Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:28][CH:27]=[N:26][CH:25]=1)CCC>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>[Cl:8][C:6]1[CH:7]=[C:2]([C:24]2[S:28][CH:27]=[N:26][CH:25]=2)[N:3]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](Nc1nc(Cl)cc(-c2cncs2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 52.3 %

Procedure:
286 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 411 mg of 5-(tributylstannyl)thiazole and 115 mg of tetrakis(triphenylphosphine)palladium were added in turn to degassed dimethylformamide, and then the mixture was stirred at 100° C. for 5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 175 mg of (S)-4-chloro-N-[1-(4-fluorophenyl)ethyl]-6-(thiazol-5-yl)pyrimidine-2-amine as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.Cl.Cl[CH2:15][C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C)C=O>[NH2:21][C:18]1[S:19][CH:20]=[C:16]([CH2:15][O:12][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[N:17]=1
Reactant: Nc1nc(CCl)cs1
Reactant: COC(=O)c1ccc(F)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1OCc1csc(N)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 4-fluoro-2-hydroxybenzoate (552 mg), 4-(chloromethyl)thiazol-2-amine hydrochloric acid (600 mg) and Cs2CO3 (2.64 g) in 15 mL N,N-dimethylformamide was stirred at room temperature for 24 hours. Water was added and the mixture was extracted with ethyl acetate (2×), washed with water (2×) and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel using 10-50% ethyl acetate in hexanes as eluent.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([I:24])C(=O)C1>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([I:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In nitrogen-purged flask is added 5.1 g (0.023 moles) of 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine in 50 ml dry acetonitrile. Cool to 0° C. and add 5.54 g (0.025 moles) of NIS dissolved in 90 ml dry acetonitrile. Allow bath to come to room temperature and the reaction to stir overnight. Evaporate solvents, take up in ethyl acetate and wash two times with 50% aqueous solution of sodium sulfate then brine. Dry over sodium sulfate, filter and evaporate to a residue. Triturate in small amount of acetonitrile and filter solid. Repeat several times to obtain the title compound as light tan solid weighing 7.29 g (0.021 moles, 91.3%). 1H-NMR (DMSO-d6): δ 6.96 (s, 1H); 3.0-3.3 (m, 1H); 2.51 (s, 3H); 2.35 (s, 3H); 1.71-1.80 (m, 4H); 0.71 (t, J=7.48 hz, 6H) ppm. MS/ES+=344 (100%, M+1).
Reaction SMILES: C[C:2]1(C)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:10]([CH:12]=[CH2:13])=[O:11]>>[O:8]=[C:5]1[CH2:4][CH2:3][CH2:2][CH2:7][CH:6]1[CH2:13][CH2:12][CH:10]=[O:11]
Reactant: CC1(C)CCC(=O)CC1
Reactant: C=CC=O
Product: O=CCCC1CCCCC1=O

Procedure:
The title compound 1 was prepared in the following way. ##STR18## Isobutyraldohyde was alkylated with methyl vinyl ketone via its pyrrolidine enamine, cyclized in acid, and then hydrogenated to give 4,4-dimethylcyclohexanone (2). Ketone 2 was alkylated with acrolein via its morpholline enamine then hydrolyzed to give 3-(2-oxocyclohexyl)propanal (3). Crude 3 was then purified through its diketal, cyclized in 7 N hydrochloric acid, and esterified to give 7,7-dimethylbicyclo(3.3.1)nonan-9-one-2-yl pivalate (4). Kettalization of 4 followed by alkaline hydrolysis, CrO,--pyridine oxidation, and alkylation with iodomethane and potassium t-butoxide yielded 3,3,7,7-tetramothyl-9,9-ethylenedioxybicyclo(3.3.1)nonan2one (5). When various attempts of Wolff-Kishner reduction failed, 5 was reduced to alcohol with lithium--ammonia then mesylated to give 3,3,7,7-tetramethyl-9,9-ethylenedioxybicyclo(3.3.1)nonan-2-exo-yl methanesulfonae (6). Lithium--ammonia reduction of 6 followed by acid hydrolysis afforded the title compound 1.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:26])[N:18]([CH2:22][C:23](O)=[O:24])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[F:35][C:2]([F:1])([F:36])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:26])[N:18]([CH2:22][C:23]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:24])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(methylsulfonyl)acetamide was prepared from [(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid (Example 59) following General Procedure L, using methanesulfonic acid amide in place of the sulfamide.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25](Cl)(=[O:27])=[O:26]>O1CCOCC1.O.Cl>[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25]([NH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])(=[O:26])=[O:27]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: NC(CC(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
4.13 g of 3-amino-3-phenylpropionic acid are dissolved in 100 ml of dioxane and 25 ml of 1N sodium hydroxide and 5.6 g of 2-naphthalenesulphonyl chloride are added portionwise, while maintaining the pH at 10.5-11 by addition of 1N sodium hydroxide. After stirring for 2 hours at RT, the mixture is diluted with 400 ml of water and 2N HCl is added in order to obtain pH=2. This mixture is extracted with EtOAc and the extracts are washed with a KHSO4/K2SO4 buffer, dried over Na2SO4 and evaporated to dryness. The residue is triturated from heptane and the product is isolated by decanting and is then dried under vacuum. 7.33 g of the expected product are obtained, m.p.=126-129° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:16][C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)n(C)n1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nn(C)c(Cl)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
A solution of 5-chloro-1,3-dimethyl-1H-pyrazole (0.500 g, 3.83 mmol) in carbon tetrachloride (2.0 mL) was charged with NBS (0.750 g, 4.21 mmol) and stirred at rt for 16 h. The reaction mixture was charged with silica gel and purified by chromatography on silica gel [ISCO Combiflash, 12 g cartridge, eluting with 100% heptane 10% EtOAc in heptane]. This resulted in 419 mg, 52% yield of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ=2.23 (s, 3H), 3.81 (s, 3H). MS (ES+): m/z 208.96, 210.93 (76/24) [MH+]. HPLC: tR=2.62 min (polar—5 min, ZQ3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:12][C:11]=1B(O)O>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:14]=[C:13]([O:16][CH:17]([CH3:18])[CH3:19])[CH:12]=[CH:11][C:10]=2[F:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)Oc1ccc(F)c(B(O)O)c1
Product: CC(C)Oc1ccc(F)c(-c2ccc(Br)cn2)c1
Yield: 45 %

Procedure:
Obtained (0.600 g, yield 45%) following the procedure described in Intermediate 27, starting with 2,5-dibromopyridine (4.22 mmol, 1.0 g), 2-fluoro-5-isopropoxyphenylboronic acid (4.22 mmol, 0.836 g).
Reaction SMILES: [CH:1]([Mg:4][Cl:5])(C)[CH3:2].[CH3:6][O:7][C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][CH2:11][CH:12](C)[CH:13]=C>O1CCCC1>[CH3:6][O:7][C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH2:2][CH2:1][Mg:4][Cl:5]
Reactant: CC(C)[Mg]Cl
Reactant: C=CC(C)CCCC(C)(C)OC
Solvent: C1CCOC1
Product: COC(C)(C)CCCC(C)CC[Mg]Cl

Procedure:
i-Propylmagnesium chloride (0.5 mol) in tetrahydrofuran (200 ml) was treated with 7-methoxy-3,7-dimethyl-1-octene (85 g), followed by dropwise addition of a tri-isobutyl vanadate (7.0 g) in tetrahydrofuran (40 ml) at room temperature. The reaction mixture was then refluxed under nitrogen for 5 h when an aliquot showed a 72% conversion and 87% theoretical yield of the Grignard reagent.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]1[C:27]2[C:28]3[C:33]([NH:34][C:26]=2[CH2:25][NH:24][CH2:23]1)=[CH:32][CH:31]=[CH:30][CH:29]=3>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:24]4[CH2:23][CH2:22][C:27]5[C:28]6[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=6)[NH:34][C:26]=5[CH2:25]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCc2c([nH]c3ccccc23)C1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and noreleagnine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=458.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].C(N(CC)CC)C.[CH3:19][O:20][P:21]([O-:24])[O:22][CH3:23]>C(OCC)(=O)C>[CH3:19][O:20][P:21]([CH:7]([OH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:24])[O:22][CH3:23]
Reactant: COP([O-])OC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COP(=O)(OC)C(O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 77 %

Procedure:
3-Nitrobenzaldehyde (20 g, 0.132 mol) was dissolved in 100 mL of ethyl acetate. Triethylamine (22 mL, 0.158 mol, 1.2 eq) was added, followed by dimethylphosphite (15.7 mL, 0.171 mmol, 1.3 eq) and the mixture was stirred at room temperature. After 2 hours the mixture was diluted with 150 mL of ethyl acetate and washed with saturated aqueous ammonium chloride (2×50 mL) and water (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was treated with ethyl ether to obtain a beige solid, which was filtered and dried under vacuum at 40° C. for 1 h (26.7 g, 77% yield).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:2]1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>CCCCCCC.CCOC(C)=O>[O:1]1[CH2:2][CH:3]([N:5]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:24](=[O:25])[C:23]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([C:20]([F:19])([F:34])[F:35])[CH:22]=2)[CH2:4]1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccncc1NC1COC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1COC1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from oxetan-3-yl-(4-o-tolyl-pyridin-3-yl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow solid (34%). MS (ESI): m/z=481.13 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]([OH:8])=[O:7].[CH3:9]OC(OC)(C)C.[ClH:16]>CO>[ClH:16].[CH3:9][O:7][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH2:1])=[O:8]
Reactant: COC(C)(C)OC
Reactant: NCCSCC(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)CSCCN
Reaction time: 12 h

Procedure:
13.5 g of S-(β-aminoethyl)mercaptoacetic acid and 10.8 g of 2,2-dimethoxy propane are added, successively, to a solution of 7.3 g of gaseous hydrochloric acid in 20 cc of methanol. The solution is permitted to stand for 12 hours at ambient temperature. The flakes formed (17.5 g) are filtered and washed with ethyl acetate. Fusion point = 100° C.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[CH:4][N:3]=1.[F:13][C:14]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:15]=1[C:16]([N:18]=[C:19]=[S:20])=[O:17]>O1CCOCC1>[CH2:9]([N:8]1[C:7]2[CH:6]=[N:5][CH:4]=[N:3][C:2]=2[S:20]/[C:19]/1=[N:18]\[C:16](=[O:17])[C:15]1[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:14]=1[F:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCNc1cncnc1Br
Reactant: O=C(N=C=S)c1cc(C(F)(F)F)ccc1F
Solvent: C1COCCO1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ncncc21
Temperature: 60 °C
Yield: 81.5 %

Procedure:
A mixture of product from Example 3A (270 mg, 1.17 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl isothiocyanate (322 mg, 1.29 mmol) in dioxane was heated at 60° C. for 12 hours. The mixture was then concentrated under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (hexanes-EtOAc 1:2) to afford 380 mg of the title compound. MS (ESI) m/z 399 (M+H)+.
Reaction SMILES: N[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:11]1([CH2:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:19][C:18]1[N:2]2[C:10]3[C:5]([CH2:4][CH2:3]2)=[CH:6][CH:7]=[CH:8][C:9]=3[C:17]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nn1ccc2ccccc21
Reactant: CC(=O)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2ccccc2)c2cccc3c2n1CC3

Procedure:
A mixture of 50 g. (0.372 mole) of 1-aminoindole, 50 g. (0.372 mole) of phenylacetone, 600 ml. of acetic acid and 50 g. of sodium acetate was heated for one hour on a steam bath. The precipitate which separated from the cooled mixture was collected and washed with isopropyl ether. The product melted at 145°C. The literature m.p. is 145°C., Chemical Abstracts 54, 19641 (1960).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][C:33]1[S:34][C:35]([S:39](Cl)(=[O:41])=[O:40])=[C:36]([CH3:38])[N:37]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:39]([C:35]1[S:34][C:33]([CH3:32])=[N:37][C:36]=1[CH3:38])(=[O:41])=[O:40]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C)c(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2,4-dimethylthiazole-5-sulfonyl chloride (12 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 25 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2,4-dimethylthiazole-5-sulfonamide (percentage yield: 87%), was obtained.
Reaction SMILES: [CH:1]1([N:7]([CH3:22])[C:8]([C:10]2[S:21][C:13]3=[N:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[N:12]3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:23]([O-])([OH:25])=[O:24].N>S(=O)(=O)(O)O>[CH:1]1([N:7]([CH3:22])[C:8]([C:10]2[S:21][C:13]3=[N:14][C:15]4[CH:20]=[CH:19][C:18]([N+:23]([O-:25])=[O:24])=[CH:17][C:16]=4[N:12]3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])O
Reactant: CN(C(=O)c1cn2c(nc3ccccc32)s1)C1CCCCC1
Agent: N
Agent: O=S(=O)(O)O
Product: CN(C(=O)c1cn2c(nc3ccc([N+](=O)[O-])cc32)s1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of Example 3 (12.3 g) was dissolved in concentrated sulfuric acid, and this was mixed with fuming nitric acid (1.95 ml) under ice-cooling and then stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and neutralized by adding saturated NH3 aqueous solution, and then the thus formed precipitate was collected by filtration. The thus collected crude crystals were washed with hot MeOH to obtain the title compound (12.7 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[C@H:30]1([NH2:37])[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1>CCOC(C)=O>[NH2:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([NH:37][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:31][CH2:32]1
Reactant: N#Cc1cc(NCc2cccc(F)c2)nc(-c2cc(F)ncc2Cl)c1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cc(NCc2cccc(F)c2)nc(-c2cc(N[C@H]3CC[C@H](N)CC3)ncc2Cl)c1
Temperature: 105 °C

Procedure:
To a scintillation vial containing 5′-chloro-2′-fluoro-6-(3-fluorobenzylamino)-2,4′-bipyridine-4-carbonitrile (72 mg, 0.202 mmol) was added DMSO (3 ml) and trans-cyclohexane-1,4-diamine (230 mg, 2.018 mmol). The homogenous yellow reaction mixture was capped and heated to 105° C. in a oil bath for 3 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3, sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude solid was purified by Prep HPLC and the collected fractions were combined and diluted with EtOAc and neutralized with sat NaHCO3 and then sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to afford 2′-(trans-4-aminocyclohexylamino)-5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridine-4-carbonitrile (73 mg, 80%). LCMS (m/z): 451.2 (MH+), retention time=0.70 min. 1H NMR (400 MHz, METHANOL-d4) d ppm 1.34-1.48 (m, 2H) 1.50-1.64 (m, 2H) 2.06-2.22 (m, 4H) 3.08-3.20 (m, 1H) 3.63-3.74 (m, 1H) 4.61 (s, 2H) 6.81 (s, 1H) 6.87 (s, 1H) 6.91-6.99 (m, 1H) 7.02 (s, 1H) 7.04-7.10 (m, 1H) 7.12-7.18 (m, 1H) 7.25-7.36 (m, 1H) 8.00 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:49][C@@H:50]([CH2:64][C:65]1[CH:70]=[C:69]([F:71])[CH:68]=[C:67]([F:72])[CH:66]=1)[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1>C(Cl)Cl>[F:71][C:69]1[CH:70]=[C:65]([CH:66]=[C:67]([F:72])[CH:68]=1)[CH2:64][C@H:50]([NH:49][C:13]([C:10]1[CH:11]=[CH:12][C:7]2[O:6][N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[C:8]=2[CH:9]=1)=[O:15])[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCc1noc2ccc(C(=O)O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1noc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.2 %

Procedure:
To a stirred solution of 3-propyl-1,2-benzisoxazole-5-carboxylic acid (70 mg, 0.3 mmol) and HATU (130 mg, 0.3 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (110 μL, 0.6 mmol). In a separate flask, N,N-diisopropylethylamine (110 μL, 0.6 mmol) was added to (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (EXA xxx)(140 mg, 0.3 mmol) in methylene chloride (2 mL). This solution was added to the above solution containing the acid and the resulting reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, gradient 97:3 to 94:6 methylene chloride/methanol) provided N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-propyl-1,2-benzisoxazole-5-carboxamide (30 mg). ESI-MS m/z 522 [M+H]+
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[N:34][CH:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3cncn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-(isobutyl-methyl-amino)-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M121) (0.76 g, 1.41 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light orange solid (530 mg, 89%).