Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CCOCC.[CH3:13][C:14]1[C:15]([C:21]([OH:23])=[O:22])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1>C1C=CC=CC=1.CO.C(OCC)(=O)C>[CH3:1][O:22][C:21]([C:15]1[C:14]([CH3:13])=[CH:19][CH:18]=[C:17]([CH3:20])[N:16]=1)=[O:23]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1ccc(C)c(C(=O)O)n1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1nc(C)ccc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.2 %

Procedure:
Trimethylsilyldiazomethane 2M in ether (5.7 ml, 11.4 mmole, 1.4 eq.) is added dropwise at RT to a suspension of 3,6-dimethyl-pyridine-2-carboxylic acid (containing potassium chloride) (3.07 g à 25%, 8.12 mmole, 1 eq.) in benzene (24 ml) and methanol (8 ml), and the yellow suspension is stirred at RT for 1.5 h. The yellow mixture is diluted with ethyl actate, washed once with sat. aqueous sodium bicarbonate sol., once with water, once with brine, dried with magnesium sulfate and the solvents are removed in vacuo. Purification of the residue (914 mg) by chromatography on a 20 g Silicycle silica cartridge (eluent heptane/ethyl acetate 5-40% 20 min) affords 3,6-dimethyl-pyridine-2-carboxylic acid methyl ester (714 mg, 53.2%) as a colorless liquid. MS (m/e)=166.3 [M+H+].
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([OH:23])=[C:17]([CH2:24][CH3:25])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30]>>[CH2:1]([C:8]1[O:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]([C:15]1[CH:16]=[C:17]([CH2:24][CH3:25])[C:18]([O:23][S:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=2)(=[O:31])=[O:30])=[C:19]([CH2:21][CH3:22])[CH:20]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1O
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Yield: 32.3 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diethyl-4-hydroxy-phenyl)-methanone (0.5 g, 1.38 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.65 g, 2.74 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with 10% EtOAc/hexane gave 0.251 g (32%) of the title compound as an off white solid, mp 143-147° C. 1H NMR (DMSO-d6) δ1.01 (t, 6H), 1.84 (s, 3H), 2.20 (s, 3H), 2.51 (q, 4 H, with DMSO peak), 3.81 (s, 2H), 7.01 (d, 2H), 7.16-7.20 (m, 1H), 7.23-7.27 (m, 2H), 7.45 (s, 2H), 7.49-7.53 (m, 2H), 8.06 (d, 1H). mass spectrum (−ESI), m/z 561 (M−H). Anal. Calcd. for C31H30O8S: C, 66.18; H, 5.37; N, 0.00. Found: C, 65.80; H, 5.50; N, 0.22.
Reaction SMILES: C=CC.[H][H].[CH2:6]([SiH3:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].N#N>C1(C)C=CC=CC=1.CCCCCC>[CH:6]([SiH3:14])=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: [H][H]
Reactant: C=CCCCCCC[SiH3]
Agent: N#N
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C=CC
Product: CCCCCCC=C[SiH3]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A 2 L Parr reactor was heated to 70° C. and charged with 270 g of propylene and pressured with 0.14 L of hydrogen. 7-Octenylsilane (containing about 14.6 percent of 6-octenylsilane) 0.13 wt percent based on total monomer content, dissolved in 0.5 ml of toluene and pressured to 100 psig over the reactor pressure with N2 was charged to the vessel. To the vessel was then added 12 μmoles of the Zr-containing catalyst, slurried in hexane under N2 pressure of 100 psig above the reactor pressure to initiate the polymerization. The polymerization was continued for 30 minutes and resulted in the formation of 45.3 g of octenylsilane modified polypropylene. The polymer had a mwt of 459,000 and a MWD of 3.2. The copolymer contained added LCB as shown by the increase in solution viscosity as a function of increased absolute molecular weight and an increase in the strain-hardening in extensional flow as a function of extension rate when compared to a polypropylene made under comparative conditions. Based on such analysis the octenylsilane-containing polymer has from 0.2 to 0.5 tetrafunctional branch sites/chain.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([C:19](OC)=[O:20])[CH:16]=[C:15]2[C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:10][CH:9]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.C(Cl)Cl.O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]2[C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(-c2cc(CO)cn2-c2ccc(F)cc2)cc1
Yield: 76.8 %

Procedure:
0.15 g (4.0 mmol) of lithium aluminum hydride was suspended in 25 ml of diethyl ether, and a solution of 0.98 g (2.6 mmol) of 1-(4-fluorophenyl)-4-methoxycarbonyl-2-(4-methylsulfonylphenyl)pyrrole [prepared as described in step (iii) above] in 20 ml of methylene chloride was added dropwise to the suspension whilst it was heated under reflux in a nitrogen atmosphere. The mixture was stirred under reflux for 1 hour, and then 0.15 ml of water, 0.15 ml of a 15% w/v aqueous solution of sodium hydroxide and 0.45 ml of water were added to the mixture, in that order. The mixture was then stirred at room temperature for 30 minutes. At the end of this time, the mixture was dehydrated by adding anhydrous magnesium sulfate, and it was filtered over a Celite (trade mark) filter aid. The solvent was then removed from the filtrate by distillation under reduced pressure. The residue was applied to a silica gel chromatography column and eluted with a 2:1 by volume mixture of ethyl acetate and hexane, to give 0.69 g (yield 76%) of the title compound as a white powder, melting at 88-90° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:9]=[N:10][N:11]=2)[C:5](Cl)=[N:6][CH:7]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[C:3]2[N:4]([N:9]=[N:10][N:11]=2)[C:5]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncc(Br)c2nnnn12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c3nnnn23)CC1
Temperature: 30 °C
Yield: 93.9 %

Procedure:
A 250 mL round bottom flask was charged with 8-bromo-5-chlorotetrazolo[1,5-c]pyrimidine (10 g, 42.7 mmol), tert-butyl piperazine-1-carboxylate (11.9 g, 64 mmol), triethylamine (13 g, 0.13 mol) and ethanol (200 mL). The resulting mixture was heated at 30° C. for 2 h under N2 and then cooled to room temperature. The mixture was concentrated under reduced pressure to dryness. The residue was diluted with water (20 mL) and extracted with dichloromethane (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo, to afford 15.4 g (94%) of the product as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]([C:19](=[O:34])[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH3:18])[CH:5]=1.O.O[Li].O.Cl>O1CCOCC1.CCOC(C)=O>[F:33][C:30]([F:31])([F:32])[C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=1)[C:19]([N:17]([CH3:18])[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([OH:35])=[O:2])=[O:34]
Reactant: COC(=O)c1ccc(C)c(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-{3-[(3,5-bis-trifluoromethyl-benzoyl)-methyl-amino]-pyridin-4-yl}-4-methyl-benzoic acid methyl ester (33 mg, 66.5 μmol, example 83) in dioxane (1 mL) was added water (2 mL) and LiOH.H2O (3.49 mg, 83.1 μmol). The reaction mixture was stirred at room temperature for 2 hours and then poured on 20 mL 1M aqueous HCl and 20 mL EtOAc. The layers were separated and the aqueous layer extracted a second time with 20 mL EtOAc. The combined organic layers were washed with 20 ml brine, dried over MgSO4, filtered and concentrated under vacuum. Colorless solid (32 mg, 99%). MS (ESI): m/z=483.113 [M+H]+.
Reaction SMILES: C(=O)(O[CH2:6][C:7](=[CH2:9])[CH3:8])OCC.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:8]([C:18]#[C:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](=[CH2:6])[CH3:9]
Reactant: C#Cc1ccccc1
Reactant: C=C(C)COC(=O)OCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)CC#Cc1ccccc1
Yield: 61.5 %

Procedure:
A mixture of ethyl methallyl carbonate (1.58 g, 0.011 mole), phenylacetylene (1.02 g, 0.010 mole) and tetrakis(triphenylphosphine) palladium (O) (0.25 g, 0.21 mmole) in tetrahydrofuran (15 ml) was refluxed for 91 hours under N2. Gas chromatographic analysis showed that the ethyl methallyl carbonate was totally consumed but about 10 percent of phenylacetylene remained. The product, methallylphenylacetylene, was isolated by preparative gas chromatography (0.96 g, 61.5 percent yield) and identified by spectroscopic techniques.
Reaction SMILES: [CH:1]1([NH:5][C@H:6]2[CH2:10][CH2:9][CH2:8][C@@H:7]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[C:31]=1[C:32](Cl)=[O:33]>C(Cl)Cl>[CH:1]1([N:5]([C@H:6]2[CH2:10][CH2:9][CH2:8][C@@H:7]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:32](=[O:33])[C:31]2[C:35]([O:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:30]=2[O:29][CH3:28])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1NC1CCC1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(OC)c1C(=O)N(C1CCC1)[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-(cyclobutylamino)cyclopentyl]carbamate (400 mg, 1.573 mmol) in dry DCM (5.3 ml) was added DIPEA (1.3 ml, 7.86 mmol) and 2,6-dimethoxybenzoyl chloride (CAS number 1989-53-3; 473 mg, 2.359 mmol). The reaction was stirred at room temperature for 1 hour and was then partitioned between DCM and water, filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].O1CCOCC1.[Br:15]Br.C(=O)(O)[O-].[Na+]>C(OCC)C.ClCCl>[Br:15][CH:3]([CH:2]=[O:1])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: BrBr
Reactant: COC(=O)CCC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)CC(Br)C=O
Reaction time: 2 h
Yield: 107 %

Procedure:
A 500-mL round bottom flask was charged with methyl 4-oxobutanoate (8.52 g, 73.3 mmol), dioxane (0.7 mL) in diethyl ether (70 mL). Bromine (3.94 mL, 77.0 mmol) was added at room temperature over 1.5 h. After this time, the mixture was diluted with dichloromethane (250 mL) and solid sodium bicarbonate (13.6 g, 161 mmol) was added. After stirring for 2 h the mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound (15.3 g, 100%) as a colorless oil. MW=195.01. 1H NMR (CDCl3, 300 MHz) δ 9.54 (s, 1H), 4.68 (dd, J=6.9, 6.6 Hz, 1H), 3.74 (s, 3H), 3.25 (dd, J=17.4, 7.2 Hz, 1H), 2.94 (dd, J=17.1, 6.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].N>[Ni].CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6]
Reactant: N#Cc1cc(F)cc(F)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc(F)cc(F)c1
Reaction time: 2.5 h
Yield: 99.6 %

Procedure:
A slurry of Raney nickel in methanol was added to a solution of 3,5-difluorobenzonitrile (12.0 g., 0863 mole) in methanol (100 ml) saturated with ammonia and the mixture was hydrogenated for 2.5 hours at 50 pounds pressure. The solution was decanted from the catalyst and the catalyst washed four times with methanol and decanted. The combined decanted solvent was evaporated and the residue dissolved in ethyl acetate and extracted twice with 1N hydrochloric acid (50 ml). The acid solution was made basic with 10% sodium hydroxide and extracted with three portions of ethyl acetate. The ethyl acetate was washed with water, brine, dried over sodium sulfate and the solvent removed to give the product as an oil (12.3 g, 100%).
Reaction SMILES: [C:1]1(=O)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH2:7][CH2:6][CH2:5][CH:4]3[CH2:3][CH2:2]1.[BH4-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-]>O1CCCC1.C(OCC)(=O)C>[CH2:11]1[C:12]2=[C:13]3[C:4](=[CH:3][CH:2]=[CH:1]2)[CH2:5][CH2:6][CH2:7][CH:8]3[CH2:9][CH2:10]1
Reactant: O=C1CCC2CCCc3cccc1c32
Agent: [Al+3]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1cc2c3c(c1)CCCC3CCC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A solution of 2,3,3a,4,5,6-hexahydro-phenalene-1-one (2.00 g) in anhydrous tetrahydrofuran (70 ml) was cooled to 0° C., and slowly added with sodium borohydride (1.62 g) and aluminum chloride (2.85 g). The reaction mixture was refluxed by heating for 3 hours, then cooled to 0° C., and diluted with ethyl acetate. The reaction mixture was slowly added with ice until foaming ceased, and then the mixture was made to be at room temperature and stirred overnight. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane) to obtain the title compound (1.47 g, yield: 80%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C1COCC1>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:38][CH:37]=2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCOCC3)cc2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.240 mmol) and THF (1 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (47.08 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified via flash silica gel chromatography (5% MeOH/95% CHCl3) yielding 67% (94 mg, 0.163 mmol) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[CH2:22][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCc1nc2ccccc2o1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2nc3ccccc3o2)c1
Yield: 51.1 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-chloromethyl benzoxazole were reacted by the same way with the example 1 to obtain the titled compound (207 mg, yield: 51.1%).
Reaction SMILES: [N:1]([C@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[N+:2]=[N-:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:9][C@H:5]1[C@@H:4]([N:1]=[N+:2]=[N-:3])[NH:7][C:6]1=[O:8]
Reactant: [N-]=[N+]=N[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=N[C@H]1NC(=O)[C@H]1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.45 g of (3S,4R)-4-azido-3-tritylamino-2-oxoazetidine in 4 ml of acetone is added under ice-cooling 0.255 g of p-toluenesulfonic acid monohydrate, and the mixture is stirred for one hour at room temperature. The solvent is distilled off, and the resulting crystals are washed with ether. The crystals are collected by filtration to give 0.33 g of tosyl salt of (3S,4R)-3-amino-4-azido-2-oxoazetidine.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=[O:17])[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]([O:18]/[N:20]=[C:21](/[C:23]3[CH:40]=[CH:39][C:26]([CH2:27][N:28]4[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:29]4)=[CH:25][CH:24]=3)\[NH2:22])=[O:17])[S:10][C:11]=2[C:12]([F:14])([F:15])[F:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/OC(=O)c3cc(-c4ccccc4)c(C(F)(F)F)s3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
A mixture of 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid (408 mg, 1.50 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 458 mg, 1.50 mmol), HOBt (345 mg, 2.250 mmol), Hunig's Base (1.05 mL, 6.00 mmol), and EDC (431 mg, 2.25 mmol) in N,N-dimethylformamide (7.5 mL) was stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate (120 mL) and a saturated aqueous solution of sodium bicarbonate (60 mL). The organic layer was washed with water (2×120 mL), washed with brine (120 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded (Z)-tert-butyl 1-(4-(N′-(4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyloxy)carbamimidoyl)benzyl)azetidine-3-carboxylate (744 mg, 1.33 mmol, 89% yield) as a light peach colored solid that was used in the next step without further purification. HPLC: ret. time=3.26 minutes (YMC Combi S-5 4.6×50 mm ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=560.25.
Reaction SMILES: C([O:3][C:4](=[O:36])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH:32]=[O:33])=[CH:26][C:25]=2[O:34][CH3:35])=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])C.[Li+].[OH-].OO.Cl.[CH2:42]1COC[CH2:43]1>>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:36])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH2:32][O:33][CH2:42][CH3:43])=[CH:26][C:25]=2[O:34][CH3:35])=[CH:22][CH:23]=1)=[O:16]
Reactant: C1CCOC1
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(C=O)cc2OC)cc1)NC(=O)c1c(F)cccc1Cl
Agent: Cl
Agent: OO
Agent: [Li+]
Product: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3Cl)C(=O)O)cc2)c(OC)c1
Temperature: 5 °C
Reaction time: 14 h

Procedure:
To a solution of the product obtained in Example 19 (210 mg) in THF (5 ml) were added 0.5N LiOH (1.54 ml) and 3% H2O2 (65 μl) at 5° C. The mixture was stirred at 5° C. for 14 hours and acidified with 1 N HCl. The mixture was concentrated, diluted with H2O and the resulting precipitate was collected by filtration and washed with H2O to yield the title compound (171 mg). mp. 182-184° C.; IR (Nujol) 3295, 1729, 1711, 1653 cm−1; MS (ESI) m/z 514 (M−H)
Reaction SMILES: [CH2:1]([C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:25]([C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)#[N:26]>CN(C)C=O>[CH2:1]([C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][O:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:25]#[N:26])[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COc1cccc(C#N)c1)Cc1ccccc1

Procedure:
8.52 g (31.6 mmol) of t-butyl N-[(1R)-1-benzyl-2-chloroethyl]carbamate, 12.1 g (87.5 mmol) of potassium carbonate and 5 g (41.9 mmol) of 3-cyanophenol were reacted in 120 ml of dimethylformamide as the solvent at 70° C. overnight. After the treatment in an ordinary manner followed by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:6]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:53](O)(=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55]>C1COCC1>[C:1]([O:4][C@H:5]1[CH2:6][C@H:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:8][C@H:9]([O:11][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC(C)(C)C(=O)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1C[C@@H](OC(=O)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h

Procedure:
To a solution of 10.67 g of (1R,3S,5S)-3-(tert-butyl-dimethyl-silanoxy)-5-hydroxycyclohex-1-yl acetate in 107 ml of THF was added at 22° 14.55 g of triphenylphosphine, the solution was cooled to 0° and treated dropwise with a solution of 11.81 g of diisopropyl azodicarboxylate and 5.67 g of pivalic acid in 85 ml of THF over 1 h and the solution was stirred at 0° for 1 h after which time t.l.c. showed completion of the reaction. The solution was evaporated, the residue triturated with 130 ml of hexane/AcOEt 9:1, the suspension was filtered and the filtrate evaporated. The residue was chromatographed on silica with hexane/AcOEt 30:1 to give 12.63 g of the pure (t.l.c.) title compound as a colorless oil. IR (neat): 1733s (C═O); MS (EI): 371/1 (M−H).