Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:20])[N:7]3[CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:12][O:11][CH:8]32)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.CCCCCC.C(OCC)(=O)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:11][CH2:12][CH:13]([N:7]1[CH2:8][C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:10]=2)[C:6]1=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc2c(c1)C1OCC(c3ccccc3)N1C2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc2c(c1)CN(C(CO)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8-methyl-3-phenyl-2,3-dihydro-9bH-oxazolo[2,3-a]isoindol-5-one (5.20 g, 19.60 mmol) was taken up in anhydrous DCM (100 mL) under argon and cooled to minus 78EC. Triethylsilane (9.12 g, 78.40 mmol, 12.52 mL) was added via syringe followed by titanium tetrachloride in DCM (1.0M, 58.80 mmol, 58.80 mL). The solution was stirred at minus 78EC for 5 h then allowed to warm to room temp and stir for 12 h. The reaction was slowly poured into ice and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (1:1 hexane/ethyl acetate) Yield 4.72 g. 1H NMR (CDCl3, 300 MHz): δ 2.40 (s, 3H), 4.12-4.42 (m, 5H), 5.31 (dd, J=4, 8 Hz, 1H), 7.10-7.39 (m, 7H), 7.67 (d, J=8, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:35][C:36]1[S:40][C:39]2[CH:41]=[CH:42][C:43]([C:45]#[N:46])=[CH:44][C:38]=2[CH:37]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH2:35][C:36]2[S:40][C:39]3[CH:41]=[CH:42][C:43]([C:45]#[N:46])=[CH:44][C:38]=3[CH:37]=2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: N#Cc1ccc2sc(CBr)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2s1)(C(=O)OCC)c1ccc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
4.1 g of ethyl 2-[4-[((2R)-1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxy]phenyl]-2-ethoxycarbonylacetate was dissolved in 100 ml of tetrahydrofuran. At room temperature, the thus prepared solution was mixed with 0.38 g of 60% sodium hydride and stirred for 30 minutes. With stirring at room temperature, to the resulting reaction solution was added dropwise 10 ml of a tetrahydrofuran solution containing 2.1 g of 2-bromomethylbenzo[b]thiophene-5-carbonitrile. After concentrating the reaction solution to dryness, the resulting residue was purified by subjecting it to silica gel column chromatography using a toluene/chloroform mixture as an elution solvent, thereby obtaining 4.34 g of the title compound in an oily form.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Sn](CCCC)(CCCC)[C:20]1[CH:24]=[CH:23][S:22][CH:21]=1)CCC.[F-].[K+]>C1(C)C(C)=CC=CC=1.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>[S:22]1[CH:23]=[CH:24][C:20]([C:2]2[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=2)[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:21]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Reactant: CCOC(=O)COc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCOC(=O)COc1cccc(-c2ccsc2)c1
Yield: 64.6 %

Procedure:
2.6 g of the resulting ether compound, 5.3 g of tri-n-butyl(3-thienyl)tin and 20 mg of tetrakis(triphenylphosphine)palladium were dissolved in 10 ml of xylene, and the mixture was refluxed for 5.5 hours. A 25% aqueous solution of potassium fluoride was added to the solution, and then the precipitate was removed by filtration. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=20/1→15/1] to give 1.7 g of ethyl 3-(3thienyl)phenoxyacetate as a white powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=[O:11])[C:4]=2[O:3][CH2:2]1.[Li][CH3:13]>C1COCC1.C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([OH:11])[CH3:13])[C:4]=2[O:3][CH2:2]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a chilled (−78° C.) solution of 10 g of benzo[1,3]dioxole4-carbaldehyde in 200 mL of THF was added by addition funnel 43.7 mL of a 1.6M MeLi solution in diethyl ether. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was monitored by TLC. The mixture was then cooled to −78° C. and quenched with saturated aqueous ammonium chloride and concentrated in vacuo. The residue was extracted with EtOAc. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 11 g of 1-benzo[1,3]dioxol-4-ylethanol as a brown oil that crystallized upon standing.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[N:4][N:3]=1.Cl[C:15]1[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[N:16]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.O>[CH3:1][C:2]1[O:6][C:5]([N:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:15]3[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=4)[N:16]=3)[CH2:11][CH2:12]2)=[N:4][N:3]=1
Reactant: Cc1nnc(N2CCC(N)CC2)o1
Reactant: CC(C)(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nnc(N2CCC(Nc3nc(-c4ccc(C(F)(F)F)cc4)cc(C(C)(C)O)n3)CC2)o1

Procedure:
A solution of 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidin-4-ylamine (36.5 mg, 0.2 mmol), 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol (69.1 mg, 0.22 mmol)) and N,N-diisopropylethylamine (52 L, 0.3 mmol) in dioxane (2 mL) was heated at 160° C. in a microwave oven for 5.5 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc/EtOH 9:1 (v/v) as eluent. The title compound was obtained as a white solid (29 mg, 31%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[C:10]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:24][CH:23]=1)=[O:21].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH:20]([OH:21])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]2
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(F)cc2F)ccc2cc(O)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Dissolve [2-(2,4-difluoro-phenyl)-6-hydroxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (3.3 g, 6.8 mmol) in dry THF (100 mL) and stir under nitrogen. Slowly add lithium aluminum hydride (0.9 g, 24 mmol) and heat to reflux. Cool to room temperature after 30 minutes and quench excess LiAlH4 with slow addition of ice. Dilute with water and adjust the pH to 7 with 1M HCl. Extract five times with 20% IPA in chloroform. Dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo to yield 3.4 g (100%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-])=O.[H][H]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1cccc(CCC(=O)O)c1

Procedure:
3-Nitrocinnamic acid (1.5 g, 7.77 mM) was suspended in a mixture of ethanol (80 ml) and water (20 ml), and palladium on charcoal (10%, 100 mg) added. The mixture was shaken in an atmosphere of hydrogen for 4.5 hours, when uptake of gas complete. After filtration through diatomaceous earth, the solvent was removed to give title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:5]=1[NH2:6])([O-])=O>CCOC(C)=O.[Pd]>[N:14]1[CH:13]=[CH:12][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:4]([NH2:1])[C:5]=2[NH2:6])=[CH:16][CH:15]=1
Reactant: Nc1c(-c2ccncc2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2ccncc2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of 2-nitro-6-(pyridin-4-yl)aniline (XCIV) (3 g, 14 mmol, 1 eq) in EtOAc (350 mL) was added Pd/C (0.3 g) and the mixture was stirred at room temperature under 1 atm of H2 atmosphere overnight, the mixture was filtered and concentrated in vacuo to give the product 3-(pyridin-4-yl)benzene-1,2-diamine (XCV) (2.4 g, 13.0 mmol, 93% yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 4.35 (s, 2H), 4.75 (s, 2H), 6.45 (dd, J=7.6 Hz, J=1 Hz, 1H), 6.58 (t, J=7.6 Hz, 1H), 6.67 (d, J=6.8 Hz, 1H), 7.47 (d, J=6 Hz, 2H), 8.65 (d, J=6 Hz, 2H); ESIMS found for C11H11N3 m/z 186 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.C(O)(=O)C.[CH2:26]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH2:44][C:45](=O)[C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:38][CH2:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>C(O)C>[CH2:26]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([CH2:42][CH2:43][CH2:44][C@@H:45]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[S:4][CH2:3]2)[C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:40][CH2:41]1)=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(=O)CCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H](CCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9 %

Procedure:
In 30 ml of ethanol is dissolved 2.1 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 0.4 g of acetic acid, 2.5 g of ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)-2-oxovalerate and 10 g of Molecular sieve 3A are added to the solution. The mixture is stirred at room temperature for 20 minutes, and a solution of 0.4 g of sodium cyanoborohydride in 50 ml of ethanol is added dropwise to the mixture at room temperature with stirring over the period of 3 hours. The reaction solution is allowed to stand at room temperature overnight, and concentrated under reduced pressure, and 300 ml of water and 300 ml of ethyl acetate are added to the residue, followed by shaking. The insoluble matter is removed by filtration, and the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (20 ml) and 2 g of oxalic acid are added to the residue, and the mixture is shaken thoroughly and admixed with 300 ml of petroleum ether, followed by allowing the mixture to stand. The solution portion is removed by decantation, and 100 ml of water and 200 ml of ethyl acetate are added to the precipitate portion, followed by adding excess sodium hydrogencarbonate to conduct neutralization. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oily material. This product is separated and purified by silica-gel column chromatography (hexane:ethyl acetate=2:1) to give from the first fraction 0.4 g of tert-butyl 3(R)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylbutyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily material.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O>>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: O=C1C=C(Br)CCC1
Product: O=C1C=C(c2cccs2)CCC1
Yield: 83 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and 2-thiophene boronic acid according to the general procedure described for the Suzuki coupling. The product was purified by passing the product through a small silica gel plug eluting with methylene chloride and recrystallization from hexanes and ethyl acetate to yield a pale yellow crystalline solid (125 mg, 83%). 1H NMR (CDCl3, 300 MHz): δ 7.42 (d, J=5.4 Hz, 1H), 7.36 (d, J=3.3 Hz, 1H), 7.08 (t, J=3.9 Hz, 1H), 6.41 (s, 1H), 2.79 (t, J=6.3 Hz, 2H), 2.46 (t, J=6.3 Hz, 2H), 2.14 (quintet, J=6.3 Hz, 2H). 13C NMR (CDCl3, 75 MHz): δ 199.2, 152.3, 142.6, 128.7, 128.2, 127.2, 122.7, 37.3, 28.1, 22.5. LCMS (ESI): mass calcd for (C10H10OS) m/z 178.05; measured [M+H]+: m/z 179.04.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.C[O:11][C:12](=[O:19])[CH2:13][O:14][CH2:15][CH2:16][C:17]#[N:18].[H][H]>C(OC(=O)C)(=O)C.O.[Pt]>[C:7]1(=[O:9])[NH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6]1.[NH2:18][CH2:17][CH2:16][CH2:15][O:14][CH2:13][C:12]([OH:19])=[O:11]
Reactant: [H][H]
Reactant: COC(=O)COCCC#N
Agent: [Pt]
Agent: NCCCOCC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1COCCCN1

Procedure:
A process for preparing 6-amino-3-oxahexanoic acid which comprises: contacting methyl-2-cyanoethoxyacetate in excess acetic acid anhydride with hydrogen in the presence of a catalytic amount of platinum to prepare N-acetyl-6-amino-3-oxamethylhexanoate, and heating in excess water at a temperature of about 260° C. to form a mixture comprising 3-oxacaprolactam and 6-amino-3-oxahexanoic acid, extracting said mixture with chloroform, and separating 6-amino-3-oxahexanoic acid from the residue of said extraction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)=O)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Cl.[NH2:31][OH:32]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)=[N:31]\[OH:32])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccnnc1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccnnc1)c1ccc(Br)cc1
Temperature: 120 °C
Yield: 89.4 %

Procedure:
To a microwave vial was added (R)-3-(4-bromophenyl)-1-(pyridazin-4-yl)-3-o-tolylpropan-1-one (30 trig, 79 μmol), sodium hydrogencarbonate (20 mg, 0.24 mmol) and hydroxylamine hydrochloride (16 mg, 0.24 mmol) in ethanol (1 mL) and water (0.02 mL). The vial was capped and heated at 120° C. for 10 min, then the reaction mixture was partitioned between ethyl acetate and poured onto water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; gradient dichloromethane to dichloromethane/methanol/25% aq. anmmonia solution 95:5:0.25) afforded the title compound (28 mg, 90%). White foam, MS: 396.1 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].[N+]([O-])(O)=O.[N+:21]([O:24][CH2:25][CH2:26][NH2:27])([O-:23])=[O:22]>>[N+:21]([O:24][CH2:25][CH2:26][NH:27][C:6](=[O:8])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)([O-:23])=[O:22]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(=O)N[C@@H](COC1CCCCO1)C(=O)O
Solvent: O=[N+]([O-])O
Product: CC(=O)N[C@H](COC1CCCCO1)C(=O)NCCO[N+](=O)[O-]
Yield: 29.8 %

Procedure:
The procedures of Example 1 were analogously repeated using 1.07 g of (2S)-2-acetylamino-3-(tetrahydropyran-2-yl)oxypropionic acid and 0.94 g of 2-nitrooxyethylamine nitrate to give 0.44 g of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]1([C:24]([NH:26][C@H:27]([C:30]([OH:32])=[O:31])[CH2:28][OH:29])=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([NH:17][C@H:18]([C:21]([OH:23])=[O:22])[CH2:19][OH:20])=[O:16].[OH-].[Na+]>CO>[C:1]([O:20][CH2:19][CH:18]([NH:17][C:15](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][S:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:24](=[O:25])[NH:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][O:29][C:10]([CH3:15])([CH3:11])[CH3:9])[C:21]([OH:23])=[O:22])([CH3:24])([CH3:6])[CH3:2]
Reactant: O=C(N[C@@H](CO)C(=O)O)c1ccccc1SSc1ccccc1C(=O)N[C@@H](CO)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OCC(NC(=O)c1ccccc1SSc1ccccc1C(=O)NC(COC(C)(C)C)C(=O)O)C(=O)O
Reaction time: 18 h

Procedure:
A solution of N,N'-[dithiobis(2,1-phenylene carbonyl)]bis L-serine bis[O(1,1-dimethylethyl) bis (1,1-dimethylethyl)ester (1.0 g, 1.4 mmol) from Example 39, in 30 mL methanol was treated with 8 mL of 1N NaOH and allowed to stir for 18 hours. The methanol was removed in vacuo and the residual was diluted with water and extracted with ethyl acetate. A slow stream of oxygen was passed thru the aqueous layer while dilute HCl was added to maintain a pH=6-7. After the disulfide formation was complete (2-18 hours), dilute HCL was added to a pH=3. The product was collected by filtration, washed with water, dried and was recrystallized from ethyl acetate to afford 0.4 g of the title compound, mp 206-207° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[NH:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[C:5]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:4]=1)#[N:2]>CO.[C].[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[NH:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[C:5]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C2NC(=O)NC2=O)c(C#Cc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(C2NC(=O)NC2=O)c(CCc2ccccc2)c1

Procedure:
A solution of 5-[4-cyano-2-(2-phenylethynyl)phenyl]hydantoin (100 mg, 0.33 mmol) in methanol (20 ml) was shaken with 10% palladium-carbon (10 mg) under an atmosphere of hydrogen for 24 hours at 60 p.s.i. The catalyst was removed by filtration to give 5-[4-cyano-2-(2-phenylethyl)phenyl]hydantoin as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])=[CH:6][C:5]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[NH:24][C:23]2=[O:33])=[C:4]([F:34])[CH:3]=1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:18]([F:21])([F:19])[F:20])=[CH:6][C:5]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[NH:24][C:23]2=[O:33])=[C:4]([F:34])[CH:3]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)c(Cl)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c(F)cc2Cl)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A suspension of 10% Pd/C and 3-[4-chloro-2-fluoro-5-(4-nitro-2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4.0 g) in ethyl acetate (100 ml) was stirred overnight under an atmosphere of hydrogen. The mixture was filtered through Celite and the filtrate concentrated. The resulting oil was chromatographed on silica gel eluting with ethyl acetate:hexane, 1:0.8. 3-[4-Chloro-2-fluoro-5-(4-amino-2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-24) was isolated as an amorphous solid (3.3 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:10]=[C:5]2[NH:4][CH2:3]1.[H-].[Na+].[N:22]1[C:30]2[CH2:29][CH:28]([CH2:31]OS(C)(=O)=O)[CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O.C(Cl)Cl>[N:22]1[C:30]2[CH2:29][C@H:28]([CH2:31][N:4]3[C:5]4=[N:10][C:9]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=5)=[CH:8][C:7](=[O:17])[N:6]4[CH2:18][C:2]([CH3:19])([CH3:1])[CH2:3]3)[CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)CNc2nc(-c3ccncc3)cc(=O)n2C1
Reactant: CS(=O)(=O)OCC1Cc2cccnc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC1(C)CN(C[C@@H]2Cc3cccnc3C2)c2nc(-c3ccncc3)cc(=O)n2C1
Reaction time: 0.67 h

Procedure:
A suspension of 0.51 g (2 mmol) of 7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 10 ml of anhydrous dimethylformamide was treated with 96 mg (2 mmol) of sodium hydride (50% suspension in mineral oil) and the resulting mixture was stirred for 40 min. 0.455 g (2 mmol) of methanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-6-ylmethyl ester in 2 ml of anhydrous dimethylformamide was added and the reaction mixture stirred at room temperature for 18 h. The solution was treated with water and extracted with ethyl acetate. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with ethyl acetate/methanol/diethyl amine in the proportions 98/2/0.2 to give 0.3839 of pure product obtained in the form of free base. Mp: 182-184° C. [α]D20=+9.15° (c=0.5, CH2Cl2).
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[CH:25]=[CH:26]/[C:27]([OH:29])=O)[CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1.Cl.[NH2:31][CH2:32][C:33](=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[F:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][C:33](=[O:42])[CH2:32][NH:31][C:27](=[O:29])/[CH:26]=[CH:25]/[C:15]2[CH:16]=[CH:17][C:18]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:13]([O:12][CH3:11])[CH:14]=2)=[CH:40][CH:39]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: NCC(=O)Cc1ccc(F)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(/C=C/C(=O)NCC(=O)Cc2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
Diethyl cyanophosphonate (0.12 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (200 mg) and triethylamine (0.54 mL) in DMF (2 mL), and the reaction solution was stirred at 0° C. for 30 minutes. A solution of 1-amino-3-(4-fluorophenyl)propan-2-one hydrochloride (CAS#93102-98-8, 158 mg) in DMF (1 mL) was added dropwise to the reaction solution over 20 minutes, and the reaction solution was stirred at 0° C. for 1.5 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 43 mg of the title compound. The property values of the compound are as follows.