Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[C:5]([NH2:11])(=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].[C:12](OC)(=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(O)C>[OH:8]/[C:7](=[C:6]1\[C:5](=[O:10])[NH:11][C:12](=[O:21])[CH2:13][CH:14]\1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[CH3:9]
Reactant: COC(=O)C=Cc1ccccc1
Reactant: CC(=O)CC(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C/C(O)=C1/C(=O)NC(=O)CC1c1ccccc1
Temperature: 25 °C
Yield: 17.3 %

Procedure:
Following the procedure of Kato and Noda (Chem. Pharm. Bull. Jpn 22, 12, 2947-2952, 1974), to a 0.6 M solution of sodium ethoxide (50 mL, 30 mmol) is added acetoacetamide (3.5 g, 35 mmol), followed by methyl cinnamate (4.9 mL, 30 mmol). After 10 minutes of stirring at room temperature an additional volume of ethanol (40 mL) is added. The reaction mixture is stirred at room temperature for three weeks, then neutralized to pH 7 by the addition of 10% aqueous hydrochloric acid solution. The quenched mixture is then concentrated under reduced pressure to give a white suspension. The suspension is partitioned between ethyl acetate and water. The aqueous phase is extracted thrice with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to give a white suspension, which is triturated with hot ethanol and then cooled in freezer. The white solid is collected by Buchner filtration, washed with ethanol, and dried under vacuum to give (3Z)-3-(1-hydroxyethylidene)-4-phenylpiperidine-2,6-dione as white powder (1.2 g, 17%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[C:14]([O-])(O)=O.[Na+].IC>CN(C=O)C.[Na+].[Cl-]>[CH3:14][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc(C(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(C(=O)OC)cc1
Yield: 77.4 %

Procedure:
4-propionylbenzoic acid (890 mg, 5 mmol), NaHCO3 (1.26 g, 15 mmol), and iodomethane (935 μL, 15 mmol) in DMF (10 mL) were stirred at RT overnight. The mixture was diluted with saturated aqueous NaCl (50 mL) and extracted with ether (3×50 mL). The organic phase was washed with water (50 mL), dried, and evaporated. Flash chromatography (90 g silica, 2/1 petroleum ether—EtOAc) gave white solids of 4-Propionyl-benzoic acid methyl ester (744 mg, 77%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[C:19]2[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:21])[CH:11]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:32])(=O)=O)=CC=1>C1COCC1>[Br:9][C:10]1[C:19]2[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH2:21][F:32])[CH:11]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Cc1cc(Br)c2cccc(O)c2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1cccc2c(Br)cc(CF)nc12
Temperature: -80 °C
Reaction time: 1 h

Procedure:
A solution of lithium diisopropylamide (1.8 M in THF, 0.70 mL, 1.3 mmol) in anhydrous THF (1.0 mL) was added dropwise to a stirred solution of 4-bromo-2-methyl-quinolin-8-ol (100 mg, 0.420 mmol) in anhydrous THF (1.0 mL) at −80° C. After stirring for 1 h at −80° C., a solution of N-fluorobenzenesulfonimide (331 mg, 1.05 mmol) in anhydrous THF (1 mL) was added dropwise at −100° C. The reaction mixture was allowed to warm to −20° C. and was then quenched by the addition of concentrated aqueous NH4Cl (0.4 mL). The mixture was partitioned between DCM (30 mL) and water (5 mL). The aqueous layer was extracted with DCM (2×10 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with DCM) to give the title compound. MS (m/z): 258.1 [M+H+].
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C([O-])([O-])=O.[K+].[K+].C([O:34][CH2:35][CH2:36][CH2:37]Br)(=O)C.[OH-].[Na+]>CN1C(=O)CCC1.O.CO>[NH2:24][C:15]1[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:37][CH2:36][CH2:35][OH:34]
Reactant: CC(=O)OCCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCO)c2n1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
To a suspension of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate (described in EP 1 728 793, Example 2-1, step (vi)) (20.0 g, 56.9 mmol) in NMP (111 g) was added water (1.7 g) and K2CO3 (23.61 g, 170.8 mmol). To the mixture 1-acetoxy-3-bromopropane (12.4 g, 68.3 mmol) was added and the mixture stirred at 30° C. for 3 hr. To the solution was added MeOH (79 g) and 2% aqueous NaOH (100 g) and stirred at 70° C. for 3 hr. After adding water (200 g) and cooling to 7° C., the suspension was filtered and the collected solid dried to give the subtitle compound as white solid. Yield 13.0 g, 78%; 1H NMR (DMSO-d6) δ 6.77 (bs, 2H), 4.57 (t, 1H), 4.16 (t, 2H), 4.04 (s, 3H), 3.89 (t, 2H), 3.42-3.38 (m, 2H), 1.85-1.78 (m, 2H), 1.68-1.61 (m, 2H), 1.41-1.35 (m, 2H), 0.92 (t, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:68]=[CH:67][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:43][C@@H:42]([CH2:44][O:45][C:46]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[C@H:32]([O:33]C(=O)C3C=CC=CC=3)[CH2:31]2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C[Sn](C)(C)C>CN1CCCC1=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:43][C@@H:42]([CH2:44][O:45][C:46]([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:47]3[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=3)[C@H:32]([OH:33])[CH2:31]2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:67][CH:68]=1
Reactant: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@@H](OC(=O)c3ccccc3)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Sn](C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@@H](O)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
A solution of the crude mixture 8, palladium acetate (3.44 g), triphenylphosphine (8.0 g) in N-methylpyrolidinone (1375 ml) with triethylamine (4.3 ml) was stirred at room temperature for 45 min. Then, tetramethyltin (42.4 ml) was added dropwise at 0C under argon. After stirring at 100-110° C. overnight, the reaction mixture was poured into water and extracted with diethyl ether. The organic solution was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography [eluant: stepwise gradient of ethyl acetate (0-10%) in toluene] to give compound 9 as a foam (42.3 g, 48.3% for the 2 steps). 1H NMR (DMSO) δ ppm 0.8.3-7.2 (m, 15H,2 C6H5CO, 1 CH3C6H4CO, H-6), 6.29 (t, 1H, H-1′, J=7.0 Hz), 5.7 (m, 1H, H-3′), 4.7-4.5 (m, 3H, H-5′, H5″, H-4′), 2.7-2.6 (m, 2H, H-2′, H-2″); FAB<0, (GT) m/e 567 (M−H)−, 449 (M−CH3C6H4CO)−, 243 (B)−, 121 (C6H5COO)−; FAB>0 (GT) 1137 (2M+H)+, 569 (M+H)+, 325 (M−B)−, 245 (B+2H)+, 119 (CH3C6H5CO)−;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([CH3:37])([CH3:36])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.I[C:39]1[CH:44]=[CH:43][N:42]([CH3:45])[C:41](=[O:46])[CH:40]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([CH3:37])([CH3:36])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:39]4[CH:44]=[CH:43][N:42]([CH3:45])[C:41](=[O:46])[CH:40]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1ccc(I)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Yield: 66.4 %

Procedure:
A mixture of 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile (100 mg, 0.21 mmol) and 4-iodo-1-methyl-1H-pyridin-2-one (40 mg, 0.17 mmol), Pd(PPh3)2Cl2 (20 mg), and aq. Cs2CO3 solution (2.0 mL, 2M) in 1,4-dioxane (5 mL) was stirred at reflux for 2 h. The organic phase was separated and concentrated to give the crude product, which was purified by preparative TLC to give 3-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-2-oxo -1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile (55 mg, 66%). LC-MS Method 2 tR=1.096 min, m/z=488.3; 1H NMR (CDCl3): δ 1.27 (s, 3H), 1.40 (s, 3H), 1.48 (d, 3H), 2.06 (s, 2H), 2.23 (m, 1H), 2.41 (m, 2H), 2.90 (m, 1H), 3.51 (s, 3H), 5.60 (m, 1H), 6.27 (m, 1H), 6.65 (d, 1H), 6.89 (d, 2H), 6.99 (t, 2H), 7.26 (m, 5H).
Reaction SMILES: [Cl-].[NH3+:2][CH2:3][C@@:4]1([OH:12])[CH:9]2[CH2:10][CH2:11][NH+:6]([CH2:7][CH2:8]2)[CH2:5]1.[Cl-].C(=O)([O-])[O-].[Cs+].[Cs+].[N:20]([C:23]1[N:24]=[CH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([O:33][CH3:34])=[C:28]([O:35][CH3:36])[CH:27]=2)=[C:21]=S.C(=NC(C)C)=NC(C)C>CN(C=O)C.C(#N)C>[CH3:34][O:33][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:35][CH3:36])[CH:25]=[N:24][C:23]([NH:20][C:21]1[O:12][C@:4]3([CH2:3][N:2]=1)[CH:9]1[CH2:8][CH2:7][N:6]([CH2:11][CH2:10]1)[CH2:5]3)=[CH:32]2
Reactant: COc1cc2cnc(N=C=S)cc2cc1OC
Reactant: [NH3+]C[C@]1(O)C[NH+]2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc2cnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)cc2cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.3 %

Procedure:
To a stirring suspension of (S)-3-(ammoniomethyl)-3-hydroxy-1-azoniabicyclo[2.2.2]octane chloride (73 mg, 0.319 mmol) and cesium carbonate (221 mg, 0.678 mmol) in DMF (5 mL) was added a solution of 3-isothiocyanato-6,7-dimethoxyisoquinoline (69 mg, 0.280 mmol) in DMF (1.5 mL) and the reaction mixture was allowed to stir at room temperature for 3 days. To the solution was then added a solution of N,N′-methanediylidenedipropan-2-amine (69 mg, 0.547 mmol) in DMF (0.4 mL) and the reaction was allowed to stand at room temperature for 14 days. Another 69 mg di-isopropylcarbodiimide was added in −0.4 mL acetonitrile and the reaction was allowed to stand for 1 more day, then it was evaporated in vacuo and the residue subjected to preparative HPLC to yield (R)—N-(6,7-dimethoxyisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine 20.9 mg. (8%) LCMS RT 0.98 min, MH+=403.2 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.73 (1H, s), 7.28 (1H, s), 7.09 (1H, s), 6.96 (1H, s), 4.01 (3H, s), 4.00 (3H, s), 3.96 (1H, d, J=8.5 Hz), 3.63 (1H, d, J=9.2 Hz), 3.39 (1H, d, J=15.0 Hz), 2.79-3.10 (5H, m), 2.24 (1H, br. s.), 2.15 (1H, br. s.), 1.75 (1H, dddd, J=13.9, 9.3, 4.7, 4.4 Hz), 1.59-1.68 (1H, m), 1.48-1.59 (1H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2ccccc2)c1
Yield: 94.6 %

Procedure:
A solution of 13.4 mL (147 mmol) of aniline in 30.7 mL of trithylamine was slowly added to a solution containing 25.1 g (147 mmol) of 3-methoxybenzoyl chloride in methylene chloride. The resulting reaction mixture was reacted for approximately thirty minutes and then diluted with 1N sodium bicarbonate. The resultant layers were separated and the organic layer was washed sequentially with water, 1M sodium hydroxide and then brine, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide 31.6 g of an off-white solid.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17][N:18]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>O.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>[CH:19]([N:15]1[CH:16]=[CH:17][N:18]=[C:14]1[C:12]1[N:13]=[C:6]2[C:5]3[CH:22]=[CH:23][C:2]([C:30]4[CH:29]=[N:28][N:27]([CH2:26][C:25]([CH3:41])([OH:42])[CH3:24])[CH:31]=4)=[CH:3][C:4]=3[O:10][CH2:9][CH2:8][N:7]2[CH:11]=1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ccnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)n1ccnc1-c1cn2c(n1)-c1ccc(-c3cnn(CC(C)(C)O)c3)cc1OCC2
Temperature: 25 °C

Procedure:
9-bromo-2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (157 mg, 0.421 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (139.9 mg, 0.5258 mmol), and Tetrakis(triphenylphosphine)palladium(0) (68.05 mg, 0.05889 mmol) dissolved in Acetonitrile (2.66 mL, 50.9 mmol) and with dissolved 2.00 M of Potassium carbonate in Water (0.421 mL). The reaction mixture was degassed. The reaction was microwaved on 150 watts, 140° C. for 10 minutes. The reaction was cooled to r.t., extracted with ethyl acetate to give crude product purified by rHPLC to give 214. MS: (ESI+)=433.2. 1H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.4 Hz, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.68 (s, 1H), 7.42-7.31 (m, 2H), 7.26 (d, J=1.7 Hz, 1H), 6.94 (s, 1H), 5.66 (dt, J=13.5, 6.7 Hz, 1H), 4.74 (s, 1H), 4.50 (s, 4H), 4.03 (s, 2H), 1.46 (d, J=6.7 Hz, 6H), 1.09 (s, 6H)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:21]1[CH2:40][N:24]2[C:25](=[O:39])[N:26]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[CH2:27][C@@H:23]2[CH2:22]1.C(Br)(Br)(Br)[Br:42]>C1COCC1>[Br:42][C@@H:21]1[CH2:40][N:24]2[C:25](=[O:39])[N:26]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[CH2:27][C@@H:23]2[CH2:22]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](O)CN12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@H](Br)CN12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Triphenylphosphine (1.7 g, 6.5 mmol) was added to a solution of (6R,7aS)-6-Hydroxy-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (1.0 g, 3.3 mmol) and CBr4 (2.2 g, 6.6 mmol) in anhydrous THF (50 mL), the mixture was stirred at room temperature for 30 minutes under N2 protection. Then the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3:1) to give 1.15 g (95%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.61 (d, 2H, J=9.3 Hz), 7.21 (d, 2H, J=8.4 Hz), 4.48-4.42 (m, 1H), 4.19 (dd, 1H, J1=13.2 Hz, J2=2.7 Hz), 4.11-4.02 (m, 2H), 3.92-3.88 (m, 1H), 3.53 (dd, 1H, J1=13.5 Hz, J2=5.4 Hz), 2.81-2.71 (m, 1H), 2.26-2.18 (m, 1H). LC-MS: 365.0 [M+1]+.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2].[C:32]1([Mg]Br)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+].C(O)(=O)C>O1CCCC1>[N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25]([OH:31])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2]
Reactant: CCCCCC(=O)C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCC(O)(C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O)c1ccccc1

Procedure:
A solution of 1.88 g. of 7-[8-nitromethyl-7-(3-oxo-1-octenyl)-1,4-dioxaspiro[4.4]non-6-yl]-5-heptenoic acid in 80 ml. of tetrahydrofuran was treated at -0° C. with 6.6 ml. of 3M phenyl magnesium bromide in tetrahydrofuran and was stirred at 0° C. for one hour. The reaction mixture was added to aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with water and drying with magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 30% ethyl acetate in hexane gave 0.90 g. of the title product as an oil, λmaxfilm 3.00 (shoulder), 3.50, 5.88, 6.28, 6.47, 6.95, 7.25, 13.30, 14.35μ . NMR: δ3.93 (S, 4, ketal), 4.35 (M, 2, --CH2NO2), 5.15-6.05 (M, 4, olefinic --H), 5.88 (S, 2, --OH) 7.45 (M, 5, aromatic-HO ppm. Mass spectrum: M+ at m/e 515 (theory 515 (theory 515), M+ -H2O at m/e 497.2776 (theory 497/2776.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:25]CC1.B1C2CCCC1CCC2.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:21]3[CH:16]([CH2:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:25])[CH2:14]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Cc3ccccc32)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: B1C2CCCC1CCC2
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C1CC=CC=C12
Temperature: 70 °C
Yield: 47 %

Procedure:
To a solution of 661 mg (2.31 mmol) of 1'-(t-butyloxycarbonyl)spiro[1H-indene-1,4'-piperidine][prepared by the method of Chambers, et al, J. Med. Chem., 1992, 35, 2036]in 5.0 ml of THF was added 5.8 ml (1.0 M THF, 2.9 mmol) of 9-BBN. The reaction mixture was heated at 70° C. until TLC analysis indicated that the starting material was consumed. The solution was concentrated and the residue was dissolved in dichloromethane. The solution was cooled to 0° C. and 4.1 g (19.2 mmol) of PCC was added slowly over 15 minutes. The reaction mixture was warmed to room temperature and then to reflux for 30 minutes. The solution was then diluted with ether and filtered through a pad of a mixture of celite and florisil. Purification by flash chromotgraphy (silica gel, hexane/ethyl acetate, 4:1) gave 326 mg (47%) of the title compound.
Reaction SMILES: N1C=NC=N1.CN(C)C=O.[H-].[Na+].ClC(C1C=CC(Cl)=CC=1)[C:15]1[CH:16]=[CH:17][C:18]2[N:22]=[N:21][N:20]([CH3:23])[C:19]=2[CH:24]=1>O>[CH3:23][N:20]1[C:19]2[CH:24]=[CH:15][CH:16]=[CH:17][C:18]=2[N:22]=[N:21]1
Reactant: Cn1nnc2ccc(C(Cl)c3ccc(Cl)cc3)cc21
Agent: [H-]
Agent: [Na+]
Agent: c1nc[nH]n1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 28.4 parts of 1H-1,2,4-triazole in 135 parts of N,N-dimethylformamide were added 11.4 parts of a sodium hydride dispersion 80% under nitrogen atmosphere. After stirring for 1 hour at room temperature, a solution of 40 parts of 6-[chloro(4-chlorophenyl)-methyl]-1-methyl-1H-benzotriazole in 90 parts of N,N-dimethylformamide was added to the mixture. The whole was stirred for 1 hour at 60° C. The reaction mixture was diluted with 50 parts of water and the whole was evaporated. The residue was extracted with ethyl acetate. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off and dried, yielding 13 parts (29.2%) of 6-[(4-chlorophenyl)-1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole; mp. 178.9° C. (compound 64).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](I)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.[Cu]>[Br:26][C:27]1[CH:28]=[C:29]([N:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:17]=3[C:18]3[C:10]2=[CH:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:19]=3)[CH:30]=[CH:31][CH:32]=1
Reactant: Brc1cccc(I)c1
Reactant: c1ccc(-c2ccc3[nH]c4ccc(-c5ccccc5)cc4c3c2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Brc1cccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)c1
Temperature: 190 °C
Yield: 86.3 %

Procedure:
3,6-Diphenylcarbazole (2.80 g, 8.77 mmol), 1-bromo-3-iodobenzene (22.18 g, 87.7 mmol), copper powder (0.279 g) and potassium carbonate (4.85 g) were mixed together, and the mixture was heated in a nitrogen atmosphere at 190° C. for 9 hours. The resultant mixture was cooled to room temperature and diluted with methylene chloride, followed by washing with water and drying, to thereby obtain a pale brown liquid. Next, the obtained liquid is purified through silica gel column chromatography using a solvent mixture of methylene chloride/hexane (2/3 by volume), to thereby obtain 3.59 g of 9-(3-bromophenyl)-3,6-diphenylcarbazole.
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.Cl.[NH2:15][OH:16].O>N1C=CC=CC=1>[C:10]1(=[N:15][OH:16])[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: NO
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: ON=C1CCCc2ccccc21

Procedure:
A solution of 7-methoxy-1-tetralone (10 g; 56.8 mmol) in pyridine (28 ml) and hydroxylamine hyrochloride (9 g; 130.6 mmol) was refluxed for 12 hours. The mixture was poured into water and extracted with CH2Cl2. The organic phase was washed with 1N HCl and 0.5N NaHC3, dried over MgSO4 and evaporated to give 7-methoxy-,1,2,3,4-tetrahydronaphthalen-1-one oxime as a brown solid (10 g; 92.5%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]=[O:11])[S:7][C:6]=2[C:12]=1[Cl:13].[BH4-].[Na+].[Cl-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][OH:11])[S:7][C:6]=2[C:12]=1[Cl:13]
Reactant: O=Cc1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc2cc(O)c(Cl)c(Cl)c2s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
To a solution of 6.0 g of 6,7-dichloro-2-formyl-5-hydroxybenzo[b]thiophene and 300 ml of 90% ethanol is added portionwise 1.5 g of sodium borohydride. The reaction mixture is stirred at room temperature for 20 min. Saturated sodium chloride solution is added and the mixture is extracted three times with ethyl acetate:ether (1:1). The combined organic extracts are washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give 4.5 g of 6,7-dichloro-5-hydroxy-2-hydroxymethylbenzo[b]thiophene, mp 167°-169°.