Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]2=[O:30])=[CH:9][CH:8]=1)(=O)=O.[CH3:33][C:34]1([CH3:41])[C:38]([CH3:40])([CH3:39])[O:37][BH:36][O:35]1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.C1COCC1>[CH3:33][C:34]1([CH3:41])[C:38]([CH3:40])([CH3:39])[O:37][B:36]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]3=[O:30])=[CH:9][CH:8]=2)[O:35]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C[Si](C)(C)CCOCn1c(=O)n(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c2ncccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(-n3c(=O)n(COCC[Si](C)(C)C)c4cccnc43)cc2)OC1(C)C
Temperature: 100 °C

Procedure:
The mixture of 4-(2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl trifluoromethanesulfonate (2.6 g), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.77 mL), triethylamine (2.23 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.218 g) and THF (21.2 mL) was heated at 100° C. for 3 h under microwave irradiation. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro -2H-imidazo[4,5-b]pyridin-2-one (1.5 g) as dark yellow oil.
Reaction SMILES: [C:1]1(=[N:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[CH:13][CH:14]=1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1ccc(N=C2CCCc3ccccc32)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(NC2CCCc3ccccc32)cc1

Procedure:
N-(1,2,3,4-Tetrahydronaphthylidene)-p-carbethoxyaniline (XXVIII) (30 g) prepared by the procedure described in example XXXIIA was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol to give 1-(p-carbethoxy-anilino)-1,2,3,4-tetrahydronaphthalene (XXIX). XXIX had a melting point of 34° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7][C:8]([CH3:11])([NH2:10])[CH3:9])[CH2:2][CH2:3][CH3:4].[C:16](ON1C(=O)CCC1=O)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1>[CH2:1]([N:5]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7][C:8]([NH:10][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:11])[CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)CCC(C)(C)N
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CCCCN(CCCC)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.3 %

Procedure:
Crude N1,N1-dibutyl-3-methylbutane-1,3-diamine (10.18 g, 47.4 mmol) was dissolved into THF (237 mL, 0.2 M). To this solution was added CbzOSu (11.8 g, 1 equiv, 47.4 mmol) in one portion. The reaction was left to stir at room temperature for 17 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (600 mL) and water (200 mL). The layers were separated and the organic layer washed with water (2×300 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on an ISCO purification system with gradient elution from 60-80% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a colorless oil (12.6 g, 76.3%). LRMS (ESI+) for C21H36N2O2 (348.3); Found: 349 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:14]=[C:15]([CH3:23])[C:16]4[N:17]([C:19]([CH3:22])=[N:20][N:21]=4)[CH:18]=3)[C:11](=[O:24])[C:10](=O)[CH:9]2[C:26](=O)[CH2:27][CH3:28])=[CH:4][CH:3]=1.Cl.[CH:31]1([NH:34][NH2:35])[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:26]([CH2:27][CH3:28])=[N:35][N:34]([CH:31]4[CH2:33][CH2:32]4)[C:10]=3[C:11](=[O:24])[N:12]2[C:13]2[CH:14]=[C:15]([CH3:23])[C:16]3[N:17]([C:19]([CH3:22])=[N:20][N:21]=3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: NNC1CC1
Reactant: CCC(=O)C1C(=O)C(=O)N(c2cc(C)c3nnc(C)n3c2)C1c1ccc(Cl)cc1
Agent: Cl
Product: CCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 68 using 5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-propionylpyrrolidine-2,3-dione (Step 70.1) and cyclopropylhydrazine hydrochloride. Further purification by preparative achiral SFC (4-ethyl-pyridine, gradient 13-18% in 6 min_total 11 min) to afford the title product as colorless foam. tR: 1.02 min (LC-MS 2); ESI-MS: 447 [M+H]+ (LC-MS 2); Rf=0.36 (EtOAc/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.6 Hz, 3H) 1.03-1.11 (m, 2H) 1.21-1.32 (m, 2H) 2.29 (dt, J=15.0, 7.6 Hz, 1H) 2.38 (dt, J=15.1, 7.7 Hz, 1H) 2.45 (s, 3H) 2.64 (s, 3H) 3.85 (tt, J=7.4, 3.8 Hz, 1H) 6.48 (s, 1H) 7.28-7.42 (m, 5H) 8.45 (s, 1H).
Reaction SMILES: [N:1]1([CH:7]2[CH:12]3[CH:8]2[CH2:9][N:10]([C:13]2[N:18]=[CH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][N:14]=2)[CH2:11]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.O>[N:1]1([CH:7]2[CH:8]3[CH:12]2[CH2:11][N:10]([C:13]2[N:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][N:18]=2)[CH2:9]3)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cnc(N2CC3C(C2)C3N2CCOCC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(N2CC3C(C2)C3N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 2-(6-morpholin-4-yl-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxylate (16 mg, 0.05 mmol) was dissolved in THF (1 ml) and a solution of 6M NaOH in water (0.5 ml) was added. The reaction was stirred at r.t. for 18 h. More 6M NaOH (0.5 ml) was added and the reaction stirred for a further 24 h. The reaction mixture was evaporated to leave only the aqueous portion, which was acidified to pH˜1 using 10% aq. HCl, then evaporated to dryness and used in the next step without further purification. LCMS purity 100%, m/z 291 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].O>N1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH:10][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[F:11]
Reactant: NNc1ccccc1Cl
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(NNc1ccccc1Cl)c1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
To a stirred solution, under nitrogen, of 89.5 g of 2-chlorophenylhydrazine hydrochloride in 600 ml of pyridine, cooled in an ice bath, was added, dropwise, 87.2 g of 2-fluorobenzoyl chloride, such that the reaction temperature did not exceed 15° C. The reaction mixture was stirred at ambient temperature for 16 hours and then poured into water. Crystallization of the resultant oil was induced by scratching. Recrystallization from toluene yielded 65.7 g (60%) of 2-fluorobenzoic acid, 2-(2-chlorophenyl)hydrazide, m.p. 105°-107° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2[nH]c(-c3ccc(O)cc3)nc2C(=O)Nc2nccs2)cc1
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2[nH]c(-c3ccc(OCCN(C)C)cc3)nc2C(=O)Nc2nccs2)cc1

Procedure:
2-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 2-dimethylaminoethanol, triphenylphosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 2-(4-(2-dimethylaminoethyloxy)phenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14](=[O:19])[NH:15][CH:16]1[CH2:18][CH2:17]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:16]1([NH:15][C:14]([C@@H:9]2[C@@H:10]([OH:13])[CH2:11][CH2:12][NH:8]2)=[O:19])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)NC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CC1)[C@H]1NCC[C@@H]1O
Yield: 99.3 %

Procedure:
A solution of (2S,3S)-2-cyclopropylcarbamoyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (5.6 g) in 30% of TFA in DCM (50 mL) was stirred at rt for 2 hours. The reaction was concentrated to give 3.5 g of (2S,3S)-3-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide as a TFA salt.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11]/[N:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:6][C:5]=1[Br:24].[OH-].[Na+]>>[Br:24][C:5]1[CH:6]=[C:7]([CH2:10][O:11]/[N:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:25])=[O:2]
Reactant: COC(=O)c1ccc(CO/N=C/c2ccc(C(C)(C)C)cc2)cc1Br
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(/C=N/OCc2ccc(C(=O)O)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 2-bromo-4-[({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)methyl]benzoic acid methyl ester (0.43 g, 1.07 mmol), in 10/5/3 tetrahydrofuran/ethanol/water (24 mL) was added 2.5 M sodium hydroxide solution (4 mL). This mixture was heated to reflux for 3 hours and then allowed to cool back to room temperature. The mixture was concentrated to approximately ¼ volume and partitioned between ethyl acetate and brine. The aqueous layer was acidified to approximately pH 1 using 1 N hydrochloric acid. The layers were then separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was dissolved in hot methylene chloride and crystallized out by the addition of room temperature hexanes (60 mL), and allowing the mixture to sit for 2 hours to give 2-bromo-4-[({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)methyl]benzoic acid (0.39 g, 94%) as a white solid. mp=162-163° C. 1H NMR (500 MHz, DMSO-d6); δ 13.35 (bs, 1H), 8.31 (s, 1H), 7.74 (d, 1H), 7.71 (s, 1H), 7.52 (d, 2H), 7.46 (d, 1H), 7.42 (d, 2H), 5.19 (s, 2H), 1.26 (s, 9H). Mass spec (MW 390.28); (ES+) m/z 390.0, (ES−) m/z 388.3. Elemental analysis; Calculated for C19H20BrNO3: C, 58.47; H, 5.17; N, 3.59. Found: C, 57.99; H, 5.03; N, 3.41.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[ClH:18].CCOC(C)=O>CC#N>[ClH:18].[CH3:1][N:2]([CH3:17])[CH2:3][C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CN(C)C(=O)C1(c2ccccc2)CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(C)CC1(c2ccccc2)CCCCC1

Procedure:
The title compound was synthesized from N,N-dimethyl-1-phenylcyclohexanecarboxamide (200 mg, 0.87 mmol) using General Procedure E, followed by HCl salt formation. The crude HCl salt was rechrystallized from 2:1 EtOAc:CH3CN to give N,N-dimethyl(1-phenylcyclohexyl)methanamine hydrochloride as an analytically pure off-white solid (8 mg, 4%). HPLC Rt=8.55 min; 1H NMR (400 mHz, MeOH-d4) 7.30 (q, 4H), 2.30 (s, 2H), 2.09-2.06 (m, 2H), 1.97 (s, 6H), 1.60-1.25 (m, 10H); LC-MS 8.09 min, (M+1)+ 252 @ 8.15 min. HPLC Rt=8.03 min; 1H NMR (400 mHz, MeOH-d4) 7.48-7.39 (m, 4H), 7.29-7.28 (m, 1H), 3.34 (d, J=2.57 Hz, 2H), 2.46 (d, J=3.30 Hz, 6H), 2.29-2.26 (m, 2H), 1.67-1.39 (m, 8H); LC-MS 6.62 min, (M+1)+ 218 @ 6.80 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].CC(C)([O-])C.[K+].I[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([NH:26][C:27]([CH:29]3[CH2:31][CH:30]3[CH3:32])=[O:28])[N:25]=2)[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:9][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([NH:26][C:27]([CH:29]3[CH2:31][CH:30]3[CH3:32])=[O:28])[N:25]=2)[N:22]=1
Reactant: Cc1ccc(O)cc1N
Reactant: CC1CC1C(=O)Nc1cn2nc(I)ccc2n1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4C)cn3n2)cc1N
Yield: 56 %

Procedure:
Using 3-amino-4-methylphenol (1.08 g, 8.77 mmol), N,N-dimethylformamide (30.0 mL), potassium tert-butoxide (1.02 g, 9.13 mmol), N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methylcyclopropanecarboxamide (2.5 g, 7.31 mmol) and potassium carbonate (0.51 g, 3.65 mmol), and in the same manner as in Example 216, the title compound (1.38 g, 56%) was obtained as a brown powder.
Reaction SMILES: C([NH:9][C:10]1[O:11][C@H:12]([C:35]([F:38])([F:37])[F:36])[CH2:13][C@:14]([C:17]2[CH:18]=[C:19]([NH:24][C:25]([N:27]3[CH2:32][CH2:31][CH:30]([O:33][CH3:34])[CH2:29][CH2:28]3)=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])([CH3:16])[N:15]=1)(=O)C1C=CC=CC=1.N12CCCN=C1CCCCC2>CO>[NH2:9][C:10]1[O:11][C@H:12]([C:35]([F:36])([F:38])[F:37])[CH2:13][C@:14]([C:17]2[CH:18]=[C:19]([NH:24][C:25]([N:27]3[CH2:28][CH2:29][CH:30]([O:33][CH3:34])[CH2:31][CH2:32]3)=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])([CH3:16])[N:15]=1
Reactant: COC1CCN(C(=O)Nc2ccc(F)c([C@]3(C)C[C@@H](C(F)(F)F)OC(NC(=O)c4ccccc4)=N3)c2)CC1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COC1CCN(C(=O)Nc2ccc(F)c([C@]3(C)C[C@@H](C(F)(F)F)OC(N)=N3)c2)CC1
Temperature: 60 °C
Yield: 50.9 %

Procedure:
To a solution of N-(3-((4S,6S)-2-benzamido-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-4-methoxypiperidine-1-carboxamide (0.166 g, 0.309 mmol) in MeOH (3 mL) at room temperature was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.100 mL, 0.669 mmol). The reaction was heated at 60° C. for 4 h. Then the reaction was cooled to room temperature, diluted with MeOH, purified by reverse-phase HPLC (Gilson; Gemini-NX 10m C18 110A AXIA, 100×50 mm column) eluting with 0.1% TFA-H2O:0.1% TFA CH3CN (9:1→1:9). The fractions containing the desired product were combined and concentrated in vacuo. The material was dissolved in MeOH and eluted with MeOH, through an Silicycle carbonate cartridge to give the titled compound as a white crystalline solid (68 mg, 51%). MS m/z=433 [M+H]+. Calculated for C19H24F4N4O3: 432
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH:10]([C:12](OCC3CC3)=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30]([OH:32])=[O:31])[CH:23]=[CH:24][CH:25]=1>ClCCCl.S(Cl)(Cl)=O>[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30]([O:32][C:12](=[O:13])[C@@H:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:11]2)=[O:31])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: O=C(OCC1CC1)C1CCC(c2ccccc2)N1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)OC(=O)[C@@H]2CCC(c3ccccc3)N2)c1

Procedure:
By proceeding in a fashion similar to that described in Example 1, but starting from 2 g of cyclopropyl-methyl (2RS,5SR)-5-phenylprolinate, 1.7 g of 2-[3-(3-methylphenyl)ureido]acetic acid in suspension in 50 cm3 of anhydrous 1,2-dichloroethane and 0.6 cm3 of sulphinyl chloride, 1.1 g of cyclopropylmethyl (2RS,5SR)-1-{2-[3-(3-methylphenyl)ureido}acetyl-5-phenylprolinate, melting at 130° C., are obtained after recrystallization in acetonitrile.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:20]([NH:28]C(=O)C(F)(F)F)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C([O-])([O-])=O.[K+].[K+]>CO>[OH:1][C@@H:2]([C@@H:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: CC(C)(C)OC(=O)NN(CC1CCCCC1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NN(CC1CCCCC1)C[C@@H](O)[C@@H](N)Cc1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, 326 mg (0.669 mmol) of 1-[2(R)-hydroxy-3(S)-(trifluoroacetylamino)-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[tert-butoxycarbonyl]-hydrazine dissolved in 52 ml of MeOH are heated to 70° C., 17 ml of 1M aqueous K2CO3 solution are added dropwise and the mixture is stirred for 16 h at 70° C. The reaction mixture is concentrated by evaporation and the residue is partitioned between 3 portions of methylene chloride, 2 portions of water and brine. Concentration by evaporation of the organic phases which have been dried with Na2SO4 yields the title compound, which is used directly in the next step: 1H-NMR (200 MHz, CD3OD): 1.42 (s, 9 H, Boc), 0.8-2.1 (m, 11 H, cyclohexyl), 2.4-3.0 (m, 6H), 3.1 (m, 1H), 3.54 (m, 1H), 7.28 (m, 5H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([N+:12]([O-])=O)[C:6]=1[CH3:15])(=[O:3])[CH3:2].[H][H]>CO.C(O)C.C(O)(=O)C.[C].[Pd]>[C:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1c(C)ccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: CC(=O)Nc1c(C)ccc(N)c1C

Procedure:
N-Acetyl-2,6-dimethyl-3-nitroaniline (30.6 g; 0.15 mole) was dissolved in a mixture of methanol (100 ml), ethanol (50 ml) and acetic acid (100 ml). To the resulting solution was added 2.0 g of 10% palladium carbon and the mixture was stirred in a stream of hydrogen at room temperature for 26 hours. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol-ether to give 22.0 g (84%) of the title object compound as crystals, m.p. 195°-197° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:4]=1[NH2:5].[N:12]([O-])=O.[Na+]>O>[ClH:1].[C:3]1([CH3:2])[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:4]=1[NH:5][NH2:12]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(NN)c(C)c1
Temperature: -5 °C
Yield: 54 %

Procedure:
A 3.0 L, 3-neck round bottom flask equipped with a mechanical stirrer and an addition funnel was charged with concentrated hydrochloric acid (0.125 L) and deionized water (0.100 L). The solution was cooled to −5° C. in an ice/salt water bath, and 2,4,6-trimethylaniline (70 mL, 0.50 mol, 1.0 equiv.) was added dropwise over 30 minutes; during this time a white precipitate formed. The mixture was stirred for an additional 15-20 minutes before 52.5 mL of a 9.5 M aq. solution of sodium nitrite (70 mL, 0.50 mol, 1.0 equiv.) was added dropwise over 30-45 minutes. The resulting brown solution was allowed to stir for 30 minutes before a 3.3 M solution of stannous chloride dihydrate in 1:1 concentrated HCl:H2O (0.455 L, 1.5 mol, 2.5 equiv.) was added over 4 hours with vigorous stirring. (Upon addition of the stannous chloride solution a thick light orange slurry had formed which sometimes caused seizure of the mechanical stirrer. Addition small amounts of deionized water helped to facilitate stirring again.) The mixture was allowed to warm to room temperature and stirred vigorously for 16 hours. The mixture was cooled to 0° C. for 1 hour before filtering through a fine porosity glass fritted buchner funnel, and the collected orange solid washed with brine and diethyl ether. This orange solid was added to a 2-L round-bottom charged with 10 M NaOH(aq) (1.0 L) and diethyl ether (0.700 L) and cooled to −5° C. Once nearly all of the solid had dissolved (ca. 1 h), the organic layer was removed, and the aqueous layer extracted with diethyl ether (2×0.400 L). The combined organic fractions were dried over Na2SO4, filtered into a flame-dried 2.0 L round-bottom flask, placed under an atmosphere of N2(g), cooled to 0° C., and treated with 4 M HCl in 1,4-dioxane (0.125 L). A white precipitate formed, was collected by vacuum filtration, washed with diethyl ether, and recrystallized from 200 proof EtOH to afford the title compound (50 g, 0.27 mol, 54%) as a white powder. 1H NMR (400 MHz, DMSO) δ 9.57 (3H, s, br, NH, varies), 6.89 (s, 2H), 2.33 (s, 6H), 2.21 (s, 3H); 13C NMR (100 MHz, DMSO) δ 138.06, 136.20, 135.01, 129.17, 20.54, 17.95; IR (thin film) ν 3294, 3002, 2964, 2911, 2680, 1564, 1513, 1481, 852, 825, 753 cm−1; HRESI+/TOF-MS calcd for C9H15N2+ [M]+ 151.1230, found 134.0921 for aniline anion radical (134.0975).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[CH:37]=[CH:36][C:27]([C:28]([NH:30][C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:29])=[CH:26][N:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:25]([O-:9])=[CH:26][C:27]([C:28]([NH:30][C:31]([CH3:33])([CH3:32])[CH2:34][CH3:35])=[O:29])=[CH:36][CH:37]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(C)(C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC(C)(C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)[n+]([O-])c1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(tert-pentyl)nicotinamide (Intermediate 32, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylpropyl)-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:23]=[C:22]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:21]([C:37]([F:40])([F:39])[F:38])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:21]([C:37]([F:40])([F:39])[F:38])=[CH:20][N:19]=2)=[CH:15][CH:16]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 2-(2-((2-(4-(1-(tert-butoxycarbonylamino)ethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate (A64) (353 mg, 0.637 mmol) and Pd/C (10%; 250 mg) in EtOAc (13 mL) was stirred under a hydrogen atmosphere at room temperature overnight. The resulting mixture was filtered through a pad of Celite then the filtrate evaporated under reduced pressure to give the title compound A65 as an off white solid (320 mg, 90%); 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 7.61 (d, J=8.64 Hz, 2H), 7.52 (s, 1H), 7.28 (m, 5H), 4.81 (m. s, 2H), 3.77 (s, 2H), 3.70 (s, 3H), 3.13 (m, 4H), 1.66 (m, 1H, peak obscured), 1.48 (d, J=6.54 Hz, 3H), 1.45 (s, 9H). LCMS-B: rt 9.07 min; m/z 559.5 [M+H]+.