Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([C:16]2[N:17]=[C:18]([CH3:48])[N:19]([C:38]3[CH:39]=[CH:40][C:41]4[O:45][CH:44]([CH3:46])[CH2:43][C:42]=4[CH:47]=3)[C:20](=[O:37])[C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([C:16]2[N:17]=[C:18]([CH3:48])[N:19]([C:38]3[CH:39]=[CH:40][C:41]4[O:45][CH:44]([CH3:46])[CH2:43][C:42]=4[CH:47]=3)[C:20](=[O:37])[C:21]=2[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:3][C:4](=[O:7])[O:5][N:36]=3)=[CH:27][CH:28]=2)[CH2:15][CH2:14]1
Reactant: O=C([O-])O
Reactant: Cc1nc(C2CC2)c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n1-c1ccc2c(c1)CC(C)O2
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc(C2CC2)c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n1-c1ccc2c(c1)CC(C)O2
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.02 g), sodium hydrogen carbonate (1.19 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-cyclopropyl-2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.81 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.18 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.32 g, 35%).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][S:7]([CH2:10][C:11](Cl)=[O:12])(=[O:9])=[O:8]>C1COCC1>[C:1]([O:5][C:11](=[O:12])[CH2:10][S:7]([Cl:6])(=[O:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CS(=O)(=O)Cl
Reactant: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CS(=O)(=O)Cl

Procedure:
To a solution of t-butanol (0.3 mL) in THF (3 mL) was added 2-chlorosulfonylacetyl chloride (0.1 mL, 1.0 mmol) at room temperature for 1 h. The volatiles were removed to provide the chlorosulfonyl-acetic acid tert-butyl ester (230 mg). The crude product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[O:18])[NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH:5]=[CH:4][C:3]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:22][CH:21]=1.Cl[C:35]1[C:44]2[C:39](=[CH:40][C:41]([CH:45]([CH3:47])[CH3:46])=[CH:42][CH:43]=2)[N:38]=[CH:37][N:36]=1>C(O)C>[CH:45]([C:41]1[CH:40]=[C:39]2[C:44]([C:35]([NH:1][C:2]3[CH:7]=[C:6]([C:8](=[O:18])[NH:9][C@H:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH3:11])[CH:5]=[CH:4][C:3]=3[S:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:25]=3)=[N:36][CH:37]=[N:38]2)=[CH:43][CH:42]=1)([CH3:47])[CH3:46]
Reactant: C[C@H](NC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1)c1ccccc1
Reactant: CC(C)c1ccc2c(Cl)ncnc2c1
Solvent: CCO
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2c1
Yield: 74.7 %

Procedure:
(S)-tert-butyl 4-(2-amino-4-(1-phenylethylcarbamoyl)phenylthio)-phenylcarbamate (50 mg, 0.1078 mmol) and the product of Example 431F (24.5 mg, 0.1186 mmol) were heated at reflux in anhydrous ethanol (2 mL) under a nitrogen atmosphere for one hour. The reaction was cooled and concentrated by rotary evaporation. The residue was purified by silica gel flash chromatography eluting with 3:97 methanol/methylene chloride to afford the title compound as an off-white solid (51 mg, 0.0805 mmol, 68%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.31 (d, J=6.99 Hz, 6 H) 1.45 (d, J=7.35 Hz, 3 H) 1.47 (s, 9 H) 3.03-3.21 (m, 1 H) 5.01-5.29 (m, 1 H) 6.96 (d, J=8.46 Hz, 1 H) 7.16-7.25 (m, 1 H) 7.26-7.43 (m, 3 H) 7.32 (d, J=8.09 Hz, 2 H) 7.51 (d, J=8.82 Hz, 2 H) 7.55-7.63 (m, 2 H) 7.72 (dd, J=8.46, 1.47 Hz, 1 H) 7.94 (d, J=1.47 Hz, 1 H) 8.41 (d, J=8.82 Hz, 1 H) 8.44 (s, 1 H) 8.80 (d, J=8.09 Hz, 1 H) 9.58 (s, 1 H) 9.95 (s, 1 H); MS (ESI+) m/z 634 (M+H)+; MS (ESI−) m/z 632 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:24]([CH3:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[C:24]([CH3:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C1CNCCN1
Reactant: Cc1c(F)ccc(C(=O)Cl)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(F)ccc(C(=O)N2CCNC(=O)C2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-piperazinone (1 g, 9.99 mmol, commercially available from e.g. Sigma-Aldrich) was then dissolved in dichloromethane (DCM) (40 mL), and to this was added triethylamine (2.78 mL, 19.98 mmol). The solution was cooled to 0° C. before 2-chloro-4-fluoro-3-methylbenzoyl chloride, (2.072 g, 10.99 mmol), from Step 1, in DCM (10 mL) was added dropwise over 1 minute. The solution was then allowed to stir at room temperature for a further 30 minutes before the solvent was evaporated in vacuo. The remaining solid was then re-dissolved in DCM (80 mL) before being washed with water (30 mL), a saturated solution of sodium bicarbonate (30 mL), and brine (30 mL). The solution was then dried over anhydrous sodium sulphate, which was hen removed by filtration and the solvent was evaporated in vacuo. The remaining solid was then stirred in hexane at 55° C. for 30 minutes, before being filtered off to yield the product in 2.496 g.
Reaction SMILES: [Cl:1][C:2]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:17](OCC)(OCC)[O:18][CH2:19][CH3:20]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6](=[CH:17][O:18][CH2:19][CH3:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)nc1Cl
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1ccc(Cl)nc1Cl
Temperature: 140 °C
Reaction time: 2 h

Procedure:
Ethyl 2-(2,6-dichloronicotinoyl)acetate (7.03 g, 26.8 mmol) was dissolved in acetic anhydride (30 ml), and after adding triethyl orthoformate (60 ml) thereto, it was stirred in an oil bath of 140° C. for 2 hours. After letting the reaction solution cool, it was concentrated under a reduced pressure, and after adding toluene (50 ml) to the residue obtained, a concentration operation under a reduced pressure was performed. This operation was repeated 3 times, and the residue obtained was dried under a reduced pressure. 8.42 g of ethyl 2-(2,6-dichloronicotinoyl)-3-ethoxyacrylate was thereby obtained in the form of a yellow oily substance.
Reaction SMILES: [CH3:1]CCCCCCCC(C)C.C(O[CH2:18][C:19]1[CH:24]=[CH:23]C=[CH:21][CH:20]=1)(=O)C(C)=C.C(OCCOCCCC)(=O)C(C)=C.S[CH2:39][CH2:40][C:41]([O:43]C)=O.N(C(C1CC1)(C)C#N)=NC(C1CC1)(C)C#N.N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH3:21][CH2:20][CH:19]([CH2:24][CH2:23][C:41]([OH:43])([CH2:40][CH3:39])[CH3:1])[CH3:18]
Reactant: COC(=O)CCS
Reactant: C=C(C)C(=O)OCc1ccccc1
Reactant: CCCCCCCCC(C)C
Agent: C=C(C)C(=O)OCCOCCCC
Agent: CC(C#N)(N=NC(C)(C#N)C1CC1)C1CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCC(C)CCC(C)(O)CC
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixed solution of 16 g of Dispersion Stabilizing Resin (Q-1) having the structure shown below and 550 g of Isopar H was heated to a temperature of 50° C. under nitrogen gas stream while stirring. To the solution was dropwise added a mixed solution of 50 g of benzyl methacrylate, 40 g of 2-butoxyethyl methacrylate, 10 g Monomer (a-1) having the structure shown below, 2.6 g of methyl 3-mercaptopropionate and 1.2 g of 2,2'-azobis-(2-cyclopropylpropionitrile) (abbreviated as ACPP) over a period of one hour, followed by stirring for one hour. To the reaction mixture was added 0.8 g of ACPP, followed by reacting for 2 hours. Further, 0.5 g of 2,2'-azobis-(isobutyronitrile) (abbreviated as AIBN) was added thereto, the reaction temperature was adjusted to 80° C., and the reaction was continued for 3 hours. After cooling, the reaction mixture was passed through a nylon cloth of 200 mesh to obtain a white dispersion which was a latex of good monodispersity with a polymerization rate of 97% and an average grain diameter of 0.19 μm. The grain diameter was measured by CAPA-500 manufactured by Horiba Ltd. (hereinafter the same).
Reaction SMILES: [C:1]([C:5]([N:7]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:15]=1)[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[O:6])([CH3:4])([CH3:3])[CH3:2].[C-:28]#N.[Na+].[CH3:31][N:32]([CH:34]=O)C>>[C:1]([C:5]([N:7]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][C:31]#[N:32])=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:15]=1)[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[O:6])([CH3:4])([CH3:3])[CH3:2].[C:1]([C:5]([NH:7][C:14]1[CH:21]=[CH:20][C:17]([CH2:28][C:34]#[N:32])=[C:16]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])[CH:15]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)N(C(=O)C(C)(C)C)c1ccc(CBr)c(OCC(F)(F)F)c1
Reactant: [C-]#N
Agent: [Na+]
Product: CC(C)(C)C(=O)N(C(=O)C(C)(C)C)c1ccc(CC#N)c(OCC(F)(F)F)c1
Product: CC(C)(C)C(=O)Nc1ccc(CC#N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
To a stirred solution of 4-(N,N-di-(tert-butyl-carbonyl)-amino)-2-(2,2,2-trifluoroethoxy)benzyl bromide (1.5 g, 3.2 mmol) from Step 4 above in DMF (20 mL) was added NaCN (0.23 g, 4.8 mmol). The mixture was stirred at ambient temperature for 24 h. The solvent was removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using 15% EtOAc:hexanes as eluant to give an inseparable mixture (~3:1) of 4-(N,N-di-(tert-butylcarbonyl)amino)-2-(2,2,2-trifluoroethoxy)phenyl-acetonitrile and 4-(tert-butylcarbonylamino)-2-(2,2,2-trifluoroethoxy)-phenylacetonitrile (TLC Rf =0.28 (15% EtOAc:hexanes)).
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[C:13]([F:14])=[C:12]([O:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:9]=1[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:7][C:8]1[C:13]([F:14])=[C:12]([O:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:9]=1[C:19]1[CH:20]=[CH:21][C:22]([C:2]2[Se:3][CH:4]=[CH:5][CH:6]=2)=[CH:23][CH:24]=1
Reactant: CCCOc1ccc(-c2ccc(B(O)O)cc2)c(F)c1F
Reactant: Brc1ccc[se]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2ccc(-c3ccc[se]3)cc2)c(F)c1F

Procedure:
A mixture of 12.7 g (60.6 mmol) of 2-bromoselenophene, 17.7 g (60.6 mmol) of 2′,3′-difluoro-4′-propoxybiphenyl-4-ylboronic acid, 5.55 g (4.80 mmol) of tetrakis(triphenylphosphine)palladium(0) and 180 ml of 2 N sodium carbonate soln. in 600 ml of toluene/ethanol (1:1) is heated under reflux for 20 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with sat. sodium chloride soln., and the solution is dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, toluene). Further purification is carried out by recrystallisation from n-heptane:EtOH=3:1. 2-(2′,3′-Difluoro-4′-propoxybiphenyl-4-yl)selenophene is obtained as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][NH:13][C:14]([C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[CH2:23][N:17]2[C:18](=[O:29])[N:19]3[O:24][S:25]([O-:28])(=[O:27])=[O:26])=[O:15])[CH2:9]1)=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([O:12][NH:13][C:14]([C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[CH2:23][N:17]2[C:18](=[O:29])[N:19]3[O:24][S:25]([OH:28])(=[O:26])=[O:27])=[O:15])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NOC1CNC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium ({[(2S,5R)-2-({[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide 40 (0.1 g, 0.15 mmol) in DCM (8.8 mL) was added trifluoroacetic acid (0.44 mL, 5.7 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)—N-(azetidin-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 8 (Table 1) (0.01 g, 20%) as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:25]=[C:24]2[C:14]([C:15]([OH:32])=[C:16]([C:27](OCC)=[O:28])[C:17](=[O:26])[C:18]32[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=1.Cl.[C:34]([O:38][C:39](=[O:42])[CH2:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>O1CCOCC1.CCOCC>[Cl:10][C:11]1[CH:25]=[C:24]2[C:14]([C:15]([OH:32])=[C:16]([C:27]([NH:41][CH2:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:42])=[O:28])[C:17](=[O:26])[C:18]32[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccc(Cl)cc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Cl)cc2C2(CCOCC2)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
DIPEA (1.47 mL, 8.42 mmol, 1.5 eq) was added to a mixture of ethyl 7-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (1.89 g, 5.61 mmol, 1.0 eq) and glycine tert-butyl ester hydrochloride (1.13 g, 6.73 mmol, 1.2 eq) in dioxane (50 mL). The reaction mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude solid was suspended in ether and filtered to give the desired ester as a white solid (2.23 g). MS (m/e)=422.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:26])[O:17][CH2:18][CH:19]1[CH2:22][N:21]([C:23](=[O:25])[CH3:24])[CH2:20]1)([O-])=O.C([O-])=O.[NH4+]>CO.C1COCC1.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:26])[O:17][CH2:18][CH:19]1[CH2:22][N:21]([C:23](=[O:25])[CH3:24])[CH2:20]1
Reactant: CC(=O)N1CC(COC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])C1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N1CC(COC(=O)Nc2cc(-c3cccs3)ccc2N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.7 %

Procedure:
To a solution of (1-acetylazetidin-3-yl)methyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.15 g, 0.40 mmol, 1 eq.) in MeOH/THF (5 mL/5 mL) was added Zinc powder (0.13 g, 2.00 mmol, 5 eq.) and ammonium formate (0.20 g, 3.20 mmol, 8 eq.). The reaction was stirred at room temperature for 3 h. The reaction was filtered through Celite and the solids washed with MeOH. The filtrate was concentrated under reduced pressure then diluted with water. The obtained solid was filtered and dried. The crude product was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to obtain (1-acetylazetidin-3-yl)methyl (2-amino-5-(thiophen-2-yl)phenyl)carbamate (0.030 g, 22% yield). ESI+ MS: m/z 346 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 8.74 (bs, 1H), 7.50 (bs, 1H), 7.34 (d, J=5.0 Hz, 1H), 7.24-7.14 (m, 2H), 7.08-7.01 (m, 1H), 6.72 (d, J=8.0 Hz, 1H), 5.14 (bs, 2H), 4.30-4.10 (m, 3H), 3.95-3.80 (m, 2H), 3.68-3.55 (m, 1H), 2.95-2.85 (m, 1H), 1.74 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]([F:21])([F:20])[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:14][CH2:13]2.Br[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:25]([Cl:38])[CH:24]=1>C1(C)C=CC=CC=1>[Cl:38][C:25]1[CH:24]=[C:23]([N:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([F:8])([F:20])[F:21])[CH:11]=3)[CH2:16]2)[CH:28]=[C:27]([CH3:29])[C:26]=1[NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:35])([CH3:34])[CH3:36]
Reactant: Cc1cc(Br)cc(Cl)c1NC(=O)CC(C)(C)C
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(C(F)(F)F)ccc3C2)cc(Cl)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (154 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6-methyphenyl)-3,3-dimethylbutanamide (200 mg, 0.63 mmol) were then added and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:38])[NH:16][C:17]2[C:18](=[O:37])[N:19]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[C:20](=[O:28])[N:21]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:22]=2[NH2:23])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:40]([O:44][C:45](=[O:75])[N:46]([C:48]1[CH:53]=[CH:52][C:51]([CH2:54][C:55](=[O:74])NC2C(=O)N(CC3C=CC=CC=3F)C(=O)NC=2N)=[CH:50][CH:49]=1)[CH3:47])([CH3:43])([CH3:42])[CH3:41]>>[C:1]([O:5][C:6](=[O:39])[N:7]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15](=[O:38])[NH:16][C:17]2[C:18](=[O:37])[N:19]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[C:20](=[O:28])[N:21]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[C:22]=2[NH2:23])=[CH:12][CH:13]=1)[CH3:40])([CH3:4])([CH3:2])[CH3:3].[C:40]([O:44][C:45]([N:46]([CH3:47])[C:48]1[CH:49]=[CH:50][C:51]([CH2:54][C:55]([OH:74])=[O:5])=[CH:52][CH:53]=1)=[O:75])([CH3:41])([CH3:42])[CH3:43]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(CC(=O)Nc2c(N)[nH]c(=O)n(Cc3ccccc3F)c2=O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)Nc2c(N)n(CC3CC3)c(=O)n(Cc3ccccc3F)c2=O)cc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(CC(=O)Nc2c(N)n(CC3CC3)c(=O)n(Cc3ccccc3F)c2=O)cc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(CC(=O)O)cc1

Procedure:
Prepared by the same procedure as described for the preparation of (4-{[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-carbamic acid tert-butyl ester (example 1, step 5) except that (4-{[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-methyl-carbamic acid tert-butyl ester was used in place of (4-{[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-carbamic acid tert-butyl ester. Purified by chromatography using silica eluted with 3% v/v methanol in chloroform to give (4-{[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-methyl-carbamic acid tert-butyl ester as a colorless solid foam (63% yield from [4-(tert-butoxycarbonyl-methyl-amino)-phenyl]-acetic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[C:8](=[CH:19][N:20]([CH3:22])[CH3:21])[CH2:7][CH2:6]2
Reactant: CCOC(OCC)N(C)C
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Product: COc1cc2c(cc1OC)C(=O)C(=CN(C)C)CC2

Procedure:
From 3,4,5-trimethoxyphenylguanidinium nitrate (1.14 g, 4.0 mmol), 3,4-dihydro-6,7-dimethoxy-2-(dimethylaminomethylene)-1(2H)-naphthalenone (1.04 g, 4,0 mmol) and sodium hydroxide (176 mg, 4.4 mmol). The crude product was purified by chromatography on silica (3% methanol in dichloromethane) and recrystallised from ethyl acetate-hexane to give the title compound as pale yellow crystals (354 mg) m.p. 179-182°. δH (CDCl3) 8.22 (1H, s), 7.83 (1H, s), 7.12 (1H, br s), 6.99 (2H, s), 6.75 (1H, s), 3.96 (3H, s), 3.94 (3H, s), 3.88 (6H, s), 3.83 (3H, s) and 2.89-2.81 (4H, m). MS (ES+) 424 (MH+, 100%). The 3,4-dihydro-6,7-dimethoxy-2-(dimethylaminomethylene)-1(2H)-naphthalenone starting material was prepared from 6,7-dimethoxy-1-tetralone (4.12 g, 20 mmol) and N,N-dimethyl formamide diethyl acetal (10.3 ml, 60 mmol) to give the product as red-brown crystals (3.26 g) m.p. 138-140°. MS (ES+) 284 (MNa+, 12%), 262 (MH+, 100%), 189 (28%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=1.FC(F)(F)S(O[C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=1[CH3:32])(=O)=O>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[CH:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH3:32])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)CCCC1
Product: COC(=O)c1ccc(C2=C(C)CCCC2)cc1

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Step A (2 g, 7.63 mmol) and a mixture of 2-methyl-cyclohex-1-en-1-yl trifluoromethanesulfonate and 6-methyl cyclohex-1-en-1-yl trifluoromethanesulfonate (2.24 g, 9.16 mmol, approximately 5:1 ratio) were reacted according to the procedure of Example 1, Step F. Purification by preparative HPLC (Primesphere 5 silica, 5% methyl tert-butyl ether in hexane) afforded the title compound as an amorphous white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([O:11]CC)=[O:10])=[N:4]1)[CH3:2].[OH-].[K+].O>C(O)C>[CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([OH:11])=[O:10])=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cc(C)n(CC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1nc(C(=O)O)cc1C
Yield: 61.1 %

Procedure:
Ethyl 1-ethyl-5-methylpyrazole-3-carboxylate (10.93 g) in ethanol (70 ml) was treated with KOH (3.69 g), followed by water (30 ml), and the mixture was stirred and heated under reflux for 6 h. The ethanol was removed using a rotary evaporator and ethyl acetate/water were added. The pH of the mixture was adjusted to 3.0 and the layers were separated. The aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate layers were extracted with excess aqueous NaHCO3. The NaHCO3 extract was poured into excess acid, and the pH was then adjusted to 3, and NaCl was added to the solution. The mixture was then repeatedly extracted with ethyl acetate, and the combined extracts were dried (MgSO4) and evaporated. The residue was triturated with diethyl ether to give the acid as a solid (5.65 g) υmax (CH2Cl2) 2754, 2598, 1698, 1498, 1464, 1387, and 1233 cm−1; δ(CDCl3) 1.40 (3H, t, J 7.3 Hz), 2.32 (3H,s), 4.19 (2H, q, J 7.3 Hz), 6.61 (1H,s) ppm; (Found m/z 154.0740. C7H10N2O2 requires m/z 154.0742).