Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]([C:25]([OH:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH2:30](Cl)CCl.CN(C1C=CC=CN=1)C>ClCCl>[C:21]([O:20][C:18]([NH:17][C@H:15]1[CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C@@H:13]([C:25]([O:27][CH3:30])=[O:26])[CH2:14]1)=[O:19])([CH3:23])([CH3:24])[CH3:22]
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of cis (+/−)-1-(benzyloxycarbonyl)-5-(tert-butoxycarbonylamino)piperidine-3-carboxylic acid (1.0 eq), methanol (20 eq.) and EDC (1.3 eq) in dichloromethane at a concentration of 0.25 M at 0*C was added dimethylaminopyridine (0.1 eq). After stirring for 48 hours as the reaction was allowed to warm to rt the volatiles were removed in vacuo. Upon addition of ethyl actetate and washing with H2O (3×), 1N HCl, NaHCO3(sat.) and brine, the solution was dried over MgSO4, filtered, concentrated and purified by column chromatography (25% ethyl acetate/hexanes) to yield cis (+/−)-1-benzyl 3-methyl 5-(tert-butoxycarbonylamino)piperidine-1,3-dicarboxylate. LCMS (m/z): 293.1 (MH-Boc+); LC Rt=4.09 min
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[N:10]=[CH:11][C:12](C(OC)=O)=[C:6]2[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+]>OS(O)(=O)=O>[N:10]1[N:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]2=[CH:12][CH:11]=1
Reactant: COC(=O)c1cnn2ccc(C(C)=O)cc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1ccn2nccc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 38.1 %

Procedure:
A suspension of methyl 5-acetylpyrazolo[1,5-a]pyridine-3-carboxylate (3-2) (90 mg, 0.41 mmol) dissolved in 50% H2SO4 (2 mL) was stirred at 80° C. for 3 h. After cooled to 0° C., the solution was treated with 5N NaOH solution, and then extracted with Et2O. The organic layer was separated, dried, concentrated and purified by flash chromatography to afford the title compound (25 mg).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2].[C:32]([O:35][CH2:36][C:37](Cl)=[O:38])(=[O:34])[CH3:33]>C(#N)C.CCOC(C)=O>[C:32]([O:35][CH2:36][C:37]([NH:14][C:13]1[C:12]2[C:7](=[N:8][C:9]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:10]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH:11]=2)[N:6]([CH3:30])[C:5](=[O:31])[C:4]=1[C:1](=[O:3])[CH3:2])=[O:38])(=[O:34])[CH3:33]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)OCC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 90 °C

Procedure:
To the product of Example 2 (120 mg) in acetonitrile (2 mL) was added acetoxyacetyl chloride (0.2 mL). The reaction was heated to 90° C. in a CEM microwave reactor for a total of 34 minutes. The reaction was diluted with EtOAc and was washed with saturated aqueous NaHCO3 solution. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-60% EtOAc in hexane affording the title compound. HPLC/MS: 572.1 (M+1), 574.1 (M+3); Rt=4.06 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C:26]([NH2:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:34][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC(=O)c1ccccc1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)c3ccccc3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and benzamide. MS obsd. (ESI+) [(M+H)+] 458, 1H NMR (400 MHz, CD3OD) δ ppm 8.64 (s, 1 H), 8.09-8.04 (m, 5 H), 7.89-7.87 (d, J=8.4 Hz, 1 H), 7.75-7.67 (m, 3 H), 7.62-7.55 (m, 3 H), 5.34 (s, 2 H), 4.62 (s, 2 H), 3.76 (s, 2 H), 2.53 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)[CH:3]=1.Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-]>CN1C(=O)CCC1.CCOC(C)=O>[C:24]([Si:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][N:6]1[C:2]([CH3:1])=[CH:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)=[N:5]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1cc(-c2ccc(C)c([N+](=O)[O-])c2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2cc(C)n(CCO[Si](C)(C)C(C)(C)C)n2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 5-Methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole, 2-bromoethoxy tertbutyldimethylsilane, Cs2CO3 and NaI in NMP was heated in a microwave oven at 100° C. for 1 hour, and then cooled to room temperature. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by “flash chromatography” (0 to 30% EtOAc in hexanes to give 867 mg of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole as an oil that also contained 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-methyl-5-(4-methyl-3-nitro-phenyl)-1H-pyrazole as a minor product.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH:17]1([C:20]2[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=2)[CH2:19][CH2:18]1>C(Cl)(Cl)Cl>[CH:17]1([C:20]2[NH:24][N:23]=[C:22]([NH:25][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:3]=3)[CH:21]=2)[CH2:19][CH2:18]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1cnc(-c2ccccc2)nc1Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 23 °C
Reaction time: 6 h
Yield: 45.6 %

Procedure:
To a suspension of 4-chloro-5-nitro-2-phenylpyrimidine (800 mg, 3.40 mmol, 1.0 eq) in CHCl3 (20 mL) was added 5-cyclopropyl-1H-pyrazol-3-amine (832 mg, 6.80 mmol, 2.0 eq). The reaction mixture was stirred for 6 hours at 23° C. The precipitate was filtered and recrystallized to give the desired product N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitro-2-phenylpyrimidin-4-amine (Compound 6) (500 mg, 45.7%). LC-MS (m/z): 323.0 [M+H]+. 1H-NMR (300 MHz, DMSO-d6): δ 0.73-0.78 (m, 2H), 0.96-1.01 (m, 2H), 1.96-2.01 (m, 1H), 6.53 (s, 1H), 7.55-7.63 (m, 3H), 8.35-8.38 (m, 2H), 9.33 (s, 1H), 10.26 (s, 1H), 12.50 (s, 1H).
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)=[O:5].CS(O)(=O)=[O:18]>>[NH:6]1[C:7]2[C:15](=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH2:10][CH2:11]3)[C:3](=[O:18])[C:4]1=[O:5]
Reactant: O=C(C=NO)Nc1cccc2c1CCC2
Reactant: CS(=O)(=O)O
Product: O=C1Nc2c(ccc3c2CCC3)C1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 72 %

Procedure:
Add 2-Hydroxyimino-N-indan-4-yl-acetamide (5.54 g, 27.1 mmol) in small portions at 80° C. to methanesulfonic acid (21 mL). Stir the mixture at this temperature for 25 min. Cool to room temperature, pour into ice water and filter the precipitate. Dissolve the solid in warmed 1N NaOH, and neutralize with acetic acid. Filter the resulting solid and acidify the filtrate with concentrated HCl. Filter the precipitate and wash with water. Dry the solid to yield the title compound (3.80 g, 72%). MS (ES−): 186 (M−H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[CH:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[NH:26][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C1CCCC1
Product: O=[N+]([O-])c1ccc(CNC(c2ccc(C(F)(F)F)cc2)C2CCCC2)cc1
Yield: 67 %

Procedure:
The same procedure as employed in the preparation of Example 223 (step b) but using cyclopentyl[4-(trifluoromethyl)phenyl]methanone and 4-nitrobenzylamine gave the title compound as an oil (67%). M−(LC/MS(ESI)): 377.2; M+(LC/MS(ESI)): 379.2
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:41][O:42][CH2:43][S:44]([C:47]1[CH:48]=[C:49]([OH:54])[C:50](=[CH:52][CH:53]=1)[OH:51])(=[O:46])=[O:45]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:41]/[O:42][CH2:43][S:44]([C:47]2[CH:53]=[CH:52][C:50]([OH:51])=[C:49]([OH:54])[CH:48]=2)(=[O:45])=[O:46])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCS(=O)(=O)c1ccc(O)c(O)c1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Yield: 93.4 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (80 mg) (0.135 mmol) and 45 mg (0.176 mmol) of 4-[[(aminooxy)-methyl]sulphonyl]pyrocatechol hydrochloride are dissolved in 4 ml of absolute dimethyl-acetamide. After stirring at room temperature for 24 hours a further 14 mg (0.06 mmol) of 4-[[(aminooxy)-methyl]sulphonyl]-pyrocatechol hydrochloride are added. After a further 24 hours the solvent is removed in a high vacuum at room temperature and the residue is treated with 4 ml of water. The precipitated product is filtered off under suction and washed in succession with water and diethyl ether. There are obtained 100 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[[2-(hydroxy-carbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[CH:20]=[C:19]([CH2:21][CH3:22])[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[CH:20]=[C:19]([CH2:21][CH3:22])[S:18][C:16]=2[N:17]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[NH:22][C:21](=[O:23])[C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:19][C:18](=[O:28])[C@@H:17]([NH2:29])[CH2:16][C:15]2=[CH:30][CH:31]=[C:12]([CH:13]=[CH:14]2)[O:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].CCN(C(C)C)C(C)C.CCOC(C)=O.C(Cl)Cl>CN(C=O)C>[CH3:2][O:3][C:4]([C@H:6]1[NH:22][C:21](=[O:23])[C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:19][C:18](=[O:28])[C@@H:17]([NH:29][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:16][C:15]2=[CH:30][CH:31]=[C:12]([CH:13]=[CH:14]2)[O:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Amine 6 (4.00 g, 8.78 mmol) was dissolved in anhydrous DMF (30 mL). Benzyl chloroformate (1.88 mL, 13.2 mmol) and DIPEA (6.11 mL, 35.1 mmol) were added and the reaction mixture was stirred at rt for 18 h before being partitioned between chloroform and 1M hydrochloric acid. The aqueous phase was extracted three more times with chloroform and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 15% EtOAc/DCM to 50% EtOAc/DCM to yield an off-white solid, 2.10 g, 43%. Rf=0.43 (30% EtOAc/DCM).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:14]2[CH:20]=[CH:19][CH:18]=[C:16]([NH2:17])[CH:15]=2)=[CH:5][C:4]=1[F:12])#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Nc1cccc(Br)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cccc(N)c2)cc1F
Temperature: 25 °C
Yield: 98 %

Procedure:
4-cyano-3-fluorophenyl boronic acid (0.144 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in dioxane (2 mL) in a flame-dried, round-bottom flask. K3PO4 (1.27M, 0.778 mL, 0.99 mmol), PCy3 (0.004 g, 0.014 mmol), and Pd2(dba)3 (0.005 g, 0.006 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (5-60% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.120 g in 98% yield.
Reaction SMILES: [OH:1][C@H:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[C:15]([C:17]([NH:19][CH:20]([CH:25]([CH3:27])[CH3:26])[C:21]([O:23]C)=[O:22])=[O:18])[O:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1>[OH:1][C@H:2]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:16]=[C:15]([C:17]([NH:19][CH:20]([CH:25]([CH3:26])[CH3:27])[C:21]([OH:23])=[O:22])=[O:18])[O:14][N:13]=2)=[CH:10][CH:11]=1)=[O:4]
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)[C@H](O)c3ccccc3)cc2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(NC(=O)c1cc(-c2ccc(NC(=O)[C@H](O)c3ccccc3)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To Methyl 2-(3-(4-((R)-2-hydroxy-2-phenylacetamido)phenyl)isoxazole-5-carboxamido)-3-methylbutanoate (135 mg) in THF (4 ml) 1 M aqueous solution of Lithium hydroxide monohydrate (0.6 ml) was added and reaction mixture was stirred at RT for 6 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was collected and dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized from EtOAc to obtain the title compound as white solid. Yield: 80 mg (61%); MS (ES+): m/z 438 (M+1); 1HNMR (DMSO-d6; 300 MHz): δ 12.86 (bs, 1H), 10.2 (s, NH), 8.97 (d, 1H), 7.88 (d, 4H), 7.7 (s, 1H), 7.54 (m, 2H), 7.39-7.29 (m, 3H), 6.51 (d, 1H), 5.13 (d, 1H), 4.27 (m, 1H), 2.19 (m, 1H), 0.97 (d, 6H).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([CH2:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]O)([O:7][CH3:8])=[O:6]>CCOCC>[C:5]([CH2:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][Cl:3])([O:7][CH3:8])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)COc1ccccc1CO
Solvent: CCOCC
Product: COC(=O)COc1ccccc1CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Thionyl chloride (0.48 mol) is added to an ether solution (1L) containing 2-carbomethoxymethoxybenzyl alcohol (0.4 mol), and a small amount of dimethylformanide (0.5 mL). The reaction is stirred at ambient temperature for 12 h, after which it is evaporated and the residue diluted again with ether (1L). This ether solution is washed with 2% sodium hydrogen carbonate solution (3X's) and then dried (magnesium sulfate). The solvent is removed to give 2-carbomethoxymethoxybenzyl chloride which is used directly in Step E.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:18]([Si:15]([CH3:17])([CH3:16])[O:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(CCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a stirring cooled (0° C.) solution of 4-[4-(tert-butyl-dimethyl-silanyloxy)-butyl]-benzoic acid methyl ester (0.80 g, 2.48 mol) in THF (5.5 mL) was added dropwise a solution of lithium aluminum hydride (4.96 mL, 1M in THF). After completion of addition the reaction mixture continued to stir at room temperature. After 2 hours, the reaction mixture was quenched with water. The aqueous layer was extracted with ethyl acetate. All combined organic layers were dried over Na2SO4, filtered, and concentrated to yield a yellow oil. The crude material was purified using silica gel chromatography (1:2 ethyl acetate:hexanes) to afford {4-[4-(tert-butyl-dimethyl-silanyloxy)-butyl]-phenyl}-methanol (0.65 g, 2.21 mol, 89% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[Br:26][CH2:27][CH2:28][CH2:29]Cl.O>CC(C)=O>[Br:26][CH2:27][CH2:28][CH2:29][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([CH3:25])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(C)(CC(=O)c2ccccc2)c2ccccc2)ccc1O
Reactant: ClCCCBr
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C(C)(CC(=O)c2ccccc2)c2ccccc2)ccc1OCCCBr
Yield: 85.5 %

Procedure:
Fifty grams (0.15 mol) of 4-hydroxy-3,5-dimethyl-β,β-diphenylpropiophenone (prepared as in Example 5), dissolved in 200 mls of acetone, are added, with stirring, to a reaction mixture consisting of 29 grams (0.184 mol) of 1-bromo-3-chloropropane in 300 mls of acetone and 42 grams (0.304 mol) of water-free potash. The preparation is boiled under reflux for one day and the precipitate is sucked off. The acetone is evaporated, the residue taken up with ether and a little acetone and, subsequently, washed with water. The ethereal phase is dried over sodium sulfate. The solvent is evaporated in vacuo. The residue is crystallized from acetone/petroleum ether. Fifty-two and five-tenths grams [85.5%] of 4-(3-bromopropoxy)-3,5-dimethyl-β,β-diphenylpropiophenone are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH:9]=1)[NH2:8].[Br:13][C:14]1[CH:21]=[C:20]([F:22])[C:17]([CH2:18]N)=[C:16]([F:23])[CH:15]=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:13][C:14]1[CH:21]=[C:20]([F:22])[C:17]([CH2:18][NH:8][C:7]2[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N+:10]([O-:12])=[O:11])=[C:16]([F:23])[CH:15]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Reactant: NCc1c(F)cc(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(NCc2c(F)cc(Br)cc2F)c1
Temperature: 140 °C
Yield: 80.4 %

Procedure:
A mixture of 5-methoxy-2-nitroaniline (513 mg, 3 mmol), 4-bromo-2,6-difluorobenzyl amine (616 g, 3 mmol), DIPEA (1.55 mL, 9 mmol) and acetonitrile (10 mL) was heated to 130-150° Celsius for 16 h. The mixture was then cooled to RT and concentrated to dryness. To the residue was added H2O (100 mL) and the resulting solid was collected by filtration and dried to afford the title compound (900 mg, 80.1%).
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[C:15]([N:17]3[CH:21]=[N:20][C:19]([NH:22][C:23]4[CH:31]=[CH:30][C:26](C(O)=O)=[CH:25][CH:24]=4)=[N:18]3)[CH:14]=[CH:13][N:12]=2)[CH2:6][CH:5]1[CH3:32])(=[O:3])[CH3:2].CC[N:35](C(C)C)C(C)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(O)(C(F)(F)F)=O.Cl>CN1C(=O)CCC1.CO>[NH2:35][C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:19]2[N:20]=[CH:21][N:17]([C:15]3[CH:14]=[CH:13][N:12]=[C:11]([N:7]4[CH2:6][CH:5]([CH3:32])[N:4]([C:1](=[O:3])[CH3:2])[CH:9]([CH3:10])[CH2:8]4)[CH:16]=3)[N:18]=2)=[CH:24][CH:25]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)N1C(C)CN(c2cc(-n3cnc(Nc4ccc(C(=O)O)cc4)n3)ccn2)CC1C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1C(C)CN(c2cc(-n3cnc(Nc4ccc(N)cc4)n3)ccn2)CC1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a solution of 8 g of 4-{1-[2-(4-Acetyl-3,5-dimethyl-piperazin-1-yl)-pyridin-4-yl]-1H-[1,2,4]triazol-3-ylamino}-benzoic acid (18.3 mMol, 1.00 equiv) in 150 mL of NMP was added 9 mL of Hunig's base followed by 6 g of DPPA (21.8 mMol, 1.19 equiv). The reaction was stirred for 30 min at 25° C. To the reaction mixture was then added 200 mL of TFA and the resulting solution was warmed to 90° C. for 12 hr. After cooling to 25° C., the reaction was quenched with 200 mL of concentrated ammonium hydroxide and concentrated. The resulting oil was triturated with CH2Cl2 and the solid was isolated by filtration. The solid was then dissolved in MeOH (100 mL) and concentrated to 50 mL. The resulting precipitate was isolated and treated with 50 mL of 1 N HCl and concentrated via rotary evaporation. The oil was triturated with ethanol and the resulting solid was removed by filtration. The ethanol solution was concentrated to give 2.5 g of 1-(4-{4-[3-(4-Amino-phenylamino)-[1,2,4]triazol-1-yl]-pyridin-2-yl}-2,6-dimethyl-piperazin-1-yl)-ethanone (6.15 mMol, 33.6% yield) as the HCl salt. 1H NMR (500 MHz, CDCl3) ∂ 8.39 (1H, s), 8.10 (1H, d), 7.22 (2H, d), 7.15 (2H, d), 6.95 (1H, s), 6.92 (2H, m), 6.75 (1H, m), 6.65 (2H, d), 4.15 (2H, m), 3.08 (2H, m), 2.99 (2H, m), 2.10 (3H, s), 1.30 (6H, m) ppm. LC/MS: 0.54 min/407.3 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH2:11]([N:4]([CH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:3]=1)[C:3]1[CH:5]=[C:6]([CH3:10])[C:7]([I:9])=[CH:8][C:2]=1[CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(I)c(C)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1I
Temperature: 50 °C
Reaction time: 12 h
Yield: 167.7 %

Procedure:
A mixture of 2,5-dimethyl-4-iodoaniline (6.44 g, 26.1 mmol), benzyl bromide (11.50 g, 67.24 mmol) and potassium carbonate (8.20 g, 59.3 mmol) in EtOH (100 mL) was stirred at 50° C. for 12 h. The reaction mixture was then concentrated under reduced pressure. The residue (a purple solid) was mixed with DCM and this mixture was filtered using vacuum. The filtrate was purified by silica gel flash chromatography (0-5% MeOH in DCM) to give the title compound (9.35 g, 83% yield) as an oil.