Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:9]=1)O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: OC(c1cccc(-c2ccncc2)c1)c1ncc[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1cc(Cc2ncc[nH]2)cc(-c2ccncc2)c1

Procedure:
4-[3-(1H-Imidazol-2-ylmethyl)-phenyl]-pyridine was prepared from rac-(1H-imidazol-2-yl)-(3-pyridin-4-yl-phenyl)-methanol, triethylsilane and trifluoroacetic acid in analogy to Example 191e): white crystals; MS (ISP): 236.1 ([M+H]+, 100%).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[N:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)([CH3:3])[CH3:2].C([N:17]=[C:18]=[N:19]C1C=NC=CC=1)(C)(C)C>>[C:18]([N:19]=[C:5]([NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[NH:4][CH:1]([CH3:3])[CH3:2])#[N:17]
Reactant: CC(C)(C)N=C=Nc1cccnc1
Reactant: CC(C)N=C=Nc1cccnc1
Product: CC(C)NC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-isopropyl-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the N"-cyano-N-isopropyl-N'-3-pyridylguanidine was obtained with a melting point of 154.5°-155.0° C. Warning: Strongly exothermic reaction was observed in this case.
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:11]=[CH:12][C:13]([NH:15][NH2:16])=[O:14])([CH3:7])[CH3:6].C(=O)(O)[O-].[Na+].O>O1CCOCC1>[NH2:1][C:2]1[O:14][C:13](/[CH:12]=[CH:11]/[C:10]2[CH:9]=[C:8]([C:5]([CH3:4])([CH3:6])[CH3:7])[C:19]([OH:20])=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=2)=[N:15][N:16]=1
Reactant: N#CBr
Reactant: CC(C)(C)c1cc(C=CC(=O)NN)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(/C=C/c2nnc(N)o2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
Cyanogen bromide (0.7 g, 0.0067 mole) is added to a solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamic acid, hydrazide (1.9 g, 0.0067 mole) and sodium bicarbonate (0.56 g, 0.0067 mole) in dioxane (10 ml)/water (10 ml). The resulting mixture is stirred two hours at room temperature. The solution is concentrated to half volume in vacuo and the residue diluted with water. The resulting solid is filtered and recrystallized from ethyl acetate/hexane to provide 1.1 g (2.1 g theor., 52%) of (E)-4-[2-(5-amino-1,3,4-oxadiazole-2-yl)ethenyl]-2,6-bis(1,1-dimethylethyl)phenol after drying in vacuo at room temperature, mp 221° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[CH:16]=1.[CH2:17](I)[CH3:18].O>C(OCC)(=O)C>[CH2:17]([N:12]1[C:11](=[O:13])[CH2:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]2[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]1=2)[CH3:18]
Reactant: CCI
Reactant: COc1ccc2c(c1)N(C)C(=O)CC(=O)N2
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1C(=O)CC(=O)N(C)c2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (220 mg) was added to the suspension at the same temperature, and stirred at 0° C. for 1 hour. Ethyl iodide (187 mg) was added to the mixture and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1→1:1). The purified product was concentrated to dryness under reduced pressure to give the title compound(190.2 mg) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:13])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(Br)c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
In 50 mL of toluene, 3.6 g (15 mmol) of 4-bromo-3-(trifluoromethyl)aniline was dissolved, and 2.06 g (18 mmol) of 2,5-hexanedione and 54 mg (0.28 mmol) of p-toluenesulfonic acid-hydrate were added thereto and the mixture solution was refluxed with stirring for two hours. The reaction solution was partitioned between a saturated sodium bicarbonate solution and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The obtained residue was purified by a silica gel column (n-hexane:ethyl acetate=9:1) to obtain 4.66 g (97%) of a target product as a pale yellow oil.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([OH:15])[C:9](C(O)=O)=[C:8]2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.O>[CH:1]1([N:7]2[C:8]([CH3:19])=[CH:9][C:10]([OH:15])=[C:11]([CH3:14])[C:12]2=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(O)c(C(=O)O)c(C)n(C2CCCCC2)c1=O
Agent: Cl
Solvent: O
Product: Cc1c(O)cc(C)n(C2CCCCC2)c1=O
Temperature: 25 °C

Procedure:
A solution of 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.15 g, 0.57 mmol) in concentrated HCl (5 mL) was heated at reflux for 4 h. The reaction mixture was cooled to room temperature, diluted with water and washed with EtOAc. The organic solution was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 1-cyclohexyl-4-hydroxy-3,6-dimethyl-1H-pyridin-2-one as a white solid (0.2 g, 77w): 1H NMR (300 MHz, DMSO-d6) δ 9.81 (s, 1H), 5.73 (s, 1H), 3.95-3.75 (m, 1H), 2.80-2.55 (m, 2H), 2.25 (s, 3H), 1.85-1.40 (m, 5H), 1.72 (s, 3H), 1.38-1.05 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15]C.Cl[C:33]1C=C(Cl)C=CC=1C1N=C(C)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C.IC(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:30])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH:28]([CH3:29])[CH3:33])=[N:13][C:14]=1[CH3:15]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CC(C)I
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1N[C@@H]1c2ccccc2C[C@@H]1OC(C)C

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and 2-iodopropane, and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.50-7.46, 7.34-7.26, 5.76, 5.43, 4.47, 3.72, 3.14-3.11, 2.41, 2.26, 1.20, 1.12; HRMS (FAB) calcd for C24H25Cl2N3O+H 442.1453, found 442.1441. Anal. Calcd for C24H25Cl2N3O: C, 65.16; H, 5.70; N, 9.50. Found: C, 65.33; H, 5.83; N, 9.34.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][S:8][CH2:9][CH:10]([C:17](=[O:24])[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2][CH2:3][CH3:4].[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH2:1]([N:5]([C:32]([NH:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:33])[CH2:6][CH2:7][S:8][CH2:9][CH:10]([C:17](=[O:24])[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCSCC(CC(=O)OCC)C(=O)c1cccnc1
Reactant: O=C=NC1CCCCC1
Product: CCCCN(CCSCC(CC(=O)OCC)C(=O)c1cccnc1)C(=O)NC1CCCCC1
Yield: 48 %

Procedure:
The title compound was prepared from ethyl 3 {[2-(butylamino)ethylthio] methyl}-4-oxo-4-(3-pyridyl)butanoate and cyclohexylisocyanate as described in the above Example 35 in 48% yield; ESMS (M+1+) 478.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH:8][C:9]([NH:11][C:12]([S:14][CH3:15])=[NH:13])=[O:10])=[CH:4][CH:3]=1.[CH:16](OCC)(OCC)OCC>>[Br:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH:16]=[N:13][C:12]([S:14][CH3:15])=[N:11][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: CSC(=N)NC(=O)NCc1ccc(Br)s1
Reactant: CCOC(OCC)OCC
Product: CSc1ncn(Cc2ccc(Br)s2)c(=O)n1
Yield: 76 %

Procedure:
Methyl N-({[(5-bromothiophen-2-yl)methyl]amino}carbonyl)-carbamimidothioate (700 mg, 2.27 mmol) synthesized in Reference Synthesis Example 295 and triethyl orthoformate were used to obtain the title compound (547 mg, yield 76%) by synthesis in a similar manner to Reference Synthesis Example 292.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C:12](=[O:13])[CH2:11][C@@H:10]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:25]([O-])=O.CO.[H][H]>C1COCC1.[Ni]>[NH2:25][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[C:12](=[O:13])[CH2:11][C@@H:10]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:9]2)=[N:7][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1nc(N2C[C@H](NC(=O)OCc3ccccc3)CC2=O)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(N2C[C@H](NC(=O)OCc3ccccc3)CC2=O)ccc1N

Procedure:
250 mg (0.68 mmol) benzyl (R)-[1-(6-methyl-5-nitro-pyridin-2-yl)-5-oxo-pyrrolidin-3-yl]-carbamate are dissolved in 4 ml THF and 5 mL methanol and combined with 50 mg Raney nickel. The mixture is hydrogenated in a Parr apparatus at ambient temperature at 1 bar hydrogen pressure for four hours. Then the catalyst is filtered off and the filtrate is evaporated down i. vac..
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:6]=1[C:7]([CH:9]1[CH2:11][CH:10]1[C:12]#[N:13])=[O:8]>C(OCC)C>[F:4][C:5]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:6]=1[C:7]([CH:9]1[CH2:11][CH:10]1[C:12]#[N:13])([OH:8])[CH3:1]
Reactant: C[Mg]Br
Reactant: N#CC1CC1C(=O)c1ccc(F)cc1F
Solvent: CCOCC
Product: CC(O)(c1ccc(F)cc1F)C1CC1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.2 ml (15.6 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were added to 2.15 g (10.4 mmol) of the compound from Example 123A in 50 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. The reaction mixture was added to a saturated, ice-cold aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 2.16 g (93% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:7]=2)[CH:3]=1.C[Si]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(C)C.CC(C)([O-])C.[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:7]=2)[CH:3]=1)[CH3:24]
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: CC(C)Cn1cc2cc(Br)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)Cc1ccc2nn(CC(C)C)cc2c1
Temperature: 90 °C
Yield: 126.9 %

Procedure:
5-Bromo-2-(2-methylpropyl)indazole (1.41 g, 0.0056 mol) and palladium acetate (0.063 g, 0.00028 mol) were stirred in toluene (10 ml) under an atmosphere of nitrogen. Ethyl trimethylsilylacetate (2.35 ml, 0.0115 mol), potassium tert-butoxide (0.66 g, 0.059 mol) and a 10% w/v solution of tri-tert-butylphosphine in toluene (0.97 ml, 0.00048 mol) were added sequentially and then the mixture was heated to 90° C. for 105 minutes. The mixture was cooled to room temperature, diluted with diethyl ether and filtered through diatomaceous earth and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2:1 diethyl ether:hexane to give ethyl[2-(2-methylpropyl)indazol-5-yl]acetate (1.85 g), as a yellow oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]2[N:6]([CH:13]=[C:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH:15]=2)[N:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])[CH3:2].[C:21]([O-])([O-])=O.[K+].[K+].CI.CCOC(C)=O>CN1C(=O)CCC1>[CH2:1]([S:3][C:4]1[C:5]2[N:6]([CH:13]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH3:21])[N:20]=3)[CH:15]=2)[N:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])[CH3:2]
Reactant: CCSc1c(C(N)=O)cnn2cc(-c3nnn[nH]3)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN1CCCC1=O
Product: CCSc1c(C(N)=O)cnn2cc(-c3nnn(C)n3)cc12
Temperature: 23 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a solution of 4-(ethylthio)-6-(1H-tetrazol-5-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (164 mg, 0.567 mmol) in NMP (2.0 mL) were added K2CO3 (196 mg, 1.417 mmol) and MeI (0.043 mL, 0.680 mmol). The solution was stirred at 23° C. for 1 hr. To the reaction mixture was added 30 mL of EtOAc which was washed with 10% LiCl solution (2×10 mL), 10 mL of brine and dried over Na2SO4. Filtration and concentration yielded a crude product which was purified on silica gel column with EtOAc to afford the desired product (64 mg, 35% yield). MS (ES+) m/z: 304.08 (M+H); HPLC retention time: 2.180 min (analytical HPLC Method F).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:11]([O:10][C:9](=[O:15])[NH:8][CH:4]1[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[CH2:3]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC1CCCC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of tert-butyl (3-hydroxycyclohexyl)carbamate (4.40 g, 20.46 mmol) in DCM (250 mL) was added Dess-Martin periodinane (13.0 g, 30.70 mmol) in portions under cooling in an ice bath. The mixture was stirred at room temperature for 2 h. The reaction was diluted with DCM and washed with aqueous sodium carbonate. The separated organic layer was dried over anhydrous sodium sulfate and concentrated. The crude compound was purified by silica gel column chromatography (40% ethyl acetate in petroleum ether) to afford the title compound (4.0 g, 18.78 mmol, 91% yield). MS (ESI) m/z 214.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.I[CH2:18][C:19]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:12]([O:11][C:10]([NH:9][CH2:8][C:2]1([OH:1])[CH2:7][CH2:6][N:5]([CH2:18][C:19]2([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:4][CH2:3]1)=[O:16])([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCC1(O)CCNCC1
Reactant: COC(=O)C1(CI)CCCCC1
Product: COC(=O)C1(CN2CCC(O)(CNC(=O)OC(C)(C)C)CC2)CCCCC1

Procedure:
The title compound was prepared by a method similar to that shown in the Step 2 of Example 3 by using tert-butyl [(4-hydroxypiperidin-4-yl)methyl]carbamate (Chem. Pharm. Bull., 2002, 50 (9) 1187-1194) and methyl 1-(iodomethyl)cyclohexanecarboxylate (Step 1 of Example 6).
Reaction SMILES: C(C1C=CC(COC2C=CC(CO)=CC=2)=CC=1)(C)(C)C.C[O:22][C:23](=[O:53])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:44][CH:43]=3)=[CH:36][CH:35]=2)=[CH:28][C:27]=1[CH3:52]>>[C:48]([C:45]1[CH:46]=[CH:47][C:42]([CH2:41][O:40][C:37]2[CH:38]=[CH:39][C:34]([CH2:33][S:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][CH2:24][C:23]([OH:53])=[O:22])=[C:27]([CH3:52])[CH:28]=3)=[CH:35][CH:36]=2)=[CH:43][CH:44]=1)([CH3:51])([CH3:49])[CH3:50]
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(C(C)(C)C)cc3)cc2)cc1C
Agent: CC(C)(C)c1ccc(COc2ccc(CO)cc2)cc1
Product: Cc1cc(SCc2ccc(OCc3ccc(C(C)(C)C)cc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 3B using 34A. MS m/z 253 (M-Cl). Step 3. Preparation of {4-[4-(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (Compound 34C)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:37]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6]>C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[C:36]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)[CH:37]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[SH:15])=[O:6]
Reactant: O=C(NCc1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc(F)cc(N2CCOCC2)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccccc1S)c1cc(F)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.8 %

Procedure:
3-Fluoro-5-(morpholin-4-yl)-N-[2-(tritylsulfanyl)benzyl]benzamide (517 mg, 0.88 mmol) was treated with a solution of triethylsilane/TFA/DCM (10 mL, 1/9/10). The reaction mixture was stirred at RT for 20 min and concentrated under reduced pressure. Purification of the residue by flash column chromatography (DCM:MeOH 98:2) afforded the title compound (219 mg, 72%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.36-7.31 (2H, m), 7.21-7.15 (3H, m), 6.85 (1H, ddd, J 8.5, 2.2, 1.4), 6.69 (1H, dt, J 11.6, 2.3), 6.57 (1H, br t, J 5.7), 5.39 (1H, br s), 4.66 (2H, d, J 5.7), 3.84 (4H, t, J 4.9), 3.20 (4H, t, J 4.9).
Reaction SMILES: C[C:2](C)(C)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[CH3:12])=[O:4].[OH-].[Na+]>Cl>[CH3:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH3:2]
Reactant: Cc1cnccc1NC(=O)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccncc1C
Temperature: 90 °C
Yield: 88.5 %

Procedure:
To 17.5 g of 2,2-dimethyl-N-(3-methylpyridin-4-yl)propionamide, 70 mL of 5N hydrochloric acid aqueous solution was added and stirred at 90° C. for a day. Under ice cooling, the solution was neutralized with 5N sodium hydroxide aqueous solution, and the solvent was evaporated. The crystals were washed with a mixed solution of dichloromethane:methanol=10:1, and the solvent of filtrate was evaporated. To a solution of the resultant crude product in 100 mL of pyridine, 17.2 mL of acetic anhydride was added at room temperature and stirred at this temperature for 6 hours. The solvent was evaporated, and the residue was purified and separated by NH silica gel column chromatography (ethyl acetate:n-hexane=1:1), to afford 12.1 g of the title compound as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1.C[Si](Cl)(C)C>C(O)CCC>[C:11]([C:10]1[C:5]2[C:4]([NH:23][CH:24]3[CH2:25][CH2:26]3)=[N:3][C:2]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:35])=[O:36])=[CH:30][CH:29]=3)=[N:7][C:6]=2[NH:8][CH:9]=1)#[N:12]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: N#Cc1c[nH]c2nc(Nc3ccc(S(N)(=O)=O)cc3)nc(NC3CC3)c12
Temperature: 135 °C
Reaction time: 20 h
Yield: 31.5 %

Procedure:
A mixture of 2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (150 mg, 0.387 mmol), 4-aminobenzenesulfonamide (103 mg, 0.599 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (4 mL) was stirred at 135° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (45 mg). MS 370.3 (M+H); UV 202.8, 254.6, 305.0 nm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[OH-].[Na+].Cl>C(O)C>[CH2:18]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[CH:3][C:2]=1[F:1])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(-c2ccc(O)c(F)c2)cc1
Reactant: CCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1F

Procedure:
The resulting 3'-fluoro-4'-hydroxybiphenyl-4-carboxylic acid was heated under reflux for 10 hours in hydrous ethanol together with 1.2 moles, per mole of the carboxylic acid, of decyl bromide and 1.95 moles, per mole of the carboxylic acid, of sodium hydroxide. Then, 10% hydrochloric acid was added to adjust the pH of the solution to 2 to 3. The solution was then heated under reflux for 1 hour. After cooling, the organic materials were extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform layer was concentrated to obtain crude crystals. Recrystallization from ethanol gave the desired 4'-decyloxy-3'-fluorobiphenyl-4-carboxylic acid. The yield in this alkoxylation reaction slightly varies depending upon the type of the alkyl bromide used, but it is generally 60 to 80%.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:23]=[C:17]1[CH:16]([N:15]2[C:5](=[O:7])[C:4]3[C:3](=[C:2]([CH3:1])[CH:12]=[CH:11][C:10]=3[CH3:13])[C:8]2=[O:9])[CH2:21][CH2:20][C:19](=[O:22])[NH:18]1
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1ccc(C)c2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(C)c2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
2-(2,6-Dioxopiperid-3-yl)-4,7-dimethylisoindoline-1,3-dione was prepared by the procedure of Example 1 from 3,6-dimethylphthalic anhydride (220 mg, 1.25 mmol), 3-aminopiperidine-2,6-dione hydrogen chloride (204 mg, 1.24 mmol) and sodium acetate (110 mg, 1.34 mmol) in acetic acid (10 mL). The product is a white solid (200 mg, 56% yield): mp 263.0-265.0° C.; 1H NMR (DMSO-d6) δ2.01-2.07 (m, 1H, CHH), 2.50-2.89 (m, 9H, CH3, CHH, CH2), 5.10 (dd, J=5.1, 12.4 Hz, 1H, NCH), 7.52 (s, 2H, Ar), 11.12 (br s, 1H, NH); 13C NMR (DMSO-d6) δ16.82, 22.02, 30.97, 48.59, 128.01, 135.04, 136.58, 167.68, 169.98, 172.83.
Reaction SMILES: C(O[C:6](=[O:32])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]=[CH:15][C:16]2[C:17](=[O:31])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=[CH:20][C:21]=2[C:22]=1[OH:23])=[O:12])(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH:47]([N:50]=C=O)([CH3:49])[CH3:48].Cl>C(Cl)Cl.CCOC(C)=O>[CH:47]([NH:50][C:6](=[O:32])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]=[CH:15][C:16]2[C:17](=[O:31])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=[CH:20][C:21]=2[C:22]=1[OH:23])=[O:12])([CH3:49])[CH3:48]
Reactant: CC(C)N=C=O
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)NCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
{2-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester (38 mg, 0.087 mmol) was dissolved in CH2Cl2 (1.5 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed in vacuo. To the residue were added CH2Cl2 (2 mL), triethylamine (0.030 mL, 0.19 mmol), and isopropyl isocyanate (0.010 mL, 0.10 mmol), and the resulting mixture was stirred at r.t. for 16 h. 1 M HCl and EtOAc were added, and the aqueous layer was extracted with additional EtOAc. The organic layers were combined and concentrated to dryness. The residue was washed with CH2Cl2, isolated by filtration, and dried to give 17 mg of the title compound as a white solid. MS: (+) m/z 424.35 (M+1).