Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[N:16]([CH2:17][C@H:18]2[CH2:20][C@@H:19]2[CH3:21])[C:10]2[C:11](=O)[NH:12][N:13]=[CH:14][C:9]=2[C:8]=1[CH3:22].[OH-].[Na+]>>[Cl:3][C:11]1[N:12]=[N:13][CH:14]=[C:9]2[C:8]([CH3:22])=[C:7]([CH3:6])[N:16]([CH2:17][C@H:18]3[CH2:20][C@@H:19]3[CH3:21])[C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(=O)[nH]ncc12
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(Cl)nncc12
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 91.8 %

Procedure:
Phosphorus oxychloride (55 ml, 590 mmol) was added to 2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]-6,7-dihydropyrrolo[2,3-d]pyridazine-7-one (6.95 g, 30.1 mmol) and the mixture was stirred at 90° C. for 3.5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into ice-water. The aqueous solution was neutralized with a 5N aqueous sodium hydroxide solution and extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated in vacuo. Hexane was added to the residue and the precipitate was collected by filtration to afford the desired compound (6.90 g, 92.0%) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([OH:22])[CH:20]=2)[CH:15]=[N:14]1.[H-].[Na+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([O:22][CH2:30][C:29]#[CH:28])[CH:20]=2)[CH:15]=[N:14]1
Reactant: C#CCBr
Reactant: O=[N+]([O-])c1cc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc2c(cnn2-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
To a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-6-hydroxy-5-nitroindazole [Compound No. 31] (3 g) in N,N-dimethylformamide, 60% sodium hydride (0.5 g) was added, and the resultant mixture was stirred while cooling with ice. After 10 minutes, propargyl bromide (1.2 g) was added thereto, and the resultant mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-nitro-6-propargyloxyindazole (2.8 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:13][CH2:14][F:15].C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:15][CH2:14][CH2:13][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)NCCC2
Reactant: FCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)N(CCF)CCC2
Yield: 44 %

Procedure:
500 mg (3.35 mmol) 1,2,3,4-Tetrahydro-quinolin-7-ol are dissolved in 8 mL DMF and stirred at 60° C. overnight with 0.325 mL (1.3 eq) 1-bromo-2-fluoroethane, in the presence of 0.63 mL (1.1 eq) diisopropylethylamine. The reaction mixture is extracted with 0.1 N aqu. HCl and ethyl acetate. The combined organic extracts are washed with brine, dried over sodium acetate and evaporated. The residue is column chromatographed (silica gel, ethyl acetate/petroleum ether 1:2 to 1:1) to yield 290 mg (44%) desired product as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:16]([O:18][CH3:19])=[O:17]>C(=O)(O)[O-].[Na+].C(OCC)C.C(Cl)Cl>[OH:12][C:13]1[CH:22]=[C:21]([O:23][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])[CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Chlorobenzenesulfonyl chloride (2.49 g, 0.018 mol) was added dropwise to a rapidly stirred mixture of methyl 3,5-dihydroxybenzoate in saturated sodium bicarbonate (20 mL) and diethyl ether (20 mL) and allowed to stir at ambient temperature. After 2 days, 1.25 g of 2-chlorobenzenesulfonyl chloride was added and stirred for an additional 1 day. The reaction mixture was diluted with methylene chloride and separated. The aqueous layer was extracted with methylene chloride. The combined methylene chloride extracts were washed with brine and water, dried, and evaporated to an oil. The oil was triturated with hexanes (4 times) before placing the residual oil on a silica gel column and eluted first with methylene chloride, then 10% ethyl acetate/methylene chloride. The appropriate fractions were evaporated to give 1.35 g of solid.
Reaction SMILES: [Cl:1][C:2]1C=[C:4](CC(O)=O)[CH:5]=[CH:6][CH:7]=1.C(O[C:16](=[O:18])[CH3:17])(=O)C.[C:19]([O-])(=O)[CH3:20].[Na+]>O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:19]=1[CH2:20][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)Cc1ccccc1Cl
Temperature: 25 °C
Yield: 41 %

Procedure:
The general pathway for making compounds of Formula (I) is outlined above. In accordance with the general pathway, approximately 17 g of 0.1 mol 3-Chlorophenylacetic acid was refluxed in acetic anhydride (75 ml, 0.8 mol) and sodium acetate (8.2 g., 0.1 mol) for 2 days. The resulting mixture was allowed to cool to room temperature and diluted with water (150 ml). The organic layer was then refluxed in concentrated HCl (80 ml) for one hour, cooled to room temperature and then 200 ml of water was added to the mixture. The mixture was extracted with ethyl ether to produce 2-chlorphenyl acetone at about a 41% yield. The intermediate product had a boiling point of about 76° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19]1.CC(C)([O-])C.[K+]>>[OH:23][CH2:18][CH2:19][C:20]1[C:21](=[O:22])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[C:13]([C:14]=1[OH:16])=[CH:12][CH:11]=[CH:10][N:9]=2
Reactant: O=C1CCCO1
Reactant: COC(=O)c1cccnc1Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=c1c(CCO)c(O)c2cccnc2n1-c1ccccc1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To a solution of 6.8 g. of methyl 2-phenylamino-3-pyridine carboxylate in 60 ml. of gamma-butyrolactone there was added, under nitrogen, 13.4 g. of potassium tertiary butoxide. The reaction mixture was heated and stirred for one hour at 95° C., poured on ice and stirred overnight. The mixture was extracted with ether, the aqueous layer acidified with acetic acid to pH 4.5 and the product was collected by filtration. Recrystallization from chloroform, acetone, isopropanol yielded the product of this example as a colorless solid; m.p. 235°-236° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]4[CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:24])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:25]([O:27]C)=[O:26])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]4[CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:24])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:25]([OH:27])=[O:26])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccc(F)cc4o3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccc(F)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of methyl 2-(6-fluoro-1-benzofuran-2-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (78 mg, 0.19 mmol) in methanol (25 mL) and water (5 mL) was added sodium hydroxide (23 mg, 0.57 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (10 mL), adjusted to pH 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford (S)-2-(6-fluorobenzofuran-2-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid (37.3 mg, 52%).
Reaction SMILES: [CH3:1][Mg]Br.[O:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[NH4+].[Cl-]>C(OCC)C>[OH:4][C:5]1([CH3:1])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3M methyl magnesium bromide in diethyl ether (2.0 mL) in diethyl ether (3 mL) at 0° C. was treated with a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (1.0 g, 5.00 mmol) in diethyl ether (5 mL), warmed to room temperature, stirred for 18 hours, treated with saturated NH4Cl, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 20%-50% ethyl acetate/heptane to provide the desired product. MS (DCI(+)) m/e 216 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:15]([Cl:25])(=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>C(Cl)Cl>[ClH:25].[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([N:4]2[CH2:3][CH2:2][N:1]([CH2:7][C:8]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[O:9])[CH2:6][CH2:5]2)=[O:24])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(CC(=O)N3CCCC3)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.4 g of piperazin-1-yl-acetic acid pyrrolidide are dissolved in 10 ml of methylene chloride. A solution of 8.75 g of anisic acid chloride in 10 ml of methylene chloride is added dropwise at 0°. After the mixture had been stirred at 25° C. for 60 minutes, the crystals are filtered off with suction and dried in vacuo.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7](Cl)=[O:8])=[O:4].[NH2:15][CH2:16][C:17](=[O:19])[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[O:19]=[C:17]([CH3:18])[CH2:16][NH:15][C:7]([CH:6]1[CH2:10][CH2:11][CH2:12][N:5]1[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])=[O:8]
Reactant: O=C(Cl)[C@@H]1CCCN1C(=O)C(F)(F)F
Reactant: CC(=O)CN
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)CNC(=O)C1CCCN1C(=O)C(F)(F)F

Procedure:
A solution of (S)-N-(trifluoroacetyl)prolyl chloride (Aldrich) 1 equiv. in DCM is treated with 1-amino-propan-2-one (1.5 equiv.) in pyridine at rt for 5 hours. After usual work up, it provides 1-trifluoroacetyl-pyrrolidine-2-carboxylic acid (2-oxo-propyl)-amide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]=3[CH:17]=[C:16]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH:15]=1)[CH2:5][CH2:6][O:7]2.[OH-].[Na+]>O1CCCC1.CC(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:34]([N:36]([CH3:37])[CH3:38])=[O:35])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: Cc1ccc(S(=O)(=O)n2c(C)nc3c(O[C@H]4CCOc5cc(F)cc(F)c54)cc(C(=O)N(C)C)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1nc2c(O[C@H]3CCOc4cc(F)cc(F)c43)cc(C(=O)N(C)C)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To a solution of (−)-4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1-[(4-methylphenyl)-sulfonyl]-1H-benzimidazole-6-carboxamide (24.2 g, 44.7 mmol, STEP 9) in tetrahydrofuran (65 mL) and 2-propanol (220 mL) was added 2M sodium hydroxide aqueous solution (220 mL, 440 mmol) at room temperature. After stirring at room temperature for 4 hours, the mixture was diluted with ethyl acetate (1.20 L) and washed with saturated ammonium chloride aqueous solution (500 mL). The organic solution was dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography on amino gel (ethyl acetate:methanol gradient elution from 50:1 to 20:1) to afford the title compound as a white solid (15.2 g, 87%, >99% ee).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].C(N=C=NC(C)C)(C)C.[F:29][C:30]1[C:35](O)=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40]>ClCCl>[F:29][C:30]1[C:35]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)CCCCCN1C(=O)c2ccccc2C1=O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: O=C(CCCCCN1C(=O)c2ccccc2C1=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Yield: 101.3 %

Procedure:
Referring to scheme 12, compound 41a (13.3 g, 51 mmol) was dissolved in anhydrous dichloromethane (40 mL) and cooled to 0° C. under argon. To the solution were added diisopropyl carbodiimide (6.31 g, 7.7 mL, 50 mmol) and pentafluoro phenol (42, 9.2 g, 50 mmol). After overnight the reaction mixture was evaporated to dryness. To the residue ethyl acetate (100 mL) was added and the filtered to remove diisopropyl urea. The precipitate was washed with ethyl acetate (50 mL). The combined organic layer was washed with saturated sodium bicarbonate and water. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. Compound 43a (Rf=0.8 in 10% EtOAc/Hexane, 21.65 g, 92%) was obtained, which was directly used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:12][CH2:13][CH2:14][CH2:15][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1]
Reactant: BrCCCBr
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1ccccc1OCCCBr
Yield: 83.4 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 4.0 grams (0.025 mole) of 2-trifluoromethylphenol, 17.8 mL (0.178 mole)of 1,3-dibromopropane, and 9.0 grams (0.065 mole) of potassium carbonate in 120 mL of acetone was heated at reflux for about 18 hours. After this time, the reaction mixture was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using petroleum ether. The product containing fractions were combined and concentrated under reduced pressure, yielding 5.9 grams of 2-trifluoromethylphenyl 3-bromopropyl ether. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1)=O.Br[C:14]1C=CC(C(O)=O)=C(C)[CH:15]=1.[Li][CH2:25]CCC.CN(C=O)C>C1COCC1>[CH3:12][C:5]1[CH:4]=[C:3]([CH:1]=[CH2:25])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:14][CH3:15])=[O:8]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: Cc1cc(C=O)ccc1C(=O)O
Reactant: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)OCC)c(C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
4-Formyl-2-methylbenzoic acid (AI15). To a stirred solution of 4-bromo-2-methylbenzoic acid (10 g, 46.4 mmol) in dry THF (360 mL) at −78° C. was added n-BuLi (1.6 M solution in hexanes; 58.17 mL, 93.0 mmol) and DMF (8 mL). The reaction mixture was stirred at −78° C. for 1 h then was warmed to 25° C. and stirred for 1 h. The reaction mixture was quenched with 1 N HCl solution and extracted with EtOAc. The combined EtOAc extracts were washed with brine and dried over Na2SO4 and concentrated under reduced pressure. The residue was washed with n-hexane to afford the title compound as a solid (3.0 g, 40%): mp 196-198° C.; 1H NMR (400 MHz, DMSO-d6) δ 13.32 (br s, 1H), 10.05 (s, 1H), 7.98 (m, 1H), 7.84 (m, 2H), 2.61 (s, 3H); ESIMS m/z 163.00 ([M−H]−).
Reaction SMILES: N1(C2N=C3C=CC(N)=CN3N=2)CCCC1.[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:44])[C:25]=1[C:26](=[O:43])[NH:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([N:37]3[CH2:42][CH2:41]O[CH2:39][CH2:38]3)[N:36]=2)[CH:33]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:44])[C:25]=1[C:26](=[O:43])[NH:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([N:37]3[CH2:42][CH2:41][CH2:39][CH2:38]3)[N:36]=2)[CH:33]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Agent: Nc1ccc2nc(N3CCCC3)nn2c1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCCC3)nn2c1

Procedure:
Using 2-Pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine, this compound was prepared following the same method as for the synthesis of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester. Brown solid (1.1 g, 65%). MS: m/z=384 (M+H+).
Reaction SMILES: CCOCC.[CH3:6][O:7][C:8]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C@H:12]1[CH2:14][O:13]1.CNC.B.O>C(Cl)Cl>[CH3:6][O:7][C:8]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C@H:12]([OH:13])[CH3:14]
Reactant: COc1cc([N+](=O)[O-])ccc1OC[C@H]1CO1
Agent: B
Agent: CNC
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OC[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To 160 mL of Et2O cooled to 0° C. was added LiClO4 (80 g; 752 mmol) in portions over 20 min. The mixture was allowed to warm to rt and (R)-2-((2-methoxy-4-nitrophenoxy)methyl)oxirane (9.55 g; 42.5 mmol) was added. The suspension was stirred for 10 min, borane dimethylamine (3.40 g; 46.6 mmol) was added and the suspension was stirred at rt for 2.5 h. The suspension was diluted with CH2Cl2 and stirred in a beaker with H2O until gas evolution ceased. The organic layer was washed with H2O, dried over anhydrous MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was triturated in CH2Cl2, filtered and the filtrate purified by flash chromatography (silica gel, Hexanes/EtOAc; 100:0 to 100:0 gradient) to afford 6.83 g (70%) of the title compound as a yellow solid. 1H NMR (CDCl3) δ 1.31 (d, J=6.59 Hz, 3H), 2.77 (br s, 1H), 3.90-3.94 (m, 4H), 4.05-4.08 (m, 1H), 4.24-4.32 (m, 1H), 6.92 (d, J=9.35 Hz, 1H), 7.74 (d, J=2.75 Hz, 1H), 7.88 (dd, J=8.79 Hz, 2.74 Hz, 1H); 13C NMR (CDCl3) δ 18.64, 56.18, 65.87, 74.85, 106.73, 111.66, 117.60, 141.76, 149.20, 153.63; HPLC (Method #1) 2.17 min retention time; LCMS (ES): m/z 228 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([F:20])[CH:11]=1)(=[O:9])=[O:8].[OH-].[Na+].Cl>C1COCC1.CO.O>[NH3:6].[F:20][C:12]1[CH:11]=[C:10]([S:7]([NH:6][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)(=[O:8])=[O:9])[CH:19]=[CH:18][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2nccs2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N
Product: O=C(O)c1ccc(S(=O)(=O)Nc2nccs2)cc1F
Yield: 22.2 %

Procedure:
A mixture of methyl 4-{[(2,4-dimethoxybenzyl)(1,3-thiazol-2-yl)amino]sulfonyl}-2-fluorobenzoate (Preparation 14, 10 g, 21 mmol, 1 eq) and sodium hydroxide 4.3 g, 0.107 mol, 5 eq) in THF: MeOH: water (25 ml:2 ml:75 ml) was heated at 50° C. for 4 hours. The reaction mixture was acidified to pH 2.0 with 2M HCl and the resulting precipitate collected by filtration. The crude material was purified by column chromatography eluting with 90:10:1 DCM:MeOH: ammonia to yield the title compound as a yellow solid (706 mg, 2.33 mmol, 11%).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:23])O1.[CH2:25]=O.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CO>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][N:10]([O:11][CH3:12])[C:8]([C:7]2[CH2:25][N:27]([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:4](=[O:23])[C:5]=2[OH:6])=[O:9])=[CH:21][CH:20]=1
Reactant: NCCN1CCOCC1
Reactant: CON(CCCc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: C=O
Solvent: CO
Product: CON(CCCc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Yield: 63 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-[3-(4-fluorophenyl)-propyl]-N-methoxy-acetamide (0.560 g, 1.66 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.446 g (63% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (DMSO-d6) δ (ppm); 1.84 (2H, m, CH2), 2.40 (4H, broad, 2×NCH2), 2.46 (2H, t, J=6.5 Hz, CH2), 2.56 (2H, t, J=8.1 Hz, CH2), 3.46 (2H, t, J=6.5 Hz, NCH2), 3.52 (3H, s, OCH3), 3.55 (4H, broad, 2×OCH2), 3.67 (2H, t, J=7.1 Hz, NCH2), 3.95 (2H, s, NCH2), 7.09 (2H, m, aromatics), 7.23 (2H, m, aromatics). HRMS (FAB+) calculated for C21H29FN3O5: [M+H]+: 422.209125. found: 422.208679.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C@@H:12]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:11]([CH3:32])[O:10][C:9]1=[O:33])(C)(C)C.[ClH:35].O1CCOCC1>C(Cl)Cl>[Cl-:35].[CH3:32][C@@H:11]1[O:10][C:9](=[O:33])[C@@H:8]([NH3+:7])[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[C@H:12]1[O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cl
Reactant: Cc1ccc(C[C@H]2CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]2Oc2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(C[C@H]2CCC[C@H]([NH3+])C(=O)O[C@@H](C)[C@@H]2Oc2ccccc2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 100 %

Procedure:
A 25 mL screw top vial was charged with tert-butyl((3S,7R,8R,9S)-9-methyl-7-(4-methylbenzyl)-2-oxo-8-phenoxyoxonan-3-yl)carbamate (300 mg, 0.642 mmol), anhydrous CH2Cl2 (4 mL), and 4.0 M HCl in dioxane (3.21 mL, 12.83 mmol). After stirring at room temperature for 80 min, the reaction mixture was concentrated under a stream of nitrogen and dried under high vacuum to provide the title compound as a beige solid (259 mg, 100%): mp 200-210° C. (dec.); 1H NMR (400 MHz, CDCl3) δ 7.46-6.81 (m, 9H), 5.14 (s, 1H), 3.78-3.52 (m, 3H), 2.86 (s, 1H), 2.60-1.12 (m, 12H), 0.96 (s, 1H); 13C NMR (101 MHz, CD3OD) δ 171.05, 160.65, 137.89, 136.19, 130.75, 129.87, 129.75, 122.14, 117.03, 81.89, 76.55, 68.05, 46.67, 37.46, 32.38, 27.71, 21.05, 20.12, 18.85; ESIMS m/z 369 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[C:7]([CH3:10])=[N:8][CH:9]=1)([O-])=O.O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: Cc1ncc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Yield: 92.3 %

Procedure:
To a stirred solution of N-(5-nitro-2-methylpyrid-3-yl)-4-(pyrid-3-yl)-2-pyrimidinamine (18.0 g) and hydrazine hydrate (9 mL) in ethanol (180 mL) was added activated nickel (0. g). The mixture was refluxed for 3 hours, filtrated and the filtrate was concentrated in vacuo to give solid, which was put in the fridge (0° C.) overnight. The residue was filtrated off and the filtrate was concentrated in vacuo to give N-(5-amino-2-methylpyrid-3-yl)-4-(pyrid-3-yl)-2-pyrimidinamine (15 g).