Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: Fc1cccnc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cccnc1N1CCN(Cc2nc3ccccc3[nH]2)CC1
Reaction time: 1.25 h
Yield: 36.2 %

Procedure:
The product of Example 28B(0.50 g, 2.76 mmol), 2-chloromethyl-1H-benzimidazole (0.48 g, 2.90 mmol), and cesium carbonate (1.8 g, 5.52 mmol) were combined in N,N-dimethylformamide (28 mL) at 23° C. and stirred for 1.25 hours. The mixture was concentrated under reduced pressure and rinsed with 10% methanol/dichloromethane. The solid was filtered off and the filtrate concentrated under reduced pressure. The residue was impregnated onto flash silica gel and chromatographed on flash silica gel (10% methanol/dichloromethane) to afford 311 mg (36% yield) of the title compound. mp 210–212° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.62 (m, 4H), 3.43 (m, 4H), 3.78 (s, 2H), 6.87 (m, 1H), 7.14 (m, 2H), 7.50 (m, 3H), 8.00 (m, 1H); MS (APCI) m/e 312 (M+H)+; Anal. calcd for C17H18FN5 0.4 H2O: C, 64.10; H, 5.95; N, 21.98. Found: C, 64.16; H, 5.86; N, 21.95.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1>C(#N)C>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:1](/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])=[O:7])=[CH:11][CH:10]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: CC#N
Product: O=C(O)/C=C\C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.1 %

Procedure:
A solution of 29.3 g (300 mmol) of maleic anhydride in 500 ml of acetonitrile was treated portionwise with 40 g (310 mmol) of 4-chloroaniline and stirred at room temperature during 24 hrs. The thick precipitate that had formed was filtered off, washed with cold acetonitrile and dried i.v. to yield 65.7 g (97%)of the title compound. Yellow solid. MS: 226 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([CH2:21]O)[CH:18]=[C:17]([CH3:23])[C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].P(Br)(Br)[Br:25]>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:20]=[C:19]([CH2:21][Br:25])[CH:18]=[C:17]([CH3:23])[C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(Oc1c(C)cc(CO)cc1C)c1cccc(Cl)c1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1c(C)cc(CBr)cc1C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To a solution of 0.560 g (1.62 mmol) of the product of Step B dissolved in 5 mL of carbon tetrachloride was added 0.154 mL (1.6 mmol) of phosphorous tribromide and the reaction mixture was stirred at room temperature for 15 minutes. Carbon tetrachloride was evaporated from the reaction mixture several times to remove the hydrogen bromide, then the residue was purified on a silica gel flash chromatography column eluted with 5% EtOAc-hexane. The purified fractions were evaporated in vacuo affording 0.523 g (81%) of the title compound.
Reaction SMILES: [Br-].O=[C:3]([CH3:16])[CH2:4][N+:5]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:6]=1[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:16][C:3]1[CH:15]=[C:6]2[N:5]([CH:4]=1)[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7]2
Reactant: COC(=O)c1ccc(C)[n+](CC(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc2cc(C)cn2c1
Yield: 92.7 %

Procedure:
A mixture of Example 50A (570 mg, 2.32 mmol) and sodium carbonate (400 mg, 5.0 mmol) in ethanol (10 mL) was refluxed for 3 hours and concentrated. The concentrate was dissolved in dichloromethane, and this solution was washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2:1 hexanes/dichloromethane to provide 407 mg (93%) of the desired product.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH2:31][NH:32]C(OC(C)(C)C)=O)[C:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH:27]=[N:26][CH:25]=[CH:24]4)=[O:19])=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:40]>C(Cl)Cl>[ClH:40].[ClH:40].[CH:1]1([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]([CH2:31][NH2:32])[C:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH:27]=[N:26][CH:25]=[CH:24]4)=[O:19])=[CH:15][CH:16]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(COC(=O)C2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Product: NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(COC(=O)C2CCCCC2)cc1
Reaction time: 9 h

Procedure:
To 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl cyclohexanecarboxylate (E142) in CH2Cl2 was added HCl (4 N in dioxane) and the solution was stirred for 8-10 h. The solvents were evaporated to give pure 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl cyclohexanecarboxylate dihydrochloride (E143).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:34]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:40]=3)[CH:36]=[CH:37][CH:38]=2)[N:18]=1>C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:45]([C:41]1[CH:40]=[C:39]([C:35]2[CH:36]=[CH:37][CH:38]=[C:33]([C:19]3[N:18]=[C:17]([C:16]([F:15])([F:49])[F:50])[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=4)[N:20]=3)[CH:34]=2)[CH:44]=[CH:43][CH:42]=1)(=[O:46])=[O:47]
Reactant: O=S(=O)(Cl)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Reactant: OCCNCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1)N(CCO)CCO
Temperature: 0 °C
Yield: 52.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of diethanolamine (0.12 g, 1.14 mmol), triethylamine (0.06 ml, 0.42 mmol) and THF (2 ml) was added drop wise a solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonyl chloride (example I.3) (0.21 g, 0.39 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (diethyl ether/hexane) yielded the title compound as a white solid (0.125 g, 53%). MS (ISP) 611.6 [(M+H)+]; mp 111.5° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][CH3:11].[Cl-].[CH3:13][O:14][C:15](=[O:19])[C:16](O)=[O:17].[Cl-].[NH4+]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH3:11][O:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:16](=[O:17])[C:15]([O:14][CH3:13])=[O:19]
Reactant: COCc1ccccc1Br
Reactant: COC(=O)C(=O)O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCc1ccccc1C(=O)C(=O)OC
Temperature: 20 °C
Reaction time: 20 h
Yield: 57.6 %

Procedure:
500 ml of an ethereal 1 M zinc chloride solution was dripped into a Grignard solution prepared from 12.0 g (0.46 mol) of magnesium shavings and 99.5 g (0.5 mol) of 1-bromo-2-methoxymethylbenzene in 500 ml of THF. The mixture was then refluxed for 1 hours, and a solution of 61.2 g (0.5 mol) of oxalic acid methyl ester chloride in 100 ml of THF was dripped in at an internal temperature of (-10)°C. After the mixture had been heated to about 20° C. it was stirred for a further 20 hours and then hydrolyzed with saturated ammonium chloride solution. After extraction with ether the combined ether phases were washed with water, dried and evaporated down. There was obtained 60 g of product (57.7%) as a mobile liquid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:8]2[C:4](=[CH:5][N:6]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:7]=2)[CH:3]=1.[CH3:41]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH3:41][C:2]1[CH:10]=[C:9]([CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)[C:8]2[C:4](=[CH:5][N:6]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:7]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c2nn(COCC[Si](C)(C)C)cc2c1
Temperature: 110 °C

Procedure:
A microwave tube was charged with tert-butyl 4-(((5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (200 mg, 0.3 17 mmol), trimethylboroxine (0.089 mL, 0.634 mmol), tetrahydrofuran (1.5 mL), sodium carbonate (4 M in water, 0.24 mL, 0.95 mmol), and tetrakis(triphenylphosphine)-palladium(0) (18.3 mg, 0.016 mmol). The tube was flushed with nitrogen, sealed, and heated at 110° C. for 2 h via microwave. The reaction was cooled, poured into diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25% EtOAc/Hex) gave 86 mg (50%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.94 (s, 1H), 7.20-7.45 (m, 6H), 6.86 (s, 1H), 5.65 (s, 2H), 4.84 (s, 2H), 3.74 (bs, 2H), 3.58 (t, J=7.9 Hz, 2H), 3.54 (s, 2H), 3.07 (m, 2H), 2.33 (s, 3H), 2.20 (m, 2H), 1.97 (m, 2H), 1.44 (s, 9H), 0.91 (t, J=7.6 Hz, 2H), −0.04 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 155.1, 146.1, 143.2, 131.6, 128.5, 127.9, 127.4, 126.4, 126.0, 122.6, 121.9, 117.3, 81.7, 79.6, 79.3, 69.0, 67.3, 41.9, 40.3 (br), 32.0, 28.6, 22.0, 17.9, −1.3. Mass spec.: 566.35 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][C:8](=[O:24])[C@@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[K+].C(O)(=O)C>C(O)C>[C:1]([O:5][C:6](=[O:25])[CH2:7][C@@H:8]([OH:24])[C@@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[CH:10]([CH3:12])[CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)CC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)[C@H](O)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
To a solution of t-butyl-(4S)-4-(N-benzyloxycarbonylamino)-5-methyl-3-oxohexanoate (6.0 g, 17.1 mmol) in 70 ml ethanol at 0° C. was added potassium borohydride (3.23 g, 58.8 mmol). After stirring for 4 h at 0° C. and 12 h at room temperature, the reaction mixture was acidified with glacial acetic acid to pH 4 and concentrated in vacuo. The residue was dissolved in a mixture of 200 ml ethyl acetate and 200 ml water. After additional washings of the aqueous phase with ethyl acetate (3×50 ml), the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using ethyl acetate-hexane (1:4) as eluent to give the alcohol as a white solid (5.31 g).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>C1COCC1>[CH2:14]([C:8]1[CH:9]=[CH:10][C:11]([B:19]([OH:24])[OH:20])=[C:12]([F:13])[C:7]=1[F:6])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCc1cccc(F)c1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCc1ccc(B(O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
n-Butyllithium (10 cm3, 10M in hexanes, 0.1 mol) was added dropwise to a stirred, cooled (-78° C.) solution of the compound from Example 22 (17.3 g, 94 m mol) in dry THF (250 cm3) under an atmosphere of dry nitrogen. The reaction mixture was stirred (2.5 h) then a previously cooled (-78° C.) solution of triisopropyl borate (35.7 g, 0.19 mol) in dry THF (70 cm3) added dropwise at -78° C. The reaction mixture was allowed to warm to room temperature overnight then stirred (1h) with hydrochloric acid (10%, 100 cm3). The product was extracted into diethyl ether (2×100 cm3), and the combined extracts washed with water and dried (MgSO4). The solvent was removed in vacuo to yield colourless crystals.
Reaction SMILES: C(N(CC)CC)C.C(O[C@@H:12]1[C@H:18]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH2:16][CH3:17])[C:14](=[O:34])[CH2:13]1)[C@@H:27]1[C:22]([CH:23]=[C:24]([O:31][CH2:32][CH3:33])[CH2:25][CH2:26]1)=[CH:21][CH2:20]3)(=O)C.O>CN(C=O)C>[CH2:32]([O:31][C:24]1[CH2:25][CH2:26][C@H:27]2[C:22](=[CH:21][CH2:20][C@@H:19]3[C@@H:28]2[CH2:29][CH2:30][C@@:15]2([CH2:16][CH3:17])[C@H:18]3[CH:12]=[CH:13][C:14]2=[O:34])[CH:23]=1)[CH3:33]
Reactant: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C[C@H](OC(C)=O)[C@@H]34)[C@H]2CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 40 °C
Reaction time: 72 h
Yield: 71.1 %

Procedure:
Triethylamine (2 ml, 14.4 mmol) was added to a suspension of 15α-acetoxy-3-ethoxy-18-methyl-estr-3,5-dien-17-one (2 g, 5.4 mmol) in DMF (20 ml). The mixture was stirred at 40° C. for 3 days, cooled to 10° C. and water (15 ml) was then added. The precipitate was filtered and washed with water. The crude product was purified by flash chromatography, eluting with heptane and ethyl acetate (7:3), crystallized from heptane, and dried under vacuum to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (1.2 g, yield: 66%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:17][CH2:18][CH3:19].C[Si](C)(C)[N-][Si](C)(C)C.[K+].O>O1CCOCC1.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:19][CH2:18][CH2:17][CH2:16][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCNCCCCO
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: OCCCCNCCCCc1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 34.4 %

Procedure:
In 75 ml of dioxane were dissolved 5.19 g (19.7 mmol) of 3-benzyloxybromobenzene and 3.72 g (25.6 mmol) of 4-butylamino-1-butanol. To this mixture was added 5.89 g (29.5 mmol) of potassium hexamethyldisilazide and the mixture was stirred with heating at 100° C. for 22 hours. After the reaction mixture was poured into 200 ml of water, extraction with chloroform, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 2.22 g of a light brown oily matter (yield: 34.4%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[C:20]([F:31])([F:30])[F:19])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccccc4C(F)(F)F)cc3CC[C@@H]12
Yield: 82.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-trifluoromethylphenylboronic acid (148 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with CHCl3 (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 201 mg (83%) of the title compound as an oil. FDMS: m/e=373. α[D]589 =+60.00 (c=0.36, chloroform).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:17])([F:16])[CH2:8][CH2:9][O:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[C:18](=O)(O)[O-:19].[Na+]>CN(C)C=O>[F:17][C:7]([F:6])([F:16])[CH2:8][CH2:9][O:10][C:11]1[S:12][C:13]([CH:18]=[O:19])=[CH:14][CH:15]=1
Reactant: O=C([O-])O
Reactant: FC(F)(F)CCOc1cccs1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(OCCC(F)(F)F)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.1 %

Procedure:
To 8 mL dimethylformamide at room temperature was added phosphorous oxychloride (4.0 mL, 43.33 mmol) dropwise. After stirring for 10 minutes at room temperature, 2-(3,3,3-trifluoropropoxyl)thiophene (1.70 g, 8.67 mmol) as a solution in 8 mL dimethylformamide. The resulting solution was heated to 100° C. for 15 minutes. After cooling to room temperature, the reaction mixture was poured into 100 mL of ice-water and stirred vigorously for 5 minutes. Sodium bicarbonate (11 g) was added carefully and the mixture stirred until homogeneous. Organics were extracted with ether (3×100 mL), washed with water (3×50 mL), brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (0-20% ethyl acetate in hexanes) to give 5-(3,3,3-trifluoropropoxyl)thiophene-2-carbaldehyde (761 mg, 39%) as an off-white solid. Used without further characterization.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH2:15])[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].N([O-])=O.[Na+].C([O-])(=O)C.[K+].[N-:27]=[N+:28]=[N-].[Na+]>Cl.O>[N:15]([C:9]1[C:10](=[O:14])[O:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:16][CH3:17])[CH:13]=2)=[N+:27]=[N-:28]
Reactant: CCN(CC)c1ccc2cc(N)c(=O)oc2c1
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: CCN(CC)c1ccc2cc(N=[N+]=[N-])c(=O)oc2c1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
7-Diethylamino-3-amino coumarin (100 mg, 0.43 mmol) was dissolved slowly in HCl aq. (17.2%, 4 mL) at room temperature. Upon cooling to 0-5° C. and addition of a solution of NaNO2 (30 mg, 0.43 mmol), the reaction mixture was stirred for 1 hour at 0-5° C. This was followed by the addition of potassium acetate (2 g) in water (5 mL) to adjust the pH of the resulting solution to 4. Sodium azide (57 mg, 0.88 mmol) was added in portions at 0-5° C., the mixture stirred at 0-5° C. for another five hours. The precipitated product was rapidly filtered, washed with ice-cold water (10 mL) and dried under vacuum to yield the final product as a yellow solid: 84 mg, 80%. The product was stored at −20° C. IR (KBr): 2113 (vs), 1710 (s), 1625 (m), 1512 (m); 1H NMR (300 MHz, CDCl3) δ 1.26 (t, J=7.25 Hz, 6H), 3.48 (q, J=7.24 Hz, 4H), 6.50 (s, 1H), 6.70 (d, J=8.04 Hz, 1H), 7.10 (s, 1H), 7.20 (d, J=9.07 Hz, 1H); EI-MS for C13H14N4O2 m/z (MH+): 259.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[CH2:2]1.S(=O)(=O)(O)O.[CH3:14]O>>[O:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][CH3:14])=[O:7])[CH2:2]1
Reactant: O=C(O)C1CCOC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCOC1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of tetrahydro-3-furancarboxylic acid (10.00 g, 86.0 mmol) in MeOH (172 mL) was added sulfuric acid (13.8 mL, 258 mmol). The reaction was heated to reflux for 18 h. The reaction was then cooled to rt and concentrated. The residue was partitioned between water (500 mL) and DCM (200 mL). The phases were separated and the aqueous fraction was extracted with DCM (200 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated to afford methyl tetrahydro-3-furancarboxylate (10.1 g, 78 mmol, 90% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.99 (t, J=8.4 Hz, 1H), 3.86-3.95 (m, 2H), 3.76-3.86 (m, 1H), 3.71 (s, 3H), 3.01-3.18 (m, 1H), 2.03-2.32 (m, 2H).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=2[O:22][CH3:23])[CH2:9]1)=O)(C)(C)C.[CH:24](O)=O>ClCCl.C(Cl)(Cl)Cl>[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=2[O:22][CH3:23])[CH2:9]1)(=[O:5])[CH3:24]
Reactant: COc1cc(C=O)ccc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(C=O)ccc1O[C@H]1CCN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.5 g of 4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]-3-methoxybenzaldehyde was dissolved in 20 ml of dichloromethane, followed by the addition of 30 ml of formic acid. The thus prepared mixture was stirred at room temperature for 1 hour and then at 50° C. for 1 hour. The solvent and formic acid were distilled off under a reduced pressure, and the resulting residue was dissolved in 100 ml of tetrahydrofuran. The thus prepared solution was mixed with 2.68 g of acetyl chloride, and 8.63 g of triethylamine was added dropwise thereto while stirring under ice cooling. Thereafter, the solvent was distilled off, and the residue thus obtained was dissolved in chloroform, and washed with water, followed by drying of the resulting organic layer. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using toluene as an elution solvent, thereby obtaining 4.3 g of 4-[((3S)-1-acetyl-3-pyrrolidinyl)oxy]-3-methoxybenzaldehyde as a viscous oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:17]=[C:16]([C:18](OC)=[O:19])[O:15][N:14]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:17]=[C:16]([CH2:18][OH:19])[O:15][N:14]=1
Reactant: COC(=O)c1cc(OCc2ccc3ccccc3n2)no1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc(OCc2ccc3ccccc3n2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
To a solution of methyl 3-(2-quinolylmethoxy)-5-isoxazolecarboxylate (7.39 g) in tetrahydrofuran (150 ml) was slowly added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 60 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-(2-quinolylmethoxy)-5-isoxazolylmethanol (4.95 g, yield 74%) as colorless crystals. The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 111–112° C.