Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][C:7]#[N:8])=[O:4].C(N(CC)CC)C.[C:24](Cl)(=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28]>ClCCl>[I:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C@H:2]([NH:1][C:24](=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:3]([O:5][CH2:6][C:7]#[N:8])=[O:4])=[CH:15][CH:14]=1
Reactant: C=CCCC(=O)Cl
Reactant: N#CCOC(=O)[C@@H](N)Cc1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.7 %

Procedure:
(S)-Cyanomethyl 2-amino-3-(4-iodophenyl)propanoate (0.65 g, 1.78 mmol) was dissolved in dichloromethane (25.0 ml) under a nitrogen atmosphere, and triethylamine (0.45 g, 4.45 mmol) was added dropwise under ice-cooling. A solution of pent-4-enoyl chloride (0.25 g, 2.14 mmol) in dichloromethane (25.0 ml) was then added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=50:50-33:67) to afford (S)-cyanomethyl 3-(4-iodophenyl)-2-(pent-4-enamido)propanoate (Compound 92) (0.57 g, 78%).
Reaction SMILES: N1C2C(=NC=CC=2)N([N:10]2[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:13]([CH3:27])[C:12]([C:28]([O-:30])=O)=[C:11]2[CH3:31])N=1.[NH2:32][C@@H:33]1[CH2:37][O:36][N:35]([CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[C:34]1=[O:44].CCN(C(C)C)C(C)C>CN(C=O)C>[O:44]=[C:34]1[C@H:33]([NH:32][C:28]([C:12]2[C:13]([CH3:27])=[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[NH:10][C:11]=2[CH3:31])=[O:30])[CH2:37][O:36][N:35]1[CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: N[C@@H]1CON(C2CCOCC2)C1=O
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)N[C@@H]1CON(C2CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of A4 (84 mg, 2 mmol) in 10 mL of DMF, were added the crude 48c from last step and DIEA (2 mL), the reaction mixture was stirred at room temperature overnight. LC/MS was applied to determine completion of the reaction. The reaction mixture was evaporated under reduced pressure and the residue was triturated with 5% diethylamine/methanol (25 mL). The solid was collected by filtration and washed with methanol, dried under vacuum to provide the title compound (58 mg, 62%) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.73 (s, 1H), 10.94 (s, 1H), 8.12-8.15 (d, 1H), 7.73-7.80 (m, 2H), 6.82-6.87 (m, 2H), 5.02-5.05 (q, 1H), 4.58-4.64 (t, 1H), 3.86-4.14 (m, 4H), 3.38-3.44 (m, 2H), 2.42-2.50 (ds, 6H), 1.65-1.88 (m, 4H). LC/MS: 469.0 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[O:39][CH3:40])C1C=CC=CC=1.[H][H].C(O)C>C1COCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[O:39][CH3:40]
Reactant: COc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1O

Procedure:
0.6 g of 5-(4-benzyloxy-3-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine is hydrogenated in a hydrogen atmosphere at normal pressure and about 50° C. for 6 h in 20 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 5% palladium/carbon. After filtration through Celite and crystallization of the residue from methylene chloride, 5-(4-hydroxy-3-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 190° C. is obtained.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)=[N:4][CH:3]=[N:2]1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[CH:20]=1>>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[O:23][N:22]=[C:21]([CH3:24])[CH:20]=3)=[CH:8][CH:7]=2)=[N:4][CH:3]=[N:2]1
Reactant: Oc1ccc(-c2ncno2)cc1
Reactant: Cc1cc(CCCCCBr)on1
Product: Cc1cc(CCCCCOc2ccc(-c3ncno3)cc2)on1

Procedure:
It is further contemplated that 4-(1,2,4-oxadiazol-5-yl)phenol can be caused to react with 5-(5-bromopentyl)-3-methylisoxazole according to the procedure of Example 1 to give 5-{5-[4-(1,2,4-oxadiazol-5-yl)phenoxy]pentyl}-3-methylisoxazole [II; R1 and R2 =H, Het=1,2,4-oxadiazol-5-yl].
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[NH:6][C:5](=[O:14])[CH:4]=1)[NH2:2].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:25]=O.[CH3:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH:33]=O>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH2:25][N:2]1[C:33]([C:29]2[N:28]([CH3:27])[CH:32]=[CH:31][N:30]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[NH:6][C:5]2=[O:14])=[N:1]1
Reactant: Cn1ccnc1C=O
Reactant: CC(C)Cn1c(NN)cc(=O)[nH]c1=O
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Product: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-chloro-1H-indole-3-carbaldehyde, followed by 1-methyl-1H-imidazole-2-carbaldehyde. Mass: 452.18 (M+H).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11](CCCCN2C(=O)C3C=CC=C4C=3C(=CC=C4)C2=O)[CH2:10][CH2:9]1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]1[C:49](=[O:50])[C:48]2[CH:51]=[CH:52][CH:53]=[C:46]3[C:47]=2[C:42](=[CH:43][CH:44]=[CH:45]3)[C:41]1=[O:54].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]2[C:49](=[O:50])[C:48]3[CH:51]=[CH:52][CH:53]=[C:46]4[C:47]=3[C:42](=[CH:43][CH:44]=[CH:45]4)[C:41]2=[O:54])[CH2:12][CH2:13]1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccn2)CC1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCN1CCN(c2ccccn2)CC1

Procedure:
Following the procedure of part (b) of example 46 but substituting 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3-(2H)-dione, one obtains 2-[6-[4-(2-pyridinyl)-1-piperazinyl]-hexyl]-1H-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:2).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[N:19]1([CH2:2][CH2:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:6])[CH3:5])[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: CC(O)(CCCl)c1ccccc1-c1ccccc1
Reactant: c1c[nH]cn1
Product: CC(O)(CCn1ccnc1)c1ccccc1-c1ccccc1

Procedure:
A mixture of 2.6 g of 1-chloro-3-p-biphenylyl-butan-3-ol and 1.36 g of imidazole is heated at 140° for 3 hours. After cooling and working up in the customary manner, 1-(1-imidazolyl)-3-p-biphenylyl-butan-3-ol is obtained.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]([N:28]2[CH2:33][CH2:32][C:31]([OH:40])([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:26][NH2:27])[CH:21]=[CH:22][C:23]=1[Cl:24]>O1CCCC1>[ClH:9].[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]([N:28]2[CH2:29][CH2:30][C:31]([OH:40])([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:32][CH2:33]2)[CH2:26][NH:27][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC(c1ccc(Cl)c(Cl)c1)N1CCC(O)(c2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(NCC(c1ccc(Cl)c(Cl)c1)N1CCC(O)(c2ccccc2)CC1)c1ccccc1
Temperature: 23 °C
Reaction time: 18 h
Yield: 43.3 %

Procedure:
Benzoyl chloride (290 mg) and triethylamine (420 mg) were added to a solution of 2-(3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenyl-piperdino)ethylamine (750 mg) in tetrahydrofuran (37.5 mL). The reaction was stirred at 23° C. for 18 hours, and was evaporated to an oil-solid mixture. The mixture was partitioned between water (100 mL) and dichloromethane (100 mL), and the seperated organic layer was dried and evaporated to an off-white solid (1.01 gm). Treatment of a solution of this solid in diethylether with hydrochloric acid (g)/diethylether followed by recrystalization of the hydrochloride salt from ethylacetate (hot,minimum volume) provided the title compound as a white solid (450 mg); mp 232-235° C.; MS: m/z=469(M+1); NMR: 1.8 (m,2), 2.44 (m,1), 2.63 (m,1), 3.17 (m,3), 3.99 (m,2), 4.27 (m,1), 4.76 (m,1), 5.4 (broad s,1), 7.26 (m,1), 7.46 (m,7), 7.8 (m,5), 11.37 (broad s,1). Analysis Calculated: C, 61.73; H, 5.38; N, 5.54; Found: C, 61.8; H, 5.5; N, 5.52.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[CH2:13][CH:12]3[NH:14][CH:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.C[Si](C)(C)CCOC[N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[CH:32]=O.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:13][CH:12]3[N:14]([CH2:32][C:24]4[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[N:23]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(CC2CC3CCC(C2)N3)cc1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: Clc1ccc(CC2CC3CCC(C2)N3Cc2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 113.3 %

Procedure:
A mixture of 0.5 g of 3-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]octane, 0.5 g of 1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole-2-carbaldehyde, 5 mL of 1,2-dichloroethane and 0.5 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was diluted with 50 mL chloroform and 10 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The crude SEM ether was heated to reflux in 50 mL of ethanol containing 5 mL of 3N HCl for 2 h, cooled, concentrated and partitioned between 10 ml of saturated aqueous Na2CO3 and 3×25 mL of chloroform. The chloroform extracts were dried over MgSO4 and concentrated. Purification by chromatography eluting with 90:10 CHCl3:MeOH gave 0.75 g of 2-[3-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]oct-8-ylmethyl]-1H-benzimidazole as a 2:1 mixture of exo:endo isomers. Chromatography on a Chiralpak™ AS column eluting with a 90:10 mixture of hexane with 0.10% diethylamine and isopropanol gave 0.25 g of endo 2-[3-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]oct-8-ylmethyl]-1H-benzimidazole: RT=5.34 min; MS (m+1)=366; 1H NMR (400 MHz, CDCl3 3.8 (s, 2H), 3.2 (s, 2H), 2.75 (d, 2H), 2.05 (m, 2H), 1.8 (d, 2H).
Reaction SMILES: Br/[C:2](/[Si:12]([CH3:15])([CH3:14])[CH3:13])=[C:3](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)\[CH2:4][CH3:5].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:16][C:17]1[CH:22]=[CH:21][C:20](/[C:2](/[Si:12]([CH3:15])([CH3:14])[CH3:13])=[C:3](/[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)\[CH2:4][CH3:5])=[CH:19][CH:18]=1
Reactant: CC/C(=C(\Br)[Si](C)(C)C)c1ccccc1
Reactant: OB(O)c1ccc(F)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: COCCOC
Product: CC/C(=C(\c1ccc(F)cc1)[Si](C)(C)C)c1ccccc1
Yield: 90.8 %

Procedure:
To a solution of (E)-1-bromo-2-phenyl-1-(trimethylsilyl)-1-butene (Miller R. B., Al-Hassam, M. I. J. Org. Chem. 1985, 50, 2121-2123) (1) (4.4 g, 15.5 mmol) in DME (50 mL) was added 4-fluorobenzene boronic acid (2.63 g, 18.9 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.9 mmol), and 2N aqueous sodium carbonate(9.5 mL, 19 mmol). After refluxing overnight the solvent was removed under reduced pressure and the residue was chromatographed (silica gel, hexanes) to give (2) as a white solid (4.2 g, 91%): 1 H NMR (CDCl3) δ 7.30 (m, 3 H), 7.19 (m, 2 H), 7.00 (m, 4 H), 2.12 (q, J=7.7 Hz, 2 H), 0.72 (t, J=7.7 Hz, 3 H), −0.35 (s, 9 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[Se](=O)=O.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C(N(CC)CC)C>C(O)C>[CH3:13][S:12][C:4]1[N:3]=[C:2](/[CH:1]=[C:21]2/[C:20](=[O:22])[NH:19][C:18](=[O:23])[S:17]/2)[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[N:5]=1
Reactant: CSc1nc(C)cc(C(F)(F)F)n1
Reactant: O=C1CSC(=O)N1
Agent: O=[Se]=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSc1nc(/C=C2\SC(=O)NC2=O)cc(C(F)(F)F)n1
Temperature: 90 °C
Reaction time: 40 h
Yield: 27.5 %

Procedure:
A 30 mL round-bottomed vial was charged with 4-methyl-2-(methylthio)-6-(trifluoromethyl)pyrimidine (0.500 g, 2.4 mmol, 1 equiv.), ethanol (5 mL, 0.48 M), selenium dioxide (0.293 mg, 2.6 mmol, 1.1 equiv.), and the reaction mixture was shaken at 90° C. for 40 h and then RT for 14 d. The crude reaction mixture was then treated with thiazolidine-2,4-dione (0.281 g, 2.4 mmol, 1 equiv.), triethylamine (1.0 mL, 7.20 mmol, 3 equiv.) and the reaction mixture was shaken for 16 h at 80° C. The solvent was concentrated under reduced pressure and the residue was partitioned between EtOAc (30 mL) and saturated NaHCO3 (25 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified using the Biotage (SiO2, 10 g cartridge, CH2Cl2/MeOH 99:1 to 9:1) that afforded 270 mg of partially purified product that was re-purified using the Biotage (SiO2, 10 g cartridge, Hexanes/EtOAc 90:10 to 0:1 then CH2Cl2/MeOH 99:1 to 9:1) afforded 212 mg of yellow solid that was still not completely pure but was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:12]2[S:16][C:15]([N:17]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:18][C@@H:19]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.O.C(O)(=O)C>CO.[Pd]>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:12]2[S:16][C:15]([N:17]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:18][C@@H:19]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)=[N:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: CNc1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CNc1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1N
Reaction time: 1 h

Procedure:
The above mentioned tert-butyl (S)-1-(5-(3-(methylamino)-4-nitrophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (1.13 g, 2 mmol) was dissolved in 200 mL MeOH in a 500 mL round bottle flask. To this flask, was added 10% Pd/C 100 mg pre-wet with water and 2 mL acetic acid. The mixture was stirred under an atmosphere of hydrogen under balloon pressure for 1 hour. After filtration through a pad of celite, the solution was evaporated to dryness. The residue was re-dissolved in 200 mL of EtOAc. The solution was washed with saturated sodium bicarbonate three times and dried over sodium sulfate. The product was obtained after removing the solvent. It was used directly in the next step.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH:21]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]2[N:48]=[C:49]([CH3:51])[N:50]=[C:24]12)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[OH:20][CH:21]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[NH:44][C:4](=[O:7])[O:5][N:3]=3)=[CH:35][CH:36]=2)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]2[N:48]=[C:49]([CH3:51])[N:50]=[C:24]12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c2nc(C)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(O)C(C)(C)C)c2nc(C)nn12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogen carbonate (2.5 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.9 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.29 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 7.5 mL) was added and the mixture was stirred at 70° C. for 5 hr. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.59 g, 72%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH-:8])=[O:7].[C:13]1([CH:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=2)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:8][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:20])=[CH:23][CH:24]=1)=[O:30])=[O:7]
Reactant: [NH-]C(=O)c1ccccc1Br
Reactant: CC(Oc1ccc(N=C=O)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(Oc1ccc(NC(=O)NC(=O)c2ccccc2Br)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 g of 50% sodium hydride dispersion in mineral oil was added at room temperature to a solution of 4.0 g of 2-bromobenzoyl amide in 25 ml of dry acetonitrile. After stirring for approximately 30 minutes at room temperature, 4.78 g of 4-(1-phenylethoxy)phenylisocyanate were added, the reaction mixture becoming warm and substantially homogeneous. After stirring for another approximately 16 hours at room temperature the reaction mixture was filtered. The filtrate was acidified with dilute hydrochloric acid. The resulting precipitate was sucked off and washed successively with acetonitrile, ethanol and petroleum ether (40-60). The desired product was obtained in a yield of 1.85 g; the melting point was determined on a "Kofler bank" and was 155.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][C:36]1[C:40]([S:41](Cl)(=[O:43])=[O:42])=[C:39]([CH3:45])[O:38][N:37]=1.O>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:41]([C:40]3[C:36]([CH3:35])=[N:37][O:38][C:39]=3[CH3:45])(=[O:43])=[O:42])[CH2:24][CH2:25]2)[N:3]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)c3c(C)noc3C)CC2)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (75 mg, 0.22 mmol, Example 59) and diisopropylethylamine (2 mL) in tetrahydrofuran (40 mL) was stirred at +5° C. To this was added dropwise 3,5-dimethyl-isoxazole-4-sulfonyl chloride (100 mg, 0.51 mmol, Maybridge). The reaction was stirred at room temperature for 2 hours, poured into water and extracted into methylene chloride (2×50 mL). The combined organic extracts were washed with 5% aqueous sodium bicarbonate. The organic solution was dried (Na2SO4) and solvent was removed under vacuum to give a crude solid. Purification was by silica gel chromatography to give [4-amino-2-[1-(3,5-dimethyl-isoxazole-4-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid. HRMS, observed: 505.1669; Calcd for M+: 505.1664.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:10](Cl)=[N:11][C:12]([Cl:15])=[N:13][CH:14]=1.[CH3:17][O:18][CH2:19][C:20]([NH2:23])([CH3:22])[CH3:21].N1C=CC=NC=1>C(#N)C>[Br:8][C:9]1[C:10]([NH:23][C:20]([CH3:22])([CH3:21])[CH2:19][O:18][CH3:17])=[N:11][C:12]([Cl:15])=[N:13][CH:14]=1
Reactant: COCC(C)(C)N
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: c1cncnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCC(C)(C)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
Triethyl amine (73.1 mL, 526.6 mmol) was added slowly to a solution of 5-Bromo-2,4-dichloro-pyrimidine (40 g, 175.5 mmol) in acetonitrile (400 mL) at 00° C. and then 2-Methoxy-1,1-dimethyl-ethylamine (Preparation 255, 23.4 g, 263.3 mmol) was added to the mixture portion wise. The reaction mixture was stirred for another 16 hours at room temperature. TLC showed the presence of unreacted starting pyrimidine, but the reaction was not continued further. All the volatiles were removed in vacuo and the residue was taken in ethyl acetate, washed with water, brine, dried over sodium sulphate and evaporated to dryness in vacuo. The crude material was purified by column chromatography on silica gel (100-200 mesh, gradient of ethyl acetate:hexane 1:9 to 2:4) to afford the title compound as white solid in 23% yield (10 g of starting pyrimidine was recovered), 12 g.