Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[N:30]=[C:31](/[CH:34]=[CH:35]/[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:32][CH:33]=2)=[CH:23][CH:22]=1)(=O)=O>>[C:36]1(/[CH:35]=[CH:34]/[C:31]2[O:32][CH:33]=[C:29]([CH2:28][O:27][C:24]3[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][CH2:18][CH2:17][N:11]4[CH:10]=[CH:9][N:8]=[C:7]4[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:26][CH:25]=3)[N:30]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(CCCCn3ccnc3-c3ccccc3)cc2)co1)\c1ccccc1
Yield: 40 %

Procedure:
In substantially the same manner as in Working Example 8, 2-phenylimidazole was allowed to react with 4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl methanesulfonate to give 2-[(E)-2-phenylethenyl]-4-[4-[4-(2-phenyl-1-imidazolyl) butyl]phenoxymethyl]oxazole. The yield was 40%. Recrystallization from ethyl acetate-isopropyl ether gave colorless prisms, mp 85-86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:37]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:37])=[O:25])=[CH:16][CH:15]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCC(c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)c1cccnc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCC(c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)c1cccnc1
Reaction time: 8 h

Procedure:
2.0 g of 5-(4-(2-(4-chlorobenzenesulphonylamino)ethyl)phenyl)-5-(3-pyridyl)pentanoic acid are dissolved in 30 ml of methanol and mixed with 3 ml of thionyl chloride at 0° C. The solution is stirred overnight, then rotary evaporated and the residue is chromatographed over a silica gel column.
Reaction SMILES: BrCC1C=CC2[C:8]3[NH:9][C:10](=[O:17])[C:11]4[C:16]([C:7]=3CC=2C=1)=[CH:15][CH:14]=[CH:13][CH:12]=4>C(O)C.CN(C=O)C>[C:10]1(=[O:17])[C:11]2[C:16]([CH:15]=[CH:14][C:13]3[C:12]=2[CH:10]=[C:11]2[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][CH:8]=[N:9]1
Reactant: O=c1[nH]c2c(c3ccccc13)Cc1cc(CBr)ccc1-2
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1N=CC=c2ccc3c(c21)C=c1ccccc1=3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 9-bromomethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline (0.425 g, 1.3 mmol) or a higher alkylene chain bromo-derivative, an appropriate amine in ethanol or DMF and ethanol and in the presence of base is refluxed for 2 hrs to overnight. The reaction mixture is stirred at room temperature for about 30 minutes and filtered. The resultant solid is washed with ethanol (2×20 mL) and dried in a vacuum oven to provide an Indenoisoquinolinone Analog of Formula IIb or IIIb.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][CH:14]=1)[C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:6]2.C(O)(C)C.[N-:31]=[N+:32]=[N-:33].[Na+].Cl>C(OCC)(=O)C.[Br-].[Zn+2].[Br-].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:19]3[NH:33][N:32]=[N:31][N:20]=3)[N:18]=1)[C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:6]2
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C#N)n1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(-c2nnn[nH]2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a mixture of 6-(5-methoxy-2-phenylindol-1-ylmethyl)pyridine-2-carbonitrile (95 mg), isopropyl alcohol (6 mL), and water (4 mL) were added sodium azide (36 mg) and zinc bromide (32 mg). This mixture was stirred overnight while heated to reflux. The reaction mixture was left to cool to room temperature, and then diluted with ethyl acetate. To the mixture was added 2 mol/L hydrochloric acid (4 mL), followed by stirring at room temperature for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: dichloromethane-methanol) to obtain the title compound (88 mg). 1H-NMR (DMSO-d6) δ ppm: 3.78 (3H, s), 5.61 (2H, s), 6.54 (1H, d, J=7.8 Hz), 6.66 (1H, d, J=0.4 Hz), 6.78 (1H, dd, J=2.5, 8.9 Hz), 7.16 (1H, d, J=2.5 Hz), 7.29 (1H, d, J=8.9 Hz), 7.35-7.55 (5H, m), 7.90 (1H, t, J=7.8 Hz), 8.05 (1H, d, J=7.8 Hz). ESI-MS (m/z): 383 (M+H)+
Reaction SMILES: C([O:3][C:4]([NH:6][C:7]([CH2:27][CH3:28])=[CH:8][C:9]([NH:11][C:12]1[C:13]([F:26])=[CH:14][C:15]2[O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][C:23]#[CH:24])[C:16]=2[CH:25]=1)=[O:10])=O)C.C[O-].[Na+].Cl>CO.O>[CH2:27]([C:7]1[NH:6][C:4](=[O:3])[N:11]([C:12]2[C:13]([F:26])=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][C:23]#[CH:24])[C:16]=3[CH:25]=2)[C:9](=[O:10])[CH:8]=1)[CH3:28]
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)C=C(CC)NC(=O)OCC)cc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C#CCN1C(=O)COc2cc(F)c(-n3c(=O)cc(CC)[nH]c3=O)cc21
Temperature: 62 °C
Reaction time: 4 h

Procedure:
A suspension of 6.45 g of 6-[3-(ethoxycarbonylamino)-2-pentenoylamino]-3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine and 3.22 g of sodium methylate in 6.5 ml of methanol is stirred at 62° C. for 4 hours. The solution which thus results is left to stand at room temperature for 64 hours and subsequently poured into a solution of 15 ml of 2N hydrochloric acid in 400 ml of water. The resulting precipitate is filtered off under suction, washed with water and recrystallized from acetone/n-hexane. In this manner there is obtained 6-ethyl-3-[3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine-6-yl]-2,4(1H,3H)-pyrimidinedione, m.p. 240° C. (with decomposition).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(C)C.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[N:38]([CH3:42])[N:39]=[N:40][CH:41]=2)=O)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[N:38]([CH3:42])[N:39]=[N:40][CH:41]=2)=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:31][CH:30]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cn1nncc1C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(OCc2ccccc2)cc1)c1cnnn1C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95.2 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (22 mmol, 1 m in THF) was added ethyl trimethylsilylacetate (31.5 mmol) dropwise at −78° C. After 20 minutes at −78° C., a solution of 3.3 (14.7 mmol) in THF (50 mL) was added dropwise, and the reaction was maintained at −78° C. for 4 hours. The reaction was quenched with saturated NH4Cl (aq) and warmed to room temperature. The mixture was extracted with EtOAc (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated with silica gel under reduced pressure. The residue was chromatographed (silica gel, 1:1 EtOAc/hexane) to afford compound 3.4 (5.1 g, 14 mmol). MS ESI (pos.) m/e 364.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:26](OCCC(C)C)=O>C(Cl)(Cl)Cl>[F:13][C:9]1[CH:10]=[C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1)[NH:1][N:26]=[CH:12]2
Reactant: COC(=O)c1cc(F)cc(C)c1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(F)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.6 %

Procedure:
To a solution of methyl 2-amino-5-fluoro-3-methylbenzoate (1.0 g, 5.5 mmol) from Step C above in chloroform (15 mL) was added acetic anhydride (1.2 ml) while maintaining the temperature below 40° C. The reaction mixture was stirred at room temperature for 90 min then potassium acetate (157 mg, 1.6 mmol) and isoamyl nitrite (1.62 ml, 12 mmol) were added to it. The reaction mixture was heated to reflux for overnight. The reaction mixture was cooled to room temperature, extracted with dichlormethane, washed with water, saturated sodium bicarbonate and brine. The organic extract was dried (Na2SO4) and concentrated in vacuo to afford a red solid, which was purified by column chromatography (silica gel, 0-50% ethyl acetate/hexanes) to afford methyl 5-fluoro-1H-indazole-7-carboxylate (455 mg, 43%) as a yellow brown solid: 1H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.96 (dd, J=9.0, 3.0 Hz, 1H), 7.81 (dd, J=9.0, 3.0 Hz, 1H), 3.98 (s, 3H); MS (ESI+) m/z 195.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1>O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:17])[CH3:18])[C:8]2[O:12][C:11](=[O:13])[CH:10]([C:26]3[CH:25]=[C:24]([CH3:27])[CH:23]=[CH:22][C:21]=3[CH3:20])[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C)cc1
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Solvent: O
Product: Cc1ccc(C)c(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)c1
Yield: 80.1 %

Procedure:
To a solution of 262.3 g (1.00 mol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (201), Table 2, Example 1a) in 500 ml (4.05 mol) of p-xylene are added 40 g of Fulcat 22B and the mixture is refluxed for 1.5 hours on a water separator. The Fulcat 22B catalyst is then removed by filtration and excess p-xylene is removed by distillation on a vacuum rotaray evaporator. Crystallisation of the residue from 400 ml of methanol yields 280.6 g (80%) of 5,7-di-tert-butyl-3-(2,5-dimethylphenyl)-3H-benzofuran-2-one, m.p. 93°-97° C. (compound (101), Table 1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[C:3]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:19]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)c1c(C)nc2ccccc2c1N
Product: COC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1

Procedure:
Methyl 4-(4-bromobenzylamino)-2-methylquinoline-3-carboxylate was synthesized by the same method as described for 1-(4-(4-bromobenzylamino-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c), starting from methyl 4-amino-2-methylquinoline-3-carboxylate and 4-bromobenzyl bromide. Melting point: 89° C.; MS(ES+): 385/387.
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](Cl)=[O:16].[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[F:26]>C(Cl)(Cl)Cl>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)=[O:16])=[CH:21][C:20]=1[F:26]
Reactant: Nc1ccc(Br)c(F)c1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Br)c(F)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
2.9 ml of triethylamine and 1.87 g of picolinic acid chloride hydrochloride were added to a chloroform (30 ml) solution of 1 g of 4-bromo-3-fluoroaniline, and stirred at room temperature for 4 hours. The reaction liquid was diluted with chloroform, washed with aqueous saturated sodium bicarbonate solution and saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1) to obtain 1.44 g of the entitled compound as a pale yellow crystal.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15](=[O:18])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:13]2[OH:27])[CH2:11][C:10]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][Si:30]([CH3:37])([CH3:36])N1C=CN=C1>>[CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15](=[O:18])[CH:14]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH:13]2[O:27][Si:30]([CH3:37])([CH3:36])[CH3:29])[CH2:11][C:10]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)OC1C(=O)C=CC2(CC(=O)N2OCc2ccccc2)C1O
Product: CC(C)(C)[Si](C)(C)OC1C(=O)C=CC2(CC(=O)N2OCc2ccccc2)C1O[Si](C)(C)C
Yield: 65.3 %

Procedure:
A solution of rac-(4R,5S,6S)-1-benzyloxy-6-tert-butyldimethylsilyloxy-5-hydroxy-1-azaspiro[3.5]nona-8-ene-2,7-dione (3) (130 mg, 0.322 mmol) in 1-trimethylsilylimidazole (0.5 ml, 3.220 mmol) was stirred at room temperature for 16 h. The reaction was quenched with Na2PO4 0.1 M buffer (2 ml) and the mixture extracted with AcOEt (3×4 ml). The combined extracts were washed with saturated aqueous CuSO4 solution (1×8 ml) and brine (2×8 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-AcOEt, 5:1) to give rac-(4R,5S,6S)-1-benzyloxy-6-tert-butyldimethylsilyloxy-5-trimethylsilyloxy-1-azaspiro[3.5]nona-8-ene-2,7-dione (6) as a white solid (100 mg, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:13][CH:12]([CH:14]=[N:15]O)[CH2:11]3)[N:7]([CH3:17])[C:6]=2[CH:18]=1.P(Cl)(Cl)(Cl)=O>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:13][CH:12]([C:14]#[N:15])[CH2:11]3)[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: Cn1c(C2CC(C=NO)C2)nc2ccc(Br)cc21
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(C2CC(C#N)C2)nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
To a stirred solution of 1-(3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutyl)-N-hydroxymethanimine (100 mg) in CH3CN (10 ml) was added phosphorous oxychloride (1 ml), and the mixture was stirred at room temperature for 16 h. The mixture was then concentrated in vacuo and poured into saturated NaHCO3 solution. The mixture was extracted with DCM, and the organic layer was washed with brine, dried over Na2SO4 and purified by column chromatography (MeOH/DCM) to afford the title compound (50 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:28]1[CH2:27][CH:26]([CH2:25][N:23]2[CH:24]=[C:20]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:12])=[O:13])[CH:7]=3)[CH:21]=[N:22]2)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CNC3)c2)c2ccc(F)cc21
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a solution of tert-butyl 3-((4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate (Intermediate 37; 330 mg; 0.65 mmol) in DCM (10 mL) was added TFA (5 mL) dropwise. The reaction mixture was stirred for 0.5 hour and concentrated, neutralized with saturated aqueous Na2CO3 (50 mL), extracted with EtOAc (50 ml×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative TLC to afford 265 mg (100%) of the title compound as a brown solid.
Reaction SMILES: [O:1]=[C:2]([CH3:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[CH:6][CH:5]=1.[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:1]=[C:2]([CH3:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([N:34]2[CH2:35][CH2:36][N:31]([C:28]3[S:29][CH:30]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=3)[CH2:32][CH2:33]2)=[O:18])=[CH:8][CH:9]=1
Reactant: CC(=O)Cc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)Cc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)cc1

Procedure:
A solution of 2,2,2-trichloroethyl [4-(2-oxopropyl)phenyl]carbamate (200 mg, 0.616 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (151 mg, 0.616 mmol), diisopropylethylamine (0.107 ml, 0.616 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (47.0 mg, 18.2%) as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:5][S:6][CH:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([NH:28][CH2:29][C:30]1[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:33]2[CH:43]=[CH:44][CH:45]=[CH:46][C:32]=2[N:31]=1)[CH3:27].CCN(C(C)C)C(C)C>CC#N>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([N:28]([CH2:2][C:3]1[C:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:5][S:6][CH:7]=1)[CH2:29][C:30]1[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[C:33]2[CH:43]=[CH:44][CH:45]=[CH:46][C:32]=2[N:31]=1)[CH3:27]
Reactant: CC(NCc1nc2ccccc2n1COCC[Si](C)(C)C)c1ccccn1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cscc1CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccccn1)N(Cc1cscc1CN1C(=O)c2ccccc2C1=O)Cc1nc2ccccc2n1COCC[Si](C)(C)C

Procedure:
Using General Procedure A: Reaction of 2-(4-bromomethyl-thiophen-3-ylmethyl)-isoindole-1,3-dione, (1-pyridin-2-yl-ethyl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-ylmethyl]-amine, DIPEA and KI in CH3CN gave 2-[4-({(1-pyridin-2-yl-ethyl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-ylmethyl]-amino}-methyl)-thiophen-3-ylmethyl]-isoindole-1,3-dione.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][C@@H:15]1[CH2:19][CH2:18][C@@H:17]([C:20]#[N:21])[CH2:16]1)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][C@@H:15]1[CH2:19][CH2:18][C@@H:17]([C:20]#[N:21])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#C[C@@H]1CC[C@@H](N)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, ((1R,3R)-3-cyano-cyclopentyl)-carbamic acid tert-butyl ester (crude from Step 2) was dissolved in dichloromethane (2.5 ml). The solution was cooled to 0° C. and trifluoroacetic acid (1.1 ml, 14.3 mmol) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h then concentrated to give (1R,3R)-3-amino-cyclopentanecarbonitrile trifluoroacetate as a light brown oil which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[CH2:26][OH:27])[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.CC(C)=[O:39].OS(O)(=O)=O.O=[Cr](=O)=O.[Na].O>CC(C)=O.C(OCC)(=O)C>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:18][C:17]=1[C:26]([OH:39])=[O:27])[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1
Reactant: OCc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reaction time: 0.5 h

Procedure:
(2-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-methanol (225 mg) is dissolved in acetone (5 ml), and thereto is added 1.94M Jones reagent (290 μl) under ice-cooling, and the mixture is stirred for 30 minutes. To the reaction solution are added sodium hydrogenesulfite, water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-benzoic acid (181 mg). MS (m/z): 602/604 [M+H]+
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([O:6][C:7]1=[O:8])[CH2:4][CH2:3][CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[OH:8][CH2:7][C@@H:1]1[CH2:2][CH2:3][CH2:4][C@H:5]([OH:6])[CH2:9]1
Reactant: O=C1OC2CCCC1C2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: OC[C@@H]1CCC[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 g of 6-oxabicyclo[3.2.1]octan-7-one are dissolved in 300 ml of tetrahydrofuran, and 160 ml of a 1 M solution of lithium aluminum hydride in tetrahydrofuran are added with ice-cooling. After 30 minutes of stirring at room temperature, a saturated ammonium chloride solution is added and the pH is adjusted to neutral by addition of a 5% strength citric acid solution. The tetrahydrofuran is removed under reduced pressure and the residue is extracted three times with in each case 150 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 10.5 g of cis-3-hydroxymethylcyclohexanol as a colorless oil. C7H14O2 (130.13), Rf(ethyl acetate)=0.14.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[CH2:3].C(OC(Cl)=O)C.C(N(CC)CC)C.[CH:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[C:22]([OH:27])[CH:21]=1.Cl>C(#N)C>[OH:27][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])=[CH:20][CH:21]=1
Reactant: Nc1ccc(O)cc1
Reactant: C=C(C)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C(=O)Nc1ccc(O)cc1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Into a 1 liter flask 600 ml of acetonitrile, 95.2 g (1.1 mol) of methacrylic acid and 120.1 g (1.1 mol) of chloroformic acid ethyl ester were added. To this mixture 111.8 g (1.1 mol) of triethylamine was added over a period of 1 hour in cool bath. Stirring was continued for 1 hour at room temperature and 120.0 g (1 mol) of p-aminophenol was added. The mixture was heated for 5 hours at 5020 C. The mixture was poured into 5 liter of 1% HCl solution. The deposit was filtered, washed and dried to produce 99.35 g of N-(4-Hydroxyphenyl)methacrylamide.