Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH:16]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]1.[NH3:24]>CO>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH2:15][CH:16]2[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]2)=[C:2]([NH2:24])[N:10]=1
Reactant: N
Reactant: CC1(C)OCC(COn2cnc3c(Cl)nc(NC=O)nc32)CO1
Solvent: CO
Product: CC1(C)OCC(COn2cnc3c(N)nc(N)nc32)CO1
Temperature: 110 °C
Yield: 63 %

Procedure:
A mixture of 6-Chloro-9-(2,2-dimethyl-1,3-dioxan-5-ylmethoxy)-2-formamidopurine (630 mg, 1.84 mmol), ammonia (10 ml) and methanol (15 ml) was heated at 110° C. for 7.5 hours in an autoclave and then allowed to cool over 16 hours. The mixture was evaporated to dryness and the residue chromatographed on silica (eluted with chloroform-ethanol, 20:1), affording the title compound (340 mg, 63%). 1R: υmax (KBr) 3409, 3321, 3158, 1669, 1640, 1589, 1488, 1457, 1409 cm-1. H NMR: δH [(CD3)2SO] 1.32(3H,s,CH3), 1.35(3H,s,CH3), 2.00(1H,m,CH3), 3.77(2H,dd, J=11.8, 6.1 Hz, 2×H(ax)), 3.98(2H,dd, J=11.8, 4.1 Hz, 2×H(eq)), 4.32(2H,d, J=7.1 Hz, CH2ON), 5.91(2H,br.s, D2O exchangeable, 6-NH2), 6.78(2H.br,s,D2O exchangeable, 2-NH2), 7.96(1H,s,H-8). Found: C, 48.34; H, 6.18; N, 28.21%; M+ 294.1437. C12H18N6O3 0.2H2O requires: C, 48.37; H, 6.24; N, 28.21%; M+ 294.1440.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C:23](OCC)=[O:24])[CH:18]=[CH:19][CH:20]=1.C(O)(=O)C>CCCCCC.C(OCC)C.O1CCCC1>[F:13][C:14]([F:28])([F:29])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C:23](=[O:24])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])[CH:18]=[CH:19][CH:20]=1
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)CCc1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCCCCC
Product: COP(=O)(CC(=O)CCc1cccc(C(F)(F)F)c1)OC
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 49.7 %

Procedure:
A solution of n-butyl lithium (5.88 g) in hexane (48 ml) and anhydrous diethyl ether (70 ml) was added to a stirred solution of dimethyl methylphosphonate (11.4 g) in anhydrous tetrahydrofuran (50 ml) at -50° C. in an atmosphere of nitrogen during 20 minutes. The solution was stirred for a further 15 minutes at -60° C., and was then treated with a solution of ethyl 3-(3-trifluoromethylphenyl)-propionate (11.3 g) in anhydrous tetrahydrofuran (20 ml) during 10 minutes at -60° C. The solution was stirred at -60° C. for 90 minutes and then at ambient temperature for 2 hours. The solution was then treated with acetic acid (10 ml) and the solvents were evaporated off under reduced pressure. Water (75 ml) was added to the resulting gelatinous residue and the mixture was extracted with diethyl ether. The ethereal solution was washed with water, with aqueous sodium bicarbonate solution (10% w/v), and with water, dried over magnesium sulphate, and evaporated. The residue was distilled to give dimethyl 4-(3-trifluoromethylphenyl)-2-oxobutylphosphonate (7.4 g) in the form of a colourless oil, b.p. 157°-159° C./0.2 mm Hg. [elemental analysis: C, 48.3; H, 5.1; P, 9.8%. C13H16F3O4P requires C, 48.15; H, 5.0; P, 9.55%. νmax 1035, 1125, 1165, 1265, 1330, 1555 and 1720 cm-1 ].
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:46][C:47](=[O:51])[CH2:48][CH2:49][NH2:50])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:50][CH2:49][CH2:48][C:47]([OH:46])=[O:51])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)NCCC(=O)O)cc2)cc1

Procedure:
The product from Example 234B and beta-alanine ethyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ11.84-12.51 (br.s, 1 H), 8.94 (s, 1 H), 7.85 (t, 1 H), 7.22 (m, 7 H), 7.03 (t, J=7.8 Hz, 1 H), 6.94 (m, 6 H), 6.82 (d, 2 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.92 (t, 2 H), 3.23 (dd, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.36 (t, 2 H), 2.11 (t, 2 H), 1.64 (m, 4 H); MS (ESI+) m/z 660 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][CH2:11][CH:12]1[CH2:14][CH2:13]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: NCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(NCC1CC1)c1csc(Br)n1
Reaction time: 16 h
Yield: 64.5 %

Procedure:
2-Bromothiazole-4-carboxylic acid (500 mg, 2.40 mmol), aminomethylcyclopropane (247 μL, 2.88 mmol), EDC.HCl (1.01 g, 5.29 mmol), HOBN (1.08 g, 6.01 mmol) and NEM (765 μL, 6.01 mmol) were dissolved in DCM (30 mL) and the reaction mixture was stirred for 16 h. The organic fraction was washed with sat aq NaHCO3 (30 mL), 1 M aq HCl (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (404 mg, 64%) as a white solid. LCMS (ES+): 261.4 [MH]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:4][C:3]=1[C:17](=O)[CH3:18].[CH3:20][O:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[C:25]([CH2:30][C:31](O)=[O:32])=[CH:24][N:23]=1>>[CH3:20][O:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[C:25]([C:30]2[C:31](=[O:32])[O:1][C:2]3[C:3]([C:17]=2[CH3:18])=[CH:4][CH:5]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=3)=[CH:24][N:23]=1
Reactant: COc1ncc(CC(=O)O)c(OC)n1
Reactant: CC(=O)c1ccc(OCOCC[Si](C)(C)C)cc1O
Product: COc1ncc(-c2c(C)c3ccc(OCOCC[Si](C)(C)C)cc3oc2=O)c(OC)n1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 9 using 1-[2-hydroxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanone and (2,4-dimethoxy-pyrimidin-5-yl)-acetic acid as the starting material.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH2:17][O:18][Si](C(C)(C)C)(C)C)([CH3:16])[C:11](=[O:15])[CH2:12][C:13]#[N:14])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:8][CH2:9][C:10]([CH2:17][OH:18])([CH3:16])[C:11](=[O:15])[CH2:12][C:13]#[N:14]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)C(=O)CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)(CO)C(=O)CC#N

Procedure:
To a stirred solution of 5-(tert-butyldimethylsilyloxy)-4-((tert-butyldimethylsilyloxy)methyl)-4-methyl-3-oxopentanenitrile (1 equivalent) in anhydrous THF at 0° C. is added tetrabutylammonium fluoride (1-5 equivalents) and stirring is continued at rt until the reaction is substantially complete as determined by LCMS or TLC. Water is added followed by extraction with EtOAc. The extracts are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 5-hydroxy-4-(hydroxymethyl)-4-methyl-3-oxopentanenitrile.
Reaction SMILES: [I:1]Cl.C[O:4]/[N:5]=[C:6](/[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])\[C:7]#[C:8][CH3:9].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:6]1[C:7]([I:1])=[C:8]([CH3:9])[O:4][N:5]=1
Reactant: ClI
Reactant: CC#C/C(=N\OC)c1ccc(F)cc1F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1onc(-c2ccc(F)cc2F)c1I
Reaction time: 1 h
Yield: 46.9 %

Procedure:
Iodine monochloride (2.13 g, 13.1 mmol) was dissolved in DCM (15 mL) then the solution was added over about 10 min to the (E)-1-(2,4-difluorophenyl)but-2-yn-1-one O-methyl oxime (2.29 g, 10.9 mmol) in DCM (100 mL). The mixture was stirred for about 1 h then saturated aqueous sodium thiosulfate (50 mL) was added. The mixture was stirred for about 10 min then the layers were separated. The aqueous layer was extracted with DCM (25 mL) then the combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel with heptane/EtOAc (95:5) as an eluent to give the title compound (1.64 g, 47%): LC/MS (Table 1, Method g) Rt=2.65 min; MS m/z: 322.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([C:21](=[O:23])[NH2:22])=[CH:16][C:15]=1[CH3:24])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[C:35]1([C:41]2[N:42]=[C:43]([CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][NH:47]3)[NH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C)CCCCN=C=NCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([C:21](=[O:23])[NH2:22])=[CH:16][C:15]=1[CH3:24])[C:10](=[O:11])[N:47]1[CH2:48][CH2:49][CH2:50][CH2:51][CH:46]1[C:43]1[NH:44][CH:45]=[C:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:42]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: c1ccc(-c2c[nH]c(C3CCCCN3)n2)cc1
Reactant: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N1CCCCC1c1nc(-c2ccccc2)c[nH]1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid (0.42 g, 1.25 mmol) was dissolved in DMF (5 mL) followed by 1-hydroxybenzotriazole (0.34 g, 1.75 mmol), and the resulting solution was cooled to 0° C. To this reaction mixture was added 2-(4-phenyl-1H-imidazol-2-yl)-piperidine (0.31 g, 1.75 mmol) followed by (4-dimethylamino-butyl)-ethyl-carbodiimide (0.34 g, 1.75 mmol). The reaction was then warmed to room temperature and stirred for 16 hours. The reaction mixture was then combined with 2N citric acid and washed multiple times with ethyl acetate. The combined organics were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 600 mg of desired product {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamic acid tert-butyl ester as a glass which was used as is without further purification. (TLC: 5:1 CHCl3: MeOH Rf=0.6)
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[NH2:27])[C:21]([OH:23])=[O:22].NC1C=C(C=CC=1N)C(N)=O>>[O:6]([C:7]1[CH:14]=[CH:13][C:10]([C:11]2[NH:27][C:26]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=3[N:17]=2)=[CH:9][CH:8]=1)[C:5]1[CH:15]=[CH:16][CH:2]=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: NC(=O)c1ccc(N)c(N)c1
Product: O=C(O)c1ccc2[nH]c(-c3ccc(Oc4ccccc4)cc3)nc2c1

Procedure:
This compound was prepared according to the methods described in Example 22 and Scheme 3, substituting 4-phenoxybenzaldehyde for 4-(4-fluoro-phenoxy)-benzaldehyde, and 3,4-diaminobenzoic acid for 3,4-diaminobenzoic acid amide.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][CH3:50])=[C:45]([Pb+3])[CH:44]=2)=[CH:39][CH:38]=1>ClCCl.Cl>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][CH3:50])=[C:45]([CH:6]3[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]3=[O:9])[CH:44]=2)=[CH:41][CH:42]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (described in U.S. Pat. No. 5,089,046A) (0.303 g, 1.78 mmol) and N,N-dimethylaminopyridine (1.09 g, 8.90 mmol) is added anhydrous chloroform (20 ml), followed by stirring at room temperature until dissolution. To this solution is added anhydrous toluene (5 ml), followed by 4′-chloro-4-ethylbiphenyl-3-yllead triacetate (1.17 g, 1.96 mmol) in one portion and the mixture heated at 80° C. for 1-2 hours. The mixture is allowed to cool to room temperature, then diluted with dichloromethane (150 ml) and dilute aqueous hydrochloric acid (30 ml), followed by stirring for 5 minutes and filtration through diatomaceous earth to remove inorganic residues (additional washing with solvents). All organic fractions are combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product is purified by column chromatography (100% hexane to hexane/ethyl acetate 5:1 ratio) then triturated with hexanes to afford 4-(4′-chloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.46 g) as a cream powder.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[CH2:9]([NH2:13])[C:10]#[C:11][CH3:12]>C(#N)C>[CH2:9]([NH:13][C:4](=[N:3][C:1]#[N:2])[S:5][CH3:6])[C:10]#[C:11][CH3:12]
Reactant: CSC(=NC#N)SC
Reactant: CC#CCN
Solvent: CC#N
Product: CC#CCNC(=NC#N)SC

Procedure:
A solution of dimethyl cyanodithioimidocarbonate (10.00 g, 0.0684 mole) and 2-butyn-1-amine (4.73 g, 0.0684 mole) in acetonitrile (200 ml) was stirred at 25° for 0.5 hour, and then at reflux for 2.5 hours. The mixture was cooled, then filtered to yield the title compound B, mp 180°-183°.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)(=[O:11])=[O:10])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)Cl)c([N+](=O)[O-])cc1F
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])cc1F
Yield: 29.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-fluoro-5-methyl-2-nitro-benzenesulfonyl chloride (Intermediate 452) (1.6 g, 6.3 mmol), 8-aminoquinoline (700 mg, 4.86 mmol), DMAP (cat.), pyridine (5 ml) and DCM (5 ml) gave the title compound (520 mg, 52%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:26])[N:13]([C:16](=[O:25])[C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=4)[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.FC1C=C(F)C=CC=1C1C=CC=CC=1C(NC(=O)C1C=CC=C(OC)C=1)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:26])[N:13]([C:16]([C:17]4[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=4)=[O:25])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: COc1cccc(C(=O)N2c3cc(F)ccc3-c3ccccc3C2C)c1
Agent: COc1cccc(C(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)c1
Solvent: C1CCOC1
Product: CC1c2ccccc2-c2ccc(F)cc2N1C(=O)c1cccc(O)c1
Temperature: 70 °C
Yield: 85.7 %

Procedure:
3-fluoro-5-(3-methoxybenzoyl)-6-methyl-5,6-dihydrophenanthridine—N-[1-(2′,4′-difluoro-1,1′-biphenyl-2-yl)ethyl]-3-methoxybenzamide (1.29 g, 3.5 mmol) was dissolved in anhydrous THF (10 mL) and the vial was capped and purged with an inert atmosphere. Lithium bis(trimethylsilyl)amide (4.0 mL, 1 M in THF) was added to the solution and the mixture heated (70° C). The reaction progress was monitored by LCMS and heating was discontinued upon the expense of the starting material. The THF was removed and 2N aqueous HCl was added. The product was extracted with ethyl acetate (3×) and the combined organic phases were dried (Na2SO4), filtered, and concentrated to provide a crude oil. The residue was purified by flash column chromatography (Biotage® 40 Mi, 30-50% methyl tert-butylether in hexane) affording 1.0 g (82%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J=6.76 Hz, 3 H) 3.71 (s, 3 H) 5.67 (s, 1 H) 6.77 (d, J=7.28 Hz, 2 H) 6.93 (s, 1 H) 7.03 (ddd, J=8.32, 2.73, 0.91 Hz, 1 H) 7.10 (td, J=8.71, 2.60 Hz, 1 H) 7.26 (t, J=7.93 Hz, 1 H) 7.40 (m, 3 H) 7.97 (d, J=7.54 Hz, 1 H) 8.01 (dd, J=8.84, 6.24 Hz, 1H); MS (ESI) m/z 348 ([M+H]+); HRMS: calcd for C22H18FNO2, 347.1322 (M), 348.13944 ([M+H]+); found (ESI_FT), 348.13903; Anal. Calcd for C22H18FNO2: C, 76.07; H, 5.22; N, 4.03. Found: C, 76.02; H, 5.32; N, 3.97.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:16]=O)=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:16]=[N:22][OH:23])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C=O)n2C)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C=NO)n2C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 2 ml of ethanol was dissolved 50 g (0.17 mmol) of 5-(3,5-dimethylphenylthio)-4-isopropyl-1-methyl-1H-imidazole-2-carbaldehyde (Compound I-6), followed by addition of 36 mg (0.5 mmol) of hydroxylamine hydrochloride and 43 mg (0.5 mmol) of sodium acetate, arid the mixture was stirred for 30 minutes at room temperature. To this reaction mixture, water was added, and the mixture was extracted with methylene chloride.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[CH3:32][C:33]1[NH:34][C:35]([CH2:38][NH2:39])=[N:36][N:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:39][CH2:38][C:35]1[NH:34][C:33]([CH3:32])=[N:37][N:36]=1)=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: Cc1nnc(CN)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nnc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)[nH]1
Reaction time: 1 h
Yield: 31.4 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 30 mg, 0.070 mmol), (5-methyl-4H-1,2,4-triazol-3-yl)methanamine (11.70 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.3 min) to provide 2-hydroxy-N-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12 mg, 0.022 mmol, 31.7% yield) as a single enantiomer. LCMS=526.4 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.51-7.76 (7 H, m), 5.21 (1 H, s), 4.46-4.66 (2 H, m), 2.52 (3 H, s); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[N:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[OH:17])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:21]=[N:20][CH:19]=[CH:18][C:3]=1[C:4]1[O:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2oc(-c3ccncc3Br)nc2c1
Temperature: 50 °C
Yield: 87.1 %

Procedure:
To a mixture of 0.29 g of 3-bromo-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 4 ml of tetrahydrofuran and 0.25 g of triphenylphosphine, 0.42 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred while heating at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.24 g of 2-(3-bromopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 27”).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH:10]=[CH:9]4)[C@H:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[CH2:33]([O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH:10]=[CH:9]4)[C@H:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:5][C:4]=2[CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC2=O

Procedure:
A solution of 2.85 g of 3-hydroxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one in 57 ml of acetone is mixed with 3.25 g of cesium carbonate and 1.14 ml of benzyl bromide, and the mixture is refluxed for 1 hour. The reaction mixture is concentrated by evaporation, the residue is mixed with water, shaken out with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate. 3.12 g of 3-benzyloxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one is obtained as foam.