Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=1[S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:24][CH2:25][N:26]([S:48]([C:42]3[CH:43]=[C:44]([Cl:47])[CH:45]=[CH:46][C:41]=3[Cl:40])(=[O:50])=[O:49])[CH2:27][CH2:28]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3cc(Cl)ccc3Cl)CC2)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 41.8 %

Procedure:
To a 0° C. solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 102 mg, 0.237 mmol) and N,N-diisopropylethylamine (124 μL, 0.711 mmol) in methylene chloride (6.0 mL) was added 2,5-dichlorobenzenesulfonyl chloride (116 mg, 0.474 mmol). After stirring for ˜15 minutes at 0° C., the light yellow reaction mixture was allowed to warm to room temperature and then was stirred overnight at room temperature under nitrogen. During this time, some solvent evaporated. Methylene chloride (˜10 mL) and water (˜25 mL) were added. The resulting mixture was extracted with methylene chloride (2×25 mL). The combined extracts were washed with brine solution then concentrated to give the crude product which was purified by elution from a silica gel plug (20% ethyl acetate in hexanes) to give {4-[1-(2,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (52 mg, 42%) as an off-white solid. MS cald. for C25H25Cl2FNO4S [(M+H)+]: 524, obsd. 524.0.
Reaction SMILES: C(OC(N[C@@H:9]1[C@@H:14](O)[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=O)(C)(C)C.[C:26]([O:30][C:31]([NH:33][C@H]1[C@H](O)CCN(C(OCC2C=CC=CC=2)=O)C1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CCCCCCC.C([OH:60])C>>[C:26]([O:30][C:31]([NH:33][C@@H:14]1[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:10][C@H:9]1[OH:60])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1O
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O

Procedure:
A solution of (+/−) benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.0 equiv.) in saturated ammonium hydroxide aqueous solution and ethanol (1:1, 0.05 M solution) in a sealed steel bomb was heated to 70° C. for 5 h. After all volatile materials were removed by N2 gas stream, ethyl acetate and water were added for work-up. The crude regioisomeric mixture, benzyl 3-amino-4-hydroxypiperidine-1-carboxylate and benzyl 4-amino-3-hydroxypiperidine-1-carboxylate was reacted with Boc2O (1.0 equiv.) and triethylamine (1.0 equiv.) in dichloromethane (0.1 M solution). After stirred for 2 h at room temperature, the reaction mixture was extracted with dichloromethane. The polar (+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxy-piperidine-1-carboxylate and nonpolar (+/−)-benzyl 4-(tert-butoxycarbonylamino)-3-hydroxypiperidine-1-carboxylate were obtained by flash column chromatography (20% to 40% EtOAc in hexanes, 28%, 51% each). LCMS (m/z): 351.1 (MH+), Rt=0.81 min, LCMS (m/z): 351.1 (MH+), Rt=0.83 min. The enantiomerically pure (3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate and (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate were resolved by chiral HPLC (For analysis Rt=6.8 min and 9.1 min respectively; n-heptane:ethanol=70:30 (v:v), Chiralpak AD-H prep 250×4.6 mm at 1 mL/min. For preparative separation, n-heptane:ethanol=80:20 (v:v), Chiralpak AS 50×500 mm at 90 mL/min).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7]CC)=[O:6])[C:3]=1[C:13]([O:15]CC)=O.NC1C=CC=C(C(OC)=O)C=1C(OC)=O.[CH2:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][C:34]1=O.[Cl-].[Cl-].[Cl-].[Al+3]>CO>[O:15]=[C:13]1[C:38]2[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:42]=3[CH2:41][CH2:40][C:39]=2[NH:1][C:2]2[C:3]1=[C:4]([C:5]([OH:7])=[O:6])[CH:10]=[CH:11][CH:12]=2
Reactant: O=C1CCc2ccccc2C1
Reactant: CCOC(=O)c1cccc(N)c1C(=O)OCC
Agent: COC(=O)c1cccc(N)c1C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Product: O=C(O)c1cccc2[nH]c3c(c(=O)c12)-c1ccccc1CC3
Temperature: 80 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of diethyl 3-aminophthalate and dimethyl 3-aminophthalate (1.0 g, 3.82 mmol), 3,4-dihydronaphthalen-2(1H)-one (0.61 g, 4.2 mmol), and aluminum trichloride (0.51 g, 3.82 mmol) was placed in a sealed tube and heated to 80° C. for 1 hour and then 130° C. for additional 4 hours. The mixture was cooled to room temperature, treated with methanol and concentrated. The remaining residue was chromatographed on silica gel using eluant of 3.2% methanol in dichloromethane and then purified by recrystalization in ethyl acetate and methanol to give the product (0.36 g, 30%) as a light brown solid. MS (ESI) m/e [M+1]+292.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.ClCCl>Br.C(O)(=O)C>[C:1]1([C:7]2([C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)CCCC1
Reactant: c1ccsc1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(C2(c3cccs3)CCCCC2)cc1
Temperature: 25 °C

Procedure:
Phenyl cyclohexene (50 mg) and thiophene (100 mg) were dissolved in 33% HBr in acetic acid (0.5 mL). The mixture was stirred at room temperature over night. Tlc indicated full conversion of the starting material. Dichloromethane (10 mL) was added. The organic phase was washed with saturated NaHCO3 (3×10 mL), dried Na2SO4 and concentrated in vacuo. The desired product was afforded after flash chromatography (eluent: dichloromethane). Yield: 39 mg. LC/MS purity (UV/MS): 100/90%, Rt 6.22 min. M+1: 243
Reaction SMILES: [ClH:1].[Cl:2][CH:3]=[C:4]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][O:5]1>>[Cl:2][CH2:3][C:4](=[O:5])[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][Cl:1]
Reactant: Cl
Reactant: CC1(C)CCOC1=CCl
Product: CC(C)(CCCl)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A powerful stream of hydrogen chloride gas from a cylinder is passed into 476 g (3.25 moles) of 2-chloromethylene-3,3-dimethyltetrahydrofuran, with ice-cooling. The gas is absorbed completely and the internal temperature rises up to 30° C. After complete saturation with hydrogen chloride, the reaction mixture is subsequently stirred at room temperature for 2 hours. Excess hydrogen chloride is initially stripped off using a water pump, and the mixture is then distilled under a high vacuum. 531 g (90% of theory) of 1,5-dichloro-3,3-dimethyl-2-pentanone of boiling point 85°-90° C./0.3 mbar are obtained. ##STR101##
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(CO)cc1
Temperature: 60 °C
Yield: 87.5 %

Procedure:
Azide 5 (1.96 g, 12.0 mmol) and PPh3 (6.50 g, 24.8 mmol, 2.05 eq) were dissolved in THF (25 ml) and heated at 60° C. for 1 hour. Water (4.5 ml, 248 mmol, 20 eq) was added and the reaction was heated overnight. The solvent was evaporated and the residue obtained was purified by flash chromatography (eluent DCM to 4:1 DCM/methanol saturated with NH3) to yield 6 as a white solid (1.44 g, 10.5 mmol, 85%). Rf=0.05 (9:1, DCM/MeOH sat. NH3); νmax=cm−1; 1H NMR (300 MHz, CDCl3) δ=7.35 (d, 3J(H,H)=8.4 Hz, 2H, ArCH α to CH2NH2), 7.30 (d, 3J(H,H)=8.4 Hz, 2H, ArCH α to CH2OH), 4.67 (s, 2H, CH2OH), 3.85 (s, 2H, CH2NH2), 1.68 (bs, 3H, OH, NH2); 13C NMR (75 MHz, CDCl3) δ=142.6 (ArCCH2NH2), 139.6 (ArCCH2OH), 127.3 (ArCH), 127.2 (ArCH), 65.0 (CH2OH), 46.2 (CH2NH2); HRMS (ESI+): m/z calculated for C8H12NO [M+H]+: 138.0913, found 138.0933.
Reaction SMILES: BrC[C@@H:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].Br[CH2:10]C1CCCCO1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:29]3=[CH:30][C:31]4[O:35][CH2:34][O:33][C:32]=4[CH:36]=[C:28]3[O:27][CH2:26]2)[C:18]1=[O:37]>>[O:8]=[C:4]1[NH:5][C@H:6]([CH2:10][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3([C:29]4=[CH:30][C:31]5[O:35][CH2:34][O:33][C:32]=5[CH:36]=[C:28]4[O:27][CH2:26]3)[C:18]2=[O:37])[CH2:7][CH2:3]1
Reactant: O=C1NCC[C@H]1CBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: BrCC1CCCCO1
Product: O=C1CC[C@@H](CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)N1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using (R)-3-bromomethyl-2-pyrrolidinone to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (47%) as a colorless solid: mp 121-130° C.; 1H NMR (300 MHz, CD3OD) δ7.34 (dd, J=7.6, 7.6 Hz, 1H), 7.22-7.06 (m, 4H), 6.48 (d, J=1.9 Hz, 1H), 6.15 (d, J=9.3 Hz, 1H), 5.82 (d, J=1.4 Hz, 2H), 4.86-4.81 (m, 2H), 4.64 (dd, J=9.3, 3.8 Hz, 1H), 4.13-4.06 (m, 1H), 3.85-3.83 (m, 2H), 2.43-2.18 (m, 2H), 2.00-1.88 (m, 1H); 13C NMR (75 MHz, CD3OD) δ177.9, 177.4, 177.3, 154.7, 154.6, 147.5, 147.4, 141.2, 140.8, 140.8, 136.0, 130.8, 130.6, 127.3, 127.2, 127.0, 126.3, 123.4, 122.0, 121.9, 121.9, 118.0, 117.8, 107.4, 101.1, 100.0, 99.9, 91.3, 91.3, 78.8, 78.7, 56.8 (2C), 51.4, 51.2, 43.2 (2C), 27.6, 22.6, 18.6; MS (ES+) m/z 401.2 (M+23), 379.2 (M+1).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.OS(O)(=O)=O.C1C(=O)N([Br:25])C(=O)C1>O>[Br:25][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]([CH:2]([F:12])[F:1])[CH:8]=1
Reactant: O=[N+]([O-])c1cccc(C(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cc(C(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
1-(Difluoromethyl)-3-nitrobenzene (866 mg, 5.00 mmol) was added to cold conc. H2SO4 and then NBS (890 mg, 5.00 mmol) was added. The mixture was warmed to room temperature for 30 minutes then 50-60° C. for 1 h. The mixture was then poured in water and ice and extracted diethyl ether twice. The organic layer was washed with dilute aqueous NaHCO3 and brine. Purification by chromatography on silica gel (0-15% ethyl acetate in hexanes) yielded 1-bromo-3-(difluoromethyl)-5-nitrobenzene (710 Mg, 2.82 mmol, 56.3%).
Reaction SMILES: [CH2:1]1[O:20][C:19]2[CH:18]=[CH:17][C:5]([C:6]([C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3C(O)=O)=O)=[CH:4][C:3]=2O1.BrC1C=CC=C[C:23]=1[C:24]([OH:26])=[O:25].C([Li])CCC.[C:36](Cl)(=O)[C:37]1[CH:45]=[CH:44][C:43]2[O:42][CH2:41][O:40][C:39]=2[CH:38]=1>C1COCC1>[CH3:1][O:20][C:19]1[CH:3]=[CH:4][C:5]([CH:6]2[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:36]([C:37]3[CH:45]=[CH:44][C:43]4[O:42][CH2:41][O:40][C:39]=4[CH:38]=3)[CH:23]2[C:24]([OH:26])=[O:25])=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1Br
Reactant: O=C(O)c1ccccc1C(=O)c1ccc2c(c1)OCO2
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Temperature: -100 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
2-(3,4-Methylenedioxybenzoyl)benzoic acid. To a solution of 2-bromobenzoic acid (12 g, 0.06 mol) in THF (200 ml) at −100° C. under an argon atmosphere was added dropwise n-butyl lithium (50 ml of 2.5M solution in hexanes, 0.125 mol), maintaining the temperature below −90° C. Upon completion of the addition, the resulting solution was stirred at −100° C. for 1 h, at which time was added slowly a solution of piperonylic acid chloride (11 g, 0.06 mol) in THF (50 ml), maintaining the temperature below −90° C. The resulting mixture was allowed to warm to −80° C. and stirred for 1 h, then was allowed to slowly warm to room temperature and left to stand for 48 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between Et2O and 1M HCl. The organic phase was extracted with 10% aqueous NaOH. The NaOH extract was acidified with concentrated HCl, and the combined aqueous material was extracted with Et2O. The Et2O extract was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a solvent gradient of 10-30% EtOAc/0.1% HOAc/hexanes to afford the title compound as an off-white solid (4.5 g, 28%).
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].OC[CH2:9][N:10]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH:11]1C>>[C:1]([O:6][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][N:10]([CH3:11])[CH3:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC1CC(C)(C)CN1CCO
Reactant: C=C(C)C(=O)[O-]
Product: C=C(C)C(=O)OCC(C)(C)CN(C)C

Procedure:
Methacrylate of N-hydroxyethyl-2,4,4-trimethyl-pyrrolidine
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11][CH3:12])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)O)nc1Br
Reactant: OB(O)c1cccc(Cl)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 37.9 %

Procedure:
A mixture of 6-bromo-5-methoxy-pyridine-2-carboxylic acid (0.3 g, 1 mmol), 3-chlorophenylboronic acid (CAN 63503-60-6, 0.23 g, 1 mmol), tris(dibenzylidene-acetone)-dipalladium(0) (CAN 52409-22-0, 0.12 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (CAN 161265-03-8, 0.15 g) and potassium carbonate (0.21 g, 2 mmol) in 1,4-dioxane (10 mL) was stirred for 12 h at 110° C. under a nitrogen atmosphere. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography (silica gel, 10 g, eluting with 10% methanol in methylene chloride) to give the title compound (0.1 g, 29%); MS (EI): m/e=264.0 [M+H]+.
Reaction SMILES: C([Mg]Br)C.[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][C:13]#[C:14]/[CH:15]=[CH:16]\C#C.[Si]([O:26]C1C=NC2C(C=1)=CC(OC)=CC=2)(C(C)(C)C)(C)C.ClC(OC12CC3CC(CC(C3)C1)C2)=O>C1COCC1.C(OCC)C>[O:26]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: C#C/C=C\C#CCOC1CCCCO1
Reactant: COc1ccc2ncc(O[Si](C)(C)C(C)(C)C)cc2c1
Agent: CC[Mg]Br
Agent: O=C(Cl)OC12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1CCC(OC2CCCCO2)OC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A solution of ethylmagnesium bromide in THF (43 ml 1M solution, 43.3 mmol) was added to a solution of z-hept-4-ene-2,6-diyn-1-ol tetrahydropyranyl ether 18 (6.89 g, 36.2 mmol) and 6-methoxy-3-(tert-butyldimethylsiloxy)-quinoline 17 (9.41 g, 32.5 mmol) in THF (210 ml) cooled to 0° C. After the initial evolution of gas the reaction mixture was stirred for 20 minutes at 0° C. and a solution of adamantyl chloroformate (11.51 g, 53.6 mmol) in THF (40 ml) was added via syringe pump over 90 minutes while maintaining the temperature at 0° C. On completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 18 hours before quenching with saturated aqueous sodium bicarbonate solution (60 ml). The resulting mixture was extracted with ether (1×300 ml, 2×150 ml), the combined organic extracts dried over magnesium sulphate and evaporated to give a brown oil. Flash column chromatography on silica gel eluting with 80% pentant, 20% diethylether yielded 16.11 g, (75%) of the desired product 19 as a clear yellow oil. 1H NMR (300 MHz, CDCl3) δ7.43 (s, 1H), 6.62 (dd, J=8.8, 2.8 Hz, 1H), 6.52 (d, J=2.8 Hz, 1H), 5.74 (dd, J=11.0, 1.4 Hz, 1H), 5.68-5.79 (s, 1H), 5.67 (d, J=11.0 Hz, 1H 5.62 (s, 1H), 4.75 (s, 1H), 4.31 (dd, J=16.0, 1.4 Hz, 1H), 4.23 (dd, J=16.0, 1.4 Hz, 1H), 3.77-3.89 (m, 1H), 3.76 (s, 3H), 3.46-3.58 (m, 1H), 2.15 (s, 9H), 1.64 (s, 6H), 1.45-1.89 (m, 6H), 0.96 (s, 9H), 0.25 (s, 3H), 0.24 (s, 3H); 13C NMR (75 MHz, CDCl3) δ156.3 (e), 152.0 (e), 128.9 (c), 125.5 (o), 124.8 (e), 119.5 (o), 119.3 (o), 110.5 (o), 109.9 (o), 103.5 (o), 96.8 (o), 93.1 (e), 92.8 (e), 82.7 (e), 81.6 (e), 80.1 (e), 61.9 (e), 55.3 (o), 54.7 (e), 48.8 (o), 41.5 (e), 36.1 (e), 30.9 (o), 30.2 (e), 25.5 (o), 25.3 (e), 1.9.0 (e), 18.1 (e), -4.3 (o), -4.7 (o); IR (CHCl3) 1687 cm-1; MS (FAB) m/e calculated for C39H51NO6Si: 657.349 , found 657.351.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]([CH:16]=O)([CH3:15])[CH3:14].[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:18]1([CH:16]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[F:11])[C:13]([CH3:14])([CH3:15])[CH3:12])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: NC(=O)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C=O
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1ccc(Cl)cc1F)n1nnc2ccccc21

Procedure:
4-Chloro-2-fluorobenzamide, pivaldehyde, benzotriazole and p-toluenesulfonic acid were processed as described in Example 53A to provide the desired product.
Reaction SMILES: [Cl:1]C1C(C)=C(C2C=CC=CC=2)C=CC=1.[Mg:15].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH3:16][C:17]1[C:22]([Mg:15][Cl:1])=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1c(Cl)cccc1-c1ccccc1
Reactant: Cc1ccccc1-c1ccccc1
Reactant: [Mg]
Solvent: C1CCOC1
Product: Cc1c([Mg]Cl)cccc1-c1ccccc1

Procedure:
Under a nitrogen atmosphere, 101.3 g (0.50 mole) of 3-chloro-2-methylbiphenyl (92% purity) in 75 g of dry tetrahydrofuran was added dropwise over two hours with stirring to a gently refluxing mixture of 13.1 g (0.54 mole) of fresh magnesium turnings, the heel from a previous run containing 0.21 mole of unreacted magnesium, and 75 g of dry tetrahydrofuran in a dry reaction vessel. Upon complete addition, the reaction mixture was heated at reflux for five additional hours. Gas chromatographic analysis of a quenched sample of the reaction mixture showed 1.2% of unreacted 3-chloro-2-methylbiphenyl and 92.4% of 2-methylbiphenyl. The reaction mixture was allowed to cool overnight.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C)C=O>[C:13]1([S:19][CH2:11][CH2:10][CH2:9][CH2:8][Br:7])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Sc1ccccc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCSc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Potassium carbonate (5.64 g) and 1,4-dibromobutane (5.88 g) were added to a solution of thiophenol (3 g) in dimethylformamide (40 ml), and the mixture was stirred at 50° C. for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 6.67 g of 4-phenylthiobutyl bromide.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[CH:13](=O)[CH3:14]>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:3]2[NH:4][CH:5]=[N:6][C:2]2=[N:1][C:13]=1[CH3:14])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC=O
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nc[nH]n1
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1nc2nc[nH]n2c1NC(C)(C)C

Procedure:
Compound 9 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) acetaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20].Cl>CCOCC.CCCCCC>[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]([NH2:3])=[NH:20]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: COc1cccc(C#N)c1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cccc(C(=N)N)c1OC
Reaction time: 16 h

Procedure:
To a solution of 20 g 1,1,1,3,3,3-hexamethyldisilazane in 150 mL dry ether was added 5 mL 2.4M n-butyllithium in hexane. After 10 min at room temperature 16.3 g 2,3-dimethoxybenzonitrile was added in one portion and the mixture was kept at room temperature for 16 h. The reaction mixture was then poured onto excess 3N HCl. The aqueous layer was separated, basified with 50% NaOH and the product was extracted three times with 10% methanol in methylene chloride. The combined organic extracts were dried over potassium carbonate and the solvents removed in vacuo to afford 2,3-dimethoxybenzamidine as a glassy solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]([CH3:21])[CH2:19][OH:20])[CH2:11][CH2:10]2.[H-].[Na+].[CH3:27]I.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]([CH3:21])[CH2:19][O:20][CH3:27])[CH2:11][CH2:10]2
Reactant: CC(CO)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Yield: 45.4 %

Procedure:
To a mixture of 6-(3-Fluoro-benzyloxy)-2-(2-hydroxy-1-methyl-ethyl)-3,4-dihydro-2H-isoquinolin-1-one (0.020 g, 0.061 mmol) and sodium hydride (55%, 2.2 mg, 0.067 mmol) in N,N′-dimethylformamide (0.2 mL), methyl iodide (0.009 mL, 0.152 mmol) was added. Water was added and the reaction was extracted with ethyl acetate. After drying of the organic layer with MgSO4, filtration and evaporation, the residue was purified by chromatography (SiO2, hexane/ethyl acetate 9:1 v:v) to give the title compound as a white solid (0.0095 g, 43%). MS: m/e=344.4 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([S:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:6]=1)[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH2:1]([NH:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([S:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Yield: 101.4 %

Procedure:
A mixture of N-ethyl-3-(2,4-difluorophenylthio)4-nitrobenzamide (0.92 g), iron powder (0.92 g) and ammonium chloride (92 mg) in ethanol (10 ml) and water (5 ml) was stirred and refluxed for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water, dried, and evaporated to give an oil of N-ethyl4-amino-3-(2,4-difluorophenylthio)benzamide (0.85 g).