Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:18]1([CH3:23])OCC[O:19]1)[C:14]([O:16][CH3:17])=[O:15])[C:5]2=[O:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:18](=[O:19])[CH3:23])[C:14]([O:16][CH3:17])=[O:15])[C:5]2=[O:24]
Reactant: COC(=O)C(CN1C(=O)c2ccc(Br)cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: COC(=O)C(CN1C(=O)c2ccc(Br)cc2C1=O)C(C)=O

Procedure:
Methyl 2-(5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (106 mg, 24%) in the same manner as described in the above example 6 (1) from methyl 3-(5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.46 g, 1.14 mmol) and pyridinium p-toluenesulfonate (50 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [CH:1]([C:4]([CH3:22])([N:7]1[C:19](=[O:20])[C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]=2)[C:8]1=[O:21])[C:5]#[N:6])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:24]>>[CH:1]([C:4]([CH3:22])([N:7]1[C:19](=[O:20])[C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]=2)[C:8]1=[O:21])[C:5]([NH2:6])=[O:24])([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)C(C)(C#N)N1C(=O)c2cc3ccccc3nc2C1=O
Product: CC(C)C(C)(C(N)=O)N1C(=O)c2cc3ccccc3nc2C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1,3-Dihydro-α-isopropyl-α-methyl-1,3-dioxo-2-H-pyrrolo[3,4-b]quinoline-2-acetonitrile (0.44 g, 0.0015 mol) is dissolved in conc. sulfuric acid (5 ml) at room temperature and stirred overnight. The reaction mixture is poured onto crushed ice (50 ml) and a white precipitate forms and is filtered off, washed with water, aqueous sodium bicarbonate and water and then vacuum dried. This gives 0.34 g (74%) of product, mp 237°-239° C. (dec.). Anal. calcd. for C17H17N3O3 : C, 65.58; H, 5.50; N, 13.50. Found: C, 65.03; H, 5.63; N, 13.19.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[C:30]([F:35])=[CH:31][C:32]([F:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:36])[CH2:15][N:14](OC(C)(C)C)[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2].[ClH:42]>O1CCOCC1>[ClH:42].[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[C:30]([F:35])=[CH:31][C:32]([F:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:36])[CH2:15][NH:14][CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CN(OC(C)(C)C)C1)C2c1ccc(Sc2nc3cc(F)cc(F)c3[nH]2)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CNC1)C2c1ccc(Sc2nc3cc(F)cc(F)c3[nH]2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of 300 mg of 6-tert-butyloxy-9-[5-(5,7-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-2,4,5,7,8,9-hexahydro-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester in 10 ml of dioxane is combined with 1.8 ml of 4N HCl in dioxane and the reaction mixture is stirred for 16 hours at room temperature. The formed insoluble material is collected by filtration, washed with dioxane (70 ml), pentane (50 ml), diisopropylether (50 ml) and dried under vacuum to yield 227 mg of 9-[5-(5,7-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester hydrochloride as a light brown powder. Yield=84%. Analytical LC/MS (method C): m/z=511 (negative ion mode [M−H]−), m/z=512 (positive ion mode [M+H]+) 500 MHz 1H NMR on a BRUKER AVANCE DRX-500 spectrometer, chemical shifts (δ in ppm) in d6 dimethylsufoxyde (DMSO-d6) solvent referenced at 2.50 ppm at 303K temperature: 1.28 (t, J=7.0 Hz, 3H); 3.72 (d broad, J=16.0 Hz, 1H); 3.81 (m, 1H); 4.22 (m, 1H); 4.28 (q, J=7.0 Hz, 2H); 4.45 (d broad, J=16.0 Hz, 1H); 5.20 (s, 1H); 6.40 (d, J=3.5 Hz, 1H); 6.85 (d, J=3.5 Hz, 1H); 6.90 (d, J=3.5 Hz, 1H); 7.06 (dt, J=2.0 et 11.0 Hz, 1H); 7.17 (dd, J=2.0 et8.5 Hz, 1H); 9.39 (s, 1H); 10.1 (m broad, 1H); 10.4 (m broad, 1H); 11.65 (d, J=3.5 Hz, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:28][CH2:29][CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][N:19]3C=C4C(C=CC=C4)=C3)[CH:15]=2)[CH:10]=1)[CH2:2][CH3:3].O.NN>CO>[NH2:19][CH2:18][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:28][CH2:29][CH3:30])[CH2:1][CH2:2][CH3:3])[CH2:17]2)=[CH:12][CH:13]=1
Reactant: CCCN(CCC)CCCCC1=Cc2ccc(Cn3cc4ccccc4c3)cc2C1
Agent: NN
Solvent: O
Solvent: CO
Product: CCCN(CCC)CCCCC1=Cc2ccc(CN)cc2C1
Yield: 65.2 %

Procedure:
The compound (82.0 mg) obtained in Example 11-12 was dissolved in methanol (4.1 ml) and added with hydrazine monohydrate (0.082 ml) and the whole was refluxed under heating for 3 hours. The reaction solution was concentrated under reduced pressure. Then, the residue was added with water and subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (40.1 mg) as a yellow oily substance.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.F[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: Fc1cnccn1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2cnccn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-fluoro-pyrazine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.43 min; Mass spectrum (ESI+): m/z=390 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[F:22][C:23]([F:33])([F:32])[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][C:23]([F:22])([F:32])[F:33])=[CH:26][CH:27]=2)[N:3]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCC(CC)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCCCO
Solvent: CC(C)O
Product: CCC(CC)n1cnc2c(Nc3ccc(OC(F)(F)F)cc3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 3 starting from 200 mg of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 0.13 ml of 4-(trifluoromethoxy)-benzenamine in place of the benzylamine. The reaction medium is agitated at ambient temperature then taken to a temperature of 80 to 85° C. for 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol, left for four hours at a temperature of approximately 0° C., followed by separating, washing with 10 ml of isopropanol and drying at a temperature of approximately 50° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:5]([CH3:7])[CH:6]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][N:5]1[CH:6]=[C:2]([C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)[N:3]=[C:4]1[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: Cn1cc(Br)nc1CCc1ccc2ccccc2n1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccsc2)nc1CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
A suspension of 2-(2-(4-bromo-1-methyl-1H-imidazol-2-yl)ethyl)quinoline (0.31 g, 0.980 mmol), thiophen-3-ylboronic acid (0.25 g, 1.960 mmol), and Pd(PPh3)4 (0.022 g, 0.441 mmol) in 1,4-dioxane (6 mL) under N2 was stirred at room temperature for 0.5 h and then Na2CO3 (0.3105 g, 2.94 mmol) in water (1 mL) was added. The mixture was refluxed overnight. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate (EtOAc). The separated organic layer was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 55.6 mg of the desired compound. LC-MS: m/z 320 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[H-].[Na+].C=O.Cl.[CH2:24]([O:31][C@@H:32]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:33][O:34][CH2:35]Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:35][O:34][CH2:33][C@@H:32]([O:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:37][O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:4]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: ClCOC[C@H](COCc1ccccc1)OCc1ccccc1
Reactant: Clc1nc(OCc2ccccc2)c2[nH]cnc2n1
Agent: C=O
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1nc(OCc2ccccc2)c2ncn(COC[C@H](COCc3ccccc3)OCc3ccccc3)c2n1
Reaction time: 0.33 h
Yield: 571 %

Procedure:
2-Chloro-6-benzyloxypurine (782 mg, 3 mmol) was dissolved in sieve-dried DMF (10 ml) and 60% NaH in oil (160 mg; 4 mmol of NaH) was added. This mixture was strired under N2 for 20 minutes and then 963 mg (3 mmol) of (S)-2,3-dibenzyl-oxy-1-chloromethoxy propane (prepared from 1,2-di-O-benzyl-D-glycerol by chloromethylation with formaldehyde and HCl in methylene chloride at 0° C. using the method disclosed in European Patent Application No. 82401571.3, publication No. 0 074 306, or U.S. Ser. No. 617,868, filed June 6, 1984 in 10 ml of dry DMF was added. This mixture was stirred at room temperature under N2 overnight after which time an additional 100 mg of (S)-2,3-dibenzyloxy-1-chloromethoxypropane was added. After 3 hours, the reaction was evaporated to dryness in vacuo, followed by an additional evaporation from toluene. The crude product was chromatographed on a column of Baker 3405 silica gel, developed first with ethyl ether and then with ethyl acetate. Fractions containing the required product were pooled and evaporated to dryness to give 970 mg (1.78 mmol, 59% yield) of pure material. 500 mg (0.92 mmol, 30.1% yield) of suspected N7 - isomer (NMR and mass spectroscopic identification) was obtained from later fractions, readily separated from the N9 isomer.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[SH:6][CH2:7][CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10].[OH-].[Na+]>N1C=CC=CC=1>[CH2:1]([NH:3][C:4]([S:6][CH2:7][CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCNC(=O)SCCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
Ethylisocyanate (0.45 ml) is added to a solution of 1-(3-mercaptopropanoyl)-L-proline (1 g) in a mixture of N sodium hydroxide (5 ml) and pyridine (5 ml). The solution is heated at 40° for four hours and concentrated in vacuo. The residue is distributed between 0.1 N hydrochloric acid and ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate and concentrated to dryness to yield 1-[3-[[(ethylamino)carbonyl]thio]propanoyl]-L-proline. The dicyclohexylammonium salt is prepared by adding dicyclohexylamine to a solution of the free acid in ethyl acetate, m.p. 150°-152°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:19][C:20]([F:26])([F:25])[S:21](Cl)(=[O:23])=[O:22]>ClCCl.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:21]([C:20]([F:26])([F:25])[F:19])(=[O:23])=[O:22])[CH:5]=[N:6][CH:7]=1
Reactant: NCc1cncc(Br)c1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(NCc1cncc(Br)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-3-pyridinemethanamine (CAS#135124-70-8, 170 mg, 0.65 mmol) in dichloromethane (5 mL) at 0° C. was added diisopropylethylamine (0.55 mL, 3.25 mmol) and trifluoromethanesulfonyl chloride (0.083 mL, 0.78 mmol). The reaction was stirred at 0° C. for 15 minutes and then warmed to room temperature and stirred for an additional 30 minutes. The reaction was then diluted with saturated aqueous sodium bicarbonate and brine, and then further diluted with dichloromethane. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to provide N-(5-bromo-pyridin-3-ylmethyl)-C,C,C-trifluoro-methanesulfonamide with out the need for further purification. MS: (ES+) m/z 318.9 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:17][O:18][CH2:19][C:20]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:9]=1)(=O)[NH2:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]([CH2:17][O:18][CH2:19][C:20]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:9]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(N)=O)cc(-c3ccc(F)cc3)c2)(c2ccccc2)CC1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C#N)cc(-c3ccc(F)cc3)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred solution of tert-butyl 4-(((5-carbamoyl-4′-fluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (0.38 g, 0.72 mmol) in pyridine (6 mL) at 0° C. was treated with trifluoroacetic anhydride (1.0 mL, 7.2 mmol). The ice bath was removed and the reaction stirred at room temperature for 4 h. The reaction was cooled to 0° C. and quenched by the addition of excess methanol. The solvents were evaporated and the crude mixture dissolved in ethyl acetate and washed with 5% citric acid (2×), then water (2×), then brine (2×), dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (30% ethyl acetate/hexanes) to afford 0.3 g (83%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 7.65 (s, 1H), 7.41-7.44 (m, 3H), 7.34-7.36 (m, 4H), 7.22-7.24 (m, 2H), 7.13-7.17 (m, 2H), 4.41 (s, 2H), 3.75 (m, 2H), 3.44 (s, 2H), 2.01-3.06 (m, 2H), 2.19-2.22 (m, 2H), 1.83-1.88 (m, 2H), 1.43 (s, 9H). Mass spec.: 501.37 (MH)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:23][C:24]2[CH:28]=[C:27]([C:29]3[S:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[O:26][N:25]=2)[C:8]([CH3:22])=[C:9]([S:12]([N:15]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[C:10]=1[CH3:11])=[O:5])C>C1COCC1.O>[Cl:34][C:31]1[S:30][C:29]([C:27]2[O:26][N:25]=[C:24]([CH2:23][N:7]3[C:8]([CH3:22])=[C:9]([S:12]([N:15]4[CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)(=[O:14])=[O:13])[C:10]([CH3:11])=[C:6]3[C:4]([OH:5])=[O:3])[CH:28]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1c(C)c(S(=O)(=O)N2CCCOCC2)c(C)n1Cc1cc(-c2ccc(Cl)s2)on1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(S(=O)(=O)N2CCCOCC2)c(C)n(Cc2cc(-c3ccc(Cl)s3)on2)c1C(=O)O
Temperature: 25 °C
Yield: 84.5 %

Procedure:
To a solution of [5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3,5-dimethyl-4-([1,4]oxazepane-4-sulfonyl)-1H-pyrrole-2-carboxylic acid ethyl ester (100 mg) in 20 mL of THF/water(3:1) was added LiOH monohydrate (200 mg) The mixture was stirred for 2h at 45° C. and for 6 h at 60° C. whereupon it was cooled to RT, concentrated, acidified with 2M HCl to pH=2 and extracted with DCM (3×30 mL). The combined organic layers were dried (MgSO4) and concentrated to give crude 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3,5-dimethyl-4-([1,4]oxazepane-4-sulfonyl)-1H-pyrrole-2-carboxylic acid (80 mg) which was used directly in the next step.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)O1.Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:32]3[C:27](=[CH:28][C:29]([S:33]([NH:36][C:37]4[CH:42]=[CH:41][N:40]=[CH:39][N:38]=4)(=[O:35])=[O:34])=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)=[C:19]([O:43][CH3:44])[CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:44][O:43][C:19]1[CH:18]=[C:17]([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[C:32]2[C:27](=[CH:28][C:29]([S:33]([NH:36][C:37]3[CH:42]=[CH:41][N:40]=[CH:39][N:38]=3)(=[O:34])=[O:35])=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)o1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2ccc(C)o2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 150 °C

Procedure:
A microwave vial charged with Pd(Amphos)2Cl2 (0.012 g, 0.018 mmol), 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (0.073 g, 0.351 mmol), 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (From Example 160; 0.075 g, 0.176 mmol), potassium phosphate (0.149 g, 0.703 mmol), 1.5 mL dioxane and 0.25 mL water was heated to 150° C. in the microwave for 30 minutes. LC/MS showed mostly product. The aqueous layer was removed, and the reaction mixture was treated with HCl (4N in dioxane). Purification of the crude residue by reverse phase column chromatography [RediSep Gold C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave the titled compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([N:22]([CH3:31])[CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:20][N:21]=3)[CH:18]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:35][C:36](=O)[NH:37][C:38]1[N:39]([C:47]2[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=2)[N:40]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:42]=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO.C(Cl)Cl>[C:43]([C:41]1[CH:42]=[C:38]([NH:37][C:36]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:5]([O:12][C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([N:22]([CH3:31])[CH2:23][CH2:24][N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[N:20][N:21]=4)[CH:18]=3)[CH2:4][CH2:3]2)=[O:35])[N:39]([C:47]2[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=2)[N:40]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CN(CCN1CCOCC1)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N(C)CCN5CCOCC5)n4c3)c3ccccc32)cc1
Yield: 14 %

Procedure:
A solution of Intermediate 45d (270 mg, 0.63 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 380 mg, 0.95 mmol) and DIPEA (325 mg, 2.52 mmol) in DMF (8 mL) was stirred at 60° C. for 1 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave a stiff yellow gum which was further purified by HPLC (C18 column, 10-45% MeCN in H2O, 0.1% HCO2H). The residue was recrystallized from boiling EtOAc to give the title compound as a white powder (60.0 mg, 14%). LCMS (Method 5): Rt 3.65 min, m/z 678.3 [MH+]. 1H NMR (400 MHz, d4-MeOH): 1.30 (9H, s), 1.87-2.15 (3H, m), 2.18-2.27 (1H, m), 2.32 (4H, t, J 4.4), 2.38 (3H, s), 2.55 (2H, t, J 5.6), 2.96 (3H, s), 3.31-3.40 (6H, m), 4.89 (1H, m), 5.40 (1H, t, J 4.2), 6.33 (1H, s), 7.19-7.36 (9H, m), 7.53 (1H, d, J 10.0), 7.92 (1H, d, J 1.6).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([NH:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:10]2)(=O)=O.[CH3:30][N:31]1[CH:35]=[C:34]([C:36]2[CH:37]=[CH:38][C:39]3[N:40]([C:42]([SH:45])=[N:43][N:44]=3)[CH:41]=2)[CH:33]=[N:32]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:21]([O:20][CH2:19][CH2:18][NH:17][C:11]1[CH:12]=[N:13][C:14]2[C:9]([CH:10]=1)=[CH:8][C:7]([S:45][C:42]1[N:40]3[CH:41]=[C:36]([C:34]4[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=4)[CH:37]=[CH:38][C:39]3=[N:44][N:43]=1)=[CH:16][CH:15]=2)([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:22])[CH3:23]
Reactant: Cn1cc(-c2ccc3nnc(S)n3c2)cn1
Reactant: CC(C)(C)[Si](C)(C)OCCNc1cnc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(NCCO[Si](C)(C)C(C)(C)C)cc5c4)n3c2)cn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
A mixture of Intermediate Q28 (0.2 g, 0.444 mmol), Intermediate E (0.103 g, 0.444 mmol), xantphos (0.051 g, 0.089 mmol), Pd2(dba)3 (0.041 g, 0.044 mmol) and DIPEA (0.155 ml, 0.888 mmol) in DMF (10 ml) was bubbled with Ar gas for 10 min and then the reaction mixture was stirred under MW radiation at 110° C. for 1 h. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=40/1) to afford the title compound as brown oil (0.1 g, 42.4% yield). LCMS (method B): [M+H]+=532, tR=2.74 min.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[S:7][C:8]=1[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])(=[O:22])=[O:21])=[CH:15][CH:14]=1)=[O:12])([CH3:3])[CH3:2].IC.[C:44](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH:1]([C:4]1[N:5]=[C:6]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=2)[S:7][C:8]=1[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:44])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])(=[O:21])=[O:22])=[CH:15][CH:14]=1)=[O:12])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CCC(=O)c1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CCC(=O)c1ccc(N(C)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
The obtained N-[4-[3-[4-isopropyl-2-[4-(trifluoromethyl)phenyl]thiazol-5-yl]propionyl]phenyl]-2-nitrobenzenesulfonamide (265 mg, 0.439 mmol) was dissolved in anhydrous dimethylformamide (10 mL). Iodomethane (30 μL, 0.483 mmol) and potassium carbonate (121 mg, 0.875 mmol) were added to the solution. The mixture was stirred at room temperature for 16 hours. The mixture was neutralized with 0.2 N aqueous solution of hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried with anhydrous sodium sulfate to remove the solvent. The obtained residue was purified by silica gel column chromatography with hexane/ethyl acetate (7:3, v/v) to give the desired compound (230 mg) as yellow oil (yield 85%).