Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[CH:9][CH:8]=[C:7]([S:20]([N:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:22])=[O:21])[CH:6]=2.[C:38]([Zn]C#N)#[N:39]>[Zn].C([Pt](CCCC)CCCC)CCC.[Pd]>[C:38]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[CH:9][CH:8]=[C:7]([S:20]([N:23]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:21])=[O:22])[CH:6]=2)#[N:39]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OC)c(Br)cnc3c2)cc1
Reactant: N#C[Zn]C#N
Agent: CCCC[Pt](CCCC)CCCC
Agent: [Pd]
Agent: [Zn]
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OC)c(C#N)cnc3c2)cc1
Temperature: 25 °C

Procedure:
A vial was charged with 3-bromo-N-(4-methoxybenzyl)-4-(2-methoxyphenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (64.6 mg, 0.108 mmol), dicyanozinc (63.6 mg, 0.541 mmol), a spatula tip of zinc dust, and palladium compound with tributylplatinum (1:2) (18.18 mg, 0.022 mmol). The vial was flushed with Ar (g), then DMAC (1 mL) was added. The vial was sealed and placed in a 100° C. heating bath for 4 h. The mixture was cooled to room temperature, and then diluted with water and EtOAc. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 20-70% EtOAc/Heptane) to give 3-cyano-N-(4-methoxybenzyl)-4-(2-methoxyphenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide an off-white solid. m/z (ESI) 543.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.O>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH:9]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a solution of ethyl 3-(2-fluorophenyl)-3-oxopropionate (20 g, 95 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 3.80 g, 95 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (22.7 g, 95 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 4 hrs. The reaction solution was poured into water (300 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) to give ethyl 3-(2-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (25.7 g, 73%) as a colorless oil.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:21])=[O:20])=[O:15])(OCC1C=CC=CC=1)=O.Br>CC(O)=O>[NH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:20])=[O:21])=[O:15]
Reactant: O=C(CCNC(=O)OCc1ccccc1)NCCS(=O)(=O)O
Agent: Br
Solvent: CC(=O)O
Product: NCCC(=O)NCCS(=O)(=O)O
Temperature: 40 °C
Yield: 87.4 %

Procedure:
N-carbobenzoxy-β-alanyl-taurine (1.00 g, 3.4 mmol) was slurried in 23 ml glacial AcOH. To the mixture was added 3.4 mL HBr in AcOH (30 wt %) to result in a clear solution. The reaction was heated to 40° C. and allowed to mix overnight. The product precipitated out of solution and acetonitrile was added to force the precipitation. The mixture was filtered, the filter cake washed and the product collected. The crude Br salt was loaded onto an ion exchange column (Dowex AG1-XB8). The column was eluted with H2O. The product cut was collected and lyophilized to give 583 mg of β-alanyl-taurine (87.3%). The zinc salt was prepared by treatment with Zn(OH)2 in H2O, followed by lyophilization.
Reaction SMILES: [OH-].[Na+].[N:3]1([C:9]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[C:12]=2[C:17]([O:19]C)=[O:18])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[N:3]1([C:9]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[C:12]=2[C:17]([OH:19])=[O:18])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1c(C)noc1C(=O)N1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1noc(C(=O)N2CCCCC2)c1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
Under a nitrogen blanket and at -15° to -10° C., 1.0 g (25.0 mmol) of sodium hydroxide in 20 ml of water was dripped over a period of 4 hours into a solution of 5.7 g (22.6 mmol) of methyl 5-piperidinocarbonyl-3-methylisoxazole-4-carboxylate in 20 ml of methanol, and the mixture was stirred for 12 hours at room temperature. The solution was evaporated down, the residue was taken up in 100 ml of water, the pH was adjusted to 8-9, and the mixture was extracted once with 100 ml of diethyl ether. The mixture was acidified to a pH of 2 with 6N HCl, and extracted four times, each time with 100 ml of dichloromethane. The combined organic phases dried over magnesium sulfate and the solvent was stripped off under reduced pressure. Yield: 91%; mp.: 128°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)([C:22]([F:25])([F:24])[F:23])[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
After adding 5.85 g of toluene to 1.95 g (4.81 mmol) of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-fluorobenzonitrile, 1.14 g (9.62 mmol) of thionyl chloride and 0.76 g (9.62 mmol) of pyridine were added at 80° C., and stirred for 2 hours. The reaction solution was cooled to room temperature, and separated by adding 20 ml of toluene and 10 ml of water. After washing the toluene phase with an aqueous solution of 0.39 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 1.59 g of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-fluorobenzonitrile (yield 85.2%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:33]1[NH2+:34][C:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)=[CH:36][N:37]=1)[NH:17]C(=O)CC1C2C(=CC=C(OC)C=2)NC=1C)([OH:10])=[O:9].CCN(C(C)C)C(C)C.[CH3:57][N:58]([CH3:63])[S:59](Cl)(=[O:61])=[O:60]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:33]1[NH:34][C:35]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)=[CH:36][NH+:37]=1)[NH:17][S:59]([N:58]([CH3:63])[CH3:57])(=[O:61])=[O:60])([OH:10])=[O:9]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1ccc2[nH]c(C)c(CC(=O)N[C@@H](CCCCCC(=O)O)C3=NC=C(c4ccc5ccccc5c4)[NH2+]3)c2c1
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)N[C@@H](CCCCCC(=O)O)c1[nH]c(-c2ccc3ccccc3c2)c[nH+]1

Procedure:
A solution of Example 107, 15 (1 eq.), DIPEA (2 eq.) and dimethylsulfamoyl chloride (2 eq.) in DMF was stirred overnight at RT. The crude was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18) and the desired fractions were lyophilized to afford the titled compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 12.04 (1H, bs), 8.33 (1H, s), 8.12 (1H, bs), 8.09-8.00 (2H, m), 7.99-7.87 (3H, m), 7.63-7.52 (2H, m), 4.62-4.51 (1H, m), 2.63 (6H, s), 2.19 (2H, t, J=7.2 Hz), 2.02-1.84 (2H, m), 1.55-1.44 (2H, m), 1.44-1.35 (1H, m), 1.35-1.16 (3H, m). MS (ES) C22H28N4O4S requires: 444, found: 445 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14])=[O:4].[OH-:17].[K+].[CH3:19]O>>[CH3:14][C:6]1[NH:7][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:13]2[C:5]=1[C:3]([O:4][CH3:19])=[O:17]
Reactant: [OH-]
Reactant: CO
Reactant: Cc1[nH]c2cnccc2c1C(=O)C(Cl)(Cl)Cl
Agent: [K+]
Product: COC(=O)c1c(C)[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A mixture of 2,2,2-trichloro-1-(2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)ethanone (5.24 g, 18.9 mmol) and KOH (1.2 g, 20.9 mmol) in MeOH (100 mL) was stirred at room temperature for 16 hour. The reaction mixture was concentrated to remove MeOH, the residue was partitioned between EA and Water. The organic layer was washed with brine, dried and concentrated to afford methyl 2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (3 g, 83%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[I:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C[Si]([C:27]#[N:28])(C)C.[OH-].[NH4+]>C(#N)C>[C:27]([C:11]1([NH:20][C:19]2[CH:21]=[CH:22][C:16]([I:15])=[CH:17][CH:18]=2)[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: Nc1ccc(I)cc1
Reactant: C[Si](C)(C)C#N
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C#N)(Nc2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Boc-piperidinone (10 g, 50.2 mmol) was dissolved in acetonitrile (50 mL) and concentrated in vacuo twice, dissolved in glacial AcOH (50 mL). To the resulting solution was added 4-iodo-aniline (10.99 g, 50.2 mmol) and trimethylsilylcyanide (8 mL, 60.2 mmol). The reaction mixture was stirred at rt for 1 h, cooled to 0° C., poured onto 50 ml ammonium hydroxide and ice/water, extracted with DCM twice. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the desired product as a purple foam. LRMS (M+1-CN)=401.
Reaction SMILES: C(OC([NH:8][CH:9]([C:48]([OH:50])=[O:49])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:46][OH:47])[C:20]([NH:22][CH:23]2[CH2:26][N:25]([CH:27]([C:42]([OH:44])=[O:43])[C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:30][CH:29]=3)[C:24]2=[O:45])=[O:21])=[CH:15][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(OCC)C>C1C=CC=CC=1>[NH2:8][CH:9]([C:48]([OH:50])=[O:49])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[N:46][OH:47])[C:20]([NH:22][CH:23]2[CH2:26][N:25]([CH:27]([C:42]([OH:44])=[O:43])[C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:30][CH:29]=3)[C:24]2=[O:45])=[O:21])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC(CCOc1ccc(C(=NO)C(=O)NC2CN(C(C(=O)O)c3ccc(OCc4ccccc4)cc3)C2=O)cc1)C(=O)O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: NC(CCOc1ccc(C(=NO)C(=O)NC2CN(C(C(=O)O)c3ccc(OCc4ccccc4)cc3)C2=O)cc1)C(=O)O
Yield: 87.7 %

Procedure:
3-[2-{4-(3-tert-Butoxycarbonylamino-3-carboxypropoxy)phenyl}-2-hydroxyiminoacetamido]-1-(α-carboxy-4-benzyloxybenzyl)-2-azetidinone (240 mg) was suspended in benzene (2 ml), and to the suspension, there was added 2,2,2-trifluoroacetic acid (0.5 ml) at 7° C. with stirring. The mixture was stirred at the same temperature for 2 hours, and diethyl ether (about 25 ml) was added to the reaction mixture, and then the precipitating crystals were collected by filtration. The crystals were suspended in ethyl acetate and then the suspension was stirred at ambient temperature for half an hour. The crystals were collected by filtration and washed with diethyl ether to give 3-[2-{4-(3-amino-3-carboxypropoxy)phenyl}-2-hydroxyiminoacetamido]-1-(α-carboxy-4-benzyloxybenzyl)-2-azetidinone (180 mg), mp 164° to 167.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29])([CH3:24])([CH3:23])[CH3:22].O>C1COCC1>[C:21]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:12][CH:13]=1)=[O:29])([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: C=CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc(NC(=O)c2ccc(OC)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
In a round bottom flask, there are introduced 5.92 g (33.4 mmoles) of allyl 4-aminobenzoate, 5.6 ml (40.25 mmoles) of triethylamine and 100 ml of THF. A solution of 8 g (38.4 mmoles) of 3-tert.butyl-4-methoxybenzoyl chloride dissolved in 50 ml of THF are slowly added and the mixture is stirred at ambient temperature for 4 hours. The reaction medium is poured into water and extracted with dichloromethane. The organic phase is decanted, washed with demineralized water up to pH 6, dried on Na2SO4 and filtered. The solvents are evaporated under reduced pressure. The resulting maroon oil is crystallized in hexane. The solid is filtered and recrystallized in absolute ethanol. After filtration on fritted glass and drying for 48 hours at 80° C. 5.1 g (42.5%) of the expected ester are obtained in the form of white crystals whose melting point is 180°-182° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24]>>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2([OH:24])[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1ccc(C(C)C)cc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: COc1ccc(C(C)C)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 83.6 %

Procedure:
With 20.0 g of the compound obtained in Step 230-1 and 10.6 g of 5-chloroisatin as starting materials, 16.2 g of the title compound (pale yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: C([O:3][C:4]([CH2:6][NH:7][C:8]([CH2:10][O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:9])=O)C.[NH3:28]>C(O)C>[NH2:28][C:4](=[O:3])[CH2:6][NH:7][C:8]([CH2:10][O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:9]
Reactant: CCOC(=O)CNC(=O)COC[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: N
Solvent: CCO
Product: NC(=O)CNC(=O)COC[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 120 h

Procedure:
(S)-Phenylmethyl 2-[[[[[(ethoxycarbonyl)methyl]amino]carbonyl]methoxy]methyl]-1-pyrrolidinecarboxylate, 4 g (0.01057 mol), is dissolved in 100 ml of ethanol and the solution saturated with ammonia at room temperature. The solution is allowed to stand at room temperature for five days, the solvent evaporated in vacuo and the residue dissolved in 100 ml of methanol and the solution saturated with ammonia at room temperature. The solution is allowed to stand at room temperature for 14 hours and the solvent evaporated in vacuo. The residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (90:10) to give (S)-phenylmethyl 2-[[[[(2-amino-2-oxoethyl)amino]carbonyl]methoxy]methyl]-1-pyrrolidinecarboxylate, 3 g; mp 109.5°-111°; [α]D25 -41.0° (c 0.57, methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=S.[NH3:34]>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[NH:34]
Reactant: N
Reactant: COc1cc2c(NC(=S)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2c(NC(=N)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Mercuric(II) oxide (0.059 g) was added to a mixture of 1-(2,6-dimethylphenyl)-3-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]thiourea (0.105 g), a 2M solution of ammonia in methanol (3 ml) and chloroform (1 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 2M solution of ammonia in methanol as eluent. There was thus obtained the title compound (0.074 g); NMR Spectrum: (CDCl3) 1.39-1.53 (m, 2H), 1.87-2.02 (q, 5H), 2.29 (s, 3H), 2.36 (s, 6H), 2.9 (d, 2H), 4.01 (m, 5H), 5.79 (br s, 1H), 7.16 (s, 1H), 7.19 (m, 3H), 7.87 (s, 1H), 8.57 (s, 1H); Mass Spectrum: M+H+ 449.
Reaction SMILES: [Na].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:29])[CH:11]2[NH:15][C:16](=[O:28])[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[C:8]=1[C:30]([OH:32])=[O:31])(=[O:4])[CH3:3].[C:33]([O:39][CH2:40]Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C)C=O.C(OCC)(=O)C>[C:33]([O:39][CH2:40][O:31][C:30]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH:15][C:16](=[O:28])[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22]1)[C:10]2=[O:29])=[O:32])(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CSC12)n1cccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(C)=O)CSC12)n1cccc1
Reaction time: 0.5 h

Procedure:
The sodium salt of 3-[(acetyloxy)methyl]-7-[[2-carboethoxy-2-(1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (3 grams) was added to about 40 ml of dry dimethylformamide (DMF) and stirred for about 30 minutes. Then 4.0 ml of chloromethyl pivalate in 5 ml of DMF was added. The mixture was stirred for about 4 hours at room temperature. This mixture is diluted with ethyl acetate and thoroughly washed with water. The ethyl acetate portion is dried over sodium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [CH:1]12CC(C[CH2:6]1)[CH:3]=[CH:2]2.[C:8]([O:11]CC)(=[O:10])[CH3:9].I([O-])(=O)(=O)=O.[Na+].[C:20](=[O:22])=[O:21]>O.[Ru](Cl)(Cl)Cl.C(#N)C>[CH:9]1([C:8]([OH:11])=[O:10])[CH2:3][CH2:2][CH:1]([C:20]([OH:22])=[O:21])[CH2:6]1
Reactant: O=C=O
Reactant: C1=CC2CCC1C2
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C(O)C1CCC(C(=O)O)C1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
A 22-L, 3-neck, round bottom flask was equipped with a mechanical stirrer, a J-KEM temperature controller, and a nitrogen inlet. The flask was charged with norbornene (200 g, 2.123 mol), ethyl acetate (1.95 L), and acetonitrile (1.95 L). The reaction mixture was cooled to 5° C. using an acetone/dry ice bath. Ruthenium trichloride (9.69 g, 46.72 mmol) was added in one portion followed by the slow addition of a suspension of sodium periodate (1.816 kg, 8.707 mol) in water (2.925 L) over 30 min. The reaction slowly began to exotherm and was monitored to keep the temperature between 10° C. and 15° C. After 90 min the reaction mixture suddenly thickened to the point where stirring was difficult and exothermed rapidly up to 39° C. (a large amount of dry ice was added to the cooling bath to control the exotherm). The reaction mixture was allowed to cool to 20° C., the dry ice/acetone bath was removed, and the mixture was stirred at room temperature overnight. The solids were removed by filtration through a pad of celite and the filtrate was concentrated to a solid which was triturated with hexane (2 L), filtered, and rinsed with hexane (2×500 mL) to yield 195 g (58%) of cyclopentane-1,3-dicarboxylic acid. 1H NMR (500 Hz, DMSO-d6) δ ppm 12.07 (s, 2H), 2.66-2.73 (m, 2H), 2.06-2.12 (m, 1H), 1.85-1.89 (m, 1H), 1.72-1.85 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:31])[C:11](=[O:30])[NH:12][CH:13]1[C:19]2([CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[O:18][C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[NH:15][C:14]1=[O:29])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CS(O[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][C:39]=1[O:48][CH:49]([F:51])[F:50])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:50][CH:49]([F:51])[O:48][C:39]1[CH:40]=[CH:41][C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:38]=1[CH2:37][N:15]1[C:14](=[O:29])[C@@H:13]([NH:12][C:11](=[O:30])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH3:31])[C:19]2([CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[O:18][C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]1=2.[F:50][CH:49]([F:51])[O:48][C:39]1[CH:40]=[CH:41][C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:38]=1[CH2:37][N:15]1[C:14](=[O:29])[C@H:13]([NH:12][C:11](=[O:30])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH3:31])[C:19]2([CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[O:18][C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]1=2
Reactant: CS(=O)(=O)OCc1c(OC(F)F)ccc2ccccc12
Reactant: C[C@@H](C(=O)NC1C(=O)Nc2ccccc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(OC(F)F)ccc3ccccc23)c2ccccc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Product: C[C@@H](C(=O)N[C@H]1C(=O)N(Cc2c(OC(F)F)ccc3ccccc23)c2ccccc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 42 %
Yield: 30 %

Procedure:
A mixture of tert-butyl methyl((2S)-1-oxo-1-(4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)propan-2-yl)carbamate (118 mg, 272 μmol), (2-(difluoromethoxy)naphthalen-1-yl)methyl methanesulfonate (98.7 mg, 327 μmol) and Cs2CO3 (115 mg, 354 μmol) in DMF (681 μL) was stirred at RT for 20 h. The mixture was diluted with EtOAc, washed with H2O and brine, then dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue that was purified by silica gel chromatography. The resulting material was purified by SFC to provide tert-butyl (S)-1-((S)-5-((2-(difluoromethoxy)naphthalen-1-yl)methyl)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (52.6 mg, 30%) as a white foam (MS m/z 662 (MNa)′) and tert-butyl (S)-1-((R)-5-((2-(difluoromethoxy)naphthalen-1-yl)methyl)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (72.8 mg, 42%) as a white foam (MS m/z 662 (MNa)+).