Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][C@H:25]3[CH3:30])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=1.[C:39](=[O:42])(O)[O-:40].[Na+]>CN1C(=O)CCC1>[F:21][C:20]([F:23])([F:22])[C:39]([OH:40])=[O:42].[Cl:38][C:37]1[C:32]([N:27]2[CH2:28][CH2:29][N:24]([C:11]3[NH:12][C:13]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=4)=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[N:10]=3)[C@H:25]([CH3:30])[CH2:26]2)=[N:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C([O-])O
Reactant: Clc1cccnc1Cl
Reactant: C[C@@H]1CNCCN1c1nc(-c2ccc(F)c(F)c2)c(-c2ccc(C(F)(F)F)cc2)[nH]1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc(-c2ccc(F)c(F)c2)c(-c2ccc(C(F)(F)F)cc2)[nH]1
Product: O=C(O)C(F)(F)F

Procedure:
A mixture of (2R)-1-(4-(3,4-difluorophenyl)-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)-2-methylpiperazine from step (d) above (150 mg, 0.355 mmol), 2,3-dichloropyridine (104 mg, 0.71 mmol, Lancaster), and sodium bicarbonate (89 mg, 1.1 mmol, Mallinckrodt) in NMP (1.2 mL) was reacted under the condition of Example 12(a) to give the title compound as a tan solid. MS (ESI, positive ion) m/z: 534 (M+1).
Reaction SMILES: [OH:1]CC1C=C(O)C=CC=1.C(N(CC)CC)C.[C:17]([O:20][C:21]1[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:23](Cl)=[O:24])(=[O:19])[CH3:18]>C1(C)C=CC=CC=1.O>[C:17]([O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:1])=[O:24])(=[O:19])[CH3:18]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: OCc1cccc(O)c1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(=O)O
Yield: 200 %

Procedure:
3-hydroxymethylphenol (10 g, 0.08 moles) is dissolved in toluene (50 ml) containing triethylamine (9.8 g, 0.1 moles). To the so obtained solution, a solution of the acetylsalicylic acid chloride (16 g, 0.08 moles) in toluene (50 ml) is added at the temperature of 5-10° C. under stirring. The mixture is maintained at a temperature within the above mentioned range, under stirring for 2 hours, then poured in water and then extracted with dichloromethane (2×100 ml) The organic phase is separated, washed in sequence with a solution of potassium carbonate at 25% w/v, with water, with a 3% hydrochloric acid solution, and lastly again with water, then anhydrified with sodium sulphate and the solvent evaporated under vacuum. The residue is crystallized from isopropanol. 3-hydroxymethylphenyl ester of the 2-acetoxybenzoic acid (45.8 g, 0.16 moles, yield 80%) is obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:20].[CH3:21][Zn]C.CO.Cl>O1CCOCC1.C(OCC)(=O)C>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][C:3]([F:20])=[C:2]([CH3:21])[CH:10]=3)[C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1cn(C2CCCC2)c2cc(Br)c(F)cc12
Reactant: C[Zn]C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cn(C2CCCC2)c2cc(C)c(F)cc12
Temperature: 88 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A mixture of methyl 6-bromo-1-cyclopentyl-5-fluoro-1H-indole-3-carboxylate (3.4 g, 10 mmol), dimethylzinc (1.2 M, 16.7 mL, 20 mmol) and PdCl2dppf (163 mg, 0.2 mmol) in dioxane (20 mL) was stirred at 88° C. for 2 hr under nitrogen atmosphere. The mixture was then cooled and methanol was added in slowly followed by 2 N HCl. The mixture was treated with ethyl acetate, washed with water and brine, dried and evaporated. The residue was purified by flash chromatography with dichloromethane and hexane (1:1) to give methyl 1-cyclopentyl-5-fluoro-6-methyl-1H-indole-3-carboxylate (2.66 g, yield 97%).
Reaction SMILES: C(C1N=[C:12]([OH:14])[CH:11]=[C:10]([OH:15])N=1)C1C=CC=CC=1.Cl.[CH2:17]([S:19][CH:20]([S:24][CH2:25][CH3:26])[C:21]([NH2:23])=[NH:22])[CH3:18].C(OCC)(=O)CC(OCC)=O>>[CH2:17]([S:19][CH:20]([S:24][CH2:25][CH3:26])[C:21]1[N:23]=[C:12]([OH:14])[CH:11]=[C:10]([OH:15])[N:22]=1)[CH3:18]
Reactant: Oc1cc(O)nc(Cc2ccccc2)n1
Reactant: CCSC(SCC)C(=N)N
Agent: Cl
Solvent: CCOC(=O)CC(=O)OCC
Product: CCSC(SCC)c1nc(O)cc(O)n1

Procedure:
Prepared in a manner similar to 2-benzylpyrimidine-4,6-diol using 2,2-bis(ethylthio)acetamidine hydrochloride 4 and diethyl malonate as the starting materials to yield a dark yellow waxy solid. MS: (ESI, Neg) m/z 245.3 (M−1). H1 NMR: 11.7 ppm (d) 2H. 5.2 ppm (s) 0.69H. 4.8 ppm (s) 1H. 2.65 ppm (m) 4H. 1.17 ppm (t) 6H. Subsequent sulfanyl oxidation can be used to generate various Y moieties, C(O), etc., as described above.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>CN(C)C=O.C(OCC)(=O)C>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:12]=1[C:13]#[N:14]
Reactant: OC1CCCCC1
Reactant: N#Cc1c(F)cccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(Br)cccc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyclohexanol (0.275 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (60%, 0.069 g). After 30 minutes, 2-bromo-6-fluorobenzonitrile (0.500 g) was added and the reaction stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 3% to 10% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH:49]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:50][CH3:51]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:50][CH3:51])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC(Br)c1ccccc1
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nn(C(CC)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 50 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with 1-bromo-1-phenylpropane was carried out as described in Example 3, Step A. After work-up, the residue was flash chromatographed over silica gel (gradient elution using 0.2-1.0% MeOH/CH2Cl2) to give the desired material in 50% yield, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) 736 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Cl[C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][C:20]([Cl:26])=[CH:21][CH:22]=2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].CCCCCC>CC(C)=O.CCOC(C)=O>[Cl:26][C:20]1[CH:19]=[C:18]2[C:23]([N:24]=[CH:25][C:16]([O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:13][CH:14]=3)=[N:17]2)=[CH:22][CH:21]=1
Reactant: Clc1ccc2ncc(Cl)nc2c1
Reactant: COC(=O)[C@@H](C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)[C@@H](C)Oc1ccc(Oc2cnc3ccc(Cl)cc3n2)cc1

Procedure:
A solution of the product of Part B (27.0 g, 0.095 moles), ethyl acetate (215 mL), conc HCl (12 drops) and Pd/C (1.7 g) was shaken on a Parr hydrogenator for 3.5 hours, after which TLC (60:40 hexane/EtOAc; Rf 0.36) indicated the reaction was complete. The mixture was filtered through celite, washed with EtOAc, and evaporated to an amber oil. The oil was dissolved in EtOAc, dried over MgSO4, filtered through celite and MgSO4, and evaporated to a clear filtrate and dried under high vacuum to afford methyl (R)-(+) 2-(4-hydroxyphenoxy)propanoate (18.5 g, 100% yield). A mixture of methyl (R)-(+) 2-(4-hydroxyphenoxy)propanoate (18.5 g, 0.094 moles), 2,7-dichloroquinoxaline (14.5 g, 0.073 mole), and powdered potassium carbonate (13.3 g, 0.964 mole) in dry acetone (170 mL) was refluxed overnight. When a TLC showed the reaction was complete (Rf 0.30, 1:1 hexane:EtOAc), the mixture was filtered and washed with acetone, dried with MgSO4, and evaporated to dryness to a beige solid. This was purified by several silica gel columns (80:20 hexane:EtOAc, then 75:25 hexane:EtOAc) to obtain a fluffy white solid which was recrystallized repeatedly from hexane to afford methyl (R)-(+) 2-[4-(7-chloroquinoxalinyloxy)phenoxy]propionate as a solid: mp 80° C. 1H NMR (CDCl3) δ8.65 (s), 7.97 (d, J=9 Hz, 1H), 7.75 (d, J=2 Hz, 1H), 7.54 (dd, J=2 Hz, 9 Hz, 1H), 7.18 (m, 2H), 6.95 (m, 2H), 4.80 (q, J=7 Hz, 1H), 3.80 (s, 3H), 1.66 (d, J=7 Hz, 3H). [α]D25 =+40.43. MS calc 358.78, found 358.78. Anal Calcd for C18H15N2O4Cl: C, 60.26; H, 4.21; N, 7.81. Found: C, 60.16; H, 4.10; N, 7.68.
Reaction SMILES: [C:1]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:23][C:24]1[S:28][C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:26][N:25]=1.Cl>N1C=CC=CC=1>[C:1]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:23][C:24]2[S:28][C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:26][N:25]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CC(=O)OCC)s2)cc1
Yield: 63 %

Procedure:
To a solution of the 4-decanamidobenzenesulfonyl chloride (608 mg, 1.76 mmol) in pyridine (8 mL) was added ethyl 2-(5-amino-1,3,4-thiadiazol-2-yl)acetate (300 mg, 1.60 mmol). The reaction mixture was stirred at room temperature for 4.5 h, than 2 M HCl was added to quench the reaction. The mixture was extracted with ethyl acetate (3×40 mL). The organic extracts were washed with water (30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with CH2Cl2:methanol 19:1 to give the product as a solid, mp 89-90° C., in 63% yield (500 mg, 1.01 mmol); 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=6.9 Hz), 1.25-1.34 (m, 15H), 1.65-1.76 (m, 2H), 2.39 (t, 2H, J=7.5 Hz), 3.87 (s, 2H), 4.24 (q, 2H, J=7.2 Hz), 7.58 (d, 2H, J=9.0 Hz), 7.74 (d, 2H, J=8.7 Hz); 13C NMR (75 MHz, DMSO-d6) δ 14.0, 14.0, 22.0, 25.5, 29.0, 29.0, 29.2, 31.3, 36.4, 37.9, 60.1, 118.9, 127.0, 139.4, 142.3, 154.0, 168.9, 169.9, 172.3; MS (LCQ, ESI+) Calcd for C22H33N4O5S2 497.2. found 497.1 (M+H)+. HRMS (ESI+, m/z) Calcd for C22H33N4O5S2 497.1875. found 497.1873 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([C:19]#[CH:20])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=[O:31])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=[O:31])[CH:25]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: C#Cc1cnc2c(c1)C(=O)N(C)c1ccc(Cl)nc1N2CC
Reactant: O=C(O)c1cc(Br)ccn1
Product: CCN1c2ncc(CCc3ccnc(C(=O)O)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 34.9 %

Procedure:
By a procedure analogous to that described in Example 51b, 2-chloro-5,11-dihydro-11-ethyl-8-ethynyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.83 g, 2.64 mmol) was coupled with 4-bromopicolinic acid (prepared by potassium permanganate oxidation of 4-bromo-2-picoline) (0.53 g, 2.62 mmol). The product was hydrogenated according to the procedure described in Example 3b to provide 0.4 g of the title compound as a mixture containing the corresponding des-chloro analog.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=2)=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:17]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:3][CH:4]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2)cc1F
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)c(F)c2)cc1
Temperature: 140 °C
Yield: 53 %

Procedure:
A mixture of 83 (317 mg, 0.877 mmol), tert-butyl acrylate (0.369 mL, 2.55 mmol), palladium acetate (15.0 mg, 0.067 mmol), P(o-tolyl)3 (40.0 mg, 0.131 mmol), and Et3N (0.520 mL, 3.73 mmol) were heated under microwave irradiation at 140° C. for 30 min. Water (30 mL) was added and the mixture was extracted with ether (3×20 mL). The combined ethereal extracts were washed with water (30 mL), brine (30 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 190 mg (54%) of 84. 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 1.57-1.60 (m, 6H), 2.23 (m, 4H), 5.07 (d, 1H), 6.31 (d, J=16 Hz, 1H), 6.78 (m, 2H), 6.90 (t, J=8.6 Hz, 1H), 7.09 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 7.54 (d, J=16.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].O[CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:29]([O:28][C:27]([NH:26][CH2:25][CH2:24][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][CH:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][C:2]=1[Cl:1])=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CCOC(=O)C(Cc1ccc(O)c(Cl)c1)Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)c(Cl)c1)Oc1ccccc1
Yield: 93.6 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 3-(3-chloro-4-hydroxyphenyl)-2-phenoxypropionate (761 mg), which is the product of Reference example 51(a), t-butyl 2-hydroxyethylcarbamate (0.96 g), triphenylphosphine (1.55 g) and solution of diethylazodicarboxylate in toluene (40%, 2.69 ml) and the reaction mixture was treated to afford the desired compound (1.03 g) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[H-].[Na+].Cl[CH2:38][C:39]([OH:41])=[O:40].Cl>CN(C)C=O>[C:39]([CH2:38][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)([OH:41])=[O:40]
Reactant: O=C(O)CCl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)O)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.953 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 10 ml of N,N-dimethylformamide is admixed with stirring at room temperature with 0.16 g of sodium hydride dispersions (60%). The reaction mixture is stirred at 60° C. over 10 minutes, admixed with 0.191 g of chloroacetic acid and then stirred at 60° C. over 24 hours. The reaction mixture is admixed with 0.5N HCl and extracted with ethyl acetate (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (95:5 dichloromethane-methanol); Rt=5.18.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:5]([CH3:21])=[N:4]1)[CH3:2].[C:22]([C:30](O)=[O:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)CCl>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[C:6]([N:8]([CH2:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[C:30](=[O:31])[C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]([CH3:21])=[N:4]1)[CH3:2]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CCn1cc(NCCc2ccc(C(F)(F)F)nc2)c(C)n1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCn1cc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)C(=O)c2ccccc2)c(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of (1-ethyl-3-methyl-1H-pyrazol-4-yl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (100 mg) in CH2Cl2 (5 mL) was added under a nitrogen atmosphere at 0° C. benzoyl formic acid (1.1 eq., commercially available) and EDC (1.1 eq). After stirring for 12 h a rt, the mixture was washed with aqueous Na2CO3 (saturated, 2.5 mL) and water (2.5 mL), the combined aqueous layers were extracted with CH2Cl2 (3×2.5 mL) and the combined organic layers dried over sodium sulfate. Concentration afforded the title compound (161 mg, >100%) as a light yellow oil which was used without further purification for the next step. MS m/e: 431.2 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].CC1(C)N(Br)C(=O)N(Br)C1=O.C(=O)(O)[O-].[Na+]>CCCCCC>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of androst-5-ene-3β,17β-diol diacetate (3.75 g, 10 mmol), dibromantin (2.03 g, 7 mmol), and sodium bicarbonate (4.54 g, 54 mmol) in hexane (200 ml) is heated under reflux for 0.5 hours. The mixture is then cooled and filtered and the filtrate evaporated to dryness. The residue is dissolved in 50 ml toluene and treated with lithium bromide (2 g) in 5 ml of acetone. The mixture is stirred at 0° C. for 2 hours and then treated with 2 ml triethylamine and 1.5 ml benzenethiol. After stirring at room temperature for 1.5 hours, 100 ml ethyl acetate is added and the organic solution is washed with 1N hydrochloric acid and water. The organic phase is dried and concentrated. The residue is then redissolved in 75 ml ethyl acetate, cooled to 0° C. and treated with 2.6 g of m-chloroperbenzoic acid for 2 hours. The mixture is washed with 10% sodium bicarbonate solution and then concentrated. The residue is dissolved in 100 ml toluene, treated with triethylamine (3.6 ml), heated at 70° C. for 24 hours, cooled, and washed with water. The organic solution was concentrated and chromatographed to yield androst-5,7-diene-3β,17β-diol diacetate. The diacetate is treated with K2CO3 in a 10:1 methanol:water solution overnight to yield, after extractive workup, androst-5,7-diene-3β,17β-diol.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:2]1[O:4][CH2:3]1.[CH3:18][C:19]([NH2:30])([CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>>[CH2:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:30][C:19]([CH3:29])([CH3:18])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCOCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: CCCCCCCCCCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 28.7 %

Procedure:
Using the method of Example 5, supra, dodecyl glycidyl ether (242 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 121 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 422 (M+1, 1), 406 (4), 300 (100), 222 (11), 163 (23), 121 (34); 1H-NMR (CDCl3) δ7.09 (2H, d, J=8.6), 6.83 (2H, d, J=8.6), 3.79 (3H, s), 3.76 (1H, m), 3.45 (4H, m), 2.81 (1H, dd, J=7.6 and 4.0), 2.65 (4H, m), 1.53 (2H, m), 1.26 (20H, m), 1.06 (3H, s), 1.05 (3H, s), 0.88 (3H, t, J=6.4); 13C-NMR (CDCl3) δ158.1, 131.3, 130.0, 113.4, 73.5, 71.7, 69.0, 55.1, 53.4, 46.4, 44.6, 31.9, 29.6, 29.4, 29.3, 26.7, 26.6, 26.1, 22.7, 14.1; FT-IR (film) cm−1 3415 (broad, s), 1612, 1512, 1246, 1121, 825.
Reaction SMILES: Cl[SiH](C1C=CC=CC=1)C1C=CC=CC=1.[CH2:15]([N:22]1[CH2:36][CH:25]2[C:26]3[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[CH:30][C:31]=3[CH:32](O)[CH:24]2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCCl>[CH2:15]([N:22]1[CH2:23][CH:24]2[CH2:32][C:31]3[CH:30]=[CH:29][C:28]([O:34][CH3:35])=[CH:27][C:26]=3[CH:25]2[CH2:36]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2O
Agent: Cl[SiH](c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
InCl3 (0.38 g, 1.7 mmol) and chlorodiphenylsilane (1.3 mL, 6.8 mmol) were added to a solution of 2-benzyl-5-methoxy-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]inden-8-ol (3.4 mmol) in DCE (17 mL), and stirred overnight at 60° C. The reaction mixture was washed with H2O, a saturated aqueous NaHCO3 solution and brine. The organic extracts were dried over MgSO4 and concentrated. The crude product was obtained without further purification. MS calculated for C13H21NO+H: 280, observed: 280.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:29])[NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([C:21]([OH:23])=O)[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:8][C:7]=1[F:28])[CH3:2].[CH2:30]([O:32][CH2:33][CH2:34][NH2:35])[CH3:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[CH2:30]([O:32][CH2:33][CH2:34][NH:35][C:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:24][CH3:25])[N:14]=[CH:13][CH:12]=[C:11]2[O:10][C:9]1[CH:26]=[CH:27][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:29])=[C:7]([F:28])[CH:8]=1)=[O:23])[CH3:31]
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1F
Reactant: CCOCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)NCCOCC)cc23)cc1F

Procedure:
4-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acid (50 mg) was treated with ethoxyethylamine, triethylamine and benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate in the same manner as Example 634, to obtain the title compound (18 mg) as a solid.