Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH2:26]([O:28][C:29](Cl)=[O:30])[CH3:27]>N1C=CC=CC=1>[CH2:26]([O:28][C:29]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Solvent: c1ccncc1
Product: CCOC(=O)n1cc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Compound 1 (1.69 g) obtained in Example 1, ethoxycarbonyl chloride (2.5 ml) and pyridine (5 ml) was stirred at room temperature for 16 hours. The reaction solution was subjected to partitioning between chloroform and a 10% aqueous solution of citric acid. The organic layer was concentrated under reduced pressure, and the residue was recrystallized from 2-propanol to give Compound 7 (1.83 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:30][C:31]2[CH:39]=[CH:38][C:34]3[O:35][CH2:36][O:37][C:33]=3[CH:32]=2)[C:7](=[O:29])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([NH:21]CC1C=CC=CC=1)=[CH:10][CH:9]=2)=[O:4].CO.[H][H]>[C].[Pd].C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:30][C:31]2[CH:39]=[CH:38][C:34]3[O:35][CH2:36][O:37][C:33]=3[CH:32]=2)[C:7](=[O:29])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([NH2:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(NCc3ccccc3)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(N)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Yield: 72.3 %

Procedure:
A mixture of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-benzylamino-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (670 mg), 10% palladium carbon (200 mg), methanol (10 ml) and THF (10 ml) was stirred at room temperature at 4-5 atm hydrogen pressure for 48 hrs. Palladium carbon was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate-hexane) to give the title compound (400 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=2.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:17][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:6]=2)[CH:11]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(C)(C)Oc1ccc2cc(Br)cc([N+](=O)[O-])c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)Oc1ccc2cc(Br)cc(N)c2c1

Procedure:
A mixture of 3-bromo-7-tert-butoxy-1-nitronaphthalene, as described above in Step G, (1.08 g, 3.33 mmol), NH4Cl (89 mg, 1.67 mmol), and iron powder (930 mg, 16.7 mmol) in EtOH (70 mL) and H2O (30 mL) was heated to reflux for 7 hours, then cooled and filtered through a pad of celite, washing with EtOH. The filtrate was concentrated under reduced pressure and the residue was partitioned between dilute aqueous NaHCO3 (50 mL) and CH2Cl2 (150 mL). The aqueous layer was extracted further with CH2Cl2 (50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane—5% to 20% EtOAc to afford the titled compound.
Reaction SMILES: [CH:1]([C:4]1[C:9]([OH:10])=[C:8]([N+:11]([O-])=O)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[NH2:11][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:9]=1[OH:10]
Reactant: CC(C)c1cccc([N+](=O)[O-])c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)c1cccc(N)c1O
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A solution of 6-isopropyl-2-nitrophenol (3.000 g, 16.56 mmol) and sodium hydrosulfite (11.53 g, 66.23 mmol) in ethanol (180 mL) and water (90 mL) was stirred at 80° C. for 20 h and then cooled to room temperature. The resulting orange solution was concentrated and then partitioned between dichloromethane (50 mL) and water (50 mL). The organic phase was separated and washed with brine (25 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 2-amino-6-isopropylphenol as an orange solid (1.792 g, 72%). RP-HPLC Rt 8.171 min, 92% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 A, 5 μm, 150×3.9 mm column); m/z 150 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[N:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25].O>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:25])[NH:1][C:2]1[C:3]([O:14][CH3:15])=[N:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1Br
Reactant: CCOC(=O)Cc1ccc(N)c(OC)n1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(OC)n1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a stirred solution of ethyl 3-amino-2-methoxy-6-pyridylacetate (1.61 g, 7.66 mmol) in THF (10 ml) were added 2-bromophenylisocyanate (948 ml, 7.66 mmol) and Et3 N (107 ml, 0.776 mmol). After stirring overnight, the mixture was poured into H2O (100 ml) and extracted with CHCl3-MeOH (4:1, 2×200 ml). The combined extracts were dried over MgSO4 and evaporated. The residue was recrystallized from CHCl3-MeOH-hexane to give ethyl 3-[N′-(2-bromophenyl)ureido]-2-methoxy-6-pyridylacetate (2.91 g, 93%) as a colorless crystalline powder. mp 160–163° C.; 1H-NMR (DMSO-d6) δ 1.19 (dt, J=7.1, 0.7 Hz, 3 H), 3.69 (s, 2 H), 3.95 (s, 3 H), 4.07–4.13 (m, 2 H), 6.90 (d, J=7.8 Hz, 1 H), 6.99 (t, J=7.8 Hz, 1 H), 7.33 (t, J=7.8 Hz, 1 H), 7.61 (d, J=7.8 Hz, 1 H), 7.96 (dd, J=7.8, 1.5 Hz, 1 H), 8.31 (d, J=7.8 Hz, 1 H), 8.82 (s, 1 H), 9.12 (s, 1 H); MS (FAB) m/z 408 (M+), 410 (M++2); Anal. Calcd for C17H18BrN3O4.0.25 H2O: C, 49.47; H, 4.52; 9.96. Found: C, 49.34; H, 4.48; N, 9.96.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16]>O>[OH:16][CH2:15][CH2:14][N:13]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1)[CH3:12]
Reactant: COc1ccc([N+](=O)[O-])cn1
Reactant: CNCCO
Solvent: O
Product: CN(CCO)c1ccc([N+](=O)[O-])cn1
Yield: 78 %

Procedure:
A mixture of 154 g (1 mole) of 2-methoxy-5-nitropyridine, 90 g (1.2 mole) of N-methylethanolamine and 200 ml of water is heated to reflux for 8 hours with stirring. After cooling, the solid substance is filtered off with suction, washed with water and is then dried in the vacuum. An intensively yellow dyed product is obtained with a melting point of 83°-4° C. and in a yield of 78% of theory.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[OH:19]O.[OH-].[Na+].Cl>C(O)C.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:12])=[O:19])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (2.7 g, 8.82 mmol), in ethanol (20 mL), was added 20 mL of a 30% commercial solution of hydrogen peroxide and 2.8 mL of 6.0 N aqueous NaOH solution. The reaction mixture was stirred at room temperature. After 3 hours, the reaction mixture was acidified with 6.0 N HCl aqueous solution. Water was added to aid precipitation. The solid was collected by filtration and was washed with small portions of water. The solid was dried under vacuum (2.77 g, 97% yield): ES-MS (m/z) 325 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:29](Cl)=[O:30].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:29]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:30]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4ccc(Cl)c(Cl)c4)C3)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, (60 mg, 0.13 mmol), 3,4-dichloro benzoyl chloride (Aldrich, 27 mg, 0.13 mmol) and Et3N (76 uL, 0.54 mmol) in DCM (4 mL) was stirred at room temperature for 1 hour followed by aqueous workup with sat NaHCO3 and DCM. The organic layer was dried (Na2SO4) and concentrated in vacuo followed by column chromatography purification (5% NH3 in MeOH mixed with EtOAc) resulting in the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[ClH:16].[CH3:17]OC(OC)(C)C>>[ClH:16].[CH3:17][O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: COC(C)(C)OC
Agent: Cl
Product: COC(=O)CCCCCCCCCCCN
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To the suspension of 12-aminododecanoic acid (2.15 g; 10 mmol) in 2,2-dimethoxypropane (100 ml) was added 36% aqueous HCl (10 ml) and the mixture was treated in an ultrasonic bath until all solid material was dissolved. The mixture was then left to stand overnight, concentrated to dryness, dissolved in 40 ml of methanol and precipitated with approximately 500 ml of dry ether to give 2.4 g of 1 (90.5% yield).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C:17]2=[CH:16][CH2:15][C@@:14]2([CH3:22])[C@H:8]3[CH2:9][CH2:10]/[C:11]/2=[CH:12]/[CH3:13])[CH2:3]1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:30]([O:1][C@@H:2]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C:17]2=[CH:16][CH2:15][C@@:14]2([CH3:22])[C@H:8]3[CH2:9][CH2:10]/[C:11]/2=[CH:12]/[CH3:13])[CH2:3]1)(=[O:32])[CH3:31]
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)C3=CC[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
Compound 1.5 (19.0 g, 63 mmol) was dissolved in CH2Cl2 (380 mL). Triethylamine (17.6 mL, 126.6 mmol), DMAP (0.772 g, 6 mmol) and acetic anhydride (8.98 mL, 94 mmol) were added sequentially at 25° C. under a nitrogen atmosphere. The resulting solution was stirred for 2 h at 25° C., at which point the reaction was determined by TLC to be complete. The reaction was quenched by the addition of ice-water (100 mL) and the phases were separated. The aqueous layer was extracted three times with DCM (3×150 mL). The organic fractions were combined and washed with saturated brine solution (100 mL), dried over anhydrous Na2SO4 (50 g), and filtered. The filtrate was concentrated under vacuum to afford compound 1.6a (22.0 g, 95% yield) as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:57][O:56][CH2:55]4)[CH2:50][CH2:49]3)=[CH:44][N:43]=2)[C:27]1=[O:58]>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].O1CCCC1>[CH3:25][N:26]1[C:27](=[O:58])[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:55][O:56][CH2:57]4)[CH2:50][CH2:49]3)=[CH:44][N:43]=2)=[CH:29][C:30]([C:2]2[C:3]([CH:23]=[O:24])=[C:4]([N:8]3[CH2:19][CH2:18][C:17]4[C:16]5[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=5[S:11][C:10]=4[C:9]3=[O:22])[N:5]=[CH:6][CH:7]=2)=[CH:31]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: CC1(C)Cc2sc3c(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 109a (75 mg, 0.2 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (94 mg, 0.2 mmol), Pd(dppf)Cl2 (17 mg, 0.02 mmol), K3PO4.3H2O (140 mg, 0.6 mmol), and tetrahydrofuran (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 4 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1) to 109b as yellow solid (60 mg, 47%). MS: [M+H]+ 666.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:5]([C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([CH3:1])[CH:3]=1)=[O:7])[CH2:47][CH2:48][CH3:49]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3,4-dimethylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.95 (m, 3 H) 1.30-1.41 (m, 2 H) 1.69-1.80 (m, 2 H) 2.23-2.32 (m, 6 H) 2.47 (s, 3 H) 4.21 (t, 2 H) 6.65 (s, 1 H) 7.15-7.27 (m, 1 H) 7.65-7.80 (m, 2 H); MS (ESI) m/z 303 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[O:18][C:17]([CH3:20])([CH3:19])[N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:15]3[CH2:28][F:29])=[CH:10][CH:9]=2)[O:5][N:4]=1.[S:30](Cl)([CH3:33])(=[O:32])=[O:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:29][CH2:28][C@@H:15]1[C@@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:6]3[O:5][N:4]=[C:3]([CH2:2][NH:1][S:30]([CH3:33])(=[O:32])=[O:31])[CH:7]=3)=[CH:13][CH:12]=2)[O:18][C:17]([CH3:19])([CH3:20])[N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CN)no3)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CNS(C)(=O)=O)no3)cc2)OC1(C)C
Temperature: 0 °C
Yield: 97.1 %

Procedure:
To a methylene chloride (10 ml) solution of (4S,5R)-tert-butyl 5-(4-(3-(aminomethyl)isoxazol-5-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate (270 mg, 0.66 mmol) that had been cooled to 0° C. is added mesyl chloride (83 mg, 0.73 mmol) and diisopropylethylamine (94 mg, 0.73 mmol) sequentially. The reaction is stirred at 0° C. for thirty minutes then quenched with water (2 ml). The quenched reaction is stirred for thirty minutes at room temperature. The organic phase is dried over sodium sulfate and concentrated to give the title compound (310 mg): m/z (Cl) 484 ([m+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:51])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[S:38][CH:39]=[C:40]([CH2:42][O:43]C3CCCCO3)[N:41]=2)[CH:32]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[S:38][CH:39]=[C:40]([CH2:42][OH:43])[N:41]=4)[CH:32]=3)[CH2:29][C:28](=[O:51])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.23 g) (Example J27) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.32 g) (Example K27) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.06 g).
Reaction SMILES: [CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:46]=[C:47]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:48]=2)[O:36][CH2:37][C@H:38]2[CH2:40][C@@H:39]2[C:41]([O:43]CC)=[O:42])[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[Na]>>[CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:46]=[C:47]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:48]=2)[O:36][CH2:37][C@H:38]2[CH2:40][C@@H:39]2[C:41]([OH:43])=[O:42])[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:24]([Cl:31])=[CH:25][C:26]([CH3:30])=[CH:27][C:28]=4[Cl:29])=[CH:17][CH:18]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@H]1C[C@@H]1COc1cc(CCCOC)cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)C2CC2)c1
Agent: [Na]
Product: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)C2CC2)cc(OC[C@H]2C[C@@H]2C(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 2 but using instead ethyl (1S,2S)-2-{[3-({cyclopropyl[((3R,4S)-4-{6-[2-(2,6-dichloro-4-methylphen-oxy)ethoxy]pyridin-3-yl}piperidin-3-yl)carbonyl]amino}methyl)-5-(3-methoxy-propyl)phenoxy]methyl}cyclopropanecarboxylate (Example 9) as the starting material. The sodium salt of the title compound was a foam.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1Cl
Product: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1Cl

Procedure:
23.0 g of 2,4-dichloro-3-nitrobenzoic acid and 150 ml of thionyl chloride were refluxed for 6 hours under heating. Then, thionyl chloride was distilled off to obtain crude 2,4-dichloro-3-nitrobenzoyl chloride. 200 ml of methanol was added to the crude compound and refluxed under heating. Methanol was distilled off, and then ethyl acetate was added thereto to obtain an ethyl acetate solution. The solution was washed sequentially with a 5% sodium hydroxide aqueous solution, diluted hydrochloric acid and water. After drying, the solvent was distilled off to obtain 21.8 g of the desired product. Melting point: 72°-74° C.
Reaction SMILES: [OH-].[Na+].O1CCCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][C:23]1[C:32]([F:33])=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[N:37][CH:36]=2)[N:24]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CO>[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][C:23]1[C:32]([F:33])=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[N:37][CH:36]=2)[N:24]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)c1cc(F)c(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cncc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Nc2cncc3ccccc23)c(C(=O)O)cc1F
Temperature: 65 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A 1N sodium hydroxide aqueous solution (2 ml) was added to a solution of tetrahydrofuran (2 ml) and methanol (2 ml) containing methyl 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoro-2-(isoquinoline 4-ylamino)nicotinate (75 mg), followed by stirring at 65° C. for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled away under reduced pressure. A saturated aqueous ammonium chloride solution was added to the obtained residue, solid matter was collected by filtration and washed with water and ethyl acetate, and a yellow solid of 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoro-2-(isoquinoline 4-ylamino)nicotinic acid (67 mg) was thus obtained.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].S(Cl)([Cl:15])(=O)=O>C(Cl)(Cl)Cl>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([Cl:15])[CH:9]=1)=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(Cl)c[nH]1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 107.4 %

Procedure:
To a solution of 2-(trichloroacetyl)pyrrole (4.0 g, 18.83 mmol) in chloroform (28 ml) at 0° C. was added sulfuryl chloride (13 mL, 13.2 mmol). The mixture was stirred for 17 hours at room temperature. TLC analysis indicated 50% conversion of starting material. Sulfuryl chloride (13 mL, 13.2 mmol) was added and the reaction mixture was stirred for another 4 hours at room temperature. The reaction was quenched with distilled water (50 mL). CH2Cl2 (50 mL) was added to the reaction and the solution was transferred to a separatory funnel and the organic layer was isolated while the aqueous layer was back extracted with CH2Cl2 (2×50 mL). The combined organic layers were collected, dried (MgSO4), filtered, and concentrated in vacuo to yield 3.5 g of the above compound (14.18 mmol, yield 75%). 1H-NMR (CDCl3-d1) δ 9.45 (s, 1H), 7.27 (dd, J=2.8, 1.6, 1H), 7.12 (dd, J=3.2, 1.6 Hz, 1H).