Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:38][C:39](OC(C)=O)=[O:40]>C(Cl)Cl.O>[C:39]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@@H:15]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:40])[CH3:38]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(N)c2)cc1)NC(=O)CCC(=O)OC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(NC(C)=O)c2)cc1)NC(=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 65 h
Yield: 92 %

Procedure:
A solution of (R)-ethyl 4-(3′-aminobiphenyl-4-yl)-3-(4-methoxy-4-oxobutanamido)butanoate (70.5 mg, 0.171 mmol), Et3N (0.027 ml, 0.205 mmol) and Ac2O (0.019 ml, 0.205 mmol) in DCM (1.7 ml) is allowed to stir at room temperature for 65 hours. The reaction mixture is diluted with water. The products are extracted with DCM in a phase separator and concentrated to give crude (98 mg). The crude is purified by silica gel flash column chromatography (eluent: DCM/MeOH=10:1) to give (R)-ethyl 4-(3′-acetamidobiphenyl-4-yl)-3-(4-methoxy-4-oxobutanamido)butanoate (71.5 mg); HPLC retention time=1.45 minutes (condition D); MS (m+1)=455.4; 1H NMR (400 MHz, CD3CN, mixture of rotamers, data for major rotamer) δ ppm 1.21 (t, J=7.1 Hz, 3H) 2.07 (s, 3H) 2.31-2.34 (m, 2H) 2.40-2.51 (m, 4H) 2.82-2.84 (m, 2H) 3.58 (s, 3H) 4.07 (q, J=7.1 Hz, 2H) 4.34-4.43 (m, 1H) 6.46 (br d, J=8.9 Hz, 1H) 7.28-7.39 (m, 4H) 7.52-7.54 (m, 3H) 7.80 (s, 1H) 8.37 (br s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][O:3][N:4]2[C:5](=[O:14])[C:6]3[C:7](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:9])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCON2C(=O)c3ccccc3C2=O)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.6 %

Procedure:
At 0° C., a 60% suspension of sodium hydride in mineral oil (0.69 g, 17.2 mmol) was added to a solution of N-hydroxyphthalimide (2.80 g, 17.2 mmol) in N,N-dimethylformamide (20 ml). The reaction mixture was stirred for 45 min at 0° C. A solution of 4-[2-(toluene-4-sulfonyloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (5.99 g, 15.6 mmol) in N,N-dimethylformamide (15 ml) and tetrabutylammonium iodide (0.17 g, 0.47 mmol) were added successively. The reaction mixture was heated to 60° C. for 2 days and cooled to room temperature. Water (5 ml) was added carefully. The reaction mixture was diluted with ethyl acetate (250 ml) and washed with a 10% aqueous solution of sodium hydrogensulphate (200 ml). The aqueous phase was extracted with ethyl acetate (200 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (150 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/heptane 1:1 as eluent to give 4.36 g of 4-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]([NH2:22])[C:14]=2[CH:13]=[CH:12][CH:11]=1.[NH:23]1[C:27]2[N:28]=[CH:29][CH:30]=[C:31]([C:32](O)=[O:33])[C:26]=2[CH:25]=[CH:24]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]([NH:22][C:32]([C:31]3[C:26]4[CH:25]=[CH:24][NH:23][C:27]=4[N:28]=[CH:29][CH:30]=3)=[O:33])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: NC1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21
Reactant: O=C(O)c1ccnc2[nH]ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NC1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21)c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
In a 100 ml round-bottomed flask, a mixture of 51 mg of 5-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-pyrrolo[1,2-a]indol-9-ylamine obtained according to the preceding stage, 28 mg of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (which can be obtained according to WO 2003/000688), 37 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) and 26 mg of 1-hydroxybenzotriazole (HOBt) in 5 ml of dimethylformamide is stirred for 4 hours under argon at ambient temperature. The reaction medium is evaporated to dryness under vacuum. The residue is triturated from 20 ml of water and then filtered. The solid is washed with a saturated solution of sodium bicarbonate and taken up in a mixture of dichloromethane and methanol, and the solution is evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a mixture of dichloromethane and methanol (98/2 v/v). 47 mg of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid [5-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-pyrrolo[1,2-a]indol-9-yl]amide are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([O:9][CH:10]([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH:23]=O)[CH:17]=[CH:16]2)[CH3:11])[CH3:8].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([O:9][CH:10]([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH:23]=[CH2:1])[CH:17]=[CH:16]2)[CH3:11])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(C)Oc1ccc2cc(C=O)ccc2c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc2cc(OC(C)OCC)ccc2c1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
In a 1 L three neck flask, equipped with an overhead mechanical stirrer, was added 45 g of methyltriphenylphosphonium bromide (0.126 mol) under nitrogen atmosphere. To this were added anhydrous 300 mL of THF and 16.02 g of potassium tert-butoxide (0.1428 mol). After 1 h of stirring, 20 g of 6-(1-ethoxy ethoxy)-2-naphthaldehyde (0.0819 mol), dissolved in 50 mL of THF, was added dropwise using a cannular and the reaction mixture was stirred overnight. After overnight stirring, deionized water (200 mL) was added with a syringe and the phases were separated. The aqueous phase was extracted with ether (2×100 mL) and the combined extracts were dried over MgSO4. After filtration and concentration, the crude product was purified by column chromatography (silica gel, hexane/CH2Cl2 40/60˜10/90) to yield 19.12 g of pure 6-(1-ethoxy ethoxy)-2-vinylnaphthalene (96%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:5]=1[CH2:6][N:7]([CH3:18])[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:2].[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:23][C:20]1[CH:21]=[CH:22][C:4]([CH2:3][C:1]#[N:2])=[C:5]([CH:19]=1)[CH2:6][N:7]([CH3:18])[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1CC#N)C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1cc(N)ccc1CC#N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of 36C (1.803 g, 5.31 mmol) in MeOH (30 mL) and THF (10 mL) was added zinc (dust) (3.47 g, 53.1 mmol) and ammonium chloride (5.68 g, 106 mmol). The resulting solution was stirred at rt for 2 h. MeOH was removed under reduced pressure. Na2CO3 (aq, 100 mL) and EtOAc (150 mL) was added, and the suspension was stirred vigorously for 10 min. The mixture was filtered through a glass frit, solid residue was washed with EtOAc (3×150 mL). Combined EtOAc fractions were washed with std. Na2CO3 (aq, 2×50 mL), water (2×50 mL), brine (1×50 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give 36D (1.459 g, 4.72 mmol, 89% yield) as a yellowish oil. MS (ESI) m/z: 310.2 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 7.29-7.46 (5H, m), 7.15 (1H, br. s.), 6.60 (1H, d, J=7.28 Hz), 6.35-6.55 (1H, m), 5.18 (2H, s), 4.44 (2H, s), 3.71 (2H, br. s.), 3.41-3.66 (2H, m), 2.85 (3H, br. s.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].B.C1COCC1.O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[CH2:7][OH:8]
Reactant: O=C(O)c1cc(Br)ccc1I
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-Bromo-2-iodobenzoic acid (100 g, 0.306 mol) is dissolved in THF (350 mL) and cooled in an ice bath. Borane-THF complex (460 mL of 1 M in THF, 0.460 mol) is added dropwise. After addition is complete, the reaction is warmed to room temp and stirred for 14 hours. The mixture is transferred a large erlenmeyer flask (4 L), cooled in an ice bath and carefully quenched with water (250 mL). Evaporation of the THF by rotary evaporator gives a white suspension which is treated with additional water (1 L) and then filtered and dried in a vacuum dessicator over P2O5 to give 5-bromo-2-iodobenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10](N)[S:11][C:12]=2[C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(ON=O)CCC>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[CH:10][S:11][C:12]=2[C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1nc(-c2cccnc2Cl)c(-c2cccnc2Cl)s1
Agent: CCCCON=O
Solvent: C1CCOC1
Product: Clc1ncccc1-c1ncsc1-c1cccnc1Cl
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a solution of 4, 5-di-(2-chloropyridin-3-yl)-2-aminothiazole (0.060 g) in tetrahydrofuran (5 mL) was added butylnitrite (0.060 g). The mixture was heated under reflux for 3 hours. Further butylnitrite was added, and heating was continued for 2 hours. The solvent was evaporated, and the residue was fractionated by chromatography over silica gel to give 4, 5-di-(2-chloropyridin-3-yl)thiazole (0.035 g) as a solid.
Reaction SMILES: [C:1]1([C:11]([CH2:13][C:14]([O:16]CC)=[O:15])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>C(#N)C.CO.[Cl-].[Zn+2].[Cl-]>[OH:12][CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH:13]([CH2:25][C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=1)[C:14]([OH:16])=[O:15]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1cccc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CC#N
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
To a solution of ethyl (1-naphthoyl)acetate (10.2 g, 39.9 mmol) in acetonitrile (100 ml) was added 4-(trifluoromethyl)benzyl bromide (9.54 g, 39.9 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water (500 ml) and extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:toluene=1:1). To a solution of the crude product of the obtained monoalkyl form (7.46 g, 18.63 mmol) in ether (100 ml) was added a solution of Zn(NH4)2 in ether (100 ml), which was prepared from zinc chloride (5.07 g, 37.3 mmol) and sodium borohydride (2.82 g, 74.5 mmol), and the mixture was stirred at room temperature for 30 min. The reaction solution was ! poured into 1N aqueous hydrochloric acid solution (100 ml) and extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene). To a solution of the crude product of the obtained reduced compound (3.74 g, 9.29 mmol) in methanol (40 ml) was added 1N aqueous sodium hydroxide solution (20 ml, 20 mmol) and the mixture was stirred at room temperature for 4 hrs. The reaction solution was poured into 1N aqueous hydrochloric acid solution (40 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (2RS,3RS)-3-hydroxy-3-(1-naphthalenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (2.48 g, 16%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].O>C1COCC1>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Sc1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1ccc(CSc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
2-mercaptopyridine (2.6 g) was dissolved in THF (52 ml), triethylamine (3.9 ml) was added to the mixture, and then, a solution of 4-nitrobenzyl bromide (4.8 g) in. THF (24 ml) was added dropwise to the mixture. The reaction solution was stirred for 30 minutes at room temperature, added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography, to give 2-[(4-nitrobenzyl)sulfanyl]pyridine (4.2 g).
Reaction SMILES: [F:1][C:2]1[C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Br[C:23]1[CH:24]=[C:25]([CH2:29][OH:30])[CH:26]=[N:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CO.C(Cl)Cl.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>[F:1][C:2]1[C:12]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([CH2:29][OH:30])[CH:24]=2)=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: Cn1c(=O)oc2cc(F)c(B3OC(C)(C)C(C)(C)O3)cc21
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: ClCCl
Solvent: COCCOC
Solvent: CO
Product: Cn1c(=O)oc2cc(F)c(-c3cncc(CO)c3)cc21
Temperature: 100 °C
Yield: 44.4 %

Procedure:
A mixture of 6-Fluoro-3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (352 mg, 1.2 mmol), (5-bromopyridin-3-yl)methanol (188 mg, 1 mmol), Na2CO3 (2 M in water, 1 mL, 2 mmol), polymer bound Pd(PPh3)4 (642 mg, 0.07 mmol) in DME (4 mL) was heated by microwave at 100° C. for 1.25 h. The reaction mixture was cooled to room temperature and the mixture was diluted with CH3OH/CH2Cl2 (1:1, 50 mL) and filtered through a pad of celite. The celite pad was further washed with CH2Cl2/CH3OH (50 mL). Ater concentration, the residue was purified by flash column (0-10%, v/v, CH3OH in CH2Cl2) and afforded 121.9 mg of the desired product as a white solid. ESI-MS m/z: 274.9 [M+1]+, Retention time 0.93 min; 1HNMR (MeOD, 400.342 MHz) δ 3.44 (s, 3H), 4.74 (s, 2H), 7.30 (d, J=9.7 Hz, 1H), 7.34 (d, J=6.4 Hz, 1H), 8.03 (s, 1H), 8.55 (s, 1H), 8.64 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C@H:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC1c2ccccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: C[C@H]1c2ccccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1

Procedure:
The enantiomers of 4-[(3-fluoro-6-methylphenanthridin-5(6H)-yl)carbonyl]phenol (720 mg, 2.16 mmol) were separated by automated, on-column solvent change, preparative, normal phase, chiral chromatography on a Chiralpak AD (20 mm×250 mm) column eluting with 35% hexane in ethanol at a flow rate of 15 mL/min with. The fractions containing the second peak were combined and concentrated in vacuo, to provide one peak (99.8%) with a retention time of 8.095 minutes was isolated as a white solid (345 mg, 96% based upon a 1:1 ratio of enantiomers with a theoretical maximum amount of 360 mg). mp 236.6-237.8° C.; [α]D25=+581° (c=0.0107 g/mL, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=6.73 Hz, 3 H) 5.68 (q, J=6.73 Hz, 1 H) 6.56 (dd, J=10.60, 2.59 Hz, 1 H) 6.70 (d, J=8.79 Hz, 2 H) 7.06 (td, J=8.54, 2.59 Hz, 1 H) 7.16 (m, 2 H) 7.35 (m, 1 H) 7.42 (m, 2 H) 7.98 (td, J=8.79, 6.98 Hz, 2 H) 10.04 (s, 1H) MS (ESI) m/z 334 ([M+H]+); MS (ESI) m/z 332 ([M−H]−).
Reaction SMILES: C(O[C:4]1[C:5]([NH:11][C@@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:26])([F:25])[F:24])[CH:20]=3)[O:15][C:14]([CH3:28])([CH3:27])[C@H:13]2[OH:29])=[N:6][S:7](=[O:10])(=[O:9])[N:8]=1)C.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:27][C:14]1([CH3:28])[C@@H:13]([OH:29])[C@H:12]([NH:11][C:5]2[C:4]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:8][S:7](=[O:10])(=[O:9])[N:6]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:25])([F:26])[F:24])[CH:20]=2)[O:15]1
Reactant: CCOC1=NS(=O)(=O)N=C1N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O
Reactant: C1CCNC1
Product: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](NC2=NS(=O)(=O)N=C2N2CCCC2)[C@@H]1O

Procedure:
In a method similar to Example 5, the product of Example 1, Step 2 (0.218 g, 0.500 mmol) was converted to the title compound with pyrrolidine (0.053 g, 0.780 mmol) in 1 hour to give 0.34 g of product which was purified by flash column (3:2 hexane/ethyl acetate) to afford 0.17 (74%) of white solid after recrystallization: mp 243°-245° C.; 1H NMR (DMSO-D6): δ 7.74 (d, 1H), 7.29 (d, 1H), 7.18 (dd, 1H), 6.89 (d, 1H), 5.81 (d, 1H), 4.94 (t, 1H), 4.00 (m, 1H), 3.87 (m, 2H), 3.57 (m, 2H), 2.10-1.90 (m, 4H), 1.41 (s, 3H), 1.17 (s, 3H); IR (KBr): 3350, 1595 cm-1 ; MS (m/z) 463 (MH +, 100%); [α]D25 =-75.5 (THF).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][N:3]=1.CCN(CC)CC.[Cl:23][CH2:24][C:25](Cl)=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]2[O:7][C:25]([CH2:24][Cl:23])=[N:9][N:8]=2)=[CH:4][N:3]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(CCl)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 6-chloro-4-(isopropylamino)nicotinohydrazide (10) (500 mg, 2 mmol) in DCM (10 mL), Et3N (6 mmol, 3 equiv.) and 2-chloroacetyl chloride (3 mmol, 1.5 equiv.) were added and stirred at room temperature for 4 h. Added tosyl chloride (3.2 mmol, 1.5 equiv.) was added at stirred overnight at room temperature. The reaction mixture was diluted with DCM. The DCM layer was washed with 10% NaHCO3 solution followed by water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and EtOAc:Pet. ether as eluent to afford the desired compound, 2-chloro-5-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)-N-isopropylpyridin-4-amine LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.95 min; LCMS (ES-API), m/z 287.6 (M+H).
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:35]=[CH:34][C:18]2[NH:19][C:20]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:17]=2[CH:16]=1)=[CH2:8])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:43]>C(Cl)Cl>[C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C:7]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:35]=[CH:34][C:18]3[NH:19][C:20]([CH2:22][O:23][C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=4)=[N:21][C:17]=3[CH:16]=2)[CH2:8][O:43]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1(c2ccccc2-c2ccc3[nH]c(COc4ccc(C(F)(F)F)cc4)nc3c2)CO1
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of 5-{2-[1-(tert-butyl-dimethyl-silanyloxy)-vinyl]-phenyl}-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.126 g, 0.240 mmol) in CH2Cl2 (5 mL) at rt was added m-chloroperoxybenzoic acid (77% max, 0.161 g, 0.720 mmol). After stirring 1 hour, the reaction mixture was concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 2:1) to afford the title compound as a colorless oil (0.115 g, 94%).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:8]([C:27]#[C:28][Si:29]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31])([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@H:6]1[N:36]1[C:45]2[N:44]=[CH:43][N:42]=[C:40]([NH2:41])[C:39]=2[N:38]=[CH:37]1)(=O)C>CO.C(N(CC)CC)C>[CH2:11]([O:10][C@@H:9]1[C@@:8]([C:27]#[C:28][Si:29]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:34][CH3:35])([CH2:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:7][C@@H:6]([N:36]2[C:45]3[N:44]=[CH:43][N:42]=[C:40]([NH2:41])[C:39]=3[N:38]=[CH:37]2)[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC[Si](C#C[C@]1(COCc2ccccc2)O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1)(CC)CC
Solvent: CO
Solvent: CCN(CC)CC
Product: CC[Si](C#C[C@]1(COCc2ccccc2)O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OCc1ccccc1)(CC)CC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Compound 20 (0.354 g, 0.565 mmol) in methanol (14 ml), triethylamine (3.3 ml) was added, and the mixture was stirred for one day at room temperature under air-tight condition. The mixture was concentrated under reduced pressure. The residue was applied to a silica gel column (10 g, eluent; ethyl acetate:n-hexane:ethanol=20:10:1), to thereby yield Compound 21 in an amount of 0.283 g (86%).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:19]1[CH2:21][CH2:20]1.B(Br)(Br)Br.ClCl>>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:19]1[CH2:21][CH2:20]1
Reactant: COc1cccc2c1cc(C1CC1)n2Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Agent: ClCl
Product: Oc1cccc2c1cc(C1CC1)n2Cc1ccccc1-c1ccccc1
Yield: 29.2 %

Procedure:
By the method used in Example 1, Part D, 1.25 g (3.7 mmol) of 1-([1,1'-biphenyl]-2-ylmethyl)-2-cyclopropyl-4-methoxyl-1H-indole was O-demethylated by treating it with 15 mL of 1M BBr3 /CH2 Cl2. The crude product was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 367 mg (29% yield) of 1-([1,1'-biphenyl]-2-ylmethyl)-2-cyclopropyl-4-hydroxy-1H-indole as an oil.