Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:23]3[CH2:24][CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC1CCCNC1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCCC(C)C2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (50 mg, 0.205 mmol), 3-methyl piperidine (19 mg, 0.205 mmol), DCC (46 mg, 0.22 mmol), and DMAP (27 mg, 0.22 mmol) in dry DCM (2.0 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator afforded 34.2 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(3-methylpiperidin-1-yl)ethanone as TFA Salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TEA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:6][CH:5]=1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].OS([O-])(=O)=O.[K+]>C1COCC1>[C:25]([O:24][C:22](=[O:23])[CH2:21][O:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=3)=[N:11][S:12][C:13]=2[CH:18]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a suspension of 0.74 g (16.9 mmol) NaH (55% in mineral oil) in 40 ml THF was added a solution of 4 g (13.1 mmol) 3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-ol in 20 ml THF at RT. The solution was stirred at RT for 1 h, 2.1 ml (14.3 mmol) t-butyl bromoacetate was added. The solution was stirred at RT over night, 1M KHSO4 was added carefully and the layers separated. The inorganic one was extracted with EtOAc, the combined organic phases were washed with water and brine and dried over Na2SO4. Column chromatography on silica gel with EtOAc:hexane 1:4 yielded 4.95 g (90%) [3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-acetic acid tert-butyl ester as colorless oil, MS: 420 (MH+, 1Br).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](Cl)=[O:11])=[N:2]1.[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]#[C:27][CH2:28][NH2:29])[CH2:21][CH2:20]1.C(N(CC)CC)C>ClCCl.O>[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]#[C:27][CH2:28][NH:29][C:10]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][N:2]=2)=[O:11])[CH2:21][CH2:20]1
Reactant: O=C(Cl)c1nsc2ccccc12
Reactant: NCC#CCN1CCN(c2ncccn2)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC#CCN1CCN(c2ncccn2)CC1)c1nsc2ccccc12
Reaction time: 8 h
Yield: 72.5 %

Procedure:
A mixture of 1,2-benzisothiazole-3-carboxylic acid chloride (2.55 g) and 1-(2-pyrimidyl)-4-(4-amino-2-butynyl)piperazine (3.0 g) in dichloromethane (100 ml) was stirred while triethylamine (3.62 ml) was added dropwise. Stirring was continued overnight. After 24 hr, the reaction mixture was diluted with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The resiude was recrystallized from dichloromethane/ether/hexane to provide 3.67 g (72.3%) of product, mp 102°-104° C.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[OH:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CCC2OC2C1
Reactant: NCc1ccccc1
Product: O[C@@H]1CCCC[C@H]1NCc1ccccc1
Temperature: 80 °C
Yield: 62.3 %

Procedure:
A mixture of cyclohexene oxide (20 g, 204 mmol) and benzylamine (44 g, 411 mmol) was heated at 80° C. for 6 hours. An excess benzylamine was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford (1RS,2RS)-trans-2-benzylaminocyclohexanol (26 g, 127 mmol, 62%) as white crystals.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1
Temperature: 80 °C
Yield: 84 %

Procedure:
Into a 30 mL vial, [A] 1-(2-Bromo-ethoxy)-4-nitro-benzene (5.00 g, 0.0203 mol), Morpholine (3.54 mL, 0.0406 mol), Acetonitrile (15.0 mL, 0.287 mol) and Potassium carbonate (5.62 g, 0.0406 mol) were added. The reaction was heated at 80° C. for 4 hours. The reaction was partitioned with water (250 mL). The solid was filtered and washed with water. The resulting solid was dried under vacuum overnight to give 4-[2-(4-Nitrophenoxy)-ethyl]-morpholine as an off-white solid (4.30 g, 84%). NMR 1H (DSMO-d6)-8.20 (d, 1H, J=9.34 Hz), 7.17 (d, 2H, J=9.34 Hz), 4.24 (t, 2H, J=5.65 Hz), 3.57 (t, 4H, J=4.60 Hz), 2.72 (t, 2H, J=4.68 Hz), 2.47 (t, 4H, J=4.52 Hz),
Reaction SMILES: [C:1]1([S:7]([CH2:9][C:10]([OH:12])=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH:14]1[C:29](=[O:30])[N:16]2[C:17]([C:25]([O:27][CH3:28])=[O:26])=[C:18]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:19][S:20][C@H:15]12>>[C:1]1([S:7]([CH2:9][C:10]([NH:13][CH:14]2[C:29](=[O:30])[N:16]3[C:17]([C:25]([O:27][CH3:28])=[O:26])=[C:18]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:19][S:20][C@H:15]23)=[O:12])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CS(=O)c1ccccc1
Reactant: COC(=O)C1=C(CN=[N+]=[N-])CS[C@@H]2C(N)C(=O)N12
Product: COC(=O)C1=C(CN=[N+]=[N-])CS[C@@H]2C(NC(=O)CS(=O)c3ccccc3)C(=O)N12

Procedure:
368 mg. of phenylsulfinylacetic acid and methyl 7-amino-3-azidomethyl-3-cephem-4-carboxylate were reacted in the same manner as described in Example 4 and 503 mg. of methyl 7-(phenylsulfinylacetamido)-3-azidomethyl-3-cephem-4-carboxylate were obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[CH3:4].[Cl:16][CH2:17][CH2:18]OS(C1C=CC=CC=1)(=O)=O>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:18][CH2:17][Cl:16])[CH3:4]
Reactant: CCOC(=O)Cc1ccccc1O
Reactant: O=S(=O)(OCCCl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccccc1OCCCl
Temperature: 100 °C
Yield: 53.6 %

Procedure:
50% Sodium hydride in mineral oil (8.11 g, 169 mmol) was added portionwise to a solution of 2-hydroxy-phenyl-acetic acid ethyl ester (30.4 g, 169 mmol) in dimethylformamide (100 ml). After the initial effervescence had ended the reaction was heated to 100° C. for 10 minutes and was cooled to room temperature. A solution of benzene sulfonic acid 2-chloro-ethyl ester (37.2 g, 169 mmol) in dimethylformamide (5 ml) was then added and the reaction was heated to 100° C. for one hour, and allowed to cool to room temperature over 18 hours. The reaction mixture was partitioned between diethylether (300 ml) and water (300 ml) and the organic phase was removed and washed with water (100 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by thermal distillation to give [2-(2-chloro-ethoxy)-phenyl]-acetic acid ethyl ester (22.0 g) as a pale yellow oil. Bp 170° C. to 180° C. νmax (thin film) 1735 cm−1 (C═O, ester); no O—H stretch. Anal. Found C, 59.35; H, 6.29. C12H15CIO3 requires C, 59.38; H, 6.23%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.O.C(=O)([O-])O.[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>O1CCCC1>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:17]([F:16])([F:27])[F:28])[CH:19]=2)[CH:3]=[CH:4][C:5]=1[CH3:9]
Reactant: Cc1ccc(N)cc1O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 5-amino-2-methylphenol (7.38 g, 59.9 mmol) in tetrahydrofuran (30 mL) was added water (30 mL) in which sodium hydrogen carbonate (6.00 g, 71.9 mmol) has been suspended, and the mixture was vigorously stirred at room temperature. 3-(Trifluoromethyl)benzoyl chloride (15.0 g, 71.9 mmol) was added dropwise to the mixture under ice-cooling, and the mixture was stirred at room temperature for 24 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and was filtrated, and the solvent was evaporated under reduced pressure. A mixture of the obtained residue, methanol (30 mL) and 2N aqueous sodium hydroxide solution (30 mL) was stirred at room temperature for 24 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and decolorized with activated carbon. The insoluble material was filtered off through a pad with two layers of silica gel and celite. The solvent was evaporated under reduced pressure, and the obtained solid was washed with a mixed solvent of ethyl acetate and hexane to give the title compound (14.8 g, 84%) as a white powder.
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[NH:22]1[C:26]2=[N:27][CH:28]=[N:29][C:30]([NH2:31])=[C:25]2[CH:24]=[N:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:29]=[CH:28][N:27]=[C:26]2[N:22]([CH:2]([C:4]3[O:5][C:6](=[O:21])[C:7]4[C:12]([C:13]=3[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:23]=[CH:24][C:25]=12
Reactant: Nc1ncnc2[nH]ncc12
Reactant: Cc1cc(-c2c(C(C)Br)oc(=O)c3ccccc23)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2c(C(C)n3ncc4c(N)ncnc43)oc(=O)c3ccccc23)ccn1
Yield: 3 %

Procedure:
The title compound was made in a similar way as that of the compound of example 15, 3-(1-bromoethyl)-4-(2-methylpyridin-4-yl)-1H-isochromen-1-one (intermediate C14, 98 mg, 0.285 mmol), 1H-pyrazolo[3,4-d]pyrimidin-4-amine (57.7 mg, 0.43 mmol) and K2CO3 (59 mg, 0.42 mmol) in DMF (2 ml) at 50° C. for 6 hrs to give the title compound (3.4 mg, 3%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[NH2:29][CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:43]=[C:38]([Cl:37])[C:39]([OH:54])=[C:40]([Cl:53])[CH:41]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 23.9 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (23 mg, 24% over 2 steps) as a orange solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.35 (s, 1H), 8.33 (s, 1H), 8.30 (dd, J=8.8, 1.9 Hz, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 8.04 (dd, J=9.6, 2.5 Hz, 1H), 7.49 (s, 2H), 7.26 (d, J=9.5 Hz, 1H), 4.22 (p, J=6.3 Hz, 1H), 4.12 (dd, J=12.0, 6.5 Hz, 1H), 3.96 (dt, J=10.9, 7.5 Hz, 1H), 3.86 (m, 2H), 2.78 (p, J=7.2 Hz, 1H), 2.65 (td, J=15.3, 14.8, 6.8 Hz, 1H), 2.40 (td, J=13.3, 5.3 Hz, 1H), 1.20 (m, 4H); ESI MS m/z 534 [C28H25Cl2N5O2+H]+; HPLC 99.6% (AUC), tR=10.29 min.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:22][CH:23]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+:31]>CO>[CH3:8][C:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:22][CH:23]=2)=[CH:14][CH:15]=1)([CH3:1])[C:3]([O-:5])=[O:4].[Na+:31]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Oc1ccc(OCCc2coc(-c3ccccc3)n2)cc1)C(=O)[O-]
Reaction time: 0.5 h
Yield: 97 %

Procedure:
2-Methyl-2-{4-[2-(2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acid, ethyl ester 2.5 g, 63.2 mmol) was dissolved in MeOH (200 mL) and 2N NaOH (100 mL) was added. The resulting cloudy solution became clear after 30 min and the reaction was stirred vigorously for 6 h. The solvents were removed, and the residual solids were triturated with water. The suspended solids were then collected and triturated with pentane to produce a white solid (2.38 g, 97%). mp 199-200° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.90-7.93 (m, 2H), 7.46-7.49 (m, 3H), 6.73 (d, J=9.0 Hz, 2H), 6.69 (d, J=9.0 Hz, 2H), 4.12 (t, J=6.4 Hz, 2H), 2.91 (t, J=6.4 Hz, 2H), 1.26 (s, 3H); MS(EI): 390 (M+H), 366 (M−Na).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[CH:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([CH:23]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:24](O)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.ON1C2C=CC=CC=2N=N1.CC[N+](CCCN(C)C)=C=N>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH:16][C:24](=[O:25])[CH:23]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Reactant: O=C(O)C(C1CCCCC1)C1CCCCC1
Agent: CC[N+](=C=N)CCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)C(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(3aS*,6aR*)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-amine (500 mg, 2.311 mmol), 2,2-dicyclohexylacetic acid (570 mg, 2.54 mmol), and 1-hydroxybenzotriazole (389 mg, 2.54 mmol) were combined in dichloromethane (20 mL). The reaction was stirred at room temperature for 10 minutes, then N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.449 mL, 2.54 mmol) was added dropwise. The reaction was stirred at room temperature for 20 hours, and then the reaction was quenched with 10 mL of water. The reaction was extracted with 2×20 mL of dichloromethane, the solvent was removed in vacuo, and the crude material was chromatographed over a silica gel cartridge (Analogix®, Burlington, Wis., RS-40) eluting with 30-50% ethyl acetate/hexanes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.60 (d, J=5.1, 1H), 7.45-7.38 (m, 4H), 7.35 (m, 1H), 4.49-4.41 (m, 1H), 3.57 (d, J=12.6, 1H), 3.37 (d, J=12.5, 1H), 2.76 (d, J=9.6, 1H), 2.69 (dd, J=7.9, 15.7, 1H), 2.50 (d, J=9.1, 1H), 2.48-2.41 (m, 1H), 2.28 (t, J=8.2, 1H), 2.15-2.08 (m, 1H), 1.99-1.06 (m, 26H), 1.04-0.92 (m, 1H); MS (ESI+) m/z 423 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1(O)[C:8]2=[C:9]3[CH2:15][CH2:14][O:13][C:10]3=[N:11][CH:12]=[C:7]2[CH2:6][CH:5]1[CH:16]([CH3:18])[CH3:17].C(N(CC)CC)C.[C:27](OC(=O)C)(=[O:29])[CH3:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.C(=O)([O-])O.[Na+]>[CH:16]([C:5]1[CH2:6][C:7]2[C:8]([C:4]=1[CH2:3][CH2:2][NH:1][C:27](=[O:29])[CH3:28])=[C:9]1[CH2:15][CH2:14][O:13][C:10]1=[N:11][CH:12]=2)([CH3:18])[CH3:17]
Reactant: CC(C)C1Cc2cnc3c(c2C1(O)CCN)CCO3
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCC1=C(C(C)C)Cc2cnc3c(c21)CCO3
Reaction time: 0.08 h
Yield: 16 %

Procedure:
To a solution of 8-(2-aminoethyl)-7-isopropyl-1,6,7,8-tetrahydro-2H-cyclopenta[d]furo[2,3-b]pyridin-8-ol (214 mg, 0.816 mmol) in tetrahydrofuran (8.2 mL) were added triethylamine (228 μL, 1.63 mmol) and acetic anhydride (92.5 μL, 0.979 mmol) under ice-cooling, and the mixture was stirred for 5 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→15/85) and dissolved in toluene (10 mL). p-Toluenesulfonic acid monohydrate (478 mg, 2.52 mmol) and magnesium sulfate (900 mg) were added, and the mixture was stirred at 100° C. for 13 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (37.4 mg, yield 16%).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>[Br-].C([N+](CCCCCCCCCCCC)(C)C)CCCCCCCCCCC>[CH3:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCO
Agent: CCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCC
Agent: [Br-]
Product: CCCCCCCCCC

Procedure:
Using the surfactant tridodecylmethylammonium chloride (TDAC) at a concentration of approximately 8%, hexanol at 10%, and the remainder octane, MOS2 particles are formed with an average diameter, as determined by lights-cattering and high-resolution transmission electron microscopy (HRTEM), of approximately 3.0 nm. In a solution using the surfactant didodecyldimethylammonium bromide (DDAB) at a concentration of approximately 10%, hexanol at 11%, and the remainder decane, MoS2 particles are formed with an average diameter, as determined by light-scattering and transmission electron microscopy techniques, of approximately 4.5 nm. In a solution using the surfactant DDAB in toluene at a concentration of approximately 0.5%, MoS2 particles are formed with an average diameter, as determined by light-scattering and TEM, of approximately 8-10 nm. The as-synthesized MOS2 clusters were purified to remove excess reactants, surfactants or reaction by-products by extraction from octane into acetonitrile, dried, and then added to water to form the catalyst solution as noted above.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Br:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[CH2:27][C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11]
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cccc(C2(Cc3cccc(Br)c3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (40 mg, 0.15 mmol) (from Example 6b supra), 1-bromo-3-bromomethyl-benzene (43 mg, 0.17 mmol) (Aldrich), potassium iodide (29 mg, 0.17 mmol) and potassium carbonate (43 mg, 0.31 mmol) in acetone (2 mL) was heated at 60° C. for 16 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-3-(3-bromo-benzyl)-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a white solid. (Yield 28 mg, 43%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O1CCCC1.[C:24]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH3:31]>>[C:24]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]([CH3:31])[C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=1
Reactant: CNc1ccccc1-c1ccccc1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CN(C(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a solution of 272 mg (1.0 mmol) 3,5-bis-(trifluoromethyl)phenylacetic acid in 1 ml tetrahydrofuran 162 mg (1.0 mmol) 1,1′-carbonyldiimidazole was added in one portion at 0°. The reaction mixture was stirred for 2 hrs at room temperature and 147 mg (0.8 mmol) biphenyl-2-yl-methyl-amine was added. Stirring was continued for 3 days at room temperature. The reaction mixture was evaporated and the residue was purified by chromatography (SiO2, hexane/ethyl acetate 3:1) to give 160 mg (46%) N-biphenyl-2-yl-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-acetamide as white crystals, MS (ISP): 438.2 (M+H)+. EXAMPLE 15
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]=[CH:29][C:30]#[N:31])=[N:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[C:30]([NH2:31])[N:12]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:11]3[CH:10]=2)=[N:26][CH:27]=1
Reactant: N#CC=Cc1ccc(Cl)cn1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Product: Nc1cc(-c2ccc(Cl)cn2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, MS m/e (%): 312 (M+H+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(5-chloro-pyridin-2-yl)-acrylonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)[CH2:4][C:3]1=[O:13].[Br:15]Br>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[CH:5]([C:6]2[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=2)[CH:4]([Br:15])[C:3]1=[O:13]
Reactant: CC1(C)C(=O)CC1c1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC1(C)C(=O)C(Br)C1c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
2.08 g (0.01 mol) of 2,2-dimethyl-3-(4-chlorophenyl)cyclobutanone are dissolved in 30 ml of chloroform, and a solution of 1.6 g of bromine in 5 ml of chloroform is added dropwise. After stirring for one hour at 20° C., the solvent is distilled off under waterpump vacuum. 2.6 g of crude 2,2-dimethyl-3-(4-chlorophenyl)-4-bromocyclobutanone are obtained as a residue which is employed further without further purification (compare: Example 1).