Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:35])[CH2:6][S:7][CH2:8][C@@H:9]1[CH2:13][C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][N:10]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N.[N+:56]([C:59]1[CH:69]=[CH:68][C:62]([CH2:63][O:64][C:65](Cl)=[O:66])=[CH:61][CH:60]=1)([O-:58])=[O:57].[OH-].[Na+]>N1C=CC=CC=1.C(OCC)(=O)C.C(Cl)(Cl)Cl.O1CCCC1>[N+:56]([C:59]1[CH:60]=[CH:61][C:62]([CH2:63][O:64][C:65]([NH:1][CH2:4][CH:5]([OH:35])[CH2:6][S:7][CH2:8][C@@H:9]2[CH2:13][C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][N:10]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])=[O:66])=[CH:68][CH:69]=1)([O-:58])=[O:57]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC(O)CN=[N+]=[N-])N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC(O)CNC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of (2S,4R)-2-[(3-azido-2-hydroxypropyl)thiomethyl]-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.94 g) in pyridine (6 ml) was added triphenylphosphine (1.55 g) and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added conc. ammonia (0.50 ml) and the mixture was allowed to stand overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure. The resulting mixture was dissolved in ethyl acetate (40 ml) and the solution was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give (2S,4R)-2-[(3-amino-2-hydroxypropyl)thiomethyl]-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrroliidine. The residue containing the compound obtained above was dissolved in a mixture of ethyl acetate and water (3:1 V/V, 40 ml). To the solution was dropwise added a solution of 4-nitrobenzyloxycarbonyl chloride (0.87 g) in tetrahydrofuran (3 ml) with stirring at 2°-5° C., keeping the pH between 9-10 with 1N sodium hydroxide. The mixture was stirred at the same temperature for 1 hour. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (9:1 v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-{3-(4-nitrobenzyloxycarbonyl)amino-2hydroxypropyl}thiomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.25 g).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:7])[NH:5][CH:6]=1.CCN(C(C)C)C(C)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.CN(C1C=CN=CC=1)C>[I:1][C:2]1[N:3]=[C:4]([CH3:7])[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1nc(I)c[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)n1cc(I)nc1C
Temperature: 0 °C
Yield: 94.3 %

Procedure:
In general, modifications were made from the procedure given in J. Org. Chem., 1999, 64, 23, 8608-8615. A solution of commercially available 4-iodo-2-methyl-1H-imidazole (520 mg, 2.5 mmol) in THF (8.3 mL), containing DIEA (1.07 mL, 6.25 mmol) and DMAP (150 mg, 1.30 mmol), was cooled in a ice bath at 0° C. A solution of ethyl chloroformate (678 mg, 6.25 mmol) in THF (2.5 mL) was slowly added over a period of 20 min to the reaction mixture. The reaction mixture was heated at 50° C. for 48h and the solvent was removed under reduced pressure. The residue was dissolved in DCM and the organic layer was washed with brine, water, dried over MgSO4, filtered and evaporated. Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH:97/3 as eluent) to afford 660 mg of ethyl 4-iodo-2-methyl-1H-imidazole-1-carboxylate (Yield: 94%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1>CN(C)C=O.C(OCC)(=O)C>[OH:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([NH:13][C:2]2[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:15][CH2:16]1
Reactant: N#Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-chloro-5-nitronicotinonitrile (3.5 g) in N,N-dimethylformamide (35 ml) was added trans-4-aminocyclohexanol (4.39 g) at 0° C. The mixture was stirred at ambient temperature for 45 minutes under nitrogen atmosphere, and diluted with ethyl acetate. The resultant organic solution was washed with water (3 times) and brine, dried over magnesium sulfate, and concentrated in vacuo. The residual solid was washed with diethyl ether to give 6-(trans-4-hydroxycyclohexylamino)-5-nitronicotinonitrile (3.38 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[N+:8]([C:11]1[CH:12]=[C:13]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]([CH3:7])([C:3]([NH:20][S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)(=[O:19])=[O:18])=[O:4])[CH3:6]
Reactant: CC(C)(C)C(=O)O
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.2 %

Procedure:
To a mixture of trimethylacetic acid (5.55 g, 54 mmol), 3-nitrobenzenesulphonamide (11 g, 54 mmol) and 4-dimethylaminopyridine (6.65 g, 54 mmol) in anhydrous dichloromethane (400 ml), under an atmosphere of nitrogen, was added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (10.43 g, 54 mmol). The mixture was stirred at ambient temperature for 24 h. The mixture was extracted with 1M NaOH (50 ml) and the separated aqueous phase was mixed with dichloromethane (200 ml) and acidified with 5M HCl. The two layers were separated and the aqueous phase was further extracted with dichloromethane (2×100 ml). The combined organic phases were dried (Na2SO4) and evaporated to dryness. The resultant solid was recrystallised from methanol to afford the title compound (9 g, 58%) as a colourless solid. mp 178°-81° C. 1H NMR (360 MHz, D6-DMSO) δ 1.07 (9H, s), 7.95 (1H, t, J=8.0 Hz), 8.30-8.34 (1H, m), 8.52-8.56 (1H, m), 8.57-8.60 (1H, m), 12.02 (1H, brs).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:32])=[C:6]([CH:10]=[C:11]([CH:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:16][C:15](=[O:31])[NH:14]2)[CH:12]=1)[C:7]([OH:9])=O)[CH3:2].[NH4+].[Cl-].CC[N:37]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:1]([O:3][C:4]1[C:5]([OH:32])=[C:6]([CH:10]=[C:11]([CH:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:16][C:15](=[O:31])[NH:14]2)[CH:12]=1)[C:7]([NH2:37])=[O:9])[CH3:2]
Reactant: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(C(=O)O)c1O
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(C(N)=O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
A mixture of Compound 77 (described previously) (280 mg, 0.65 mmol), NH4Cl (41 mg, 0.78 mmol), EDCI (149 mg, 0.78 mmol), HOBT (105 mg, 0.78 mmol), and NMM (0.29 mL, 2.6 mmol) in DMF (5 mL) was stirred at room temperature for two hours. LCMS showed most of the starting material was consumed. 100 mL of a mixture of EtOAc and MeOH (v/v=10:1) was added to dilute the mixture. The organic layer was washed with brine (20 mL×2), dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to afford Compound 82 as a yellow solid (46 mg, yield: 16.4%). 1H NMR (DMSO-d6 400 MHz): δ 12.94 (s, 1H), 8.58 (s, 1H), 8.30 (s, 1H), 7.86 (s, 1H), 7.37 (s, 1H), 7.33 (s, 1H), 7.20-7.25 (m, 5H), 7.11 (s, 1H), 6.97-7.02 (m, 3H), 6.80 (d, J=6.8 Hz, 2H), 5.10 (d, J=2.4 Hz, 1H), 4.00 (q, J=7.2 Hz, 2H), 1.32 (t, J=6.8 Hz, 3H); MS (ESI): m/z 430.1 [M+1]+.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:11]([CH3:22])[C:12](=[O:21])[C:13]([OH:20])=[C:14]([C:16](OC)=[O:17])[N:15]=1>C1COCC1>[CH3:1][NH:2][C:16]([C:14]1[N:15]=[C:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([CH3:22])[C:12](=[O:21])[C:13]=1[OH:20])=[O:17]
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)n(C)c(=O)c1O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1nc(Cc2ccccc2-c2ccccc2)n(C)c(=O)c1O
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 40.2 %

Procedure:
A sealed tube containing 2M solution of methylamine (1.71 ml, 3.42 mmol) in THF and methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.1 g, 285 μmol) was heated at 100° C. in a microwave oven for 20 min, cooled and filtered. The solid was stirred in MeOH, in the presence of Amberlyst 15 IE resin, at 60° C. for 5 min and then at room temperature for 1 h, filtered, evaporated to dryness and triturated with Et2O to give the title compound as a white solid (0.040 g; 40%). LCMS: m/z=351 (MH+).
Reaction SMILES: N12CCCN=C1CC[CH2:4][CH2:3][CH2:2]2.IC(C)C.[Cl:16][C@H:17]1[C@H:21]([CH2:22][CH2:23][CH2:24][C:25]2[S:29][C:28]([C:30]([OH:32])=[O:31])=[CH:27][CH:26]=2)[C@@H:20]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([CH2:41][OH:42])[CH:38]=[C:37]([Cl:43])[CH:36]=2)[C@H:19]([OH:44])[CH2:18]1>CC(C)=O>[Cl:16][C@H:17]1[C@H:21]([CH2:22][CH2:23][CH2:24][C:25]2[S:29][C:28]([C:30]([O:32][CH:3]([CH3:4])[CH3:2])=[O:31])=[CH:27][CH:26]=2)[C@@H:20]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([CH2:41][OH:42])[CH:38]=[C:37]([Cl:43])[CH:36]=2)[C@H:19]([OH:44])[CH2:18]1
Reactant: O=C(O)c1ccc(CCC[C@@H]2[C@@H](CCc3cc(Cl)cc(CO)c3)[C@H](O)C[C@H]2Cl)s1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Solvent: CC(C)I
Product: CC(C)OC(=O)c1ccc(CCC[C@@H]2[C@@H](CCc3cc(Cl)cc(CO)c3)[C@H](O)C[C@H]2Cl)s1
Reaction time: 72 h
Yield: 83.4 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 5.4 μL, 0.036 mmol) and 2-iodopropane (48 μL, 0.48 mmol) were added to a solution of acid 11c (11 mg, 0.024 mmol) in acetone (0.3 mL) at room temperature under nitrogen. After 3 days at room temperature, the reaction mixture was concentrated in vacuo. The residue was acidified with 1.0 N HCl (5 mL) extracted with EtOAc (10 mL). The organic phase was washed with brine (5 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on 3 g silica (10% MeOH/CH2Cl2, gradient) afforded 10 mg (83%) of the title compound (18). 1H NMR (500 MHz, CDCl3) δ□ppm 1.21-1.32 (m, 6 H), 1.32 (s, 3 H), 1.34 (s, 3 H), 1.75-1.80 (m, 6 H), 2.62 (ddd, J=13.91, 9.69, 6.72 Hz, 1 H), 2.71 (td, J=9.35, 5.01 Hz, 1 H), 2.84 (t, J=7.40 Hz, 2 H), 4.03 (q, J=7.09 Hz, 1 H), 4.08-4.18 (m, 1 H), 4.65 (s, 2 H), 5.17 (dt, J=12.47, 6.24 Hz, 1 H), 6.77 (d, J=3.67 Hz, 1 H), 7.08 (d, J=9.54 Hz, 2 H), 7.18 (s, 1 H), 7.60 (d, J=3.67 Hz, 1 H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([SH:6])[CH3:5].[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10](F)[CH:9]=1.O>CS(C)=O>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([S:6][CH:4]([CH3:5])[CH3:3])[CH:9]=1
Reactant: CC(C)S
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Sc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (32.87 g) in dimethyl sulfoxide (600 ml) was added 2-propanethiol (41.73 ml) at ° C. under nitrogen atmosphere and stirred at room temperature for 1 hour. The reaction mixture was cooled with ice bath and added 4-bromo-2-fluorobenzoic acid (60 g). The reaction mixture was stirred at 70° C. for 1.5 hours and then cooled to room temperature. The mixture was poured into water (3 l) and washed with hexane (600 ml). The water layer was acidified with concentrated hydrochloric acid and then the resulting white solid was collected by filtration. The white solid was dried at 60° C. to give 4-bromo-2-(isopropylthio)benzoic acid (75.49 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12].FC1C=CC([B:23]([OH:25])[OH:24])=C(O[C@H](CC=C)C)C=1>>[F:8][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[C:2]([B:23]([OH:25])[OH:24])[CH:7]=1
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1B(O)O
Reactant: C=CC[C@H](C)Oc1cc(C)c(F)cc1Br
Product: C=CC[C@H](C)Oc1cc(C)c(F)cc1B(O)O
Yield: 100 %

Procedure:
Prepared in 100% yield from (S)-1-bromo-5-fluoro-4-methyl-2-(pent-4-en-2-yloxy)benzene following the procedure for (S)-(4-fluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid. NMR is complex and suggests an oligomeric mixture. The material, however, was used as is and was fully compentent for undergoing a Suzuki coupling.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([N:15]=[C:16]=[O:17])[CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].C(N(CC)CC)C>C(Cl)Cl>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:16](=[O:17])[NH:15][C:13]1[CH:14]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][C:3]([C:21]([F:22])([F:23])[F:24])=[C:2]([Cl:1])[CH:7]=2)[CH:10]=[CH:11][C:12]=1[N+:18]([O-:20])=[O:19])[CH3:27]
Reactant: CCOC(=O)CN
Reactant: O=C=Nc1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)Nc1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 5-[(2-chloro-α,α,α-trifluoro-p-tolyl)oxy]-2-nitrophenyl isocyanate (107 g, 0.299) mol) in methylene chloride is cooled to 0° C., treated with a mixture of glycine ethyl ester hydrochloride (50.1 g, 0.359 mol) and triethylamine (166 mL, 1.20 mol) in methylene chloride over 10 minutes, refluxed overnight, cooled to room temperature, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. A solution of the solid in methylene chloride is placed on a silica gel plug, eluted with methylene chloride and concentrated in vacuo to give the title product as a yellow solid which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[CH2:34][NH2:35]>>[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[CH2:34][NH:35][C:15]([C:14]1[CH:18]=[CH:19][N:20]=[CH:21][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:28]=[N:27][CH:26]=[N:25][CH:24]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=1)=[O:11])=[O:17]
Reactant: NCC1CCCO1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Product: O=C(NCC1CCCO1)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Yield: 77 %

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with (tetrahydrofuran-2-yl)methanamine, providing the title compound as yellow solid (77%).
Reaction SMILES: [CH3:1][Mg]Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19](=[O:20])[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]2=[O:21])=[C:7]([F:22])[CH:6]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:12]([OH:21])([CH3:1])[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=3[C:19]2=[O:20])=[C:7]([F:22])[CH:6]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Reaction time: 2 h

Procedure:
Twenty parts of a 3.13M methylmagnesium chloride solution in tetrahydrofuran was added dropwise to a solution of 20 parts of 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-2 H-isoindole-1,3-dione in 200 parts of anhydrous tetrahydrofuran at 0° C over 1/2 hour. After stirring for 2 hours at 0° , 10 parts of a saturated aqueous ammonium chloride was added dropwise at 0°, resulting in a granular precipitate. After filtering the precipitate, the filtrate was evaporated at 300 mm. Hg and 50° to give 23.5 parts of 2-(4-chloro-2-fluorophenyl) -2,3,4,5,6,7-hexahydro-3-hydroxy-3methyl-1H-isoindol-1-one as indicated in particular by adsorption in the infrared spectrum of 1690 cm-1 (amide) and 3300 cm-1 (hydroxyl) and in the nuclear magnetic resonance spectrum of 4.6δ (1H, hydroxyl) and 1.1δ (3H, singlet methyl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH3:21])=[C:6]([CH:8]2[C:16](=[O:17])[CH:15]3[CH:10]([CH:11]4[O:18][CH:14]3[CH:13]=[CH:12]4)[C:9]2=[O:19])[CH:7]=1>CO.[Pd]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH3:21])=[C:6]([CH:8]2[C:9](=[O:19])[CH:10]3[CH:15]([CH:14]4[O:18][CH:11]3[CH2:12][CH2:13]4)[C:16]2=[O:17])[CH:7]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C2C3C=CC(O3)C2C1=O
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Br)cc1C1C(=O)C2C3CCC(O3)C2C1=O

Procedure:
A solution of (1RS, 2SR,6RS,7SR)-4-(5-bromo-2-ethylphenyl)-10-oxatricyclo[5.2.1.02,6]-dec-8-en-3,5-dione (3.00 g, 8.6 mmol) in methanol (250 ml) is hydrogenated at 3.5 bar over 5% palladium on carbon for 2 hours at room temperature. The catalyst is removed by filtration through diatomaceous earth and the solvent is evaporated under reduced pressure to give (1RS,2SR,6RS,7SR)-4-(5-bromo-2-ethylphenyl)-10-oxatricyclo-[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [C:1](OCC(CC)CCCC)(=[O:15])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5].[H][H]>C(C(CCCC)CO)C>[CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][OH:5].[CH2:13]([CH:8]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7][OH:6])[CH3:14]
Reactant: CCCCC(CC)COC(=O)/C=C\C(=O)OCC(CC)CCCC
Reactant: [H][H]
Solvent: CCCCC(CC)CO
Product: OCCCCO

Procedure:
The resulting solution of di-(2-ethylhexyl) maleate in 2-ethylhexan-1-ol is treated with hydrogen, in a trickle procedure, over a Cu/Mg silicate catalyst, at 190° C. and under a pressure of 200 bar, and the ester is cleaved to give butane-1,4-diol and 2-ethylhexanol. The mean space-time yield in a 3,300 hour experiment is 40 g of butanediol per liter per hour.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Br)=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13].[OH2:14]>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH2:8][OH:14])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13]
Reactant: O
Reactant: Clc1c(Cl)c(Cl)c(CBr)c(Cl)c1Cl
Solvent: CN(C)C=O
Product: OCc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
A solution of 20.7 g of pentachlorobenzyl bromide in 300 ml DMF containing 30 ml of water was heated at reflux for two hours. On dilution with water solids precipitated. The solid was filtered out and washed on the filter until the wash water was free of bromide ions. On drying, 15.2 g of pentachlorobenzyl alcohol of m.p. 193°-195° C. were obtained.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:16])[C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:20][CH2:19]1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C#N
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C#N
Temperature: 112 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
500 mg (2.1865 mmol) 6-chloro-4-o-tolyl-nicotinonitrile were dissolved in 10.0 ml toluene and heated to 112° C. At this temperature 2.19 g (21.865 mmol) 1-methylpiperazine were added, and the reaction mixture was stirred for further 60 minutes. The mixture was cooled down to 50° C. and concentrated under reduced pressure. 5 ml toluene were added to the obtained residue at a temperature of 20-25° C., followed by 900 mg sulfuric acid (95%). The organic phase was washed with 5 ml water. Evaporation in vacuo gave 520 mg of 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinonitrile as a beige foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH3:2].[C:14]([Cl:19])(=O)[C:15](Cl)=O>CN(C)C=O.O1CCCC1>[Cl:19][C:14]1[CH:15]=[CH:7][C:6]([C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[O:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 196.8 %

Procedure:
N,N-dimethylformamide(1 drop) was added to a tetrahydrofuran solution(40 ml) of pimelic acid monoethyl ester(25.5 g), and thereto oxalyl chloride(18.8 g) was added dropwise. After stirring for 2 hours at room temperature, the reaction mixture was concentrated. The residue was added dropwise to a mixture of chlorobenzene(61.0 g) and aluminum chloride anhydrous (36.1 g) under ice water. After stirring for 3 hours, the reaction mixture was poured into IN-hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 6-(4-chlorobenzoyl)hexanate (37.7 g, 97%) as an oily substance.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc2ccccc2c1O
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCc1nn(Cc2ccc(C#N)cc2)c2ccccc2c1=O
Yield: 72.2 %

Procedure:
Using the procedure of Example 1, 406 mg of the product of Step B and 430 mg of 4-bromomethyl benzonitrile and 830 mg of potassium carbonate were reacted to obtain after chromatography on silica (eluant: methylene chloride-methanol (98-2)), 460 mg of the desired product melting at 180° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)O1.Br[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>COCCOC>[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH2:13][CH2:12]2
Reactant: Brc1nccs1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Solvent: COCCOC
Product: O=C1CCc2cc(-c3nccs3)ccc21
Reaction time: 8 h

Procedure:
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indan-1-one (SM-1a, 350 mg, 0.95 mmol) and 2-bromothiazole (156 mg, 0.95 mmol) were combined in DME (10 mL), and the mixture was purged with nitrogen for 10 minutes. Aqueous sodium carbonate solution (2M, 0.95 mL) and Pd(dppf)Cl2 (34 mg, 5 mol %) were added. The solution was purged with nitrogen for 10 minutes and was heated at reflux for 5 hours. The reaction was cooled and held at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water and separated. The aqueous layer was washed with 15 mL ethyl acetate (2×), and the combined organic portions were washed with brine and dried over MgSO4. Filtration and solvent removal afforded the crude product as a brown paste which was purified by silica chromatography on Combiflash ISCO purification system (Teledyne Corp., Lincoln Nebr.) eluting with a heptanes/ethyl acetate gradient. The final product was obtained as a light yellow flaky solid (SM-1f, 195 mg, 95%). MS (ES+) 216.2, 1H NMR (CDCl3) δ 2.72-2.75 (m, 2H), 3.20 (t, 2H), 7.42 (d, 1H), 7.80 (d, 1H), 7.92 (d, 1H), 7.94-7.97 (m, 1H), 8.10 (br s, 1H).