Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][CH3:15])([O-])=O.[H][H]>NC1C(C)=CC=CC=1.O>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][CH3:15]
Reactant: [H][H]
Reactant: CCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: O
Solvent: Cc1ccccc1N
Product: CCOc1ccc(N)cc1N
Yield: 97.2 %

Procedure:
100 g (0.472 mol) of 2,4-dinitrophenetole were hydrogenated, in a 700 ml stirred autoclave, in 300 ml of o-toluidine with 12 g of water-moist palladium catalyst (1.0% by weight of palladium on active charcoal), corresponding to 4.8 g of dry catalyst, at about 80° C and a hydrogen pressure of between 5 and 10 bars. After about 23/4 hours, the hydrogen absorption and the reaction had ended. The catalyst was filtered off and the solvent and water of reaction were distilled off under normal pressure. 69.8 g (97.3% of theory) of crude 2,4-diaminophenetole of solidification point 63.5° C were obtained. The compound purified by distillation under reduced pressure had a solidification point of 64.2° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[N:9]1.[CH3:14]N(C)C=O.[H-].[Na+].CI>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]1
Reactant: CN(C)C=O
Reactant: Cc1ccccc1-n1nn[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1ccccc1-n1nnn(C)c1=O
Temperature: 25 °C

Procedure:
To a mixture of the above-mentioned 1-(2-methylphenyl)-1,4-dihydrotetrazole-5-one 69.8 g and N,N-dimethylformamide 380 mL was added 55% sodium hydride 18.2 g under ice-cooling. After stirring the resulting mixture for twenty minutes, thereto was added methyl iodide 59.4 g. The mixtures were raised to room temperature and were stirred for two and a half hours. To the reaction mixtures was added water and the mixtures were extracted with methyl tert-butyl ether. The organic layers were washed with 10% hydrochloric acid, water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 52.5 g.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[CH:6]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)OC1>O1CCOCC1.O.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>[CH3:28][N:27]1[C:23]([C:2]2[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[CH:6]=2)=[CH:24][CH:25]=[N:26]1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: O=C(O)c1csc(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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(C(=O)O)cs1
Temperature: 80 °C

Procedure:
To a solution of 2-bromo-4-thiophenecarboxylic acid (104 mg, 0.5 mmol) in dioxane/H2O (4:1, 10 mL) was added K2CO3 (271 mg, 1.99 mmol), tetrakistriphenylphosphine Pd(0) (28.7 mg, 0.025 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (97 mg, 0.5 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (104 mg, quant.): LC-MS (ES) m/z=209 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=3)[N:7]=[CH:6][C:5]=2[C:16]#[N:17])[CH2:3][CH2:2]1.COC1C=CC(/C=[C:33]2/[C:34]([NH:36][C:37]([S:39]/2)=[NH:38])=[O:35])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:38][C:37]1[S:39]/[C:33](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([C:16]#[N:17])=[C:4]3[CH:1]2[CH2:3][CH2:2]2)/[C:34](=[O:35])[N:36]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: N#Cc1cnc2ccc(C=O)cc2c1C1CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(/C=C3\SC(N)=NC3=O)cc2c1C1CC1

Procedure:
Similar procedure as described in example 38 was used, starting from 4-cyclopropyl-6-formyl-quinoline-3-carbonitrile (example 57c), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-cyclopropyl-quinoline-3-carbonitrile. LC-MS m/e 321 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH2:27][CH2:28][CH3:29])[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])C1C=CC=CC=1>C1COCC1.CO>[CH3:20][C:14]1([CH3:19])[CH2:13][CH:12]([N:21]([CH2:27][CH2:28][CH3:29])[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[O:15]1
Reactant: CCCN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(=O)(=O)CC
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(C1CC(C)(C)Oc2ccc(O)cc21)S(=O)(=O)CC

Procedure:
6.0 g of N-[6-benzyloxy-2,2-dimethylchroman-4-yl]-N-(1-propyl)ethanesulfonamide were dissolved in 150 ml of THF/methanol (1:1) and hydrogenated in a shaking duck using Pdlcarbon, 4.4 g of product, m.p. 173-175° C. (from petroleum ether).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]Br)[N:7]=1>CS(C)=O.O>[N:1]([CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Br:5])[N:7]=1)=[N+:2]=[N-:3]
Reactant: BrCc1cccc(Br)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium azide (3.11 g, 47.8 mmol) and 2-bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (4.00 g, 15.94 mmol) were combined in DMSO (30 mL) and stirred at room temperature for 4 h. The mixture was subsequently diluted with water and extracted with Et2O (2×). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (0-10% EtOAc/hexanes) to yield the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[CH:38]([Mg]Br)=[CH2:39].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]([OH:9])[CH:38]=[CH2:39]
Reactant: C=C[Mg]Br
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(C=O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
A solution of 6-(N-(3-chloro-4-formylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.25 g, 0.46 mmol) in THF (10 mL) was cooled to 0° and treated with vinylmagnesium bromide (1 M in THF, 1.02 mL). The reaction mixture was allowed to warm to rt as the bath melted. After 5 h, the reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc (2×). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient of 0 to 60% EtOAc in hexanes) afforded the title compound (188 mg, 72%) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (q, 1H), 8.11 (s, 1H), 7.93-8.01 (m, 2H), 7.36-7.56 (m, 5H), 7.18 (s, 1H), 5.90 (ddd, 1H), 5.71 (d, 1H), 5.35 (t, 1H), 5.22 (dt, 1H), 5.04-5.11 (m, 1H), 3.40 (s, 3H), 2.83 (d, 3H), 2.09-2.19 (m, 1H), 0.76-1.07 (m, 3H), 0.39-0.54 (m, 1H). LCMS (m/z, ES+)=569 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].Cl.N[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1.[OH-].[Na+]>O>[CH3:1][O:2][C:3](=[N:4][N+:5]([O-:7])=[O:6])[NH:8][CH2:11][C:12]1[CH:17]=[N:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: COC(=N)N[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 47.3 %

Procedure:
To a mixture of O-methyl-N-nitroisourea (1.25 g, 10.53 mmol), water (20 ml) and concentrated hydrochloric acid (0.85 ml, 10.03 mmol) was added 5-(aminomethyl)-2-chloropyridine (1.43 g, 10.03 mmol) dropwise over 5 minutes at room temperature with stirring. The reaction mixture was neutralized with 40% aqueous sodium hydroxide solution and adjusted to pH 7.2. After 17 hours of stirring at room temperature, the resulting crystals were collected. The crystals were washed with water and dried. As a result, 1.16 g (47.3% yield) of O-methyl-N-(6-chloro-3-pyridylmethyl)-N'-nitroisourea was obtained as white crystals. M.p. 112-113° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[O:22].N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:21](=[O:22])[N:20]([CH3:24])[CH3:19])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CN(C)C(=O)OC1CCN(C)C(=O)N1c1nnc(C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N,N-dimethylcarbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(N,N-dimethylcarbamoyloxy-2(1H)-pyrimidinone.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 67 %

Procedure:
A mixture of 13.4 parts of 1-(4-methoxyphenyl)piperazine dihydrochloride, 7.9 parts of 1-chloro-4-nitrobenzene, 10 parts of potassium carbonate and 90 parts of N,N-dimethylformamide is stirred and refluxed overnight. The reaction mixture is diluted with water and the product is extracted twice with trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is triturated in 4-methyl-2-pentanone. The product is filtered off and crystallized from 1,4-dioxane, yielding 10.5 parts (67%) of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine; mp. 195.1° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].NO.CC(O)=O.CO[CH:38](OC)[N:39](C)C>O1CCOCC1>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]4[O:26][N:39]=[CH:38][N:27]=4)=[CH:28][CH:29]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C(N)=O)cc3)CC2)nc1
Reactant: COC(OC)N(C)C
Agent: NO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(-c4ncno4)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the product of step B (80 mg, 0.203 mmol) in N,N-dimethylformamide dimethyl acetal (2 mL) was stirred at 120° C. for 4 h. Upon cooling to RT, the solvent was removed under vacuum to leave a residue. The resulting residue was dissolved in 1,4-dioxane (1 mL) followed by the addition of NH2OH (0.016 mL of 50% solution in H2O, 0.243 mmol) and HOAc (0.5 mL). The reaction was stirred at 90° C. for 4 h before being cooled to RT. The reaction was quenched with a saturated aqueous solution of NaHCO3 and the layer was extracted with EtOAc (×3). The combined organic layers were washed with brine (1×), dried over MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by silica gel column chromatography (elution with 5:1 hexane:ethyl acetate) to give the title compound. MS (ESI) m/z 420 [M+H]+. GPR119 Human EC50: 5.5 nM
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:25]([CH:27]4[CH2:29][CH2:28]4)=[O:26])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:9]=1)(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:15]1[N:20]=[C:19]2[S:21][C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])=[N:23][C:18]2=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Yield: 78.7 %

Procedure:
A solution of tert-butyl[3-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)phenyl]carbamate (900 mg, 2.11 mmol) and anisole (1 mL) in trifluoroacetic acid (10 mL) was stirred at 0° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue, and the mixture was extracted with tetrahydrofuran-ethyl acetate mixture (1:1, 50 mL, 15 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with a tetrahydrofuran-ethyl acetate mixture to give the title compound (542 mg, 79%) as a pale-yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:19]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=2[Cl:28])=[C:18]([F:29])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]=2[CH:6]=1)=O.[BH4-].[Na+]>CCO.C1COCC1>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:19]2[C:5]([CH2:3][OH:2])=[CH:6][C:7]3[N:11]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[N:9][C:8]=3[C:18]=2[F:29])=[C:22]([Cl:28])[CH:23]=1
Reactant: COC(=O)c1cc2c(ncn2CCS(C)(=O)=O)c(F)c1Nc1ccc(Br)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(CO)cc21
Reaction time: 96 h
Yield: 79.5 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carboxylic acid methyl ester 11 cc (0.300 g, 0.594 mmol) is suspended in a mixture of EtOH (6 mL) and THF (4 mL) under N2. NaBH4 (0.112 g, 2.97 mmol) is added. After approximately 4 days stirring, reaction mixture is quenched by the addition of AcOH until the reaction mixture reaches pH 7. The reaction mixture is concentrated to dryness under reduced pressure and the residue partitioned between ethyl acetate and water. The layers are separated and the organic layer is washed with water (3×), brine, and dried (Na2SO4). The organic layer is concentrated under reduced pressure until a white precipitate forms which is collected by filtration to give 0.225 g (79%) clean desired product: LC/MS ESI (+) m/z 478, 476 (M+ Br pattern) detected.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=C)=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:50]CC1.I([O-])(=O)(=O)=O.[Na+]>O.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=[O:50])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
Benzyl (2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-vinylquinolin-3-yl)carbamate (520 mg, 0.84 mmol) was mixed with THF (20 mL), 0.25 M osmium tetroxide in water (1.0 mL, 0.3 mmol) and sodium metaperiodate (840 mg, 3.9 mmol) in water (2 mL). The reaction mixture was stirred at 70° C. for 2 h, then allowed to cool. After cooling, the mixture was filtered through a diatomaceous earth plug, which was rinsed with fresh THF. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluting with EtOAc in hexanes (0-100%) to give the sub-title compound (320 mg, 61%) as yellow powder. LCMS calc. for C34H37N6O6 (M+H)+: m/z=625.2. Found: 625.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCN(CC)CC>C(Cl)Cl>[CH3:16][C:10]1([CH3:17])[C@@H:11]([C:13]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:15])[CH2:12][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N2CCOCC2)C1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (Intermediate 1-Step 3, 0.3 g, 1.23 mmol) in DCM (5 ml) EDCI (0.237 g, 1.23 mmol) and HOBt (0.167 g, 1.23 mmol) were added at about 0° C., after 10 minutes morpholine (0.2 ml, 2.469 mmol) and Et3N (0.9 ml, 6.2 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude purified by a silica gel column (100-200 mesh, elution 90% EtOAC in hexane) to afford the title compound as a syrup. Wt: 0.205 g; Yield: 53.1%; 1H NMR (300 MHz, CDCl3): δ 4.75 (d, 1H, J=8.4 Hz), 3.90-3.40 (m, 8H), 2.83-2.74 (m, 1H), 2.40-2.21 (m, 2H), 1.43 (s, 9H), 1.32 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[CH2:10][CH2:11][OH:12].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:12][CH2:11][CH2:10][C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1)(=[O:4])=[O:3]
Reactant: OCCc1cccc(O)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccc(OS(C)(=O)=O)c1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
9.09 g (79.6 mmole) methanesulfonyl chloride was slowly added to a solution of 5 g (36.2 mmole) 3-hydroxyphenethyl alcohol and 9.14 g (90.5 mmole) triethylamine in 150 ml dichloromethane at 0° C. After stirring at room temperature over night the salts were filtered off, the organic phase was washed with sodium bicarbonate and brine, dried (magnesium sulfate) and evaporated in vacuo to give 9.3 g (yield 87%) of 3-(methylsulfonyloxy)phenethyl methanesulfonate.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:17](=O)([O-])[O-].[Na+].[Na+]>O.CCOCC>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[CH2:12][CH2:13]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1

Procedure:
A solution of 1-(3-nitrophenyl)piperazine hydrochloride (1.80 g) in water (7 ml) was basified with anhydrous sodium carbonate (0.8 g) and the mixture evaporated to dryness in vacuo. The solid was mixed with formic acid (17 ml) and a solution of formaldehyde 36% in water (1.3 ml, ≡0.47 g CH2O) added and the mixture heated at 95°-98° for 3 h. The mixture was diluted with water (35 ml) and basified with anhydrous sodium carbonate. The suspension was extracted with ethyl acetate (2×80 ml) and the extract dried for 1 h. The mixture was filtered and the filtrate evaporated to dryness to give a dark red oil which was dissolved in ether (20 ml) and filtered. The filtrate was evaporated to dryness to give a red oil which was purified by FCC eluting with System A (500:8:1) to give an orange oil which was dried in vacuo. Upon scratching, crystallisation began and the oil was left to stand until crystallisation of the title compound was complete (1.10 g) m.p. 53°-54° C.
Reaction SMILES: [SH:1][CH:2]1[N:5]([C:6](=[C:15]([OH:17])[CH3:16])[C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[C:4](=[O:18])[CH:3]1[NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl[C:31]([O:33][CH2:34][CH:35]1[CH2:37][CH2:36]1)=[O:32]>[Ag].C(N(CC)CC)C>[CH:35]1([CH2:34][O:33][C:31]([S:1][CH:2]2[N:5]([C:6](=[C:15]([O:17][C:31]([O:33][CH2:34][CH:35]3[CH2:37][CH2:36]3)=[O:32])[CH3:16])[C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:12])[Cl:13])=[O:8])[C:4](=[O:18])[CH:3]2[NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:32])[CH2:37][CH2:36]1
Reactant: O=C(Cl)OCC1CC1
Reactant: CC(O)=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1S
Agent: [Ag]
Solvent: CCN(CC)CC
Product: CC(OC(=O)OCC1CC1)=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a solution of silver salt of 2,2,2-trichloroethyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate (695 mg) in hexamethyl phoshorotriamide (8 ml) is added a mixture of cyclopropylmethyl chloroformate (480 mg) and triethylamine (180 mg), and the mixture is stirred for 1 hour. The reaction mixture is poured into ice water, and is extracted with benzene. The extract solution is washed with water, dried, and evaporated in leave residue. Purification of the residue by chromatography over silica gel to give 2,2,2-trichloroethyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-cyclopropylmethoxycarbonyloxyethylidene)acetate (650 mg). Yield: 64.4%.