Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:10][C:11]2[N:16]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:15]3[N:14]=[CH:13][C:12]=2[C:23]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])[CH:3]=[CH:2]1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:10][C:11]2[N:16]3[N:17]=[CH:18][C:19]([C:20]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:21])=[C:15]3[N:14]=[CH:13][C:12]=2[C:23]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])[CH:3]=[CH:2]1
Reactant: O=C(O)c1cnn2c(Nc3cccc4cc[nH]c34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc4cc[nH]c34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 26.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(7-indolylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.080 g, 0.73 mmol), the title compound (0.015 g, 27%) was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[F:15][C:16](=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:17](Cl)=[O:18].Cl>O.CC(C)=O>[F:15][C:16](=[CH:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:17]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:18]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1ccc(C=C(F)C(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(C=C(F)C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
L-phenylalanine (13.2 g, 0.080 mole) and 6N NaOH (43 ml, 0.086 mole) were dissolced in a solvent prepared by mixing water (77 ml) with acetone (240 ml). To the mixture, while cooling to less than 10° C. the acetone solution of α-fluoro-4-methyl cinnamic acid chloride prepared as above and 2N NaOH (38 ml, 0.076 mole) were alternately added over 20 minutes. Next, the mixture was stirred at normal temperature for 30 minutes, and the reaction solution was made acidic by the addition of 2N HCl. Then, water (200 ml) was gradually added thereto. The thus precipitated crystals were recovered by filtration and dried to give crude crystals (16.7 g). The crude crystals were recrystallized from a mixture of methanol and water to obtain N-(α-fluoro-4-methylcinnamoyl)-L-phenylalanine (yield 15.5 g) in the form of white needle-like crystals having a melting point of 163° to 163.5° C.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4](C)([CH3:6])[CH3:5])[NH2:2].C(=O)(O[C:12]([CH3:15])([CH3:14])[CH3:13])N.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:25]=CC(N)=C[CH:20]=1>O1CCCC1>[C:1](=[O:8])([O:3][C:4]1[CH:6]=[CH:20][C:19]([C:18]([F:17])([F:26])[F:27])=[CH:25][C:5]=1[C:12]([CH3:15])([CH3:14])[CH3:13])[NH2:2]
Reactant: CC(C)(C)OC(N)=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(F)(F)F)ccc1OC(N)=O

Procedure:
First, di-tert-butyl dicarbamate (30 mL) was added to a tetrahydrofuran (50 mL) solution of 4-trifluoromethylaniline (10 mL). The reaction mixture was then refluxed for 10 hours. The solvent was distilled off under reduced pressure. Water was added to the residue to solidify the resulting product. The product was then washed with hexane. The title compound (18.7 g) was obtained as colorless crystals.
Reaction SMILES: [CH:1]1([C:8]2([C:13]3[CH:18]=[C:17]([O:19]C)[CH:16]=[C:15]([O:21]C)[CH:14]=3)[S:12][CH2:11][CH2:10][S:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(O)C=C(O)C=2)SCCS1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:8]2([C:13]3[CH:14]=[C:15]([OH:21])[CH:16]=[C:17]([OH:19])[CH:18]=3)[S:9][CH2:10][CH2:11][S:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1cc(OC)cc(C2(C3CCCCCC3)SCCS2)c1
Agent: CCCCC1(c2cc(O)cc(O)c2)SCCS1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Oc1cc(O)cc(C2(C3CCCCCC3)SCCS2)c1

Procedure:
Compound 19 was prepared from Compound 12 using the same procedure as described above for Compound 16. Yield 0.582 g (41.5%) as a waxy solid. Rf=0.28 (hexane:ethyl acetate 8:2); 1H NMR δ 6.85 (d, J=2.4 Hz, 2H), 6.22 (t, J=2.25 Hz, 1H), 5.16 (br s, 2H), 3.31–3.07 (m, 4H), 2.35–2.28 (m, 1H), 1.97–1.29 (m, 12H); 13C NMR δ 156.07, 149.33, 107.65, 101.25, 50.92, 39.00, 32.55, 27.70, 27.43; MS: (ESI, Pos.) m/z 333 ([M+23]+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:3]1=[O:21].O=[C:23]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24]([OH:26])=[O:25].C([BH3-])#N.[Na+]>>[C:18]([CH:9]([N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:2]([NH:1][CH:23]([C:24]([OH:26])=[O:25])[CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:3]1=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([OH:20])=[O:19]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: N[C@H]1CCCCN(C(Cc2ccc(O)cc2)C(=O)O)C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1)N[C@H]1CCCCN(C(Cc2ccc(O)cc2)C(=O)O)C1=O

Procedure:
Methyl 3-(p-phydroxyphenyl)-2-oxopropionate and α-t-Boc-L-lysine are condensed in the presence of sodium cyanoborohydride as described in Example 19. Subsequent ring closure, saponification of methyl ester, and removal of the t-butoxycarbonyl group with formic acid gives 3-(S)-amino-1-[1-carboxy-2-(4-hydroxyphenyl)ethyl]perhydroazepin-2-one. The caprolactam and 2-oxo-4-phenylbutyric acid are condensed in the presence of sodium cyanoborohydride to yield 1-[1-carboxy-2-(4-hydroxyphenyl)ethyl]-3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one.
Reaction SMILES: O[C@@H:2]([CH3:19])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:11]([O:10][C:8](=[O:9])[NH:7][C@H:3]1[C:4](=[O:6])[O:5][C@H:2]1[CH3:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](O)[C@@H](NC(=O)OCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 57.1 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2R,3S)-3-hydroxy-2-(phenethyloxycarbonylamino)-butanoic acid (0.35 g, 1.30 mmol) in dry CH2Cl2 (35 mL), Et3N (0.54 mL, 3.90 mmol) and subsequently TBTU (0.50 g, 1.56 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy/AcOEt (from 100:0 to 0:100) to afford the title compound (0.185 g, 57%) as white solid. MS (ESI) m/z: 250 [M−H]+; (ESI) m/z: 249 [M−H]−. 1H NMR (DMSO-d6): δ 1.33 (d, J=6.3 Hz, 3H), 2.89 (t, J=6.8 Hz, 2H), 4.15-4.29 (m, 2H), 4.84 (dq, J=6.3 Hz, 1H), 5.40 (dd, J=6.1, 9.4 Hz, 1H), 7.19-7.36 (m, 5H), 8.23 (d, J=9.4 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[S:12])=[CH:9][CH:8]=1.N1C=CC=CC=1>CC(C)=O>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:13][C:1](=[O:3])[CH3:2])=[S:12])=[CH:9][CH:8]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(N)=S)cc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: COc1ccc(C(=S)NC(C)=O)cc1
Yield: 72.2 %

Procedure:
A solution of acetyl chloride (4.69 g, 59.8 mmol) in acetone (20 mL) was added dropwise to a solution of 4-methoxythiobenzamide (5.00 g, 29.9 mmol) and pyridine (4.76 g, 60.1 mmol) in acetone (30 mL). The reaction mixture was heated to reflux for 30 min then poured onto ice water. The resulting precipitate was isolated via filtration and dried under vacuum overnight to provide a light yellow/orange solid (4.52 g, 72%). 1H NMR (400 MHz, CDCl3) δ 2.56 (s, 3H), 3.87 (s, 3H), 6.89 (dd, J=6.9, 2.0 Hz, 2H), 7.77 (dd, J=6.9, 2.0 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:35]1[C:31](=[O:41])[C:32]3[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:34]1=[O:36])=[C:12]2[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Cn1c(CCl)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 86.3 %

Procedure:
A solution of 6-(benzyloxy)-3-(chloromethyl)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone (1.31 g, 3 mmol) and potassium phthalimide (0.83 g, 4.5 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-{[6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindole-1,3(2H)-dione (1.42 g, 86.6%) as an amorphous solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([O:19]CC)=O)[N:8]=2)=[N:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1>C1COCC1>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[OH:19])[N:8]=2)=[N:2]1
Reactant: CCOC(=O)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Temperature: -40 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
To a stirred solution of ethyl 4-(1H-pyrazol-3-ylamino)quinazoline-2-carboxylate (595 mg, 2.1 mmol) in THF (15 mL) at −40° C., was added dropwise a 2 M solution of 4-fluorophenylmagnesium bromide in THF (4.2 mL, 8.4 mmol). The mixture was stirred at −40° C. for 2 h and then stored at −30° C. for 18 h. The reaction was quenched by adding 0.5 N HCl at 0° C. and the mixture was extracted with EtOAc (2×20 mL). The solid precipitate from the combined organic layers was removed by filtration and the resulting filtrate was washed with brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with 0-5% MeOH/DCM to afford (4-(1H-pyrazol-3-ylamino)quinazolin-2-yl)bis(4-fluorophenyl)methanol as a solid (75 mg, 8%). 1H NMR (300 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.66 (s, 1H), 8.67 (d, J=8.1, 1H), 7.81-7.87 (m, 2H), 7.60-7.62 (m, 2H), 7.42-7.47 (m, 4H), 7.07-7.13 (m, 4H), 6.66 (s, 1H), 6.26 (s, 1H); LC-MS (ESI) m/z 430 (M+H)+.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:5].[N:22]#[C:23][NH2:24]>C(O)C>[ClH:13].[CH3:2][CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:23]([NH2:24])=[NH:22])[CH:16]=1)[C:4]([O:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:5]
Reactant: CC(Cc1cccc(N)c1)C(=O)Oc1ccc(Cl)cc1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Product: CC(Cc1cccc(NC(=N)N)c1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In 200 ml of ethanol were dissolved 23.0 g of the p-chlorophenyl α-methyl-β-(m-aminophenyl)-propionate hydrochloride thus obtained and 4.2 g of cyanamide, and the resulting solution was subjected to reaction at 70° C. for 5 hours. After the reaction, the solvent was removed by distillation under reduced pressure, to obtain p-chlorophenyl α-methyl-β-(m-guanidinophenyl)-propionate hydrochloride in the form of an oily matter. This compound was dissolved in 50 ml of ethanol, and then added to saturated aqueous NaHCO3 solution, upon which colorless crystals precipitated. The crystals were collected by filtration and washed with water and acetone, to obtain p-chlorophenyl α-methyl-β-(m-guanidinophenyl)-propionate carbonate. Yield: 19.4 g (70%); melting point: 87°-90° C.; IR (cm-1); 3500-2500, 1748, 1660, 1490; MS: M+ =m/e 331 (M.W. - H2CO3).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[C:14]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:12]=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:29]([O:36][C:37](ON1C(=O)CCC1=O)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC#N>[CH2:29]([O:36][C:37]([NH:1][CH:2]([CH2:8][C:9]1[C:14]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:12]=[C:11]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(N)Cc1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CC#N
Product: CCOC(=O)C(Cc1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
To a solution of 1K (1.14 g, 2.96 mmol) in CH3CN (15 mL) was added N-(benzyloxy carbonyloxy)succinimide (819 mg, 3.25 mmol). The reaction was stirred at RT for 16 h. After this time, no starting material was detected by LC-MS. The reaction was concentrated under reduced pressure. The resulting residue was purified by silica gel (110 g) column chromatography eluting with a gradient of EtOAc (0-50%) in hexane to give the title compound as an white foam (1.50 g, 97%). LC/MS (method A): retention time=3.63 min, (M+H)+=526.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:23]S(C2C=CC(C)=CC=2)(=O)=O)=[N:7][N:8]2[C:13]=1[C:12]([CH3:14])=[N:11][N:10]=[C:9]2[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([N:36]1[C:40]([CH2:41]O)=[N:39][CH:38]=[N:37]1)[CH3:35].[H-].[Na+].O>CN(C=O)C>[C:1]([C:5]1[C:6]([O:23][CH2:41][C:40]2[N:36]([CH2:34][CH3:35])[N:37]=[CH:38][N:39]=2)=[N:7][N:8]2[C:13]=1[C:12]([CH3:14])=[N:11][N:10]=[C:9]2[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4cc(F)ccc4F)nnc(C)c3c2C(C)(C)C)cc1
Reactant: CCn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncnc1COc1nn2c(-c3cc(F)ccc3F)nnc(C)c2c1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-tert-butyl-7-(2,5-difluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (0.3 g, 0.636 mmol) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (97.3 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (30 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (150 ml) was added then the solution was extracted with diethyl ether (4×50 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-tert-Butyl-7-(2,5-difluorophenyl)-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-4-methylpyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether/isohexane (10 mg, mp=109° C.). 1H NMR (360 MHz, CDCl3) δ 1.40 (3H, t, J=7.3 Hz), 1.55 (9H, s), 3.08 (3H, s), 4.14 (2H, q, J=7.3 Hz), 5.48 (2H, s), 7.18-7.41 (3H, m), 7.88 (1H, s); MS (ES+) m/e 428 [MH]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][CH:14]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:15]([NH:17][CH2:18][C:19]#[N:20])=[O:16])[C:9](F)(F)F)=[CH:4][CH:3]=1.C[N:26]([CH:28]=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[C:19]([CH2:18][NH:17][C:15](=[O:16])[C@@H:14]([O:13][C@@H:8]([C:9]1[CH:6]=[CH:7][C:2]([C:28]#[N:26])=[CH:3][CH:4]=1)[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])#[N:20]
Reactant: CC(C)CC(OC(c1ccc(Br)cc1)C(F)(F)F)C(=O)NCC#N
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(C#N)cc1)C(=O)NCC#N
Temperature: 80 °C

Procedure:
To a solution of 2-[1-(4-bromophenyl)-2,2,2-trifluoroethoxy]-N-(cyanomethyl)-4-methylpentanamide from example 69 step 5 (2.03 mmol, 1.0 g) in DMF (2.5 mL), was added zinc cyanide (1.22 mmol, 144 mg) followed by palladium tetrakistriphenylphosphine (0.08 mmol, 92 mg). The mixture was degassed three times via the freeze-thaw method. The mixture was heated at 80° C. overnight. The next day, more zinc cyanide (0.61 mmol, 72 mg) and tetrakistriphenylphosphine (0.04 mmol, 46 mg) were added The mixture was heated at 80° C. overnight. The mixture was cooled to r.t. and diluted with AcOEt (20 mL). The phases were separated and the organic extract was washed with ammonium chloride, brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification: 50:50 (AcOEt:Hex.) gave the title amide.
Reaction SMILES: [CH3:1][S-:2].[Na+].[C:4]([O:8][C:9](=[O:22])[N:10]([C:12]1[CH:17]=[C:16](Cl)[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])[CH3:11])([CH3:7])([CH3:6])[CH3:5].CN(C=O)C>O1CCCC1>[C:4]([O:8][C:9](=[O:22])[N:10]([C:12]1[CH:17]=[C:16]([S:2][CH3:1])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a suspension of sodium thiomethoxide (1.47 g) in anhydrous tetrahydrofuran (50 ml) was added dropwise a solution of N-(2-nitro-5-chlorophenyl)-N-methylcarbamic acid t-butyl ester (6.0 g) in anhydrous tetrahydrofuran (120 ml) while cooling at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. At the end of this time anhydrous DMF (30 ml) was added and the resulting mixture stirred at room temperature for 1 hour. DMF (20 ml) was added and then sodium thiomethoxide (0.73 g) and further DMF (50 ml) were added. The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to afford the desired compound (6.15 g).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1(=[O:15])[NH:13][C:12](=[O:14])[CH:11]=[CH:10]1>O.CO>[O:15]=[C:9]1[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:7][CH:10]1[CH2:11][C:12]([NH2:13])=[O:14]
Reactant: Nc1ccccc1N
Reactant: O=C1C=CC(=O)N1
Solvent: O
Solvent: CO
Product: NC(=O)CC1Nc2ccccc2NC1=O
Temperature: 95 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2-phenylenediamine (21.5 g, 0.2 mol) in water (450 mL) was added dropwise a solution of maleimide, (20.0 g, 0.2 mol) in methanol (180 mL) over 60 min. The mixture was then stirred at 95° C. for 2 hours followed at rt overnight. The precipitate was collected via filtration and was washed with small amount of water for a few times to yield the title compound as a pale gray solid (pure product): 1H NMR (DMSO-d6) δ=10.2 (bs, 1H), 7.37 (bs, 1H) 6.88 (bs, 1H), 6.74–6.68 (m, 3H), 6.31–6.57 (m, 1H), 5.78 (bs, 1H), 4.08–4.04 (m, 1H), 2.63 (dd, 1H, J=3.6, 15.5 Hz), 2.32 (dd, 1H, J=3.3, 15.5 Hz); HPLC (CH3CN—H2O-0.1% TFA): Rf=9.49 min.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:17]=2)[C:12](O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:25][C:26]1[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][N:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:32][C:29]1[N:30]=[CH:31][C:26]([NH:25][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:17]=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:10]=2)=[N:27][CH:28]=1
Reactant: Cc1cnc(N)cn1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OC2CCOCC2)c1
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: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(OC3CCOCC3)c2)cn1
Yield: 42.7 %

Procedure:
3-[(Phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid (3.14 g, 9.5 mmol), 2-amino-5 methylpyrazine (2.08 g, 19.0 mmol) and HATU (4.70 g, 12.35 mmol) were dissolved in DMF (12.5 mL) and DIPEA (3.31 mL, 19.0 mmol) added. The resultant mixture was stirred at RT for 20 hours. The mixture was quenched with water (150 mL) and extracted with ethyl acetate (2×75 mL), washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica, eluting with 0-50% ethyl acetate in isohexane, to give the desired compound as a pale yellow gum (1.70 g). m/z 420 (M+H)+
Reaction SMILES: [F:1][C:2](I)([F:7])[C:3]([F:6])([F:5])[F:4].[C:9]([C@@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20]2[C:25](I)=[C:24]([CH2:27][CH3:28])[N:23]=[CH:22][N:21]=2)[CH2:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([C@@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:20]2[C:25]([C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4])=[C:24]([CH2:27][CH3:28])[N:23]=[CH:22][N:21]=2)[CH2:17][CH2:18]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1I
Reactant: FC(F)(F)C(F)(F)I
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1C(F)(F)C(F)(F)F

Procedure:
Prepared as in Example 43 from pentafluoroethyl iodide and 4-(cis-4-tert-butylcyclohexylamino)-6-ethyl-5-iodopyrimidine (Example 1), colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C:25](=[O:28])[CH:26]=[CH2:27])=[CH:10][N:9]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)C>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C:25]([CH2:26][CH2:27][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[CH:10][N:9]=1
Reactant: C1COCCN1
Reactant: C=CC(=O)c1cnc(N2CCC[C@H]2CO)nc1NCc1ccc(OC)c(Cl)c1
Solvent: CCO
Product: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C(=O)CCN2CCOCC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(acryloyl)pyrimidine (72 mg) in ethanol (2 ml) is added morpholine (78 μl) at room temperature, and the mixture is stirred at room temperature for 40 minutes. The reaction mixture is concentrated under reduced pressure, and the residue is poured into water, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-morpholinoethyl)carbonyl]-pyrimidine (91 mg).