Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[O:4][N:3]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Cc1ccc(-c2cc(O)no2)cc1
Product: Cc1ccc(-c2cc(OCCNC(=O)OC(C)(C)C)no2)cc1
Yield: 80.7 %

Procedure:
3-Hydroxy-5-(4-methylphenyl)isoxazole (1.5 g) and 2-(N-tert-butoxycarbonylamino)ethanol (1.5 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (2.2 g, 82%) as a colorless powder.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13](=[O:28])[CH2:14][C:15]([O:17][C:18]([CH3:27])([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:19]=[CH2:20])=[O:16].[CH3:29]I.Cl>O1CCCC1>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13](=[O:28])[CH:14]([CH3:29])[C:15]([O:17][C:18]([CH3:27])([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:19]=[CH2:20])=[O:16]
Reactant: CI
Reactant: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)C(C)C(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (3.92 g, 0.098 mol, 60%) and tetrahydrofuran (100 mL) are placed into a 250 mL three-necked round-bottomed flask fitted with a magnetic stirrer, ice bath, addition funnel, internal thermometer and argon inlet. The contents of the flask are cooled to 0° C. 3,7-Dimethyl-1,6-octadien-3-yl 3-(β-naphthyl)-3-oxo-propionate (15.28 g, 0.044 mol) dissolved in 50 mL of tetrahydrofuran is added dropwise to the flask over 30 min. During addition, the mixture evolves gas. After stirring for 1 h, methyl iodide (10.65 g, 0.075 mol) is added to the reaction mixture. Stirring continues for 2 h at 0° C. and then at room temperature for 18 h. The mixture is neutralized with 20% HCl and extracted with diethyl ether. The organic layers are washed with saturated NaHCO3 solution, water, dried over MgSO4, filtered, concentrated by rotary evaporation and purified by flash chromatography to yield the desired compound. Structure is confirmed my 1H and 13C NMR.
Reaction SMILES: FCC(F)(F)C(F)(F)O.[C:10]([CH:17]([O:19][CH2:20][C:21]([C:24]([F:27])([F:26])[F:25])([F:23])[F:22])[OH:18])([C:13]([F:16])([F:15])[F:14])([F:12])[F:11].C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]([F:42])([F:41])[C:36]([F:40])=[C:37]([F:39])[F:38].C(C(COC(C(C(F)(F)F)F)(F)F)(F)F)(F)(F)F>O.C(#N)C>[C:10]([CH:17]([O:18][C:37]([CH:36]([C:35]([F:42])([F:41])[F:34])[F:40])([F:39])[F:38])[O:19][CH2:20][C:21]([C:24]([F:25])([F:26])[F:27])([F:22])[F:23])([C:13]([F:16])([F:15])[F:14])([F:12])[F:11]
Reactant: OC(OCC(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: FC(F)=C(F)C(F)(F)F
Agent: FC(C(F)(F)F)C(F)(F)OCC(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: OC(F)(F)C(F)(F)CF
Solvent: O
Solvent: CC#N
Product: FC(C(F)(F)F)C(F)(F)OC(OCC(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 40 °C

Procedure:
The entire contents of the pentafluoropropanol solution (containing the desired C2F5CH(OH)OCH2C2F5) were placed in a 600 mL Parr reaction vessel along with acetonitrile (167 g) and powdered potassium carbonate (2.9 g). The reactor was sealed, evacuated and heated to 40° C. Hexafluoropropene (64.8 g, 0.43 mole) was added in portions over about two hours and the reactor then held at temperature overnight. The reaction mixture was worked up by pouring into water and washing the resulting lower phase three times with water followed by distillation. The distillation afford a main fraction of boiling point 142° C. The product identity was confirmed by GC-MS and H-1 and F-19 NMR as a mixture of diastereomers in a ratio of 55/45%. One diastereomeric fraction was thought to contain SS and RR enantiomers and the other SR and RS enantiomers. The NMR data showed that the product contained about 4.2% olefin [—OCF═CFCF3] as a 43/57% cis/trans mixture. The excess pentafluoropropanol was converted to CF3CF2CH2OCF2CFHCF3 which was removed during the distillation.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[N:11]=1.[H-].[Na+]>CN(C)C=O.CCCCCC>[CH3:19][O:18][C:12]1[CH:13]=[C:14]([O:16][CH3:17])[N:15]=[C:10]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:11]=1
Reactant: OCc1ccccc1
Reactant: COc1cc(OC)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(OCc2ccccc2)n1

Procedure:
Benzyl alcohol (Compound II-64) (0.434 g, 4.0 mmol) and 2-chloro-4,6-dimethoxypyrimidine were dissolved in dimethylformamide (10 ml) and cooled with ice. Sodium hydride (168 mg, 4.0×1.05 mmol) which had been washed with hexane (1 ml×2) was added thereto. After allowed to react for 2 hours, the reaction solution was poured onto ice and extracted with toluene. The organic phase was concentrated and thereafter purified on silica gel column chromatography (Wakogel C300, 100 ml, ethyl acetate/hexane=30 ml/300 ml) to obtain the compound (I-372).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[Cl:38])[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][NH:30][C:26]1[CH:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccccc5Cl)c4)nn(COCC[Si](C)(C)C)c3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccccc5Cl)c4)n[nH]c3n2)CC1
Reaction time: 4 h

Procedure:
To a stirred solution of {4-[3-[3-(2-chloro-benzylamino)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (110 mg, 0.162 mmol) in dichloromethane (3 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred for another four hours at this temperature. The solvent was evaporated under reduced pressure and the residue was treated with saturated aqueous NaHCO3 (5 mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine (5 mL) and dried to give crude product. It was purified by prep-HPLC to give N-{3-[3-(2-chloro-benzylamino)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine as solid. (Yield 15 mg, 21%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 120 °C

Procedure:
2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole (11.93 g, 1.0 eq), sodium azide (3 eq), and ammonium chloride (3 eq) were mixed and stirred in DMF (150 mL) in a round bottom connected to a reflux condenser under N2. An oil bath with a temperature controller was then used to heat the reaction at 100° C. for 2 days, after which the temperature was raised to 120° C., for 6 days. The reaction was cooled and 3 more equivalents of ammonium chloride and sodium azide were added. The reaction was again heated for 5 more days at 120° C. The reaction was cooled, the inorganic salts filtered, and the filtrate solvent removed in vacuo. Water (200 mL) and ethyl acetate (200 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×200 mL), the organic layers were collected, dried (MgSO4) and the solvent removed in vacuo, to yield a dark yellow oil. The product was purified by flash chromatography in 100% ethyl acetate to 100% ethanol over silica gel to yield 5.60 g of a light yellow solid. Recrystallization from acetonitrile yielded 4.36 g of light yellow crystals which still melted broadly. The crystals were taken up in 100 mL of hot acetonitrile. The solid that did not dissolve was filtered off to yield 1.04 g of product as a light yellow solid; m.p. 183.5°-184.5°. Upon cooling, the mother liquor yielded an additional 1.03 g of product as a light yellow solid; m.p. 179.0°-180.0°. NMR (200 MHz, DMSO-d6)δ7.75-7.48 (m, 4H); 7.07 (d, 2H, J=9 Hz); 7.04 (d, 2H, J=9 Hz); 5.24 (s, 2H); 5.24 (bs, 1H); 4.34 (s, 2H); 2.48 (t, 2H, J=7 Hz); 1.48 (t of t, 2H, J=7,7 Hz); 1.27 (t of q, 2H, J=7,7 Hz); 0.81 (t, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[C:6]([C:13]([NH2:15])=[O:14])=[CH:5]2.[H-].[Na+].CN(C)C=O.[C:23](OCC)(=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[N:12]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:15][C:13](=[O:14])[C:6]1=[CH:5]2
Reactant: NC(=O)c1cc2cc(Cl)ccc2nc1N
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2nc3ccc(Cl)cc3cc2c(=O)[nH]1
Reaction time: 0.25 h

Procedure:
A mixture of 6-chloro-2-aminoquinoline-3-carboxamide (2.2 g., 0.01 mole), sodium hydride (0.52 g., 0.012 mole as 56% dispersion in oil) and N,N-dimethylformamide (20 ml.) is added to a solution of diethyl oxalate (5 ml.) and N,N-dimethylformamide (5 ml.). The reaction mixture is stirred for 15 minutes, a second portion of sodium hydride (0.52 g., 0.012 mole) added and stirring continued for an additional 15 minutes. Acetic acid (25.0 ml.) is cautiously added to the mixture followed by water (50 ml.). The tan precipitate is removed by filtration and dried (2.0 g. of crude ester). It is purified by chromatography on silica gel using chloroform: 2B ethanol (99:1) as eluant. The product, recovered by concentration of the eluate, is recrystallized from acetic acid. Yield = 1.3 g. (37.3%). M.P. 260.5° C. (dec.). Mass spectra gave m/e = 303.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([N+:12]([O-])=O)=[C:10]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:9]=[C:8]([CH3:21])[N:7]=1.[H][H]>O1CCOCC1.CO.[Ni]>[NH2:12][C:11]1[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:7][C:8]([CH3:21])=[CH:9][C:10]=1[O:15][CH2:16][C:17]([F:18])([F:19])[F:20]
Reactant: [H][H]
Reactant: COCCOc1nc(C)cc(OCC(F)(F)F)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CO
Product: COCCOc1nc(C)cc(OCC(F)(F)F)c1N

Procedure:
2-[(2-Methoxyethyl)oxy]-6-methyl-3-nitro-4-[(2,2,2-trifluoroethyl)oxy]pyridine (1.65 g, 5.32 mmol) was dissolved in a mixed solvent of dioxane (30 mL)-methanol (30 mL). Raney nickel (ethanol suspension, 3 mL) was added to the solution. In a hydrogen atmosphere, the mixture was stirred at room temperature for 26 hours. The reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure, to thereby yield 3-amino-2-[(2-methoxyethyl)oxy]-6-methyl-4-[(2,2,2-trifluoroethyl)oxy]pyridine as a pale yellow oil (1.49 g, 99%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:7][CH:6]=1)=O>O1CCCC1>[C:10]1([C:8]2[S:7][CH:6]=[C:5]([CH2:3][OH:2])[CH:9]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1csc(-c2ccccc2)c1
Solvent: C1CCOC1
Product: OCc1csc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
Prepare a solution of 5-phenylthiophene-3-carboxylic acid methyl ester (500 mg, 2.29 mmol) in tetrahydrofuran (30 mL) and cool to 0° C. under nitrogen. Slowly add LiAl4 (1 M in tetrahydrofuran). After stirring for 1 hour at 0° C., quench the reaction with water, filter through Celite®, and rinse with ethyl acetate. Concentrate the filtrate to afford 416 mg of (5-phenylthiophene-3-yl)methanol as a white solid. 1H NMR (CDCl3) δ7.60-7.61 (m, 2H), 7.25-7.37 (m, 4H), 7.16 (s, 1H), 4.69 (d, J=2 Hz, 2H), 1.58 μm, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:21][N:19]=[C:16]3[CH:15]=[CH:14][C:13]([C:12]4[N:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=[CH:10][CH:11]=4)=[CH:18][C:17]=23)=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(Cl)cc2)cc1
Reactant: N#CCc1ccc(Cl)cc1
Product: Clc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc23)cc1

Procedure:
The title compound, light green solid (111 mg, 82%), MS (ISP) m/z=406.2 [(M+H)+], mp 222° C., was prepared in accordance with the general method of example 1 from 1-(4-chloro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate H) (100 mg, 353 μmol) and commercially available 2-(4-chloro-phenyl)-acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([C:18]([NH:20][CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.S1C=CN=C1C(O)(C#C)C.[CH3:32][C:33]1[O:37][N:36]=[C:35]([C@:38]([OH:42])([C:40]#[CH:41])[CH3:39])[CH:34]=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:41]#[C:40][C@@:38]([OH:42])([C:35]4[CH:34]=[C:33]([CH3:32])[O:37][N:36]=4)[CH3:39])[CH:15]=3)[C:10]([C:18]([NH:20][CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: CNC(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Agent: C#CC(C)(O)c1nccs1
Product: CNC(=O)c1nn(-c2ccnc(N)n2)c2cc(C#C[C@@](C)(O)c3cc(C)on3)ccc12

Procedure:
The title compound was prepared by procedure described in Example 62-c, by substituting 1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide with 1-(2-aminopyrimidin-4-yl)-6-bromo-N-methylindazole-3-carboxamide and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol in Step 3: 1H NMR (500 MHz, DMSO) delta 1.87 (3H, s), 2.42 (3H, s), 2.87 (3H, d, J=4.73 Hz), 6.42 (1H, s), 6.60 (1H, s), 7.17 (2H, br. s.), 7.32 (1H, d, J=5.36 Hz), 7.46 (1H, dd, J=8.35, 1.10 Hz), 8.27 (1H, d, J=8.20 Hz), 8.40 (1H, d, J=5.36 Hz), 8.78 (1H, d, J=4.73 Hz), 8.94 (1H, s); LC-MS: m/z=+418.05 (M+H)+.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([C:10]([C:13]2[CH:18]=[C:17](C)[C:16]([OH:20])=[C:15](C)[CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[C:6](C)[C:7]=1[OH:8].ClC1C=C(C(C2C=C(Cl)C(O)=C(Cl)C=2)(C)C)C=C(Cl)C=1O.BrC1C=C(C(C2C=C(Br)C(O)=C(Br)C=2)(C)C)C=C(Br)C=1O.OC1C=CC(C2(C3C=CC(O)=CC=3)CCCCC2)=CC=1>>[OH:8][C:7]1[CH:2]=[CH:3][C:4]([C:10]([C:13]2[CH:14]=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=2)([CH3:12])[CH3:11])=[CH:5][CH:6]=1
Reactant: Cc1cc(C(C)(C)c2cc(C)c(O)c(C)c2)cc(C)c1O
Agent: CC(C)(c1cc(Br)c(O)c(Br)c1)c1cc(Br)c(O)c(Br)c1
Agent: CC(C)(c1cc(Cl)c(O)c(Cl)c1)c1cc(Cl)c(O)c(Cl)c1
Agent: Oc1ccc(C2(c3ccc(O)cc3)CCCCC2)cc1
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
2,2-bis-(3,5-dimethyl-4-hydroxyphenyl)-propane; 2,2-bis-(3,5-dichloro-4-hydroxyphenyl)-propane; 2,2-bis-(3,5-dibromo-4-hydroxyphenyl)-propane and 1,1-bis-(4-hydroxyphenyl)-cyclohexane.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2]([O:4]C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1.C[O-].[Na+].Cl>CO>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH2:17][C:2](=[O:4])[C:1]([O:7][CH3:8])=[O:6])=[CH:12][CH:11]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethyl oxalate (18.80 g, 0.159 mol) and 4'-fluoroacetophenone (20.0 g, 0.145 mol) were charged to a 1000 mL round-bottom flask and diluted with methanol (400 mL). The reaction flask was placed in a sonication bath (Bransonic 1200), and sodium methoxide (25% in methanol, 70 mL) was added over 25 minutes. The reaction was sonicated at 45° C. for 16 hours. The reaction became an insoluble mass during this time. The solid was mechanically broken up, then poured into a hydrochloric acid solution (1N, 500 mL). A magnetic stirrer was added, and the white suspension was stirred vigorously at room temperature for 60 minutes. The suspension was cooled to 0° C. and held for 30 minutes. The solid was filtered, and the filter cake was then washed with cold water (100 mL). Upon drying, methyl 4-[4-fluorophenyl]-2,4-diketobutanoate was obtained (22.91 g, 70.6%) as the enol: 1H NMR (CDCl3 /300 MHz) 8.03 (ddd, J=8.86 Hz, J=8.66 Hz, J=5.03 Hz, 2H), 7.19 (dd, J=8.86 Hz, J=8.66 Hz, 2H), 7.04 (s, 1H), 3.95(s, 3H). 19F NMR (CDCl3 /282.2 MHz) -103.9(m).
Reaction SMILES: F[C:2]([F:7])(F)[C:3](O)=O.[F:8][C:9]1[C:14]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(OCCF)(=O)=O>C(#N)C>[F:8][C:9]1[C:14]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:3][CH2:2][F:7])[CH2:17][CH2:16]2)=[N:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1nccnc1C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: FCCN1CCC(c2nccnc2F)CC1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
In a glass microwave vial containing 2-fluoro-3-(piperidin-4-yl)pyrazine 2,2,2-trifluoroacetate (0.2 g, 0.68 mmol), cesium carbonate (0.12 mL, 1.5 mmol) was added 2-fluoroethyl tosylate (0.22 mL, 1.0 mmol) and Acetonitrile (2.5 mL). The reaction mixture was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N C) at 120° C. for 10 min (300 watts, Powermax feature on), then at the same temperature for another 10 min. LCMS showed desired product formation 104960-15-1.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]([CH3:70])[C:44]([CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH2:65])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:55][CH:54]=1)=[O:45]>CN(C=O)C>[CH3:70][N:43]([CH3:42])[C:44]([CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH:65][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:57][CH:58]=1)=[O:45]
Reactant: CN(C)C(=O)COC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)COC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid dimethylcarbamoylmethyl ester (49 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (51 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H31N5O5, 494.23. found 494.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][S:23][C:21]1[O:22][C:18]([C:15]2[CH:16]=[CH:17][C:12]3[O:11][CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:13]=3[CH:14]=2)=[N:19][N:20]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Product: COc1ccc(-c2coc3ccc(-c4nnc(SCc5cccc(Cl)c5)o4)cc23)cc1
Yield: 88 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-chlorobenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 88%) was obtained as colorless crystals.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1C(P(C)C)P(C)C.[CH3:20][C:21]([CH3:24])([O-])C.[Na+].N#N.F[C:29]1[CH:30]=[C:31](CNC(=O)C)[C:32]([NH:45][C@H:46]([C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=2)C)=[N:33][C:34]=1[NH:35][C:36]1[CH:40]=[C:39](OC(C)C)[NH:38][N:37]=1.C1(C2NN=C(N)C=2)CC1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:24]1([C:39]2[NH:38][N:37]=[C:36]([NH:35][C:34]3[CH:29]=[CH:30][CH:31]=[C:32]([NH:45][CH2:46][C:48]4[CH:49]=[CH:50][C:51]([F:54])=[CH:52][CH:53]=4)[N:33]=3)[CH:40]=2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)NCc1cc(F)c(Nc2cc(OC(C)C)[nH]n2)nc1N[C@@H](C)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CP(C)C(c1ccccc1-c1ccccc1)P(C)C
Solvent: Cc1ccccc1
Product: Fc1ccc(CNc2cccc(Nc3cc(C4CC4)[nH]n3)n2)cc1
Temperature: 110 °C
Yield: 2 %

Procedure:
To a flask was added Pd(OAc)2 (22.4 mg, 0.1 mmol), (biphenyl-2-ylmethylene)bis(dimethylphosphine) (60 mg, 0.2 mmol) and sodium tert-butoxide (240 mg, 2.5 mmol). The flask was sealed and refilled with N2. To the mixture was added a solution of 6-bromo-N-(4-fluorobenzyl)pyridin-2-amine (Method 19; 281 mg, 1.0 mmol) and 5-cyclopropyl-1H-pyrazol-3-amine (123 mg, 1.0 mmol) in toluene (5 ml). The reaction mixture was heated at 110° C. overnight. The solvent was removed and EtOAc was added and the mixture was washed with brine and was concentrated. Semi-prep HPLC (Gilson) purification gave the title compound (6.4 mg, 2%). 1H NMR (CDCl3) δ 0.65 (m, 2H), 0.95 (m, 2H), 1.80 (m, 1H), 4.43 (m, 2H), 4.91 (br s, 1H), 5.60 (br s, 1H), 5.80 (m, 1H), 6.18 (m, 1H), 6.73 (m, 1H), 7.00 (m, 2H), 7.25 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[CH3:21][C:22]1[C:27]([CH:28]=O)=[CH:26][N:25]=[C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)[N:23]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:28]([C:27]3[C:22]([CH3:21])=[N:23][C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[N:25][CH:26]=3)=[N:9][C:4]=2[C:3]=1[CH3:10]
Reactant: Cc1c(F)ccc(N)c1N
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Agent: Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1-c1nc2c(C)c(F)ccc2[nH]1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a 2 L Erlenmeyer flask were added 4-fluoro-3-methyl-benzene-1,2-diamine.HCl (46.32 g, 262.3 mmol), Na2S2O5 (64.82 g, 341.0 mmol), and 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde (72.5 g, 262.3 mmol) in DMF (725 mL). To the resultant mixture was then added triethylamine (36.6 mL, 262.3 mmol), and the reaction was warmed on a hot plate with stirring to 90° C. and held at this temperature for 2 hours. The resultant mixture was then concentrated to near dryness and partitioned between dichloromethane (1 L) and 1 N NaOH (1 L). After separation of the layers, the aqueous layer was extracted a second time with dichloromethane (1 L). The combined organic layers were then washed with saturated aqueous NaHCO3 (1.6 L). The organics were then extracted with a 1 M mono/dibasic phosphate buffer (pH 5.62, 1.23 L). The aqueous layer was then basified with 50% NaOH (80 mL) to pH 10.8. The resultant heterogeneous layer was then extracted with dichloromethane (1.5 L and 500 mL), and the combined organics were concentrated to yield the title compound.