Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:26])[C@@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[C:11]([OH:13])=[O:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[NH:14][C@H:10]1[C:11](=[O:13])[O:12][C@H:9]1[CH3:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCOC(=O)N[C@H]1C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
In a four-necked round bottom flask, Et3N (1.5 mL, 10.9 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-{[(octyloxy)carbonyl]amino}butanoic acid (1 g, 3.63 mmol) in dry CH2Cl2 (40 mL) under argon. After cooling at 0° C., HBTU (2.07 g, 5.45 mmol) was added and the mixture stirred 3 h at 0° C., then 3.5 h at rt. The obtained solid was filtered-off and the solvent removed under vacuum. The crude was purified by typical silica gel column chromatography, eluting with Cy/AcOEt (from 95:5 to 60:40). The resulting white solid (ca. 0.19 g) was further triturated with cyclohexane, to afford a pure compound (0.165 g, 18%) as white solid. MS (ESI) m/z: 256.31 [M−H]−. FTIR (cm−1): 3326, 2958, 2924, 2856, 1857, 1692, 1547, 1333, 1270, 1087, 1025, 845. 1H NMR (CDCl3): δ 0.87-0.90 (t, 3H); 1.28-1.36 (m, 10H); 1.47 (t, 3H); 1.59-1.66 (m, 2H); 4.06-4.15 (m, 2H); 4.84-4.91 (m, 1H); 5.38-5.48 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[Cl:26])=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[CH2:19]([O:18][C:16]([NH:15][C@@H:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[C:6]([Cl:26])[CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc2c(cc1Cl)[C@@H](NC(=O)OCc1ccccc1)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(N[C@H]1CCSc2cc(C(=O)O)c(Cl)cc21)OCc1ccccc1
Yield: 98 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 6 using (S)-4-(benzyloxycarbonylamino)-6-chlorothiochromane-7-carboxylic acid methyl ester (450 mg) and potassium carbonate (317 mg), the objective (S)-4-(benzyloxycarbonylamino)-6-chlorothiochromane-7-carboxylic acid (425 mg) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[S:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[S:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:14]([C:17]([NH2:18])=[O:32])=[N:15][CH:16]=1
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 3-methylisothiazol-5-amine hydrochloride (50 mg, 0.332 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 5 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carbonitrile (80 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carbonitrile (80 mg, 0.219 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (44 mg). MS 384.2 (M+H); UV 209.0, 270.7, 321.3 nm; t 0.362 min.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)([OH:17])[CH:10]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH3:11])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:32]I>CN(C)C=O>[F:27][C:24]([F:25])([F:26])[C:21]1[CH:22]=[CH:23][C:18]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=2)([O:17][CH3:32])[CH:10]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH3:11])=[CH:19][CH:20]=1
Reactant: CI
Reactant: CC(n1cncn1)C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C(C)n1cncn1
Reaction time: 2 h

Procedure:
1,1-Bis-(4-trifluoromethylphenyl)-2-(1,2,4-1H-triazolyl)propan-1-ol (0.5 g) was added portionwise over a period of 15 minutes to a suspension of sodium hydride (58 mg, freed from dispersion in oil by washing with hexane) in dry dimethylformamide (50 cm3) under a nitrogen atmosphere. The mixture was stirred for 2 hours then methyliodide (0.17 g) in dimethylformamide (2 cm3) was added dropwise. After stirring for 3 hours the mixture was partitioned between water and chloroform. The chloroform layer was separated, washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent to yield 1,1-bis(4-trifluoromethylphenyl)-1-methoxy-2-(1,2,4-1H-triazolyl)propane as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:11]([CH:12]=[C:25]2[NH:19][C:20](=[O:21])[NH:22][C:23]2=[O:24])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1OCc1ccccc1

Procedure:
This compound is prepared from 3-benzyloxy-4-methoxybenzaldehyde (Aldrich) and hydantoin by the procedure described in Example 3; mp 242°-244° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C@@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]([N:11]([CH3:13])[CH3:12])=O.C(OCC)(=O)C.[OH-].[Na+]>CCOCC.O1CCCC1>[CH2:14]([C@H:8]([NH2:7])[CH2:9][N:11]([CH3:13])[CH3:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(C)C[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.8 %

Procedure:
Lithium aluminum hydride (759 mg) was suspended in anhydrous ether (20 ml) with ice cooling in the nitrogen gas atmosphere and then a solution of (2S)-2-amino-N1,N1-dimethyl-3-phenylpropionamide (1.92 g) in anhydrous tetrahydrofuran (10 ml) was dropwise added to the resulting suspension. This mixture was stirred at room temperature for 1.5 hour. Ethyl acetate was gradually and dropwise added to the reaction liquid till the latter did not undergo foaming any more, with ice cooling. Then a 2N aqueous sodium hydroxide solution was added to the reaction liquid and the resulting mixture was extracted with chloroform. The organic phase thus obtained was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting oily product was purified through the silica gel column chromatography to give the title compound (Reference Compound 1-1, 1.35 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([OH:23])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([N:26]2[CH2:31][CH2:30][S:29][CH2:28][CH2:27]2)=[O:23])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CSCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)O)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)N2CCSCC2)=C(C)C1=O
Yield: 34.3 %

Procedure:
3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (25 mg, 0.070 mmol) obtained in Example 69 and thiomorpholine (0.011 ml, 0.11 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (10 mg, 0.024 mmol, yield 34%).
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:31]=[CH:30][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:27])[C:23]([O:25]C)=[O:24])=[CH:17][C:16]=2[O:28][CH3:29])=[C:8]([CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:7]=1[OH:38])(=[O:5])[CH3:4].Cl>CO>[C:3]([C:6]1[CH:31]=[CH:30][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:27])[C:23]([OH:25])=[O:24])=[CH:17][C:16]=2[O:28][CH3:29])=[C:8]([CH2:32][CH2:33][C:34]([F:36])([F:35])[F:37])[C:7]=1[OH:38])(=[O:5])[CH3:4]
Reactant: COC(=O)C(=O)Nc1ccc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(NC(=O)C(=O)O)ccc1OCCCOc1ccc(C(C)=O)c(O)c1CCC(F)(F)F

Procedure:
18 ml of N sodium hydroxide solution are added to a solution of 7.95 g of methyl N-{{4-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-3-methoxy-phenyl}}-oxamate in 100 ml of methanol and the mixture is refluxed for 1 hour. The hot solution is then poured into 200 ml of 0.1N hydrochloric acid. The product which has precipitated out is filtered off, washed with water and dired over phosphorus pentoxide in a drying cabinet. The N-{{4-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-3-methoxy-phenyl}}-oxamic acid thus obtained is dissolved hot again in 100 ml of methanol, and one equivalent of triethanolamine in 10 ml of methanol is added. After addition of 400 ml of ether, crystallisation starts. The triethanolammonium salt of N-{{4-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-3-methoxy-phenyl}}-oxamic acid is thus obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[C:4]([CH3:14])[CH:3]=1.B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[CH3:27])(O)O>>[CH3:27][C:19]1[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[CH:25]=[CH:26][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(C(=O)O)ccc1B(O)O
Reactant: Cc1nnc(-c2ccc(Br)cc2C)o1
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3C)cc2C)o1

Procedure:
The title compound was prepared from 2-(4-bromo-2-methylphenyl)-5-methyl-1,3,4-oxadiazole (D35) and 4-borono-3-methylbenzoic acid (D33) using a similar procedure to Description 11 as a white solid (24%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:11][CH2:12][C:13]([OH:15])=O)[NH:3]1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:32](=[CH:33][CH:34]=1)[CH2:31][C:21]1([C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]1=[O:30])[CH2:20]2>>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:11][CH2:12][C:13]([NH:16][C:17]2[CH:18]=[C:19]3[C:32](=[CH:33][CH:34]=2)[CH2:31][C:21]2([C:29]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:23][C:22]2=[O:30])[CH2:20]3)=[O:15])[NH:3]1
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)CNc1cccc2c1CC(=O)N2
Product: O=C(CNc1cccc2c1CC(=O)N2)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
Essentially following the procedures described for Example 1, but using N-(2-oxo-2,3-dihydro-1H-indol-4-yl)glycine (described in Intermediate 8) in place of 3-phenylpropionic acid and (−)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (described in Intermediate 4) in place of (+)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, the title compound was obtained. MS: m/z=440 (M+1). HRMS: m/z=440.1750; calculated m/z=440.1717 for C25H22N5O3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C@H:11]1[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]1)[N:17]=[C:18]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccc(S(C)(=O)=O)cc2)cc1OC
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(S(C)(=O)=O)cc1

Procedure:
8.0 g of (−)-cis-N-[2-(3,4-dimethoxyphenyl)cyclohexyl]-4-methanesulfonylbenzamide are suspended in 150 ml of toluene, treated with 4 ml of phosphorus oxychloride and heated under reflux for 5.5 h. The reaction solution is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is extracted with satd sodium hydrogencarbonate solution and water. After chromatography on silica gel using petroleum etherlethyl acetate/triethylamine in the ratio 6/3/1, the title compound is obtained.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:2][CH3:3].[CH3:20]I>>[CH3:20][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:17][CH2:18][CH3:19])=[O:16]
Reactant: CI
Reactant: CCCN(CCC)C(=O)c1ccccc1[Si](C)(C)C
Product: CCCN(CCC)C(=O)c1c(C)cccc1[Si](C)(C)C

Procedure:
The compound of Example 13 was reacted with MeI using General Method A to prepare the title compound.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:9]1([O:15][C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:16]1([O:15][C:9]2[CH:14]=[CH:13][C:12]([C:2]3[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:11][CH:10]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(OC2CCCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(OC2CCCCC2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
n-Butyllithium (1.6 M in hexane) (136 mL) was dropwised to a mixture of 1-bromo-4-(cyclohexyloxy)benzene (46.3 g) and THF (dry) (500 mL) at −78° C. and the mixture was stirred at the same temperature under nitrogen for 40 min. Triisopropyl borate (51.2 g) was dropwised to the mixture at −78° C. for 15 min and the mixture was stirred at the same temperature for 5 min. Then the mixture was warmed up to room temperature and stirred for additional 30 min. The mixture was poured into 1N NaOH aq. (250 mL) and water (750 mL) and the mixture was further stirred for 30 min. The organic layer was separated and the aqueous phase was washed with Et2O (300 mL×2) and acidified by 6N HCl aq. The mixture was extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-(cyclohexyloxy)phenylboronic acid (29.5 g) as a white powder. Tetrakis(triphenylphosphine)palladium(0) (0.656 g) was added to a suspension of 3-bromopyridin-2-amine (9.83 g), 4-(cyclohexyloxy)phenylboronic acid (15.0 g) and sodium carbonate (12.0 g) in DME (325 ml) and water (65.0 mL) and the mixture was stirred at 100° C. under nitrogen for 3 hr and at 90° C. for 12 hr. Volatiles were removed in vacuo with silica-gel. The silica-supported mixture was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (14.1 g) as a white powder.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:25][C@@H:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)[N:19]=[N:20][C:21]=3[C:22]([NH2:24])=[O:23])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:31](O)(=[O:35])[C:32]#[C:33][CH3:34].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[C:31]([N:28]1[CH2:29][CH2:30][C@@H:26]([NH:25][C:18]2[N:19]=[N:20][C:21]([C:22]([NH2:24])=[O:23])=[C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])=[CH:10][CH:11]=3)[N:17]=2)[CH2:27]1)(=[O:35])[C:32]#[C:33][CH3:34]
Reactant: NC(=O)c1nnc(N[C@@H]2CCNC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CC#CC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC#CC(=O)N1CC[C@@H](Nc2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(pyrrolidin-3-ylamino)-1,2,4-triazine-6-carboxamide (83) (90 mg, 0.22 mmol) in NMP (4 mL) were 2-butynoic acid (55 mg, 0.66 mmol), DIEA (380 μL, 2.2 mmol) and then PyBOP (230 mg, 0.44 mmol). The mixture was stirred at RT for 30 min, quenched with TFA (0.6 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC using 0.1% formic acid in water and neat MeCN to isolate the title compound, (R)-3-(1-but-2-ynoylpyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide (505) as formic acid salt. LC-MS (ESI): m/z (M+1) 479.1. UV: λ=280 nm. Proton NMR (CD3OD): δ 7.87 (2H, m), 7.47 (2H, m), 4.56 (1H, m), 4.07 (1H, m), 3.88-3.77 (2H, m), 3.75-3.44 (9H, m), 2.37 (1H, m), 2.15 (1H, m), 2.05 (3H, s) ppm.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: COc1ccccc1Br
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3ccccc3OC)c2)cn1

Procedure:
This compound is prepared by method C using compound 12c and 2-bromoanisole
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][C:4]([N:6]([CH3:23])[C:7]1[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]([NH:13]C(=O)OC(C)(C)C)[CH:12]=1)=[O:5].Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:13][C:11]1[CH:12]=[C:7]([N:6]([CH3:23])[C:4](=[O:5])[CH2:3][N:2]([CH3:24])[CH3:1])[CH:8]=[CH:9][C:10]=1[O:21][CH3:22]
Reactant: COc1ccc(N(C)C(=O)CN(C)C)cc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)C(=O)CN(C)C)cc1N
Reaction time: 3 h
Yield: 84.1 %

Procedure:
A solution of 1,1-dimethylethyl [5-[(N,N-dimethylglycyl)(methyl)amino]-2-(methyloxy)phenyl]carbamate (2.01 g, 5.96 mmol) in 1,4-dioxane (40 ml) was treated with 4.0M HCl in dioxanes (7.45 ml, 29.8 mmol) and stirred for 3 hours. Additional 4.0M HCl in dioxanes (7.45 ml, 29.8 mmol) was added and the reaction was stirred for 16 hours. The solution was poured into ethyl acetate, diluted with water, and neutralized by careful addition of solid potassium carbonate. The aqueous layer was washed with chloroform and the organic layers were combined, dried over sodium sulfate, filtered, and taken to a residue under reduced pressure to afford N1-[3-amino-4-(methyloxy)phenyl]-N1,N2,N2-trimethylglycinamide (1.19 g, 5.01 mmol, 84% yield) as a tan oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.78 (d, J=8.2 Hz, 1 H), 6.48 (d, J=2.4 Hz, 1 H), 6.41 (d, J=8.2 Hz, 1 H), 4.91 (br. s., 2 H), 3.77 (s, 3 H), 3.05 (s, 3 H), 2.82 (s, 2 H), 2.12 (s, 6 H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14]OC(N[C@H](C(O)=O)CC3C=CC=CC=3C)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH2:14]=[C:12]1[C:13]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Cc1ccccc1C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=C1c2ccccc2-c2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of 3.2 g (8.1 mmol) of N-[(9-fluorenyl)methoxycarbonyl]-3-(2-methylphenyl)-L-alanine and 2.17 g (6.75 mmol) of 2-(lH-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 22 ml of dimethylformamide was added to the resin from paragraph viii) and subsequently 1.5 ml (13.5 mmol) of N-methylmorpholine were added. The mixture was agitated for 30 minutes and then the resin was drained and washed five times with 30 ml of dimethylformamide, twice with 30 ml of dichloromethane, twice with 30 ml of ethyl acetate and twice with 30 ml of diethyl ether. After drying there were obtained 8.95 g of 5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-N-[3,3 ,3-trifluoro-1(RS)-(dimethoxy-methyl)propyl]amino]methyl]-3,5-dimethoxyphenoxy]-N-(4-methyl-α-(RS)-phenylbenzyl)valeramide-polystyrene conjugate as a pale brown solid (0.31 mmol/g loading estimated by quantitation of dibenzofulvene at 301 nm).
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[CH2:4][CH2:5][C:6]=1[O:7][CH3:8].[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH2:24][CH3:25])=[C:19](B(O)O)[CH:20]=2)=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:24][CH3:25])=[C:17]([C:2]3[C:3](=[O:9])[CH2:4][CH2:5][C:6]=3[O:7][CH3:8])[CH:16]=2)=[CH:13][CH:12]=1
Reactant: COC1=C(Br)C(=O)CC1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1=C(OC)CCC1=O
Temperature: 90 °C
Yield: 75.5 %

Procedure:
To a stirred suspension of 2-bromo-3-methoxycyclopent-2-enone (1.0 g, 5.23 mmol), 4′-chloro-4-ethylbiphen-3-ylboronic acid (2.03 g, 7.80 mmol) and potassium phosphate (2.23 g, 10.50 mmol) in anhydrous, degassed toluene (25 ml) under an atmosphere of nitrogen is added palladium(II)acetate (24 mg, 0.105 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (86 mg, 0.209 mmol). The reaction is heated at 90° C. for 4 hours and then allowed to cool to room temperature, quenched with water (40 ml) and extracted with ethyl acetate (3×30 ml). The organic extracts are combined, washed with brine (15 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 2-(4′-chloro-4-ethylbiphen-3-yl)-3-methoxycyclopent-2-enone (1.29 g, 75%).