Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.CON(C)[C:44](=[O:46])[CH3:45].[NH4+].[Cl-]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:44](=[O:46])[CH3:45])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Reaction time: 1 h

Procedure:
To a stirred solution of (2R,6S)-4-[6-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3, 15.0 g, 30.0 mmol) in THF (150 mL) was added sec-butyllithium (1.4 M in cyclohexane, 66.4 mL, 93 mmol) at −78° C. under a nitrogen atmosphere. After stirring for 1 h, N-methoxy-N-methyl-acetamide (3.4 mL, 45 mmol) was added and, after stirring for ½ h at −78° C., the solution was allowed reach room temperature with stirring continuing for 12 hours. The reaction mixture treated with saturated aqueous NH4Cl solution and the aqueous layer extracted by EtOAc (2×100 mL). The organic phases were combined, dried (Na2SO4) and concentrated. The residue was purified over a silica gel flash column using a gradient of ethyl acetate in pet. ether to give the title compound as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[Br:12][CH2:13][CH2:14]Br.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:14][CH2:13][Br:12]
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCBr)c(Br)c1
Temperature: 82.5 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A portion (2.3 g, 10.6 mmol) of the 2-bromo-4-nitrophenol produced in (1) above and 1,2-dibromoethane (7.9 g, 42.1 mmol) were added to N,N-dimethylformamide (20 ml); to the mixture, potassium carbonate (1.6 g) was added, followed by stirring at 80-85° C. for 3 h. The reaction mixture was added to water (100 ml) and extraction was conducted with ethyl acetate, followed by the drying of the extract with magnesium sulfate and concentration. The residue was subjected to column chromatography using a 10:3:1 solvent system of n-hexane, ethyl ether and ethyl acetate as an eluent to yield the end compound 1-(2-bromo-4-nitrophenoxy-2-bromoethane (2.14 g).
Reaction SMILES: COCCOCCOCCOC.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24])([O-:15])=[O:14].[CH3:27][C:28]1([CH3:35])[NH:32][C:31](=[O:33])[NH:30][C:29]1=[O:34]>>[F:24][C:23]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([N:30]2[C:29](=[O:34])[C:28]([CH3:35])([CH3:27])[NH:32][C:31]2=[O:33])[CH:20]=[CH:21][C:16]=1[N+:13]([O-:15])=[O:14]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Solvent: COCCOCCOCCOC
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
The following were introduced into 282 ml of triglyme: 112.8 grams of 2-nitro-5-chloro-trifluoromethylbenzene, 64.1 grams of 5,5-dimethyl-hydantoin and 33.5 grams of cuprous oxide. The mixture was heated to about 215° C.±5° C. for 4 hours, then cooled to 20° C. and filtered. The triglyme solution was recovered and a 22 Be ammonia solution (1V), toluene (1V) and demineralized water (4V) were added to the solution of triglyme (1V). The solution was stirred at 20° C. for 15 minutes, then cooled to about -10° C. and stirred again at -10° C. After washing and drying, 47.6 grams of the desired product were obtained.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13](=[O:15])[CH3:14].B(Br)(Br)Br>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[C:13](=[O:15])[CH3:14]
Reactant: COc1ccc(C(F)(F)F)cc1C(C)=O
Agent: BrB(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Product: CC(=O)c1cc(C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.2 %

Procedure:
To a stirred solution of 1-[2-methoxy-5-(trifluoromethyl)phenyl]ethanone (35 g, 0.160 mol) in dry dichloromethane (400 mL) at 0° C. was added solid tetrabutylammonium iodide (2.96 g, 0.008 mol) followed by boron tribromide (33.96 mL, 0.353 mol) dropwise. After addition, the reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was cooled to 0° C. and quenched with ice. The mixture was extracted with diethyl ether (1000 mL). The organic layer was washed with water (2000 mL) and then saturated aqueous sodium chloride (1000 mL). After concentration of the organic layer at room temperature in vacuo, the crude product was purified by column chromatography (100-200 silica gel, 2% v/v diethyl ether in hexane) to give 11.5 g (35%) of the title compound as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.N1C2C(=CC=C(C(OC)=O)C=2)C=C1.C([O-])([O-])=O.[K+].[K+].[C:40]([O:44][C:45]([N:47]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C:48](=[CH2:53])[C:49]([O:51][CH3:52])=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41]>CC#N>[C:40]([O:44][C:45]([N:47]([C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])[CH:48]([C:49]([O:51][CH3:52])=[O:50])[CH2:53][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[Br:1])=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: C=C(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in WO 2004087714 from commercially available methyl indole-6-carboxylate) in MeCN (0.08 M) were added 6 eq of K2CO3 and 1.2 eq of methyl 2-[bis(tert-butoxycarbonyl)amino]acrylate. The mixture was stirred at RT for 16 h before being filtered and concentrated in vacuo to afford the title compound as a viscous oil which solidified on standing (quantitative); MS (ES+) m/z 659 (M+Na)+, 661 (M+Na)+.
Reaction SMILES: C1(C[NH:8][CH:9]([C@:18]2([CH2:32][OH:33])[O:22][C@@H:21]([N:23]3[CH:30]=[CH:29][C:27](=[O:28])[NH:26][C:24]3=[O:25])[CH2:20][C@@H:19]2[OH:31])NCC2C=CC=CC=2)C=CC=CC=1.C1CCCCC=1.C(O)(=O)C.NC[C@]1(CO)O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1O>[Pd].C(O)C>[NH2:8][CH2:9][C@:18]1([CH2:32][OH:33])[O:22][C@@H:21]([N:23]2[CH:30]=[CH:29][C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:20][C@@H:19]1[OH:31]
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@](CO)(C(NCc3ccccc3)NCc3ccccc3)O2)c(=O)[nH]1
Agent: [Pd]
Agent: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(CO)O2)c(=O)[nH]c1=O
Solvent: C1=CCCCC1
Solvent: CCO
Solvent: CC(=O)O
Product: NC[C@]1(CO)O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Yield: 101.7 %

Procedure:
4′-C-(1,1′-diphenylmethylaminomethyl)-2′-deoxyuridine (12) (0.056 g, 0.13 mmol) was treated with cyclohexene (1 mL), glacial acetic acid 0.5 mL) and 5% palladium on charcoal (0.06 g) in ethanol (5 mL) according to the procedure used for the preparation of compound (4). The crude product was purified by dissolving in water and washing with toluene. The aqueous layer was separated and the solvent removed under vacuum to give the title compound (13) as an amorphous solid (0.034 g, 100%). δH(300 MHz, D2O) 7.64(1H, d, H-6), 6.22(1H, dd, H-1′), 5.72(1H, d, H-5), 4.43(1H, m, H-3′), 3.56(2H, 2d, H-5′), 3.26(1H, d, CH2NH2), 3.05(1H, d, CH2NH2), 2.40(2H, m, H-2′); δC(75.45 MHz, D2O) 166.95, 152.46, 142.67, 103.11, 86.77, 86.43, 73.97, 64.82, 41.59, 39.25; ES +ve m/z 258(M+H)+, 242(M−NH3)+.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=[CH:5][N:4]=1.[ClH:17]>O1CCOCC1>[ClH:17].[N:12]1[CH:13]=[CH:14][N:15]=[CH:16][C:11]=1[C:6]1[C:7](=[O:9])[NH:8][C:3](=[O:2])[NH:4][CH:5]=1
Reactant: COc1ncc(-c2cnccn2)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]cc(-c2cnccn2)c(=O)[nH]1

Procedure:
2,4-Dimethoxy-5-pyrazin-2-yl-pyrimidine (Prep124, 481 mg, 2.19 mmol) was dissolved in 4M HCl in dioxane solution (7 ml). After refluxing the reaction mixture for 1 hour, the solvent was removed under vacuum to give the title compound (quantitative yield)
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10](=[CH2:14])[CH2:11][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[CH3:9][CH:10]([CH3:14])[CH:11]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:8]
Reactant: C=C(C)C[Mg]Cl
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a solution of benzaldehyde (3.05 mL, 30 mmol) in THF (30 mL) was added 2-methylallylmagnesium chloride (0.8 M in THF, 45 mL, 36 mmol, 1.2 equiv) under N2 at 0° C. (internal). The mixture was warmed to room temperature and was stirred for 1.5 h. The mixture was then poured into saturated aqueous NH4Cl solution (30 mL) and was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (30 mL), then were dried (Na2SO4) and filtered. The solvent was removed by rotary evaporation and the residue was purified by Kugelrohr distillation to afford 4.33 g (89%) of 3-methyl-1-phenyl-1buten-1-ol as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:20]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH3:20])[CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CNCCN1Cc1ccccc1
Reactant: CI
Product: CCOC(=O)C1CN(C)CCN1Cc1ccccc1
Yield: 72.8 %

Procedure:
Ethyl 1-benzylpiperazine-2-carboxylate (3.03 g, 12.2 mmol) was reacted with iodomethane (1.73 g, 12.2 mmol) according to the procedure as described in Example 48, Step A to give the title compound as yellow oil (2.33 g, 73%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[C:5]([NH:7][CH2:8][C:9]([CH3:15])([CH3:14])[CH2:10][N:11]([CH3:13])[CH3:12])=[O:6].[Cl-].[NH4+].O>C(O)C.C(O)(=O)C.[Fe]>[NH2:19][C:18]1[CH:17]=[CH:16][C:4]([C:5]([NH:7][CH2:8][C:9]([CH3:14])([CH3:15])[CH2:10][N:11]([CH3:13])[CH3:12])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: CN(C)CC(C)(C)CNC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)CC(C)(C)CNC(=O)c1ccc(N)c(Cl)c1

Procedure:
3-chloro-N-(3-dimethylamino-2,2-dimethyl-propyl)-4-nitro-benzamide (2.29 g, 7.67 mmol), iron powder (2.45 g, 43.79 mmol) and ammonium chloride (781 mg, 14.60 mmol) were heated in ethanol (50 mL) and water (18 mL) at reflux for one hour. A few drops of acetic acid were added and heating continued for a further hour. The reaction mixture was cooled, filtered and the filtrate concentrated. This residue was partitioned between saturated NaHCO3 (aq.) and DCM. The organic phase was washed with brine, dried with MgSO4 and concentrated. Column chromatography gave the title compound as an orange crystalline solid. (850 mg, 39%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:19]([O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24])[CH3:20]>CN(C=O)C>[CH2:19]([O:21][C:22](=[O:32])[C@@H:23]([NH:24][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:20]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccccc1)NCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 24 %

Procedure:
3-Nitrobenzyl bromide (10.0 g, 46 mmol) was dissolved in DMF (180 ml) and potassium carbonate (12.7 g, 92 mmol) added, followed by L-phenylalanine ethyl ester hydrochloride (10.6 g, 46 mmol). The reaction was stirred for 17 h at room temperature before evaporating to dryness. The residue was re-dissolved in EtOAc (150 ml) and washed with water (3×80 ml), dried (Na2SO4) filtered and concentrated to dryness. After purification by flash column chromatography (30% EtOAc/hexane) the product was obtained (3.7 g, 24% yield). LCMS purity 86%, m/z 329 [M++H]+.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][C:9]([C:12]#[N:13])=[CH:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:63]1[CH:72]=[CH:71][C:66]([C:67]([NH:69][CH3:70])=[O:68])=[C:65]([F:73])[CH:64]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([C:9]1[CH2:10][CH2:11][C@@H:7]([N:1]2[CH2:6][CH2:5][N:4]([C:63]3[CH:72]=[CH:71][C:66]([C:67]([NH:69][CH3:70])=[O:68])=[C:65]([F:73])[CH:64]=3)[CH2:3][CH2:2]2)[CH:8]=1)#[N:13]
Reactant: N#CC1=C[C@H](N2CCNCC2)CC1
Reactant: CNC(=O)c1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(N2CCN([C@H]3C=C(C#N)CC3)CC2)cc1F
Temperature: 110 °C
Yield: 29.2 %

Procedure:
To a mixture of (R)-3-(piperazin-1-yl)cyclopent-1-enecarbonitrile (0.500 g, 2.82 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS) (0.326 g, 0.564 mmol), palladium (II) acetate (Pd(OAc)2) (63.3 mg, 0.282 mmol) and cesium carbonate (1.838 g, 5.64 mmol) in toluene (15 ml) was added 4-bromo-2-fluoro-N-methylbenzamide (WO2006064251, 0.500 g, 2.82 mmol). The reaction mixture was heated to 110° C. for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The filtrated was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 1-5% methanol in dichloromethane as an eluent to obtain the title compound (0.270 g, 29.1%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[N:6][CH:7]=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH:19]=[CH2:20].CCN(C(C)C)C(C)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2](/[CH:20]=[CH:19]/[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:3][CH:4]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1ccc(-c2ccc(Br)cn2)cc1OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(/C=C/C(=O)OC(C)(C)C)cn2)cc1OC
Reaction time: 18 h
Yield: 82.4 %

Procedure:
To a degassed solution of bromide 37 (0.47 g, 1.6 mmol), tert-butyl acrylate 38 (1.12 mL, 7.7 mmol), POT (0.34 g, 1.1 mmol) and Hunig's base (1.11 mL, 6.4 mmol) in DMF (8 mL) was added tris(dibenzylideneacetone)dipalladium (0) (0.124 g, 0.16 mmol). The solution was placed in a preheated oil bath at 120° C., stirred for 18 h and concentrated. Flash chromatography purification of the residue (eluent: 3:1 hexane:AcOEt) afforded title compound 39 (0.45 g, 83% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:23]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:23])=[CH:3][CH:4]=2)[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl (2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2) (19.53 g, 0.0639 mol) in dry MeOH (300 mL) under an argon atmosphere at room temperature was treated with paraformaldehyde (5.76 g, 0.1918 mol) and sodium methoxide (17.27 g, 0.3197 mol). The reaction mixture heated at 50° C., stirred overnight then cooled to room temperature. Sodium borohydride (7.26 g, 0.1918 mmol) was added portionwise and the reaction mixture was then re-heated to 50° C. and stirred for 2 days. The reaction mixture was cooled to rt and stirred for a further 24 h, then concentrated and re-dissolved in DCM (200 mL). Saturated aq. NaHCO3 solution (200 mL) was added portionwise with stirring and on completion of addition the mixture was stirred at room temperature for a further 0.5 h. The DCM phase was separated, washed with brine, dried (MgSO4) and concentrated to give a yellow oil which was purified by column chromatography. Elution with 0%, 10% and then 20% EtOAc/hexane yielded the title compound as a yellow oil which crystallised on standing (16.7 g).
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:22]=2)=[CH:6][CH:5]=1.B(Br)(Br)Br>ClCl>[ClH:1].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[CH:22]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(OCCN3CCCCC3)c2)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: ClCl
Product: Oc1ccc(-c2sc3cc(O)ccc3c2-c2cccc(OCCN3CCCCC3)c2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-(4-Methoxyphenyl)-3-[3-[2-(1-piperidinyl)ethoxy]phenyl]-6-methoxybenzo[b]thiophene hydrochloride, 2 g (4 mmol) was dissolved in 125 mL of CH2 Cl2 and cooled to 0+ C. 1.0 mL (10 mmol) of BBr3 was added and the reaction mixture was stirred at 0° C. for 3 hours under a nitrogen atmosphere. The reaction was quenched by pouring into a mixture of 125 mL of aqueous NaHCO3, 25 mL of isopropanol, and 250 mL of CHCl3. The organic layer was separated and washed twice with brine, dried with Na2SO4, and evaporated to dryness. The resulting solid was re-dissolved in 150 mL of EtOAc and dry HCl gas was bubbled through. The solvents were removed by evaporation. This yielded 850 mg of the title compound as a white powder.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CC([O:18]O)(C)C>>[C:1]1(=[O:18])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: CC(C)(C)OO
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Product: O=C1C=CC=C2C1=Cc1ccccc12

Procedure:
We initially studied oxidation of methylene substituted benzylic aromatics to ketones (Scheme 1, R≠H). When a mixture of fluorene with 10 equivalents 70% aqueous TBHP was irradiated with microwave in a sealed vessel for 10 minutes (250 W, 170° C.), an almost quantitative yield of fluorenone was isolated (Table 1). As a control experiment, when we simply refluxed the same reaction mixture by conventional oil bath heating for 8 hours, only a trace amount of fluorenone could be detected by TLC. Oxidation of another substrate with a doubly activated benzylic position, diphenylmethane, also afforded benzophenone in high yield. For the mono-activated methylene units, ethylbenzene to acetophenone and tetrahydronaphthalene to alpha-tetralone, the oxidations under this green protocol also went smoothly. The results are summarized in Table 1.
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=[O:5])#[N:2].[CH2:9]([O:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:17])=[NH:16])[CH2:10][CH3:11]>C(O)C.O>[NH2:2][C:1]1[N:17]=[C:15]([C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH2:9][CH2:10][CH3:11])[NH:16][C:4](=[O:5])[CH:3]=1
Reactant: CCCOc1ccccc1C(=N)N
Reactant: CCOC(=O)CC#N
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1-c1nc(N)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl cyanoacetate (4.52 g) was added to a stirred solution of 2-propoxybenzamidine in ethanol (prepared from sodium, 1.84 g., in ethanol, 100 ml, and 2-propoxybenzamidine methanesulphonate, 11.61 g). The reaction mixture was stirred at ambient temperature for 18 hours and then evaporated under reduced pressure to leave a residue which was dissolved in water. The aqueous solution was extracted with diethyl ether (2×25 ml) and the combined ether extracts were washed with water. The combined aqueous phase was treated with glacial acetic acid to pH 5 to precipitate a crude product. Further crude product was obtained by extracting the ether extracts with 1 normal sodium hydroxide (2×30 ml) and acidifying the combined alkaline extracts with glacial acetic acid to pH 5. The combined crude product was recrystallised from isopropanol to yield the title compound, 2.34 g, m.p. 183.5°-184.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([NH2:17])=[O:16])[NH:10]2.[N:18]1([C:24]2[CH:29]=[C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:27]=[C:26]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[N:35]1([C:26]2[N:27]=[C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:29]=[C:24]([N:18]3[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[C:9]([C:15]([NH2:17])=[O:16])[NH:10]5)[CH2:20][CH2:19]3)[N:25]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: NC(=O)c1cc2c(OCCCCl)cccc2[nH]1
Reactant: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc2c(OCCCN3CCN(c4cc(N5CCCC5)nc(N5CCCC5)n4)CC3)cccc2[nH]1

Procedure:
4-(3-Chloropropoxy)indole-2-carboxamide (0.44 g), 4-(1-piperazinyl)-2,6-di-1-pyrrolidinylpyrimidine (0.525 g), powdered potassium carbonate (0.12 g) and sodium iodide (0.075 g) are combined in acetonitrile (50 ml) and heated at reflux for 96 hr. Although TLC showed both starting material and product remained in the reaction mixture, the mixture was concentrated under reduced pressure and the residue partitioned between 1N potassium bicarbonate and methylene chloride. The layers are separated, the aqueous layer is extracted with methylene chloride, the pooled organic extract is washed with water, then saline, dried over magnesium sulfate and concentrated. The residue is chromatographed over silica gel (250 ml) and eluted with methanol/methylene chloride (3.5/96.5). The appropriate fractions are pooled and concentrated. Crystallization from acetonitrile gives the title compound, mp 151°-2° (foam); the proposed structure is supported by NMR, IR and mass spectra.