Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH:10]=[CH:11][C:7]=2[CH:6]=1.[CH3:14]I>CS(C)=O>[CH3:14][O:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH:10]=[CH:11][C:7]=2[CH:6]=1
Reactant: OCc1ccc2occc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCc1ccc2occc2c1

Procedure:
To a stirred mixture of powdered KOH in dimethylsulfoxide is added 5-hydroxymethylbenzo[b]furan in dimethylsulfoxide. Then methyl iodide is added dropwise at ambient temperature over several minutes to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](Cl)=[O:9])=[CH:4][CH:3]=1.ClCCl.[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc(Cl)cc2)cc1
Reaction time: 0.5 h

Procedure:
The 21.8 g. of p-chlorocinnamoyl chloride is dissolved in 250 ml. of dichloromethane. To this is added, with stirring, a solution of 35.7 g. of ethyl 4-aminobenzoate in 250 ml. of dichlormethane. The mixture is stirred overnight, then 300 ml. of water are added, stirring is continued for 30 minutes, and the solid is collected by filtration and dried. This solid is boiled in 600 ml. of ethanol and 100 ml. of chloroform, filtered, and the volume reduced to 450 ml., giving a solid, 15.0 g. of which is recrystallized from a mixture of 800 ml. of ethanol and 250 ml. of chloroform by boiling to a volume of 250 ml., giving 13.57 g. of the desired product as off-white crystals, m.p. 203°-204° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:14][C:15]1([CH3:23])[C:20](=[O:21])[CH2:19][C:18](=[O:22])[CH2:17][O:16]1.C(N(CC)CC)C.CC(C)(O)C#N>[Cl-]>[N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([CH:19]1[C:18](=[O:22])[CH2:17][O:16][C:15]([CH3:23])([CH3:14])[C:20]1=[O:21])=[O:7])([O-:3])=[O:2]
Reactant: CC1(C)OCC(=O)CC1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: CC(C)(O)C#N
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC1(C)OCC(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Yield: 43 %

Procedure:
2-Nitro-4-chlorobenzoyl chloride (2.2 g, 10 mmol) and, 2,2-dimethyl-2H-pyran-3,5-(4H,6H)-dione (1.4 g, 10 mmol) were dissolved in 150 milliliters (ml) chloride. Triethylamine (3 ml, 22 mmol) was added and the resulting solution stirred at room temperature for fifteen minutes. The solution was washed with dilute hydrochloric acid, 5% potassium carbonate and saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was dissolved in 10 ml acetonitrile. Triethylamine (3 ml, 22 mmol) and acetone cyanohydrin (0.2 g) were added and the mixture stirred at room temperature for 2 hours. After dilution with either, the solution was washed with dilute hydrochloric acid and extracted with 5% potassium carbonate. The basic extract was acidified with hydrochloric acid and extracted with ether. The ether extract was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under vacuum, yielding 1.4 g of the desired product as a viscous oil. It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[N:36]2.Br[CH2:43][C:44]#[N:45]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:31]1[CH:40]=[CH:39][C:38]([O:41][CH2:43][C:44]#[N:45])=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[N:36]2
Reactant: COc1ccc(-c2cc3ccccc3o2)c2cccnc12
Reactant: N#CCBr
Agent: Oc1ccc(-c2cc3ccccc3o2)c2cccnc12
Product: N#CCOc1ccc(-c2cc3ccccc3o2)c2cccnc12
Yield: 34 %

Procedure:
5-(1-Benzofuran-2-yl)-8-hydroxy-quinoline was prepared as a solid (0.264 g, 99%) from 5-(1-benzofuran-2-yl)-8-methoxy-quinoline following the procedure described in the first part of Step 4 of Example 2. Mass spectrum (+ESI, [M+H]+) m/z 262. Reaction of 5-(1-benzofuran-2-yl)-8-hydroxy-quinoline with bromoacetonitrile according to the procedure described in Step 2 of Example 1 afforded the title compound as a solid (0.104 g, 34%). Mass spectrum (+ESI, [M+H]+) m/z 301. 1H NMR (500 MHz, DMSO-d6): δ 9.02 (d, 1H, J=1.4 Hz), 8.99 (d, 1H, J=9.3 Hz), 8.07 (d, 1H, J=8.3 Hz), 7.68-7.81 (m, 3H), 7.54 (d, 1H, J=8.3 Hz), 7.28-7.46 (m, 3H), and 5.51 ppm (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[O:22][CH2:21]2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[H][H]>O1CCOCC1.[Pd]>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[O:22][CH2:21]2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=Cc1ccc(OCCN2COc3ccccc3C2=O)cc1)OCC
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C(Cc1ccc(OCCN2COc3ccccc3C2=O)cc1)OCC
Yield: 80.6 %

Procedure:
A solution of ethyl 2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]-ethoxy]phenyl]-2-propenoate (4.5 g, 10.5 mmol) obtained in Example 1, in 1,4-dioxane (50 mnl) was reduced with hydrogen in the presence of 10% palladium charcoal (450 mg) at 50-60 psi for 12 h. The reaction mixture was filtered through a bed of celite and the celite bed was washed with 1,4-dioxane. The filtrate was evaporated to dryness under reduced pressure to yield the title compound (3.5 g, 78%): mp 78-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CC(C)CN(c1ccc(C(=O)O)c(Cl)c1)S(C)(=O)=O
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CC(C)CN(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1)S(C)(=O)=O

Procedure:
175 μL of 1-iodo-2-methylpropane and 740 mg of Cesium Carbonate were added to 200 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in 2 mL of DMF and stirred in the microwave at 140° C. for 30 minutes. The reaction mixture was extracted in Ethyl Acetate twice with water, dried over Magnesium Sulfate, filtered, concentrated and purified on ISCO Combi-Flash to give methyl 2-chloro-4-(N-isobutylmethylsulfonamido)benzoate. 120 mg of methyl 2-chloro-4-(N-isobutylmethylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 110 mg of crude 2-chloro-4-(N-isobutylmethylsulfonamido)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-isobutylmethylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-isobutylmethylsulfonamido)benzamide. MS (Q1) 492 (M)+.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[Cl:22])[CH2:10][CH2:9]1)=[O:7])C.CO.O.O[Li].O>C1COCC1>[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][C:4]([OH:23])=[O:3])[CH2:13][CH2:12]1
Reactant: CCOC(=O)CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a stirred solution of malonic acid monoethyl ester (0.5 g, 0.00377 mole) in DMF (10 mL) was added DIPEA (1.18 g, 0.0094 mole), HOBt (0.608 g, 0.0045 mole) and EDCI.HCl (0.865 g, 0.0045 mole). After 2 minutes 4-(2-chloro-5-fluoro-phenoxy)-piperidine hydrochloride (1 g, 0.003 7 mole) and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure to get afford 0.9 g (70%) of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester. LC-MS purity: 344.78 (M+1)+, 82.56%. To a stirred solution of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester (0.9 g, 0.0026 mole) in a mixture of THF (10 mL), methanol (3 mL) and H2O (2 mL) was added LiOH.H2O (0.218 g, 0.0052 mole) at ambient temperature and the resulting mixture was stirred for 30 minutes. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The product was extracted with ethyl acetate, and the organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.6 g (73%) of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid. LC-MS purity: 316.72 (M+1)+, 75.8%.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>C(=O)(O)[O-].[Na+]>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])=[CH:22][CH:21]=1
Reactant: COc1ccc(O)cc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (14 g), p-methoxyphenol (9.3 g), and 1N sodium bicarbonate (200 ml) was stirred at 90° C for 5 hours. After cooling, the resulting 4-(p-methoxyphenoxy)-3-nitro-5-sulphamyl-benzoic acid was precipitated by the addition of 4N hydrochloric acid until the pH was 1, and collected by suction. The crude acid was dissolved in hot methanol (100 ml) and precipitated by the addition of water (100 ml) and cooling. After collection and drying in vacuo, the melting point was 229°-230° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[O:14])[C:9]=2[CH3:26])=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:37][C@H:38]1[C@H:42]([CH3:43])OS(=O)(=O)[O:39]1.Cl>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C@H:42]([CH3:43])[C@@H:38]([OH:39])[CH3:37])[CH:11]=[C:10]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=3)=[O:14])[C:9]=2[CH3:26])=[C:4]([C:27]([F:29])([F:28])[F:30])[CH:3]=1
Reactant: C[C@@H]1OS(=O)(=O)O[C@H]1C
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c[nH]c1-c1ccc(F)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cn([C@H](C)[C@H](C)O)c1-c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of 5-[4-fluoro-2-(trifluoromethyl)phenyl]-4-methyl-N-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carboxamide (23 g, 52 mmol) in anhydrous DMA (160 ml) was added sodium tert-butoxide (12 g, 0.12 mol) and stirred at room temperature for 30 min under N2. (4S,5S)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (12 g, 78 mmol) in anhydrous DMA (20 ml) was added to the solution and stirred at 70° C. for 2.0 h. The reaction mixture was cooled to room temperature and added 2N HCl (80 ml) and concentrated on a rotary evaporator. To this residue was added anhydrous THF (0.12 L) and 5N HCl (0.14 L) and stirred at 60° C. for 80 min. The mixture was diluted with ethyl acetate and washed with water, satd NaHCO3 and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (1:2, dichloromethane:ethyl acetate) to give an atropisomeric mixture of the title compound (14.3 g, 52%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]=1[O:18][CH3:19].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]([O:18][CH3:19])=[C:2]([N:66]2[CH2:71][CH2:70][O:69][CH2:68][CH2:67]2)[CH:7]=1)([O:12][CH3:13])[CH3:9]
Reactant: C1COCCN1
Reactant: COc1c(Br)cc(C(C)(OC)OC)cc1C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: COc1c(N2CCOCC2)cc(C(C)(OC)OC)cc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
1-Bromo-5-(1,1-dimethoxyethyl)-2-methoxy-3-trifluoromethylbenzene (2 g) was initially introduced and argon was passed through with stirring for 0.5 h. Subsequently, the mixture was treated with Pd(II) acetate (13 mg), BINAP (54 mg) and sodium tertiary-butylate (784 mg), followed by morpholine (0.6 ml). The mixture obtained was stirred under argon at 85° C. for 8 h and after standing overnight at RT it was stirred at 85° C. for a further 8 h and allowed to stand overnight. The solvent was then stripped off and the residue was purified on silica gel (n-heptane-ethyl acetate gradient). 468 mg of the desired product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[CH:34]1([C:40]2[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:37]3[CH:36]=[CH:35][C:34]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:39][CH:38]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C4CCCCC4)cc3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (1.5 g, 2.7 mmol) was coupled with 4-cyclohexyl phenyl-boronic acid (700 m g, 3.4 mmol) according to general procedure G to give {4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}acetic acid methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[S:40]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:42]3[CH:43]=[CH:44][S:40][CH:41]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Yield: 52.4 %

Procedure:
A similar procedure as described in Example 44, step 3 was used, starting from 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (305 mg, 0.5 mmol), 3-thiophenylboronic acid (131 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 0.075 mmol), and cesium carbonate (331 mg, 1.0 mmol) to obtain 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-ethoxy-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy]-butyric acid ethyl ester (160 mg, 52%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C35H46O7S (M+Na)+ 633.2856. found 633.2860.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][C:36]([F:39])([F:38])[F:37])[CH:10]=2)[CH2:4][CH2:3]1.[C:40](OC(=O)C)(=[O:42])[CH3:41].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:38][C:36]([F:39])([F:37])[O:35][C:11]1[CH:10]=[C:9]([O:8][CH:5]2[CH2:4][CH2:3][N:2]([C:40](=[O:42])[CH3:41])[CH2:7][CH2:6]2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH2:27][O:26][C:25]2=[O:34])[CH2:20][CH2:19]1)=[O:17]
Reactant: O=C(Cc1ccc(OC2CCNCC2)cc1OC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-(trifluoromethoxy)-phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.45 g, 0.77 mmol) from Example 39 in CH2Cl2 (50 mL) was added acetic anhydride (0.15 mL, 1.5 mmol) and DIEA (0.26 mL, 1.5 mmol). The solution was stirred at ambient temperature for 1 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 0.25 M aqueous citric acid (50 mL), H2O (25 mL), and saturated aqueous NaHCO3 (75 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9](I)[O:10][C:3]=12.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)[O:10][C:3]=12
Reactant: OB(O)c1ccc(F)cc1
Reactant: Clc1ccnc2cc(I)oc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(-c2cc3nccc(Cl)c3o2)cc1
Temperature: 150 °C
Yield: 57.4 %

Procedure:
To a 30 mL microwave vial with stirbar was added 7-chloro-2-iodo-furo[3,2-b]pyridine (300.00 mg; 1.07 mmol; 1.00 eq.), 4-fluorophenylboronic acid (157.71 mg; 1.13 mmol; 1.05 eq.), palladium(II) acetate (12.05 mg; 0.05 mmol; 0.05 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (44.07 mg; 0.11 mmol; 0.10 eq.), and potassium carbonate (445.09 mg; 3.22 mmol; 3.00 eq.). Reagents were suspended in dioxane (6.00 ml)/water (0.60 ml) under N2 and heated in microwave reactor at 150° C. for 15 min. The reaction mixture was cooled to room temperature and concentrated on a rotary evaporator. The crude mixture was purified by Biotage chromatography (20-100% EtOAc/hex 30 column vol.) to afford the title compound as a white solid (152 mg, 57%). (HPLC (method F): 95%, RT: 7.11 min); 1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.47 (d, J=5.2, 1H), 8.11-8.05 (m, 2H), 7.79 (s, 1H), 7.53 (d, J=5.3, 1H), 7.47-7.39 (m, 2H); MS (m/z) 248 [M+H]+, RT: 3.9 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[Cl:10].[Na+].[I-].[C:13]([S-:15])#[N:14].[K+]>CN(C=O)C.O>[Cl:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[CH2:2][N:14]=[C:13]=[S:15]
Reactant: Fc1ccc(Cl)c(CBr)c1
Reactant: N#C[S-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cl)c(CN=C=S)c1
Temperature: 90 °C

Procedure:
To a solution of 2-(bromomethyl)-1-chloro-4-fluorobenzene (25, 22.3 g, 100 mmol) in dry DMF (150 mL) were added NaI (16.0 g, 107 mmol) and KSCN (19.5 g, 200 mmol) The mixture was heated under N2 at 90° C. for 18 h. After cooling to RT, the mixture was diluted with water (200 mL), and extracted with EtOAc (200 mL×2). The combined extracts were washed with brine, dried over MgSO4, and concentrated to give crude product. This was purified by column chromatography on silica gel, and eluted with petroleum ether to provide 1-chloro-4-fluoro-2-(isothiocyanatomethyl)benzene (26).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:37][CH3:38])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:31])[N:16]([CH:28]([CH3:30])[CH3:29])[CH2:17][CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][C:13]=4[C:12]([C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)=[C:9]3[C:10]=2[CH:11]=1.C1(OC)C=CC=CC=1.CO.Cl>O1CCOCC1>[CH:28]([N:16]1[C:15](=[O:31])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:37][CH3:38])[C:2]([Br:1])=[CH:11][C:10]=4[C:9]3=[C:12]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:13]=2[CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:30])[CH3:29]
Reactant: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: COc1ccccc1
Product: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Reaction time: 5 h
Yield: 87.7 %

Procedure:
To a solution of 130 mg of 10l, 30 mg of anisole and 100 ul of methanol in 1 ml of dioxane was added 400 μl of 4N HCl in dioxane. The reaction mixture was stirred for 5 h and then quenched by addition of 10 ml of 5% aq. NaHCO3 and extracted with ethyl acetate. The organic layer was washed once with water, dried and concentrated. The residue was treated with diisopropyl ether, to afford 95 mg of 10u as white crystalline material; Mp 201-203° C.; Rf 0.20 (heptane-acetone 1/1). MS-ESI: [M+1] 499.94 and 501.95. NMR (CDCl3) 1.30 (d, 6, isoC3H7), 3.88 (s, 3, OCH3), 4.72 (m, 1, isoC3H7), 6.70, 7.18 (2×s, 2, Ar—H), 6.93, 7.13, 7.41 (3×m, 3, thiophene-H).
Reaction SMILES: [Cl:1]Cl.[CH3:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3>C(O)(=O)C>[Cl:1][C@@H:17]1[CH2:18][C@@:19]2([CH3:20])[C@@H:14]([CH2:13][CH2:12][C@@H:11]3[C@@H:21]2[CH2:22][CH2:23][C@@:6]2([CH3:7])[C@H:8]3[CH2:9][CH2:10][C@@H:5]2[O:4][CH3:3])[CH2:15][C:16]1=[O:24]
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: ClCl
Solvent: CC(=O)O
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)[C@H](Cl)C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Chlorine in acetic acid (0.84 M, 12 ml.) is added dropwise with stirring to 17β-methoxy-5α-androstan-3-one (3.0 g.) in acetic acid (10 ml.). When the addition is complete the reaction mixture is chilled, and the precipitate which forms is filtered off, washed with water, dried and recrystallized from acetone-methylene chloride to give the title compound, m.p. 202°-210°; MS (m/e) 338, 306, 302, 291 and 265; NMR (CDCl3) 0.77, 1.10, 3.20, 3.30 and 4.06 δ.