Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH2:19]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)(=[O:28])=[O:29])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(NCc1ccccc1)c1ccc(B(O)O)cc1
Reactant: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and 4-benzylsulfamoylbenzeneboronic acid. The crude product was purified by preparative HPLC (Gilson) (35%, pink crystals).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH2:16][CH3:17])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH2:23][CH3:24])=[C:19](/[F:22])\[CH2:20][OH:21])[C:3]=1[O:25][CH2:26][CH3:27].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH2:16][CH3:17])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH2:23][CH3:24])=[C:19](/[F:22])\[CH:20]=[O:21])[C:3]=1[O:25][CH2:26][CH3:27]
Reactant: CCOc1c(/C(CC)=C(/F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)CC
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCOc1c(/C(CC)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)CC

Procedure:
As described in General Procedure H-1, (2E)-3-(4-bromo-8-sec-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-pent-2-en-1-ol (Compound A-143, 411 mg, 0.94 mmol), tetrapropylammonium perruthenate (10 mg, 0.028 mmol) and 4-methylmorpholine N-oxide (274 mg, 2.34 mmol) were reacted in acetonitrile and dichloromethane to give the title compound as a yellow oil after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([C:8]2[NH:12][N:11]=[CH:10][CH:9]=2)=[N:6][N:7]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[N:13]([CH2:2][C:3]1[S:4][C:5]([C:8]2[NH:12][N:11]=[CH:10][CH:9]=2)=[N:6][N:7]=1)=[N+:14]=[N-:15]
Reactant: ClCc1nnc(-c2ccn[nH]2)s1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nnc(-c2ccn[nH]2)s1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a 1 mL DMF solution of 2-(chloromethyl)-5-(1H-pyrazol-5-yl)-1,3,4-thiadiazole (58 mg, 0.29 mmol) was added sodium azide (20 mg, 0.30 mmol). Stirring continued at rt for 3 hr. The reaction mixture was concentrated and diluted with AcOEt and water. The organic layer was separated. The aqueous layer was extracted with AcOEt twice and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (60 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][S:8]([NH2:11])(=[O:10])=[O:9].Cl[C:17]1[C:18]([CH3:26])=[CH:19][C:20]2[N:21]([N:23]=[CH:24][N:25]=2)[N:22]=1>>[CH2:12]([C:3]([CH2:14][CH3:15])([CH2:4][CH2:5][CH2:6][CH2:7][S:8](=[O:9])(=[O:10])[NH2:11])[CH2:2][O:1][C:17]1[C:18]([CH3:26])=[CH:19][C:20]2[N:21]([N:23]=[CH:24][N:25]=2)[N:22]=1)[CH3:13]
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: CCC(CC)(CO)CCCCS(N)(=O)=O
Product: CCC(CC)(CCCCS(N)(=O)=O)COc1nn2ncnc2cc1C

Procedure:
Using 6-hydroxy-5,5-diethyl-1-hexanesulfonamide and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction was conducted as in Example 5 to produce the title compound. m.p. 132°-133° C.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:34][CH2:35][CH2:36][O:37][CH3:38])[C@@H:21]1[CH2:39][I:40])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.F.F.F.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[I:40][CH2:39][C@@H:21]1[C@@H:20]([CH2:19][OH:18])[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:22]1[O:34][CH2:35][CH2:36][O:37][CH3:38]
Reactant: COCCO[C@@H]1[C@H](CI)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Agent: F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCO[C@@H]1[C@H](CI)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Yield: 69.4 %

Procedure:
A solution of 5′-O-(tert-butyldiphenylsilyl)-3′-deoxy-3′-(iodomethyl)-2′-O-(2-methoxyethyl)-5-methyluridine (1.12 g, 1.65 mmol) and triethylamine trihydrofluoride (1.1 mL, 1.1 g, 6.7 mmol) in 20 mL of THF was stirred at rt for 24 h. The reaction mixture was diluted with 50 mL of ethyl acetate and washed with water and brine. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on a silica gel column. Gradient elution with 2:1, 1:2 and then 1:3 hexanes-EtOAc provided 504 mg of the title compound as a white foam.
Reaction SMILES: CO[C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([NH:15][CH3:16])[CH2:8]2.[CH2:17]([OH:19])C>>[NH2:15][CH2:7][CH2:6][CH2:5][N:15]([CH3:16])[CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][C:11]([O:19][CH3:17])=[C:12]([O:13][CH3:14])[CH:3]=2)[CH2:8]1
Reactant: CCO
Reactant: CNC1CCc2c(ccc(OC)c2OC)C1
Product: COc1cc2c(cc1OC)CC(N(C)CCCN)CC2

Procedure:
Rf value: 0.27 (alumina, eluant: 95 parts by volume of methylene chloride+5 parts by volume of ethanol).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH3:15])C.FC1C=CC(OC)=C(O)C=1.C(=O)([O-])[O-].[K+].[K+].C(OC(OCC)CCl)C.[I-].[K+]>CN(C)C=O>[F:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH3:15])=[C:7]([CH:12]=1)[O:6][CH2:5][CH:4]=[O:3]
Reactant: CCOC(COc1cc(F)ccc1OC)OCC
Agent: CCOC(CCl)OCC
Agent: COc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1OCC=O
Temperature: 100 °C

Procedure:
2-(5-Fluoro-2-methoxyphenoxy)acetaldehyde diethylacetal A suspension of 10.8 g of 5-fluoro-2-methoxyphenol and 12.6 g of potassium carbonate in 45 ml of N,N-dimethylformamide was heated for 45 minutes at 100° C. To the reaction mixture were added 18.5 ml of chloroacetaldehyde diethylacetal and 12.7 g of potassium iodide and the reaction mixture was heated for 4 hours at 140° C. After cooling, the reaction mixture was poured into ice water and extracted with ether. The extract was washed with aqueous sodium hydroxide solution and water, dried and evaporated. The residue was chromatographed on silica gel using chloroform as an eluant to give 11.8 g of the desired compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH2:6][CH2:7][CH:8]([OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=1)=[O:4].[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH2:20][C:21]#[CH:22]>>[F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH2:6][CH2:7][CH:8]([OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:22]#[C:21][CH2:20][CH2:19][C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[CH:10]=1)=[O:4]
Reactant: O=C(NCCC(O)c1cccc(I)c1)C(F)(F)F
Reactant: C#CCCc1ccc(C)cc1
Product: Cc1ccc(CCC#Cc2cccc(C(O)CCNC(=O)C(F)(F)F)c2)cc1

Procedure:
Sonogashira reaction of (2,2,2-trifluoro-N-(3-hydroxy-3-(3-iodophenyl)propyl)acetamide) with 1-(but-3-ynyl)-4-methylbenzene yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-p-tolylbut-1-ynyl)phenyl)propyl)acetamide as yellow oil. Yield (0.310 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.29-7.51 (m, 4H), 7.17 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 4.84-4.86 (m, 1H), 3.66-3.70 (m, 1H), 3.38-3.43 (m, 1H), 2.89 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 2.33 (s, 3H), 2.25 (bs, 1H), 1.92-1.97 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:35])[C:8]=1[CH2:9][S:10][C:11]1[N:12]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:13]([C:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH3:27])[CH:20]=2)([CH3:18])[CH3:17])=[CH:14][N:15]=1)[NH2:5].C([O:40][C:41](=[O:55])[CH2:42][C@H:43]([NH:47]C(OC(C)(C)C)=O)[C:44](O)=[O:45])(C)(C)C.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.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:47][C@H:43]([C:44]([NH:5][C:4]1[CH:6]=[C:7]([F:35])[C:8]([CH2:9][S:10][C:11]2[N:12]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:13]([C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH3:27])[CH:20]=3)([CH3:17])[CH3:18])=[CH:14][N:15]=2)=[C:2]([Cl:1])[CH:3]=1)=[O:45])[CH2:42][C:41]([OH:55])=[O:40]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(N)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(NC(=O)[C@@H](N)CC(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
To a solution of 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluoroaniline (50 mg, 93.6 μmol) and (S)-4-t-butoxy-2-(t-butoxycarbonylamino)-4-oxobutanoic acid (2.4 equiv, 66 mg, 0.244 mmol) in DCM (3 mL) was added HATU (2.2 equiv, 80 mg, 0.204 mmol) followed by DIPEA (3.0 equiv, 49 mL, 0.281 mmol). The mixture was stirred at room temperature overnight. Purification by column chromatography provided the protected product. Deprotection was performed by stirring with TFA (1 mL) and DCM (1 mL) for 1 h. Purification by HPLC using NH4CO3 as a modifier afforded the title compound as a white solid (11 mg, 18%). 1H NMR (400 MHz, MeOD) δ 7.43 (s, 1H), 7.37 (d, J=11.6 Hz, 1H), 7.25 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.80 (m, 2H), 6.56-6.49 (m, 2H), 6.38-6.30 (m, 1H), 6.22 (m, 1H), 4.19 (t, J=7.6, 1H), 4.00 (dd, J=13.5, 7.4 Hz, 2H), 3.71 (s, 3H), 2.89-2.78 (m, 1H), 2.67 (dd, J=17.0, 8.1 Hz, 1H), 1.54 (s, 3H), 1.53 (s, 3H); MS (EI) m/z 649 (MH+).
Reaction SMILES: [OH-].[Na+].C([O:11][CH2:12][CH2:13][CH2:14][C:15]1[C:16]2[C:17]([C:22](=[O:32])[N:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:24]=2)=[CH:18][NH:19][C:20]=1[CH3:21])(=O)C1C=CC=CC=1>CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([N:23]2[C:22](=[O:32])[C:17]3=[CH:18][NH:19][C:20]([CH3:21])=[C:15]([CH2:14][CH2:13][CH2:12][OH:11])[C:16]3=[N:24]2)=[CH:26][CH:27]=1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1CCCOC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1CCCO
Reaction time: 18 h
Yield: 61.4 %

Procedure:
To a solution of sodium hydroxide (0.075 g, 1.88 mmol) in methanol (10 ml) was added the product of Example 105 (0.1 g, 0.42 mmol) and the mixture stirred for 18 hours. The solvent was evaporated in vacuo and the residue taken up in water and adjusted to pH 6 with 1N HCl. The yellow precipitate was extracted into 10% methanol/CH2Cl2 and the organic phase separated, dried, filtered and evaporated to give a yellow solid. Recrystallisation from MeOH/CH2Cl2/EtOAc afforded the title compound as a yellow solid (0.082 g, 60.5%). 1H NMR (360 MHz, DMSO-d6) δ12.22 (1H, br s), 8.44 (1H, s), 8.23 (2H, d, J 8.9 Hz), 7.46 (2H, d, J 8.9 Hz), 4.54 (1H, t, J 5.3 Hz), 3.44 (2H, dt, J 5.5, J 6.2 Hz), 2.71 (2H, t, J 7.2 Hz), 2.35 (3H, s), 1.78 (2H, t, J 7.2 Hz); MS (ES+) m/z 318/320 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].C(O)(=O)C>C1C=CC=CC=1.N1CCCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:11]([C:12]([CH3:14])=[O:13])[C:10]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccccc1Cl)C(C)=O
Yield: 98.1 %

Procedure:
A mixture of 25.0 g of 2-chlorobenzaldehyde, 23.1 g of ethyl acetoacetate, 2.1 g of acetic acid and 0.6 g of piperidine in 100 cc of benzene was heated under reflux for 8 hours and removed water by a Dean-Stark trap. After cooling, to the reaction mixture was added ethylacetate and water. The organic layer was further washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane=1/9) to obtain 44.0 g of compound A. Yield: 97.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl.[CH:39]1[CH:40]=[CH:41]C2N(O)N=[N:45][C:43]=2[CH:44]=1.N1CCCCC1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([N:45]2[CH2:41][CH2:40][CH2:39][CH2:44][CH2:43]2)=[O:23])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(OCC(=O)N4CCCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenoxy}-acetic acid (100 mg), WSC.HCl (81 mg), and HOBT.H2O (57 mg) were dissolved in chloroform (3 ml) to prepare a solution. Piperidine (29 mg) was then added to the solution, and the mixture was stirred at room temperature for 3 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (31 mg, yield 26%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH2:58][C:59]#[CH:60])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH:61][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]#[CH:60])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: C#CC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 46 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)but-3-ynylamine in tetrahydrofuran. Yield: 46%; Rf value: 0.42 (silica gel: dichloromethane/ethanol=9:1); C24H23ClN4O2 (434.925); mass spectrum: (M+H)+=435/437 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:28])[O:22][C:21](=[O:23])/[C:20](=[CH:24]/[C:25](Cl)=[O:26])/[O:19]1>>[CH3:17][C:18]1([CH3:28])[O:19][C:20](=[CH:24][C:25]([N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:26])[C:21](=[O:23])[O:22]1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)Cl)O1
Reactant: Fc1ccc(CNc2ccc(F)cc2)cc1
Product: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccc(F)cc2)c2ccc(F)cc2)O1

Procedure:
Acylation of (4-fluorobenzyl)-(4-fluorophenyl)-amine (Pombrik, S. I. et al., Izv. Akad. Nauk. SSSR Ser. Khim., 6, 1982, 1289-1294) with (Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one as described in the preparation of Intermediate 71A gave the title amide as a syrup. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.72 (6H, s, CH3), 4.88 (2H, s, NCH2), 5.29 (1H, s, CH), 6.94 (4H, m, aromatics), 7.03 (2H, m, aromatics), 7.19 (2H, m, aromatics). HRMS (MAB N2) calculated for C20H17F2NO4 [M+]: 373.112565: found: 373.112320.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])([CH3:20])[CH2:9][O:10][C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:14])=O)[C:5]([F:34])=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:21][S:22]([C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)(=[O:23])=[O:24])([CH3:20])[CH2:9][O:10][C@@:11]([C:12]#[N:14])([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:5]([F:34])=[CH:4][CH:3]=1
Reactant: C[C@@](CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1nc(Br)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[C@](C#N)(OC[C@](C)(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1nc(Br)ccc1F)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
A suspension of (R)-2-[(R)-2-(6-bromo-3-fluoro-pyridin-2-yl)-2-(4-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide (8.43 g, 14.70 mmol) and triethylamine (5.12 ml, 36.8 mmol) in 85 ml DCM was cooled to 0-5° C. Trifluoroacetic anhydride (2.49 ml, 17.64 mmol) was added dropwise over 30 min. Additional triethylamine (1.54 ml, 11.07 mmol) and trifluoroacetic anhydride (0.75 ml, 5.29 mmol) were added to complete the reaction. The reaction mixture was quenched by addition of 14 ml aqueous ammonia (25%) and 14 ml water. The emulsion was stirred for 15 min, more water and DCM were added and the layers were separated. The organic layer was dried with MgSO4H2O, filtered and evaporated. Purification by column chromatography on a silica gel (hexanes/10-25% EtOAc) gave 8.09 g of the title compound as a yellow resin.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C>[OH:10][CH2:9][C:7]1[N:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(CO)[nH]n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CO
Temperature: 40 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with acetonitrile (30 mL), (3-nitro-1H-pyrazol-5-yl)methanol (1.43 g, 10.0 mmol), Cs2CO3 (490 mg, 1.5 mmol), and ethyl 2-bromoacetate (2.00 g, 12 mmol). The mixture was stirred at 40° C. for 5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 151a (1.65 g, 72%) as a yellow solid. MS-ESI: [M+H]+ 229.9
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:48])([CH3:47])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:46])([C@@:13]3([CH3:45])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:59]2[CH2:69][CH2:68][C:62]3([C:66](=[O:67])[O:65][CH2:64][CH2:63]3)[CH2:61][CH:60]=2)O1>>[CH3:45][C@:13]12[C@@:12]3([CH3:46])[C@@H:21]([C@:22]4([CH3:25])[C@@H:9]([CH2:10][CH2:11]3)[C:8]([CH3:48])([CH3:47])[C:7]([C:59]3[CH2:69][CH2:68][C:62]5([C:66](=[O:67])[O:65][CH2:64][CH2:63]5)[CH2:61][CH:60]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19][C@@H:18]1[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:42])=[O:43])[CH2:37][CH2:36]1)[CH2:15][CH2:14]2
Reactant: CC1(C)OB(C2=CCC3(CCOC3=O)CC2)OC1(C)C
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC7(CCOC7=O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 59 %

Procedure:
The title compound was prepared following the procedure described in general procedure Step 5, using (1R,3 aS,5aR,5bR,7aR,11aR,11bR,13 aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-oxaspiro[4.5]dec-7-en-1-one as reactants. The product was isolated as diastereomers (solid, 59% yield). MS: m/e 749.7 (M+H)+, 4.10 min (method 7). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.35 (d, J=2.8 Hz, 1H), 5.24-5.19 (m, 1H), 4.72 (d, J=2.0 Hz, 1H), 4.59 (dd, J=2.3, 1.5 Hz, 1H), 4.37-4.25 (m, 2H), 3.12 (dd, J=14.6, 12.0 Hz, 2H), 2.87-2.78 (m, 1H), 2.84 (s, 3H), 2.67-2.53 (m, 3H), 2.50-2.40 (m, 3H), 2.33-0.90 (m, 35H), 1.70 (s, 3H), 1.09 (s, 3H), 0.98-0.92 (m, 6H), 0.96 (s, 3H), 0.86 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:47])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:28]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:20]>CC(C)=O.CN(C=O)C>[CH2:19]([O:21][C:22](=[O:47])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:12][C:4]2[CH:5]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:7]=[C:2]([Br:1])[CH:3]=2)[C:28]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:20]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CS(=O)(=O)c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
To a solution of 3-bromo-5-methanesulfonyl-phenol (1.3 g) in a mixture of acetone and DMF (2:1, 60 mL) were added potassium carbonate (7.1 g) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.7 g). The resulting mixture was stirred at 75° C. for 1 day. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (2.9 g, 87% yield). LRMS calcd for C30H41O8BrS [M+H]+ 641.2, observed 641.1.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH:12]=[O:13])=[C:10]3[C:14]([CH3:21])([C:19]#[N:20])[CH2:15][C:16]([CH3:18])([CH3:17])[C:9]3=[C:8]2[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:24].[K+].N1C=CC=CC=1>O>[C:1]1([N:7]2[C:11]([C:12]([OH:24])=[O:13])=[C:10]3[C:14]([CH3:21])([C:19]#[N:20])[CH2:15][C:16]([CH3:17])([CH3:18])[C:9]3=[C:8]2[CH3:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c2c(c(C=O)n1-c1ccccc1)C(C)(C#N)CC2(C)C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1c2c(c(C(=O)O)n1-c1ccccc1)C(C)(C#N)CC2(C)C

Procedure:
Following a procedure similar to that described in Example 13C, 17.48 g. (0.06 mole) of 2-phenyl-3-formyl-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carbonitrile was oxidized with 18.9 g. (0.12 mole) of potassium permanganate in 120 ml. of pyridine and 90 ml. of water to give 4.03 o 2-phenyl-3-carboxy-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carbonitrile which was esterified by reaction of 9.83 g. (0.032 mole) of the acid with 1.713 g. (0.035 mole) of a 50% mineral oil dispersion of sodium hydride followed by 2.23 ml (0.036 mole) of methyl iodide. There was thus obtained 4.18 g. of 2-phenyl-3-carbomethoxy-2,4,5,6-tetrahydro-1,4,6,6-tetramethylcyclopenta[c]pyrrole-4-carbonitrile.