Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CO.[OH-].[Na+]>C1COCC1>[C:1]([N:8]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(CN(Cc2ccccn2)C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)Cc1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
The compound obtained in Example 1-1 (200.6 mg) was added with methanol (2 ml), THF (2 ml), and 1 mol/l aqueous solution of sodium hydroxide (2 ml), and the mixture was stirred for one day at room temperature. After the completion of the reaction, the solvent was removed by distillation and water (5 ml) was added. Aqueous solution of hydrochloric acid (1 mol/l) was added dropwise to the resulting solution to adjust the pH to 3. The deposited crystals were collected by filtration and dried to obtain the title compound (123.2 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([NH2:19])[CH:18]=3)=[O:12])=[CH:9][N:8]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=2[N:7]=1.[CH:24]1([C:27]2[CH:28]=[N:29][N:30]([CH2:32][C:33](O)=[O:34])[CH:31]=2)[CH2:26][CH2:25]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:18]=[C:17]([NH:19][C:33](=[O:34])[CH2:32][N:30]4[CH:31]=[C:27]([CH:24]5[CH2:25][CH2:26]5)[CH:28]=[N:29]4)[CH:16]=[N:15][CH:14]=3)=[O:12])=[CH:9][N:8]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=2[N:7]=1
Reactant: CC(C)(C)n1cc(C(=O)c2cncc(N)c2)c2cnc(N)nc21
Reactant: O=C(O)Cn1cc(C2CC2)cn1
Product: CC(C)(C)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C4CC4)cn3)c2)c2cnc(N)nc21

Procedure:
The title compound was prepared according to the method described for Example 1 using (2-Amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-amino-pyridin-3-yl)-methanone (see Preparation 65) and (4-cyclopropyl-pyrazol-1-yl)-acetic acid to afford the title compound as a pale yellow solid in 16% yield, 12 mg. LCMS (System 10): Rt=2.80 min; m/z 459 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.[Na].[CH3:14][CH2:15][OH:16]>>[CH2:15]([O:16][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1)[CH3:14]
Reactant: CCO
Reactant: CCOC(=O)c1ccc(Br)cn1
Agent: [Na]
Product: CCOC(=O)c1ccc(OCC)cn1

Procedure:
To a solution of ethyl 5-bromopyridine-2-carboxylate 2 (1.5 g, 6.5 mmol) in 20 mL of EtOH was added a solution of sodium (0.18 g, 7.8 mmol) in 20 mL of EtOH. The mixture was stirred at reflux for 3 h. After removal of all solvent, the residue was purified by column (2:1 of hexane/ethyl acetate) to give ethyl 5-ethoxypyridine-2-carboxylate 3 as an oil. Yield: 0.26 g, 20%. 1HNMR (CDCl3) δ (ppm): 8.38 (d, 1H), 8.10 (d, 1H), 8.23 (d, 1H), 7.22 (dd, 1H), 4.45 (m, 2H), 4.25 (m, 1H), 1.40 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](O)=[O:8].[CH:15]([NH2:17])=O>O>[CH3:13][O:12][C:11]1[CH:10]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:14]=[CH:15][NH:17][C:7]2=[O:8]
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: NC=O
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 190 °C
Reaction time: 3 h

Procedure:
A mixture of 4,5-dimethoxyanthranilic acid (19.7 g) and formamide (10 ml) was stirred and heated at 190° C. for 5 hours. The mixture was allowed to cool to approximately 80° C. and water (50 ml) was added. The mixture was stored at ambient temperature for 3 hours. The precipitate was isolated, washed with water and dried to give 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (3.65 g).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([C:12]1([C:25]([O:27]C)=O)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[OH:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+].O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O>C(Cl)Cl>[OH:11][CH:10]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:25](=[O:27])[NH:8][CH2:9]1
Reactant: COC(=O)C1(C(O)CNC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCC2O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-(2-((tert-butoxycarbonyl)amino)-1-hydroxyethyl)piperidine-1,4-dicarboxylate (4000 mg, 9.94 mmol) in DCM (100 mL) was added TFA (23 mL, 298 mmol) at 0° C. and the resulting solution was stirred for 2 h. After removing the volatiles, it was put on high vacuum briefly to remove excess TFA, and the residue was dissolved in MeOH (100 mL), and potassium carbonate (13.7 g, 99 mmol) was added. The reaction mixture was heated at 60° C. for 2 h. After cooling to room temperature, aqueous NaHCO3 (50 mL) was added to the reaction mixture. (BOC)2O (6.51 g, 29.8 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was extracted with DCM, dried with MgSO4, and concentrated to give the crude product, which was purified by column chromatography (0-20% MeOH/DCM, monitor at 210 nm) to afford the title compound. LC/MS: [(M+1)]+=271
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=O.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([N:14]1[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]1)=[O:5]
Reactant: CCCCC(Br)C(=O)O
Reactant: CN1CCNCC1
Product: CCCCC(Br)C(=O)N1CCN(C)CC1

Procedure:
Using the mixed anhydride procedure of Example 6F, 2-bromohexanoic acid was coupled to 1-methylpiperazine to provide the desired compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][C:13](C)(C)[CH3:14])=[O:11])=[C:5]([F:17])[CH:4]=1)#[N:2].Cl.O1CCOCC1>CCO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([F:17])[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Cc1ccc(C#N)cc1F
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(C#N)cc1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
Combined tert-butyl 2-(4-cyano-2-fluorophenyl)acetate (227.3 mg, 0.966 mmol) with EtOH (5 mL) and added a 4M hydrogen chloride solution in dioxane (0.121 mL, 0.483 mmol) and stirred in a heating block at 60° C. for 16 h. Then the reaction mixture was concentrated via rotary evaporation and re-constituted in EtOH (5 mL). An additional portion of a 4M hydrogen chloride solution in dioxane (17.61 mg, 0.483 mmol) was added to the vial and the mixture was stirred at 60° C. for an additional 1 h. The reaction mixture was then concentrated via rotary evaporation and dried in vacuo to give the title compound (198 mg, 99% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 1.27 (t, J=7.07 Hz, 3H) 3.72 (d, J=1.26 Hz, 2 H) 4.19 (q, J=7.24 Hz, 2 H) 7.36-7.40 (m, 1 H) 7.40-7.43 (m, 1H) 7.43-7.46 (m, 1 H). MS m/z [M+H]+ 208.0.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.N1C=CC=N1.Cl[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)(Cl)Cl>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:17](=[O:18])[O:19][CH3:20])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)c1cc(N)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cn[nH]c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 26.8 %

Procedure:
10 g of 3-amino-5-t-butylpyrazole as prepared in Reference Example (this pyrazole compound being hereinafter referred to as "Compound [II]") was dissolved in 100 ml of carbon tetrachloride, and 6.8 g of methyl chloroformate was added to the solution. The mixture was then allowed to react for 5 hours under refluxing. After cooling the reaction solution, a potassium carbonate aqueous solution was added thereto whereby crystals were formed. The crystals were collected by filtration, and washed with carbon tetrachloride and water to obtain 3.8 g of methyl N-(5-t-butyl-3-pyrazolyl)carbamate. This compound was recrystallized from a mixed solvent of carbon tetrachloride and chloroform and found to have a melting point of 177° C.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:15][N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH3:16])[CH2:24][CH2:25]2)=[CH:6][CH:7]=1)[C:12](=[O:14])[CH3:13]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CC(=O)Cc1ccc(OCC2CO2)cc1
Product: CC(=O)Cc1ccc(OCC(O)CN2CCN(c3ccccc3C)CC2)cc1

Procedure:
4-(2,3-Epoxypropoxy)-phenylacetone is reacted with 2-methylphenyl-piperazine analogously to Example 2(a). 1-[4-(propan-2-on-yl)-phenoxy]-3-[4-(2-methylphenyl)-piperazin-1-yl]-propan-2-ol is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=3)[N:11]=2)[N:8]=1.[Cl:22]N1C(=O)CCC1=O>C(#N)C.O.C([O-])(O)=O.[Na+]>[Cl:22][C:9]1[N:7]2[N:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]2=[N:11][C:10]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)cn2n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(Cl)n2n1
Temperature: 60 °C
Yield: 98.9 %

Procedure:
To a stirred solution of 6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.250 g, 0.879 mmol) in acetonitrile (20 mL) is added N-chlorosuccinimide (0.879 mmol) and the mixture is heated at 60° C. for 8 hours. The reaction mixture is diluted with water (50 mL), and sat. aqueous NaHCO3 (50 mL). The precipitate that forms is collected by filtration, washed with water (3×25 mL) and dried under vacuum to give the title compound (0.277 g, 98% yield) as a yellow solid: Rf 0.60 (1:1 EtOAc:hexanes); LCMS (m/z)=319.3, 321.2 [M+H]+, tR=3.02 min.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2([C:14]([S:16]C)=S)[S:13][CH2:12][CH2:11][CH2:10][S:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:18][NH2:19].C(OCC)(=O)C.C>C(O)C>[CH3:18][NH:19][C:14]([C:8]1([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[S:13][CH2:12][CH2:11][CH2:10][S:9]1)=[S:16]
Reactant: CN
Reactant: CSC(=S)C1(c2cccc(C)n2)SCCCS1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=S)C1(c2cccc(C)n2)SCCCS1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a suspension of methyl 2-(6-methyl-2-pyridyl)-1,3-dithiane-2-carbodithioate (130.5 g) in 1.2 liters of ethanol maintained at a temperature in the region of 20° C., a 33% (weight/volume) solution (840 cc) of methylamine in ethanol is added dropwise in the course of 10 minutes. The mixture is then stirred for 4 hours at the same temperature. The crystals which appear are separated by filtration, washed twice with ethyl acetate (100 cc in total), 4 times with isopropyl ether (400 cc in total) and dried under reduced pressure (0.2 mm Hg; 0.03 kPa) at a temperature in the region of 20° C. The product thereby obtained (100.2 g), to which is added some product (18.4 g) prepared under the same conditions in a previous operation, is dissolved in boiling ethyl acetate (3.3 liters); to this solution is added decolorising charcoal (33 g), and the solution is filtered hot. The filter is washed 4 times with boiling ethyl acetate (400 cc in total). The filtrate and the washing liquors are combined and cooled for 4 hours to a temperature in the region of 0° C. The crystals which appear are separated by filtration, washed 4 times with ethyl acetate (200 cc in total, 6 times with isopropyl ether (600 cc in total), and then dried under reduced pressure (0.2 mm Hg; 0.03 kPa) at 55° C. N-Methyl-2-(6-methyl-2-pyridyl)-1,3-dithiane-2-carbothiamide (99.1 g), m.p. 168° C., is thereby obtained.
Reaction SMILES: [Li]CCCC.[CH:6]1[C:18]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.Br[CH2:20][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1.CCOC(C)=O>C1COCC1.CCCCCC>[CH2:21]([C:22]1([CH:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[C:18]2=[CH:6][CH:7]=[CH:8][CH:9]=3)[O:26][CH2:25][CH2:24][O:23]1)[CH3:20]
Reactant: BrCCC1OCCO1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC1(C2c3ccccc3-c3ccccc32)OCCO1
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of BuLi (2.35 M in hexane, 25.6 mL, 60.2 mmol) was slowly added into a cooled (-78° C.) solution of fluorene (10 g, 60.2 mmol) in 200 mL THF. The reaction mixture turned dark red and solid started to precipitate out. After 30 minutes 2-(2-bromoethyl)-1,3-dioxolane (12 g, 66.3 mmol) was added to the cold solution and the solution was warmed up to room temperature. TLC (silica, 5% EtOAc in hexane) was used to monitor the reaction. After two hours the reaction was quenched with water and the product was extracted into EtOAc. The organic layer was washed with water (×3), dried over magnesium sulfate and evaporated. Short path chromatography afforded 8.34 g (52%) of the product as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])=[N:4][N:5]([C:14]2[CH:19]=[C:18]([S:20][CH2:21][C:22]([F:25])([F:24])[F:23])[C:17]([CH3:26])=[CH:16][C:15]=2[F:27])[C:6]=1[NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].[H][H]>C(O)C.[C].[Pd]>[F:27][C:15]1[CH:16]=[C:17]([CH3:26])[C:18]([S:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:19][C:14]=1[N:5]1[C:6]([NH:7][C:8](=[O:13])[C:9]([F:12])([F:10])[F:11])=[CH:2][C:3]([O:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:32])([F:33])[F:34])=[N:4]1
Reactant: [H][H]
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)c(Br)c2NC(=O)C(F)(F)F)cc1SCC(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2NC(=O)C(F)(F)F)cc1SCC(F)(F)F
Yield: 95.3 %

Procedure:
1.2 g of 4-bromo-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)-5-trifluoroacetylaminopyrazole was dissolved in 200 mL of ethanol, and 1.2 g of 10% palladium carbon was added. 430 mL of hydrogen was blown over a period of 10 days at room temperature under reduced pressure, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane:acetic acid=10:40:1) to obtain 1.0 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)-5-trifluoroacetylaminopyrazole.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH:6]2[C:18](=[O:20])[NH2:19])[CH2:2]1.CCN(CC)CC.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>C(Cl)Cl>[C:28]([N:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH:6]2[C:18](=[O:20])[NH2:19])[CH2:2]1)(=[O:31])[CH:29]=[CH2:30]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CNC2)C(C(N)=O)C1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CC(N2CCN(C(=O)OC(C)(C)C)CC2C(N)=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.6 %

Procedure:
To a solution of tert-butyl 4-(azetidin-3-yl)-3-carbamoylpiperazine-1-carboxylate (640 mg, 2.22 mmol) and Et3N (463 mg, 4.58 mmol) in DCM (10 mL) at 0° C., acryloyl chloride (248 mg, 2.74 mmol) was added dropwise and the resulting mixture was stirred at RT for 1.5 h. The mixture was partitioned between dichloromethane and saturated NaHCO3 solution. The organic layer was washed with saturated brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (350 mg, 47% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:16])=[C:4]([CH2:11][CH:12]([OH:15])CO)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[BH4-].[Na+].Cl>O.CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][CH2:12][OH:15])[C:3]=1[OH:16]
Reactant: O=[N+]([O-])c1cc(F)c(O)c(CC(O)CO)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(F)c(O)c(CCO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
Compound 4 (3.7 g, 16 mmol) was suspended in water and dissolved by adding a few drops of acetone. NaIO4 (3.42 g, 16 mmol) was added portionwise at 0° C. After 7 min NaBH4 (4.84 g, 128 mmol) was added slowly. The solution was stirred for 1 h at room temperature, the acidified with dilute hydrochloric acid and extracted with ethyl acetate. The filtrate was concentrated to yield the desired compound 5 (2.4 g, yield 75%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11])([O:6]CC)=[O:5])[CH3:2].CO.[OH-].[Na+]>C1COCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11])([OH:6])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOP(=O)(O)CC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 24 h

Procedure:
To a stirring solution of 0.58 g (1.2 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(diethoxyphosphinyl)acetyl]hydrazide (20), prepared as described above in Example 20, in 5 mL of THF:methanol (THF:MeOH) (3:2) was added 2 mL of N NaOH. After 24 hours of stirring, an additional 2 mL of NaOH was added to the reaction. After 7 days of stirring, the reaction mixture was filtered, and the resulting filtrate was extracted with 25 mL of EtOAc. The aqueous layer was neutralized with N HCl to pH 2, and was extracted with 25 mL of dichloromethane (DCM). The organic layer was dried over Na2SO4 anhydrous, filtered, and then concentrated in vacuo. The yield of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(ethoxyhydroxyphosphinyl)acetyl]hydrazide (27), which was a beige foam, was 0.20 g (37%). Analysis calculated for C18H19N3O6PCl. 025 H2O (M.W. 443.30): C, 48.66; H, 4.42; N, 9.46. Found: C, 48.62; H, 4.37; N, 9.24.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+].O>CN(C)C=O>[F:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:3]=[CH:4][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC#CCO
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1cc(-c2cccc(F)c2)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.7 %

Procedure:
In 7 ml of N,N-dimethylformamide were dissolved 204 mg of 4-chloro-6-(3-fluorophenyl)pyrimidine and 82 mg of 2-butyn-1-ol, to which 47 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 6 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 151 mg of 4-(3-fluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (57)).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.CCOC(C)=O>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 52.6 %

Procedure:
Under nitrogen dissolve 1-benzhydrylazetan-3-ol (5 g, 20.9 mmol), imidazole (3.5 g, 52.25 mmol) in anhydrous DMF (25 mL). Cool solution in an ice bath, add slowly tert-butyldimethylsilyl chloride (50 wt. % solution in toluene, 6.3 g, 41.8 mmol). Stir at RT for 22 h. Dilute with EtOAc and wash with saturated aqueous sodium bicarbonate solution. Separate organic layer, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 EtOAc:hexanes) to give the title compound (3.89 g, 53%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[CH2:10][CH:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:12](=[O:16])[N:13]([CH3:15])[CH2:14][C:8]=2[CH:7]=1.CS[C:26]1[NH:27][CH2:28][CH2:29][N:30]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[NH:30]1[CH2:29][CH2:28][N:27]=[C:26]1[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[CH2:10][CH:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:12](=[O:16])[N:13]([CH3:15])[CH2:14][C:8]=2[CH:7]=1
Reactant: CSC1=NCCN1
Reactant: COC(=O)CC1Cc2ccc(OCCCN)cc2CN(C)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)CC1Cc2ccc(OCCCNC3=NCCN3)cc2CN(C)C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A mixture of methyl (±)-8-[3-amino-1-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.3 g, 1 mmol), 2-methylthioimidazoline (0.46 g, 2 mmol), diisopropylethylamine (0.42 mL, 2 mmol) and dimethylacetamide (3 mL) was heated to 100° C. under argon. After 2 hr, the reaction was concentrated under vacuum and the residue was partitioned between CHCl3 and H2O. The organic phase was dried (MgSO4) and concentrated, and the residue was purified by preparative HPLC to give the title compound (0.24 g, 51%) as a yellow oil: MS (ES) m/e 389.4 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][NH:11][N:10]=2)[CH:8]=1)#[N:2].Cl[CH2:29][C:30]1[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][N:11]([CH2:29][C:30]3[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=3)[N:10]=2)[CH:8]=1)#[N:2]
Reactant: COc1ccc(C#N)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Reactant: Cn1nccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1-c1nn(Cc2ccnn2C)cc1NC(=O)c1cnn2cccnc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 32.1 %

Procedure:
To a solution of N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (144 mg, 0.40 mmol) in 3 mL of DMF was added 5-(chloromethyl)-1-methyl-1H-pyrazole (78 mg, 0.6 mmol) and cesium carbonate (391 mg, 1.20 mmol). The reaction mixture was stirred at 60° C. for 6 hours, then cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 58.3 mg (32%) of N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=454.1; 1H NMR (400 MHz, CDCl3) δ: 9.58 (s, 1H), 8.74 (dd, 1H), 8.64 (s, 1H), 8.48 (dd, 1H), 8.21 (s, 1H), 7.81 (s, 1H), 7.69 (dd, 1H), 7.39 (s, 1H), 7.07 (d, 1H), 6.96 (dd, 1H), 6.31 (s, 2H), 5.33 (s, 2H), 3.86 (d, 6H).