Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[C:3]=1[C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+].ClC([Si](C)(C)C)C.Cl>CN(C)C=O>[C:10](#[N:11])[C:3]1[C:4](=[CH:7][CH:8]=[CH:9][CH:2]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(O)c1C#N
Agent: CC(Cl)[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C#N
Temperature: 25 °C
Reaction time: 36 h
Yield: 95.1 %

Procedure:
In 200 ml of N,N-dimethylformamide were dissolved with heating 20 g of 3-hydroxyphthalonitrile and 10.55 g of potassium carbonate, to which 20 g of 1-chloroethyl-trimethylsilane were added dropwise at 30° C. in the atmosphere of argon. Immediately after the addition, the mixture was stirred for 36 hours while maintaining the reaction temperature at 85°-100° C. The reaction vessel was then cooled to room temperature and 200 ml of dilute hydrochloric acid was added. The mixture was extracted with 1 liter of toluene. The organic layer was washed well with water and water was removed with magnesium sulfate. Thereafter, toluene was removed by distillation and the residue was purified with a toluene/silica gel column to obtain 16.9 g (yield: 49.9%) of a compound having the formula (XVIII) below. The compound is in the form of white crystals and has a melting point of 67.5° C. The IR spectrum of the compound is shown in FIG. 4. ##STR40##
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[C:37]([CH:39]1[CH2:42][NH:41][CH2:40]1)#[N:38].C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C.O>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([CH3:10])[C:11]([N:41]1[CH2:42][CH:39]([C:37]#[N:38])[CH2:40]1)=[O:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#CC1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
Boc-D-alanine (1.0 g, 5.29 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.87 g, 5.81 mmol) were dissolved in dichloromethane. 3-Cyanoazetidine hydrochloride (0.94 g, 7.93 mmol) and then N,N-diisopropylethylamine (2.3 mL, 13.2 mmol) were added and the mixture was stirred at room temperature for 16 h. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to provide 0.91 g (68%) of [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: C1(C)C=CC=C(CC[O:9][C:10](=[O:29])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[C:13]([CH:27]=[O:28])[CH:12]=2)C=1.[Li+].[OH-].O>C1COCC1>[CH:27]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1)[C:10]([OH:29])=[O:9])=[O:28]
Reactant: Cc1cccc(CCOC(=O)c2ccc(OCCc3cccc(C)c3)c(C=O)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(CCOc2ccc(C(=O)O)cc2C=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.2 %

Procedure:
8.0 g of 3-Formyl-4-(2-m-tolyl-ethoxy)-benzoic acid 2-m-tolyl-ethyl ester and 1.7 g of LiOH (Monohydrate) were stirred in 30 ml of THF and 2 ml of water at room temperature for 16 h. Then, an additional 1 g of LiOH (monohydrate) was added and the mixture stirred at room temperature for 4 h. Then, 100 ml of water were added, the THF evaporated and the aqueous layer was washed twice with diisopropylether, 100 ml each. The aqueous layer was then acidified to pH=3 using aqueous HCl-solution and the crude product collected by filtration. Chromatography on silica gel using a gradient EA/HEP to EA yielded 1.2 g of the title compound that was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:17][CH3:18])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:2][C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4])=[C:12]([O:17][CH3:18])[CH:11]=1
Reactant: COc1cc(Br)ccc1O
Reactant: CON(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1OCC(=O)N(C)OC
Temperature: 60 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-N-methoxy-N-methylacetamide (2.7 g, 19.63 mmol), 4-bromo-2-methoxyphenol (3.98 g, 19.63 mmol), and potassium carbonate (5.43 g, 39.3 mmol) in DMF (20 mL) was heated at 60° C. for 1 hour and stirred at RT overnight (16 hours). The reaction mixture was diluted with CH2Cl2, washed with sat NaHCO3, brine and dried (Na2SO4). After concentration, the crude product was purified by ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 0:100 gradient) to afford 2-(4-bromo-2-methoxyphenoxy)-N-methoxy-N-methylacetamide 16A (4.86 g, 15.98 mmol, 81% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 6.97-7.04 (2H, m), 6.76 (1H, d, J=8.03 Hz), 4.86 (2H, s), 3.87 (3H, s), 3.75 (3H, s), 3.23 (3H, s).
Reaction SMILES: CC1NC=NC=1CSCCN[C:12]1[NH:17][C:16](=[O:18])[C:15]([CH2:19][C:20]2[CH:25]=[C:24]([O:26]C)[CH:23]=[CH:22][N:21]=2)=[CH:14][N:13]=1.[BrH:28]>>[BrH:28].[BrH:28].[BrH:28].[OH:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([CH2:19][C:15]2[C:16](=[O:18])[NH:17][CH:12]=[N:13][CH:14]=2)[CH:25]=1
Reactant: COc1ccnc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)c1
Agent: Br
Product: O=c1[nH]cncc1Cc1cc(O)ccn1

Procedure:
A mixture of 2-[2-(5-methyl-4-imidazolylmethylthio) ethylamino]-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone (0.97 g) and aqueous hydrobromic acid (48%, 20 ml) was boiled under reflux for 20 hours and evaporated to dryness. The residue was recrystallised from a mixture of ethanol and 2-propanol to give 2-]2-(5-methyl-4-imidazolylmethylthio) ethylamino]-5-(4-hydroxy-2-pyridylmethyl)-4-pyrimidone trihydrobromide, m.p. 167-169°. On recrystallisation from a mixture of ethanol and 2-propanol the melting point of the sample was lower owing to loss of hydrogen bromide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:12]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]1)=[O:14]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)NCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
To a stirred solution of 1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (10.0 g, 49.7 mmol) in CH2Cl2 (80 mL) was added EDC.HCl (13.8 g, 71.8 mmol) followed by 2,2,2-trifluoroethylamine (8.21 g, 82.8 mmol) and 4-(dimethylamino)pyridine (7.31 g, 59.8 mmol). The reaction mixture was stirred at ambient temperature for 18 h, taken up in 300 mL of EtOAC, then washed with aq. 10% HCl (3×), aq. 10% K2CO3 (2×) and aq. sat. NaCl (1×). The organic phase was dried (MgSO4) and concentrated in vacuo to afford the title compound as a white solid (11.8 g, 84%): mp 166-167° C.; 1H NMR (400 MHz, DMSO-d6) rotamers δ8.43 (s, 0.3H), 8.20 (s, 0.7H), 7.41 (s, 0.7H), 7.11 (s, 0.3H), 3.84 (dt, J=9.9, 4.9 Hz, 2H), 1.38 (d, J=11.4 Hz, 9H), 1.24 (q, J=4.3 Hz, 2H), 0.92 (q, J=4.3 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −70.57; 13C NMR (101 MHz, DMSO-d6) rotamers δ 172.82, 155.37, 124.64 (q, J=281 Hz), 78.29, 40.18 (q, J=34 Hz), 35.43, 34.70, 28.05, 27.84, 17.28, 16.62.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:30][CH2:31][CH2:32][CH2:33][OH:34])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[C:11]([O:30][CH2:31][CH2:32][CH:33]=[O:34])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=CCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
To a solution of 91.4 g of oxalyl chloride in 1.12 1 of methylene chloride, pre-cooled to -70° C., a solution of 123.4 g of dimethylsulfoxide in 0.18 l of methylene chloride was added within 25 minutes. The solution was stirred for 10 minutes at -70° C. Then, a solution of 143.3 g of 3-trityloxy-1-propanol in 0.6 l of methylene chloride was added within 25 minutes, the temperature being maintained at -65° to -70° C. Stirring was continued for another 10 minutes, and then, 182 g of triethylamine were added within 5 minutes at -65° to -70° C. The mixture was stirred for 20 minutes at -70° C. and then allowed to warm up to 10° C. within 1 hour. After the addition of 1.2 1 of water, stirring was continued for 5 minutes. The layers were separated, and the aqueous phase was extracted with 1.2 l of methylene chloride. The organic phases were washed with 1.2 l of water, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was crystallized from ethyl acetate/hexane to yield 116.0 g of 3-trityloxypropionaldehyde as white crystals of m.p. 97°-98° C.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[N:13]=[C:12]([CH2:14][OH:15])[C:11]2[C:16]([O:38][CH3:39])=[N:17][N:18]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[CH:9]=1.[C:40](=[O:50])([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH2:41]>C1COCC1>[CH2:43]([O:42][C:40](=[O:50])[NH:41][C:8]1[N:13]=[C:12]([CH2:14][OH:15])[C:11]2[C:16]([O:38][CH3:39])=[N:17][N:18]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[CH:9]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CO)c12
Reactant: NC(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)OCc3ccccc3)nc(CO)c12
Temperature: 50 °C
Reaction time: 10 h
Yield: 57.8 %

Procedure:
A 20 mL scintillation vial was charged with sodium tert-butoxide (105 mg, 1.097 mmol), (6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (35B, 250 mg, 0.548 mmol), benzyl carbamate (124 mg, 0.822 mmol) and BrettPhos-Pd-G3 (24.85 mg, 0.027 mmol). THF (5 ml) was added, the vial flushed with argon, capped and the contents heated to 50° C. with stirring for 10 h. The mixture was cooled, diluted with ethyl acetate (10 mL), washed with aqueous sodium hydrogen carbonate (saturated, 2×20 mL), dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel ISCO; 24 g prepacked, eluting with EtOAc/hexanes to afford benzyl(4-(hydroxymethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)carbamate (181 mg, 0.317 mmol, 57.8% yield) as a white solid. MS: [M+H]+ m/z 571.
Reaction SMILES: C([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[N:10]([CH2:16][CH2:17][CH2:18][NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[O:33][CH3:34])[CH2:22][CH2:21]2)[C:9]1=[O:35])C1C=CC=CC=1>CO.C([O-])=O.[NH4+].[Pd]>[F:32][C:29]1[CH:30]=[CH:31][C:26]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][CH2:18][CH2:17][CH2:16][N:10]3[C:11](=[O:15])[C:12]([CH3:14])=[CH:13][NH:8][C:9]3=[O:35])[CH2:25][CH2:24]2)=[C:27]([O:33][CH3:34])[CH:28]=1
Reactant: COc1cc(F)ccc1N1CCC(NCCCn2c(=O)c(C)cn(Cc3ccccc3)c2=O)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(F)ccc1N1CCC(NCCCn2c(=O)[nH]cc(C)c2=O)CC1

Procedure:
1-Benzyl-3-{3-[1-(4-fluoro-2-methoxyphenyl)piperidin-4-ylamino]propyl}-5-methyl-1H-pyrimidine-2,4-dione (Example 8) (100 mg, 0.2 mmol) was dissolved in a methanol solution of ammonium formate (0.1 M, 20 mL), treated with 10% palladium on carbon (100 mg) and the reaction heated to reflux for 24 h. The reaction mixture was filtered through a pad of celite, the filtrate concentrated and purified by pressurized silica gel chromatography (97.5:2:0.5 dichloromethane:methanol:ammonium hydroxide) to provide 3-{3-[1-(4-fluoro-2-methoxyphenyl)piperidin-4-ylamino]propyl}-5-methyl-1H-pyrimidine-2,4-dione. The hydrochloride salt was prepared according to conventional methods to provide a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=1)[C:7]([NH:9][CH2:10][CH2:11][OH:12])=[O:8].C(=O)([O-])[O-].[K+].[K+].F[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=1)[C:7]([NH:9][CH2:10][CH2:11][O:12][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1)=[O:8]
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc(Cl)cc1C(=O)NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Cl)cc1C(=O)NCCOc1ccc(C=O)cc1

Procedure:
A mixture of 2-(N-(5-chloro-2-methoxybenzoyl)amino)ethanol (4.5 g), potassium carbonate (5 g) and 4-fluorobenzaldehyde (2.5 g, 2.16 ml) were heated at 100° C. in dry dimethylsulphoxide (50 ml) for 18 hours. The mixture was cooled, diluted with water and extracted with diethyl ether containing a little methanol. The organic layers were combined, dried (MgSO4) and evaporated. The residual oil was chromatographed on silica gel with 2% methanol in dichloromethane as solvent to afford the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[C:3]1=[O:21]>CCO.[Pd]>[NH2:18][C:14]1[CH:13]=[C:12]([C:4]2[C:3](=[O:21])[N:2]([CH3:1])[C:7]3[N:8]=[CH:9][N:10]=[CH:11][C:6]=3[CH:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1c(=O)c(-c2cccc([N+](=O)[O-])c2)cc2cncnc21
Agent: [Pd]
Solvent: CCO
Product: Cn1c(=O)c(-c2cccc(N)c2)cc2cncnc21
Reaction time: 1.5 h
Yield: 49.5 %

Procedure:
To a solution of 8-methyl-6-(3-nitrophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (0.35 g, 1.2 mmol) in EtOH (10 mL) was added Pd (0.2 g). The mixture was stirred under an atmosphere of H2 (30 psi) for 1.5 h. After removal of the catalyst by filtration, the solvent was evaporated under vacuum to give 6-(3-aminophenyl)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (150 mg, 50% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.08 (d, J=4.2 Hz, 1H), 8.18 (s, 1H), 7.85 (m, 1H), 7.80 (d, J=5.4 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.43 (d, J=5.4 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.[CH3:17]O>>[OH:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[I:1])[C:6]([O:8][CH3:17])=[O:7]
Reactant: CO
Reactant: O=C(O)c1ccc(I)c(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(I)c(O)c1

Procedure:
4-Iodo-3-hydroxybenzoic acid (VI) is esterified with methanol in the presence of sulphuric acid in order to provide methyl 3-hydroxy-4-iodobenzoate (VII).
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(N(C(C)C)C(C)C)C>[OH:11][CH2:10][CH2:9][CH2:8][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCCBr
Reactant: OCCCNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(CCCO)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A mixture of 3-(phenylamino)propan-1-ol (Huang, et al., J.Org.Chem.; 58(23):6235-6246(1993)) (65.6 g, 0.43 mol), ethyl 4-bromobutyrate (104.5 g, 0.54 mol) and 100 mL of ethyldiisopropylamine is stirred at 100° C. for 1 h. The reaction is cooled to room temperature and partitioned between water 400 mL and ethyl acetate (500 mL). The organic layer is washed with saturated NaHCO3, brine and dried over Na2SO4. The oil obtained after concentration is chromatographed on silica eluting with 10% EtOH/CHCl3. Concentration of the appropriate fractions affords 115 g (100%) of the desired product as a colorless, viscous oil. 1H NMR (CDCl3) δ 7.23 (m, 2H), 6.72 (m, 3H), 4.14 (q, J=7 Hz, 2H), 3.72 (t, J=6 Hz, 2H), 3.43 (t, 7 Hz, 2H), 3.34 (t, 7 Hz, 2H), 2.35 (t, 7 Hz), 1.88 (m, 4H), 1.26 (t, 7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[C:7]([F:13])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[S:4][C:3]=1[C:14]([O:16]C)=[O:15].O.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[C:6]2[C:7]([F:13])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[S:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1sc2c(OC)ccc(F)c2c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c2c(Cl)c(C(=O)O)sc12
Temperature: 40 °C
Yield: 57.4 %

Procedure:
Methyl 3-chloro-4-fluoro-7-methoxy-1-benzothiophene-2-carboxylate (2.00 g, 7.29 mmol) was suspended in THF:H2O[10:1] and lithium hydroxide (260 mg) added, the resulting suspension was heated to 40° C. for 1 h. After cooling to room temperature the mixture was extracted with diethyl ether (50 mL) and the aqueous phase acidified to pH 2 and the solid collected by filtration and vacuum dried to give a white solid (1.09 g, 58%); δH (300 M , DMSO) 7.32-7.20 (1H, m, Ar), 7.15-7.05 (1H, dd, Ar), 3.98 (3H, s, OCH3).
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([C@@H:7]2[O:11][C@H:10]([CH2:12][O:13][P:14]([O:17][P:18]([O:21][CH2:22][C@H:23]3[O:27][C@@H:26]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH2:37])[C:31]=5[N:30]=[CH:29]4)[C@H:25]([OH:38])[C@@H:24]3[OH:39])([OH:20])=[O:19])([OH:16])=[O:15])[C@@H:9]([OH:40])[C@H:8]2[OH:41])[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH:2]=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>C(O)C(N)(CO)CO>[CH:34]1[N:35]=[C:36]([NH2:37])[C:31]2[N:30]=[CH:29][N:28]([C@@H:26]3[O:27][C@H:23]([CH2:22][O:21][P:18]([O:17][P:14]([O:13][CH2:12][C@H:10]4[O:11][C@@H:7]([N:5]5[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH2:2][CH:1]=[CH:6]5)[C@H:8]([OH:41])[C@@H:9]4[OH:40])([OH:16])=[O:15])([OH:20])=[O:19])[C@@H:24]([OH:39])[C@H:25]3[OH:38])[C:32]=2[N:33]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NC(CO)(CO)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
A mixture of substrate (5 mM), oxidized cofactor NAD+ (100 μM), glucose (20 mM) in 50 mM Tris buffer pH 7.5 (0.8 ml) was admixed with (D)-GDH (10 u), after the enzyme (100-200 μg) had been added, and the reaction was carried out at 30° C. (140 rpm) for 48 hours.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:23]=[CH:22][C:10]([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][CH:8]=1)=O.Cl.[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([NH:37][NH2:38])=[CH:36][C:31]=2[O:30][CH2:29]1>>[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([N:37]3[C:5]([C:7]4[CH:23]=[CH:22][C:10]([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][CH:8]=4)=[CH:4][C:3]([C:2]([F:26])([F:25])[F:1])=[N:38]3)=[CH:36][C:31]=2[O:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Reactant: NNc1ccc2c(c1)OCO2
Agent: Cl
Product: CC(C)(C)OC(=O)NCCOc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc3c(c2)OCO3)cc1
Yield: 56.7 %

Procedure:
The title compound (371.3 mg, 56.7%) was prepared from tert-butyl 2-[4-(4,4,4-trifluoro-3-oxobutanoyl)-phenoxy]ethylcarbamate obtained by Example 78-2 and 1-(1,3-benzodioxol-5-yl)hydrazine hydrochloride obtained by Example 83-1 in a similar manner to that of Example 78-3.
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:8][N:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[OH2:18].[OH-].[Li+]>C1COCC1.CO.O>[C:11]1([CH2:10][O:9][NH:7][CH2:8][C@@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([OH:17])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCC[C@@H]1CN(OCc2ccccc2)C1=O
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC[C@H](CNOCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of (3R)-3-butyl-1-[(phenylmethyl)oxy]-2-azetidinone (7) (52.8 g, 0.23 mol) in THF/MeOH (3:1, 1500 mL) at 0° C. was added Lithium hydroxide monohydrate (11.4 g, 0.27 mol) in water (375 mL). The mixture was warmed up to rt and stirred overnight. TLC indicated completion of the reaction. Organic solvents were removed under vacuum, and the aqueous solution was washed with DCM, acidified with 4 N HCl to pH ˜2.0, and extracted with DCM. The extracts were dried, filtered and concentrated to provide the title compound (40 g, 69%). LCMS: (M+H)+: 252.2.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=2)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCOCC1.O>[CH3:35][O:34][C:32]1[CH:31]=[C:30]([O:36][CH3:37])[N:29]=[C:28]([NH:27][C:26]([NH:18][S:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][C:6]2[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)(=[O:16])=[O:17])=[O:25])[N:33]=1
Reactant: CSc1nnc(Cc2ccccc2S(N)(=O)=O)s1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2Cc2nnc(SC)s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a suspension containing 0.63 g of the sulfonamide prepared in Example 3 in 10 ml of p-dioxane was added 0.6 g phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate followed by dropwise addition of 0.33 g of 1.8-diazabicyclo[5.4.0]undec-7-ene (DBU). The solution was stirred at room temperature for two hours then diluted with about 75 ml of water. After extracting the cloudy aqueous solution 1×30 ml of diethyl ether, the clear aqueous layer was acidified with concentrated hydrochloric acid (red to litmus paper), and the suspension was filtered. The residue was triturated with 5 ml of warm ethyl acetate to give 0.2 g of the subject compound; m.p. 171°-175° C. NMR (CDCl3, DMSO-d6): δ 2.7(s, SCH3); 4.0(s, OCH3); 4.95(s, CH2); 5.9(s, pyrimidine H); 7.6-8.4(m, ar); 9.8(s, NH) ppm.
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:11](O)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(#N)C.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:11]1[C:12]2[CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CC(C)C1CCc2ncnc(O)c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)C1CCc2ncnc(Cl)c21
Temperature: 80 °C
Yield: 26 %

Procedure:
A solution of 5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (4.29 g, 24.09 mmol) in acetonitrile (94.75 mL, 1814 mmol) was treated with POCl3 (6.62 mL, 72.28 mmol). The mixture was heated at 80° C. overnight. No reaction was observed by LC-MS or HPLC. An additional 3 equivalents of POCl3 were added, and the reaction was heated at 80° C. for 4 hours. The reaction was charged with an additional 10 equivalents of POCl3 and TEA (6.716 mL, 48.18 mmol) and heated at 80° C. overnight. The reaction was cooled to room temperature, and the solvent and POCl3 were removed under reduced pressure. The residue was taken up in DCM and was carefully added to stirring saturated NaHCO3. The mixture was stirred for 1 hour to confirm complete neutralization. The organics were combined and washed with brine, dried Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (25% EtOAc/Hexane) to yield 4-chloro-5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (1.23 g, 26%). LCMS (APCI+) m/z 196.9 [M+H]+; Rt=3.57 min