Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([O:20][CH2:21][C:22]#[N:23])[CH:14]=[CH:13]4)=[C:7]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=2[CH:30]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].CO>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH2:21][C:22]5[NH:33][N:32]=[N:31][N:23]=5)[CH:16]=4)[CH:11]=3)=[C:7]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=2[CH:30]=1
Reactant: CCCCC(=O)c1c(-c2ccc3cc(OCC#N)ccc3c2)oc2ccc(Cl)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCC(=O)c1c(-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)oc2ccc(Cl)cc12
Yield: 76.2 %

Procedure:
Following the procedure described in Step 6, of Example 1, the title compound was prepared from [6-(5-Chloro-3-pentanoyl-benzofuran-2-yl)-naphthalen-2-yloxy]-acetonitrile (0.31 g, 0.74 mmol), sodium azide (0.325 g, 5 mmol) and ammonium chloride (0.268 g, 5 mmol) in DMF (20 mL). Trituration with methanol afforded the title compound as a yellow solid (0.26 g), mp 178-180° C. Mass spectrum (+APCl, [M+H]+) m/z 461. 1HNMR (400 MHz, DMSO-d6): δ8.4 (s, 1H), 8.07-7.99 (m, 3H), 7.85 (dd, 1H, J=8.5, 1.7 Hz), 7.77 (d, 1H, J=8.8 Hz),), 7.64 (d, 1H, J=2.2 Hz),), 7.48 (dd, 1H, J=8.8, 2.2 Hz),), 7.38 (dd, 1H, J=8.8, 2.4 Hz), 5.66 (s, 2H), 2.70 (t, 2H, J=7.4 Hz), 1.56-1.48 (m, 2H), 1.15-1.06 (m, 2H), and 0.69 ppm (t, 3H, J=7.5 Hz). Elemental Analysis for C25H21ClN4O3.0.5H2O: Calculated: C, 64.52; H, 4.66; N, 12.04. Found: C, 64.40; H, 4.42; N, 12.07.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:57]2[CH2:62][CH:61]3[CH:59]([CH:60]3[C:63]([O:65][CH2:66][CH3:67])=[O:64])[CH:58]=2)O1>>[O:42]=[S:38]1(=[O:41])[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][NH:32][C@:16]23[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]2[C@@H:18]2[C@@:13]([CH3:43])([CH2:14][CH2:15]3)[C@@:12]3([CH3:44])[C@@H:21]([C@:22]4([CH3:25])[C@@H:9]([CH2:10][CH2:11]3)[C:8]([CH3:45])([CH3:46])[C:7]([C:57]3[CH2:62][CH:61]5[CH:59]([CH:60]5[C:63]([O:65][CH2:66][CH3:67])=[O:64])[CH:58]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19]2)[CH2:36][CH2:37]1
Reactant: CCOC(=O)C1C2C=C(B3OC(C)(C)C(C)(C)O3)CC21
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described in step 1 for the preparation of Example 1, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[3.1.0]hex-2-ene 6-carboxylate as the reactants. The title compound was obtained as a mixture of diastereomers in 54% yield. MS: m/e 721.55 (M+H)+, 2.901 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.81 (dd, J=6.3, 1.5 Hz, 1H), 5.50-5.37 (m, 1H), 4.72 (d, J=2.0 Hz, 1H), 4.60 (d, J=0.8 Hz, 1H), 4.19-4.05 (m, 3H), 3.11-3.00 (m, 7H), 2.97-2.82 (m, 1H), 2.74-2.43 (m, 6H), 2.17 (td, J=6.6, 3.1 Hz, 1H), 2.09-2.01 (m, 2H), 2.00-1.73 (m, 3H), 1.70 (s, 3H), 1.66-1.18 (m, 20H), 1.16-1.01 (m, 11H), 0.97 (m, 3H), 0.83 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH2:21][O:22][CH2:23][O:24][CH3:25])=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH2:21][O:22][CH2:23][O:24][CH3:25])=[CH:4][CH:3]=1
Reactant: COCOCc1nc(-c2ccccc2)oc1CCc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOCc1nc(-c2ccccc2)oc1CCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 100.1 %

Procedure:
A mixture of 5-[2-(4-hydroxyphenyl)ethyl]-4-methoxymethoxymethyl-2-phenyl-1,3-oxazole (3.12 g), 4-chloromethyl-5-methyl-2-phenyl-1,3-oxazole (2.28 g), potassium carbonate (1.27 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 5-{2-[4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxyphenyl]ethyl}-4-methoxymethoxymethyl-2-phenyl-1,3-oxazole as colorless crystals (4.70 g, yield 85%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v). The crystals were recrystallized from ethyl acetate-hexane. melting point: 124-125° C.
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH:3]=[CH2:4].N1C=CC=CC=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14]>C(Cl)Cl>[CH2:2]([O:5][NH:6][S:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[CH:3]=[CH2:4]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C=CCON
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a stirred solution of O-allylhydroxylamine hydrochloride (147.05 g, 1341.59 mmol) in DCM (2.5 L) at 0° C., pyridine (318 mL, 3948 mmol) was added followed by the addition of 2-nitrobenzene-1-sulfonyl chloride (250 g, 1128.05 mmol) portionwise as a solid. The reaction mixture was then stirred at the same temperature for 1 h. Completion of the reaction was monitored by TLC. The reaction mixture was quenched with 1.5 N HCl (1 L). The organic layer was separated, washed with water (250 mL), brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield the residue. The crude was purified by crystallization using EtOAc:petroleum ether (1:3) (800 mL) and afforded 202 g of the title compound as a light brown solid. The mother liquor was concentrated and purified by silica gel column chromatography (mesh 60-120) using petroleum ether:EtOAc (7:3) to yield another 19.1 g of the title compound as a yellow solid. The total yield is 76%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.Br[CH2:23][CH2:24][C:25]([F:29])=[C:26]([F:28])[F:27].O>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:23][CH2:24][C:25]([F:29])=[C:26]([F:28])[F:27])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: FC(F)=C(F)CCBr
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(OCCC(F)=C(F)F)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
To a stirred solution of 1.6 grams (0.01 mole) of 4-chlorobenzoic acid in 35 ml of acetonitrile was added 1.5 ml (0.01 mole) of 1,8-diazabicyclo[5.4.0]-undec-7-ene, followed by 1.9 grams (0.01 mole) of 4-bromo-1,1,2-trifluoro-1-butene. The reaction mixture was heated under reflux for four hours then allowed to cool to ambient temperature. Water, 25 ml, was added to the reaction mixture, and the reaction mixture was extracted with three 20 ml portions of diethyl ether. The combined extracts were washed in succession with one 25 ml portion of water, two 25 ml portions of aqueous 5% sodium hydroxide and, finally, one 25 ml portion of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 1.2 grams of (3,4,4-trifluoro-3-butenyl) 4-chlorobenzoate as an oil. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]=1>[Pt]>[CH:5]1([Si:2]([Cl:4])([Cl:3])[Cl:1])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cl[SiH](Cl)Cl
Reactant: C1=CCCC1
Agent: [Pt]
Agent: *C(F)(F)C(*)(F)F
Product: Cl[Si](Cl)(Cl)C1CCCC1
Yield: 91 %

Procedure:
The experiment was conducted in substantially the same manner as in Example 1 by preparing a reaction mixture from 19.5 g (0.144 mole) of trichlorosilane, 9.9 g (0.146 mole) of cyclopentene and 0.14 g of the catalyst I corresponding to 238 ppm by weight as platinum based on the total amount of trichlorosilane and cyclopentene and heating the mixture in a polytetrafluoroethylene-made pressure-resistant vessel at 60° C. for 26 hours under a spontaneously produced pressure of 3 kg/cm2G. About 97% of the starting reactants had been reacted at the end of the reaction time as determined by the gas chromatographic analysis. Treatment of the reaction mixture after the reaction was performed in the same manner as in Example 1 to give cyclopentyl trichlorosilane in a yield of 91% as isolated based on the theoretical value.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][CH:12]=[CH:13][C:6]=12.[Cl-].[NH4+]>O1CCCC1.CO.[Zn]>[NH:11]1[C:7]2=[N:8][CH:9]=[CH:10][C:5]([O:4][C:3]3[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:2]=3[F:1])=[C:6]2[CH:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a suspension of 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.1 mmol) in tetrahydrofuran (5 mL) and methanol (10 mL), was added zinc powder (350 mg, 5.5 mmol) and ammonium chloride (294 mg, 5.5 mmol). The mixture was stirred at rt overnight. The mixture was filtered through a pad of Celite®, rinsed with methanol. The filtrate was concentrated in vacuo and the resulting residue was purified by flash column chromatography (silica gel, 1-5% MeOH in CH2Cl2) to afford the desired product (205 mg, 77%) as an off-white solid. MS(ESI+) m/z 244 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+].O>CO>[N:1]1([CH2:6][CH2:7][CH2:8][CH:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[OH:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCCn1ccnc1)c1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(CCCn1ccnc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 4-(1H-imidazol-1-yl)-1-(2-naphthyl)-1-butanone (0.793 g) in MeOH (5 ml) was added NaBH4 (0.213 g) and the mixture was stirred at room temperature for 2 hours. Water was added and the whole was concentrated. The residue was extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel (ethyl acetate-MeOH=20:1) followed by crystallization to give the titled compound (0.615 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[C:19]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][CH:29]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:18])=[CH:9][CH:8]=3)=[CH:12][CH:13]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1ccc(Oc2ccc(N)cc2)cc1
Product: COC(=O)c1ccc(Oc2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Yield: 93.9 %

Procedure:
Using general procedure A, 4-(4-aminophenoxy)-benzoic acid methyl ester (Fokin; et al., Chem. Abstr., 72, 12294, 1970) (556 mg, 2.29 mmol) and 1-Boc-4-piperidone (478 mg, 2.40 mmol) gave 4-[4-(4-methoxycarbonyl-phenoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (917 mg, 94%) as a crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12.[H-].[Na+].[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[S:35](Cl)(=[O:37])=[O:36]>CN(C=O)C.O>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[S:35]([N:9]1[C:10]2[C:6](=[C:5]3[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]3=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1cc2[nH]ccc2c2c1OCCN(C(=O)OC(C)(C)C)C2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(ccn2S(=O)(=O)c2ccc(Cl)cc2Cl)c2c1OCCN(C(=O)OC(C)(C)C)C2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
tert-Butyl 6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 36, 25 mg, 0.059 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2,4-dichlorobenzenesulfonyl chloride (28 mg, 0.113 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2,4-dichlorophenyl)sulfonyl]-6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (6 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (4.2 mg). MS m/z 442 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][C:10]([Cl:16])=[C:9]([CH3:17])[C:8]=1[C:18]#[N:19])(=O)=O.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.N#N>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([C:12]1[CH:11]=[C:10]([Cl:16])[C:9]([CH3:17])=[C:8]([C:18]#[N:19])[C:7]=1[C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:22])[CH:28]=1)(=[O:15])[CH3:14]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cccc(F)c1
Temperature: 80 °C
Yield: 98.6 %

Procedure:
A biphasic solution of 6-acetyl-4-chloro-2-cyano-3-methylphenyl trifluoromethanesulfonate (2.54 g, 7.4 mmol) and (3-fluorophenyl)boronic acid (1.6 g, 11 mmol) in toluene (70 mL) and saturated sodium bicarbonate (70 mL) was bubbled with N2 to degas. After tetrakis(triphenylphosphine)palladium(0) (0.43 g, 0.37 mmol) was added, the mixture was bubbled with N2 for 5 min more and then heated at 80° C. for 2 hours. After cool to room temperature, the mixture was diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel column, eluting with 0 to 40% ethyl acetate in hexane, to give the desired product (2.1 g, 99%). LCMS calculated for C16H12ClFNO (M+H)+: m/z=288.1. found: 288.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14](Cl)[C:13]3=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][N:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:13]3=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][N:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc2c(Cl)nc(-c3ccc([N+](=O)[O-])cc3)nn2c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(N3CCOCC3)nc(-c3ccc([N+](=O)[O-])cc3)nn2c1

Procedure:
Compound 8 (4.6 g, 13.8 mmol) was suspended in 150 mL of tetrahydrofuran, 3.6 mL of morpholine was added dropwise and reacted for 5 hours at room temperature. 3.9 g of solid was obtained by filteration, and the filtrate was separated through a column chromatography with dichloromethane to give 1.1 g of yellow compound 9a (94.3%). m.p. 296-300° C. 1H NMR (300 MHz, CDCl3): δ 8.45 (d, J=8.7 Hz, 2H), 8.29 (d, J=8.7 Hz, 2H), 8.14 (d, J=1.3 Hz, 1H), 7.23 (d, J=1.3 Hz, 1H), 4.17 (t, J=4.8 Hz, 4H), 3.91 (t, J=4.8 Hz, 7H). LC-MS: 384 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([N-]C(C)C)(C)C.[Li+].CI.O>O1CCCC1.ClCCl>[CH2:1]([O:8][C:9]1[CH2:13][CH:12]([CH3:15])[C:11](=[O:14])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C(OCc2ccccc2)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC1CC(OCc2ccccc2)=CC1=O
Temperature: 25 °C

Procedure:
A solution of 3-(benzyloxy)cyclopent-2-enone (intermediate 21, 300 mg, 1.59 mmol) in dry tetrahydrofuran (4.0 mL) is cooled at −50° C. with an acetone/dry ice bath and treated with lithium diisopropylamide (2.0 M in tetrahydrofuran, 890 mL, 1.78 mmol). After 15 min methyl iodide (100 μL, 1.59 mmol) is added, and the mixture is warmed to room temperature over night. Water and dichloromethane is added, and the phases are separated. The organic layer is concentrated under reduced pressure, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 210 mg; ESI mass spectrum [M+H]+=203; Retention time HPLC: 0.57 min (X012_S01).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]([OH:13])[C:7]2=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.[I-].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]([O:13][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:7]2=[O:14]
Reactant: Cn1cc(O)c(=O)c2cccc(Br)c21
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(C)c3c(Br)cccc3c2=O)cc1
Temperature: 90 °C
Yield: 77.5 %

Procedure:
A suspension of 8-bromo-3-hydroxy-1-methylquinolin-4(1H)-one (2.4 g, 8.97 mmol) and potassium carbonate (1.488 g, 10.77 mmol) in N,N-dimethylformamide (50 mL) was heated at 90° C. for 0.5 h. Then 1-(chloromethyl)-4-methoxybenzene (1.442 mL, 9.87 mmol) and potassium iodide (0.149 g, 0.897 mmol) were added, and the mixture was heated at the same temperature for another 2 h. After cooling. N,N-dimethylformamide was removed in vacuo and the residue was partitioned between dichloromethane and brine. The organic phase was separated, the aqueous phase was extracted with dichloromethane for several times. The combined organic extracts were dried over sodium sulfate, filtered and concentrated, The residue was purified by automatic silica gel column chromatography (Combiflash RF), eluting with ethyl acetate/hexanes (0-100%) to afford 8-bromo-3-((4-methoxybenzyl)oxy)-1-methylquinolin-4(1H)-one (2.6 g, 6.95 mmol, 77% yield) as a light brown solid. LCMS: (M+H)+: 374.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:28].C(=O)([O-])[O-].[Na+].[Na+].[CH3:35][C:36]1[O:40][C:39](B(O)O)=[CH:38][CH:37]=1.C>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:39]4[O:40][C:36]([CH3:35])=[CH:37][CH:38]=4)=[C:3]([F:28])[CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: Cc1ccc(B(O)O)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)c(F)c1
Temperature: 25 °C

Procedure:
A stirred suspension of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-3-fluorobenzenesulfonamide (3.4 g, 7.2 mmol) in 1,2-dimethoxyethane (80 ml) was treated with a solution of sodium carbonate (3.8 g, 36 mmol) in water (20 ml). (5-Methyl-2-furanyl)boronic acid (1.4 g, 10.8 mmol) and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.2 mol %) were added with some water and the mixture was stirred at reflux for 3 hours. Additional (5-methyl-2-furanyl)boronic acid (420 mg, 3.3 mmol) was added and the mixture was heated at reflux for a further 30 minutes. After cooling to room temperature, ethyl acetate (50 ml), water (50 ml) and charcoal (3 g) were added and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered through celite, the ethyl acetate layer separated and the aqueous layer was further extracted with ethyl acetate. The ethyl acetate extracts were combined washed with water and brine dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography on a 100 g column eluting with 1:40 to 1:10 2M ammonia in methanol: dichloromethane. Residue was then triturated in ether, dissolved in ether/pentane and evaporated. Residue was then triturated in pentane, washed in pentane, air dried and then dried at 50° C. under argon and high vacuum to give the title compound (E248). MS (ES+) m/e 474 [M+H]+.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.S(C)C.[F:25][C:26]([F:45])([F:44])[C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][C:33]3[CH2:42][CH2:41][CH2:40][C:39](=[O:43])[C:34]=3[CH:35]=2)[CH2:30]1)=[O:28]>C1(C)C=CC=CC=1.C1COCC1>[F:45][C:26]([F:25])([F:44])[C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][C:33]3[CH2:42][CH2:41][CH2:40][C@H:39]([OH:43])[C:34]=3[CH:35]=2)[CH2:30]1)=[O:28]
Reactant: O=C1CCCc2cc3c(cc21)CCN(C(=O)C(F)(F)F)C3
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CSC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(N1CCc2cc3c(cc2C1)CCC[C@@H]3O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-methyl-CBS-oxazaborolidine (1M solution in toluene, 0.56 mL, 0.56 mmol) in 15 mL of toluene at −10° C. was added BH3.SMe2 (1.27 mL, 13.38 mmol). To this stirred solution was then added 2-(2,2,2-trifluoroacetyl)-1,2,3,4,8,9-hexahydrobenzo[g]-isoquinolin-6(7H)-one(3.31 g, 11.15 mmol)in 5 mL of dry THF dropwise while keeping the temperature around −10° C. After stirring at room temperature for 2 h, the reaction mixture was cooled down to −10° C. and was quenched with 6 mL of MeOH and was then evaporated to dryness and directly submitted to flash chomatography (SiO2, hexane/EtOAc=3:1 to 2:1 to 1:1) to afford (S)-2,2,2-trifluoro-1-(6-hydroxy-3,4,6,7,8,9-hexahydrobenzo[g]isoquinolin-2(1H)-yl)ethanone as a white solid.