Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]([C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14]2[C:15](=[O:45])[N:16]([CH3:44])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[N:35]=[CH:34][C:33]5[C:28](=[C:29]([F:40])[CH:30]=[C:31]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:32]=5)[C:27]4=[O:41])[C:21]=3[CH2:42][OH:43])[CH:19]=2)=[CH:11][CH:12]=1)([CH3:6])[CH3:5].[H-].[OH-].[Li+]>O1CCOCC1.O>[C:36]([C:31]1[CH:32]=[C:33]2[C:28](=[C:29]([F:40])[CH:30]=1)[C:27](=[O:41])[N:26]([C:22]1[C:21]([CH2:42][OH:43])=[C:20]([C:18]3[CH:19]=[C:14]([NH:13][C:10]4[N:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:46])=[O:2])=[CH:12][CH:11]=4)[C:15](=[O:45])[N:16]([CH3:44])[CH:17]=3)[CH:25]=[CH:24][CH:23]=1)[N:35]=[CH:34]2)([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)C(C)(C)c1ccc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nc1
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(C)(C)C(=O)O)cn2)c1=O
Temperature: 25 °C
Yield: 85.7 %

Procedure:
2-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-2-methyl-propionic acid methyl ester (390 mg, 0.62 mmol) was dissolved in dioxane (5 ml). Lithium hydroxide monohydride (78 mg, 1.86 mmol) was dissolved in 5 ml of water and added dropwise. The reaction was heated at 50 degrees centigrade for three hours. The reaction mixture was concentrated, ethyl acetate was added and the layers were separated. The aqueous layer was acidified with 1 M HCL. Ethyl acetate was added and the layers were separated. The organic layer was dried and concentrated. Isopropyl acetate was added to the residue and the mixture was heated to form a solution which was cooled to room temperature and allowed to stand at room temperature for several hours. The amorphous solid was filtered and dried to give 325 mg (86%) of 2-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-2-methyl-propionic acid. A portion of this material was recrystallized from acetonitrile to provide a crystalline solid. MS: (M+H)+=612; MP=218.0-220.0° C. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9 H) 1.46 (s, 6 H) 3.17 (d, J=4.91 Hz, 1 H) 3.60 (s, 3 H) 4.27-4.42 (m, 2 H) 4.57-4.66 (m, 1 H) 7.26 (d, J=8.69 Hz, 1 H) 7.33-7.45 (m, 3 H) 7.54 (s, 2 H) 7.75 (d, J=13.22 Hz, 1 H) 7.87 (s, 1H) 8.18 (d, J=2.27 Hz, 1 H) 8.51 (d, J=2.64 Hz, 1 H) 8.60 (s, 1 H) 8.65 (d, J=1.89 Hz, 1H) 12.35 (br s, 1 H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].[O:10]1[CH2:31][CH:11]1[CH2:12][O:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[N:17]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:16]([CH3:30])([CH3:29])[CH2:15]1>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:31][CH:11]([OH:10])[CH2:12][O:13][CH:14]2[CH2:15][C:16]([CH3:30])([CH3:29])[N:17]([O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:18]([CH3:21])([CH3:20])[CH2:19]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(O)cc1
Reactant: CC1(C)CC(OCC2CO2)CC(C)(C)N1OC1CCCCC1
Product: C=Cc1ccc(OCC(O)COC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)cc1

Procedure:
4-Vinylphenol is reacted with 4-(2,3-epoxypropoxy)-1-cyclohexyloxy-2,2,6,6-tetra-methylpiperidine (=epoxide A5) analogously to Example B6) to form the title product.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:3]1.[CH3:20]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH3:20])[C:5](=[O:7])[C:4]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 91.2 %

Procedure:
A mixture of tert-butyl 2,4-dioxo-1,3,8-triaza-8-spiro[4.5]decane-carboxylate (4.9 g, 18.2 mmol), dimethylsulfate (2.9 g, 23 mmol), potassium carbonate (10.8 g, 78.3 mmol) and DMF (60 mL) was stirred approximately 60 hours at 25° C. The mixture was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with water (3×), dried (Na2SO4), filtered and concentrated to give tert-butyl 2,4-dioxo-3-methyl-1,3,8-triaza-8-spiro[4.5]decanecarboxylate (4.7 g, 16.6 mmol), m.p. 206°-208° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[NH2:16])([O-:3])=[O:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:16][C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(-c2ccncc2)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(-c2ccncc2)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
To a solution of 2-nitro-4-pyridin-4-ylphenylamine (1 mmol) in pyridine (3 mL), 4-chloro-benzenesulfonyl chloride (1.2 mmol) was added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (20 mL). The contents were washed with brine (25 mL), dried over sodium sulfate and concentrated under vacuum. The residue obtained was purified by column chromatography eluting with hexanes/ethyl acetate (1:1) then ethyl acetate to give 156 mg of 4-chloro-N-(2-nitro-4-pyridin-4-ylphenyl)benzene sulfonamide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:33])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=4)[CH:21]=3)[CH2:17][C:16](=[O:33])[NH:15][C:9]=2[CH:10]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(F)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(C3=Nc4ccc(F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (4-fluoro-2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M8) (320 mg, 0.69 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (41 mg).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9].C(OC(=O)C)(=O)C>>[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH:27]([NH:29][C:3](=[O:5])[CH3:2])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9]
Reactant: CC(N)/C=C/c1ccc(Oc2ccc(OC(C)C)nc2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC(C)/C=C/c1ccc(Oc2ccc(OC(C)C)nc2)cc1

Procedure:
(E)-3-[4-(6-Isopropoxy-pyridin-3-yloxy)-phenyl]-1-methyl-allylamine trifluoroacetate (63 mg, 0.154 mmol) was reacted with acetic anhydride in analogy to example 2a. M+H+: 341.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH:16]=3)[C:11](=[O:24])[C:10]([C:25](O)=[O:26])=[CH:9]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:30]1C=CN=C1)=O.[OH-].[NH4+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH:16]=3)[C:11](=[O:24])[C:10]([C:25]([NH2:30])=[O:26])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Temperature: 150 °C

Procedure:
A mixture of 1.65 g 1-(4-fluorophenyl)-1,4-di-hydro4-oxo-7-(4-pyridinyl)-3-quinolinecarboxylic acid, 2.2 g of 1,1'-carbonyldiimidazole and 15 ml dimethylformamide (DMF) was heated at 150° C. for 1.5 hrs. The reaction mixture was poured into 50 ml concentrated ammonium hydroxide. The product was extracted with methylene dichloride and recovered therefrom to give 2.2 g 1-(4-fluorophenyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide which was converted to its monomethanesulfonate salt hemihydrate, m.p. 301°-303° C. (decompn.). The free base, prepared from the salt with potassium carbonate solution, had m.p. 315°-317° C. when recrystallized from DMF.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:15]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:16]2=[O:28])[CH2:3]1.[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH3:41])[C:38](O)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH3:41])[C:38]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:16]3=[O:28])[CH2:3][C@H:2]2[F:1])=[CH:9][CH:10]=1)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
To a solution of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (0.03 g, 0.078 mmol, example 1) in DCM (5 mL) was added (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.077 g, 0.408 mmol) followed by DCC (0.049 g, 0.235 mmol) and DMAP (9.58 mg, 0.078 mmol). The reaction mixture was stirred at rt for 18 h. Water (15 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (3×15 mL) and the organic layers were combined, dried over Na2SO4, and concentrated to a crude product. The crude product was purified by preparative TLC eluting with 20% ethyl acetate in petroleum ether to provide the purified product (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)propanoate (0.032 g, 0.058 mmol, 74% yield) as off-white semi solid. LC-MS (Method A) RT=2.40 min, (M+H)+=554.2. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J=7.0 Hz, 1H), 7.44-7.32 (m, J=8.5 Hz, 2H), 7.21-7.09 (m, 4H), 7.07-6.98 (m, J=8.5 Hz, 2H), 4.62 (d, J=4.5 Hz, 1H), 4.39 (d, J=15.1 Hz, 1H), 4.30 (d, J=15.1 Hz, 1H), 4.27-4.17 (m, 1H), 3.58 (t, J=8.5 Hz, 1H), 3.50-3.40 (m, 1H), 3.22-3.07 (m, 2H), 2.81-2.64 (m, 3H), 2.39-2.31 (m, 1H), 2.29 (s, 3H), 2.17-2.04 (m, 1H), 1.93 (dd, J=12.8, 8.3 Hz, 1H), 1.78 (br. s., 1H), 1.74-1.59 (m, 1H), 1.41 (s, 9H), 1.39 (d, J=2.5 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ −180.172.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](OC)=[O:9])=[N:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(N)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc(CO)nc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
To a 250 ml three necked round bottom flask was added methyl 5-aminopicolinate (2.0 g) in THF (40 ml) under nitrogen atmosphere and cooled to 0-5° C. After 15 min, 2.0 M solutions of LiAlH4 (19.7 ml) was added under nitrogen atmosphere and allow it to warm up to room temperature and stirred at same temperature for 1 hr. After completion of the reaction, the reaction mixture was cooled to 5° C. and quenched with sat. NH4Cl solution (25 ml) and diluted with water, followed by extraction with ethyl acetate. The combined organics were washed with water, dried over Na2SO4 and evaporated to afford brown oil product. The aqueous layer was concentrated to give residue which was washed with 30% methanol in ethyl acetate. Resultant washing was concentrated to afford brown oil (crude). Both the crude material were combined and subjected for column purification using 8% methanol in chloroform to yield 1.3 g of (5-aminopyridin-2-yl)methanol.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[S:44][CH:45]=[CH:46][N:47]=1)CCC.BrC1C=CC(=O)N(CC2C=CC(CC)=CC=2)C=1>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[S:44][CH:45]=[CH:46][N:47]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: CCc1ccc(Cn2cc(Br)ccc2=O)cc1
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2nccs2)s1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene obtained in Example 159-(1) and tri-n-butyl(2-thiazolyl)tin were treated in a manner similar to Example 128-(5) and (6) to give the target compound. APCI-Mass m/Z 434 (M+H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[O:17])[CH2:12][CH2:11]1.[NH2:26][OH:27]>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:25]=[CH:24][C:21]([C:22](=[NH:23])[NH:26][OH:27])=[CH:20][CH:19]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: N#Cc1ccc(C(=O)N2CCC(c3nc4ccccc4[nH]3)CC2)cc1
Reactant: NO
Solvent: CCO
Product: N=C(NO)c1ccc(C(=O)N2CCC(c3nc4ccccc4[nH]3)CC2)cc1
Temperature: 80 °C
Yield: 108.9 %

Procedure:
To a stirred suspension of 4-{[4-(1H-benzimidazol-2-yl)piperidin-1-yl]carbonyl}benzonitrile (0.30 g, 0.91 mmol) in ethanol (2 mL) is added 50% aqueous hydroxylamine (0.24 mL, 3.64 mmol). The reaction is heated at 80° C. for 18 h. The mixture is concentrated under reduced pressure to give 0.36 g (94%) of 4-{[4-(1H-benzimidazol-2-yl)piperidin-1-yl]carbonyl}-N-hydroxybenzene carboximidamide. m/z=364 [M++H].
Reaction SMILES: [ClH:1].C([O:5][C:6](=[O:45])[C@H:7]([N:25]1[CH2:29][CH2:28][C@H:27]([NH:30][S:31]([C:34]2[S:38][C:37]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[N:36][CH:35]=2)(=[O:33])=[O:32])[C:26]1=[O:44])[CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][C:20]([F:23])([F:22])[F:21])[C:15]([NH2:24])=[N:14][CH:13]=[CH:12]2)CC.O>Cl>[ClH:1].[NH2:24][C:15]1[C:16]2[C:11](=[CH:10][C:9]([CH2:8][C@@H:7]([N:25]3[CH2:29][CH2:28][C@H:27]([NH:30][S:31]([C:34]4[S:38][C:37]([N:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)=[N:36][CH:35]=4)(=[O:33])=[O:32])[C:26]3=[O:44])[C:6]([OH:45])=[O:5])=[C:18]([O:19][C:20]([F:22])([F:21])[F:23])[CH:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: CCCOC(=O)[C@@H](Cc1cc2ccnc(N)c2cc1OC(F)(F)F)N1CC[C@H](NS(=O)(=O)c2cnc(N3CCCC3)s2)C1=O
Agent: Cl
Solvent: O
Product: Nc1nccc2cc(C[C@H](C(=O)O)N3CC[C@H](NS(=O)(=O)c4cnc(N5CCCC5)s4)C3=O)c(OC(F)(F)F)cc12
Yield: 90 %

Procedure:
A solution of 600 mg (0.82 m.mole) of (R)-3-(1-Amino-7-trifluoromethoxy-isoquinolin-6-yl)-2-[(S)-2-oxo-3-(2-pyrrolidin-1-yl-thiazole-5-sulfonylamino)-pyrrolidin-1-yl]-propionic acid propyl ester hydrochloride (compound of example 3) in 20 ml of 1N hydrochloric acid is heated at 80° C. for 4 h. The reaction mixture is evaporated to dryness. The crude material is taken up in acetone, and the precipitate formed is filtered, washed with acetone and dried under vacuum. 510 mg of a white powder containing 1.7 moles of HCl and 2 moles of H2O are collected (90% yield)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18].O>N1C=CC=CC=1>[NH2:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[NH:10][C:17]([C:13]1[O:12][CH:16]=[CH:15][CH:14]=1)=[O:18]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1NC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.1 %

Procedure:
To a stirred solution of 4-nitro-o-phenylene diamine (76.5 g, 0.5 mole) in 500 ml of pyridine, is added dropwise 2-furoyl chloride (65 g, 0.5 mole). After the addition is complete the reaction solution is stirred at room temperature for 15 minutes and then at reflux for 2 hr. The hot reaction solution is poured into 6 liters of water to give an oil, which solidifies upon standing overnight at room temperature to give 125 g (100 percent) of yellow intermediate. The solid is used in part B without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[C:5]([CH3:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCCCCC>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[O:22][C:6]1[C:5]([CH3:10])=[CH:4][C:3]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[C:7]=1[Cl:8]
Reactant: Cc1ccc(O)c(C)c1
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2c(C)cc([N+](=O)[O-])c(C)c2Cl)c(C)c1
Yield: 69.6 %

Procedure:
Into a round bottom reaction flask equipped with a magnetic stirrer, condenser, thermometer and nitrogen inlet was added 50.0 grams (0.23 mol) of 2,5-dimethyl-3,4-dichloronitrobenzene, 38.5 grams (0.32 mol) of 2,4-dimethylphenol, 50 grams (0.36 mol) of potassium carbonate and 125 milliliters of dimethylformamide. The reaction mixture was heated to a temperature of 90° C.-100° C. and maintained at this temperature for a period of 72 hours. The reaction mixture was then cooled, filtered and concentrated to give a dark oil. The dark oil was partitioned between toluene (300 milliliters) and 4% sodium hydroxide (250 milliliters) and then separated. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to give a dark oil. The dark oil was trituated with hexane and a solid was formed. The solid was washed with cold hexane and vacuum dried to give 47.8 grams (0.16 mol) of 4-(2,4-dimethylphenoxy)-2,5-dimethyl-3-chloronitrobenzene as a tan powder having a melting point of 78° C.-80° C. Elemental analysis of the tan powder indicated the following:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:17])=[C:2]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]([F:18])([F:31])[F:30])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1=[O:14])[CH3:13]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3ccccc3OC(F)(F)F)cc21

Procedure:
Compound 9A was prepared from Compound 1A using the procedure described in Example 1B, except using 2-trifluoromethoxy benzene boronic acid as the starting material. MS (electrospray): mass calculated for C21H22F3NO2 377.16; m/z found m/z found, 378.2 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].FC(F)(F)C([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])=O.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>O1CCCC1>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][CH:13]2[CH2:14][CH2:15][NH:11][C:12]2=[O:16])=[CH:22][CH:21]=1
Reactant: O=C1CCCN1C(=O)C(F)(F)F
Reactant: O=Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1NCCC1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a suspension of potassium tert-butoxide (2.00 g, 18.0 mmol) in anhydrous tetrahydrofuran (40 mL) was added a mixture of 1-(2,2,2-trifluoroacetyl)-pyrrolidin-2-one (2.12 g, 12.0 mmol) and 4-fluorobenzaldehyde (1.24 mL, 12.0 mmol) in anhydrous tetrahydrofuran (5 mL) dropwise at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours, then refluxed for 1 hour and concentrated in vacuo. Water (150 mL) was added to the residue. The white solid precipitated was filtered and re-dissolved in ethyl acetate (50 mL) and then hydrogenated in the presence of catalytic amount of palladium on carbon (20% w/w) at ambient temperature and atmospheric pressure for 3 hours. The reaction mixture was filtered through a bed of celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate) to afford the title compound as a white solid (0.72 g, 35%): 1H NMR (300 MHz, CDCl3) δ 7.20-7.09 (m, 2H), 7.00-6.90 (m, 2H), 6.42 (s, 1H), 3.31-3.07 (m, 3H), 2.71-2.54 (m, 2H), 2.19-2.03 (m, 1H), 1.89-1.69 (m, 1H); MS (ES+) m/z 194.1 (M+1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][O:6][CH2:5][C@H:4]1[OH:8].S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1.C(N(C(C)C)C(C)C)C>C(O)C>[OH:8][C@@H:4]1[CH2:5][O:6][CH2:7][C@H:3]1[NH:2][C:10]1[CH2:14][S:13][C:12](=[O:15])[N:11]=1
Reactant: N[C@@H]1COC[C@H]1O
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1N=C(N[C@@H]2COC[C@H]2O)CS1
Yield: 40.8 %

Procedure:
To a solution of trans-4-aminotetrahydrofuran-3-ol hydrochloride (1.00 g) in ethanol (30 mL) were added 4-thioxo-1,3-thiazolidin-2-one (954 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (3.87 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (591 mg).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH3:22].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:33]([F:34])=[C:25]([F:24])[CH:26]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH3:22]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CC1CCCN1CCOc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1CCCN1CCOc1ccc(NC(=O)c2ccc(F)c(F)c2)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
A mixture of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-phenylamine (95 mg, 0.25 mmole), 3,4-difluoro-benzoyl chloride (40 μL, 0.301 mmole), and triethylamine (70.2 μL, 0.501 mmole) in 1 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 60 mg, 46% yield). 1H NMR (DMSO-d6, 400 MHz) δ 1.22 (dd, J=19.71, 6.57 Hz, 3H), 1.45-1.53 (m, 1H), 1.72-1.89 (m, 2H), 2.07-2.14 (m, 1H), 2.79-2.98 (m, 1H), 3.08-3.15 (m, 1H), 3.31-3.44 (m, 2H), 3.59-3.65 (m, 1H), 3.68 (d, J=4.80 Hz, 3H), 4.21-4.46 (m, 2H), 7.29 (dd, J=9.85 Hz, 6.82 Hz, 1H), 7.60-7.67 (m, 1H), 7.66 (s, 1H), 7.70-7.72 (m, 1H), 7.84-7.88 (m, 1H), 7.94 (dt, J=9.09, 2.78, 2.53 Hz, 1H), 8.01-8.06 (m, 1H), 9.22-9.48 (m, 1H from TFA), 10.4 (s, NH). Exact mass calculated for C24H2579BrF2N4O2, 518.1, found 519.3, 521.5 (MH+).