Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[Cl:16][CH2:17][C:18]([CH2:20]Cl)=[CH2:19]>C1COCC1>[Cl:16][CH2:17][C:18](=[CH2:19])[CH2:20][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C=C(CCl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C(CCl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Benzyl alcohol (3.5 mL, 33.6 mmol) and DMF (8 mL) were added to a suspension of NaH (60% suspension in mineral oil, 1.8 g, 43.7 mmol, washed with hexane before use) in THF (35 mL). The resulting mixture was stirred for 30 minutes at room temperature and then 1 h at reflux. The mixture was cooled to room temperature and slowly added over 1 h to a solution of 3-chloro-2-chloromethyl-propene (4.2 g, 33.6 mmol) in THF (40 mL). The reaction was stirred at room temperature for 18 h, quenched with brine/water (1:1) and extracted with Et2O. The organic phase was dried (MgSO4), filtered and concentrated. Chromatography (SiO2, EtOAc:Petrol 1:9) to give the title compound (3.1 g) as a colourless oil. 1H NMR (CDCl3): 7.46-7.29 (5H, m), 5.35 (1H, s), 5.30 (1H, d), 4.56 (2H, s), 4.24-4.06 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl-].[CH2:23]([NH+:30]1[CH2:35][CH2:34][CH:33]2[CH2:36][NH2+:37][CH2:38][CH:32]2[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-]>>[CH2:23]([N:30]1[CH2:35][CH2:34][CH:33]2[CH2:36][N:37]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[N:13]=[CH:12][C:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:20]4)[CH2:38][CH:32]2[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Reactant: c1ccc(C[NH+]2CCC3C[NH2+]CC3C2)cc1
Agent: [Cl-]
Product: O=S(=O)(c1cccc(F)c1)c1cnc2c(N3CC4CCN(Cc5ccccc5)CC4C3)cccc2c1

Procedure:
0.367 g of 8-(5-benzyl-1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-fluorophenylsulfonyl)quinoline were prepared by analogy to the method of Example 27 by coupling of 3-(3-fluorophenylsulfonyl)-8-iodoquinoline with 5-benzyloctahydro-1H-pyrrolo[3,4-c]pyridine-2,5-diium chloride
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)C=C.[C:18]1(OC2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1.CCCCCC>C1(C2C=CC=CC=2)C=CC=CC=1>[CH2:23]([C:6]1[C:5](=[O:4])[C:14]2[C:9](=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH:18]=[CH2:19]
Reactant: C=CCOc1ccnc2c([N+](=O)[O-])cccc12
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: C=CCc1c[nH]c2c([N+](=O)[O-])cccc2c1=O
Temperature: 90 °C
Yield: 84.1 %

Procedure:
A solution of 4-allyloxy-8-nitroquinoline (3.72 g) in biphenyl (2.59 g) and diphenyl ether (7.4 g) was heated at 200° C. for 10 minutes. After cooling, n-hexane (40 ml) was added thereto, and the mixture was warmed at 90° C. After cooling, the resulting precipitate was collected by filtration to give 3-allyl-1,4-dihydro-8-nitro-4-oxoquinoline (3.13 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][C:15]([C:17]3[O:18][C:19]4[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:16][C:4]=2[N:3]=1.[H][H]>[Pd].CO>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[C:5]2[CH:13]=[CH:14][C:15]([C:17]3[O:18][C:19]4[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:16][C:4]=2[N:3]=1
Reactant: [H][H]
Reactant: Cc1nc2cc(-c3nc4ccc([N+](=O)[O-])cc4o3)ccc2n1C1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccc(N)cc4o3)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 40.2 %

Procedure:
2-Methyl-5-(6-nitrobenzoxazol-2-yl)-1-(tetrahydropyran-4-yl)benzimidazole (see Working Example 47-2) (135 mg, 0.357 mmol) was added to methanol (20 mL) containing palladium/carbon (Pd: 10%, 0.06 g), hydrogen was substituted in by successively reducing the pressure and purging with hydrogen gas 3 times, and this was stirred at room temperature for 2.5 hours. After substituting in nitrogen, the insoluble material was filtered off through a Celite layer (20 mm thickness), and this same layer was washed with methanol (20 mL, 3 times). The filtrate was combined with the wash solutions and the solvent was distilled out at reduced pressure, the residue obtained was purified by silica gel column chromatography to yield the title compound (50 mg, 40.2% yield) as brown crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:14]([C:16]1[CH:28]=[C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[C:26]([O:34][CH3:35])=[CH:25][C:17]=1[O:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=O>>[CH3:35][O:34][C:26]1[C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:28][C:16](/[CH:14]=[CH:2]/[C:1](=[O:3])[C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[C:17]([CH:25]=1)[O:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21]
Reactant: COc1cc(OC(C)(C)C(=O)O)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Product: COc1cc(OC(C)(C)C(=O)O)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Yield: 85 %

Procedure:
The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 2-(2-formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-2-methyl-propionic acid (Ex-59B) in a similar manner as described in Ex-22. Yellow solid, mp 164–165° C., 85% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.21–8.28 (m, 3H), 7.96–8.12 (m, 4H), 7.67 (d, 1H, J=3.0 Hz), 7.56 (brs, 3.0H), 7.14 (dd, 1H, J=5.7, 3.0 Hz), 6.57 (s, 1H), 3.88 (s, 3H), 1.66 (s, 6H). MS (ESI) m/z=502 ([M+H]+, 100%). Anal. Calcd. for C24H23NO7S2: C, 57.47; H, 4.62; N, 2.79; S, 12.79. Found: C, 57.70; H, 4.74; N, 2.85; S, 12.51.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][N:25]([CH3:39])[C:26]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1>C1COCC1>[CH3:24][N:25]([CH3:39])[C:26]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH:29]([CH:2]=[O:3])[CH2:28][CH2:27]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(C=O)CC1
Reaction time: 2 h

Procedure:
Tert-BuOK (8.41 g, 75 mmol) dissolved in abs. THF (100 mL) was added in drops to a solution of (methoxymethyl)triphenyl phosphonium chloride (25.7 g, 75.0 mmol) in abs. THF (100 mL) at 0° C. in argon. The resulting red solution was mixed after 30 min at 0° C. with a solution of 4-dimethylamino-4-phenyl cyclohexanone (10.9 g, 50.0 mmol) in abs. THF (100 mL) and stirred overnight at RT. The solvent was removed in a vacuum, the residue mixed with 1N sulphuric acid (150 mL) and stirred for 2 h. The precipitate precipitated out during this was separated and the filtrate (pH 1) washed with ether (6×100 mL). The aqueous solution was adjusted to pH 11 with 5N NaOH and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[S:9](=O)(=[O:12])([OH:11])[OH:10]>>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([S:9]([OH:12])(=[O:11])=[O:10])=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=S(=O)(O)O
Product: Nc1ccc(S(=O)(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroaniline, 0.4 ml, was slowly added to 4 ml of fuming sulfuric acid and stirred at room temperature overnight. While cooling to 0°, the reaction solution was poured onto water and the solid precipitated was separated by filtration. The solid filtered was dissolved in 2N sodium hydroxide aqueous solution and conc. hydrochloric acid was then added to the solution to make the liquid acidic. The solid precipitated was taken by filtration to give the crude product of 4-amino-2-chlorobenzenesulfonic acid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C:7]=1[CH2:25][CH3:26])C.[NH2:28][NH2:29].O>C(O)C>[Cl:24][C:20]1[CH:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:6]([CH2:5][C:4]([NH:28][NH2:29])=[O:3])=[C:7]2[CH2:25][CH3:26])[CH:23]=[CH:22][CH:21]=1
Reactant: NN
Reactant: CCOC(=O)Cc1c(CC)n(Cc2cccc(Cl)c2)c2ccc(OC)cc12
Solvent: CCO
Solvent: O
Product: CCc1c(CC(=O)NN)c2cc(OC)ccc2n1Cc1cccc(Cl)c1
Yield: 62 %

Procedure:
A mixture of 1.93 g (5 mmol) of 1-[(3-chlorophenyl)methyl]-2-ethyl-5-methoxy-1H-indole-3-acetic acid ethyl ester and 5 mL of hydrazine in 20 mL of ethanol was heated to maintain reflux for 19 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4), and concentrated to give 1.144 g (62% yield) of 1-[(3-chlorophenyl)methyl]-2-ethyl-5-methoxy-1H-indole-3-acetic acid hydrazide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH:34]=O)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18].[OH-].[Na+]>CO>[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:8])[CH3:7])[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)c[nH]c34)no2)cc1Cl
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H](C)NCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
D-alanine methyl ester hydrochloride (420 mg) and 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D71) (382 mg) was added to a solution of NaOH (120 mg) in methanol (20 mL). After stirring for 0.5 hour, methanol was evaporated off. A solution of AcOH (0.5 mL) in dichloromethane (40 mL) was added to the residue. NaBH(OAc)3 (847 mg) was added to the above mixture. The reaction mixture was stirred at room temperature overnight, and quenched by saturated NaHCO3 solution. The organic layer was separated and washed with water and brine. After the solvent was evaporated off the residue was purified by Mass Directed AutoPrep to afford methyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-D-alaninate (D75) (262 mg) as a white solid. MS (ES): C24H25ClN4O4 requires 468; found 491.1 (M+Na+).
Reaction SMILES: CO.[OH-].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]1[C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[C:32]([C:36]([O:38]C)=[O:37])=[CH:31][CH:30]=[CH:29]4)=[CH:22][CH:21]=2)=[C:16]([CH:40]([CH3:42])[CH3:41])[O:15][N:14]=1>O1CCCC1>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=1[C:13]1[C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[C:32]([C:36]([OH:38])=[O:37])=[CH:31][CH:30]=[CH:29]4)=[CH:22][CH:21]=2)=[C:16]([CH:40]([CH3:42])[CH3:41])[O:15][N:14]=1
Reactant: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)cc1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
Methanol (380 mL) and 5 N sodium hydroxide solution (190 mL) were added to a stirred solution of methyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (190 g, 0.35 mol) in tetrahydrofuran (1 L). The resulting solution was heated to reflux for 1.5 h. The mixture was cooled to room temperature and concentrated to remove methanol and tetrahydrofuran. The residue was diluted with water (500 mL), acidified with 6 N HCl and the supernatant was decanted from the taffy-like solid. The solid was crystallized from ethyl acetate (1 L) to give 170 g of the product as off-white crystals. 1H NMR (DMSO-d6): δ 9.02 (d, J=9 Hz, 1H), 8.01 (s, 1H), 7.80 (d, J=8 Hz, 1H), 7.73 (d, J=7 Hz, 1H), 7.68-7.61 (m, 5H), 7.53 (dd, J=7, 9 Hz, H), 7.38 (t, J=8, 15 Hz, 1H), 6.88 (d, J=9 Hz, 2H), 4.85 (s, 2H), 3.46 (septet, J=7 Hz, 1H), 1.32 (d, J=7 Hz, 6H). ESI-LCMS m/z 532 (M+H)+.
Reaction SMILES: O[CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12].[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(#N)C>[N:13]1([CH2:2][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]2=[O:12])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=C1Cc2ccccc2N1CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=C1Cc2ccccc2N1Cn1cnc2ccccc21
Yield: 25 %

Procedure:
A solution of 1-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one a25 (1 eq, 3.06 mmol, 500 mg), benzimidazole (4 eq, 12.26 mmol, 1.45 g) and carbonyldiimidazole (1 eq, 3.06 mmol, 500 mg) in acetonitrile (3 ml) was irradiated in a microwave apparatus (CEM discover) for 10 minutes (100 w). After evaporation of the acetonitrile under reduced pressure, the crude product was purified by preparative HPLC on reverse phase to give 203 mg of 1-(1H-benzimidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one 167 (25%) after recrystallization in diisopropylether.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:6]=1[C:7]#[N:8])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[O:24]1[CH2:3][CH:2]1[CH2:1][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:6]=1[C:7]#[N:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOc1cccc([N+](=O)[O-])c1C#N
Solvent: ClC(Cl)Cl
Product: N#Cc1c(OCC2CO2)cccc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
22.5 g of 2-allyloxy-6-nitro-benzonitrile are introduced into a solution of 26.8 g of m-chloroperbenzoic acid (85% strength) in 1 liter of chloroform and the mixture is warmed to 50° in the course of 3 hours. The reaction mixture is kept at this temperature for 24 hours and then cooled and the solution is washed with 100 ml of 1 M sodium sulphite solution, then with 100 ml of 2 N sodium hydroxide solution and finally with 100 ml of water. After drying over magnesium sulphate and evaporating the solution, a colourless crystalline residue is obtained and this is ground with 20 ml of isopropanol, the mixture is filtered and the material on the filter is dried in vacuo, after which crude 2-(2,3-epoxypropoxy)-6-nitro-benzonitrile with a melting point of 131°-135° is obtained and this is used further in the form of the crude product.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Br:25])[C:23]=1O)[C:19]#[N:20]>O1CCOCC1>[Br:25][C:22]1[C:23]2[O:11][C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([O:3][CH3:2])=[O:14])=[CH:13][CH:12]=3)=[N:15][C:16]=2[CH:17]=[C:18]([C:19]#[N:20])[CH:21]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: N#Cc1cc(N)c(O)c(Br)c1
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc3cc(C#N)cc(Br)c3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a 3-l round-bottom flask fitted with a stir bar and a Claisen adapter fitted with a thermocouple and a condenser blanketed with nitrogen was added terephthalic acid monomethyl ester chloride (37.3 g) and a solution of 3-amino-5-bromo-4-hydroxybenzonitrile (40 g, Step B) in dioxane (675 ml). The mixture was heated to reflux and stirred at this temperature overnight. The mixture was then cooled to room temperature and the dioxane was removed in vacuo. The flask was fitted with a Dean-Stark trap and p-toluenesulfonic acid monohydrate (35.8 g) and toluene (2.5 l) were added. The mixture was heated to reflux and stirred at this temperature overnight. The mixture was then allowed to cool, transferred to a new 5-l flask, and concentrated to a brown solid. The crude product was triturated with methanol to provide 55.5 g (83%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.50 (s, 1H), 8.34 (d, J=8.0 Hz, 2H), 8.29 (s, 1H), 8.19 (d, J=8.0 Hz, 2H), 3.91 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=2)[CH2:4]1)[CH3:2].[OH-].[Na+:18].O>C(O)C>[CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]([CH3:16])[C:13]([O-:15])=[O:14])[CH:9]=2)[CH2:4]1)[CH3:2].[Na+:18]
Reactant: CCC1Cc2ccc(C(C)C(=O)O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC1Cc2ccc(C(C)C(=O)[O-])cc2C1

Procedure:
To 12.2g. of 2-(2-ethylindan-5-yl)propionic acid was added a solution of 2.2g. of sodium hydroxide in 9 ml. of water and 21 ml. of ethanol. After complete dissolution, the solvent was distilled off under reduced pressure and to the residue was added ether. The precipitates thus separated were recovered by filtration and washed with either to give 12.9g. of a white powder. The powder was recrystallized from a mixture of ethanol and ether to give the desired product as white needles of m.p. 178° - 181° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O>[ClH:12].[N:16]1[CH:17]=[CH:18][C:13]([NH:1][C:2]2[C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=3[S:5][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Nc1csc2ccccc12
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc2c(Nc3ccncc3)csc2c1
Yield: 95.1 %

Procedure:
A solution of 3-aminobenzo[b]thiophene (3 g, 20 mmol) and 4-chloropyridine hydrochloride (3.5 g, 23 mmol) in 50 mL of 1-methyl-2-pyrrolidinone was stirred at 80° for three hours, and thereafter cooled, stirred with water, basified with sodium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution and dried (anhydrous magnesium sulfate), filtered and concentrated to 8 g dark oil. Elution through silica with ethyl acetate via flash column chromatography yielded 5 g of an amber oil. Conversion to the hydrochloride salt in methanol-ether yielded 3 g of a hygroscopic solid. Recrystallization from 50% methanol in ether yielded 1.8 g of rust colored crystals, mp 268-270° (dec.).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:35]=[CH:34][C:22]([C:23]([NH:25][CH2:26][C:27]([CH3:33])([CH3:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[O:24])=[CH:21][C:20]=1OC>>[CH3:31][N:29]([CH3:30])[CH2:28][C:27]([CH3:32])([CH3:33])[CH2:26][NH:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:12]=[C:11]3[C:5](=[CH:4][N:3]=2)[N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]3[CH:13]([CH3:15])[CH3:14])=[CH:35][CH:34]=1
Reactant: COc1cc(C(=O)NCC(C)(C)CN(C)C)ccc1N
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Product: CC(C)N1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)NCC(C)(C)CN(C)C)cc3)nc21

Procedure:
Prepared from Intermediate 76 and Intermediate 22.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:46])[CH2:10][C:11]1[CH:45]=[CH:44][CH:43]=[CH:42][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[N:16]=1>C(Cl)Cl>[CH3:21][C:20]1[C:15]([CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[CH2:10][C:9]([NH2:8])=[O:46])=[N:16][C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[N:18][CH:19]=1
Reactant: Cc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(C3CCNCC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
TFA (0.37 mL, 4.8 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A56) (64 mg, 0.12 mmol) in DCM (20 mL) under nitrogen and the resulting mixture stirred for 24 hours at room temperature. The volatiles were removed in vacuo and the residue was taken up in MeOH and loaded onto an SCX cartridge (10 g). The column was eluted with 5 column volumes of MeOH and then 5 column volumes of 5% v/v aqueous ammonia in MeOH. The volatiles from the ammoniacal filtrate were evaporated under reduced pressure and the resulting solid dried under high vacuum to give the title compound 16 as a white solid (36 mg, 69%); 1H NMR (400 MHz, d6-DMSO) δ 9.28 (s, 1H), 8.15 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.44 (s, 1H), 7.25-7.13 (m, 4H), 7.10 (d, J=8.6 Hz, 2H), 6.93 (s, 1H), 3.50 (s, 2H), 3.10-2.98 (m, 4H), 2.94-2.82 (m, 2H), 2.65-2.53 (m, 3H), 2.06 (s, 3H), 1.67 (d, J=10.6 Hz, 2H), 1.49 (qd, J=12.4, 3.7 Hz, 2H). LCMS-A: rt 4.463 min; m/z 430 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[Mg]Br>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:28]3[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=3[CH3:26])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Cc1ccc([Mg]Br)c(C)c1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c(C)c1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 2,4-dimethylphenylmagnesium bromide. Yield: 57 mg of a white solid. LC-MSD, m/z for C24H19BrN2O2 [M+H]+=447.0, 449.0; HPLC retention time: 2.7 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
A solution of (3,4-dichloro-phenyl)-acetic acid (14.0 g, 0.068 mol) in methanol (71 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 12 h. The reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (3,4-dichloro-phenyl)-acetic acid methyl ester (15.0 g, quant.) as a white solid: mp 30-32 ° C.; EI-HRMS m/e calcd for C9H8Cl2O2 (M+) 217.9901, found 217.9907.