Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[O:41]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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.O>[O:41]1[CH:45]=[CH:44][C:43]([C:2]2[CH:40]=[CH:39][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:4][CH:3]=2)=[CH:42]1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccoc3)cc2)CCCC1

Procedure:
To a 5 mL microwave vial were added ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate (62 mg, 0.1 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), furan-3-boronic acid (18 mg, 0.16 mmol), K3PO4 (99 mg, 0.47 mmol), DME (1.1 mL) and water (0.56 mL). The vial was capped and irradiated in the microwave reactor at 120° C. for 30 minutes. The mixture was then partitioned between water (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous further extracted with EtOAc (2×20 mL). The organics were combined, dried (Na2SO4), filtered and concentrated to dryness. The residue was purified using reverse phase HPLC to afford the title compound. MS (ESI): mass calcd. for C37H35N3O4, 585.26; m/z found, 586.2 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[N+:8]([C:4]1[CH:3]=[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 120 °C

Procedure:
A mixture of 3-fluoronitrobenzene (20 ml; 0.19 mol) and 1-methylpiperazine (40 ml; 0.36 mol) was heated to 120° C. for a week. The cooled mixture was purified by column-chromatography on silica gel using a mixture of ethyl acetate and methanol (9:1 v/1) as the eluent. Yield: 33 g (79%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:14][CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1.CC(C)([O-])C.[Na+]>CS(C)=O.O>[O:11]1[CH2:12][CH:13]=[C:8]([C:7]2[C:2]([O:14][CH:15]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Clc1ncccc1C1=CCOCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ncccc2C2=CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
2-chloro-3-(3,6-dihydro-2H-pyran-4-yl)-pyridine (see PREPARATION P13.1; 3.5 g, 17.9 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.8 g, 17.9 mmol) were dissolved in DMSO (20 mL) and sodium tert-butoxide (t-BuONa) (3.4 g, 35.8 mmol) was added to the above solution. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product. The crud product was purified by silica gel column chromatography to give the title compound (2.3 g, 7.8 mmol, yield 75%). 1H NMR (DMSO-D6, 300 MHz) δ (ppm) 1.38 (s, 9H), 2.41-2.47 (m, 2H), 3.75-3.86 (m, 4H), 4.19-4.30 (m, 4H), 5.26-5.35 (m, 1H), 6.15-6.20 (m, 1H), 7.01 (dd, 1H, J=7.31 Hz, 4.97 Hz), 7.62 (d, 1H, J=7.45 Hz), 8.02 (d, 1H, J=4.82 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18](=[O:23])[CH2:19][CH2:20][CH:21]=C)[C:5]2=[O:24].[O:25]=[O+][O-].CSC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[O:25])[C:5]2=[O:24]
Reactant: C=CCCC(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: O=CCCC(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Temperature: -78 °C

Procedure:
A mixture of 6-chloro-2-hydroxy-3-(4-pentenoyl)-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-4-one (0.65 g, 1.9 mmol) in 50 mL DCM was stirred at −78° C. and treated with O3 until the solution remained blue. The mixture was stirred at −78° C. for 30 minutes and then treated with 1 mL dimethyl sulfide and stirred from −78° C. to 0° C. for 2 hours. The mixture was concentrated in vacuo and purified by column eluting with 40:100=EtOAc/hexane to give the desired product. MS m/e: 349 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:11][C:12]([CH3:14])=[O:13].[Li]CCCC>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([OH:13])([CH3:14])[CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CC(C)=O
Reactant: COc1cc(Br)ccc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1C(C)(C)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
To a solution of 5-bromo-2-iodoanisole (668 mg, 2.14 mmol) and acetone (0.471 mL, 6.40 mmol) in tetrahydrofuran (7.62 mL) at −78° C. was added n-BuLi (2.5M in hexane, 0.940 mL, 2.35 mmol) in a dropwise manner. The reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, warmed to room temperature and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate and filtered, and concentrated under reduced pressure yielding 680 mg of crude oil. Purification by column chromatography (0-10% ethyl acetate/heptanes) afforded the title compound (133 mg, 25% yield) as a clear, colorless oil. MS (ES+) 226.9 (M−H2O+H)+. 1H NMR (400 MHz, CDCl3) δ: 7.20 (d, 1H), 7.06-7.10 (m, 1H), 7.04 (d, 1H), 3.91 (s, 3H), 1.58 (s, 6H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.[NH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28]>>[NH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]3)=[CH:9][CH:8]=2)=[CH:31][CH:30]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccc(C(N)=O)cc3)cc2C1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 7-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinoline carboxylate (Ex V-17) and 4-(aminocarbonyl)-phenyl boronic acid according to the procedure described for I-VII-9. Tan solid; LC/MS (method A) 2.62 min; m/z 353 (M+H, 75%), 297 ([M−C4H8]+H, 100%).
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[C:9]([OH:16])(=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13].[NH3:17].C([O-])(=O)/C=C\C([O-])=O.[NH4+].[NH4+]>>[NH2:17][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5].[C:9]([OH:16])(=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13]
Reactant: N
Reactant: O=C([O-])/C=C\C(=O)[O-]
Agent: O=C(O)/C=C\C(=O)O
Agent: [NH4+]
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
Still alternatively, both an immobilized biocatalyst with immobilized cells containing maleate isomerase and an immobilized catalyst with immobilized cells containing aspartase are combined and packed into a column and an aqueous solution of maleic acid and ammonia or an aqueous solution of ammonium maleate is passed through the column, to produce L-aspartic acid by a single-step process from maleic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)COc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Into a 100-mL round-bottom flask, was placed tert-butyl 2-(4-nitrophenoxy)acetate (2 g, 7.74 mmol, 1.00 equip, 98%), Palladium on carbon (200 mg), and methanol (50 mL). To the above hydrogen was introduced. The resulting solution was stirred for 18 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield tert-butyl 2-(4-aminophenoxy)acetate as a reddish oil.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=O)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:7]=[C:8]([CH:9]=[CH:22][CH:23]=[O:24])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cccc(-n2cccn2)c1
Product: O=CC=Cc1cccc(-n2cccn2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(1H-pyrazol-1-yl)-benzaldehyde (prepared as described in Reference Example 3) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 199 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2.C(N(CC)C(C)C)(C)C>CC(O)C>[CH3:33][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[CH:32][C:23]=2[O:22][CH2:21][CH2:20][N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8]3[CH:17]=[C:16]4[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]4)=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)[N:28]=1
Reactant: O=C1CCc2ccc(OC3CCNCC3)cc2N1
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc2c(OCCN3CCC(Oc4ccc5c(c4)NC(=O)CC5)CC3)cccc2n1
Yield: 46.3 %

Procedure:
7-(Piperidin-4-yloxy)-3,4-dihydro-1H-quinolin-2-one (0.064 g, 0.25 mmol) and 5-(2-bromoethoxy)-2-methylquinoline (0.069 g, 0.25 mmol) were mixed together in propan-2-ol (20 mL), N,N-diisopropylethylamine (0.336 g, 2.6 mmol) added and the mixture heated at reflux for 48 h. The volatiles were removed by evaporation to dryness under reduced pressure and the residue partitioned between ethyl acetate and saturated NaHCO3 aq. The phases were separated, the organic phase washed with water, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography on SiO2, eluting with a gradient of ethyl acetate in 60–80° C. petroleum ether, gave the title compound (0.05 g, 45%) as a white solid, after trituration under 60–80° C. petroleum ether.
Reaction SMILES: [CH:1]1([C:6]([OH:31])([CH2:21][C:22]2[O:23][C:24]([CH3:30])([CH3:29])[O:25][C:26](=[O:28])[CH:27]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]#[N:19])[CH2:17][CH2:16]3)=[C:11]([F:20])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.[OH-].[OH-].[Pd+2]>[CH:1]1([C:6]([OH:31])([CH2:21][C:22]2[O:23][C:24]([CH3:29])([CH3:30])[O:25][C:26](=[O:28])[CH:27]=2)[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]#[N:19])[CH2:17][CH2:16]3)=[C:11]([F:20])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Reaction time: 6 h
Yield: 99 %

Procedure:
To a solution of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile (1.0 g, 2.4 mmol) from Step 5 above dissolved in EtOH (20 mL) was added Pd(OH)2/C (20% wt dry basis, 100 mg) and the reaction was stirred under a hydrogen atmosphere for 6 hours. The palladium catalyst was removed by filtration, and the solvent removed by rotary evaporation. The resulting oil was used without further purification (1.02 g, 99% yield). MS (ESI): 426 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:28](=[O:29])[N:27]([CH3:31])[CH3:26]
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 399.9 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and N,N-dimethylcarbamoyl chloride (0.08 g, 0.075 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.15 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([M−H]−); IR (thin film) 3350, 1705, 1114, 808 cm−1.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
tert-Butyl 3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate (0.50 g, 1.4 mmol) was dissolved in trifluoroacetic acid (3 ml) under ice cooling condition, and the mixture was stirred for 2.5 hrs. The reaction mixture was combined with isopropylether to give the precipitated solid, which was collected by filtration and recrystallized from tetrahydrofuran-ethanol to give the titled compound (0.33 g, 77%) as white crystals.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:10]1[N:11]=[C:12]([NH:15][C:16]([C:18]2[CH:34]=[CH:33][N:21]3[C:22](=[O:32])[CH:23]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:25]=[C:20]3[CH:19]=2)=[O:17])[S:13][CH:14]=1)([CH3:9])([CH3:8])[CH3:7].[C:35](=O)([O-])[OH:36].[Na+]>CN(C)C=O>[C:6]([C:10]1[N:11]=[C:12]([NH:15][C:16]([C:18]2[CH:34]=[CH:33][N:21]3[C:22](=[O:32])[C:23]([CH:35]=[O:36])=[C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[N:25]=[C:20]3[CH:19]=2)=[O:17])[S:13][CH:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)cc(N4CCOCC4)nc3c2)n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(C=O)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dimethylformamide (1 ml) was added dropwise with phosphorus oxychloride (66 μl, 0.712 mmol) under ice cooling, then warmed to room temperature, and stirred for 15 minutes. The reaction solution was cooled to 0° C. with ice, added with N8-[4-(tert-butyl)-1,3-thiazol-2-yl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carboxamide (147 mg, 0.356 mmol) dissolved in dimethylformamide (4 ml) under ice cooling, and stirred at 0° C. for 2 hours and 30 minutes. The reaction solution was neutralized with saturated aqueous sodium hydrogencarbonate and concentrated under reduced pressure. The resulting residue was added with chloroform for extraction, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=40:1) to obtain 98.2 mg of the title compound as yellow crystals in a mixture with dimethylformamide.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C@@H:5]([N:17]1[CH2:25][C:24]2[C:19](=[C:20]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:21]=[CH:22][C:23]=2[Cl:26])[C:18]1=[O:33])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1.[OH-].[Na+].O>C1COCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([NH:27][C:28]([CH:30]2[CH2:31][CH2:32]2)=[O:29])=[C:19]2[C:24]=1[CH2:25][N:17]([C@@H:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:4][C:3]([OH:34])=[O:2])[C:18]2=[O:33]
Reactant: CCOc1cc([C@@H](CC(=O)OC)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid methyl ester (3.0 g, 6.2 mmol) in THF (60 ml) was added NaOH (10 N, 1.2 ml, 12 mmol). The mixture was stirred at room temperature overnight. To it was added water (50 ml). The mixture was extracted with EtOAc (50 ml×2). The aqueous layer was acidified by conc. HCl until pH=6. The resulted cloudy mixture was extracted with EtOAc (50 ml×2). The organice layer was washed with water (30 ml×2), brine (30 ml), dried over Na2SO4, filtered and concentrated in vacuo to give (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid as a white solid (2.8 g, 99%): mp, 118-120° C.; 1H NMR (CDCl3) δ 0.86-0.91 (m, 2H, c-CH2), 1.05-1.11 (m, 2H, c-CH2), 1.45 (t, J=7.0 Hz, 3H, OCH2CH3), 1.65-1.70 (m, 1H, c-CH), 3.13 (dd, J=6, 15 Hz, 1H, CHH), 3.23 (dd, J=10, 15 Hz, 1H, CHH), 3.86 (s, 3H, OCH3), 4.00-4.11 (m, 3H, NCHH+OCH2CH3), 4.32 (d, J=18 Hz, 1H, NCHJH), 5.80-5.86 (m, 1H, CHN), 6.83-6.92 (m, 3H, Ar), 7.35 (d, J=9 Hz, 1H, Ar), 8.41 (d, J=9 Hz, 1H, Ar), 10.39 (s, 1H, NHCO). 13CNMR (CDCl3): 8.4, 8.5, 14.7, 16.1, 36.7, 45.9, 51.8, 55.9, 64.6, 111.5, 112.4, 118.9, 119.0, 1198, 121.9, 130.1, 132.9, 136.7, 139.0, 148.7, 149.5, 168.7, 172.8, 173.8; Anal Calcd for C24H25ClN2O6+0.37H2O: C, 60.11; H, 5.41; N, 5.84. Found: C, 60.11; H, 5.25; N, 5.64, H2O, 1.40.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[NH2:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[NH:10][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1N
Temperature: 5 °C
Yield: 62.3 %

Procedure:
4-Nitro-o-phenylenediamine (30.6 g; 0.2 mole) was nearly dissolved in pyridine (ca. 500 ml.) The mixture was chilled to 5° C. and methanesulfonyl chloride (22.8 g; 0.2 mole) was added dropwise, while stirring, at <10° C. After the addition, the solution was left stirring at the ice bath temperature for about one hour. The reaction solution was poured into ice cold water (~2 liter) and stirred while scratching vigorously. The product was filtered and dried to yield 28.8 g (62 percent) beige solid, m.p. 201° to 204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[C:11]([NH:15][CH3:16])[N:10]=[CH:9]2)=[CH:5][CH:4]=1.[CH3:19][CH:20]([C:26]([O:28]CC)=O)[C:21]([O:23]CC)=O>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:28][C:26]1[C:12]2[C:13](=[O:14])[N:8]([CH2:7][C:6]3[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:9]=[N:10][C:11]=2[N:15]([CH3:16])[C:21](=[O:23])[C:20]=1[CH3:19]
Reactant: CNc1cc(=O)n(Cc2ccc(OC)cc2)cn1
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(Cn2cnc3c(c(O)c(C)c(=O)n3C)c2=O)cc1
Temperature: 240 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
3-(4-Methoxybenzyl)-6-(methylamino)pyrimidin-4(3H)-one (14.8 g, 60.2 mmol, 1 eq, compound 8A) and diethyl methylmalonate (61.6 mL, 361 mmol, 6 eq) were mixed in phenyl ether (25 mL) and heated at 240° C. for 2 days. The solution was allowed to RT and left standing overnight. The tan precipitate which formed was collected and washed with ether to give 15.2 g of the title compound as a tan solid (78%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.89 (s, 3 H) 3.55 (s, 3 H) 3.74 (s, 3 H) 5.14 (s, 2 H) 6.93 (d, J=8.59 Hz, 2 H) 7.37 (d, J=8.59 Hz, 2 H) 8.89 (s, 1 H) 11.82 (s, 1 H). %). [M+H] calc'd for C17H17N3O4, 328; found, 328.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(Cc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Cc2ccccc2)c1
Yield: 92 %

Procedure:
To a solution of methyl 3-benzylbenzoate (0.610 g; 2.70 mmol) in THF (14 mL) was added a solution of lithium hydroxide hydrate (0.403 g; 5.39 mmol) in water (12 mL). The mixture was refluxed for 2 hours and concentrated under reduced pressure to remove the THF. The aqueous solution was acidified with 6N hydrochloric acid. The white precipitate formed was collected by filtration, washed with water and dried to afford 0.527 g (92%) of 3-benzylbenzoic acid which was directly used in the next step.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:21]#[N:22])=[N:6][CH:7]=[C:8]([C:10]2[N:14](C3CCCCO3)[N:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-:3])=[O:2].O.C(=O)(O)[O-].[Na+]>Cl.CCO>[N+:1]([C:4]1[C:5]([C:21]#[N:22])=[N:6][CH:7]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-:3])=[O:2]
Reactant: N#Cc1ncc(-c2ccnn2C2CCCCO2)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ncc(-c2ccn[nH]2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
3-Nitro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinonitrile (8.77 mmol) was dissolved in 10% HCl (g) in EtOH (15 ml) and stirred at RT overnight. 20 ml of water was added to the reaction mixture, followed by addition of sat. sodium bicarbonate solution until pH was neutral. Thus resulting precipitate was filtered, washed with water and dried in vacuum to yield 1.76 g (93%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 7.22 (m, 1H), 7.98 (m, 1H), 8.99 (d, 1H), 9.50 (d, 1H), 13.5 (bs, 1H).