Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Na+].[Na+].[OH:16][CH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.O>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:16][CH2:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: N#Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2cccc(CO)c2)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of 3-bromobenzonitrile (1.20 g, 6.58 mmol) in toluene (40 mL) was added a solution of tetrakistriphenylphosphinepalladium (0.38 g, 0.33 mmol), 2N aqueous sodium carbonate solution (21 mL) and [3-(hydroxymethyl)phenyl]boronic acid (1.00 g, 6.58 mmol) in EtOH (19 mL), and the mixture was heated under reflux for 10 hr under nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/9→1/1) to give the title compound as a yellow oil (1.28 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:26])[C:9](=[O:25])[CH2:10][CH:11]([CH2:18][CH2:19]OS(C)(=O)=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:27]([NH:30][C:31]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:29])[CH3:28].C(N(C(C)C)C(C)C)C.CCOC(C)=O>CN(C=O)C.O>[C:27]([NH:30][C:31]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:32][CH2:33][N:34]([CH2:19][CH2:18][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:9]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:26])=[O:25])[CH2:35][CH2:36]1)(=[O:29])[CH3:28]
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Reactant: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccccc1)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)NC1(c2ccccc2)CCN(CCC(CC(=O)N(C)c2ccc(Cl)cc2)c2ccccc2)CC1
Temperature: 80 °C

Procedure:
N-(4-Chlorophenyl)-beta-(2-methanesulfonyloxyethyl)-N-methyl-benzenepropanamide (2.0 g) in DMF (10 mL) was treated with 4-acetylamino-4-phenylpiperidine hydrochlorode (3.21 g) and ethyl-N,N-diisopropylamine (2.48 g) and the mixture heated at 80° C. for 2 hours. The cooled reaction mixture was diluted the EtOAc (50 mL) and water (50 mL) and the aqueous phase removed. The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts, washed with water (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. Silica gel chromatography eluting with 10% MeOH:CHaCl2 gave the title compound (0.29 g). Mass spectrum (FAB): 518.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[NH2:36].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:36][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][N:30]=4)=[O:26])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Nc1cnccn1
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4cnccn4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (30 mg, 0.07 mmol) and pyrazin-2-amine (7 mg, 0.07 mmol) in pyridine (6 mL) was added POCl3 (0.2 mL, 2.19 mmol) at 0° C., the reaction mixture was stirred at room temperature for 15 hours, a sat. NaHCO3 solution was added slowly, the solvent was removed in vacuo, and water (5 mL) and methanol (3 mL) were added. The precipitate was collected by filtration and washed with water (3 mL) and methanol (3 mL) to afford 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(pyrazin-2-yl)piperidine-3-carboxamide (30 mg, 87.2%) as a brown solid. 1H NMR (300 MHz, DMSO): δ 10.87 (s, 1H), 9.62 (s, 1H), 9.30 (s, 1H), 8.83 (s, 1H), 8.39-8.33 (m, 2H), 7.61 (d, 1H, J=2.1 Hz), 7.31 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 6.82 (d, 1H, J=8.4 Hz), 4.76 (d, 1H, J=11.4 Hz), 4.60 (d, 1H, J=12.3 Hz), 3.68 (s, 3H), 3.64 (s, 3H), 3.13 (t, 1H, J=10.8 Hz), 3.01-2.93 (m, 1H), 2.79-2.71 (m, 1H), 2.04-2.00 (m, 1H), 1.81-1.67 (m, 2H), 1.46-1.42 (m, 1H). LC-MS: 493 [M+H]+, tR=1.50 min. HPLC: 95.75% at 214 nm, 96.29% at 254 nm, tR=5.38 min.
Reaction SMILES: C([N:9]=[C:10]=[O:11])CCCCCCC.NC(N)=O.[NH:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[O:18]>C(OCC)(=O)C>[N-:9]=[C:10]=[O:11].[NH:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: CCCCCCCCN=C=O
Agent: NC(N)=O
Agent: O=C1CNC(=O)N1
Solvent: CCOC(C)=O
Product: [N-]=C=O

Procedure:
To a stirred solution of 111 g of aspartic ester (obtained from Bayer #XP 7059) in 200 g of ethyl acetate were added dropwise 75 g of octyl isocyanate (available from Aldrich). After four days the solvent was evaporated to leave the product which was shown by NMR spectroscopy to be a mixture of the urea addition product and the hydantoin cyclization product (ratio=~1:2).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[O:12][C:11]([CH2:13][S:14][CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[C:23](OC)=[N:22][S:21](=[O:26])[N:20]=1>CO>[NH2:18][C:19]1[C:23]([NH:17][CH2:16][CH2:15][S:14][CH2:13][C:11]2[O:12][C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=2)=[N:22][S:21](=[O:26])[N:20]=1
Reactant: NCCSCc1ccc(CN2CCCCC2)o1
Reactant: COC1=NS(=O)N=C1N
Solvent: CO
Product: NC1=NS(=O)N=C1NCCSCc1ccc(CN2CCCCC2)o1
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of 2-[(5-piperidinomethyl-2-furyl)methylthio]ethylamine (4.0 g; 15.7 mmoles) [prepared according to the procedure described in Belgian Patent No. 857,388 (U.S. Pat. No. 4,128,658)] in 25 ml of methanol was added all at once to a stirred suspension of 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (2.31 g; 15.7 mmoles) [prepared in Step A] in 25 ml of methanol at ambient temperature. After stirring for 16 hours, the solution was evaporated under reduced pressure and the residue chromatographed by flash chromatography on 100 g of silica gel (230-400 mesh) using methanol-acetonitrile. The appropriate fractions were combined and evaporated to give 3.71 g of product. Recrystallization from 95% aqueous ethanol with charcoal treatment yielded the title compound, mp 161°-163°.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:10](=O)[CH2:11][C:12]1[N:17]=[C:16]([NH:18][CH3:19])[CH:15]=[CH:14][CH:13]=1)C.C1C[O:24]CC1>>[CH3:19][NH:18][C:16]1[N:17]=[C:12]([CH:11]([OH:24])[CH3:10])[CH:13]=[CH:14][CH:15]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)Cc1cccc(NC)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNc1cccc(C(C)O)n1
Temperature: 0 °C

Procedure:
To a mechanically stirred solution of LiAlH4 in THF (1.0 M, 20 mL, 20.4 mmol) was added dropwise a solution of ethyl-2-(methylamino)-6-pyridylacetate (0.38 g, 2 mmol) in THF (10 mL). After the addition was completed, the reaction mixture was warmed to 0° C. and quenched with 10% NaOH solution. The solids were removed by filtration, and the filtrate was concentrated in vacuum. The residue was dissolved in CH2Cl2 and the solution was dried (MgSO4) and concentrated. Reconcentration from toluene (3×) gave the title compound as a colorless oil: MS (ES) m/e 153 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@@H:15]2[C@@H:18]([CH2:19][C:20]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:21])[NH:17][C:16]2=[O:29])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[N+:41]([C:44]1[CH:54]=[CH:53][C:47]([CH2:48][O:49][CH2:50][CH2:51]Cl)=[CH:46][CH:45]=1)([O-:43])=[O:42].P([O-])([O-])([O-])=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@@H:15]2[C@@H:18]([CH2:19][C:20]([S:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:21])[N:17]([CH2:51][CH2:50][O:49][CH2:48][C:47]3[CH:53]=[CH:54][C:44]([N+:41]([O-:43])=[O:42])=[CH:45][CH:46]=3)[C:16]2=[O:29])[CH3:14])=[O:11])=[CH:30][CH:31]=1)([O-:3])=[O:2]
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)Sc1ccccc1
Reactant: O=[N+]([O-])c1ccc(COCCCl)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(CCOCc2ccc([N+](=O)[O-])cc2)[C@@H]1CC(=O)Sc1ccccc1
Reaction time: 0.25 h
Yield: 104.8 %

Procedure:
1.00 g (2.25 mmole) of (3S, 4R)-3-[(R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-4-[(phenylthio)carbonyl-methyl]-2-azetidinone was dissolved in 20 ml of methylene chloride. To the solutiion were added 350 mg (2.71 mmole) of diisopropylethylamine and then 660 mg (2.71 mmole) of p-nitrobenzyloxyethyl chloride, with stirring at 0° C. After 15 minutes, a further 230 mg (1.78 mmole) of diisopropylethylamine and 433 mg (1.78 mmole) of p-nitrobenzyloxyethyl chloride were added, and the mixture was stirred at that temperature for 15 minutes. After completion of the reaction, 30 ml of a 0.1M phosphate buffer solution (pH 7.1) was added to the reaction mixture and the organic layer was separated. The aqueous lager was extracted with chloroform. The organic layer was combined with the chloroform extract and then the solvent was distilled from the mixture. The residue was dissolved in 50 ml of a 1:1 by volume mixture of benzene and ethyl acetate, washed successively with 0.02N hydrochloric acid, water, a 5% w/v aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solvent was distilled off, to afford 1.47 g (yield 100%) of the title product as crystals which were recrystallized from a mixture of benzene and ethyl acetate, to afford the pure product melting at 129°-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]([O:20]CC)=[O:19])[CH:7]=[CH:6][C:5]2=1.[OH-].[Li+]>C1COCC1.CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]([OH:20])=[O:19])[CH:7]=[CH:6][C:5]2=1
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Br)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)O)ccc12
Yield: 284.9 %

Procedure:
A solution of ethyl 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (4.7 g, 8.85 mmol) and lithium hydroxide (0.848 g, 35 4 mmol) in THF/EtOH/H2O (3/1/1) (70 mL) was heated at 75° C. overnight. The reaction was concentrated and the resulting yellow solid was suspended in water. To above suspension, was added 1M HCl/conc. HCl until pH=2-3. The light yellow solid was collected by filtration and air-dried to furnish 8.4 g of 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylic acid with ˜80% purity. This material was carried forward to the next step. MS (ESI) m/z−=331/363 [M−H]−, 1 Br isotope pattern. HPLC retention time 9.79 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN-95% H2O-0.1% TFA; Solvent B: 95% CH3CN-5% H2O-0.1% TFA). 1H NMR (DMSO-d6) δ ppm 13.0-12.65 (b, 1H), 11.80 (s, 1H), 8.65 (d, 1H, J=1.8), 8.39 (d, 1H, J=0.6), 8.30 (s, 1H), 8.29 (d, 1H, J=8.2), 8.20 (d, 1H, J=1.8), 7.79 (dd, 1H, J=1.5, 8.3), 7.66 (br. s., 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg].II.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1>C(OCC)C>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccc(Br)c1
Reactant: Brc1cccs1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: c1csc(-c2ccccc2-c2cccs2)c1
Reaction time: 1 h
Yield: 2.6 %

Procedure:
The Grignard was prepared by adding 2-bromothiophene (8.15 g, 0.05 m) in diethyl ether (10 ml) to magnesium turnings (1.22 g, 0.05 m) and iodine (trace) in diethyl ether (15 ml). After 1 h, the Grignard was slowly added to 1,3-dibromobenzene (5.0 g, 0.021 m) and catalyst in diethyl ether (20 ml). Workup after 24 h afforded a residue which crystallized from hot hexanes yielding a green solid (540 mg, 10% crude yield). The green solid (190 mg) was purified by column chromatography using petroleum ether as the eluant. A light green crystalline solid (136 mg, 7.6% yield) was separated; m.p. 83°-84° C., m/z 242 (M+); Found: C, 69.22; H, 4.04; S, 26.09; C14H10S2 requires: C,69.4; H, 4,1; S, 26.4H NMR(CDCl3) δ7.35 (dd, J=<1, 3 Hz, 2 H), δ7.085 (dd, J=5,3 Hz, 2H), δ7.29 (dd, J=<1, 5 Hz, 2H), δ7.81 (t, J=<1 Hz, 1H), δ7.38 (dd, J=8 Hz, 1H), δ7.51 (ddd, J=<1,2, 8 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14]CC)=O)[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].C(OC([N:28]1[CH2:32][C@H:31]([CH:33]([C:38]([CH3:43])([CH3:42])[CH:39]([CH3:41])[CH3:40])[O:34][SiH:35]([CH3:37])[CH3:36])OS1(=O)=O)=O)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.ClCCl>[CH3:37][SiH:35]([CH3:36])[O:34][CH:33]([C:38]([CH3:42])([CH3:43])[CH:39]([CH3:40])[CH3:41])[C@H:31]1[N:9]2[C:10]3[CH:11]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=[CH:5][C:6]=3[CH:7]=[C:8]2[C:12](=[O:14])[NH:28][CH2:32]1
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C(C)(C)C(O[SiH](C)C)[C@@H]1CNC(=O)c2cc3ccc(C(F)(F)F)cc3n21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of 0.700 g ethyl 6-(trifluoromethyl)indole-2-carboxylate in 7 ml DMF was added 0.13 g sodium hydride (55% in mineral oil) and the mixture was stirred at room temperature for 30 min. To the resulting solution was added 1.30 g (R)-5-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester and the mixture was stirred at room temperature for 18 h. The reaction mixture was distributed between 10% aqueous citric acid and dichloromethane and the organic phase was purified by chromatography on silica gel with dichloromethane as eluant. The product (1.15 g) was taken up in 11 ml TFA was stirred at 0° C. for 45 min. The solvent was evaporated and the residue was taken up in 10 ml methanol. To the resulting solution was added 1.00 g potassium carbonate and the mixture was stirred at room temperature for 3 h. The reaction mixture was purified by chromatography on silica gel with ethyl acetate to yield 0.36 g of the tide compound (m.p.: 143-144° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH:17]([OH:24])[CH2:18][NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:6]([CH:14]=1)[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8].Cl.[C:26](=O)([O-])[O-].[Na+].[Na+]>CO.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH:17]([OH:24])[CH2:18][NH:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[C:6]([CH:14]=1)[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:26])=[O:12])=[O:8]
Reactant: CC(C)(C)NCC(O)COc1ccc(N)cc1C(=O)CCC(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CCC(=O)c1cc(N)ccc1OCC(O)CNC(C)(C)C

Procedure:
3-[5-Amino-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionic acid was esterified with hydrogen chloride in methanol. Evaporation of the solution under reduced pressure gave a residue which was dissolved in the minimum of water and the solution was neutralised with sodium carbonate and extracted with dichloromethane. The combined extracts were washed with saturated brine, dried, and evaporated to give methyl 3-[5-amino-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3](=[O:27])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7]Br.[CH3:29][C:30]1([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CC#N.CCOC(C)=O>[CH3:1][N:2]([CH3:28])[C:3](=[O:27])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][N:33]1[CH2:34][CH2:35][C:30]([OH:36])([CH3:29])[CH2:31][CH2:32]1
Reactant: CC1(O)CCNCC1
Reactant: CN(C)C(=O)C(CCCBr)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C(CCCN1CCC(C)(O)CC1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reaction time: 16 h
Yield: 34.9 %

Procedure:
A solution of 107 mg (0.23 mmol) of (rac)-5-bromo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-pentanoic acid dimethylamide in 4 ml of CH3CN was treated with 115 mg (0.28 mmol) of 4-methyl-piperidin-4-ol (intermediate 8) and 63 mg (0.46 mmol) of potassium carbonate. After 16 h at RT, the reaction mixture was diluted with AcOEt and a white solid was filtered off. The filtrate was evaporated and chromatographed by amine-silica gel column (AcOEt:MeOH 19:1) to yield 40 mg (35%) of the title compound as yellow oil. MS: 499.2 (MH+).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18][C:19]4[NH:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[N:20]=4)[C:12]=3[CH3:28])[O:5][CH2:4]2)[CH2:2]1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH2:2]1[C:3]2([CH2:4][O:5][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:19]4[NH:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[N:23]=4)=[O:37])[C:12]=3[CH3:28])[O:7][CH2:8]2)[CH2:1]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -50 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
The 2-(((4-(5,7-dioxaspiro[2.5]oct-6-ylmethoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (629 mg, 1.58 mmol) obtained by the step (2e) was mixed with methanol (5 ml) and toluene (15 ml) and the mixture was cooled to −50° C. Then, 3-chloroperbenzoic acid (378 mg, 1.42 mmol as the content was regarded as 65%) dissolved in a solvent mixture of methanol and toluene was slowly added dropwise to the mixture, and stirred at −47° C. to −70° C. for 4 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over potassium carbonate, and the solvent was distilled off. The residue was purified with silica gel column chromatography (NH silica gel: 40 g, elution solvent: dichloromethane/heptane=7/3→methanol/dichloromethan=3/97 to 1/9) to obtain the title compound (623 mg, yield: 95.4%) as a colorless foam.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([Se:23][C:24]#[C:25][C:26]([CH3:32])=[CH:27][C:28]([O:30]C)=[O:29])=[CH:16][C:17]=3[C:18]([CH3:22])([CH3:21])[CH2:19][CH:20]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([Se:23][C:24]#[C:25][C:26]([CH3:32])=[CH:27][C:28]([OH:30])=[O:29])=[CH:16][C:17]=3[C:18]([CH3:22])([CH3:21])[CH2:19][CH:20]=2)=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C=C(C)C#C[Se]c1ccc2c(c1)C(C)(C)CC=C2c1ccc(C(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C#C[Se]c1ccc2c(c1)C(C)(C)CC=C2c1ccc(C(C)(C)C)cc1)=CC(=O)O

Procedure:
In a manner similar to that of Example 3d, by reacting 0.19 g (0.37 mmol) of methyl 5-[5-(4-tert-butylphenyl)-8,8-dimethyl-7,8-dihydro-2-naphthylselanyl]-3-methylpent-2-en-4-ynoate with 0.19 g (4.5 mmol) of lithium hydroxide monohydrate, a cream-colored powder is obtained (0.06 g; yield=33%; m.p.=231° C.).
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([NH2:28])[CH2:23]1.Cl>>[OH:27][C@H:25]1[CH2:26][CH2:22][CH2:23][C@@H:24]1[NH:28][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20]
Reactant: N[C@H]1CCC[C@@H]1O
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Agent: Cl
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)N[C@H]2CCC[C@@H]2O)s1
Yield: 65 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using trans-(1S,2S)-2-aminocyclopentanol hydrochloride instead of rac-2-amino-1-butanol, to the title compound (127 mg, 65%) which was obtained as an off white solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) and recrystallization from ethyl acetate/heptane. MS: m/e=390.3 [M+H]+.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:14]([CH3:37])[CH:13]=2)[C:5]1=[O:38])(=O)C>CO.[C].[Pd]>[Si:20]([O:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:6]2[NH:7][C:8](=[O:10])[CH2:9][NH:4][C:5]2=[O:38])=[CH:13][C:14]=1[CH3:37])([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)N1CC(=O)NC(=Cc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(C)c2)C1=O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(CC2NC(=O)CNC2=O)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A solution of 1-acetyl-3-(4-tert-butyldiphenylsilyloxymethyl-3-methylphenyl)methylene-2,5-piperazinedione (6.3 g) in methanol (300 ml) was hydrogenated over 10% palladium-carbon (50% wet) for 4 hours at atmospheric pressure. After removal of the catalyst by filtration, to the filtrate was added hydrazine monohydrate (721 mg). The mixture was stirred for 1 hour at room temperature and concentrated under reduced pressure. The residue was triturated with a mixture of isopropyl ether (200 ml) and n-hexane (400 ml) and the precipitates were collected by filtration, and washed with isopropyl ether to give a crude product. This was purified by flash column chromatography on silica gel using ethyl acetate and a mixture of dichloromethane and methanol (15:1) as eluent to give 3-(4-tert-butyldiphenylsilyloxymethyl-3-methylbenzyl)-2,5-piperazinedione (4.67 g) as a powder.