Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.Cl[C:27]([O:29][CH3:30])=[O:28].C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[C:7]([C:27]([O:29][CH3:30])=[O:28])=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: COC(=O)Cl
Agent: [Li]C(C)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.50 g, 1.612 mmol, see Example 1) was dissolved in THF (15 mL) and cooled to −78° C. s-BuLi (2.54 mL, 3.56 mmol) was then added dropwise, and the solution was stirred at −78° C. for 30 minutes. Methyl chloroformate (0.38 mL, 4.98 mmol) was then added as a THF (2 mL) solution, and the reaction was stirred for an additional 30 minutes. The reaction was then quenched with saturated NH4Cl and allowed to warm to room temperature. The reaction was then extracted with DCM (3×50 mL), dried, and filtered to give a crude residue. The crude residue was purified by column chromatography with 5:1 hexane:DCM to give methyl 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.55 g, 91% yield).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOc1ccccc1
Reactant: O=C(Cl)C1CC1
Agent: [Al+3]
Agent: [Cl-]
Product: CCOc1ccc(C(=O)C2CC2)cc1

Procedure:
Alternatively, the substituted-phenyl cyclopropyl ketones may be prepared by reacting cyclopropanecarboxylic acid chloride with an appropriately substituted-phenyl compound in the presence of a Friedel-Crafts catalyst, e.g., aluminum chloride. In Example 6, Step A, cyclopropanecarboxylic acid chloride is reacted with ethoxybenzene in the presence of aluminum chloride, yielding cyclopropyl (4-ethoxyphenyl) ketone.
Reaction SMILES: N([CH:4]([OH:20])[C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([Br:18])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:19])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N.C(Cl)(Cl)Cl.CO>N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:18][C:16]1[C:14](=[O:15])[NH:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:8]1[O:9][C@H:5]([CH2:4][OH:20])[C@@H:6]([OH:19])[CH2:7]1
Reactant: [N-]=[N+]=NC(O)[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)C[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1Br

Procedure:
The 5'-azido derivative of 5-bromo-2'-deoxy uridine is prepared via the method described above. The 5'-azido-5-bromo-2'-deoxyuridine (1 mmol) is treated with triphenyl phosphine (1.5 mmol) in pyridine at room temperature for 2 h. Concentrated ammonia (1 ml) is added to the reaction vessel. After 14 h the solvent is removed under vacuum. The residue is dissolved in chloroform/ methanol containing one equivalent of p-toluene sulfonic acid, and this solution is added to hexanes. The 5'-amino-5-bromo-2'-deoxyuridine precipitate is collected and dried.
Reaction SMILES: O=[C:2]1[NH:7][CH:6]=[N:5][C:4]2[CH:8]=[C:9]([C:11]3[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=3)[NH:10][C:3]1=2.P(Cl)(Cl)([Cl:24])=O>O1CCOCC1>[ClH:24].[Cl:24][C:2]1[C:3]2[NH:10][C:9]([C:11]3[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc(-c2cc3nc[nH]c(=O)c3[nH]2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(-c2cc3ncnc(Cl)c3[nH]2)cc1
Product: Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
A mixture of ethyl 4-(4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate (2.97 g) and phosphoryl chloride (16.45 g) was stirred at 110° C. for 1 hr, dioxane (10 mL) was added and the mixture was heated under reflux for 4 hrs. After concentration under reduced pressure, ethanol (30 mL) was added to the residue and, after stirring at room temperature for 30 min, the precipitated solid was collected by filtration. The solid was washed with ethanol and dried under reduced pressure at 60° C. to give the title compound (3.34 g).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:16][C:17]1[C:25]2[CH:24]=[CH:23][S:22][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH:13]([CH3:15])[CH3:14].[C:26](=[O:28])=[O:27]>C(OCC)C>[CH2:12]([O:16][C:17]1[C:25]2[CH:24]=[C:23]([C:26]([OH:28])=[O:27])[S:22][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C=O
Reactant: CC(C)COc1cccc2sccc12
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)COc1cccc2sc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1.6 M solution of n-butyl lithium in hexane (18 ml, 28.8 mmol) is dissolved under an argon atmosphere in 100 ml of dry diethyl ether, followed by dropwise addition of a solution of 4-Isobutoxy-benzo[b]thiophene (201, 5.4 g, 26.1 mmol) in 40 ml of diethyl ether. The reaction mixture is refluxed for 45 min, then cooled down and transferred via syringe to a mixture of excess dry ice (115 g, 2.61 mol) in diethyl ether (the dry ice is washed before twice with diethyl ether). The mixture is allowed to stir overnight at room temperature, then distributed between diethyl ether and water. The ether layers are reextracted with water. The aqueous layers are acidified with 2M aqueous HCl solution, and the precipitate is filtered off, washed with water and dried under high vacuum.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>C1C=CC=CC=1.[Ag]>[C:15]([C:14]([O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:13])[C:2](=[O:1])[CH:11]=1)=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [Ag]
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)OC1=CC(=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
A mixture of the silver salt of 2-hydroxy-1,4-naphthoquinone (842 mg, 3 mmol), and pivaloyl chloride (434 mg, 3.6 mmol) in benzene (5 mL) was stirred for 8 h at room temperature. The reaction mixture was filtered through Celite, the precipitate washed with EtOAc, and the combined organic solutions were concentrated in vacuo and purified by flash chromatography (EtOAc/hexane 1:10, 1:5). The product was recrystallized from hexane to afford a yellow solid (190 mg, 25%); mp 125-126° C.; 1H NMR (CDCl3) 8.15(dd, J=7.7, 1.1 Hz, 1H), 7.71(dt, J=7.7, 1.5 Hz, 1H), 7.59 (dt, J=7.5, 1.2 Hz, 1H), 7.57 (dd, J=7.6, 1.1 Hz, 1H), 6.48 (s, 1H), 1.44 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH2:17])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30]>C(#N)C.CO.C(OCC)C>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30].[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH:17][CH2:2][CH2:3][S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:13]
Reactant: CCN(CC)CCN
Reactant: O=S(CCCl)c1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: CO
Product: CCN(CC)CCNCCS(=O)c1ccccc1
Yield: 50.3 %

Procedure:
A mixture of 20.0 g (0.106 mole) of [(2-chloroethyl)sulfinyl]benzene, 30.0 g (0.259 mole) of N,N-diethylethylenediamine and excess sodium carbonate in 600 ml of acetonitrile was refluxed for 16 hr. The reaction mixture solution was filtered, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over sodium sulfate and the solvent was removed in vacuo to give an oil. This was dissolved in methanol, and a solution of 2 equivalents of maleic acid in methanol was added. Diethyl ether was added and a whie solid precipitated to give 26.7 g (50.3%) of title compound, a white crystalline solid, mp 111°-112.5° C.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][C:6]=1[Cl:25].[OH-].[Na+]>CO.O1CCCC1.O>[Cl:25][C:6]1[CH:7]=[C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:9]=[CH:10][C:5]=1[C:4](=[O:26])[C:3]([OH:27])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1Cl
Yield: 80.6 %

Procedure:
A solution of 2-chloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.56 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from acetone-hexane provided 0.435 g of purified 2-chloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 152°-153° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[C:13]2=[CH:17][N:18]=[CH:19][N:12]2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[I:25]I>C1COCC1>[CH2:1]([O:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[C:13]2=[CH:17][N:18]=[C:19]([I:25])[N:12]2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: O=c1[nH]c(COCc2ccccc2)nn2cncc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=c1[nH]c(COCc2ccccc2)nn2c(I)ncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of compound 4 (4.9 g, 19.1 mmol) in THF (120 mL) was added n-BuLi (23 mL) dropwise at −78° C. and the resulting reaction mixture was stirred below −70° C. for one hour, followed by dropwise addition of iodine (19.4 g, 76.3 mmol) in THF (60 mL) at the same temperature. The reaction was allowed to warm to room temperature slowly. The reaction was quenched with saturated aqueous Na2SO3 solution (60 mL), and it was then extracted with EtOAc (60 mL×3). The organic phases were combined and dried over Na2SO4. The solid was filtered and the filtrate was concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel column (eluted with PE/EtOAc=10:1 to 2:1) to afford compound 5 (4.1 g, 56% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.16 (s, 1H), 7.84 (s, 1H), 7.42˜7.29 (m, 5H), 4.62 (s, 2H), 4.40 (s, 2H). LC-MS: m/z 383.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][C@@H:9]1[CH2:21][N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:37]([CH3:36])(=[O:39])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CNc3ccccc3)C2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
A 250-mL round-bottomed flask was charged with N-(((2S)-1,4-dibenzyl-2-piperazinyl)methyl)aniline (0.734 g, 1.98 mmol), DMAP (0.027 g, 0.22 mmol), triethylamine (0.85 mL, 6.1 mmol) and CH2Cl2 (8 mL). Methanesulfonyl chloride (0.23 mL, 3.0 mmol) was added drop wise at room temperature and the mixture was stirred at room temperature for 2 h. Additional methanesulfonyl chloride (0.20 mL, 2.6 mmol) and triethylamine (1.0 mL, 7.2 mmol) were added. The mixture was stirred at room temperature for another 1.5 h and then the mixture was concentrated to half the original volume and partitioned between water (40 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica gel, 0 to 60% EtOAc in hexanes) to afford N-(((2R)-1,4-dibenzyl-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.528 g) as a light yellow solid.
Reaction SMILES: [I:1]I.[CH3:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][N:5]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O>[NH2:10][C:8]1[CH:9]=[C:4]([CH3:3])[N:5]=[CH:6][C:7]=1[I:1].[NH2:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:3])[C:9]=1[I:1]
Reactant: II
Reactant: Cc1cc(N)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(N)c(I)cn1
Product: Cc1nccc(N)c1I
Temperature: 25 °C
Yield: 5 %
Yield: 11 %

Procedure:
A solution of KI (1.96 g, 11.9 mmol) and I2 (1.87 g, 7.36 mmol) in 10 mL of water was added to a refluxing solution of the 2-methylpyridin-4-ylamine (1.00 g, 9.25 mmol) and sodium carbonate (683 mg, 6.44 mmol) in 5 mL of water. The mixture was heated at reflux for 2 hours, cooled to room temperature, and treated with 20 mL of ethyl acetate (EtOAc). Phases were separated and the aqueous layer was extracted with three 20 mL portions of ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium thiosulfate (Na2S2O3) solution, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography (30% ethyl acetate in hexanes to 100% ethyl acetate, gradient) of the resulting residue yielded 4-amino-3-iodo-6-methylpyridine (first eluting: 226 mg, 11% yield) and 4-amino-3-iodo-2-methylpyridine (second eluting: 116 mg; 5% yield).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C(/N=N/C(N(C)C)=O)=O)C.[Br:40][C:41]1[CH:42]=[C:43](O)[CH:44]=[C:45]2[C:50]=1[CH:49]=[N:48][CH:47]=[CH:46]2>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:43]1[CH:44]=[C:45]2[C:50](=[C:41]([Br:40])[CH:42]=1)[CH:49]=[N:48][CH:47]=[CH:46]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Oc1cc(Br)c2cnccc2c1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Brc1cc(OCc2ccccc2)cc2ccncc12
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Benzyl alcohol (0.25 mL; Ald), triphenylphosphine (1.29 g), and TMAD (850 mg; Ald) were added to a toluene (30 mL) solution of Intermediate 7 (500 mg) and the resulting mixture was stirred at room temperature for 13 hours. The reaction mixture solution was filtrated, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (Yamazen; n-hexane/ethyl acetate) to give the title compound (186 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH3:15].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>CCCCCCC.O>[CH2:11]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: O
Product: CCCCCOc1ccc(C(C)=O)cc1
Reaction time: 3 h
Yield: 105.6 %

Procedure:
p-Hydroxyacetophenone (40.0 g), n-pentyl bromide (48.8 g) and dimethylformamide (200 ml) were charged in 1-liter three-necked flask, and disintegrated potassium carbonate (48.7 g) was added thereto with stirring. The mixture was heated, and the reaction was carried out for 3 hours at the inner temperature of 65 to 70° C. After completion of the reaction, the mixture was cooled, water (360 ml) and n-heptane (360 ml) were added thereto and, after the mixture was stirred, it was separated to collect a n-heptane layer. The n-heptane layer was washed with 0.5N aqueous solution (200 ml) of sodium hydroxide twice and, finally, washed with a saturated saline solution (200 ml). The n-heptane solution was concentrated in vacuo to give p-pentyloxyacetophenone (64.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[NH:14][CH:15]1[CH2:17][CH2:16]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([C:18](=[O:20])[CH3:19])[CH:15]1[CH2:16][CH2:17]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1ncc2c1C(=O)C(Cl)=C(NC1CC1)C2=O
Agent: O=S(=O)(O)O
Product: CC(=O)N(C1=C(Cl)C(=O)c2c(cnn2C)C1=O)C1CC1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
6-Chloro-5-cyclopropylamino-1-methyl-1H-indazole-4,7-dione (3 grams prepared as in Example II) was added to acetic anhydride (10 milliliters) containing a few drops of concentrated sulphuric acid. The mixture was stirred at 50° C for 15 minutes and then poured into ice-water. The aqueous mixture was extracted with methylene chloride and the extracts washed with aqueous sodium bicarbonate solution and dried. The solvent was then removed under reduced pressure to give a yellow solid which on recrystallization from ethanol gave the desired product having a melting point of 171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=2)[O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[O:26][C:25]([C:27]([O:29]CC)=O)=[N:24][N:23]=3)[CH:17]=2)=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].[NH4+:40].[OH-]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=2)[O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[O:26][C:25]([C:27]([NH2:40])=[O:29])=[N:24][N:23]=3)[CH:17]=2)=[CH:4][C:3]=1[C:36]([F:38])([F:37])[F:39]
Reactant: [NH4+]
Reactant: CCOC(=O)c1nnc(-c2cc(Oc3cccc(CCC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)ccn2)o1
Agent: [OH-]
Product: NC(=O)c1nnc(-c2cc(Oc3cccc(CCC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)ccn2)o1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of ethyl 5-{4-[3-(3-{[4-chloro-3-(trifluoromethyl)phenyl]-amino}-3-oxopropyl)phenoxy]pyridin-2-yl}-1,3,4-oxadiazole-2-carboxylate (100 mg) in NH4OH (10 mL) was allowed to stir at rt for 90 min. The reaction mixture was concentrated and the residue recrystallized from MeOH to give A-102. 1H NMR (300 MHz, d6-DMSO) δ: 8.70 (br s, 1H), 8.62 (d, 1H), 8.29 (br s, 1H), 8.13 (d, 1H), 7.76 (dd, 1H), 7.58-7.64 (m, 2H), 7.45 (t, 1H), 7.23-7.28 (m, 1H), 7.14-7.19 (m, 2H), 7.07-7.13 (m, 1H), 2.97 (t, 2H), and 2.69 (t, 2H). LCMS, FA: Rt=1.77 min, [MH+ 532.1].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[CH2:14][N:15]3C(OC(C)(C)C)=O)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:26]1([CH3:36])[C:27]([S:32]([Cl:35])(=[O:34])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=1>>[ClH:35].[ClH:35].[C@H:13]12[CH2:18][C@H:16]([NH:15][CH2:14]1)[CH2:17][N:12]2[CH2:11][C:4]1[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=[C:2]([NH:1][S:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH3:36])(=[O:34])=[O:33])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1cc(N)cc2ccoc12
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)Nc1cc(CN2C[C@@H]3C[C@H]2CN3)c2occc2c1
Product: Cl
Yield: 42.5 %

Procedure:
starting from tert-butyl (1S,4S)-5-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (44 mg crude starting material, 0.10 mmol; obtained in Example 118, Step 2) and o-toluenesulfonyl chloride (22 μL, 0.15 mmol). The title compound (15 mg, 31%) was obtained as an off-white solid. HPLC 98%, RT=1.37 min (System A; 10-97% MeCN over 3 min), 97%, RT=1.21 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) δ ppm 2.28-2.34 (m, 1H) 2.66 (s, 3H) 2.67-2.72 (m, 1H) 3.52-3.59 (m, J=13.68, 2.64 Hz, 1H) 3.63-3.76 (m, 1H) 3.85-3.93 (m, J=12.80 Hz, 1H) 4.45-4.51 (m, 1H) 4.65 (s, 1H) 4.69-4.78 (m, 1H) 4.78-4.83 (m, 2H) 6.86 (d, J=2.26 Hz, 1H) 7.23-7.29 (m, 1H) 7.31-7.36 (m, J=7.53 Hz, 1H) 7.37-7.46 (m, 2H) 7.48 (d, J=2.26 Hz, 1H) 7.84-7.88 (m, 2H). MS (ESI+) for C21H23N3O3S m/z 398 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([Br:12])[C:5]=2[O:4][CH2:3]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:12][C:11]1[C:5]2[O:4][CH2:3][C@H:2]([N:1]([CH2:7][C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:5]=3)[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7][C:6]=2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=1
Reactant: COc1ccc(Br)c2c1C[C@@H](N)CO2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Br)c2c1C[C@@H](N(Cc1ccccc1)Cc1ccccc1)CO2
Temperature: 85 °C
Yield: 155.5 %

Procedure:
(R)-3-Amino-8-bromo-5-methoxy-3,4-dihydro-2H-1-benzopyran (11.5 g, 44 mmol) was dissolved in 400 mL anhydrous acetonitrile and to the reaction were benzyl bromide (13 mL, 110 mmol), anhydrous potassium carbonate (grounded) (16 g, 116 mmol), and a catalytic amount of KI added and then heated to 85° C. for 48 h. The solvent was removed in vacuo, the remains were taken into a 2M solution of NH3 and then extracted twice with ether. The combined ether portions were treated with brine, dried (MgSO4), filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: CH2Cl2) gave 15 g (78% yield) of the title compound as a clear oil. [α]21D =-15.5° (C=0.1 CHCl3) GC-MS (70eV) M=437 (15%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[S:23][CH:24]=[CH:25][N:26]=3)[CH:17]=2)[C:13](=[O:27])[CH2:12][CH2:11][CH2:10][CH2:9]1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.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.CCOC(C)=O>[N:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[S:23][CH:24]=[CH:25][N:26]=4)[CH:17]=3)[C:13](=[O:27])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1CCCCC(c2ccccc2Br)N1Cc1cccc(-c2nccs2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCCCC(c2ccccc2-c2ccncc2)N1Cc1cccc(-c2nccs2)c1
Temperature: 80 °C

Procedure:
A mixture of 7-(2-bromophenyl)-1-(3-(thiazol-2-yl)benzyl)azepan-2-one (50 mg; 0.11 mmol), commercially available pyridin-4-ylboronic acid (14 mg; 0.11 mmol), and Pd(PPh3)4 (7 mg; 0.006 mmol) in THF (2 ml), and aq. 2 M Na2CO3 (0.2 ml) was heated to 80° C., under nitrogen, for 24 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by preparative HPLC afforded 7-(2-(pyridin-4-yl)phenyl)-1-(3-(thiazol-2-yl)benzyl)azepan-2-one. LC-MS (conditions A): tR=0.62 min.; [M+H]+: 440.15 g/mol.