Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:16][C:17]1[C:22]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3F)[N:27]=[CH:26][N:25]=2)=[C:21]2[O:35][CH2:36][O:37][C:20]2=[CH:19][CH:18]=1>Cl.C(OCC)C>[ClH:16].[ClH:16].[Cl:16][C:17]1[C:22]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:27]=[CH:26][N:25]=2)=[C:21]2[O:35][CH2:36][O:37][C:20]2=[CH:19][CH:18]=1
Reactant: Fc1cccc2ncnc(Nc3c(Cl)ccc4c3OCO4)c12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: Cl
Solvent: CCOCC
Product: Clc1ccc2c(c1Nc1ncnc3cccc(OCC4CCNCC4)c13)OCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Using an analogous procedure to that described in Example 37, N-(tert-butoxycarbonyl)piperidin-4-ylmethanol was reacted with 4-(6-chloro-2,3-methylenedioxyanilino)-5-fluoroquinazoline (0.1 g). The product so obtained was dissolved in a 2M solution of hydrogen chloride in diethyl ether (20 ml) and stirred at ambient temperature for 3 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The solid so obtained was washed with diethyl ether and dried under vacuum. There was thus obtained the tilte compound (0.121 g); NMR Spectrum: (DMSOd6) 1.5–1.6 (m, 2H), 1.9–2.0 (m, 2H), 2.3–2.4 (m, 1H), 2.8–2.9 (m, 2H), 3.3 (d, 2H), 4.42 (d, 2H), 6.15 (s, 2H), 7.07 (d, 1H), 7.15 (d, 1H), 7.53 (m, 2H), 8.06 (m, 1H), 8.87 (s, 1H), 10.57 (br s, 1H); Mass Spectrum: M+H+ 413 and 415.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:28])[CH2:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[S:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:18][C:15]2[S:16][CH:17]=[C:13]([CH2:12][C:11]([N:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][NH:29][CH2:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:6][CH2:7]3)=[O:28])[N:14]=2)=[O:27])=[CH:21][CH:22]=1
Reactant: NCC1CCCCC1
Reactant: O=C(Nc1nc(CC(=O)N2CCN(C(=O)CBr)CC2)cs1)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1nc(CC(=O)N2CCN(C(=O)CNCC3CCCCC3)CC2)cs1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
55.2 To a stirred mixture of 100 mg N-(4-{2-[4-(2-bromo-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-4-chloro-benzamide in 5 ml THF at r.t. were added 0.04 ml (aminomethyl)cyclohexane and 0.09 ml triethylamine. After 48 hrs stirring at r.t. under argon atmosphere, the reaction mixture was concentrated. The crude product was purified by chromatography on silica using a gradient from CH2Cl2 to CH2Cl2/MeOH 95:5 in 20 min to give 19 mg 4-chloro-N-[4-(2-{4-[2-(cyclohexylmethyl-amino)-acetyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide. White solid. MS 518.5 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[CH2:8](O)[CH3:9]>>[NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:8][CH3:9])=[O:4]
Reactant: CCO
Reactant: CC(C)(N)C(=O)O
Product: CCOC(=O)C(C)(C)N
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 2-aminoisobutyric acid (3.3 g, 32 mmol) in absolute ethanol (100 mL) was cooled to -78° C. and HCl(g) bubbled in for 10 minutes. The flask was sealed with a septum and stirred at ambient temperature. After 14 hours the mixture was concentrated in vacuo to afford 5.3 g (99% yield) of ethyl 2-aminoisobutyrate as a white solid; NMR (CDCl3) 8.9 (br s, 3), 4.1 (q, 2), 1.7 (s, 6), 1.3 (t, 3) ppm.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.C([O:12][C:13](=O)/[CH:14]=[CH:15]\[O-])C.[Na+]>CCO.C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]3[N:9]=[CH:15][CH:14]=[C:13]([OH:12])[N:7]3[N:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: CCOC(=O)/C=C\[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Oc1ccnc2cc(C3CC3)nn12
Temperature: 80 °C

Procedure:
A mixture of 5-cyclopropyl-1H-pyrazol-3-amine (415 mg, 3.37 mmol) and sodium (Z)-3-ethoxy-3-oxoprop-1-en-1-olate (0.791 g, 5.73 mmol) in EtOH (3 mL) and toluene (1 mL) was heated to 80° C. in a resealable tube. After 16 hrs the solvent was removed in vacuo. The resulting residue was dissolved in a minimal amount of warm water and triturated with 1 N HCl with cooling (0° C.) until the pH ˜1. The resulting solid was filtered and washed with water to afford 2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-ol as an off-white solid that was advanced without further purification. M+H+ found=176.2.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[C:6]=1[C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13].C(N(CC)C(C)C)(C)C.CO.[C:46]([O:49][CH2:50]C)(=[O:48])C>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:50][O:49][C:46]([C:2]1[CH:3]=[N:4][N:5]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[C:6]=1[C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13])=[O:48]
Reactant: CCOC(C)=O
Reactant: Cc1c(-c2c(Br)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cnn(-c2ccc(C#N)cc2)c1-c1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1=O
Temperature: 10 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-bromo-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 93) (50.4 mg) in 1,4-dioxane (1.0 ml) were added bis(tri-tert-butylphosphine)palladium (4.9 mg), N,N-diisopropylethylamine (32.0 L) and methanol (1.0 mL), and the resulting mixture was stirred at 10° C. under carbon monoxide atmosphere for four hours. To the reaction mixture was added ethyl acetate (100 ml) and the resulting mixture was washed with water (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford methyl-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylate (9.4 mg) as white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1)([O-:28])=[O:27]>C(Cl)Cl>[CH2:10]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][C:31]=2[C:39]([F:40])([F:41])[F:42])(=[O:37])=[O:36])[CH2:22][CH2:21]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c(C(F)(F)F)c1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
Diisopropylethylamine (1.2 ml, 7.0 mmol) was added in one portion to a stirred solution of piperazine-1-carboxylic acid benzyl ester (0.76 g, 3.5 mmol) in DCM (15 ml) at room temperature. To this mixture was added 4-nitro-2-trifluoromethyl-benzenesulfonyl chloride (1.0 g, 3.5 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was diluted with DCM (20 ml), washed with HCl (1M, 20 ml) and NaOH (1M, 20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum to give the title compound (1.43 g, 87% yield) as a purple solid. δH (500 MHz, DMSO) 8.65-8.60 (2H, m), 8.31 (1H, d), 7.38-7.29 (5H, m), 5.07 (2H, s), 3.56-3.46 (4H, m), 3.30-3.25 (4H, m). Tr=2.25 min m/z (ES+) (M+Na+) 496.
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[NH2:13])=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[NH2:2].[N+:14]([C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=1)[CH:20]=[C:21]([C:30]([CH3:32])=O)[C:22]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])=[O:23])([O-:16])=[O:15].C(OC(C)C)(C)C.CCCCCC>C(O)(C)C>[C:1]([O:4][CH2:5][C:6]1[NH:13][C:30]([CH3:32])=[C:21]([C:22]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])=[O:23])[CH:20]([C:19]2[CH:33]=[CH:34][CH:35]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[NH2:2]
Reactant: CCOCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: CCOC(=O)/C=C(\N)COC(N)=O
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Product: CCOCCOC(=O)C1=C(C)NC(COC(N)=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 54 %

Procedure:
9.4 g (50 millimoles) of ethyl 4-carbamoyloxy-3-aminocrotonate and 15.4 g (50 millimoles) of β-ethoxyethyl 2-(m-nitrobenzylidene)acetoacetate were dissolved in 200 ml of isopropyl alcohol and reacted at a temperature of from 60° to 70° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was crystallized from diisopropylether-hexane, whereby 12.9 g (yield: 54%) of 2-carbamoyloxymethyl-6-methyl-4-(m-nitrophenyl)-3-ethoxycarbonyl-5-(β-ethoxyethoxy)carbonyl-1,4-dihydropyridine in crystal form was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[CH:11]=[CH:10][C:9]3[O:8][CH2:7][C:6]4[CH:12]=[C:13]([C:15]([N:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH3:18])=[O:16])[S:14][C:5]=4[C:4]=3[CH:3]=2)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2ccc3c(c2)-c2sc(C(=O)N(C)c4ccc(F)cc4F)cc2CO3)CC1

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and 1-acetylpiperazine were reacted to give 120bp. 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 1H), 6.82-6.93 (m, 5H), 5.99 (s, 1H), 5.01 (s, 2H), 3.86 (m, 2H), 3.73 (m, 2H), 3.32 (s, 3H), 3.21 (m, 2H), 3.16 (m, 2H), 2.13 (s, 3H). LCMS (ESI) m/z: 484.1
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH:21]([OH:28])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:29](O)[CH:30]([OH:32])[CH3:31]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]3([CH3:2])[O:32][CH:30]([CH3:31])[CH2:29][O:3]3)=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[C:15]([C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[O:28])[CH:16]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(O)c2ccncc2)cc1
Reactant: CC(O)CO
Product: CC1COC(C)(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3ccncc3)cc2)O1

Procedure:
The title compound was prepared using 4-Acetyl-N-[4-chloro-2-(hydroxy-pyridin-4-yl-methyl)-phenyl]-benzenesulfonamide and propane-1,2-diol following the procedure described in the preceding example. MS: m/z 473 M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])=O)[C:5]([CH3:12])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2.[H][H]>C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])[C:5]([CH3:12])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2
Reactant: [H][H]
Reactant: Cc1c(C(=O)c2ccccc2C(=O)O)cc(F)c2c1CCCO2
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1c(Cc2ccccc2C(=O)O)cc(F)c2c1CCCO2

Procedure:
A mixture of 2-(8-fluoro-5-methylchroman-6-carbonyl)benzoic acid (673 mg, 2.141 mmol) in acetic Acid (15 mL) was treated with Pd/C (60.0 mg) and the mixture was stirred under 50 psi of hydrogen at 65° C. until the reaction was judged complete by LCMS. The mixture was filtered over Celite and the filtrate was concentrated to give the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80-2.05 (m, 5 H), 2.63 (t, J=6.44 Hz, 2 H), 3.95-4.15 (m, 2 H), 4.24 (s, 2 H), 6.57 (d, J=12.29 Hz, 1 H), 6.95 (d, J=7.61 Hz, 1 H), 7.21-7.34 (m, 1 H), 7.42 (td, J=7.56, 1.27 Hz, 1 H), 7.81 (dd, J=7.71, 1.07 Hz, 1 H), 12.92 (br. s., 1H); LC/MS (m/z) ES+=301 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(Cl)cc1

Procedure:
The 1-benzyl-4-aminopiperidine prepared in Example 30 was treated with p-chlorobenzoyl chloride in a similar manner to that described in the sameexample and the product converted to a salt.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:36])[CH2:15][CH:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[CH2:29][C:28]([CH3:31])([CH3:30])[NH:27][C:26]([CH3:33])([CH3:32])[CH2:25]3)=[CH:19][CH:18]=2)[CH2:13][C:12]([CH3:35])([CH3:34])[NH:11]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC)=O>[CH2:1]([N:27]1[C:26]([CH3:33])([CH3:32])[CH2:25][CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][CH:14]3[CH2:13][C:12]([CH3:35])([CH3:34])[N:11]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:10]([CH3:36])([CH3:9])[CH2:15]3)=[CH:22][CH:21]=2)[CH2:29][C:28]1([CH3:31])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(Cc2ccc(CC3CC(C)(C)NC(C)(C)C3)cc2)CC(C)(C)N1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1(C)CC(Cc2ccc(CC3CC(C)(C)N(Cc4ccccc4)C(C)(C)C3)cc2)CC(C)(C)N1Cc1ccccc1

Procedure:
8.72 g of benzyl bromide were added dropwise in the course of one hour to a mixture of 9.6 g of 1,4-bis-(2,2,6,6-tetramethylpiperidin-4-yl-methyl)-benzene (compound No. 9) 7.6 g of finely powdered potassium carbonate and 0.5 g of potassium iodide in 50 ml of ethyl methyl ketone, at the boil (bath temperature about 100° C.), whilst stirring, and the reaction mixture was stirred at this temperature for a total of 96 hours. For working up, the reaction mixture was filtered at the boiling point to remove the sediment (potassium bromide and a little potassium carbonate) and the filter residue was repeatedly rinsed with dichloromethane. The combined filtrates were freed from the solvent in vacuo, and the crystalline residue was recrystallised from ethyl methyl ketone to yield 1,4-bis(1-benzyl-2,2,6,6-tetramethylpiperidin-4-yl-methyl)-benzene, m.p. 207°-208° C. (compound No. 15).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.CN1CCCC1=O.[Cl:29][CH2:30][C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:6]([C:12]#[N:13])=[CH:7][N:8]=[C:9]3[C:4]=2[CH:3]=[C:2]([NH:1][C:31](=[O:32])[CH2:30][Cl:29])[CH:11]=[N:10]3)[CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1cnc2ncc(N)cc2c1Nc1cccc(Br)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: N#Cc1cnc2ncc(NC(=O)CCl)cc2c1Nc1cccc(Br)c1
Temperature: 0 °C
Yield: 76.4 %

Procedure:
To a solution of 0.74 g (2.2 mmol) of 6-amino-4-(3-bromo-phenylamino)-[1.8]naphthyridine-3-carbonitrile and 0.7 g (5.44 mmol) of disopropylethyl amine in a 7 ml of N-methylpyrrolidone was added with stirring at 0° C. a solution of 0.29 g (2.6 mmol) of chloroacetyl chloride in 5 ml of tetrahydrofuran over 5 min. After 1 hr at 0° C. the mixture was warmed to room temperature. The mixture was poured into saturated sodium bicarbonate. Solid was collected and air dried. The solid was purified by chromatography on silica gel eluting with ethyl acetate-methanol mixtures giving 0.7 g of the title compound as a tan solid: mass spectrum (electrospray, m/e): M+H 416.1, 418.1.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=O)=[CH:26][CH:25]=1>>[F:18][C:17]([F:19])([F:20])[C:4]1[C:3]([C:1]#[N:2])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:12][C:13]1[N:16]=[C:28]([C:27]2[CH:31]=[CH:32][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:25][CH:26]=2)[O:15][N:14]=1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(OC(F)(F)F)cc3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 4-[(trifluoromethyl)oxy]benzoic acid: MS (ESI): m/z 453 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([OH:15])[CH:10]([N+:12]([O-])=O)[CH3:11])=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[NH2:12][CH:10]([CH3:11])[CH:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[OH:15]
Reactant: COc1ccc(C(O)C(C)[N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(O)C(C)N)cn1
Yield: 23.7 %

Procedure:
1-(6-methoxypyridin-3-yl)-2-nitro-propan-1-ol (2.20 g, 10.37 mmol) was dissolved in methanol (410 mL) and hydrogenated using a H-Cube™ hydrogenation reactor (THALES nanotechnology) equipped with a cartridge of 10% Pd/C. The flow rate was set to 0.8 mL/min, temperature 80° C. and full the hydrogen production at full mode. After evaporation of the solution diastereomers can be separated on preparative HPLC (XTerrra C18, 19×50 mm) using a gradient of 5-30% acetonitrile in water (+1% NH3) gave the pure subtitle compound (448 mg, 24%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][CH:12]=[CH:13][N:14]=1)([O-])=O.[H][H]>[Ni].C(O)C>[O:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccccc1-c1ncco1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccccc1-c1ncco1
Yield: 108.7 %

Procedure:
To 19.0 g of 2-(2-nitrophenyl)oxazole, (prepared by the procedure of W. E. Cass, J. Am. Chem. Soc., 64, 785 [1942]) 3.0 g of Raney-Nickel catalyst (purchased from Aldrich Chemical Company, Milwaukee, Wisc. 53201) and 200 ml ethanol were combined and reduced at ambient temperature and at a H2 pressure of 5-50 psi on a Paar Hydrogenator until the hydrogen uptake ceased. The catalyst was filtered through celite under a blanket of nitrogen. The solvent was removed on a rotary evaporator. 17.4 g of crude product with m.p. 31°-32° was obtained and used in the next step.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[C:14]([O:16][CH2:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:13]=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[N:15]=[C:14]([O:16][CH2:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1COc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1COc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (2S)-2-({[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]oxy}methyl)piperidine-1-carboxylate (729 mg, 1.67 mmol) was dissolved in THF (10 ml) and tetrabutylammonium fluoride (1.0 M in THF, 2.5 ml, 2.5 mmol) added. The reaction stirred at rt. for 1 h and the solvent removed in vacuo. Purification by silica gel flash chromatography using a Biotage 25+M column with EtOAc/heptane 1:1 yielded the title compound as a colorless oil. Yield: 520 mg (97%). 1H NMR (400 MHz, CDCl3) δ 7.52 (t, 1H, J=7.8 Hz), 6.76 (d, 1H, J=7.3 Hz), 6.59 (d, 1H, J=8.2 Hz), 4.68-4.61 (m, 3H), 4.50 (dd, 1H, J=10.6 Hz, J=7.2 Hz), 4.32 (dd, 1H, J=10.2 Hz, J=7.7 Hz), 4.01 (d, 1H, J=11.6 Hz), 3.59 (bs, 1H), 2.86 (dt, 1H, J=13.1 Hz, J=2.3 Hz), 1.81 (d, 1H, J=11.9 Hz), 1.67-1.49 (m, 5H), 1.38 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:33][O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:32])[C@H:13]([CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:14][C:15]([O:17][CH3:18])=[O:16].[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([S:61](Cl)(=[O:63])=[O:62])=[CH:57][CH:56]=1)([O-:54])=[O:53].S(Cl)(Cl)(=O)=O>N1C=CC=CC=1>[Si:35]([O:34][CH2:33][C@@H:2]([NH:1][S:61]([C:58]1[CH:57]=[CH:56][C:55]([N+:52]([O-:54])=[O:53])=[CH:60][CH:59]=1)(=[O:62])=[O:63])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:32])[C@H:13]([CH:19]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:14][C:15]([O:17][CH3:18])=[O:16])([C:48]([CH3:51])([CH3:50])[CH3:49])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 101.2 %

Procedure:
A solution of N-{2-[(3S)-3-amino-4-{[tert-butyl(diphenyl)silyl]oxy}butyl]phenyl}-Nα-(methoxycarbonyl)-β-phenyl-L-phenylalaninamide (8, 255.1 mg, 0.364 mmol) in pyridine (2 mL) was treated with solid p-nitro benzenesulfonyl chloride (247 mg, 1.115 mmol) (or any other suitable sulfonyl chloride) and the mixture stirred at room temperature for 13 h, quenched with sat. NaHCO3 (0.5 mL), diluted with DCM, washed with sat. NaHCO3 then aqueous 5% KHSO4 then saturated NaHCO3, dried over MgSO4, filtered and concentrated to get 326 mg (100% yield) of the title compound, which was used without further purification for the next step. MS: m/z=885.3 (MH+).
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[N:13]=[CH:12][CH:11]=1)(=O)C.Cl>CO>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:14]1[C:10]([NH:9][C:5]2[NH:6][CH2:7][CH2:8][N:4]=2)=[CH:11][CH:12]=[N:13]1
Reactant: CC(=O)N1CCN=C1Nc1ccnn1-c1ccccc1Cl
Agent: Cl
Solvent: CO
Product: Clc1ccccc1-n1nccc1NC1=NCCN1

Procedure:
1-Acetyl-2[1-(2-chlorophenyl)-5-pyrazolyl] amino-2-imidazoline (14.0 g.) was treated with HCl in methanol as described in Example II to give 11.10 g. product mp 185°-188° (crystallized from CH3CN)
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][CH2:11]2)[C:6]1=[O:17].C(N(CC)CC)C.FC(F)(F)S(O[Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])(=O)=O>ClCCl>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:11][CH2:12][C@@H:13]([O:16][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:14][CH2:15]2)[C:6]1=[O:17]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1C(Cc2ccc(Cl)cc2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
Dissolve 3-(2,4-dichloro-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one (0.5 g, 1.46 mmol) in dichloromethane (15 mL), cool to 0° C., and add triethylamine (0.26 mL, 1.90 mmol) and t-butyldimethylsilyl trifluoromethanesulfonate (0.40 mL, 1.75 mmol). After 16 h, wash the mixture with 1 N HCl, saturated aqueous NaHCO3 and brine, dry over Na2SO4 and evaporate the solvent. Purify the residue by column chromatography on silica gel (eluting 0% to 40% ethyl acetate in hexanes) to give the desired intermediate (0.54 g, 81%).