Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22]([OH:24])=O)[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.C(N(CC)CC)C.[NH2:32][CH2:33][CH:34]([OH:37])[CH2:35][OH:36].O>CN(C)C=O>[OH:37][CH:34]([CH2:35][OH:36])[CH2:33][NH:32][C:22]([C:9]1[C:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:14][C:15]=2[C:4]2[N:3]=[C:2]([CH3:1])[N:6]([CH3:7])[C:5]=2[CH:8]=1)=[O:24]
Reactant: NCC(O)CO
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc2c3c(c(C(=O)NCC(O)CO)cc2n1C)CCC(c1ccccc1)O3
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
To a solution of 0.3 g (0.93 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid and 0.3 g (0.93 mmol) O(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoro-borate (TBTU) in dimethylformamide (5 ml) were added 240 μl (1.9 mmol) triethylamine and 71 μl (0.93 mmol) 3-amino-propane-1,2-diol and the suspension was stirred overnight at room temperature. The reaction was poured into water, the precipitate filtered off and purified by column chromatography on silica gel (dichloromethane/methanol=8:1) to afford 100 mg (270%) of the title compound as a white solid.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][CH3:8])[N:6]=1.B(F)(F)F.CCOCC.N(OC(C)(C)C)=O.[Na].[OH-].[Na+]>C1COCC1>[CH2:7]([C:5]1[N:6]=[CH:2][S:3][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: CCOC(=O)c1sc(N)nc1CC
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1scnc1CC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.3 %

Procedure:
To a 0° C. solution of ethyl 2-amino-4-ethyl-1,3-thiazole-5-carboxylate (2.6 g, 13.0 mmol) in anhydrous THF (40 mL) was added boron trifluoride diethyl etherate (2.0 mL, 16.5 mmol). After 15 minutes of stirring at 0° C., tert-butyl nitrite (7 mL, 59 mmol) was added. The mixture was stirred at 0° C. for 3 hours, and then an aqueous solution of sodium hypophosphonate (4.1 g, 47 mmol, 15 mL) was added. The mixture was stirred at 0° C. for 2 hours and at room temperature overnight. The solution was basified to pH 8-9 with 5 N NaOH and then was extracted with EtOAc (3×75 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording ethyl 4-ethyl-1,3-thiazole-5-carboxylate (1.91 g, 80% yield). The product was used without further purification.
Reaction SMILES: [F:1][CH:2]([F:21])[C@H:3]1[CH2:8][C@@H:7]([C:9](=[O:16])[CH2:10][C:11](OCC)=[O:12])[CH2:6][CH2:5][N:4]1[C:17]([O:19][CH3:20])=[O:18].[OH-].[Na+].[NH2:24]O.Cl>CO.O.C(Cl)Cl>[F:1][CH:2]([F:21])[C@H:3]1[CH2:8][C@@H:7]([C:9]2[O:16][NH:24][C:11](=[O:12])[CH:10]=2)[CH2:6][CH2:5][N:4]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](C(F)F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1C(F)F
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
Cis-methyl 2-(difluoromethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.38 g, 4.49 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.180 g, 4.49 mmol) dissolved in water (2.000 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.275 mL, 4.49 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (23.20 mL, 139.22 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 5-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(difluoromethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (650 mg, 52%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.77-1.88 (m, 1H), 2.03-2.24 (m, 3H), 2.93-3.03 (m, 1H), 3.22-3.33 (m, 1H), 3.75 (s, 3H), 3.92-4.02 (m, 1H), 4.21-4.34 (m, 1H), 5.73 (s, 1H), 5.92 (dt, 1H). MS m/z 275 (M−H)−
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]2[N:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][C:24]=3[O:33][CH3:34])[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].N1C=CC=CC=1.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([N:11]1[C@@H:10]([CH3:12])[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8](=[O:21])[N:7]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][C:24]=2[O:33][CH3:34])[C:6]2[CH:35]=[CH:36][C:3]([C:1]#[N:2])=[CH:4][C:5]1=2)(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc2cc(C#N)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a 0° C. solution of tert-butyl(3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (448 mg, 921 μmol) in CH2Cl2 (9.21 ml) was added pyridine (375 μl, 4.6 mmol), followed by acetyl chloride (78.8 μl, 1.1 mmol), dropwise. The reaction was stirred at 0° C. for 1 h, then allowed to warm to rt and stirred for an additional 20 h, then quenched by the addition of H2O and extracted with CH2Cl2. The combined organic layers were washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (316 mg, 65%) as a white solid. MS m/z 551 (MNa)+.
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH2:5]([NH:12][N:13]=[CH:14][C:15](=[O:17])[CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.CO>[CH2:5]([N:12]1[CH:16]=[C:15]([OH:17])[C:14]([C:1](=[O:2])[CH3:3])=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CC=O
Reactant: CC(=O)C=NNCc1ccccc1
Solvent: CO
Solvent: O
Product: CC(=O)c1nn(Cc2ccccc2)cc1O
Temperature: 25 °C
Yield: 33 %

Procedure:
To a 40% aqueous solution of glyoxal (8.28 g, 6.55 mL, 57.1 mmol) was added a slurry of 2-oxopropanal benzylhydrazone (10.1 g, 57.1 mmol) in water (250 mL) and methanol (25 mL). The resulting mixture was heated at reflux for 3 hours before cooling to room temperature. The mixture was extracted with EtOAc (2×100 mL) and the combined organic extracts were washed with water, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (120 g column, 0-100% EtOAc/heptane gradient) to provide 1-(1-benzyl-4-hydroxy-1H-pyrazol-3-yl)ethanone (4.07 g, 33%).
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)c(Cl)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,4-dichlorophenyl isocyanate (0.19 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a tan solid (0.21 g, 57% yield), mp=88–90° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=−24.8° (c=1, EtOH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12](=[O:22])[O:13][C@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O>CC([O-])=O.CC([O-])=O.[Pd+2]>[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@H:14]([O:13][C:12](=[O:22])[NH:11][C:8]1([C:5]3[CH:6]=[CH:7][C:2]([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:29][C:28]=4[F:30])=[CH:3][CH:4]=3)[CH2:10][CH2:9]1)[CH2:15]2
Reactant: O=C(NC1(c2ccc(Br)cc2)CC1)O[C@@H]1CN2CCC1CC2
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: O=C(NC1(c2ccc(-c3ccc(F)cc3F)cc2)CC1)O[C@@H]1CN2CCC1CC2
Yield: 22.8 %

Procedure:
Using general procedure E, (S)-quinuclidin-3-yl 1-(4-bromophenyl)cyclopropylcarbamate (0.446 g, 1.22 mmol), 2,4-difluorophenyl boronic acid (0.386 g, 2.44 mmol) and Pd(OAc)2 (0.015 g, 0.067 mmol) gave the title compound as a tan solid (0.111 g, 23%). 1H NMR (CDCl3) δ 7.43 (dd, J=8.4, 1.6 Hz, 2H), 7.40-7.33 (m, 1H), 7.31 (d, J=7.7 Hz, 2H), 6.99-6.81 (m, 2H), 5.54 (d, J=48.0 Hz, 1H), 4.82-4.65 (m, 1H), 3.30-3.07 (m, 1H), 2.98-2.44 (m, 5H), 1.97 (d, J=32.7 Hz, 1H), 1.83 (d, J=10.3 Hz, 1H), 1.64 (s, 1H), 1.52 (s, 1H), 1.39 (s, 1H), 1.31 (d, J=6.8 Hz, 4H) ppm. 13C NMR major rotomer (CDCl3) δ 162.2 (dd, J=12.8, 249.1 Hz), 159.8 (dd, J=11.8, 251.0 Hz), 156.9, 156.0, 142.6, 133.1, 131.3 (m), 128.9, 125.6, 124.9, 111.5 (dd, J=3.9, 21.2 Hz) 104.4 (dd, J=25.2, 29.4 Hz), 72.1, 71.6, 55.7, 47.4, 46.5, 35.7, 35.3, 25.5, 24.6, 24.4, 19.5, 18.1 ppm. Purity: LCMS>99.3% (214 nm & 254 nm); retention time 0.90 min; (M+1) 399.0
Reaction SMILES: [BH4-].[Na+].[CH:3]1([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[CH2:7][CH2:6][CH2:5][CH2:4]1>>[CH:3]1([NH:8][C@@H:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C@H:10]2[OH:18])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C1c2ccccc2CC1NC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Product: O[C@@H]1c2ccccc2C[C@H]1NC1CCCC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
0.5 g of sodium borohydride, divided into 4 portions, is added over a period of about 1 hour while stirring to the 2-cyclopentylaminoindanone obtained in step 1 in aqueous solution of pH 3 (about 20 ml). After further stirring at room temperature for about 3-4 hours, a white precipitate separates out. After filtration with suction and drying in air, it is stirred with n-heptane. 320 mg of trans-2-cyclopentylamino-1-hydroxyindane are obtained.
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])(=O)C.O.[BrH:16]>>[Br:16][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11]
Reactant: Br
Reactant: CC(=O)OCCCCC(C)(C)C(=O)O
Solvent: O
Product: CC(C)(CCCCBr)C(=O)O
Temperature: 130 °C
Yield: 91 %

Procedure:
6-Acetoxy-2,2-dimethylhexanoic acid (4.5 g) was dissolved in 47% aqueous hydrobromic acid (25 ml), and the solution was heated at 130° C. for 4 hours. After the completion of the reaction, water (100 ml) was added to the solution, and the product was extracted with ether. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel, and development with isopropyl ether yielded 6-bromo-2,2-dimethylhexanoic acid (4 g, 91%).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Li+].CS(O[CH2:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:36]=2)[CH:32]=[CH:33][CH:34]=1)(=O)=O.[I-].[K+]>CN(C=O)C>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:28][C:29]3[CH:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:36]=4)[CH:32]=[CH:33][CH:34]=3)[N:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)COc1cccc(-c2cccc(COS(C)(=O)=O)c2)c1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)n[nH]1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(-c2cccc(Cn3nc(C(c4ccccc4)c4ccccc4)ccc3=O)c2)c1
Reaction time: 5 h
Yield: 95.1 %

Procedure:
To a solution of 6-(diphenylmethyl)pyridazin-3(2H)-one (97.2 mg) in DMF (2.7 mL) was added LiH (5.89 mg) at ambient temperature. After 5-minutes, ethyl [(3′-{[(methylsulfonyl) oxy]methyl}biphenyl-3-yl)oxy]acetate (135 mg) in DMF (1 mL) and potassium iodide (12.3 mg) were added to the solution at ambient temperature and stirred for 5 hours. The resulting mixture was quenched with 1M HCl aqueous solution and diluted with EtOAc. The organic layer was washed successively with water and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=100:0-97:3) to give ethyl [(3′-{[3-(diphenylmethyl)-6-oxopyridazin-1(6H)-yl]methyl}biphenyl-3-yl)oxy]acetate (187 mg) as a colorless gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17]OCC.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH3:17])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cccc(Br)c1

Procedure:
In DMF (96 ml) was dissolved 3-bromophenol (12 g). To the mixture was added potassium carbonate (12.5 g) and then 2-bromoethylethylether (6.7 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-3-ethoxybenzene (11.6 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15]CC)=O.[C:18]([O:21][CH2:22][C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[CH:25][C:24]=1Br)(=[O:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.O1CCOCC1>[Br:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([N:1]2[CH2:2][CH2:3][N:4]3[C:12]4[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=4[CH:6]=[C:5]3[C:13]2=[O:15])[C:23]=1[CH2:22][O:21][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)OCc1c(Br)cccc1Br
Reactant: CCOC(=O)c1cc2c(n1CCN)CCCC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A 350-mL sealed tube equipped with a magnetic stirring bar was charged with 3,4,6,7,8,9-hexahydro-2H-pyrazino[1,2-a]indol-1-one 101k (5.0 g, 0.026 mol), 2,6-dibromobenzyl acetate 104g (16.2 g, 0.052 mol) N,N′-dimethylethylenediamine (2.6 mL, 0.026 mol), Cs2CO3 (17.0 g, 0.052 mol), and 1,4-dioxane (80 mL). After a stream of nitrogen was passed through the resulting suspension for 30 min., CuI (2.5 g, 0.013 mol) was added and the resulting reaction mixture was stirred at 95° C. for 16 h. Then the mixture was cooled to room temperature, partitioned between EtOAc (50 mL) and water (50 mL), and the organic phase was extracted with EtOAc (30 mL×3). The combined organic phases were washed with water (20 mL×2) and brine (20 mL×1), dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (dichloromethane:MeOH, 97:3) to give 35% yield (4.5 g) of 113a as white solids.
Reaction SMILES: [C:1]([C:4]([C@@:6]([C:20](=[O:22])[CH3:21])([C@:8]([C:17](=[O:19])[CH3:18])([C@H:10]([CH2:15][OH:16])[O:11][C:12](=[O:14])[CH3:13])[OH:9])[OH:7])=[O:5])(=O)[CH3:2].[C:23]1([SH:29])C=CC=C[CH:24]=1.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:29]1[CH:23]=[CH:24][CH:2]=[C:1]1[C:4]([C@@:6]([C:20](=[O:22])[CH3:21])([C@:8]([C:17](=[O:19])[CH3:18])([C@H:10]([CH2:15][OH:16])[O:11][C:12](=[O:14])[CH3:13])[OH:9])[OH:7])=[O:5]
Reactant: Sc1ccccc1
Reactant: CC(=O)O[C@@H](CO)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)C(=O)C(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@@H](CO)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)C(=O)c1cccs1
Temperature: -78 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
Dry 1,2,3,4-O-tetraacetyl-L-arabinose (18.3 g, 57.5 mmol) was dissolved in dry CH2Cl2 (200 mL) and was cooled to −78° C. Thiophenol (6.5 mL, 63.3 mmol) was added followed by addition of SnCl4 (1M, 17.3 mL, 17.3 mmol). The reaction solution was stirred at −78° C. for 6 hours until the disappearance of the starting material in TLC. Saturated aqueous NaHCO3 (100 mL) was added. The organic layer was separated and the water layer was extracted with CH2Cl2 (30 mL) three times. The combined organic layer was washed with brine and dried over Na2SO4. The solvent was removed and the product was purified by silica gel column chromatography to afford thiophenyl-2,3,4-O-triacetyl-L-arabinose (16.95 g, 80%). Thiophenyl-2,3,4-O-triacetyl-L-arabinose (8.88 g, 24.1 mmol) was dissolved in MeOH (120 mL) followed by the addition of sodium methoxide (65 mg, 2 mmol ). The reaction solution was stirred at 25° C. for three hours, then saturated aqueous NH4Cl was added. The organic layer was separated and the water layer was extracted with CH2Cl2 (30 mL) three times. The combined organic layer was washed with brine and dried over Na2SO4. The solvent was removed and the product was purified by silica gel column chromatography to afford 22 (5.53 g, 22.9 mmol, 95%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:16](O)[CH2:17][OH:18]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:17]1[O:18][C:12]2([CH2:13][CH2:14][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)=[CH:10][CH2:11]2)[O:15][CH2:16]1
Reactant: N#Cc1cccc(C2=CCC(=O)CC2)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cccc(C2=CCC3(CC2)OCCO3)c1
Yield: 87.5 %

Procedure:
4-(3-cyanophenyl)-3-cyclohexene-1-one (from step 1 of method 2, 1.8 g, 9.0 mmole), ethylene glycol (2.8 g, 45 mmole) and p-toluenesulfonic acid monohydrate (0.1 g, 0.5 mmole) were dissolved in 50 ml toluene. The reaction was refluxed for 2 hours. The organic layer was washed with water (2×50 mL) and dried over sodium sulfate. The residue from the organic layer was purified by column chromatography using ethyl acetate/hexane (15/85) as the eluent to afford 4-(3-cyanophenyl)-3-cyclohexene-1-one ethylene ketal(1.9 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[C:25]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)=[CH:4][CH:3]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1CCC(c2cccc3ccc(N)cc23)C1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCC(c2cccc3ccc(NC(=O)c4ccccc4)cc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A solution of 7-amino-1-(1-methyl-3-pyrrolidinyl)-naphthalene (0.139 g, 0.615 mmol, product of Example 68) and triethylamine (0.103 mL, 0.738 mmol) in tetrahydrofuran (5 mL) was chilled to 0° C. and benzoyl chloride (0.086 mL, 0.738 mmol) was added. The reaction was warmed to room temperature and stirred overnight. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic layer was washed with 0.5N, sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1×2 inches). Elution proceeded as follows: 50% to 75% ethyl acetate/hexane (375 mL), nil; ethyl acetate (200 mL), nil; 2% triethylamine/2% methanol/ethyl acetate (200 mL), 0.14 g of brown oil which partially crystallized. Recrystallization from ethyl acetate gave 0.058 g, (28%) of the title compound as white crystals. mp 137°-145° C.; 1H NMR δ 8.57 (d, J=2 Hz, 1 H), 8.06 (br s, 1 H), 7.95 (dd, J=1.5, 8 Hz, 2 H), 7.86 (d, J=9 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.59-7.49 (m, 4 H), 7.40 (t, J=7.5 Hz, 1 H), 4.15 (sym m, 1 H), 3.04 (t, J=9 Hz, 1 H), 2.93-2.81 (m, 2 H), 2.80-2.68 (m, 1 H), 2.66-2.50 (m, 1 H), 2.47 (s, 3H), 2.08-1.96 (m, 1 H). Analysis calculated for C22H22N20: C, 79.97; H, 6.71; N, 8.48. Found: C, 79.36; H, 6.72; N, 7.94.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]=1[S:22](Cl)(=[O:24])=[O:23])[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:22]([C:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[S:17][C:13]=1[CH2:11][CH3:12])(=[O:23])=[O:24]
Reactant: Cc1noc(N)c1Br
Reactant: CCc1sc2ccccc2c1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1sc2ccccc2c1S(=O)(=O)Nc1onc(C)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-ethylbenzo[b]thiophene-3-sulfonyl chloride (1.2 mmoles, 0.31 g) and THF (7 ml). Recrystallization from chloroform and hexanes provided 0.24 g (60%) of a tan crystalline solid, m.p. 118.5-120° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([O:11][C@H:12]3[CH2:17][CH2:16][CH2:15][C@H:14]([OH:18])[CH2:13]3)=[N:8][CH:7]=[N:6][C:5]=2[O:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].[C:27]([O:31][C:32](=[O:35])[CH2:33]Br)([CH3:30])([CH3:29])[CH3:28].Cl>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:27]([O:31][C:32](=[O:35])[CH2:33][O:18][C@H:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([O:11][C:9]2[C:10]3[C:2]([Br:1])=[C:3]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:4][C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:13]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O[C@H]1CCC[C@H](Oc2ncnc3oc(-c4ccccc4)c(Br)c23)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CO[C@H]1CCC[C@H](Oc2ncnc3oc(-c4ccccc4)c(Br)c23)C1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Add a solution of 625 mg (1.606 mmol) of cis/trans-3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]cyclohexanol in 3 ml of toluene to a mixture of 2 ml of toluene and 1.28 g of 50% sodium hydroxide solution (16.05 mmol). Then add 54.5 mg (0.16 mmol) of tetra-n-butylammonium hydrogen sulphate and 626 mg (3.21 mmol) of bromoacetic acid tert-butyl ester to the biphasic mixture, and stir the reaction mixture vigorously at 60° C. for 3 h. Then add to water and neutralize with conc. hydrochloric acid. Extract the aqueous phase three times with ethyl acetate, combine the organic phases and dry over magnesium sulphate. The residue is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1→8:1). 592 mg of the target compound are obtained (73.2% of theory).