Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH:10]([CH2:14][O:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22]OS([O-])=O.[K+].[OH2:28]>CO>[CH2:1]([S:8]([CH2:9][CH:10]([CH2:14][O:15][CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:11]([OH:13])=[O:12])(=[O:22])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: O=C(O)C(COC1CCOCC1)CSCc1ccccc1
Reactant: O
Agent: [K+]
Solvent: CO
Product: O=C(O)C(COC1CCOCC1)CS(=O)(=O)Cc1ccccc1

Procedure:
A solution of 3-Benzylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid (1.16 g, 3.7 mmol) in a mixture of MeOH (10 ml) and water (30 ml) was treated oxone (3.5 g, 5.6 mmol) overnight. Methanol evaporated off under reduced pressure, aqueous layer extracted with ethyl acetate, dried (Na2SO4) and evaporated under reduced pressure to give the title compound as white solid (1.36 g); MS: 365 (M+Na), 343 (MH+); LCMS retention time 3.1 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[NH:9][N:8]=2)[S:5][CH:6]=1.P(Cl)(Cl)([Cl:20])=O>ClC(Cl)C>[Cl:20][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1csc(-c2n[nH]c(=O)c3ccccc23)c1
Solvent: CC(Cl)Cl
Product: Cc1csc(-c2nnc(Cl)c3ccccc23)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
200 mg of 4-(4-methyl-2-thienyl)phthalazinone and 2 ml of phosphorus oxychloride were dissolved in 4 ml of dichloroethane, and the solution was stirred at 100° C. for 4 hours. The reaction solution was distilled off, and a 1-N aqueous NaOH solution was added thereto under cooling with ice. The solution was extracted with chloroform, dried and concentrated to obtain 206 mg of 1-chloro-4-(4-methyl-2-thienyl)phthalazine.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C1C=CC=CC=1>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([Cl:19])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1ccccc1-c1ccccc1
Reaction time: 1 h

Procedure:
To a stirring solution of 1,1'-biphenylcarboxylic acid (1.0 g, 4.6 mmol) in 10 ml of dry benzene, under argon was added oxalyl chloride (0.40 ml, 2.0 eq.). To this solution was added DMF dropwise in 10 minute intervals, until no gas was evolved and the solution turned slightly cloudy (two drops). The mixture was stirred for 1 hour, then reduced on the rotovap without heating. The crude product, white solid, was carried directly on to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([I:11])[C:3]=12.[H-].[Na+].[CH3:14][CH:15]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH3:16]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:14])[CH:9]=[C:10]([I:11])[C:3]=12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Clc1ccnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2c(Cl)ccnc21
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
The 4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (5.00 g, 17.9 mmol, US 2006128661 Example 1) in DMF (50 mL) was treated with 60 wt % NaH (0.790 g, 19.7 mmol) then stirred for about 15 min. The TIPSCl (4.18 mL, 19.8 mmol) was then added to the mixture and the mixture was stirred for about 30 min. The solvents were evaporated under reduced pressure then the material was partitioned between saturated aqueous NaHCO3 (50 mL) and EtOAc (50 mL). The layers were separated then the aqueous layer was extracted with EtOAc (25 mL). The combined organics were washed with water (25 mL) then brine (25 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 120 g silica column and eluting with heptane to give 4-chloro-3-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.34 g, 68%): LC/MS (Table 2, Method g) Rt=2.58 min; MS m/z 435 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:19]1([NH:25][C:26]([N:9]2[C:10]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccccc1
Reactant: c1ccc(Sc2cc(-c3ccccc3)n[nH]2)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)n1nc(-c2ccccc2)cc1Sc1ccccc1
Yield: 70 %

Procedure:
12.6 parts of 3-phenyl-5-phenylthiopyrazole, 100 parts of toluene and 6 parts of phenyl isocyanate are stirred for 12 hours at 20° C. After the toluene has been distilled off, there is obtained 13 parts (70% of theory) of 1-(phenylcarbamoyl)-3-phenyl-5-phenylthiopyrazole; m.p.: 138° to 139.5° C (recrystallized from acetonitrile).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:15])=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1
Reactant: NN1CCOCC1
Reactant: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 84 %

Procedure:
As described for example 2b, 6-(3-methyl-5-phenyl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.5 mmol) was converted, using N-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (165 mg, 84%) which was obtained as a white solid. MS: m/e=395.2 [M+H]+.
Reaction SMILES: C[Si](C)(C)Cl.Br[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1.N>CCOCC.[Zn]>[OH:18][C:14]1([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1CCC1
Agent: C[Si](C)(C)Cl
Agent: N
Agent: [Zn]
Solvent: CCOCC
Product: CCOC(=O)C(C)C1(O)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trimethylchlorosilane (950 μL, 7.43 mmol) was added by syringe to a suspension of zinc powder (6.65 g, 0.102 mol) in absolute Et2O (170 mL). The mixture was stirred for 15 minutes at room temperature, heated to reflux, the heat source removed, and ethyl 2-bromopropionate (10.1 mL, 77.8 mmol) was added at such a rate that the ether gently boiled. After being heated to reflux for 1 hour, the mixture was stirred for 1 hour at room temperature. A solution of cyclobutanone (5.00 g, 63.2 mmol) in Et2O (10 mL) was added while the temperature of the mixture was maintained at 19-20° C. by intermittent cooling. After stirring for 1 hour at room temperature, the mixture was poured into iced 25% ammonia (400 mL). The aqueous phase was extracted with ether, the combined organic phases were dried over K2CO3, and concentrated. the title compound was given as a colorless oil (12.9 g, 100%). 1H-NMR (400 MHz, CDCl3) δ1.21 (3H, d, J=6.8 Hz), 1.29 (3H, t, J=7.3 Hz), 1.51-1.64 (1H, m), 1.80-1.90 (1H, m), 1.96-2.17 (4H, m), 2.70 (1H, q, J=7.3 Hz), 3.44 (1H, s), 4.18 (2H, qd, J=7.3 and 1.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([C:22]([S:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:23][N:24]=1)[C:16](N(OC)C)=[O:17])(=[O:11])=[O:10].[CH2:41]([Mg]Cl)[CH2:42][CH3:43]>C1COCC1>[C:16]([C:15]1[C:22]([S:25][C:26]2[CH:27]=[CH:28][C:29]([S:32]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)(=[O:33])=[O:34])=[CH:30][CH:31]=2)=[CH:23][N:24]=[C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:11])[CH:14]=1)(=[O:17])[CH2:41][CH2:42][CH3:43]
Reactant: CCC[Mg]Cl
Reactant: CON(C)C(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Solvent: C1CCOC1
Product: CCCC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Reaction time: 8 h
Yield: 6.8 %

Procedure:
2-(2,4-Dichloro-benzenesulfonylamino)-N-methoxy-N-methyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-isonicotinamide (150 mg, 0.233 mmol) was stirred in THF (30 ml) under nitrogen at room temperature. 2M Propylmagnesium chloride (1.2 ml, 2.33 mmol) was added and the reaction stirred overnight. The reaction was quenched using 1N HCl solution partitioned between a mixture of NaHCO3 solution (30 ml) and ethyl acetate (30 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate 2/3 hexane as eluent to give N-{4-butyryl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-2,4-dichloro -benzenesulfonamide as an off-white solid (10 mg, 6%). 1H NMR (CDCl3): 8.21 (1H, s, Ar); 8.06 (1H, d, Ar); 7.60 (2H, d, Ar); 7.47 (1H, s, Ar); 7.38 (1H, d, Ar); 7.26 (3H, m, py and Ar); 2.89 (4H, m, 2×CH2N pip); 2.70 (2H, t, COCH2); 1.56 (6H, m, 2×CH2 pip, COCH2CH2); 1.47 (2H, m, CH2 pip); 0.90 (3H, t, COCH2CH2CH3). HPLC (Luna 2, Gradient 1): rt=6.92 minutes. LCMS: rt=7.61 minutes, 629 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=O)[C:4]=2[CH:3]=1.N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO>[CH3:21][O:22][N:23]=[C:10]1[C:4]2[CH:3]=[C:2]([I:1])[CH:13]=[CH:12][C:5]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C1CCCCc2ccc(I)cc21
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CCCCc2ccc(I)cc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a stirred suspension of 3-iodo-6,7,8,9-tetrahydrobenzocylohepten-5-one prepared as described in example P3a (0.806 g; 2.82 mmol) in methanol (5.7 ml) was added pyridine (0.7 ml; 9.02 mmol) followed by a portion wise addition of methoxyamine hydrochloride (0.754 g; 9.02 mmol). The reaction mixture was stirred at 20° C. for 16 h under nitrogen. The solvent was removed in vacuo to afford 0.86 g (97% of theory) of crude 3-iodo-6,7,8,9-tetrahydrobenzocylohepten-5-one-O-methyl-oxime E/Z-mixture as a brown oil.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][O:7][CH3:8].Br[C:10]1[CH:15]=[C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])[C:13]([Cl:21])=[CH:12][N:11]=1.CCOC(C)=O>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:13]1[C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=[CH:15][C:10]([CH2:4][CH2:5][CH2:6][O:7][CH3:8])=[N:11][CH:12]=1
Reactant: COC(OC)c1cc(Br)ncc1Cl
Reactant: COCCCBr
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: II
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCCc1cc(C(OC)OC)c(Cl)cn1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a suspension of Mg (911 mg, 37.5 mmol) and iodine (one crystal) in dry THF (30 mL) was added dropwise 5% of the total amount of 1-bromo-3-methoxypropane (4.59 g, 30.0 mmol). The mixture was heated to reflux with the help of a heat gun until the Grignard-formation started. The rest of the 1-bromo-3-methoxypropane was added slowly, while an exothermic reaction proceeded. After the end of the addition, the reaction mixture was stirred under reflux for 20 min, and was allowed to cool to rt. This Grignard-sol. (1M in THF, 23.5 mL, 23.5 mmol) was added dropwise to a mixture of 2-bromo-5-chloro-4-dimethoxymethyl-pyridine (2.50 g, 9.38 mmol) and Ni(dppp)Cl2 (495 mg, 0.938 mmol) in THF (50 mL) at 0° C. The reaction mixture was stirred at rt for 30 min, and was then heated to reflux for 2 h. The mixture was allowed to cool to rt, and was dissolved with EtOAc. This mixture was washed with aq. sat. NaHCO3. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane→EtOAc/heptane 1:1) yielded the title compound (1.51 g, 62%). LC-MS: tR=0.80 min; ES+: 260.15.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18](Cl)[N:17]=1>CN1C=CC=CC1=O>[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][NH:22]2)=[C:18]([O:11][C:7]2[C:6]([CH3:12])=[CH:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:8]=2[CH3:10])[N:17]=1
Reactant: Cc1cc(C2CC2)cc(C)c1O
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2[nH]cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 4-cyclopropyl-2,6-dimethylphenol (263 mg, 1.62 mmol) in 1-methyl-2-pyridone (3 mL) at 0° C. was added NaH (65 mg, 1.62 mmol). The reaction mixture was stirred at room temperature for 30 min and a solution of 2,6-dichloropurine (102 mg, 0.54 mmol) in 1-methyl-2-pyridone (2 mL) was added to the mixture. The mixture was heated at 100° C. for 16 h and then cooled to room temperature. The reaction was poured into ice water and extracted with CHCl3 (3×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (MeOH:CHCl3=5:95) yielded 114 mg (67%) of 2-chloro-6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purine.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[O:17][C:18]([CH2:21][O:22]CC2C=CC=CC=2)=[N:19][N:20]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CC=CCC=1>CC(O)=O.CO.[Pd]>[OH:22][CH2:21][C:18]1[O:17][C:16]([C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:20][N:19]=1
Reactant: O=C(CCCCCCOc1ccccc1)c1nnc(COCc2ccccc2)o1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(CCCCCCOc1ccccc1)c1nnc(CO)o1
Reaction time: 2 h
Yield: 25 %

Procedure:
To a stirred suspension of 73.1 (80 mg, 0.2 mmol) and Pd/C (160 mg) in AcOH/MeOH (1:10 mixture, 5 mL) at 45° C. was added 1,4-cyclohexadiene (304 mg, 4 mmol) over a period of 30 min. The mixture was stirred for an additional 2 h at the same temperature. The catalyst was removed by filtration through celite and the filtrate was evaporated under reduced pressure. The residue was purified through a column of silica, eluting with 45% ethyl acetate in petroleum ether to give 74.1 as a white solid (m p 83-85° C.) in 25% yield (15 mg).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[S:6][C:7]([CH2:9][OH:10])=[CH:8][C:4]=2[CH:3]=1.C(OCC)(=O)C>C(Cl)Cl.CCCCCC.O=[Mn]=O>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[S:6][C:7]([CH:9]=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: OCc1cc2cc(F)ccc2s1
Agent: O=[Mn]=O
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1cc2cc(F)ccc2s1
Temperature: 52 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
MnO2 (4.298 g, 49.45 mmol) was added to a solution of (5-fluorobenzo[b]-thiophen-2-yl)methanol (I-50b: 1.8 g, 9.89 mmol) in DCM (50 mL) and the resulting reaction mass was stirred at 52° C. for 2 hours. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was cooled to room temperature, filtered off the catalyst through a celite bed and washed the celite bed with DCM. The filtrate was concentrated under reduced pressure and dried under vacuum to afford 1.5 g of the product (88.23% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18])[CH3:2]
Reactant: CCc1ccccc1N
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CCc1ccccc1NC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-ethylaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (95%) as a colorless solid: mp 184-186° C.; 1H NMR (300 MHz, DMSO-d6) δ10.06 (s, 1H), 7.69-7.61 (m, 1H), 7.50-7.34 (m, 3H), 7.31-7.13 (m, 6H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.40 (s, 1H), 5.20-5.01 (m, 2H), 4.86 (d, J=8.9 Hz, 1H), 4.72 (d, J=8.9 Hz, 1H), 4.47 (t, J=8.7 Hz, 2H), 2.93 (t, J=8.7 Hz, 2H), 2.68 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.9, 168.1, 161.6, 161.2, 142.8, 139.8, 136.4, 135.8, 134.5, 132.7, 130.8, 129.1, 129.0, 128.3, 127.9, 127.8, 127.0, 126.9, 126.5, 124.2, 123.6, 120.9, 120.4, 119.6, 109.7, 92.9, 80.4, 72.6, 57.5, 41.4, 28.8, 24.5, 14.8; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:20][CH2:21][CH:22]=[CH2:23].[H-].[Na+].O>CN(C=O)C>[CH2:23]([N:12]1[C:13](=[O:16])[CH2:14][CH2:15][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH2:10][CH2:11]1)[CH2:22][CH:21]=[CH2:20]
Reactant: C=CCCBr
Reactant: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCN1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reaction time: 6 h
Yield: 28.8 %

Procedure:
To a solution of 1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one 0.29 g (1 mmol) and 4-bromobut-1-ene 0.3 g (2 mmol) in DMF (2 ml) was added NaH 0.1 g (2 mmol of 55% dispersion in oil) and the mixture stirred for 6 h. The reaction was then poured into water and extracted with EtOAc, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc/n-heptane 1:1) afforded the title compound 0.09 g (25%) as a yellow gum. MS: 313.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH:11]=[CH:17][N:18]([CH3:20])[CH3:19])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 94 %

Procedure:
To a solution of 5-fluoro-2-methyl-1,3-dinitrobenzene (15 g, 0.075 mol) in N,N-dimethylformamide (300 mL) was added dimethylformamide dimethylacetal (89 g, 0.75 mol). The bright red reaction mixture was heated at 120° C. for 5 h, then concentrated in vacuo to provide 18 g crude product, which was used in the next step without further purification. LC/MS m/z=256.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH2:12]O)=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:12][C:9]1[S:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cnc(-c2ccccc2)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cnc(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
(2-phenylthiazol-5-yl)methanol (390 mg, 2.03 mmol) was dissolved in dry CH2Cl2 (10 mL) and cooled to 0° C. Triphenyl phosphine (800 mg, 3.05 mmol) was then added, followed by carbon tetrabromide (1.35 g, 4.07 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product was purified by column chromatography (silica 60-120 mesh, eluant 5% EtOAc in petroleum ether) to get 5-(bromomethyl)-2-phenylthiazole (250 mg, yield 48%) as light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.95-7.92 (m, 2H), 7.80 (s, 1H), 7.46-7.45 (m, 3H), 4.77 (s, 2H). MS (ESI) m/z: Calculated for C10H8BrNS: 254.95. found: 256.0 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:11][O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15]>>[CH3:11][O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH:15][C:7](=[O:9])[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)CC1CCCC1
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)CC1CCCC1

Procedure:
Following General Procedure BD above, and using cyclopentylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma) the title compound was prepared.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Reactant: CN1CCNCC1
Product: CN1CCN(c2ncccc2C(=O)Nc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)CC1

Procedure:
Using the conditions of Example 334 and 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide and 5 ml of N-methylpiperazine gives 1 g of the desired product :M+ =500.