Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH:5]=[C:6]([C:8]([NH2:10])=[O:9])[CH:7]=1.[CH2:20]([C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl)[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(Cl)Cl.CC(C)=O>[NH2:10][C:8]([C:6]1[CH:7]=[C:2]([NH:1][CH2:24][C:23]2[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:22]=2[CH2:20][CH3:21])[C:3]2[N:4]([C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH:5]=1)=[O:9]
Reactant: CCc1cccc(C)c1CCl
Reactant: CCOC(=O)c1c(C)nc2c(N)cc(C(N)=O)cn12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc2c(NCc3c(C)cccc3CC)cc(C(N)=O)cn12
Yield: 56 %

Procedure:
Ethyl 8-amino-6-(aminocarbonyl)-2-methylimidazo[1,2-a]pyridine-3-carboxylate (0.41 g, 1.6 mmol), 2-ethyl-6-methylbenzylchloride, sodium carbonate (0.7 g, 6.6 mmol), sodium iodide (0.15 g, 1.0 mmol) and acetone (20 ml) were refluxed for 44 h. Methylene chloride was added and the solids were removed by filtration. The filtrate was evaporated under reduced pressure and purification of the residue by column chromatography on silica gel eluting with methylene chloride:methanol (100:4) gave 0.35 g (56%) of the title compound. 1H-NMR (300 MHz, CDCl3): δ1.25 (t, 3H), 1.45 (t, 3H), 2.35 (s, 3H), 3.65 (s, 3H), 2.7 (q, 2H), 4.4-4.45 (m, 4H), 5.0 (t, 1H), 6.95 (s, 1H), 7.0-7.2 (m, 3H), 9.2 (s, 1H)
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:21][CH2:22][CH2:23][CH2:24]O>C(Cl)Cl>[Br:21][CH2:22][CH2:23][CH2:24][O:19][C:18](=[O:20])[C@H:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: OCCCBr
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)OCCCBr
Temperature: 0 °C
Reaction time: 12 h
Yield: 79.6 %

Procedure:
N-Boc-Homophenylalanine (5.00 g, 17.9 mmol) and 3-bromo-1-propanol (1.60 mL, 17.7 mmol) were dissolved in CH2Cl2 (25 mL) and the mixture was cooled to 0° C. A solution of N,N-dicyclohexylcarbodiimide (4.80 g, 23.3 mmol) and N,N-dimethylaminopyridine (0.23 g, 1.90 mmol) in CH2Cl2 (25 mL) was slowly added and the reaction was slowly warmed to room temperature and stirred for 12 hours. The dicyclohexylurea was filtered off and the mother liquor was concentrated and purified by flash chromatography (Hexane/EtOAc 8:2) affording N-Boc-Homophenylalanine 3-bromopropyl ester as a clear oil (5.64 g, 79%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:12](=[O:14])[CH3:13])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[H-].[Na+].[CH2:18](I)[CH2:19][CH3:20].[Na+].[Cl-]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:12](=[O:14])[CH3:13])([CH2:18][CH2:19][CH3:20])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCCI
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCC(CC(=O)OCC)(C(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-acetyl-succinic acid diethyl ester (30 g, 139 mmol) in DMSO (250 ml) is added NaH (5.8 g, 60% in mineral oil, 145 mmol) in 10 portions over a period of 1 hour. The resulting solution is stirred at room temperature for another 1.5 hours. PrI (17.1 ml, 174 mmol) is added slowly over the period of 45 minutes and the resulting solution is stirred at room temperature overnight. Water (500 ml) is added, the solution is saturated with NaCl and extracted with EtOAc (3×250 ml). The combined extracts are washed with brine (400 ml), dried over Na2SO4 and evaporated in vacuo. The resulting 2-acetyl-2-propyl-succinic acid diethyl ester is obtained as a yellow oil, which is used for the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:21])=[O:2])=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
A solution of 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid methyl ester (260 mg, 0.834 mmol) in tetrahydrofuran (3 mL) at 25° C. was treated with a 0.8M aqueous lithium hydroxide solution (1.25 mL, 1.00 mmol). The reaction mixture was stirred at 25° C. for 15 h. The resulting reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and then treated with a 1N aqueous hydrochloric acid solution (10 mL). The layers were shaken and separated. The aqueous layer was further extracted with ethyl acetate (50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (243 mg, 98%) as a yellow solid which was used without further purification: mp 112-115° C.; FAB-HRMS m/e calcd for C14H16ClNO4 (M+H)+298.0847, found 298.0851.
Reaction SMILES: N#N.[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[CH:15])[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4].I[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>CCN(CC)CC.C1COCC1.[Cu]I>[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: C#Cc1ccnc(NC(C)(C)C)n1
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nccc(C#Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
To a mixture of Pd(PPh3)Cl2 (0.4 g) in Et3N (150 mL) and THF (150 mL) under a stream of N2, was added tert-butylamino-4-ethynylpyrimidine (18.6 g, 0.11 mol). After bubbling N2 into the solution for 15 min, 4-iodo-fluorobenzene (23.6 g, 0.11 mol) and CuI (0.22 g) were added sequentially. The mixture was stirred at rt for 2.5 h. The precipitate was filtered and washed with EtOAc. The filtrate was concentrated and the residue was diluted with EtOAc and loaded directly onto a short pad of silica gel. The product was eluted with 10% EtOAc in hexanes to afford the crude product, which was recrystallized from EtOAc/hexanes to give the title compound as a light yellow solid (25 g, 84%). TLC: Rf=0.30. mp 97-99° C. IR: 3287 (w), 2964 (w), 2222 (w), 1566 (s). 1H NMR: 8.26 (d, J=4.2 Hz, 1H), 7.60-7.55 (m, 2H), 7.10-7.00 (m, 2H), 6.65 (d, J=4.9 Hz, 1H), 5.22 (s, 1H), 1.45 (s, 9H). 13C NMR: 164.19, (162.19, 162.03), 157.77, 150.83, (134.35, 134.29), (117.84, 117.81), (115.94, 115.76), 112.37, 89.91, 87.24, 51.07, 28.86. Anal. Calcd for C16H16FN3: C, 71.36; H, 5.99; N, 15.60. Found: C, 71.25; H, 5.95; N, 15.66.
Reaction SMILES: [Cl:1][CH:2]([Cl:8])[C:3](=O)[CH:4]=[CH:5]Cl.[CH3:9][N:10](C)[NH2:11]>C(OC)(C)(C)C>[Cl:1][CH:2]([Cl:8])[C:3]1[CH:4]=[CH:5][N:10]([CH3:9])[N:11]=1
Reactant: O=C(C=CCl)C(Cl)Cl
Reactant: CN(C)N
Solvent: COC(C)(C)C
Product: Cn1ccc(C(Cl)Cl)n1
Temperature: 34 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
At 20° C., 1,1,4-trichloro-3-buten-2-one (15 g, 0.078 mol) was added dropwise over a period of 37 min to a solution of 1,1-dimethylhydrazine (9.5 g, 0.156 mol) in methyl tert-butyl ether (MTBE, 500 ml), with warming to 34° C. After 2 h, a sticky brown suspension had formed, which was filtered through kieselguhr. The filtrate was concentrated under reduced pressure. The residue (7.6 g of a viscous oil) was subjected to fractional distillation under reduced pressure. As the main fraction, 3 g of 3-dichloromethyl-N-methylpyrazole were obtained in a purity of 96.4% (GC area) (boiling point 65° C./0.3 mbar), and the product crystallized on standing. Recrystallization gave a sample having a purity of >99% (GC area).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:8][C:1]1[CH:2]=[C:3]([CH3:7])[CH:4]=[CH:5][C:6]=1[C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:15]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CCC(=O)O)c(C)c1
Yield: 92 %

Procedure:
m-Xylene 10f (98%, 5.5 eq) was reacted with succinic anhydride (99%, 1 eq) and AlCl3 (95%, 2 eq) for 42 h according to the general procedure. Extractive purification of the crude product afforded white crystals of 11f were obtained in 92% yield. 1H-NMR: 7.66 (d, 1H, Ar--H); 7.07 (d, 2H, Ar--H); 3.22 (t, 2H, CH2CH2COOH); 2.77 (CH2CH2COOH); 2.49 (s, 3H, CH3); 2.35 (s, 3H, CH3).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:3].[CH2:13]([CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[C:14]#[CH:15]>>[CH2:13]([CH:16]1[CH2:21][CH2:20][N:19]([C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][CH3:12])=[O:3])[CH2:18][CH2:17]1)[C:14]#[CH:15]
Reactant: COc1ccccc1OC(=O)Cl
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Product: C#CCC1CCN(C(=O)Oc2ccccc2OC)CC1

Procedure:
2-(methoxy)phenyl chloroformate (5.00 g, 26.8 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (4.60 g, 20.6 mmol) according to general procedure 1. Yield=5.03 g, 89%. m/z MH+=274.04. HPLC rt=8.7 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Cl:11])=[N:6][C:5]=1Cl.C[O-].[Na+].[C:17](O)(=[O:19])C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Cl:11])=[N:6][C:5]=1[O:19][CH3:17]
Reactant: COC(=O)c1c(C)cc(Cl)nc1Cl
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C)cc(Cl)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of 6.50 g (29.5 mmol) of 2,6-dichloro-4-methyl-nicotinic acid methyl ester in 75 ml of CH2Cl2 was added at 0° C. 6.56 ml (35.4 mmol) of a sodium methoxide solution (5.4 molar in MeOH). After 16 hours, the reaction mixture was warmed up to RT and stirred again 16 hours at this temperature and subsequently poured into crashed ice; then, the pH was adjusted to 4-5 with 2N acetic acid and the reaction mixture was extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 1.0 to 98:2) to give 5.79 g (91%) of the title compound as colorless solid. MS: 216.1 (MH+, 1Cl).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.[H-].[Na+].I[CH3:14]>C1COCC1>[Br:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH3:14])[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Brc1ccnc2cn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc2nccc(Br)c2n1
Temperature: 25 °C

Procedure:
A solution of 7-bromo-1H-pyrazolo[4,3-b]pyridine (100 mg, 0.505 mmol) and sodium hydride (24.24 mg, 0.606 mmol) in THF (2.0 mL) was stirred at 0° C. for 15 minutes. Iodomethane (71.7 mg, 0.505 mmol) was added, and the reaction was warmed to room temperature for 1 hour. The reaction was quenched with water, extracted with EtOAc, dried over MgSO4, and evaporated to dryness to give 7-bromo-2-methyl-2H-pyrazolo[4,3-b]pyridine which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]([CH2:18][CH2:19][C:20]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[C:21]([NH:23][O:24]C3CCCCO3)=[O:22])[C:14](=[O:36])[CH:13]=2)=[CH:8][CH:7]=1.Cl>O1CCOCC1.CO>[OH:24][NH:23][C:21](=[O:22])[C:20]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:19][CH2:18][N:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:7][CH:8]=2)=[CH:13][C:14]1=[O:36]
Reactant: CC(CCn1ccc(-c2ccc(OCCCO)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(CCn1ccc(-c2ccc(OCCCO)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
To 4-(4-(4-(3-hydroxypropoxy)phenyl)-2-oxopyridin-1 (2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (120 mg, 0.230 mmol) was added 4 N hydrogen chloride in dioxane (5.0 mL) and methanol (0.50 mL). The reaction was stirred for 30 minutes and then evaporated in vacuo onto silica gel. Chromatography on silica gel with a dichloromethane-methanol gradient (1%-25%) gave the title compound as a white foam (20.8 mg, 20.1%). 1H NMR: 400 MHz, (CD3OD) δ ppm 1.71 (s, 3H), 2.06 (m, 2H), 2.38 (ddd, J=13.2, 10.8, 4.8 Hz, 1H), 2.53-2.62 (m, 1H), 3.11 (s, 3H), 3.76 (t, J=6.2 Hz, 2H), 3.88-3.96 (m, 1H), 4.14 (t, J=6.3 Hz, 2H), 4.29 (ddd, J=12.5, 10.8, 4.9 Hz, 1H), 6.75 (m, 2H), 7.04 (d, J=8.7 Hz, 2H), 7.62-7.69 (m, 3H). LCMS: 437.2 (M−1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][CH:5]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([N:6]1[CH:5]=[C:4]([Br:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1[nH]cc(Br)c2ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccccc2c(Br)cn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.656 g, 16.4 mmol) was carefully added to a solution of 4-bromoisoquinolin-1(2H)-one (3.5 g, 15.6 mmol) in anhydrous DMF (60 mL) cooled to 0° C. The reaction was stirred at 0° C. for 30 min, then benzyl bromide (8.02 g, 46.9 mmol) was added slowly. The reaction was allowed to warm to rt and stirred for 17 h. After that time the reaction was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The organic phase was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 hexanes/ethyl acetate to 75:25 hexanes/ethyl acetate) to give 2-benzyl-4-bromoisoquinolin-1(2H)-one (4.55 g, 93%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=7.4 Hz, 1H), 7.79-7.84 (m, 1H), 7.71-7.79 (m, 1H), 7.53-7.60 (m, 1H), 7.29-7.38 (m, 6H), 5.21 (s, 2H); ESI MS m/z 314 [M+H]+ and 316 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21]C)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:35]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([OH:21])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)O)nc32)[C@H](O)[C@@H]1O
Yield: 30.8 %

Procedure:
A solution of methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylate (Preparation 9) (0.7 g, 1.28 mmol) and 10% w/w aqueous sodium hydroxide solution (1.3 ml, 3.2 mmol) in methanol (2.3 ml) was stirred at room temperature for 14 hours. The solution was adjusted to pH 4 by the addition of 2N aqueous hydrochloric acid and the precipitated white solid collected by filtration. The solid was washed with water and dried under reduced pressure to give the target compound as a white powder, (0.21 g, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]([CH2:46][CH:47]=O)[CH2:29][C@H:30]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:47][CH2:46][N:28]([CH2:29][C@@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[O:38][Si:39]([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:41])[CH3:40])[C:26]([O:25][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:27])[CH:15]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2cccc(N)c2)cc2c1OCC2
Reactant: CC(C)(C)OC(=O)N(CC=O)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cccc(NCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OC(C)(C)C)c2)cc2c1OCC2

Procedure:
TLC Rf (4:1 hexane/ethyl acetate)=0.14; from 5-(3-aminophenyl)-2,3-dihydro-7-benzofurancarboxylic acid methyl ester (500 mg) and (R)-[(tert-butoxycarbonyl)-[2-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino]-acetaldehyde (1.3 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N+:12]([O-])(O)=O>S(=O)(=O)(O)O.[Fe]>[NH2:12][C:11]1[C:2]([F:1])=[CH:3][C:4]2[S:8][C:7](=[O:9])[NH:6][C:5]=2[CH:10]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2ccc(F)cc2s1
Agent: [Fe]
Agent: O=S(=O)(O)O
Product: Nc1cc2[nH]c(=O)sc2cc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
6-fluoro-2(3H)-benzothiazolone (82.9 g) was nitrated in conc. sulfuric acid (800 g) with a 98% nitric acid (5% excess of the theoretical amount) at a temperature of 0° to 5° C. under stirring for 1.5 hours. The reaction mixture was poured into ice water and filtered. The solid material separated by the filtration was dried, and recrystallized from acetone, so that 6-fluoro-5-nitro-2(3H)-benzothiazolone (67.7 g) was obtained. The purity of this compound was 92% (this purity was determined by HPLC). The whole amount of this compound was reduced with iron powder to obtain 5-amino-6-fluoro-2(3H)-benzothiazolone (52.4 g). 4 g of the amino compound were subjected to an alkylation operation with the aid of 3-chloromethyl-5-methyl-1,2,4-oxadiazole (2.9 g), in acetonitrile (100 ml) in the presence of potassium carbonate (3 g) as the dehydrochlorinating agent. This operation was carried out under reflux for 2 hours, so that the aimed compound, i.e. 5-amino-6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (5.3 g) was obtained. m.p. 156°-157° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]([C@@H:17]3[CH2:21][CH2:20][C@H:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18]3)=[O:16])[CH:9]=2)=[C:4]([O:30][CH3:31])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C@H:19]1[CH2:20][CH2:21][C@@H:17]([C:15]([NH:14][C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:30][CH3:31])[CH:13]=[CH:12][N:11]=2)=[O:16])[CH2:18]1
Reactant: COc1cc(F)ccc1-c1ccnc(NC(=O)[C@@H]2CC[C@H](NC(=O)OC(C)(C)C)C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1ccnc(NC(=O)[C@@H]2CC[C@H](N)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1R,3S)-3-Amino-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)cyclopentanecarboxamide was prepared according to Method C using tert-Butyl (1S,3R)-3-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-ylcarbamoyl)cyclopentylcarbamate (1.00 g, 2.33 mmol), TFA (2 ml) in DCM (6 ml) starting at 0° C. which was allowed to warm up to room temperature and stirred for 2 h.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(O)(CC)C>[F:16][C:17]([F:26])([F:27])[O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc2c(Cl)ncnc2c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCC(C)O
Product: COC(=O)c1ccc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of methyl 4-chloroquinazoline-7-carboxylate (610 mg, 2.75 mmol) in sec-BuOH (5 mL) was added 4-trifluoromethoxyaniline (535.5 mg, 3.02 mmol) at room temperature. The mixture was heated at 100° C. and stirred for 2 h. The solvent was evaporated and the compound was crystallized from CHCl3 and Et2O mixture (3:1). The white crystals were collected by filtration and washed with Et2O. (890 mg, 91% Yield). MS m/z 364.10 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:18](=[O:20])[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:12](=[O:22])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)[O:34][C@@H:33]([CH2:35][O:36]N)[CH2:32][O:31]1>CC(N(C)C)=O>[OH:34][C@H:33]([CH2:35][OH:36])[CH2:32][O:31][N:17]1[C:18](=[O:20])[C:19]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:11][C:12](=[O:22])[N:13]([CH3:21])[C:14]=2[N:15]=[CH:16]1
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc21
Reactant: CC1(C)OC[C@H](CON)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(OC[C@H](O)CO)cnc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 13.2 %

Procedure:
Compound 5F (1.31 g, 3.17 mmol), potassium carbonate (1.1 g, 7.92 mmol) and 1-chloro-2,4-dinitronbenzene (1.60 g, 7.92 mmol) were stirred in DMA at 80° C. for 2 hours. (R)—O-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (4.66 g, 31.7 mmol) was added at r.t and the reaction was stirred for 1 hour at 80° C. Purification by prep-HPLC gave 210 mg (13%) of the title compound as a clear yellow solid (Deprotection occurred while concentrating the purification fractions containing 0.5% of TFA). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.18 (s, 1 H) 8.93 (s, 1 H) 7.81 (dd, J=10.11, 1.77 Hz, 1 H) 7.62 (dd, J=7.58, 1.01 Hz, 1 H) 7.37 (t, J=8.46 Hz, 1 H) 5.56 (s, 1 H) 4.39 (dd, J=10.74, 3.16 Hz, 1 H) 4.21 (dd, J=10.61, 7.33 Hz, 1 H) 3.82-3.88 (m, 1 H) 3.50 (s, 3 H) 3.42-3.46 (m, 2 H). MS (ES) [m+H] calc'd for C17H16FIN4O5, 503; found 503.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.Cl.[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH2:16].C(N(CC)CC)C.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:16][CH2:15][C:14]([O:13][CH3:12])=[O:17])=[C:4]([Cl:10])[CH:3]=1
Reactant: COC(=O)CN
Reactant: O=Cc1ccc(Br)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)CNCc1ccc(Br)cc1Cl
Temperature: 50 °C
Yield: 31.5 %

Procedure:
4-bromo-2-chlorobenzaldehyde (2B1) (4.56 mmol, 1.0 g) and glycine methyl ester hydrochloride (2C2) (4.56 mmol, 572 mg) were dissolved in ethanol (15 ml) under nitrogen with stirring and triethylamine (135 mmol, 19.0 ml, 13.7 g) was added. The reaction mixture was heated to 50° C. for 1 hour, then evaporated to dryness and the residue taken up in methanol (15 ml) and cooled in an ice bath. Sodium borohydride (5.01 mmol, 0.190 g) was added portionwise and stirring continued until no starting material remained as determined by TLC. The reaction mixture was concentrated to dryness and partitioned between DCM and water and the phases separated. The organic layer was dried over sodium sulphate, filtered and concentrated before purification on silica eluting with 15% EtOAc/heptane to yield methyl 2-(4-bromo-2-chlorobenzylamino)acetate (2C3) 420 mg (31%); 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H) 7.38 (d, 1H) 7.31 (d, 1H) 3.86 (s, 2H) 3.73 (s, 3H) 3.43 (s, 2H).