Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH2:39][CH3:40])=[C:35](/[F:38])\[CH:36]=O)[C:20]=1[O:41][CH2:42][CH3:43]>>[Cl:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:32])[CH3:33])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH2:39][CH3:40])=[C:35](/[F:38])\[CH:36]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:20]=1[O:41][CH2:42][CH3:43]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: CCOc1c(/C(CC)=C(/F)C=O)cc2c(c1Cl)C(C)(C)CC=C2C(C)C
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(c(Cl)c1OCC)C(C)(C)CC=C2C(C)C

Procedure:
Following General Procedure I-1, ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (139 mg, 0.53 mmol) and (2E)-3-(4-chloro-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-2-fluoro-pent-2-enal (Compound A-156, 32 mg, 0.09 mmol) were reacted to give the title compound as a colorless oil after purification by column chromatography (silica gel, 1% to 2% ethyl acetate in hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([C:20]3[N:21]=[N:22][NH:23][N:24]=3)[CH:17]=[CH:16][N:15]=2)[N:11]=[CH:10]1.[C:25]([O:28][CH2:29]Cl)(=[O:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:25]([O:28][CH2:29][N:22]1[N:23]=[N:24][C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:12]3[N:11]=[CH:10][N:9]([CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:13]=3)[CH:19]=2)=[N:21]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCCl
Reactant: Clc1ccccc1Cn1cnc(-c2cc(-c3nn[nH]n3)ccn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCn1nnc(-c2ccnc(-c3cn(Cc4ccccc4Cl)cn3)c2)n1
Yield: 15 %

Procedure:
The title compound was prepared in 15% yield from 2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]-4-(2H-tetrazol-5-yl)pyridine (Example 129), chloromethyl acetate and potassium carbonate in DMF. 1H NMR (400 MHz, DMSO): δ 2.12 (3H, s), 5.41 (2H, s), 6.67 (2H, s), 7.27-7.29 (1H, m), 7.38-7.41 (2H, m), 7.53-7.55 (1H, m), 7.81 (1H, s), 7.94 (1H, s), 8.51 (1H, s), 8.68 (1H, d, J=5.0 Hz). [M+H] Calc'd for C19H16ClN7O2, 410. Found, 410.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20](Cl)=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:29][NH2:30]>>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20]([NH:30][CH3:29])=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Reactant: CN
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(NC)cccc23)n1
Yield: 77 %

Procedure:
In a similar manner as described in Example 14, from N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (53 mg, 0.13 mmol) and methylamine (5 mL, 40% aqueous) in a sealed tube was obtained 3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-methylpyrazolo[1,5-α]pyridin-7-amine (40.5 mg, 77%) as a pale yellow solid. 1H NMR (CDCl3): δ 8.01 (d, 1H), 7.75 (d, 1H), 7.62 (m, 2H), 7.34 (t, 1H), 7.13 (t, 2H), 6.30 (d, 1H), 6.03–5.99 (m, 2H), 5.11 (broad, 1H), 3.46 (q, 2H), 3.10 (d, 3H), 1.69–1.42 (m, 4H), 0.97 (t, 3H); 19F NMR (CDCl3) δ −113.39; MS m/z 391 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[Li]CCCC.[O:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>C1COCC1>[OH:27][C:24]1([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=2)[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: O=C1CCOCC1
Reactant: CN(C)CCn1ccc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)CCn1ccc2ccc(C3(O)CCOCC3)cc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
To a solution of compound (ii), above, (380 mg, 1.4 mmol) in THF (5 mL) at −78° C. was added n-BuLi (1 mL, 1.6 M sol. in hexane, 1.6 mmol). The mixture was stirred at −78° C. for 20 min. Tetrahydro-4H-pyran-4-one (280 mg, 2.8 mmol) dissolved in THF (1 mL) was added and the reaction mixture stirred at −78° C. for 2 hrs. The mixture was then quenched with NH4Cl (saturated) and extracted with ethyl acetate. The organic extract was washed with brine and dried over anhydrous Na2SO4. The crude residue was purified by flash chromatography to give the title product as a yellow solid (150 mg, 37% yield).
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21][CH2:20]2)=[C:10]([F:31])[CH:9]=1)C>O1CCOCC1>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([OH:32])=[O:6])=[CH:9][C:10]=2[F:31])[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1ccc(OCCCCN2CCN(CCC(C)(C)C)CC2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)CCN1CCN(CCCCOc2ccc(C(=O)O)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Sodium hydroxide (0.5 g, 13.2 mmol) and water (5 ml) were added to a solution of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-butoxy}-3-fluoro-benzoic acid ethyl ester from Example E72.2 (1.35 g, 3.3 mmol) in dioxan (20 ml). The mixture was stirred for 1 h at room temperature then heated at 60° C. for 20 h. Solvents were concentrated in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:19% methanol:80% chloroform) to yield the title compound (0.85 g, 67%).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:19][CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=2)[CH2:7][C:6]([OH:28])=[O:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 2-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,3-oxazole-4-carboxylate (Preparation 62) (1.58 g, 4.01 mmol) in anhydrous dichloromethane (25 ml) was treated with trifluoroacetic acid (7 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The solvent was removed under reduced pressure and the residue azeotroped from dichloromethane to afford the title compound (1.66 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][O:28]1)[C:4]1[C:5]2[CH2:25][NH:24][CH2:23][CH2:22][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[N:9]=1)[CH3:2].[C:32](O)(=[O:34])[CH3:33].C(O)C=O.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:3]([CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][O:28]1)[C:4]1[C:5]2[CH2:25][N:24]([CH2:33][CH2:32][OH:34])[CH2:23][CH2:22][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[N:9]=1)[CH3:2]
Reactant: CCN(CC1CCCO1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: CC(=O)O
Agent: O=CCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CC1CCCO1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CN(CCO)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
N4-Ethyl-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (125 mg, 0.30 mmol) was dissolved in methanol (3 mL). Acetic acid (0.017 mL, 0.30 mmol) was added followed by glycoaldehyde (17.85 mg, 0.30 mmol). The reaction mixture was stirred for 15 minutes at room temperature and sodium cyanoborohydride (18.68 mg, 0.30 mmol) (MP—CNBH3) was added. The reaction was stirred overnight at room temperature, the MP—CNBH3 was filtered off, the solvent was evaporated under reduced pressure and the crude was purified by preparative HPLC yielding 2-(4-(ethyl((tetrahydrofuran-2-yl)methyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (54.0 mg, 34.6%) as acetate salt. MS (ES+) m/z 465.3 (M+H)+
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:30]([CH3:31])=[CH:29][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([O:26]C)=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2].C1COCC1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH3:32])=[CH:9][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][C:16]=3[CH:28]=2)=[CH:29][C:30]=1[CH3:31])[CH3:2]
Reactant: CCOCCOc1c(C)cc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCCOc1c(C)cc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To methyl 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.39 g) dissolved in methanol (5 ml) and THF (10 ml) was added a 1 M aqueous solution of potassium carbonate (2.5 ml), and the resulting mixture was stirred overnight at 70° C. The reaction mixture was concentrated, was then neutralized with 1 N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (0.33 g) as colorless crystals.
Reaction SMILES: O1CCOC1C1C=C(NC(=O)C2C=C(C)C=NC=2)C=CC=1.[F:22][C:23]([F:34])([F:33])[C:24]1[N:29]=[C:28]([C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=1.[NH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:44])=[C:40]([CH2:42][OH:43])[CH:41]=1>>[F:44][C:39]1[CH:38]=[CH:37][C:36]([NH:35][C:30]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[N:29]=2)=[O:31])=[CH:41][C:40]=1[CH:42]=[O:43]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)n1
Reactant: Nc1ccc(F)c(CO)c1
Agent: Cc1cncc(C(=O)Nc2cccc(C3OCCO3)c2)c1
Product: O=Cc1cc(NC(=O)c2cccc(C(F)(F)F)n2)ccc1F

Procedure:
The title compound is prepared according to the reaction 4.01a described above using 6-(trifluoromethyl)picolinoyl chloride and (5-amino-2-fluorophenyl)methanol, followed by the oxidation of the alcohol intermediate 6-trifluoromethyl-pyridine-2-carboxylic acid (4-fluoro-3-hydroxymethyl-phenyl)-amide: LC-MS A: tR=0.80 min; [M+H]+=315.06.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH3:20])[OH:4].Br[CH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=1.[H-].[Na+].O>CN(C)C=O>[F:33][C:27]1[CH:26]=[C:25]([CH2:24][O:4][CH:3]([C:5]2[S:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH3:20])[C:2]([F:1])([F:21])[F:22])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(OCc1ccc(C#N)c(F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
1.30 g 2,2,2-Trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol and 815 mg 4-Bromomethyl-2-fluoro-benzonitrile were dissolved in 40 ml dimethylformamide. 192 mg sodium hydride were added and the mixture stirred at room temperature for one hour. Then 15 ml water were added and the mixture extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed in vacuo. The residue was purified by reversed phase HPLC to obtain 840 mg 2-Fluoro-4-{2,2,2-trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxymethyl}-benzonitrile as an oil.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B#B.[O:19]1CCC[CH2:20]1>>[C:1]1([CH2:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:20][OH:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCOC1
Reactant: CCCCCCC(C(=O)O)c1ccccc1
Agent: B#B
Product: OCCCCCCCCc1ccccc1

Procedure:
A solution of 8 phenyloctanoic acid (19.8 mmoles in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmoles) at 0° C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmoles) and carbon tetrabromide (21.98 mmoles) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmoles) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 8-phenyloctyl bromide as an oil.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].O>CS(C)=O>[NH2:3][C:4]1[C:9]([O:10][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: ClCCCCBr
Reactant: Nc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncccc1OCCCCCl
Reaction time: 0.25 h

Procedure:
To a suspension of 20 g (500 mmol) of 60% oily sodium hydride in 500 ml of dimethyl sulfoxide, 55.06 g (500 mmol) of 2-amino-3-hydroxypyridine was added at room temperature, followed by stirring for 15 minutes. To this mixture, 57.62 ml (500 mmol) of 1-bromo-4-chlorobutane was added, followed by stirring at 80° C. for 3 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: n-hexane/ethyl acetate=1/1→1/4→1/9). The resulting crude crystal was purified by recrystallization (solvent: chloroform-diethyl ether) to yield 10.35 g (10.3%, white crystal) of the desired product.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:8][S:9]([O:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1)(=[O:11])=[O:10]
Reactant: N#CC1(CO)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At r.t. to a solution of 1-(hydroxymethyl)cyclopropanecarbonitrile (0.41 g, 4.2 mmol) in methylene chloride (10 mL) was added methanesulfonyl chloride (490 uL, 6.3 mmol), followed by triethylamine (1.5 mL, 10.0 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol). The mixture was stirred at r.t. for 3 h. It was diluted with methylene chloride, washed with water and brine, dried over Na2SO4. After filtration the filtrate was concentrated to yield the crude product which was used in the next step reaction without further purification.
Reaction SMILES: [F-].[Cs+].[CH3:3]OCCOCCOC.[CH3:12][O:13][C:14](=[O:24])[CH:15]([C:20]([F:23])([F:22])[F:21])[C:16]([O:18][CH3:19])=[O:17].CI>O>[CH3:3][C:15]([C:20]([F:22])([F:23])[F:21])([C:16]([O:18][CH3:19])=[O:17])[C:14]([O:13][CH3:12])=[O:24]
Reactant: COCCOCCOC
Reactant: COC(=O)C(C(=O)OC)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CI
Product: COC(=O)C(C)(C(=O)OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of dried CsF (9.11 g, 60 mmol), diglyme (41 ml), dimethyl(trifluoromethyl)malonate (4 g, 20 mmol), and methyl iodide (3.12 g, 22 mmol) was stirred overnight at room temperature. The reaction mixture was poured into water and the resultant oily layer and the ether-extract from the aqueous layer were combined and washed with water to remove diglyme. After drying over MgSO4, the ether was evaporated and the residue was subjected to distillation, giving dimethyl methyl(trifluoromethyl)malonate (2.56 g, 60%), b.p. 63°-65° C./10 mmHg. This product showed the following analytical properties: 19F NMR: δ--7.5 (s, CF3); 1H NMR: δ 3.81 (s, 6H, CO2CH3), 1.66 (s, CH3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(OC([N:37]([CH2:45][CH3:46])[C:38]1([C:42](O)=[O:43])[CH2:41][CH2:40][CH2:39]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:42]([C:38]4([NH:37][CH2:45][CH3:46])[CH2:41][CH2:40][CH2:39]4)=[O:43])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CCN(C(=O)OC(C)(C)C)C1(C(=O)O)CCC1
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: CCNC1(C(=O)N2CCC(c3cc(F)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (50.0 mg, 0.12 mmol), 1-(tert-butoxycarbonyl(ethyl)amino)cyclobutanecarboxylic acid (29.2 mg, 0.12 mmol), HATU (45.8 mg, 0.12 mmol) and di-isopropylethylamine (20 μL, 0.12 mmol) in 1 mL of DMF was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na2SO4), and concentrated in vacuo. The resulting crude mixture was dissolved in 5 mL of DCM and 4 mL of TFA and was then stirred for 2 h followed by concentration in vacuo. The crude product was purified by RP-HPLC to afford (4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)(1-(ethylamino)cyclobutyl)methanone; ESMS m/z 541.3 (M+H+).
Reaction SMILES: C[OH:2].[CH3:3][C:4]1[O:8][C:7]([CH2:9][CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1.ClCl>O>[CH3:11][C:10]1[O:12][C:5]([CH2:4][CH3:3])=[C:6]([OH:2])[C:7](=[O:8])[CH:9]=1
Reactant: CO
Reactant: Cc1ccc(CC(C)O)o1
Agent: ClCl
Solvent: O
Product: CCc1oc(C)cc(=O)c1O
Temperature: -15 °C
Yield: 30 %

Procedure:
In a three necked round bottom flask were combined 28 ml of methanol and 38 ml of water. The solution was cooled to -15° C. and 0.166 mole of 5-methyl-2-(2-hydroxy-propyl)furan (J. Org. Chem., 26, 1673, 1960) and 0.416 mole of chlorine were added simultaneously. During the addition, the reaction was maintained between -16° and -8° C. When addition was completed, the solution was warmed to 80° C. and refluxed for about 3 hours. Upon cooling to room temperature, the pH was adjusted to 2.1 and extracted with chloroform (3×100 ml). The combined organic layers were washed with water, brine and dried over magnesium sulfate. The organic solution was filtered and evaporated to give a thick dark solid. The solid was recrystallized twice from methanol to give 8.06 grams (30% yield) of white solid. Sublimation yielded pure product, m.p. 157°-159° C.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:36][C:37]1[N:42]=[CH:41][C:40]([C:43]2[CH:65]=[CH:64][C:46]3[N:47]([C:60]([CH3:63])([CH3:62])[CH3:61])[C:48]([C:50]4[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=4[C:52]([NH:54]O)=[NH:53])=[N:49][C:45]=3[CH:44]=2)=[CH:39][N:38]=1>CN(C=O)C>[C:60]([N:47]1[C:46]2[CH:64]=[CH:65][C:43]([C:40]3[CH:41]=[N:42][C:37]([NH2:36])=[N:38][CH:39]=3)=[CH:44][C:45]=2[N:49]=[C:48]1[C:50]1[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=1[C:52]1[N:54]=[C:1]([CH3:2])[O:4][N:53]=1)([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(C)(C)n1c(-c2ccccc2C(=N)NO)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
To a solution of acetic acid (30 mg, 0.5 mmol) and HATU (189 mg, 0.5 mmol) in DMF (2 mL) is added triethylamine (0.07 mL, 0.5 mmol). The reaction mixture is stirred at room temperature for 10 minutes and 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-N-hydroxy-benzamidine (200 mg, 0.5 mmol) is added. The reaction mixture is stirred at room temperature for 0.5 hours then warmed to 80° C. and stirred for 15 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. EtOAc (20 mL) is added and the organics washed with H2O (30 mL) then dried (Na2SO4), filtered and concentrated. Purification via prep HPLC (0.1% TFA/MeCN) affords the title compound (27 mg, 8%) as 2TFA salt. LCMS (ESMS): m/z 426.20 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:12].C(N(CC)CC)C.[Cl:20][C:21]1[C:22]([N:27]2[C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]([C:35]([F:38])([F:37])[F:36])=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1>C(Cl)Cl>[Cl:20][C:21]1[C:22]([N:27]2[C:31]([C:32]([NH:12][C:3]3[C:4]([C:5]([OH:7])=[O:6])=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=3[Cl:1])=[O:33])=[CH:30][C:29]([C:35]([F:38])([F:36])[F:37])=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dichloroanthranilic acid (7.89 g, 38.3 mmol) in methylene chloride (130 mL) at 0° C. was added triethylamine (18.6 mL, 134.0 mmol). A solution of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl chloride (13.7 g, 44.0 mmol) in methylene chloride (130 mL) at 0° C. was then added, the reaction allowed to warm to room temperature and then stirred further for 16 h. The reaction was concentrated in vacuo and used directly in the following reaction step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]([CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CNc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)CN(C)c1ccccc1
Yield: 76.3 %

Procedure:
The mixture of N-phenylglycine methyl ester (0.99 g, 6 mmol), potassium carbonate (1.66 g, 12 mmol), and iodomethane (1.28 g, 9 mmol) in acetonitrile (20 mL) was refluxed overnight. The solids were filtered and the filtrate was diluted with water (100 mL), extracted with dichloromethane (4×50 mL). The combined organic extracts were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane) to afford the title compound (0.82 g, 77%). 1H NMR (400 MHz, CDCl3) δ: 7.24 (m, 2H), 6.75 (m, 1H), 6.67 (m, 2H), 4.07 (s, 2H), 3.71 (s, 3H), 3.06 (s, 3H).