Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][CH:3]=1.C1C(=O)N([Cl:31])C(=O)C1>CN(C)C=O>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][C:3]=1[Cl:31]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)cnc2C1
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nc(Cl)c2Br)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (E18) (409 mg, 1 mmol) was dissolved in N,N-dimethylformamide (DMF) (5 mL) and NCS (147 mg, 1.100 mmol) was added. The solution was stirred at RT for 24 h. Solvents were removed in vacuo and the residue was purified by flash chromatography (Isolera, 25 g, 0-100% ethyl acetate/iso-hexane) to afford crude product. This was further purified by MDAP to afford desired product in 215 mg.
Reaction SMILES: [NH2:1][CH:2]([CH3:31])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)=O>O=P(Cl)(Cl)Cl>[CH3:31][CH:2]1[CH2:3][NH:4][C:5]([C:7]2[N:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[O:30])[CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[N:1]1
Reactant: CC(N)CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CNC(c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)=N1
Yield: 55 %

Procedure:
6-[4-(2-Trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (2-aminopropyl)amide (0.100 g, 0.229 mmol) was refluxed in POCl3 (3 mL) for 6 hours. The mixture was cooled, concentrated and quenched with 1 N NaOH (3 mL). The brown solution was extracted with dichloromethane. The organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to afford the title compound as thick syrup in 55% yield (0.053 g). 1H NMR (300 MHz, CDCl3) 8.10 (d, J=9.6 Hz, 1H), 7.71 (d, J=7.4 Hz, 1H), 7.65-7.50 (m, 2H), 7.34 (d, J=7.4 Hz, 1H), 6.94 (d, J=9.6 Hz, 1H), 4.25-4.12 (m, 1H), 4.10-3.60 (m, 7H), 3.41 (dd, J=7.6, 11.8 Hz, 1H), 3.30 (t, J=5.1 Hz, 2H), 1.30 (d, J=6.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ167.6, 160.9, 159.5, 143.2, 134.2, 134.2, 132.4, 129.5, 127.5, 127.2, 127.1, 126.9, 126.9, 126.8, 126.7, 125.4, 121.8, 112.2, 46.3, 44.5, 44.4, 41.2, 21.6. MS (ES+) m/z 419.2 (M+1).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[C:6]([F:14])[C:7]([N+:11]([O-:13])=[O:12])=[C:8](F)[CH:9]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([F:14])[C:7]([N+:11]([O-:13])=[O:12])=[C:8]([NH:2][CH3:1])[CH:9]=1
Reactant: CN
Reactant: O=[N+]([O-])c1c(F)cc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CNc1cc(Br)cc(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2 M MeNH2 in THF (82 mL) was added dropwise to a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (164 mmol) and Cs2CO3 (197 mmol) in THF (1 L). The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc and H2O. The two phases were separated and the organic layer was dried (Na2SO4) and concentrated to afford the desired product.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:21][NH:20][CH2:19][CH:18]([CH2:22][O:23]CC2C=CC=CC=2)[NH:17][CH2:16][CH2:15][S:14][CH2:13][CH2:12][NH:11]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:23][CH2:22][CH:18]1[CH2:19][NH:20][CH2:21][CH:10]([CH2:9][OH:8])[NH:11][CH2:12][CH2:13][S:14][CH2:15][CH2:16][NH:17]1
Reactant: c1ccc(COCC2CNCC(COCc3ccccc3)NCCSCCN2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: OCC1CNCC(CO)NCCSCCN1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
5,9-Bis (benzyloxymethyl) -1-thia-4,7,10-triazacyclododecane (0.28 g, 0.65 mmol) was dissolved in methanol (10 ml). Ammonium formate (0.39 g) and 10% Palladium on carbon (1.3 g) were added under nitrogen and the mixture was stirred at 50° C. for 16 hours. The catalyst was filtered off and washed with methanol (5 ml). The filtrate was evaporated and 5,9-bis(hydroxymethyl)-1-thia-4,7,10-triazacyclododecane was isolated as a white solid. Mp. 210°-220° C. (subl.). Yield: 0.099 g (61%).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:13][NH:14]2)=[CH:10][CH:9]=1)[C:3]([O:5]C)=[O:4].O.[OH-].[Li+].O>O1CCOCC1>[CH3:1][C:2]([CH3:29])([CH:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:13][NH:14]2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(-c3ccccc3)n[nH]c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(-c3ccccc3)n[nH]c2c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of methyl 2,2-dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)propanoate (45 mg, 0.12 mmol), lithium hydroxide monohydrate (50 mg, 1.2 mmol), water (2 mL), and dioxane (4 mL) was stirred at 110° C. overnight. The mixture was cooled to rt and partitioned between water (5 mL) and diethyl ether (10 mL). The ether layer was extracted with water (10 mL). The combined aqueous solutions were acidified with 6N hydrochloric acid, extracted with ethyl acetate (15 mL), washed with brine (10 mL), dried (Na2SO4) and concentrated to give 2,2-dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)propanoic acid (46 mg, 0.12 mmol, 100% yield) as a glassy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2(O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:25](N(CC)CC)[CH3:26].S(Cl)(Cl)=O.C([Mg]Br)C>C1COCC1>[CH2:25]([C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[NH:8][C:7](=[O:12])[N:6]1[CH2:13][C:14]([F:17])([F:16])[F:15])[CH3:26]
Reactant: O=C1Nc2ccc(Cl)cc2C(O)(c2ccccc2)N1CC(F)(F)F
Reactant: CCN(CC)CC
Agent: CC[Mg]Br
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCC1(c2ccccc2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a −20° C. solution of 6-chloro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (5.5 g, 15 mmol) in THF (50 mL) was added triethylamine (10.7 mL, 77 mmol) and then thionyl chloride (1.2 mL, 17 mmol) was added dropwise. After 20 min, 1M ethylmagnesium bromide in THF (46 mL, 46 mmol) was added over 10 min. and the reaction mixture warmed to 0° C. After an additional 30 min at 0° C., the reaction was quenched by pouring into a well stirred mixture of 300 mL EtOAc and 200 mL water which was acidified with 1N HCl solution. The layers were mixed and separated and the organic layer washed with 200 mL brine and filtered to remove unreacted starting material. The filtrate was concentrated in vacuo. Purification by normal phase chromatography (120 g silica gel cartridge, 10-75% EtOAc/hexanes) provided 4-ethyl-6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) δ 8.73 (s, NH); 7.39 (m, 3H); 7.35 (m, 2H); 7.09 (dd, 1H, J=8.43 and 2.2 Hz); 6.70 (d, 1H, J=8.43 Hz); 6.49 (d, 1H, J=2.38 Hz); 3.92 (dq, 1H, J=9.52 and 15.9 Hz); 3.47 (dq, 1H, J=8.61 and 17 Hz); 2.41 (dq, 1H, J=7.14 and 14.29 Hz); 2.28 (dq, 1H, J=7.14 and 14.28 Hz); 0.91 (t, J=7.14 Hz, 3H); MS (Electrospray): m/z 369.2 (M+H)
Reaction SMILES: [Cl:1][C:2]1[N:30]=[CH:29][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:14][C:13]=3[O:27][CH3:28])[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1.S(C1C=CC(C)=CC=1)(OC[CH2:36][F:37])(=O)=O>>[Cl:1][C:2]1[N:30]=[CH:29][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:14][C:13]=3[O:27][CH2:28][CH2:36][F:37])[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: COc1cc(OCCCN2CCCC2)ccc1-c1nc2cnc(Cl)cc2c(=O)n1C
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Product: Cn1c(-c2ccc(OCCCN3CCCC3)cc2OCCF)nc2cnc(Cl)cc2c1=O

Procedure:
The intended compound was produced according to the method of Example 60 but starting from 6-chloro-2-[2-methoxy-4-(3-pyrrolidin-1-ylpropoxy)phenyl]-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one and 2-fluoroethyl tosylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]CCCC.C[O:27]B(OC)OC.O>O1CCCC1>[CH:12]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([OH:27])[CH:3]=[C:4]2[CH:10]=[CH:9]1)([CH3:14])[CH3:13]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(O)cnc21
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a mixture of EXAMPLE 337F (24.3 g) in tetrahydrofuran (500 mL) at −78° C. was added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate (11.5 mL) was added, and the mixture was allowed to warm to room temperature over 1 hour. The reaction was poured into water, extracted three times with ethyl acetate, and the combined extracts were washed with brine and concentrated. The crude product was taken up in tetrahydrofuran (200 mL) at 0° C., and 1M aqueous NaOH (69 mL) was added, followed by 30% aqueous H2O2 (8.43 mL), and the solution was stirred for 1 hour. Na2S2O3 (10 g) was added, and the pH was adjusted to 4-5 with concentrated HCl and solid NaH2PO4. The solution was extracted twice with ethyl acetate, and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed on silica gel with 5-25% ethyl acetate/hexanes.
Reaction SMILES: [NH:1]([C:25]([CH3:27])=[O:26])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17]CC1C=CC=CC=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H][H]>CC(=O)OCC.[OH-].[OH-].[Pd+2]>[NH:1]([C:25]([CH3:27])=[O:26])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: [H][H]
Reactant: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O
Yield: 87.7 %

Procedure:
To a stirred solution of N-Ac-L-Leu-L-Leu-OBn (9.09 g, 23.9 mmol) in EA (100 mL) at R.T. was added 20% palladium hydroxide on carbon (Pd (OH)2 /C) (0.9 g, 10% by weight). The reaction mixture was placed under 20 psi hydrogen (H2). After 1 h the reaction mixture was filtered through celite and concentrated in vacuo to give N-Ac-L-Leu-L-Leu-OH as a white solid (6.0 g, 87.67%): 1H NMR (300 MHz, CDCl3) δ 0.82-0.90 (m, 12H), 1.39-1.82 (m, 9H), 4.18-4.34 (m, 2H), 7.94-8.13 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH:6]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=[O:4].[C:19]1([C:25]2[N:26]=[C:27]([CH2:36]Br)[O:28][C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:17])([F:18])[C:3]([N:5]([CH:6]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH2:36][C:27]1[O:28][C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]=1)=[O:4]
Reactant: COc1cccc2c1CCC2NC(=O)C(F)(F)F
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CCC2N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C(=O)C(F)(F)F
Reaction time: 12 h
Yield: 35.9 %

Procedure:
To a solution of 1-trifluoroacetamido-2,3-dihydro-4-methoxy-1H-indene (0.44 g) and 4,5-diphenyl-2-bromomethyloxazole (0.55 g) in DMF was added K2CO3 (0.30 g). After being stirred for 12 hours, the solution was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-(N-trifluoroacetyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.30 g).
Reaction SMILES: CC1(C)C(C)(C)OB(/[CH:9]=[CH:10]/[CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)O1.I[C:27]1[C:35]2[O:34][CH2:33][C:32](=[O:36])[C:31]=2[CH:30]=[CH:29][C:28]=1[O:37][CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:38][O:37][C:28]1[CH:29]=[CH:30][C:31]2[C:32](=[O:36])[CH2:33][O:34][C:35]=2[C:27]=1/[CH:9]=[CH:10]/[CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]1
Reactant: COc1ccc2c(c1I)OCC2=O
Reactant: CC(C)(C)OC(=O)N1CCC(C/C=C/B2OC(C)(C)C(C)(C)O2)CC1
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: C1COCCO1
Product: COc1ccc2c(c1/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Yield: 16.1 %

Procedure:
A solution of tert-butyl (E)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]piperidine-1-carboxylate (0.176 g, 0.501 mmol) in 1,4-dioxane (5 mL) was added with 7-iodo-6-methoxybenzofuran-3(2H)-one (0.145 g, 0.501 mmol) synthesized in Example B46, Step 2, 2 M aqueous sodium carbonate (0.750 mL, 1.50 mmol) and tetrakis(triphenylphosphine)palladium (0.0579 g, 0.0501 mmol), and the mixture was refluxed for 12 hours by heating. The reaction mixture was cooled to room temperature, concentrated, and added with water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (E)-4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)allyl]piperidine-1-carboxylate (0.0313 g, 16%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH:60]([CH3:62])[CH3:61].FC(F)(F)S(O)(=O)=O>C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:60]([CH3:62])[CH3:61])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: CC(C)OC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Yield: 13.3 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (300 mg in 4.5 ml 33% methylene chloride in cyclohexane) isopropyl trichloroacetimidate (142 mg neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (13.4 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 5 days the reaction was diluted with ethyl acetate and quenched with saturated sodium bicarbonate. The layers were separated, and the organic layer was washed with brine then dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (42 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][OH:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31]>>[CH3:26][C:23]1[C:22]([CH2:27][O:28][CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CO)cc3)cc2)CC1
Reactant: CC(Br)c1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COC(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 45, Step 2, using 1-[4′-(4-hydroxymethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (1-bromo-ethyl)-benzene.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C:14]1[C:15]([OH:29])=[C:16]([S:21]([N:24]([O:27][CH3:28])[CH2:25][CH3:26])(=[O:23])=[O:22])[C:17]([Cl:20])=[CH:18][CH:19]=1>C(O)C>[Cl:20][C:17]1[C:16]([S:21]([N:24]([O:27][CH3:28])[CH2:25][CH3:26])(=[O:22])=[O:23])=[C:15]([OH:29])[C:14]([NH:13][C:4]2[C:5](=[O:12])[C:6](=[O:11])[C:7]=2[O:8][CH2:9][CH3:10])=[CH:19][CH:18]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CCN(OC)S(=O)(=O)c1c(Cl)ccc(N)c1O
Solvent: CCO
Product: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (0.30 g, 1.76 mmol) in ethanol (5 ml) was treated with TEA (250 μl, 1.80 mmol) and the reaction mixture was heated to 45° C. A solution of 3-amino-6-chloro-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (0.58 g, 2.07 mmol) in EtOH (5 ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at 45° C. for 1 hour and then concentrated in vacuo. The residue was purified using flash chromatography (50% EtOAc in iso-hexane) to furnish a solid [M+H]+ 405.2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:21]=[C:20]([C:22]4[C:27]([CH3:28])=[CH:26][C:25](/[CH:29]=[CH:30]/[C:31]([O:33]C)=[O:32])=[CH:24][C:23]=4[CH3:35])[NH:19][C:18]=3[CH:36]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO>O.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:21]=[C:20]([C:22]4[C:23]([CH3:35])=[CH:24][C:25](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])=[CH:26][C:27]=4[CH3:28])[NH:19][C:18]=3[CH:36]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)/C=C/c1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cc3[nH]2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(/C=C/C(=O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl (E)-3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-benzimidazol-2-yl]-3,5-dimethylphenyl}-acrylate (200 mg, 420 μmol), 1N NaOH (520 μL), and methanol (260 μL) was diluted with 3 mL of water/methanol (2:1) and stirred at ambient temperature for 18 h. The solution was then quenched with 1N HCl (520 μL), filtered, and the precipitate washed with water and dried, to yield (E)-3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-benzimidazol-2-yl]-3,5-dimethylphenyl}-acrylic acid. 1H-NMR (DMSO-d6, 400 MHz): δ 8.31 (s, broad, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.74 (d, J=8.7 Hz, 2H), 7.67 (m, 1H), 7.58 (m, 3H), 7.37 (d, J=8.7 Hz, 2H), 6.63 (d, J=16.2 Hz, 1H), 2.15 (s, 6H), 1.29 (s, 9H). MS (ESI) m/z 468.2 (M+H): Retention time=1.24 min (Method 10).
Reaction SMILES: [SH2:1].C(OC([C@@H](N[C@H](C(N1N=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)[S:23][C@H:22]1[C:34]([OH:36])=[O:35])=O)C)CCC1C=CC=CC=1)=O)C>CO>[CH3:33][S:32][C:29]1[CH:30]=[CH:31][C:26]([C:24](=[S:1])[S:23][CH2:22][C:34]([OH:36])=[O:35])=[CH:27][CH:28]=1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccc(SC)cc2)S[C@H]1C(=O)O
Reactant: S
Solvent: CO
Product: CSc1ccc(C(=S)SCC(=O)O)cc1

Procedure:
Hydrogen sulphide was passed through a solution of the product of step (b) (25.0g) in methanol (250ml) and cooled in an ice bath, for a period of 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].O.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([CH:22]=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:24]([F:25])([F:27])[F:26]
Reactant: COCN(c1cc(Cl)cnc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
The unpurified aldehyde from the previous reaction was magnetically stirred in dioxane (20 mL), water (20 mL), and 4N HCl in dioxane (40 mL); and heated at 80° C. (oil bath) overnight. LCMS indicated complete reaction; the reaction was concentrated and the residue was neutralized (pH 6) with aqueous sodium bicarbonate and extracted with ethyl acetate (3×80 mL). The extracts were dried (Na2SO4), filtered, and purified by flash column chromatography on silica gel using ethyl acetate-hexane to provide 4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide. MS: (M+H)/z=398.9.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].F[C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].C(N(CC)CC)C>CN(C=O)C>[CH:2]([S:4][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([CH3:3])[CH3:1]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
Isopropylthiol (3.06 mL, 32.8 mmol) was added to a solution of 2-fluoro-5-nitrobenzoic acid (5.06 g, 27.3 mmol) and triethylamine (8.4 mL, 60.3 mmol) in DMF (86 mL). The reaction mixture was stirred overnight at rt and then most of the DMF was removed in vacuo. The residual solution was poured into ice water (500 mL) and the resulting yellow solid was isolated by filtration to give 16A (6.5 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc([N+](=O)[O-])cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc([N+](=O)[O-])ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.