous sodium hydroxide (15 ml) and the aqueous layer was extracted with ether (3×15 ml). The combined organic layers were washed with 2M hydrochloric acid (3×15 ml), brine (3×15 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel, and the product was isolated as an oil (222 mg: 12%). IR (cm−1; KBr): (3400, OH) (1400; C═C) (1250; OCH3); 1H-NMR CDCl3: (3.8, s; 3H) (4.3, dd; 2H) (6.3, m; 1H) (6.6, d; 1H) (6.8, dd; 1H) (6.9, t; 1H) (7.0, d; 1H) (7.2, t: 1H); 13C-NMR CDCl3: 55.3, 63.6, 111.9, 113.4, 119.2, 128.9, 129.6, 131.0, 138.2, 158.2, 159.9; Mass Spectrum (M+) m/e: 164.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[H-].[Na+].[Cl:33][C:34]1[N:39]=[C:38](Cl)[CH:37]=[CH:36][N:35]=1.C(OCC)(=O)C>O1CCCC1>[Cl:33][C:34]1[N:39]=[C:38]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[N:6][N:5]3[CH:30]=2)[CH:37]=[CH:36][N:35]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccc3nc(Nc4ccnc(Cl)n4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.5 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (103 mg, 0.25 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (60% in oil, 80 mg, 2.0 mmol), and the mixture was stirred at room temperature for 10 min. 2,4-Dichloropyrimidine (149 mg, 1.00 mmol) was added to the reaction mixture, and the mixture was heated to 60° C. After 1 hr, the reaction mixture was cooled to room temperature and ethyl acetate was added thereto. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/19→ethyl acetate alone) and the obtained solid was washed with ethyl acetate/hexane (=1/2) to give the title compound (27 mg, 21%) as a light blue solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[C:4]([Cl:9])[CH:3]=1
Reactant: OC1CCOCC1
Reactant: Oc1ccc(Br)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(Br)ccc1OC1CCOCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A mixture of 4-bromo-2-chloro-phenol (4 g, 19.28 mmol), tetrahydro-4-pyranol (2.20 ml, 23.13 mmol) and polymer supported triphenylphosphine (17.29 g, 39.29 mmol; purchased from Argonaut, loading 2.23 mmol/g) was suspended in DCM (250 ml) and then cooled to 0° C. Di-tert-butyl azadicarboxylate (6.65 g, 28.92 mmol) was added portionwise and the reaction mixture was warmed to r.t. and shaken for 2 h. The resin was filtered off and washed with DCM. The combined filtrates were evaporated to dryness. The crude product thus obtained was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 2%). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D27 as colorless oil (5.38 g, 95%).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([C:23]3[CH:28]=CC(F)=C[C:24]=3F)[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.C(OC(N1CC(C2C=CC3C4C(CCOC=3C=2)=CN(C2N(C(C)C)N=CN=2)N=4)C1)=O)(C)(C)C>>[ClH:1].[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([CH:23]([CH3:28])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Agent: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(C3CN(C(=O)OC(C)(C)C)C3)cc1OCC2
Agent: Cl
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(C3CNC3)cc1OCC2

Procedure:
8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was prepared similarly to 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride from 3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester. LCMS: RT=2.86 min, M+H+=351 (20%), M+H+−iPr=308 (100%).
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH+:5]([CH2:15][CH2:16]Cl)[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl.[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][NH2:43])=[CH:37][C:36]=1[O:44][CH3:45])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.C(OCC)(=O)C.O>[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][N:43]2[CH2:16][CH2:15][N:5]([CH2:6][CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:4][CH2:3]2)=[CH:37][C:36]=1[O:44][CH3:45])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCC[NH+](CCCl)CCCc1ccccc1
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CCN2CCN(CCCc3ccccc3)CC2)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
A mixture of bis(2-chloroethyl)-(3-phenylpropyl)ammonium chloride (116 mg, 0.39 mmol), potassium carbonate (119 mg, 0.86 mmol), sodium iodide (134.9 mg, 0.9 mmol), and 2-(4-(benzyloxy)-3-methoxyphenyl)ethanamine hydrochloride (100 mg, 0.34 mmol) in dimethylformamide (3 ml) is stirred at 70° C. for 5 h and then cooled to ambient temperature. To the resultant mixture is added water and ethyl acetate. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue is then purified by column chromatography, eluting with methanol-dichloromethane (1:9) to yield 112 mg of 1-(4-(benzyloxy)-3-methoxyphenethyl)-4-(3-phenylpropyl)piperazine (83%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[OH:28][CH:29]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:30]1>>[OH:28][CH:29]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:37][CH:36]=2)[CH2:30]1
Reactant: Nc1ccc(CN2CCC(O)C2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCC(O)C2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((3-hydroxy-pyrrolidin-1-yl)-methyl)-aniline Rf value: 0.1 (silica gel, methylene chloride/methanol=10:1) C28H27N3O4
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[C:11]([Cl:14])(Cl)Cl.[C]=[O:16].Cl>[Fe](Cl)(Cl)Cl.C(O)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[C:11]([Cl:14])=[O:16]
Reactant: [C]=O
Reactant: Fc1cc(F)c(F)c(C(Cl)(Cl)Cl)c1F
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O=CO
Product: O=C(Cl)c1c(F)c(F)cc(F)c1F
Temperature: 60 °C

Procedure:
268 g of 2,3,5,6-tetrafluorobenzotrichloride were placed in a 0.5 1 four necked flask. After addition of 5.4 g of iron(III) chloride, the mixture was heated to 60° C. with stirring. 46 g of formic acid were metered in over 6 hours at 60°-65° C. Vigorous gas development (carbon monoxide, hydrogen chloride) began immediately. The gas stream was fed to an absorption tower via a cooler. After addition was complete, the mixture was further stirred for two more hours at 60° C. The product was then distilled under reduced pressure.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.Cl.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)[CH2:30][CH2:31]1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Reactant: COC(=O)C1(c2ccc(CCl)cc2)CC1
Agent: Cl
Product: COC(=O)C1(c2ccc(CN3CCN(c4ccc(F)cc4F)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using methyl 1-(4-chloromethylphenyl)cyclopropanecarboxylate obtained in Example 75(2) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2,4-difluorophenyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as an orange oil.
Reaction SMILES: [CH:1]1([N:4]([C:12]2[N:17]3[N:18]=[CH:19][CH:20]=[C:16]3[N:15]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=3)[N:13]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.FC(F)(F)[C:34](O)=[O:35]>ClCCl>[CH:1]1([NH:4][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:34]=[O:35])=[C:16]3[N:15]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:29])([F:30])[F:31])[CH:22]=3)[N:13]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N(c1nc(-c2cccc(OC(F)(F)F)c2)nc2ccnn12)C1CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1cnn2c(NC3CC3)nc(-c3cccc(OC(F)(F)F)c3)nc12
Reaction time: 1 h

Procedure:
Tert-butyl cyclopropyl(2-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)carbamate was dissolved in dichloromethane (0.7 mL) and trifluoroacetic acid (0.7 mL). After 1 h, the solution was concentrated under a stream of air to give crude 4-(cyclopropylamino)-2-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a][1,3,5] triazine-8-carbaldehyde which was used without further purification. LCMS (ES): >90% pure, m/z 336 [M+1]+. 4-(cyclopropylamino)-2-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a][1,3,5]triazine-8-carbaldehyde (87 mg, 0.26 mmol) was dissolved in DMF (0.8 mL). Phosphorus(V) oxychloride (318 μL, 3.47 mmol) was added was added dropwise and the reaction was heated to 70° C. After 6 h, the solution was added dropwise to 6M NaOH (˜10 mL) cooled to 0° C. The pH was adjusted to 7 by the addition of 12N HCl. The precipitate was filtered off and dried in vacuo to furnish 4-(cyclopropylamino)-2-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a][1,3,5]triazine-8-carbaldehyde (71 mg, 75%) as a tan solid. LCMS (ES): >95% pure, m/z 364 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[CH2:9]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20](Cl)=[O:21])=[CH:15][CH:14]=1)[CH:10]([CH3:12])[CH3:11].C(N(CC)CC)C.O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:20](=[O:21])[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=1)[CH3:23]
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Reactant: OCc1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)OCc2ccccn2)cc1
Yield: 88.2 %

Procedure:
To a solution of 2.2 g of 2-pyridinemethanol in 20 ml of tetrahydrofuran were added 3 g of 2-(4-isobutylphenyl)propionic acid chloride and subsequently 2.7 g of triethylamine, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the crystals produced were removed by filtration. The filtrate was freed of solvent by distillation to leave a residue, to which was added water. The resulting mixture was extracted with ether. The ether extract was dehydrated and freed of ether by distillation. The oily residue thus obtained was distilled in vacuo to give 3.5 g of 2-(4-isobutylphenyl)propionic acid-2-pyridylmethyl ester as a pale yellow oil, boiling at 138°-140° C./0.15 mmHg. Mass spectrum: parent ion 297 m/e.
Reaction SMILES: C([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9](OC)[CH:8]=[CH:7][CH:6]=2)C.[H-].[Na+].C(Br)C1C=CC=CC=1>CN(C=O)C.O>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:3]1
Reactant: CCc1cc2c(OC)cccc2[nH]1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2[nH]ccc2c1
Reaction time: 1.5 h

Procedure:
2-Ethyl-4-methoxy-1H-indole (4.2 g, 24 mmol) was dissolved in 30 mL of DMF and 960 mg (24 mmol) of 60% NaH/minerial oil was added. After 1.5 hours, 2.9 mL(24 mmol) of benzyl bromide was added. After 4 hours, the mixure was diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate was washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 3.1 g (49% yield) of 2-ethyl-4-methoxy-1-phenylmethyl)-1H-indole.