Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[CH:17]=[N:18][C:19](SC)=[N:20][CH:21]=3)[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:24].O[O:31][S:32]([O-:34])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[CH3:44]O>CC(C)=O.O>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[CH:21]=[N:20][C:19]([S:32]([CH3:44])(=[O:34])=[O:31])=[N:18][CH:17]=3)[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:24]
Reactant: O=S([O-])OO
Reactant: CSc1ncc(-c2ccc3nc(C)c(Cc4ccccc4OC(F)F)n3c2)cn1
Reactant: CO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc2ccc(-c3cnc(S(C)(=O)=O)nc3)cn2c1Cc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of Example 268 (4 g, 9.697 mmol) in MeOH (150 mL) and acetone (20 mL) at 0° C. was treated with Oxone® (potassium peroxymonosulfate; 11.92 g, 19.39 mmol) in water (100 mL). The resulting suspension was allowed to warm to r.t. and stirred for 18 h. The reaction mixture was treated with water and extracted with DCM (4×300 mL). The combined organic layers were concentrated in vacuo. A portion of the resulting crude yellow solid (4.4 g, 100%) was further purified by preparative HPLC to give the title compound (56 mg was obtained from 130 mg of crude material) as a white solid. HPLC-MS (pH 10): MH+ m/z 445.6 [M+H]+, RT 1.54 minutes.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[N:17]=[C:16]([CH:18]([OH:20])[CH3:19])[CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[Br:11][C:12]1[N:17]=[C:16]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(O)c1cccc(Br)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)c1cccc(Br)n1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
Oxalyl chloride (2.1 mL, 3.81 mmol) in dry CH2Cl2 was cooled to −70° C. followed by adding DMSO (0.6 mL, 8.39 mmol) dropwise. After stirred for 5 min under −60° C., 1-(6-bromo-pyridin-2-yl)-ethanol (770 mg, 3.81 mmol) in dry CH2CL2 (10 mL) was added dropwise. After stirred for 30 min, TEA (2.7 mL, 19.83 mmol) was added and the resulting mixture was warmed to RT and stirred for 1 h. The reaction mixture was quenched with H2O. The organic layer was washed with H2O, brine, and dried over MgSO4. Solvent was removed and the crude compound was purified by chromatography on silica gel. Elution with hexane:acetone mixture (90:10) gave a white solid. MS m/z: 200.3(M+H). Calc'd. for C7H8BrNO-198.96.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[H-].[Na+].Cl[CH2:17][O:18][CH3:19]>CN(C)C=O>[CH3:17][O:18][CH2:19][O:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6]
Reactant: COCCl
Reactant: CON(C)C(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc(C(=O)N(C)OC)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
69.0 g (380 mmol) of B5 were dissolved in 500 ml of dry dimethylformamide, cooled to 0° C. and 11.5 g (480 mmol) sodium hydride were added and the mixture was allowed to stirr for 10 minutes. A solution of 31.2 ml (418 mmol) (chloromethyl)methylether in 100 ml of dry diemthylformamide was added at this temperature over a period of 30 minutes. After stirring at room temperature overnight, the solvent was distilled off and the residue was partitionated between 400 ml of dichloromethane and 100 ml of water. The organic layer was washed with 50 ml of aqueous sodium hydrogen carbonate and two times with water (80 ml each) and finally dried over sodium sulfate. Removing the solvent in vacuo yielded 73.5 g (87%) B6 as a colorless oil which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (300 mg, 0.83 mol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (156 mg, 0.83 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (239 mg, 1.25 mmol) and 1-hydroxybenzotriazole hydrate (127 mg, 0.83 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (283 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Cl[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:6][N:7]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Cc1cc(Cl)ncc1O
Product: Cc1cc(Cl)ncc1OCc1ccc(F)cc1
Yield: 96 %

Procedure:
The title compound is prepared in 96% yield (3.38 g, white solid) from 6-chloro-4-methylpyridin-3-ol (2.00 g, 13.9 mmol) and 1-(chloromethyl)-4-fluorobenzene (3.22 g, 22.3 mmol) in a similar manner to Step-1 of Amine-49.
Reaction SMILES: [I-].[K+].[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]([C:20]1[O:21][C:22]([CH3:27])=[C:23]([CH2:25]Cl)[CH:24]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:16][O:17][C:18]([C:20]1[O:21][C:22]([CH3:27])=[C:23]([CH2:25][NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][CH:7]=2)[CH:24]=1)=[O:19]
Reactant: COC(=O)c1cc(CCl)c(C)o1
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(CNc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
Potassium iodide (32 mg) and a solution of biphenyl-4-ylamine (74 mg, 0.438 mmoles) in tetrahydrofuran (1 ml) was added to a mixture of 4-chloromethyl-5-methyl-furan-2-carboxylic acid methyl ester (159)(75 mg, 0.398 mmoles) and potassium carbonate (83 mg) in tetrahydrofuran (1 ml). The mixture was stirred at room temperature under an argon atmosphere for 16 hours, and then refluxed with the exclusion of light for 16 hours. After cooling, the mixture was concentrated and the residue was purified by by flash chromatography, using a gradient elution of petrol/diethyl ether 9:1 v/v to 4:1 v/v, to afford compound 158(91 mg). LC/MS System A; Rt=3.93 mins, m/z (ES+)=322(M+H for C20H19NO3).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:22]1=[CH:23][C:24]2[C:25]([CH:30]([O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:32]1)=[N:26][CH:27]=[CH:28][CH:29]=2)(=O)=O>C1(C)C=CC=CC=1.CO.C(OCC)(=O)C.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>[C:1]1([C:22]2=[CH:23][C:24]3[C:25]([CH:30]([O:33][Si:34]([CH:38]([CH3:40])[CH3:39])([CH:41]([CH3:43])[CH3:42])[CH:35]([CH3:36])[CH3:37])[CH2:31][CH2:32]2)=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[Si](OC1CCC(OS(=O)(=O)C(F)(F)F)=Cc2cccnc21)(C(C)C)C(C)C
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC1CCC(c2ccccc2)=Cc2cccnc21)(C(C)C)C(C)C
Temperature: 80 °C

Procedure:
The mixture of phenylboronic acid (0.060 g, 0.495 mmol), sodium carbonate (0.382 mL, 0.764 mmol), (E)-9-(triisopropylsilyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridin-6-yl trifluoromethanesulfonate (0.1922 g, 0.413 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.021 mmol) in Toluene (5 mL) and MeOH (1 mL) was heat to 80° C. under N2 for 3 hours. LCMS showed no more starting material. The reaction was diluted with ethyl acetate and washed with water one time. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated to give the crude product. The crude was used as it is. MS(ESI)[M+H+]=394.32.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[O:28]1[C:30]2([CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)[CH2:29]1>C(O)(C)C>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([CH2:29][C:30]4([OH:28])[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(O)(CN2CC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)C2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
To a mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.4 g, 0.0011 mol) in isopropanol (40 mL) was added tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.27 g, 0.0013 mol) at room temperature under an atmosphere of nitrogen. The mixture was stirred at 80° C. for three and a half hours. Additional tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.13 g, 0.00061 mol) was added and the mixture was stirred at 80° C. for seven hours. Furthermore, tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.13 g, 0.00061 mol) was added and the mixture was stirred at 60° C. for 18 hours, then 80° C. for eight hours. The solvent was removed under reduced pressure. The residue was suspended in water (50 mL) and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (1×50 mL) and brine (1×50 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (5:95) followed by methanol/dichloromethane (10:90) as mobile phase to yield tert-butyl 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-hydroxy-1-piperidinecarboxylate (0.243 g, 0.000425 mol).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:21][C@H:10]3[C:11]=2[N:12]([C:14]2[N:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:13]=1)=[O:5])C.[OH-:22].[Na+].[CH3:24]O>C1COCC1>[Cl:20][C:17]1[N:16]=[N:15][C:14]([N:12]2[C:11]3[C@@H:10]4[CH2:21][C@@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:5])=[O:3])=[N:13]2)=[CH:19][CH:18]=1.[CH3:24][O:22][C:17]1[N:16]=[N:15][C:14]([N:12]2[C:11]3[C@@H:10]4[CH2:21][C@@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:3])=[O:5])=[N:13]2)=[CH:19][CH:18]=1
Reactant: [OH-]
Reactant: CO
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)nn2)c2c1C[C@H]1C[C@@H]21
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)nn1
Product: O=C(O)c1nn(-c2ccc(Cl)nn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a solution of (1aR,5aR)-2-(6-chloropyridazin-3-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (245 mg, 0.804 mmol) in methanol (2 mL) and THF (2 mL) was added a 2.0 M aqueous solution of sodium hydroxide (1.206 mL, 2.412 mmol). The reaction was stirred at 23° C. for 4 h. The organic solvents were removed by distillation. To the remaining residue was added 15 mL water. The aqueous solution was acidified to pH 2 by addition of 1 M HCl. The resulting precipitate was collected by filtration, rinsed with water, then dried to provide a 4:1 mixture (based on LC) of (1aR,5aR)-2-(6-chloropyridazin-3-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and (1aR,5aR)-2-(6-methoxypyridazin-3-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (180 mg) which was used without further purification. LCMS m/z=273.3 [M+H]+ and 277.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:14][OH:15].O.[OH-].[Na+]>C(O)C.CCOCC>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:14][OH:15])=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
The first step of the process of the present invention was conducted as follows. At first, 8.79 g (50.5 mmol) of 4-trifluoromethylbenzaldehyde and 3.83 g (55.1 mmol) of hydroxylamine hydrochloride were dissolved in 12.5 ml of ethanol and 34 ml of water followed by the addition of 2.5 g of sodium hydroxide and stirring for 1 hour at room temperature. After adding ether and washing with dilute hydrochloric acid, the reaction liquid was further washed with saturated brine followed by drying with mirabilite and concentrating to obtain 9.25 g (48.2 mmol) of 4-trifluoromethylbenzaldehyde oxime (yield: 95.5%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:30])([F:29])[F:28])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.O[N:60]=[C:61]([C:63]1[CH:68]=[CH:67][C:66]([C:69]2[CH:74]=[CH:73][C:72]([CH3:75])=[CH:71][CH:70]=2)=[CH:65][CH:64]=1)[NH2:62].C([O-])(O)=O.[Na+]>O1CCOCC1.CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([N:8]([CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:43])[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([C:38]4[O:40][N:62]=[C:61]([C:63]5[CH:64]=[CH:65][C:66]([C:69]6[CH:74]=[CH:73][C:72]([CH3:75])=[CH:71][CH:70]=6)=[CH:67][CH:68]=5)[N:60]=4)=[CH:41][CH:42]=3)=[O:32])=[CH:11][CH:12]=2)=[O:31])=[C:20]([C:27]([F:29])([F:30])[F:28])[CH:21]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)O)cc3)cc2)c(C(F)(F)F)c1
Reactant: Cc1ccc(-c2ccc(C(N)=NO)cc2)cc1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37 (150 mg, 0.25 mmol) in dioxane (4 mL) were added N-methylmorpholine (60.0 μl, 0.55 mmol) and isobutyl chloroformate (34.0 μl, 0.26 mmol). After stirring at room temperature for 1 h, the reaction mixture was added drop wise to a stirring solution of N′-hydroxy-4′-methyl-[1,1′-biphenyl]-4-carboximidamide INT-40 (62.0 mg, 0.275 mmol) in dioxane (2 mL) and DMF (2 mL). The reaction mixture was allowed to stir at room temperature for 1 h, then heated to 90° C. for 2 h, and then heated to 120° C. for 16 h. The reaction mixture was allowed to cool to room temperature then poured into NaHCO3 (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (EA/isohexanes) to yield 77 mg (35%) of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-41. LCMS-ESI (m/z) calculated for C45H41F3N4O6: 791; no m/z observed, tR=3.26 min (Method 10). 1H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.35-8.04 (m, 4H), 8.04-7.80 (m, 2H), 7.80-7.28 (m, 11H), 7.28-7.08 (m, 2H), 4.80 (s, 1H), 4.70 (s, 1H), 4.00 (s, 2H), 3.92-3.79 (m, 5H), 2.40 (s, 3H), 1.47 (s, 4.5H), 1.33 (s, 4.5H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]([C:7]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[O:16][CH2:15][CH2:14][C:13]3=O)[CH2:9][CH2:8]1)=[O:6]>FC(F)(F)C(O)=O>[CH3:3][O:4][C:5]([C:7]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[O:16][CH2:15][CH2:14][CH2:13]3)[CH2:8][CH2:9]1)=[O:6]
Reactant: COC(=O)C1(c2ccc3c(c2)C(=O)CCO3)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(c2ccc3c(c2)CCCO3)CC1
Reaction time: 0.08 h
Yield: 92.7 %

Procedure:
To trifluoroacetic acid (20 mL) was added NaBH4 (0.70 g, 130 mmol) in portions at 0° C. under N2 atmosphere. After stirring for 5 min, a solution of 1-(4-oxo-chroman-6-yl)-cyclopropanecarboxylic methyl ester (1.6 g, 6.5 mmol) was added at 15° C. The reaction mixture was stirred for 1 h at room temperature before being slowly quenched with water. The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic extracts dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-chroman-6-yl-cyclopropanecarboxylic methyl ester (1.4 g, 92%), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 7.07-7.00 (m, 2H), 6.73 (d, J=8.4 Hz, 1H), 4.17 (t, J=5.1 Hz, 2H), 3.62 (s, 3H), 2.79-2.75 (m, 2H), 2.05-1.96 (m, 2H), 1.57-1.54 (m, 2H), 1.16-1.13 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](OC)=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].[NH2:32][C:33]1([C:43]([OH:45])=[O:44])[CH:40]2[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:42][CH:34]1[CH2:35]3)[CH2:39]2>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:32][C:33]3([C:43]([OH:45])=[O:44])[CH:40]4[CH2:39][CH:38]5[CH2:37][CH:36]([CH2:35][CH:34]3[CH2:42]5)[CH2:41]4)=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31]
Reactant: COC(=O)c1ccc(-c2ccccc2Cl)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1
Reactant: NC1(C(=O)O)C2CC3CC(C2)CC1C3
Product: CN(C)CCCOc1cc(-c2nc(C(=O)NC3(C(=O)O)C4CC5CC(C4)CC3C5)ccc2-c2ccccc2Cl)ccc1Cl
Product: Cl
Yield: 57.8 %

Procedure:
According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 290 mg (0.63 mmol) of methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridine-2-carboxylate and 184 mg (0.94 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain 120 mg of 2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride in the form of white powder.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[NH:21][S:22]([CH2:25][C:26]([O:28]C)=O)(=[O:24])=[O:23])[N:6]=1.C(OCC)C.C(O)(C)C>CO>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[NH:21][S:22]([CH2:25][C:26]([NH:2][CH3:1])=[O:28])(=[O:24])=[O:23])[N:6]=1
Reactant: COC(=O)CS(=O)(=O)Nc1c(F)cccc1Oc1nc(OC)cc(OC)n1
Reactant: CN
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CO
Product: CNC(=O)CS(=O)(=O)Nc1c(F)cccc1Oc1nc(OC)cc(OC)n1
Reaction time: 552 h

Procedure:
Methylamine (4.2 g of a 33% solution in industrial methylated spirits) was added to a solution of the product of stage (a) (3 g) in methanol (60 ml) at room temperature. After standing for 23 days, the solution was run down under vacuum at less than 35° C. to give a brown oil. Trituration with a mixture of diethyl ether and isopropanol gave an off-white solid which was dried without heat to give 1.3 g of the desired product, mp 193°-198° C.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH:7]([O:16][C:17]1[C:22]([Br:23])=[CH:21][C:20]([C:24]2[C:33]3[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[S:36][C:32]=3[C:31]([Br:41])=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[CH:29]3)=[CH:19][C:18]=1[Br:42])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)(C)(C)C.O>FC(F)(F)C(O)=O>[Br:23][C:22]1[CH:21]=[C:20]([C:24]2[C:33]3[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[S:36][C:32]=3[C:31]([Br:41])=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[CH:29]3)[CH:19]=[C:18]([Br:42])[C:17]=1[O:16][CH:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]([OH:43])=[O:5]
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(F)cc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(Cc1ccc(F)cc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 55 °C

Procedure:
A suspension of 2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11 -yl)-phenoxy]-3-(4-fluoro-phenyl)-propionic acid tert-butyl ester (0.232 g 0.295 mmol) in trifluoroacetic acid (5 mL) was heated at 55° C. for 11 hours. After cooling to room temperature the reaction mixture was poured into water (60 mL) and extracted with ether. The combined ether extracts were washed with water and brine, concentrated, and dried in vacuo at 60° C. to provide the title compound as an off white solid (0.187 g, 98%): NMR (CDCl3); δ8.36 (d, J=7 Hz, 1 H), 7.82 (d, J=7 Hz, 1 H), 7.68 (ddd, J=8, 6, 2 Hz, 1 H), 7.58 (dd, J=8, 2 Hz, 2 H), 7.55-7.48 (m, 2 H), 7.45-7.35 (m, 3 H), 7.15 (dt, J=7, 1, 1H), 7.03 (tt J=10, 3, 1, 2H), 6.71 (d, J=8 Hz, 1 H), 5.44 (t, J=6 Hz, 1 H), 3.56 (d, J=7 Hz, 2 H); MS (+FAB): [M+], 3 bromine isotope pattern, 726 (15%), 728 ( 30%) 730 (35%) 732 (15%); Anal. Calc. for C31H18Br3FO3S: C, 51.06, H, 2.49, N, 0.00. Found: C, 50.80, H, 2.46, N, 0.10.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:24][O:23][C:18]1[CH:17]=[C:16]([O:25][CH3:26])[CH:15]=[C:14]2[C:19]=1[C:20](=[O:22])[NH:21][C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:3][CH2:2][NH:1][S:36]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)(=[O:38])=[O:37])=[C:6]([CH3:27])[CH:7]=1)=[N:13]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN)c(C)c3)nc2c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCCOc2c(C)cc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)cc2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
A mixture of 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.060 g, 0.162 mmol), 4-methoxybenzenesulfonyl chloride (0.044 mg, 0.211 mmol), and triethylamine (29.4 μL, 0.211 mmol) in CH2Cl2 (812 μL) was stirred at room temperature for 3 h. The mixture was chromatographed directly on silica gel to yield N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzenesulfonamide (0.046 g, 53%) as a white solid after lyophilization from MeCN/H2O, Selected data: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.81 (s, 1H), 7.88 (s, 2H), 7.83-7.73 (m, 3H), 7.17-7.07 (m, 2H), 6.73 (d, J=2.31 Hz, 1H), 6.52 (d, J=2.29 Hz, 1H), 3.91-3.75 (m, 11H), 3.12 (q, J=5.75 Hz, 2H), 2.24 (s, 6H); MS (APCI) m/z 540 [M+H]+.