Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)(=[O:13])=[O:12])[CH2:9][C@@H:2]12.C(=O)([O-])[O-].[Na+].[Na+].I[CH:31]([CH3:33])[CH3:32].O>CS(C)=O>[CH:31]([N:6]1[CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=3)(=[O:13])=[O:12])[CH2:9][C@H:2]2[CH2:1]1)([CH3:33])[CH3:32]
Reactant: O=S(=O)(N[C@H]1C[C@H]2CNCCN2C1)c1cccc(C(F)(F)F)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N1CCN2C[C@@H](NS(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Example 42 (30 mg, 0.078 mmol) in dimethyl sulfoxide (1 mL) was added sodium carbonate (8.24 mg, 0.078 mmol) and 2-iodopropane (13.22 mg, 0.078 mmol). The mixture was stirred at room temperature for 3 days. The mixture was poured into 10 mL water, and the crude product was extracted with dichloromethane (3×8 mL). The combined organic fractions were concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.91 (dd, 6H, J=7 Hz), 1.10 (m, 1H), 1.85 (m, 3H), 2.12 (m, 1H), 2.22 (m, 1H), 2.69 (m, 3H), 3.69 (m, 4H), 7.85 (m, 1H), 8.06 (m, 3H); MS (ESI) m/z 392 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][O:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:49][CH2:48][C:47]4[CH:50]=[CH:51][C:44]([O:43][CH3:42])=[CH:45][CH:46]=4)[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: CS(=O)(=O)c1nccc(-c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2-c2cccc(C(F)(F)F)c2)n1
Product: COc1ccc(CNc2nccc(-c3[nH]c(C4CCN(C(=O)OCc5ccccc5)CC4)nc3-c3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 140 °C
Yield: 92.4 %

Procedure:
A mixture of 4-[5-(2-methylsulfonylpyrimidin-4-yl)-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (1.5 g, 0.00256 mole) and 4-methoxybenzylamine (3.51 g, 0.026 mole) was heated in a pressure tube at 140° C. for 10 minutes. The mixture was allowed to cool and the residue column chromatographed on silica using 5% methanol/methylene chloride to give 1.52 g of a yellow powder upon concentration in vacuo of product containing fractions.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[Cl:19].CN([CH:23]=[O:24])C>C1COCC1>[Br:13][C:14]1[CH:18]=[C:17]([CH:23]=[O:24])[S:16][C:15]=1[Cl:19]
Reactant: CN(C)C=O
Reactant: Clc1sccc1Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc(Br)c(Cl)s1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
n-BuLi (2.5 M in hexanes, 105 mL) is slowly added to a solution of diisopropylamine (36.8 mL) in THF (600 mL) at 0° C. After 15 min, the mixture is cooled to −70° C. A solution of 3-bromo-2-chlorothiophene (49.4 g) in THF (20 mL) is added maintaining the internal temperature <−65° C. After 15 min, DMF (25.2 mL) is added. The mixture is stirred at −70° C. for 15 min and then allowed to warm to room temperature. The reaction mixture is quenched with saturated aq. NH4Cl solution (200 mL) and concentrated in vacuo to one-half volume. The residue is diluted with EtOAc (500 mL) and the aqueous layer is separated. The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (100 mL), dried (MgSO4), and concentrated to afford an oil. The oil is purified by column chromatography (heptane; heptane/EtOAc, 20/1; 10/1) and the resulting solid is suspended in heptane (75 mL) and filtered to afford 30.3 g (54%) of the title compound as a light yellow solid. Physical characteristics: M.p. 61-62° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.82, 8.14; 13C NMR (100 MHz, CDCl3) δ 181.6, 140.9, 138.5, 138.1, 112.8.
Reaction SMILES: NC1C=CC(OC2C=CN=C3C=C(C(NN(C)C)=O)SC=23)=C(F)C=1.[F:25][C:26]1[CH:48]=[C:47]([N+:49]([O-])=O)[CH:46]=[CH:45][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[CH:35]=[C:36]([C:38]([N:40]([CH3:44])[N:41]([CH3:43])[CH3:42])=[O:39])[S:37][C:30]=12>>[NH2:49][C:47]1[CH:46]=[CH:45][C:27]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]3[CH:35]=[C:36]([C:38]([N:40]([CH3:44])[N:41]([CH3:42])[CH3:43])=[O:39])[S:37][C:30]=23)=[C:26]([F:25])[CH:48]=1
Reactant: CN(C)N(C)C(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: CN(C)NC(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: CN(C)N(C)C(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Yield: 33 %

Procedure:
Following the procedure described above for compound 239 (step 3, example 95, scheme 63) but replacing 238 with compound 243, title compound 244 was obtained in 33% yield. MS (m/z): (M+1) 361.1 (100%).
Reaction SMILES: O=[CH:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1.[NH2:19][C:20]1[C:21]([NH:30][CH3:31])=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>C(O)C.C(O)(=O)C>[CH3:31][N:30]1[C:21]2=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=[C:20]2[N:19]=[C:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:17][CH:18]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=CCOc1ccc(CC2SC(=O)NC2=O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 7.6 %

Procedure:
4.16 g of 5-(4-(2-oxoethoxy)benzyl) thiazolidine-2,4-dione (prepared as described in Preparation 47) were added to a solution of 3.00 g of 3-amino-2-methylamino-5-trifluoromethylpyridine in a mixture of 6 ml of ethanol and 6 ml of acetic acid, and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. 50 ml of 1,2-dimethoxyethane and 5.2 g of iodine were added to the residue, and the resulting mixture was stirred at 60° C. for one day. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent-was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent. The product was crystallized by trituration with ethyl acetate, to give 520 mg of the title compound, melting at 212-214° C.
Reaction SMILES: N[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.N([O-])=[O:20].[Na+].N>F[B-](F)(F)F.[H+]>[CH:14]1([C:5]2[C:6]([O:12][CH3:13])=[CH:7][CH:8]=[C:9]3[C:4]=2[NH:3][C:2](=[O:20])[N:11]=[CH:10]3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc2cnc(N)nc2c1C1CCCC1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: N
Agent: [H+]
Product: COc1ccc2cnc(=O)[nH]c2c1C1CCCC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
To a solution of 2-amino-8-cyclopentyl-7-methoxyquinazoline (1.38 g,) in tetrafluoroboric acid (30 mL), sodium nitrite solution (1.16 g in 10 mL of water) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 18 hours. The reaction mixture was cooled in a ice bath and neutralized with 30% ammonia solution. The product was extracted with ethyl acetate (3×50 mL), combined organic extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound as a orange solid (1.0 g, 73%). mp 201–204° C.; 1H NMR (CDCl3): δ 1.7–2.0 (complex, 8H, 4×CH2), 3.43 (m, 1H, CH), 3.96 (s, 3H, OCH3), 6.89 (d, 1H, Ar-H, J=8.8 Hz), 7.59 (d, 1H, Ar-H, J=8.8 Hz), 8.92 (brs, 1H, NH), 9.03 (s, 1H, Ar-H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:17]([NH2:22])(=[O:21])[CH:18]([CH3:20])[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[O:14]1[CH2:15][CH2:16][N:11]([C:4]2[CH:3]=[C:2]([NH:22][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=2)[CH2:12][CH2:13]1
Reactant: CC(C)C(N)=O
Reactant: O=[N+]([O-])c1cc(Cl)cc(N2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)(C)O
Product: CC(C)C(=O)Nc1cc(N2CCOCC2)cc([N+](=O)[O-])c1

Procedure:
Prepared according to Procedure W by stirring palladium (II) acetate (0.028 g, 0.124 mmol), tetramethyl tert-butyl XPhos (0.178 g, 0.371 mmol), 4-(3-chloro-5-nitrophenyl)morpholine (0.300 g, 1.236 mmol), isobutyramide (0.129 g, 1.484 mmol), potassium phosphate (0.367 g, 1.731 mmol), and tert-butanol (3 mL) at 110° C. for 4 h. Purification by column chromatography (silica; 0-30% EtOAc in hexanes) afforded N-(3-morpholino-5-nitrophenyl)isobutyramide as an orange amorphous solid. Mass Spectrum (ESI) m/e=293.9 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1)([CH3:15])[CH3:14].C(N(CC)CC)C>C(O)C>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[NH:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH:13]([CH3:15])[CH3:14])=[CH:17][CH:18]=1
Reactant: Fc1cccc2c(Cl)ncnc12
Reactant: CC(C)c1ccc(CCN)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)c1ccc(CCNc2ncnc3c(F)cccc23)cc1

Procedure:
A mixture of 2 g of 4-chloro-8-fluoroquinazoline, 1.94 g of 2-[4-(i-propyl)phenyl]ethylamine, and 1.21 g of triethylamine in 100 mL of ethanol was heated at reflux for one hour. The ethanol was removed and the remaining product was dissolved in 100 mL of methylenechloride and then washed with aqueous sodium carbonate. The organic layer was then dried and the solvent was removed. The residue was slurried in pentane. Yield: 2.4 g. M.P. 170°-172° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[C:32]([OH:34])[CH:31]=[C:30]([F:35])[CH:29]=2)[CH:19]=1)=[O:17].O[Li].O>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[C:32]([OH:34])[CH:31]=[C:30]([F:35])[CH:29]=2)[CH:19]=1)=[O:17]
Reactant: CCOC(=O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3cc(O)cc(F)c3)cc3ccccc23)c1
Agent: [Li]O
Solvent: O
Product: O=C(O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3cc(O)cc(F)c3)cc3ccccc23)c1

Procedure:
Compound 17g was synthesized from 16g (0.42 mmol) and LiOH.H2O (4.2 mmol) using the procedure according to Method E described above.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[N:6][N:7]([C:9]2[CH2:10][C@@H:11]3[CH2:28][C:27](=[O:29])[N:12]3[C:13]=2[C:14]([O:16]CC2C=CC([N+]([O-])=O)=CC=2)=[O:15])[CH:8]=1.N1(CCCS(O)(=O)=O)CCOCC1>O1CCOCC1.O.C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][C:4]1[N:5]=[N:6][N:7]([C:9]2[CH2:10][C@@H:11]3[CH2:28][C:27](=[O:29])[N:12]3[C:13]=2[C:14]([OH:16])=[O:15])[CH:8]=1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(n2cc(CCO)nn2)C[C@@H]2CC(=O)N12
Agent: [Pd]
Agent: O=S(=O)(O)CCCN1CCOCC1
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: O=C(O)C1=C(n2cc(CCO)nn2)C[C@@H]2CC(=O)N12
Reaction time: 0.67 h

Procedure:
A solution of p-nitrobenzyl 2-(4-[2-hydroxyethyl]-1,2,3-triazol-1-yl)-carbapen-2-em-3-carboxylate (3.5 mg, 8.8 micromol) in dioxane (300 microliter), deionized water (180 microliter), absolute ethanol (24 microliter), and pH 7.0 4-morpholinepropanesulfonic acid buffer (60 microliter of 0.5M) was shaken with 10% (w/w) palladium on charcoal (7.0 mg) under hydrogen (50 psig) at ambient temperature. After 40 min. the mixture was centrifuged and the pellet washed with deionized water (3×0.5 ml). The combined supernate and washes were extracted with ethyl acetate (3×0.5 ml) and concentrated under vacuum to provide 0.5 ml of a solution of 2-(4-[2-hydroxyethyl]-1,2,3-triazol-1-yl)-carbapen-2-em-3-carboxylic acid, UV λmax 299 nm which quenched upon addition of hydroxylamine hydrochloride and dipotassium hydrogen phosphate.
Reaction SMILES: [OH:1][CH:2]([C:16]([CH3:18])=[CH2:17])[CH2:3][CH2:4]/[C:5](/[CH3:15])=[CH:6]/[CH2:7][CH2:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([NH2:13])=[O:12]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:14]/[C:9](/[CH2:8][CH2:7]/[CH:6]=[C:5](\[CH3:15])/[CH2:4][CH2:3][C:2](=[O:1])[C:16]([CH3:18])=[CH2:17])=[CH:10]\[C:11]([NH2:13])=[O:12]
Reactant: C=C(C)C(O)CC/C(C)=C/CC/C(C)=C/C(N)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C/C(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1.9 g of (E,E)-10-hydroxy-3,7,11-trimethyl-2,6,11-dodecatrienamide in 50 ml of methylene chloride is treated with 19.0 g of manganese dioxide ("precipitated", activated by heating to 110° for 15 minutes) and the resulting suspension is stirred at room temperature for 16 hours. After filtration over Hyflo the filtrate is concentrated and the yellow oil obtained is chromatographed on 100 g of aluminum oxide (neutral, activity III) with hexane-ethyl acetate (50% to 100%). There is obtained (E,E)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienamide as a colourless oil which crystallizes upon standing, m.p. 42°-44°. IR (film): 3428, 3347, 3194, (NH2); 1671 (amide C=O, ketone conj. C=O). MS (CI with NH3): 250 (M+H)+.
Reaction SMILES: CO[C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:23][NH:24][C:25]([NH2:27])=[O:26].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=2)[C:3]([NH:27][C:25]([NH:24][CH3:23])=[O:26])=[O:22])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Yield: 18.1 %

Procedure:
3-Cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methyl ester (210.1 mg, 0.63 mmol) and methyl urea (140.5 mg, 1.90 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 3.6 mL, 2.53 mmol). The resulting reaction mixture was then heated under reflux for 64 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The celite was thoroughly washed with ethyl acetate until the solvent passing through the celite showed absence of desired product by thin layer chromatography. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)-propionyl]-3-methyl urea (42.7 mg, 18%) as a white solid: mp 144-145° C.; EI-HRMS m/e calcd for C17H21F3N2O2S (M+) 374.1276, found 374.1270.
Reaction SMILES: C([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([O:14][CH3:15])=[C:6]([N:16](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:5]=1)(=O)C.COCCN(S(F)(F)F)CCOC.[C:44](O)([C:46]([F:49])(F)[F:47])=O>ClCCCl>[NH2:16][C:6]1[CH:5]=[C:4]([C:46]([F:49])([F:47])[CH3:44])[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]=1[O:14][CH3:15]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1nc(C(C)=O)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1OC
Agent: COCCN(CCOC)S(F)(F)F
Solvent: ClCCCl
Product: COC(=O)c1nc(C(C)(F)F)cc(N)c1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of methyl 6-acetyl-4-[bis(tert-butoxycarbonyl)amino]-3-methoxypyridine-2-carboxylate (0.7 g, 1.649 mmol) in DCE (3.30 ml) was added Deoxo-Fluor® (1.520 ml, 8.25 mmol) and the reaction mixture was stirred at 80° C. overnight. The mixture was allowed to cool down to room temperature and TFA (2 mL) was added. The reaction mixture was stirred at room temperature (LC monitoring). After 12 h, the reaction was completed and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (ISCO, SiO2 24 g, hexane/EtOAc 100:0 to 0:100 gradient) to afford methyl 4-amino-6-(1,1-difluoroethyl)-3-methoxypicolinate (336 mg, 1.365 mmol, 83% yield) as an orange oil. ESIMS m/z 245 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 4.59 (s, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 1.98 (t, J=18.7 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −89.99.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]=[N:6][OH:7].[C:8]([Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])#[CH:9].ClN1C(=O)CCC1=O>C(Cl)Cl>[CH2:19]([Sn:10]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[C:8]1[O:7][N:6]=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:9]=1)[CH2:20][CH2:21][CH3:22]
Reactant: OCCCC=NO
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cc(CCCO)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
4-Hydroxybutyraldehyde oxime (Paul, R.; Fluchaire, M.; Collardeau, G. Bull. Soc. Chim. France, 1950, 668; 11.5 g, 112 mmol) was dissolved in CH2Cl2 (600 mL). KHCO3 (16.8 g, 168 mmol), then ethynyltributyltin (35.3 g, 112 mmol), then N-chlorosuccinimide (16.4 g, 123 mmol) were added, and the mixture was stirred at rt overnight. The mixture was washed with brine. The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:5→1:4→1:3→1:2→1:1) yielded the title compound (13.0 g, 28%). LC-MS: tR=1.17, ES+: 418.20.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[N:16]=[CH:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:35])[N:9]([CH3:34])[C:10]=3[CH:17]=[N:16][C:15]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[CH:32][CH:31]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)ncc21
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)ncc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.4 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-(3-chlorophenoxy)-1-methyl-2,4-dioxo-1,2-dihydro pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (20 mg, 0.0389 mmol) in THF (2 mL) and water (2 mL) was added LiOH.H2O (3.2 mg, 0.078 mmol). The reaction was stirred at RT for 15 min, then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(3-chlorophenoxy)-3-(3-hydroxypropyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (5 mg, 26% yield) as a white solid. 1H NMR (CDCl3) δ: 8.20 (s, 1H), 7.74 (dd, J=11.1, 9.8, 5.7 Hz, 2H), 7.32 (t, J=8.1 Hz, 1H), 7.23-7.16 (m, 3H), 7.03 (t, J=2.1 Hz, 1H), 6.90 (dd, J=8.2, 1.5 Hz, 1H), 4.82 (s, 2H), 4.24 (t, J=6.2 Hz, 2H), 3.60 (d, J=13.0 Hz, 3H), 3.56 (d, J=5.6 Hz, 2H), 2.87 (s, 1H), 1.99-1.84 (m, 2H). LCMS: MH+ 486 and TR=3.024 min
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[NH2:11].C([Sn](CCCC)(CCCC)[CH2:18][O:19][CH3:20])CCC.[F-].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:18][O:19][CH3:20])=[N:6][C:5]=1[NH2:11]
Reactant: COC(=O)c1ccc(Cl)nc1N
Reactant: CCCC[Sn](CCCC)(CCCC)COC
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COCc1ccc(C(=O)OC)c(N)n1
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 61.8 %

Procedure:
A mixture of 2-amino-6-chloro-nicotinic acid methyl ester (1.4 g, 7.6 mmol) described in Production Example 4-1-2, tributyl methoxymethyl stannane (3.1 g, 9.1 mmol) described in Production Example 4-1-3, tetrakis(triphenylphosphine) palladium (440 mg, 0.38 mmol) and N-methylpyrrolidinone (20 mL) was stirred for 3.5 hours at 130° C. The reaction mixture was allowed to cool on standing followed by the addition of aqueous potassium fluoride solution while cooling with ice and filtering through Celite. After washing the organic layer with sat. NaCl, the organic layer was distilled under a reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=2/1) to obtain the title compound (0.93 g, 4.7 mmol, 63%) as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][CH2:15][N:16]([CH3:19])[C:17](=[O:18])[CH:10]3[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][CH2:15][N:16]([CH3:19])[C:17](=[O:18])[CH:10]3[CH2:9]2)[C:2]=1[Cl:1])[C:20]#[N:21]
Reactant: CN1CCN2CCN(c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN2CCN(c3cc(C#N)cc(N)c3Cl)CC2C1=O
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of racemic tert-butyl (2-chloro-5-cyano-3-(8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)phenyl)carbamate (60 mg, 0.143 mmol) in DCM (1.5 mL) was added 1 mL of TFA. After stirring for 1 h, LC-MS indicated completion. It was concentrated and purification via flash chromatography (0-5% MeOH in DCM, 12 g) gave racemic 3-amino-4-chloro-5-(8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)benzonitrile (35 mg, 0.109 mmol, 77% yield) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2](C(OCC1C=CC=CC=1)=O)[CH2:3][CH2:4][CH2:5][C@H:6]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]1[NH:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:10][N:11]=1>CO.[Pd]>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:7]1[NH:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:10][N:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCC(N)C(=O)OCc1ccccc1)c1ncc(-c2ccc3ccccc3c2)[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN)c1ncc(-c2ccc3ccccc3c2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A stirred solution (0.2 M) of the product from example 1 step 1 in MeOH was added to 10% Pd on carbon (20% w/w) and the heterogeneous mixture was stirred under H2 (g) at RT overnight. Then, the reaction mixture was filtered through a pad of celite and washed with MeOH. Evaporation of the solvent yielded (95%) the title compound as a solid.