Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.C1COCC1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:29](=O)[C:23]3([CH2:25][CH:24]3[C:26]([O-])=[O:27])[C:18]3=[N:19][N:20]=[C:21]([CH3:22])[N:17]3[C:16]3[CH:31]=[CH:32][CH:33]=[CH:34][C:15]2=3)=[CH:10][CH:9]=1>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:29][C:23]3([CH2:25][CH:24]3[CH2:26][OH:27])[C:18]3=[N:19][N:20]=[C:21]([CH3:22])[N:17]3[C:16]3[CH:31]=[CH:32][CH:33]=[CH:34][C:15]2=3)=[CH:12][CH:13]=1
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C21CC1C(=O)[O-]
Agent: B
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)CC21CC1CO
Temperature: 25 °C
Reaction time: 48 h
Yield: 3 %

Procedure:
BH3-THF complex (1.8 mL, 1M in THF) was added dropwise to a solution of 6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropane]-2′-carboxylate (70 mg, 0.18 mmol) in anhydrous THF (10 mL) at 0° C. The resulting mixture was stirred at room temperature for 48 hrs, then quenched with NH4Cl solution (5 mL), extracted with ethyl acetate (10 mL), dried with Na2SO4, concentrated and purified with prep-HPLC to afford (6-(4-chlorophenyl)-1-methyl-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropan]-2′-yl)methanol (2 mg, 3%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:17])([F:18])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: NCc1ccccn1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CBr)c(Br)c2)=NO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: COC(C)(C)C
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CNCc3ccccn3)c(Br)c2)=NO1
Yield: 52.9 %

Procedure:
A solution of 3-[3-bromo-4-(bromomethyl)phenyl]-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (1.8 g), 2-aminomethylpyridine (0.38 g) and potassium carbonate (0.97 g) in acetonitrile (20 mL) was heated to reflux for 3 hours. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to yield 1-{2-bromo-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]phenyl}-N-(pyridin-2-ylmethyl)methanamine (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21](O)=[O:22])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:24][C:25]5[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=5)=[O:22])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(Cl)cc21
Reactant: N#Cc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)Nc4cccc(C#N)c4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.3 %

Procedure:
A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (70 mg, 0.23 mmol), 3-aminobenzonitrile (41 mg, 0.344 mmol), EDCI (88 mg, 0.46 mmol) and DMAP (56 mg, 0.46 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. Then the mixture was poured into water (5 mL) and filtered to give a crude product. The crude product was triturated with DMSO and MeOH, then decanted and dried to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(3-cyanophenyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (20 mg, 20%) as a white solid. MS: (M+H)+=428; 1H NMR (300 MHz, DMSO): δ 10.55 (s, 1H), 8.81 (s, 1H), 8.55-8.50 (m, 2H), 8.15 (brs, 1H), 8.03-8.00 (m, 1H), 7.92 (s, 1H), 7.59 (d, 1H, J=8.1 Hz), 7.48 (d, 1H, J=7.8 Hz), 7.26 (d, 1H, J=7.5 Hz), 4.14 (s, 3H).
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.[F:13][C:14]([F:32])([F:31])[C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][OH:30])=[CH:24][CH:23]=2)=[N:19][CH:20]=1.Cl>C1(C)C=CC=CC=1>[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[O:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:32])([F:13])[F:31])=[CH:20][N:19]=2)=[CH:27][CH:26]=1
Reactant: Fc1cccc2c(Cl)ncnc12
Reactant: OCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Fc1cccc2c(OCCc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)ncnc12

Procedure:
A mixture of 4-chloro-8-fluoroquinazoline (2.12 g, 12 mmol) and 2-(4-(5-(trifluoromethyl)-2-pyridinyloxy)phenyl)ethanol (2.83 g, 10 mmol) in 50 mL of toluene containing a catalytic amount of hydrogen chloride was stirred for several days. The title product was isolated by column chromatography. Yield 1.6 g. MP 116°-118° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](Cl)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH3:39][CH:40]([OH:42])[CH3:41]>>[CH:40]([O:42][C:21]([C@@:19]12[CH2:18][N:17]([S:24]([C:27]3[CH:28]=[N:29][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:16][CH2:15][C:14]1=[CH:13][C:12]1[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]=1[CH2:20]2)=[O:22])([CH3:41])[CH3:39]
Reactant: CC(C)O
Reactant: O=C(Cl)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Product: CC(C)OC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 48c using (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbonyl chloride and propan-2-ol. LCMS (Method F): 582 (M+H)+, Retention time 5.1 minutes.
Reaction SMILES: S(=O)(=O)(O)O.CC1(C)C[O:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=N1.[OH-:27].[Na+]>O>[OH:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:9]([OH:10])=[O:27])=[CH:19][CH:20]=1
Reactant: [OH-]
Reactant: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1-c1ccc(CO)cc1
Yield: 65 %

Procedure:
Water (6 ml) and sulfuric acid (3.6 g) were added to 2.0 g (7.11 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline, followed by heating under reflux for 30 hours. After the reaction liquid was cooled, it was neutralized with a 10% aqueous solution of sodium hydroxide and extracted with chloroform. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a chloroform/methanol system) to give 1.05 g of the title compound (yield 65%).
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.Br[C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[NH:31][C:30]=2[CH:38]=1.O1CCOCC1.CCN(C(C)C)C(C)C>C(OCC)(=O)C.O>[F:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:26]4[CH:27]=[CH:28][C:29]5[NH:33][C:32]([NH:34][C:35](=[O:37])[CH3:36])=[N:31][C:30]=5[CH:38]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1
Reactant: CC(=O)Nc1nc2ccc(Br)cc2[nH]1
Reactant: O=C(N1CCC(CF)CC1)N1CCOc2ccc(B(O)O)cc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1nc2cc(-c3ccc4c(c3)CN(C(=O)N3CCC(CF)CC3)CCO4)ccc2[nH]1
Temperature: 85 °C

Procedure:
(4-{[4-(fluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (67.2 mg, 0.2 mmol), N-(6-bromo-1H-benzimidazol-2-yl)acetamide (34.8 mg, 0.14 mmol) and dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (6 mg) was taken into dioxane (0.5 mL) followed by addition of water (0.1 mL) and DIPEA (0.14 mL). The resulting mixture was heated in a sealable vessel at 85° C. for 12 h then cooled to room temperature. The mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and filtered through a silica plug with an ethyl acetate wash. The organic filtrate was washed once with 1M aqueous sodium hydroxide, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (100% ethyl acetate to 4:1 ethyl acetate:ethanol) to give N-[5-(4-{[4-(fluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]acetamide as a colorless solid. 1H NMR (400 MHz, d4-methanol): 7.64 (dd, 1H), 7.51-7.48 (m, 2H), 7.46 (dd, 1H), 7.40 (dd, 1H), 7.03 (d, 1H), 4.49 (s, 2H), 4.35 (d, 1H), 4.23 (d, 1H), 4.19 (m, 2H), 3.74 (d, 2H), 3.68 (m, 2H), 2.85 (br tr, 2H), 2.25 (s, 3H), 1.88 (br, 1H), 1.71 (d, 2H), 1.36 (d q, 2H). MS (EI) for C25H28FN5O3: 337 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:40])[CH2:20][CH2:21][CH2:22][C:23](=[O:39])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33](=[O:38])[CH2:34][C:35](=[O:37])[CH3:36])=[CH:27][CH:26]=1)(C)(C)C.CCN(C(C)C)C(C)C.O[N:52]1[C:56](=[O:57])[CH2:55][CH2:54][C:53]1=[O:58].C(Cl)CCl>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[O:58]=[C:53]1[CH2:54][CH2:55][C:56](=[O:57])[N:52]1[O:5][C:6](=[O:41])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:40])[CH2:20][CH2:21][CH2:22][C:23](=[O:39])[NH:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33](=[O:38])[CH2:34][C:35](=[O:37])[CH3:36])=[CH:29][CH:30]=1
Reactant: O=C1CCC(=O)N1O
Reactant: CC(=O)CC(=O)CCc1ccc(NC(=O)CCCC(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)CC(=O)CCc1ccc(NC(=O)CCCC(=O)NCCOCCOCCOCCC(=O)ON2C(=O)CCC2=O)cc1
Reaction time: 8 h

Procedure:
3-{2-[2-(2-{4-[4-(3,5-Dioxo-hexyl)-phenylcarbamoyl]-butyrylamino}-ethoxy)-ethoxy]-ethoxy}-propionic acid tert-butyl ester (400 mg, 0.692 mmol) was dissolved in TFA/CH2Cl2 (1:1, 3 mL) and the mixture stirred overnight. The solvent was removed to give an oil as the acid intermediate. This oil was dissolved in CH2Cl2 (4 mL) containing DIEA (569 μL, 3.09 mmol), N-hydroxysuccinimide (119 mg, 1.03 mmol) and EDC (197 mg, 1.0 mmol) and the mixture stirred over the night. The solvent was removed and the residual oil was purified using column chromatography EtOAc/MeOH (95:5) to give an oil as the title compound, (M+1)=620.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[O:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:9][N:8]([CH3:10])[CH2:7][CH2:6][O:5][C:4]1[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:2]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CN(C)CCOc1ccc([N+](=O)[O-])c(F)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A mixture of [2-(3-fluoro-4-nitro-phenoxy)-ethyl]-dimethyl-amine (2.8 g, 12 mmol) and phenol (1.4 g, 15 mmol) in DMF (100 mL) was treated with potassium carbonate (3.4 g, 25 mmol) and the mixture heated at 110° C. under N2 with stirring. After 4 hours, the mixture was cooled to ambient temperature. The mixture was evaporated in vacuo, and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with 10% potassium carbonate (2×100 mL) and water (2×100 mL), and were then extracted with dilute aqueous HCl (3×75 mL). The combined aqueous extracts were washed with CH2Cl2 (2×100 mL), basified (NaOH), and extracted into ethyl acetate (3×75 mL). The combined organic phases were washed with water (2×100 mL), dried (MgSO4) and evaporated, providing 3.1 g, in 84% yield; 1H NMR (CDCl3) δ 2.29 (s, 6H), 2.67 (t, J=5.8 Hz, 2H), 4.00 (t, J=5.8 Hz, 2H), 6.46 (d, J=2.6 Hz, 1H), 6.68 (dd, J=9.2 Hz, J=2.6 Hz, 1H), 7.03-7.07 (m, 2H), 7.18-7.22 (m, 1H), 7.35-7.42 (m, 2H), 8.06 (d, J=9.2 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1([N:32]([CH3:34])[CH3:33])[CH2:10][CH2:9][C:8]([C:21]2[N:22]([CH3:31])[C:23]3[C:28]([C:29]=2[CH3:30])=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Cl:35][Si](C)(C)C>C1CCCCC1>[ClH:35].[CH2:1]([C:5]1([N:32]([CH3:34])[CH3:33])[CH2:6][CH2:7][C:8]([C:21]2[N:22]([CH3:31])[C:23]3[C:28]([C:29]=2[CH3:30])=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)Cl
Agent: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2C)(c2c(C)c3ccccc3n2C)CC1
Solvent: C1CCCCC1
Product: Cl
Temperature: 24 °C
Reaction time: 0.5 h

Procedure:
1-butyl-4-(1,3-dimethyl-1H-indol-2-yl)-N,N-dimethyl-4-(3-methyl-1H-indol-2-yl)cyclohexylamine (97 mg, 0.213 mmol) was dissolved in cyclohexane (10 ml). The solution was mixed with chlorotrimethyl silane (40 μl, 0.313 mmol) at 24° C. The clear reaction mixture immediately became cloudy. The mixture was stirred for 30 min at 24° C. The white precipitate was aspirated. The solid was washed with cyclohexane (3×0.5 ml) and then dried. The hydrochloride (95 mg, 91%, melting point 183-187° C.) was obtained as a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[C@H:13]([C:26]([O:28]C)=[O:27])[CH2:12]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH-].[Li+].Cl>O1CCCC1.O>[CH2:19]([O:18][C:16]([N:14]1[CH2:15][C@@H:11]([N:8]2[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]2)[CH2:12][C@H:13]1[C:26]([OH:28])=[O:27])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)[C@@H]1C[C@H](N2CCN(S(C)(=O)=O)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCN([C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of the compound prepared in Example 3 (0.90 g, 2.11 mmol) in tetrahydrofuran (20 mL) and water (20 mL) at 0° C. was added lithium hydroxide (0.203 g, 8.4 mmol). The reaction was warmed to room temperature and stirred overnight. The reaction mixture was carefully acidified to pH 5 with 2 M hydrochloric acid. The aqueous solution was extracted with ethyl acetate (2×300 mL) and the combined organic extracts were dried and concentrated to give the title compound (0.565 g, 65%) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:41]=[CH:40][N:14]3[C:15](=[O:39])[C:16](/[CH:30]=[CH:31]/[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:17](OS(C4C=CC(C)=CC=4)(=O)=O)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C)C=O>[CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:41]=[CH:40][N:14]3[C:15](=[O:39])[C:16](/[CH:30]=[CH:31]/[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[C:17]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3cc(/C=C/c4nc(C(C)C)cs4)ccn3c(=O)c2/C=C/C(=O)OC(C)(C)C)cc1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
The tert-butyl (E)-3-{8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-2-{[(4-methylphenyl)sulfonyl]oxy}-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (9.0 mg, 0.0152 mmol) obtained in (A) was dissolved in dimethylformamide (0.75 ml), added with morpholine (13.2 μl, 0.152 mmol), and stirred overnight at room temperature. The reaction mixture was concentrated, and then the residue was purified by thin layer chromatography (n-hexane:ethyl acetate=1:1, v/v) to obtain the title compound (6.7 mg, 87%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.[OH:13][N:14]=C(C1C=CC=CN=1)C(OCC)=O>>[OH:13][N:14]=[C:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=NO)c1ccccn1
Reactant: CCOC(=O)Cc1ccncc1
Product: CCOC(=O)C(=NO)c1ccncc1
Yield: 82 %

Procedure:
The oxime was prepared in 82% yield from ethyl pyridine-4-acetate using a procedure similar to that described above under Examples 321-324 for the preparation of ethyl hydroxyimino-pyridine-2-acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]([CH3:20])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:4][CH:3]=1>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:12])[N:10]([CH3:20])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN(CC(=O)c1ccc(F)cc1)C(=O)Nc1ccccc1
Solvent: CC(=O)O
Product: Cn1cc(-c2ccc(F)cc2)n(-c2ccccc2)c1=O

Procedure:
3.5 g (12.2 mmol) of the compound from Example 3 are heated under reflux for 24 hours in 50 ml of glacial acetic acid, the solvent is removed and the residue is washed with water. After drying 3.12 g are obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH:7](O)[C:6]=2[C:5]([CH3:14])=[C:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=1[CH3:23].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH:7]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:6]=2[C:5]([CH3:14])=[C:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[C:3]=1[CH3:23]
Reactant: C1CCNC1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(O)C(C)(C)O2
Product: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(N1CCCC1)C(C)(C)O2
Yield: 43 %

Procedure:
Using tert-butyl (7-bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 236 and pyrrolidine, the title compound was synthesized in the same manner as in Example 297.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([CH2:14][CH:15]([C:18]2[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:16][NH2:17])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([C:18]1[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=1)[CH2:14][CH:11]1[CH2:12][CH2:13]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(CC1CC1)c1ccc(F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-fluoropyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=333.1, tR (minutes, Method F)=2.43
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].C1CCN2C(=NCCC2)CC1.[F:34][C:35]([F:40])([F:39])[CH2:36][CH:37]=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[CH:37][CH2:36][C:35]([F:40])([F:39])[F:34]
Reactant: O=CCC(F)(F)F
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=CCC(F)(F)F)NC(=O)OCc1ccccc1
Temperature: -30 °C

Procedure:
N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester and DBU were dissolved in dry methylene chloride (50 mL) and the reaction mixture was chilled to −30° C. 3,3,3-trifluoropropanal (1 eq) was added dropwise to the chilled and stirred solution and the reaction was allowed to stir for an additional hour at −30° C., and then overnight at ambient temperature. Methylene chloride (ca. 100 mL) was added and the organic phase was washed with 1N HCl (ca. 100 mL), then saturated brine (ca. 100 mL). The organic phase was dried over MgSO4, filtered, and concentrated by rotary evaporation. This crude product was purified by silica gel chromatography with a gradient of 10-30% ethyl acetate in hexanes to yield 2-benzyloxycarbonylamino-5,5,5-trifluoro-pent-2-enoic acid methyl ester as a white, crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][N:27]2[CH2:30][CH:29](O)[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.C(N(S(F)(F)[F:38])CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][N:27]2[CH2:30][CH:29]([F:38])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Solvent: ClCCl
Product: Fc1cc(CN2CC(F)C2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1

Procedure:
To a slurry of 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methyl)azetidin-3-ol (0.100 g, 0.2 mmol) in 1 mL DCM under nitrogen at 0° C. was added (diethylamino)sulfur trifluoride (0.05 ml, 0.3 mmol). Upon consumption of starting material, the reaction was quenched with ice and 1 N NaOH. The reaction mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM 3, and the combined cloudy organics were treated with a small amount of MeOH to give a solution, were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by RPHPLC, gradient, TFA/ACN in TFA/H2O provided material that was taken up in DCM and washed with saturated aq. NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo to give 2-(2-fluoro-4-((3-fluoroazetidin-1-yl)methyl)-phenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a solid. MS (ESI) m/z: Calculated: 433.1; Observed: 434.1 (M++1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>C(O)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Product: COc1ccc(CNc2cncc(Cl)n2)cc1
Temperature: 115 °C
Yield: 85.1 %

Procedure:
To a stirred solution of 2,6-dichloropyrazine (25 g, 0.167 mol) and ethanol (120 mL) in a sealed tube is added 4-methoxybenzylamine (68.6 g, 0.5 mol). The mixture is heated to 115° C. for 12 h and cooled. The white solid is removed by filtration and the filtrate evaporated. The residue is dissolved in ethyl acetate and washed successively with 2M sodium hydroxide, water and aqueous sodium chloride. The organics are dried (magnesium sulfate), filtered, and evaporated to give (6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]amine (35.5 g), a white solid.