Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]([CH3:15])[C:12]([OH:14])=O)=[CH:5][CH:4]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[N:24][CH:25]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O>[Cl:26][C:23]1[N:24]=[CH:25][C:20]([CH2:19][NH:18][C:12](=[O:14])[C:11](=[N:10][NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:16])=[CH:8][CH:7]=2)[CH3:15])=[CH:21][CH:22]=1
Reactant: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: NCc1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)NCc1ccc(Cl)nc1
Yield: 78 %

Procedure:
2-(4-Trifluoromethylphenyl hydrazono) propionic acid (12.31 g, 50.0 mmol) was dissolved in dichloromethane (250 ml) and N,N-dimethylformamide (25 ml), and 5-aminomethyl-2-chloropyridine (7.13 g, 50.0 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloric acid salt (9.59 g, 50.0 mmol) were added thereto. 30 hours later, the mixture was washed with 1N hydrochloric acid, a saturated sodium bicarbonate water and a saturated brine, and dried on sodium sulfate and then filtrated. The residue obtained by concentrating the resulting filtrate was purified with a silica gel chromatography to obtain N-(6-chloro-3-pyridylmethyl)-2-(4-trifluoromethylphenyl hydrazono) propionic acid amide (Compound No. 63) (14.47 g, 39.02 mmol, 78%).
Reaction SMILES: [NH2:1]/[C:2](=[CH:38]\[C:39](=[O:49])[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])/[CH2:3][C@@H:4]1[C@H:7]([NH:8][C:9](=[O:36])/[C:10](=[N:24]\[O:25][C:26]([CH3:35])([CH3:34])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])/[C:11]2[N:12]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:14][CH:15]=2)[C:6](=[O:37])[NH:5]1.Cl.NO.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:45]([O:44][C:42]([NH:41][CH2:40][C:39]1[O:49][N:1]=[C:2]([CH2:3][C@@H:4]2[C@H:7]([NH:8][C:9](=[O:36])/[C:10](=[N:24]\[O:25][C:26]([CH3:34])([CH3:35])[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])/[C:11]3[N:12]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:14][CH:15]=3)[C:6](=[O:37])[NH:5]2)[CH:38]=1)=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)NCC(=O)/C=C(\N)C[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: NO
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cc(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)no1
Temperature: 60 °C
Reaction time: 6 h
Yield: 17 %

Procedure:
To a solution of tert-butyl 2-(((Z)-(2-(((2R,3S)-2-((Z)-2-amino-5-((tert-butoxycarbonyl)amino)-4-oxopent-2-en-1-yl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (77 mg, 0.108 mmol)) in ethanol (0.4 mL) was added hydroxylamine hydrochloride (19 mg, 0.27 mmol) and potassium carbonate (18 mg, 0.13 mmol) and heated to 60° C. After 6 h, the reaction mixture was partially concentrated in vacuo and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc-Heptane, 5-90%) to afford the title compound (13 mg, 17%). LCMS: Rt=1.04 min, m/z=708.3 (M+1). Method 2m_acidic.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:30]([O:32][CH3:33])=[O:31])#[N:2].B(O)(O)[C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:23]=[C:24]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)[CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:30]([O:32][CH3:33])=[O:31])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(I)c4)cc3)c(C#N)cc21
Reactant: Cc1ccc(B(O)O)cc1
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: O
Solvent: Cc1ccccc1
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)cc5)c4)cc3)c(C#N)cc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
In a vial were placed methyl 6-cyano-7-(4-(3-iodophenylcarbamoyl)phenoxy)chroman-4-carboxylate (Preparation 3) (56 mg, 0.1010 mmol), p-tolylboronic acid (17.855 mg, 0.1313 mmol), Na2CO3 (32.121 mg, 0.3030 mmol), toluene (1 ml), and water (0.1 ml). The mixture was degassed with Argon for few minutes. Tetrakis(triphenylphosphine)palladium(0) (5.836 mg, 0.005 mmol) was added and the vial was sealed. The mixture was stirred at 100° C. for 24 hours. The crude mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 33.1 mg of the title compound as foamy solid (63%).
Reaction SMILES: C(O)C.Cl.[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-])=O)=[CH:13][N:12]=2)=[CH:8][C:7]=1[C:23]([F:26])([F:25])[F:24]>[Fe].O>[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[N:12]=[CH:13][C:14]([NH2:18])=[CH:15][C:16]=2[CH3:17])=[CH:8][C:7]=1[C:23]([F:26])([F:24])[F:25]
Reactant: Cc1cc([N+](=O)[O-])cnc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(N)cnc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C
Yield: 79.5 %

Procedure:
A 250 ml two-necked round-bottomed flask equipped with a KPG-stirrer, a thermometer and a reflux condenser is charged with ethanol (100 ml), water (10 ml), iron (3.11 g) and hydrochloric acid 37% (0.3 ml). The reaction mixture is heated at 50° C. 2-(4-chloro-3-trifluoromethyl-phenoxy)-3-methyl-5-nitro-pyridine (5.81 g) is added portionwise. The mixture was heated at reflux for 2 hours. After cooling the mixture to 50° C. it is filtered through celite. The filtrate is poured into water (200 ml) and extracted with ethylacetate (2×50 ml). The combined organic layers are washed with brine (100 ml), dried over sodium sulfate, filtered and the solvent is removed in vacuo to obtain 4.20 g of the compound as yellow solid (MP: 92-94° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20](OCC)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CC1CCCO1>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)CCn1c(CCOC)nc2cnc3ccccc3c21
Solvent: CC1CCCO1
Product: COCCc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Temperature: 25 °C
Yield: 101.3 %

Procedure:
A solution of ethyl 3-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propanoate (4.0 g, 15 mmol), morpholine (13.49 mL, 154.3 mmol), and 2-methyltetrahydrofuran (10 mL) was heated for three days in a high-pressure vessel at 120° C., allowed to cool to ambient temperature, and concentrated under reduced pressure to provide 5.6 g of 2-(2-methoxyethyl)-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][OH:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26]>CN(C=O)C.OS([O-])(=O)=O.[K+]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(OC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
(S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (5.5 g, 26.8 mmol, Eq: 1.00) was dissolved in DMF (90 mL) at 0° C. and NaH (60% in mineral oil, 2.57 g, 64.3 mmol, Eq: 2.4) was added in small portions The mixture was stirred for 30 min. and 2-fluoro-4-methyl-1-nitrobenzene (4.16 g, 26.8 mmol, Eq: 1.00) in DMF (10 mL) was added dropwise. The resulting mixture was stirred for 60 min., diluted with 1.0 M KHSO4 and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to afford (S)-2-(tert-butoxycarbonylamino)-3-(5-methyl-2-nitrophenoxy)propanoic acid (7.60 g, 83%) as red oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21](I)[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:16]([C:17]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:19])=[CH:20][C:21]([C:17]([O:18][CH3:13])=[O:19])=[CH:22][C:23]=3[CH3:24])=[O:18])=[CH:11][C:10]([C:26]([F:28])([F:27])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(C(=O)NC(C)C)c1
Temperature: 60 °C
Yield: 160.7 %

Procedure:
The title compound of step B (3.07 g, 5.7 mmol) was dissolved in tetrahydrofuran (30 mL) and treated with isopropylamine (1.69 g, 28.7 mmol). The mixture was heated at 60° C. for 2 hours and concentrated to dryness under reduced pressure. The residue was subjected to chromatography on silica gel using ethyl acetate/hexanes (40:60) as eluent. Pooling appropriate fractions and evaporation of solvent provided the title compound of Step C (2.4 g): m.p.: 199–200° C. 1H NMR (CDCl3): δ 10.3 (NH), 8.42 (1H), 7.84 (1H), 7.61 (1H), 7.44 (2H), 7.42 (1H), 6.01 (1H), 4.21 (m, 1H), 2.13 (s, 3H), 1.2 (6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:42])[C:16]2[CH:21]=[C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)[CH:19]=[C:18]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>C1COCC1.[Fe]>[C:1]([O:5][C:6](=[O:43])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:42])[C:16]2[CH:17]=[C:18]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[CH:19]=[C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3cccc([N+](=O)[O-])c3)cc(Oc3ccc(C#N)cc3)c2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3cccc(N)c3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 66 %

Procedure:
1.2 g (2.04 mmol) of {4-[3-(4-cyano phenoxy)-5-(3-nitro benzyloxy)benzoyl amino]cyclohexyl}carbamic acid tert-butyl ester, dissolved in 10 ml of THF, 0.455 g (8.16 mmol) of iron powder and 0.436 g (8.16 mmol) of NH4Cl solution (5 ml water) were mixed. The resulting reaction mixture was refluxed overnight. After completion of reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. 100 ml water was added to the concentrated mixture and the mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed with water followed by saturated brine, dried over anhydrous sodium sulphate and concentrated to afford crude compound which was purified by column chromatography using hexane-ethylacetate (10:2) to afford 0.75 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.0 (2H, s), 5.15 (2H, s), 6.5 (2H, m), 6.62 (1H, s), 6.78 (1H, d), 6.94 (1H, s), 7.0 (1H, t), 7.12 (3H, m), 7.4 (1H, s), 7.82 (2H, d), 8.26 (1H, d).
Reaction SMILES: Cl.[CH:2]1([CH2:5][CH2:6][NH2:7])[CH2:4][CH2:3]1.[CH2:8]([O:15][C:16]([CH2:18][N:19]1[C:24]([CH3:25])=[C:23]([Cl:26])[N:22]=[C:21](Cl)[C:20]1=[O:28])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[CH:2]1([CH2:5][CH2:6][NH:7][C:21]2[C:20](=[O:28])[N:19]([CH2:18][C:16]([O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:17])[C:24]([CH3:25])=[C:23]([Cl:26])[N:22]=2)[CH2:4][CH2:3]1
Reactant: NCCC1CC1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(Cl)nc(NCCC2CC2)c(=O)n1CC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2-cyclopropylethylamine hydrochloride (73 mg, 0.60 mmol), 1-benzyloxycarbonylmethyl-3,5-dichloro-6-methylpyrazinone (164 mg, 0.50 mmol) and sodium hydrogen carbonate (101 mg, 1.20 mmol) in toluene (1 mL) and water (0.5 mL) was stirred at 80° C. for 3 h. The reaction was then cooled and partitioned between methylene chloride and 10% citric acid solution. The organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound as a crystalline solid:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:39])([F:38])[C:9]([NH:11][C:12]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:13]=1[O:14][CH2:15][CH2:16][N:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[O:10].CI>>[CH3:1][C:13]1([CH:31]=[CH:32][CH:33]=[C:34]([N+:35]([O-:37])=[O:36])[CH:12]1[NH:11][C:9](=[O:10])[C:8]([F:38])([F:39])[F:7])[O:14][CH2:15][CH2:16][N:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18](=[O:23])[C:19]([F:21])([F:20])[F:22]
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1c(OCCN(Cc2ccccc2)C(=O)C(F)(F)F)cccc1[N+](=O)[O-])C(F)(F)F
Agent: [K+]
Solvent: CI
Product: CC1(OCCN(Cc2ccccc2)C(=O)C(F)(F)F)C=CC=C([N+](=O)[O-])C1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
A suspension of potassium carbonate (1.44 g, 10.4 mmol), N-[2-(2-{2,2,2-trifluoroacetamidyl}-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide (1.0 g, 2.09 mmol) and methyl iodide (2.96 g, 20.9 mmol, previously filtered through basic alumina) in anhydrous dimethylsulfoxide (11 mL) was allowed to stir at room temperature for 24 h. The reaction mixture was poured into methylene chloride (200 mL) and extracted with water (2×80 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to afford a yellow thick oil. Purification by chromatography (30% ethyl acetate-hexanes) afforded 960 mg (93.3%) of a light yellow solid, mp 90-92.5° C.; MS m/e EI 493 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:6](Cl)=[N:7][C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[N:9][C:10]=1[CH3:11].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:10]([CH3:11])=[N:9][C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[N:7][C:6]=1[N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)Cc1c(C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N1CCCC1
Temperature: 85 °C
Reaction time: 13 h
Yield: 83.1 %

Procedure:
A solution of methyl[4-chloro-6-methyl-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (0.45 g, 1.3 mmol) and pyrrolidine (0.13 mL, 1.6 mmol) in DMF (10 mL) at room temperature was treated with triethylamine (0.22 mL, 1.6 mmol) and the resulting mixture was stirred at 85° C. for 13 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The combined organic extracts was washed with saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was chromatographed over silica gel eluting with 50% EtOAc in CH2Cl2 to give methyl[4-methyl-2-(4-nitrobenzyl)-6-pyrrolidin-1-ylpyrimidin-5-yl]acetate (0.40 g, 80% yield) as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][N:11]([CH:13]=O)[CH3:12]>CC(N(C)C)=O>[CH3:10][N:11]([CH3:13])/[CH:12]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CN(C)C=O
Reactant: CC(=O)c1ccccc1
Solvent: CC(=O)N(C)C
Product: CN(C)/C=C/C(=O)c1ccccc1
Yield: 29.1 %

Procedure:
A mixture of acetophenone (8.0 g, 66.58 mmol, 1.0 eq) and DMF (5.8 g, 79.90 mmol, 1.2 eq.) in 10.0 mL of DMA in a 25-mL microwave vial was irradiated at 115° C. for 0.5-1 h. The crude reaction mixture was triturated with n-hexane, and the resultant solid was filtered to afford the title compound as a pale yellow solid (3.4 g. 29.3% yield). [M+H] Calc'd for C11H13NO, 176. Found, 176.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([NH:10]C(OC(C)(C)C)=O)[CH2:5][CH2:6][N:7]([CH3:9])[CH3:8].[ClH:19]>O1CCOCC1>[ClH:19].[ClH:19].[NH2:10][C@@H:4]([CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)[C@H](CCN(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CCN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a cooled (0° C.) solution of (S)-2-tert-butoxycarbonylamino-4-dimethylaminobutyric acid methyl ester (23.4 g, 90 mmol) in dioxane (100 mL) was added drop-wise HCl (225 mL, 4M in dioxane). The mixture was warmed to room temperature and stirred for 3 hours. The solid was filtered, washed with ether (3×100 mL), and dried under high vacuum to afford 20.2 g of product (96% yield).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.[C:13]([O:21][CH2:22][C@@H:23]1[CH2:27][C@@H:26]([O:28][C:29](=[O:31])[CH3:30])[CH:25](OC(=O)C)[O:24]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[C:13]([O:21][CH2:22][C@@H:23]1[CH2:27][C@@H:26]([O:28][C:29](=[O:31])[CH3:30])[C@H:25]([N:8]2[C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:12])[C:5]=3[S:10][C:9]2=[O:11])[O:24]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)C[C@H]1OC(C)=O
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)O[C@@H]1C[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-amino-3,6-dihydrothiazolo[4,5-d]pyrimidine-2,7-dione (4.42 g, 24.0 mmol) in ACN (20 mL) was added BSA (14.8 mL, 60.0 mmol). The resulting reaction mixture was then stirred at 70° C. under argon for 0.5 hr to form a clear solution. After the solution was cooled to room temperature, [(2S,4R)-4,5-diacetoxytetrahydrofuran-2-yl]methyl benzoate (CAS #: 4613-71-2, Cat.#: MD04725, commercially available from Carbosynth Limited, 6.45 g, 20.0 mmol) and TMSOTf (5.5 mL, 30.0 mmol) were added in sequence. After being heated with stirring at 70° C. for 14 hours, the solvent was removed in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution (30 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (100 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford 5.7 g of [(2S,4R,5R)-4-acetoxy-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]methyl benzoate (compound 38a) as a light yellow solid.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]2)[CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:19][C:20]3[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]4[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]4)[CH:21]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Cc1nc(N)cc(N2CCN(CCO)CC2)n1
Reactant: Clc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc(Nc2nccc3nc(-c4c(Cl)cccc4Cl)sc23)cc(N2CCN(CCO)CC2)n1
Temperature: 25 °C
Yield: 17.1 %

Procedure:
To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17 mmol), 2-(4-(6-amino-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol (0.052 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature the solid was removed via filtration. The filtrate was concentrated under reduced pressure and the residue was purified with reverse phase column chromatography, eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a white solid (15 mg, 18% yield). 1H NMR (500 MHz, DMSO-d6): δ 10.16 (s, 1H), 8.38 (d, J=5.5 Hz, 1H), 7.74-7.70 (m, 4H), 6.70 (s, 1H), 4.46 (t, J=5.5 Hz, 1H), 3.54-3.52 (m, 6H), 2.51-2.47 (m, 4H), 2.44-2.41 (m, 2H), 2.32 (s, 3H). LCMS (Method A): RT=5.52 min, m/z: 516.1 [M+H+].
Reaction SMILES: Br[CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[NH2:22][C:23]([NH2:25])=[S:24].C([O-])(=O)C.[Na+]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:22]=[C:23]([NH2:25])[S:24][C:2]=2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(F)cc1)C(Br)Cc1ccc([N+](=O)[O-])cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1
Yield: 71.4 %

Procedure:
A procedure similar to step 5 of Example 6 was used. 2-bromo-1-(4-fluoro-phenyl)-3-(4-nitro-phenyl)-propan-1-one prepared in the step 2, thiourea and anhydrous sodium acetate were used as starting materials. The obtained crude product was recrystallized with a solvent mixture of ethyl acetate and acetone to give a product, which was a yellow solid in a yield of 71.4%, mp: 217-218 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 4.22 (2H, s, CH2), 6.99 (2H, s, NH2), 7.21 (2H, t, 3JFH=3JHH=8.72 Hz, ArH), 7.47 (2H, d, J=8.96 Hz, ArH), 8.03 (2H, dd, 3JHH=9.02, 4JFH=5.60 Hz, ArH), 8.19 (2H, d, J=8.68 Hz, ArH); EI-MS m/e (%): 329.1 (M+, 100), 207.0 (21); HREI-MS Calcd. for C16H12FN3O2S: 329.0634. found: 329.0627. Anal. Calcd. for C16H12FN3O2S: C, 58.35; H, 3.67; N, 12.76. found: C, 58.61; H, 3.52; N, 12.61.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][O:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])=[CH:4][CH:3]=1.[H][H]>O1CCCC1.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1OCCC=Cc1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCCCCc1ccc(F)cc1

Procedure:
71.5 g (0.23 mol) of N-(4-(4-fluorophenyl)-3-butenyloxy)-phthalimide (prepared according to German Laid-Open Application DOS 3,838,310) were dissolved in 300 ml of tetrahydrofuran, 2 g of palladium on active carbon (10% strength) were added and hydrogenation was carried out under slightly superatmospheric pressure until 1.2 times the theoretical amount of hydrogen had been consumed.