Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.Br[CH2:17][CH:18]1[CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH2:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)[C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: BrCC1CCC1
Reactant: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1CC1CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
i)—To a solution of 1-(4-bromo-benzyl)imidazolidine-2,4-dione (Example 4, step iii) (5.91 g, 21.96 mmol) in DMF (50 ml) were added (bromomethyl)cyclobutane (6.55 g, 43.9 mmol) and potassium carbonate (9.11 g, 65.9 mmol) under a nitrogen atmosphere. After stirring for 20 h at room temperature, the reaction mixture was concentrated under reduced pressure. The product was extracted in ethyl acetate and the combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give 1-(4-bromo-benzyl)-3-cyclobutylmethyl-imidazolidine-2,4-dione (5.30 g).
Reaction SMILES: [NH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:5][N:4]=1)[NH2:2].Cl.CN(C)[CH:22]=[C:23]([N:29]1[CH:34]=[CH:33][C:32](=[O:35])[CH:31]=[CH:30]1)[C:24](OCC)=[O:25].C(O)(=O)C>CC(O)C.CS(C)=O>[OH:25][C:24]1[N:1]([C:3]2[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:8])=[CH:5][N:4]=2)[N:2]=[CH:22][C:23]=1[N:29]1[CH:30]=[CH:31][C:32](=[O:35])[CH:33]=[CH:34]1
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccc(=O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CC(C)O
Product: O=C(NCC1CCOCC1)c1ccc(-n2ncc(-n3ccc(=O)cc3)c2O)nc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
Combined 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide, 1.0 HCl (30 mg, 0.105 mmol), ethyl 3-(dimethylamino)-2-(4-oxopyridin-1(4H)-yl)acrylate (37.1 mg, 0.157 mmol) and acetic acid (0.018 mL, 0.314 mmol) in 2-propanol (0.8 mL) and stirred at 20° C. for 1 hour and then at 50° C. for 16 hours and then 80° C. for 24 h. The reaction mixture was then diluted with 200 uL DMSO and purified by prep HPLC (ACN/water with formic acid) to give the title compound (11 mg, 26.6% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.32 (m, 2H) 1.62 (d, J=13.4 Hz, 2H) 1.73-1.90 (m, 1H) 3.20 (t, J=6.2 Hz, 2H) 3.25 (s, 2H) 3.86 (dd, J=11.4, 2.8 Hz, 2H) 6.56 (br. s., 2H) 8.19 (br. s., 2H) 8.40 (t, J=7.7 Hz, 3H) 8.71 (t, J=5.3 Hz, 1H) 8.91 (s, 1H). MS m/z 396 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[CH:13](I)(I)[I:14]>O1CCCC1.C(Cl)Cl>[Br:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[CH:13][I:14])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: IC(I)I
Reactant: O=C1CCNc2nc(Br)ccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: Brc1ccc2c(n1)NCCC2=CI
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
To a suspension of 7-bromo-2,3-dihydro-1H-[1,8]naphthyridin-4-one (1.5 g) in anhydrous tetrahydrofuran (195 mL) was added a solution of CrCl2 (6.79 g, 8.35 eq) and CHI3 (5.55 g, 2.13 eq) in anhydrous tetrahydrofuran (66 mL). The reaction was stirred at room temperature for 16 hours, diluted with methylene chloride (300 mL), and then washed with saturated NaHCO3 (300 mL). The aqueous phase was extracted twice with methylene chloride (100 mL) and the combined organic layers were washed with brine and then dried over Na2SO4. The solution was filtered and concentrated under reduced pressure. Silica gel chromatography using a gradient of 0-30% ethyl acetate/hexane as the eluting solvent gave the title compound as a yellow solid (27% yield). Alkene geometry was determined by nOe. LCMS: m/z=352 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.69 (t, J=6.0 Hz, 2H), 3.43-3.51 (m, 2H), 5.25 (bs, 1H), 6.23 (s, 1H), 6.74 (d, J=8.0 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][C:17](=[O:20])[CH2:18][CH3:19])[CH3:13].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][CH:32]=[N:31]2)=[CH:26][CH:25]=1>O1CCCC1.O>[CH2:12]([O:14][C:15](=[O:21])[CH:16]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH:34]=[CH:33][CH:32]=[N:31]2)=[CH:28][CH:29]=1)[C:17](=[O:20])[CH2:18][CH3:19])[CH3:13]
Reactant: CCOC(=O)CC(=O)CC
Reactant: BrCc1ccc(-n2cccn2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)CC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of potassium tert-butoxide (0.57 g) in tetrahydrofuran (40 mL) at 0° C. was treated with a mixture of tert-butanol (2.0 mL) and 3-oxopentanoic acid ethyl ester (0.73 mL), and the resulting mixture was stirred at 0° C. for 45 minutes. The mixture was then treated with a solution of 1-(4-bromomethylphenyl)-1H-pyrazole (1.0 g) in tetrahydrofuran (10 mL), and stirred at 0° C. for 2 hours. The mixture was diluted with water, concentrated to low bulk under reduced pressure, and the residue extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate gave title compound as a pale yellow oil (0.63 g).
Reaction SMILES: C([Mg]Br)C.[Br:5][C:6]1[CH:21]=[CH:20][C:9]2[C:10]3[N:11]([C:15](I)=[C:16]([I:18])[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1.[NH4+].[Cl-]>C(OCC)C.C1COCC1>[Br:5][C:6]1[CH:21]=[CH:20][C:9]2[C:10]3[N:11]([CH:15]=[C:16]([I:18])[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1
Reactant: Brc1ccc2c(c1)OCCn1c-2nc(I)c1I
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A 3.0 M solution of ethylmagnesium bromide in ethyl ether (1.1 mL) was added dropwise to a suspension of 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.1 g, 2.2 mmol) in THF at −15° C. The mixture was stirred and followed by LC/MS. After 1 hour, there is no starting material left and the reaction was poured into sat. NH4Cl and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The crude residue was purified by flash column chromatography to provide 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine as white solid (0.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1F)[C:32]#[N:33]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:8]=[C:9]([O:11][C:36]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=2[Cl:28])[CH:10]=1)[CH3:2]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)c1cc(O)cc(Oc2ccc(C#N)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(C#N)cc2)cc(Oc2ccc(C#N)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To 1.2 g (4.23 mmol) of 3-(4-cyano-phenoxy)-5-hydroxy-benzoic acid ethyl ester, dissolved in 10 ml of DMF, potassium carbonate 1.17 g (8.46 mmol) was added and stirred for 30 min at RT. 1.31 g (8.46 mmol) of 3-chloro-4-fluoro-benzonitrile, dissolved in 5 ml of DMF, was added dropwise to the reaction mixture during 15 min and final contents were stirred at 80° C. overnight. The reaction mixture was concentrated, residue was dissolved in 200 ml of ethyl acetate and partitioned with water. The organic layer was washed with brine followed by of water. Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was subjected to column chromatography, using silica-gel and eluted with hexane:ethyl acetate (8:2) to afford 1.4 g of pure product. 1H NMR (DMSO-d6): δ 1.3 (3H, t), 4.3 (2H, q), 7.2-7.36 (4H, m), 7.44 (2H, dd), 7.88 (3H, m), 8.26 (1H, d).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]([CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][C:27]=2[CH2:28]C)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:8].[NH2:36][C:37]([NH2:39])=[O:38].C(Cl)(Cl)Cl>O>[CH3:5][O:6][C:7]([CH:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:26][C:27]=2[CH3:28])=[CH:18][CH:19]=1)[C:10]([NH:36][C:37]([NH2:39])=[O:38])=[O:12])=[O:8]
Reactant: CCc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C(=O)O)C(=O)OC)cc1
Reactant: NC(N)=O
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)NC(N)=O
Temperature: 60 °C
Yield: 82.2 %

Procedure:
Thionyl chloride (4.0 ml) was added to 2-methoxycarbonyl-3-[4-(2-(5-ethyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (4.10 g, 10.0 mmol) obtained in Example 1 and the mixture was stirred with heating at 60° C. for 1 hr. Excess thionyl chloride was evaporated under reduced pressure and urea (900 mg, 15.0 mmol) was added to the residue obtained, which was followed by stirring with heating at 100° C. for 45 min. Chloroform (100 ml) and water (50 ml) were added for partition. The organic layer was washed with saturated brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=1:1) to give the title compound (3.71 g, yield 82%) as a white solid.
Reaction SMILES: [OH2:1].CN(N=[C:6]([CH3:20])[CH2:7][CH2:8][C:9]1[S:13][C:12]([NH:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[N:11][CH:10]=1)C>O1CCCC1>[O:1]=[C:6]([CH3:20])[CH2:7][CH2:8][C:9]1[S:13][C:12]([NH:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[N:11][CH:10]=1
Reactant: CCCC(=O)Nc1ncc(CCC(C)=NN(C)C)s1
Reactant: O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ncc(CCC(C)=O)s1
Yield: 95 %

Procedure:
To a stirred solution of 200 mg (1 mmol) of cupric acetate in 10 ml of water 141 mg (0.5 mmol) of N-[5-(3-dimethylaminoimino-butyl)-1,3-thiazol-2-yl]-butanamide in 10 ml of tetrahydrofuran were added. After 2 hours the solvent was removed under reduced pressure, a mixture of aqueous ammonium chloride and ammonium hydroxide was added and the product extracted with methylene chloride to give after drying and concentration 114 mg (95% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[C:15]([CH3:27])[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].[Br:36][CH2:37][CH2:38][CH2:39]Br.O>CN(C)C=O>[Br:36][CH2:37][CH2:38][CH2:39][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[C:15]([CH3:27])[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: CCCNC(=O)Nc1cc(C)c(Oc2ccnc3cc(O)c(OC)cc23)cc1C
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1cc(C)c(Oc2ccnc3cc(OCCCBr)c(OC)cc23)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A starting compound (N-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 1,3-dibromopropane(0.10 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)-N′-propylurea). The intermediate, potassium carbonate (138 mg), and 1-methylpiperazine (0.055 ml) were dissolved in N,N-dimethylformamide (1 ml), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 33 mg (yield 31%) of the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH:10]([CH3:20])[CH2:11][N:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]1=[O:19]>O1CCCC1>[Br:18][C:15]1[CH:16]=[CH:17][N:12]([CH2:11][CH:10]([CH3:20])[CH2:9][OH:8])[C:13](=[O:19])[CH:14]=1
Reactant: COC(=O)C(C)Cn1ccc(Br)cc1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)Cn1ccc(Br)cc1=O

Procedure:
LiAlH4 (1 M solution in tetrahydrofuran, 1.16 mL) was added to a solution of 3-(4-bromo-2-oxo-2H-pyridin-1-yl)-2-methyl-propionic acid methyl ester (0.53 g) in tetrahydrofuran (6 mL) chilled in an ice bath. After stirring the solution with cooling for 2 h, another portion of LiAlH4 (1 M in tetrahydrofuran, 0.29 mL) was added. After stirring with cooling for 1 more hour, the reaction was quenched by the addition of water. The resulting mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated to give the title compound. Yield: 0.37 g (78% of theory); Mass spectrum (ESI+): m/z=246/248 (Br) [M+H]+.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6]([O:10][C:11]1[C@@:16]([CH2:21][CH:22]([CH2:24][OH:25])[OH:23])([C@H:17]([CH2:19][OH:20])[OH:18])[O:15][C:13](=[O:14])[C:12]=1[OH:26])[CH2:7][CH2:8][CH3:9].[CH2:27](Br)[CH:28]=[CH2:29]>O>[CH2:6]([O:10][C:11]1[C@@:16]([CH2:21][CH:22]([CH2:24][OH:25])[OH:23])([C@H:17]([CH2:19][OH:20])[OH:18])[O:15][C:13](=[O:14])[C:12]=1[O:26][CH2:29][CH:28]=[CH2:27])[CH2:7][CH2:8][CH3:9]
Reactant: C=CCBr
Reactant: CCCCOC1=C(O)C(=O)O[C@]1(CC(O)CO)[C@@H](O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CCOC1=C(OCCCC)[C@@](CC(O)CO)([C@@H](O)CO)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Under an argon atmosphere, water and sodium hydrogen carbonate (0.98 g) were added to 3-O-butylglyceryl ascorbic acid (3.56 g) obtained in Example 6, and the mixture was stirred at room temperature for 30 minutes. To the mixture, allyl bromide (1.68 g) was added, and the resultant mixture was heated up to 60° C. and stirred for 5 hours, followed by extraction with ethyl acetate. Then, the extracted liquid was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 3.53 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:30/3/0.3), and concentration was performed under reduced pressure to obtain to obtain 3-O-butylglyceryl-2-O-allyl ascorbic acid (3.00 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.C([Li])CCC.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:36](=[O:41])N(OC)C)=[O:29])([CH3:26])([CH3:25])[CH3:24].[NH4+].[Cl-]>COCCOC>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:36]([C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:17])([CH3:16])[CH3:1])[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:41])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[Si](C)(C)CCOCn1ccc2ccccc21
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2ccccc2n1COCC[Si](C)(C)C
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
A stirring, ice-cooled solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole, D66 (742 mg, 3 mmol) in DME (5 ml) was treated drop-wise with n-butyl lithium (2.2 ml, 1.6M in hexanes, 3.5 mmol). The resulting green solution was stirred at 0-5° C. for 15 min. then was treated with (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine, D1 (952 mg, 3.5 mmol) in DME (2.5 ml). After stirring at this temperature for a further 45 min. saturated aqueous NH4Cl was added (10 ml) and the product was extracted with diethyl ether. The organics were combined, the solvent removed in vacuo and the residue chromatographed (silica gel, 10% diethyl ether-pentane) to afford the title compound as a colourless oil (510 mg, 37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([OH:23])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26][O:27][CH2:28][CH2:29]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([O:23][CH2:29][CH2:28][O:27][CH3:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1nc2c(cc1O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCOc1cc2c(nc1C)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1 intermediate d), from (4R,9aR)-7-hydroxy-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 7, intermediate), sodium hydride and 2-bromoethyl methyl ether.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.Cl.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21]([NH2:23])=[NH:22]>>[CH3:19][C:20]([C:21]1[N:22]=[CH:4][C:5]2[CH2:6][C:7](=[O:17])[NH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:23]=1)([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=N)N
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Agent: Cl
Product: CC(C)(C)c1ncc2c(n1)-c1ccccc1NC(=O)C2
Yield: 90 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and 2,2-dimethylpropionamidine hydrochloride. Yield: 90%.
Reaction SMILES: [C:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[N:13]([C:21](=[O:27])[C:22]3[S:26][CH:25]=[CH:24][CH:23]=3)[CH2:12][CH:11]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35](C(OCC)=O)=[CH:34][CH:33]=3)=[O:30])[C:10]2=[O:43])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[OH2:44].[OH-].[Li+].[O:47]1[CH2:51]CCC1>>[C:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[N:13]([C:21](=[O:27])[C:22]3[S:26][CH:25]=[CH:24][CH:23]=3)[CH2:12][CH:11]([NH:28][C:29](=[O:30])[NH:31][C:32]3[CH:37]=[C:36]([CH:35]=[CH:34][CH:33]=3)[C:51]([OH:47])=[O:44])[C:10]2=[O:43])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(NC(=O)NC2CN(C(=O)c3cccs3)c3ccc(C)cc3N(CC(=O)c3cccs3)C2=O)cc1
Reactant: O
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc2c(c1)N(CC(=O)c1cccs1)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)c1cccs1
Temperature: 45 °C
Reaction time: 6 h

Procedure:
1-[1-(2-Thenoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-ethoxycarbonylphenyl)urea (1.3 g) was suspended in tetrahydrofuran (30 ml), aqueous lithium hydroxide monohydrate (0.44 g) solution (15 ml) was added, the mixture was stirred at 40-50° C. for 6 hours. The solvent was concentrated under reduced pressure, 1N hydrochloric acid and chloroform were added to the residue, crystals so precipitated were collected by filtration, washed with a mixed solvent(chloroform:methanol=10:1), and filtrated by means of suction, to thereby obtain 102 mg of the title compound.
Reaction SMILES: C(OCC)C.[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[C:14]([O:16][CH2:17][CH3:18])(=[O:15])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:13]
Reactant: CCOC(=O)C(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(O)c1ccccc1

Procedure:
According to JP-A-11-193271, ethyl benzoylformate and cyclohexylmagnesium bromide are condensed to give ethyl 2-cyclohexyl-2-hydroxy-2-phenylacetate, which is hydrolyzed to give 2-cyclohexyl-2-hydroxy-2-phenylacetic acid. In this condensation reaction, diethyl ether having a boiling point of 35° C. is used in an amount of about 12-fold volume relative to ethyl benzoylformate, manipulation of dangerous reaction using the boiling point of diethyl ether is required and the yield is as low as 53.3%. In an attempt to improve this method into an industrially safe one, the present inventors used tetrahydrofuran instead of diethyl ether as a solvent and reproduced the reaction. As a result, there occurred reduction due to Grignard reagent to produce ethyl mandelate as a by-product, as well as addition of the Grignard reagent to ester bond. The proportion of the starting material that became a by-product was 42% and the yield of the objective product was as low as 58%. After hydrolysis of the obtained crude ethyl 2-cyclohexyl-2-hydroxy-2-phenylacetate, it was subjected to recrystallization and the like to increase the purity but the yield from ethyl benzoylformate of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid did not exceed 43%.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=2)[C:3]1=[O:19].[C:20]12([CH2:30][C:31](O)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[C:20]12([CH2:30][C:31]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=4)[C:3]3=[O:19])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: Nn1nc(-c2ccccc2)c2cc(F)ccc2c1=O
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2ccccc2)c2cc(F)ccc2c1=O

Procedure:
The product from Example 35E and 2-(adamant-1-yl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.49-1.76 (m, 12H) 1.86-1.99 (m, 3H) 2.06 (s, 2H) 7.39 (dd, J=9.46, 2.44 Hz, 1H) 7.52-7.67 (m, 5H) 7.71-7.94 (m, 1H) 8.49 (dd, J=8.85, 5.49 Hz, 1H) 11.29 (s, 1H); MS (ESI) m/z 432 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1)(=[O:25])=[O:24]
Reactant: Nc1ccc(CCn2ccnc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(CCn2ccnc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a -10° C. solution of 8 g (0.064 mole) of 1-[2-(4-aminophenyl)ethyl]-1H-imidazole and 10 mL triethylamine in 200 mL of methylene chloride add 5 mL of methanesulfonyl chloride dropwise. Stir the resulting solution at -10° C. for about 30 minutes then warm to ambient temperature for about 30 minutes. Wash the reaction mixture with water (2×100 mL). Extract with 10% aqueous sodium hydroxide (2×50 mL). The combined aqueous extracts are neutralized with ammonium chloride then extracted with methylene chloride (2×100 mL) and combined. Remove the solvent in vacuo to provide the title compound, which may be recrystallized from tetrahydrofuran.