Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]=1[CH3:19].Br[C:22]1[N:27]=[N:26][C:25]([NH2:28])=[N:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.CO.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>[NH2:28][C:25]1[N:26]=[N:27][C:22]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:2][CH3:1])=[O:20])=[C:5]([CH3:19])[CH:6]=2)=[CH:23][N:24]=1
Reactant: Nc1ncc(Br)nn1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
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: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: CNC(=O)c1ccc(-c2cnc(N)nn2)cc1C
Temperature: 130 °C
Yield: 45.2 %

Procedure:
A mixture of N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Step 2, 0.3 g, 0.001 mol), 6-bromo-1,2,4-triazin-3-amine (0.21 g, 1.2 mmol, Example 2, Step 1), tetrakis(triphenylphosphine)palladium(0) (0.06 g, 0.05 mmol) and potassium carbonate (0.45 g, 3.3 mmol) in toluene (1.9 mL), ethanol (0.94 mL) and water (0.94 mL). The resulting mixture was heated at 130° C. for 2.5 h. The mixture was diluted with MeOH, filtered, and washed with DCM/methanol (90%). The filtrate was concentrated. The residue was purified by flash chromatography on a silica gel column with 10% MeOH in DCM to afford the desired product (110 mg, 41%). LCMS (M+H)+: m/z=244.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)=[CH:4][CH:3]=1.C[Al](C)C.C([O:20][C:21]([C:23]1[C:28]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:27][CH:26]=[C:25]([CH3:36])[N:24]=1)=O)C.O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:21]([C:23]3[C:28]([NH:29][C:30]4[CH:35]=[N:34][CH:33]=[N:32][CH:31]=4)=[CH:27][CH:26]=[C:25]([CH3:36])[N:24]=3)=[O:20])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccn(-c2ccc(F)cc2)n1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cncnc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2ccn(-c3ccc(F)cc3)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(4-Fluoro-phenyl)-1H-pyrazol-3-ylamine (55 mg, 0.31 mmol) was dissolved under inert gas atmosphere in dioxane (2 ml) and trimethylaluminium (0.154 ml, 2M toluene solution) was added. After stirring for 30 min at ambient temperature, 6-methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester (A-1; 20 mg, 0.08 mmol) was added and the reaction mixture was heated at reflux for 18 hours. Upon cooling to room temperature water (0.5 ml) was added and intensive stirring was continued for 5 min. Sufficient sodium sulfate for water absorption and dichloromethane were added while stirring is continued. The resulting solution was then filtered through decalite and washed with dichloromethane. The solvent was evaporated and the final product was obtained after silica gel chromatography using a heptane/ethyl acetate gradient as off-white solid (5 mg, 16%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=[C:3]1[CH:9]=O.[NH:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>C(O)(=O)CC>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=[C:3]1[C:9]1[C:15]2[NH:11][C:12]([C:9]([C:3]3[N:2]([CH3:1])[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=3)=[C:12]3[N:11]=[C:15]([C:9]([C:3]4[N:2]([CH3:1])[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=4)=[C:12]4[NH:11][C:15](=[C:9]([C:3]5[N:2]([CH3:1])[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=5)[C:12]5[CH:13]=[CH:14][C:15]=1[N:11]=5)[CH:14]=[CH:13]4)[CH:14]=[CH:13]3)=[CH:13][CH:14]=2
Reactant: c1cc[nH]c1
Reactant: Cc1nc(C=O)n(C)c1C
Solvent: CCC(=O)O
Product: Cc1nc(-c2c3nc(c(-c4nc(C)c(C)n4C)c4ccc([nH]4)c(-c4nc(C)c(C)n4C)c4nc(c(-c5nc(C)c(C)n5C)c5ccc2[nH]5)C=C4)C=C3)n(C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,4,5-Trimethylimidazole-2-carboxaldehyde (37, 750 mg, 5.42 mmol), prepared according to literature procedure (Alcalde, E. et al., Tetrahedron 52:15171-15188 (1996)), was dissolved in propionic acid (120 mL) in a 250 mL three neck round-bottom flask equipped with a thermometer and a condenser. The solution was heated to reflux then pyrrole (0.38 mL, 5.42 mmol) was added. The reaction mixture was heated at reflux for an additional 5 h, then cooled to room temperature while exposed to air overnight. The propionic acid was removed by vacuum distillation yielding a dark solid residue which was adsorbed onto silica gel. Purification by column chromatography (gradient elution 5-10% MeOH/CH2Cl2) provided porphyrin 38 as a mixture of atropisomers (108 mg, 10.7%). 1H NMR (300 MHz, CDCl3)*−2.90, −2.85, −2.78 (3 s, 2H, atropisomer NH), 2.50 (s, 12H), 2.57 (s, 12H), 3.15-3.42 (multiple s, 12H, atropisomer N—CH3), 8.91 (multiple s, 8H, atropisomer).
Reaction SMILES: [Mg].[F:2][C:3]1([F:16])[C:7]([F:9])([F:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([Mg]Cl)[C:5]=2[O:4]1.C[CH:18](OC(C)=O)[O:19]C(C)=O.Cl.CCCCCCCC>C1(C)C=CC=CC=1>[F:2][C:3]1([F:16])[C:7]([F:9])([F:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:18][OH:19])[C:5]=2[O:4]1
Reactant: FC1(F)Oc2c([Mg]Cl)cccc2C1(F)F
Reactant: CC(=O)OC(C)OC(C)=O
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCCCCCCC
Product: OCc1cccc2c1OC(F)(F)C2(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, the reaction mixture from above is decanted into a clean, dry reaction vessel, leaving the unreacted magnesium turnings in the first vessel. This solution containing 2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmagnesium chloride is heated at reflux, and 16.5 grams (0.55 mole based on formaldehyde) of polyoxymethylene diacetate (avg. mol. wgt. approx. 50,000, commercially available from E. I. du Pont De Nemours & Co., Inc. Wilmington Del., under the trade name Delrin 500 acetal homopolymer resin), milled to about 80 mesh, is added with stirring during about a three hour period. Upon completion of addition, the reaction mixture is heated at reflux for an additional four hours and then is allowed to cool to ambient temperature as it stood for about 18 hours. The reaction mixture is warmed to about 53° C. and then is poured into 100 grams of ice, 52 grams of concentrated hydrochloric acid, and 200 grams of a mixture of 95% n-octane and 5% toluene (wt/wt). This mixture is filtered, and the organic layer is separated. The organic layer is concentrated under reduced pressure, yielding 2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethanol.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38](O)=[O:39]>>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38]([N:16]([C:13]1[CH:14]=[N:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)=[O:39]
Reactant: COc1ccccc1CC(=O)O
Reactant: COc1ccc(NCCc2ccc(C(F)(F)F)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N(CCc2ccc(C(F)(F)F)cc2)C(=O)Cc2ccccc2OC)cn1

Procedure:
In analogy to example 33, step 2, without TFA addition, (6-methoxy-pyridin-3-yl)-[2-(4-trifluoromethyl-phenyl)-ethyl]-amine, prepared in example 33, step 1) was coupled to (2-methoxy-phenyl)-acetic acid (commercially available) to give the title compound. MS m/e: 445.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([CH3:23])[CH:15]=3)=[N:11][C:10]=2[C:24]([O:26]CC)=[O:25])=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([CH3:23])[CH:15]=3)=[N:11][C:10]=2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])c(C)c2)[nH]c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])c(C)c3)nc2C(=O)O)cc1
Yield: 77.8 %

Procedure:
Ethyl 5-(4-methoxyphenyl)-2-(3-methyl-4-nitrophenyl)-imidazole-4-carboxylate (29 g) was dissolved in ethanol and 2 M sodium hydroxide solution was added. The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methoxyphenyl)-2-(3-methyl-4-nitrophenyl)imidazole-4-carboxylic acid (20.9 g), melting point 229-230° C.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:32])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:32])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:7]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COCCOCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: COCCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8-Cyclopentyl-6-(2-methoxy-ethoxymethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.46 g, 4.18 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (1.31 g, 5.01 mmol) were dissolved in dichloromethane (10 mL) and stirred at ambient temperature for 12 hours. The reaction mixture was then purified by silica gel chromatography to give 8-cyclopentyl-2-methanesulfinyl-6-(2-methoxy-ethoxymethyl)-8H-pyrido[2,3-d]pyrimidin-7-one as a white waxy solid (0.60 g, 39.3%). 1H NMR δ(400 MHz, CDCl3) 8.94 (s, 1H), 7.88 (t, J=1.7 Hz, 1H), 5.95 (m, 1H), 4.52 (d, J=1.7 Hz, 1H), 3.80 (m, 2H), 3.65 (m, 2H), 3.43 (s, 3H), 2.98 (s, 3H), 2.25 (m, 2H), 2.13 (m, 2H), 1.94 (m, 2H), 1.70 (m, 2H).
Reaction SMILES: [ClH:1].[OH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[C:9]#[N:10].[CH2:14]([OH:16])[CH3:15]>>[ClH:1].[OH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[C:9](=[NH:10])[O:16][CH2:14][CH3:15]
Reactant: COc1ccc(CO)cc1C#N
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cc(CO)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride gas was passed through a solution of 5-hydroxymethyl-2-methoxy-benzonitrile (250 mg, 1.226 mmol) in anhydrous ethanol (25 mL) at room temperature. After 2 h, hydrogen chloride gas was stopped and the reaction vessel was sealed. After stirring at room temperature for 12 h, the reaction vessel was cooled to 0° C. and opened. The solvent was evaporated in vacuo to dryness to afford crude ethyl 5-hydroxymethyl-2-methoxy-benzimidate hydrochloride. meso-1,2-Bis-(4-chloro-phenyl)-ethane-1,2-diamine (200 mg, 0.711 mmol), triethylamine (145 μL, 1.422 mmol) and ethanol (10 mL) were added and the resulting mixture was heated at reflux for 12 h. The solvent was removed and the residue was taken up in methylene chloride (2 mL) and sodium bicarbonate solution (2 mL). The product was extracted with methylene chloride (2×30 mL). The organic layers were washed with brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-20% methanol in ethyl acetate to afford 4,5-bis-(4-chloro-phenyl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-4,5-dihydro-1H-imidazole (17 mg, 6%). LR-MS (APCI): 427 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5]([OH:7])=O.[NH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34]>>[C:33]([NH:32][CH2:31][CH2:30][NH:29][C:5]([C:4]1[CH:8]=[CH:9][C:10]([N:11]([CH3:28])[C:12]([C:14]2[S:27][C:17]3[C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[O:20][CH2:21][CH2:22][C:16]=3[CH:15]=2)=[O:13])=[C:2]([Cl:1])[CH:3]=1)=[O:7])(=[O:35])[CH3:34]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Reactant: CC(=O)NCCN
Product: CC(=O)NCCNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and N-(2-aminoethyl)acetamide were reacted by a procedure similar to that to prepare 137 in Example 47 to give 230. MS: (ESI+) 498.1
Reaction SMILES: N#N.[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9].[CH2:11](O)[CH2:12][OH:13].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCOCC>[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1([CH3:9])[O:13][CH2:12][CH2:11][O:10]1
Reactant: CC(=O)CCCCBr
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1(CCCCBr)OCCO1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus under inert atmosphere (N2), a solution of 6-bromo-hexan-2-one (3.34 g, 18.65 mmol) in toluene (71.3 mL) was treated with ethylene glycol (10.4 mL, 186.92 mmol) and TsOH (35 mg, 0.19 mmol). The reaction mixture was heated to reflux for 3 h, allowed to cool to rt and sat. aq. NaHCO3 (100 mL) and ether (100 mL) were added and the aq. phase was washed with water (2×100 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound. 1H NMR (400 MHz, CDCl3) δ 1.34 (s, 3H), 1.50-1.65 (m, 2H), 1.65-1.75 (m, 2H), 1.84-1.98 (m, 2H), 3.43 (t, J=6.8 Hz, 2H), 3.90-4.04 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9](O)[C:8]1=[O:15])=[O:5])[CH3:2].P(Br)(Br)([Br:18])=O.[OH-].[NH4+]>C(Cl)(Cl)Cl.ClCCl>[Br:18][C:9]1[C:8](=[O:15])[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:12]([CH3:13])=[CH:11][N:10]=1
Reactant: CCOC(=O)Cn1c(C)cnc(O)c1=O
Reactant: O=P(Br)(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)cnc(Br)c1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A slurry of 1-(ethoxycarbonylmethyl)-3-hydroxy-6-methylpyrazinone (4.24 g, 20 mmol), as prepared in the preceding step, and phosphorous oxybromide (6.3 g, 22 mmol) in chloroform (15 mL) was stirred at 50° C. under nitrogen for 2 hours, then allowed to cool to room temperature overnight. The reaction mixture was diluted with dichloromethane and ice-water, basified with ammonium hydroxide, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, treated with activated carbon, filtered and concentrated. The solid was collected, washed with 15% ethyl acetate in hexane, and dried under high vacuum to give the title compound as an orange colored solid (5.1 g, 93%). 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 4.77 (s, 2H), 4.26 (q, 2 H, J=7.1 Hz), 2.24 (s, 3H), 1.31 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[NH:12][C:11]=3[C:10](=O)[NH:9][C:8]2=[O:20])=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24].[OH-].[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[NH:12][C:11]=3[C:10](=[S:24])[NH:9][C:8]2=[O:20])=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)c1nc2c([nH]1)c(=O)[nH]c(=O)n2Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc2c([nH]1)c(=S)[nH]c(=O)n2Cc1ccc(Cl)cc1
Temperature: -5 °C
Yield: 135.5 %

Procedure:
12.75 g of 3-(4-chlorobenzyl)-8-isopropyl-xanthine and 10.67 g of phosphorus pentasulfide were heated under reflux in 200 ml of pyridine for 5.5 hours. After cooling to -5° C., 52.5 ml of 2N NaOH was added over 15 minutes. The solid was filtered off and the filtrate evaporated in vacuo to dryness. The residue was suspended in 250 ml of water (pH 7), the solid collected and washed. The crude product was redissolved in 200 ml of 2N NaOH, treated with 1.4 g of charcoal, filtered and neutralized with 38 ml of 5N HCl to pH 7. The solid was collected, washed and dried to give the crude title compound (12.36 g). This was dissolved in chloroform and filtered through 60 g of silica gel, thereby affording the title compound (10.89 g) as an off-white solid mp 235-6° C. (from acetone).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].N[C:13]1([O:22]O)[CH2:18][CH:17]([CH3:19])[CH2:16][C:15]([CH3:21])([CH3:20])[CH2:14]1>C(O)C>[C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][CH:17]1[CH2:16][C:15]([CH3:21])([CH3:20])[CH2:14][C:13](=[O:22])[CH2:18]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O=C1CCCC1
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 8 h

Procedure:
To a stirred mixture of cyclopentanone (33.8 g.) and ethanol (100 c.c.) containing ammonium acetate (3.2 g.) and kept at or below 0°, was added 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (44.6 g., 68% pure). After storing at 0°C overnight the reaction mixture was worked up as in the previous Examples to give unreacted cyclopentanone and dihydroisophorone together with a fraction (20.0 g.) b.p. 82° - 86°/0.5 mm. This last fraction was redistilled to give: material b.p. 74° - 76°C/0.3 mm.Hg., peroxide equivalent 202, shown by mass spectroscopy to be a mixture of the peroxide ##SPC28##
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]([CH3:2])=[C:4]2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:21][CH:22]=1)(=[O:27])=[O:28]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: Cl
Product: Cc1c(-c2cccnc2)n(Cc2ccc(S(C)(=O)=O)cc2)c2ccccc12

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1) and 1-bromomethyl-4-methanesulfonyl-benzene are processed according to the method described in Example 11 to give 1-(4-methanesulfonyl-benzyl)-3-methyl-2-pyridin-3-yl-1H-indole. 1H NMR (400 MHz, MeOD) δ ppm 2.33 (s, 3H), 3.08 (s, 3H), 5.46 (s, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.18 (t, J=7.3 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.55 (dd, J=7.8, 4.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.85 (dt, J=7.8, 1.9 Hz, 1H), 8.52 (d, J=2.3 Hz, 1H), 8.59 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 377.1318 [(M+H)+ Calcd for C22H21N2O2S: 377.1324].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=O.B.O1CCCC1.Cl.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[CH2:5][NH2:7]
Reactant: COc1cc(C)ccc1C(N)=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)ccc1CN
Temperature: 60 °C
Yield: 63.8 %

Procedure:
To a solution of 2-methoxy-4-methylbenzamide (14.55 g, 88.08 mmol) in dry THF (50 mL) was added dropwise Borane-tetrahydrofuran complex (1.0 M in THF, 220 mL, 2.5 eq) at 0° C. under N2 atmosphere. The reaction mixture was then heated to 60° C. overnight. The reaction was cooled to room temperature, aq.HCl (6 N, 37 mL) was added carefully and the reaction mixture was then heated at 70° C. for 2 hrs. After cooling, water was added and the resulting solution was washed with ether. The aqueous layer was basified with aq. NaOH (10 N) at 0° C. and saturated with K2CO3 then extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give 8.5 g of (2-methoxy-4-methylphenyl)methanamine. (64% yield)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:9]1([S:15][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(I)c1
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Brc1cccc(Sc2ccccc2)c1
Yield: 90.5 %

Procedure:
The general procedure in example 39 was followed. 3-bromoiodobenzene (283 mg, 1.0 mmol), thiophenol (103 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 3-bromophenyl phenyl sulfide (240 mg, 91% yield) as colorless liquid. Column chromatography solvent (hexane). Rf=0.6 (hexane). 1H NMR (CDCl3, 300 MHz) δ 7.11-7.22 (m, 2 H), 7.28-7.40 (m, 7 H). 13C NMR (CDCl3, 75 MHz) δ 139.2, 134.1, 132.5, 132.4, 130.6, 129.8, 129.7, 128.6, 128.2, 123.2. MS (EI) m/z (relative intensity) 266 (40), 264 (40).
Reaction SMILES: BrC1C=C2C(C(N[C@H]3CCN(C(OC(C)(C)C)=O)C3)=N[C:8]([C:12]3C=CC=C[C:13]=3[OH:18])=N2)=CC=1.[OH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[N:48]=[C:47]([NH:49][C@H:50]2[CH2:54][CH2:53][N:52](C(OC(C)(C)C)=O)[CH2:51]2)[C:46]2[C:41](=[CH:42][CH:43]=[C:44](C#CCO)[CH:45]=2)[N:40]=1>>[OH:18][CH2:13][CH2:12][CH2:8][C:43]1[CH:42]=[C:41]2[C:46]([C:47]([NH:49][C@H:50]3[CH2:54][CH2:53][NH:52][CH2:51]3)=[N:48][C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[OH:32])=[N:40]2)=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3cc(Br)ccc23)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Product: OCCCc1ccc2c(N[C@H]3CCNC3)nc(-c3ccccc3O)nc2c1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 59 and 60, replacing (S)-tert-butyl 3-(6-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate with (S)-tert-butyl 3-(7-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate in Synthesis 59-A.
Reaction SMILES: C([O:3][C:4](=[O:36])[C@@H:5]([O:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[C:9]([CH2:31][CH:32]=[CH2:33])[CH:8]=1)C>C(O)C>[CH3:35][O:34][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)=[C:9]([CH2:31][CH2:32][CH3:33])[CH:8]=1)[C:4]([OH:36])=[O:3]
Reactant: C=CCc1cc(C[C@H](OC)C(=O)OCC)ccc1OCCCOc1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCCc1cc(C[C@H](OC)C(=O)O)ccc1OCCCOc1ccc(Oc2ccccc2)cc1

Procedure:
A solution of (2S)-3-{3-Allyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester, from Example 148, Step B, was dissolved in ethanol and treated with H2 under balloon pressure. Filtered through a pad of celite and concentrated to dryness. The compound thus obtained was treated under, standard hydrolysis procedure C to give the title compound.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[O:8][C:7](=[O:11])[C:6](=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH3:13])[C:5]=1[OH:22])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>O1CCCC1>[C:30]([O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12](=[C:6]2[C:5]([OH:22])=[C:4]([C:1](=[O:3])[CH3:2])[C:9](=[O:10])[O:8][C:7]2=[O:11])[CH3:13])=[CH:20][CH:19]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CC(=O)C1=C(O)C(=C(C)Nc2ccc(O)cc2)C(=O)OC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)cc1

Procedure:
To a solution of 3.03 g. (0.01 m.) of 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, 1.0 g. (0.01 m.) of triethylamine in 150 ml. of tetrahydrofuran is added 0.78 g. (0.01 m.) of acetyl chloride. The resulting mixture is refluxed for two hours, cooled and filtered. The solid is recrystallized to give 3-[1-(p-acetoxyphenylamino)ethylidene]-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 199°-201° C.