Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[C:25]4[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=4[NH:19][C:18]4[NH:29][N:30]=[C:31]([C:32]([O:34][CH2:35][C:36]([CH3:47])([CH3:46])[CH2:37][NH:38]C(OC(C)(C)C)=O)=[O:33])[C:17]3=4)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>C(Cl)Cl>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[C:25]4[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=4[NH:19][C:18]4[NH:29][N:30]=[C:31]([C:32]([O:34][CH2:35][C:36]([CH3:47])([CH3:46])[CH2:37][NH2:38])=[O:33])[C:17]3=4)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)COC(=O)c1n[nH]c2c1C(/C=C/c1ccc(-c3cccc(F)c3)cn1)C1=C(CC(C)(C)CC1=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CN)COC(=O)c1n[nH]c2c1C(/C=C/c1ccc(-c3cccc(F)c3)cn1)C1=C(CC(C)(C)CC1=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 mg of 3-tert-butoxycarbonylamino-2,2-dimethylpropyl 4-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-7,7-dimethyl-5-oxo-4,5,6,7,8,9-hexahydro-1H-pyrazolo[3,4-b]quinoline-3-carboxylate are dissolved in DCM (2.5 ml), admixed with TFA (2.5 ml) and stirred at RT for 3 h. The solvent is removed under reduced pressure, and the residue is suspended in toluene and concentrated by rotary evaporation once again. Yield: 63 mg; LC/MS (method J): m/z=543 (M+1); Rt=0.680 min
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10]C)=[O:9].[OH-].[Na+].CO>O>[NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1scc(C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1csc(C(=O)O)c1N
Temperature: 25 °C
Yield: 84.5 %

Procedure:
To a solution of methyl 3-amino-4-methyl-2-thiophene carboxylate (5 g, 29 mmol) and sodium hydroxide (3.5 g, 88 mmol) in a mixed solution (methanol:H2O/30 ml:120 ml) was heated at 50° C. for over night. The solution was cooled to room temperature and extracted with methylene chloride. The aqueous phase was acidified with 6N HCl until pH equal to 5. The aqueous phase was extracted again with ethyl acetate, and solvent phase washed with brine and dried over by sodium sulfate. After filtered and dried over the solvent, evaporated solvent to give 3.85 g of 3-amino-4-methyl-thiophene-2-carboxylic acid as a white solid in 84% yield: 1H NMR (300 MHz, CDCl3) δ 7.05 (d, 1H), 3.12 (br, 2H), 2.16 (s, 3H); MS (m/e): 157.9 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[K+].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH-:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].O>CS(C)=O>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=2)(=[O:28])=[O:29])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.3 %

Procedure:
A mixture of 0.8 g of 4,6-dichloro-5-(p-tolyl)-pyrimidine and 1.68 g of 4-tert.-butylbenzene sulfonamide potassium salt in 20 ml of DMSO was stirred at room temperature for 24 h. The mixture was poured onto 200 ml of water and extracted twice with 100 ml of diethyl ether. The organic layers was extracted twice with 50 ml of water. The combined aqueous layers was acidified with conc. hydrochloric acid. The resulting fine suspension was extracted twice with ethyl acetate. The combined organic layers was dried over Na2SO4 and evaporated. The residue was dried under high vacuum to give 1.34 g 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide as a white powder. LC-MS: tR=5.92 min, [M+1]+=416.20, [M−1]−=414.24.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][C:14]#[N:15])[N:8]=1.[NH3:19]>CO>[F:1][C:2]([F:18])([F:17])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][C:14]#[N:15])[N:8]=1
Reactant: N#CCCn1ccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CO
Product: N#CCCn1ccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[3-(2,2,2-trifluoroethyl)-thioureido]-1-(2-cyanoethyl)pyrazole (2.8 g.), yellow mercuric oxide (4.0 g.), methanol (100 ml.) and saturated ethanolic ammonia solution (10 ml.) was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated to dryness and the residue partitioned between ether and water. The ether phase was dried and evaporated to give 3-[2-(2,2,2-trifluoroethyl)guanidino]-1-(2-cyanoethyl)pyrazole characterised as the hydrogen maleate, m.p. 141°-142° after recrystallisation from acetone.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1.[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C)C=O>[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:2][C:3]2[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CN2CCC(O)CC2)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.3 %

Procedure:
In 45 ml of dimethylformamide was dissolved 6.0 g (31.8 mmol) of ethyl 5-chloromethyl-2-furancarboxylate followed by addition of 9.64 g (95.5 mmol) of 4-hydroxypiperidine and the mixture was stirred at room temperature for 20 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with 100 ml of chloroform and washed with saturated aqueous sodium chloride solution twice. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to give 7.84 g (97.4%) of ethyl 5-(4-hydroxypiperidinomethyl)-2-furancarboxylate (Compound s) as light brown oil.
Reaction SMILES: [CH:1]1[CH:2]=C[C:4]2[N:9](O)N=[N:7][C:5]=2[CH:6]=1.[CH3:11][N:12]([CH3:32])[C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:19]([CH:23]=1)[C:20]([OH:22])=O)=[O:14].N1C=CC=C(N)C=1.C(Cl)CCl>CN(C)C=O.O>[CH3:32][N:12]([CH3:11])[C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:19]([C:20]([NH:7][C:5]2[CH:4]=[N:9][CH:2]=[CH:1][CH:6]=2)=[O:22])[CH:23]=1)=[O:14]
Reactant: CN(C)C(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: On1nnc2ccccc21
Agent: Nc1cccnc1
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
HOBT (102 mg, 0.67 mmol) was added in one charge to a stirred solution of 5-[(dimethylamino)carbonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 59; 200 mg, 0.67 mmol), 3-pyridinamine (62.9 mg, 0.67 mmol) and EDC (128 mg, 0.67 mmol) in N,N-dimethylformamide (5 ml) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with water (50 ml). The precipitate was collected by filtration. The solid was dissolved in ethyl acetate (100 ml), and the organic phase was washed with NaOH (1 mol/l 25 ml), water (25 ml), saturated brine (25 ml), dried over sodium sulfate, and evaporated in vacuo to yield the title compound as a white solid. 78 mg.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12]C)=O.[NH3:14].O>CO>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([NH2:14])=[O:12]
Reactant: N
Reactant: COC(=O)c1cc2cccnc2[nH]1
Solvent: CO
Solvent: O
Product: NC(=O)c1cc2cccnc2[nH]1
Temperature: 80 °C

Procedure:
To a solution of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate (H-1) (880 mg, 5.0 mmol) in MeOH (2 mL) was added NH3.H2O (6 mL). The reaction was heated at 80° C. overnight. After being cooled to room temperature, the mixture was concentrated in vacuo to afford the title compound (805 mg) as a yellow solid, which was used for the next step without further purification. MS (m/z): 162 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(O)CCC(C)C)ccc1OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COc1cc(C(=O)CCC(C)C)ccc1OCc1ccccc1
Yield: 82.4 %

Procedure:
The previously obtained 63.0 g of 1-(4'benzyloxy-3'-methoxyphenyl)-4-methylpentanol was dissolved in 310 ml of acetone. To this mixture, Jones reagent was added dropwise at 0° to 10° C. while cooling in an ice bath. After the completion of dropping, 50 ml of isopropyl alcohol was added to the solution and the resultant mixture was stirred at room temperature until the solution turned to green. Subsequently, the reaction solution was extracted with 400 ml of dichloromethane three times. The extraction solution obtained was washed with 300 ml of water, 300 ml of saturated aqueous sodium hydrogen carbonate solution, and 300 ml of brine, in this order. After dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure, affording a brown crystal. The crystal were recrystallized from ether-hexane, affording 51.6 g of 4'-benzyloxy-3'-methoxy-4-methylvalerophenone (82.6% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([N+:10]([O-])=O)[C:3]=1[CH3:13]>CO.[Pt]>[NH2:10][C:4]1[C:3]([CH3:13])=[C:2]([Br:1])[CH:7]=[C:6]([F:8])[C:5]=1[OH:9]
Reactant: Cc1c(Br)cc(F)c(O)c1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Product: Cc1c(Br)cc(F)c(O)c1N
Reaction time: 8 h
Yield: 106.5 %

Procedure:
A mixture of 4-bromo-6-fluoro-3-methyl-2-nitrophenol (0.69 g, 2.76 mmol) in methanol (10 mL) was purged with nitrogen, treated with 10% platinum on carbon (0.027 g, 0.014 mmol) and then stirred under hydrogen (50 psi) overnight. The mixture was filtered over Celite (washing with methanol and dichloromethane) and the filtrate was concentrated to afford 2-amino-4-bromo-6-fluoro-3-methylphenol (647 mg) as a light brown solid, which was used directly without further purification. 1H NMR (400 MHz, DMSO-d6) δ=6.68 (d, J=10.0 Hz, 1 H), 2.11 (s, 3 H); LC/MS (m/z) ES+=219.98 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:16])=[C:8]([N+:13]([O-])=O)[CH:9]=[N:10]2)=[CH:5][CH:4]=1.[OH-].[NH4+].[ClH:19]>[Pd].CO.C(OCC)C>[ClH:19].[NH2:13][C:8]1[CH:9]=[N:10][C:11]2[C:6]([C:7]=1[OH:16])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2
Reactant: COc1ccc2c(O)c([N+](=O)[O-])cnc2c1
Agent: [Pd]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Product: COc1ccc2c(O)c(N)cnc2c1
Reaction time: 2 h

Procedure:
7-Methoxy-3-nitroquinolin-4-ol (4.5 g, 20.4 mmol), methanol (250 mL), ammonium hydroxide (5 mL) and palladium on carbon (400 mg of 10%) were combined. The mixture was placed on a Parr apparatus under a hydrogen atmosphere at 40 psi (2.8 Kg/cm2) for 2 hrs. The reaction mixture was filtered. The filtrate was concentrated under vacuum to provide a green solid. This material was dissolved in methanol (20 mL) and then 1N hydrochloric acid in diethyl ether (75 mL) was added. The resulting precipitate was isolated by filtration and dried to provide 2.6 g of 3-amino-7-methoxyquinolin-4-ol hydrochloride as a pink solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.[NH2:64][C:65]1[CH:70]=[CH:69][C:68]([NH:71][S:72]([CH3:75])(=[O:74])=[O:73])=[CH:67][C:66]=1[O:76][CH3:77]>>[CH3:75][S:72]([NH:71][C:68]1[CH:69]=[CH:70][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:66]([O:76][CH3:77])[CH:67]=1)(=[O:74])=[O:73]
Reactant: COc1cc(NS(C)(=O)=O)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NS(C)(=O)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 46.4 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with N-(4-amino-3-methoxyphenyl)methanesulfonamide hydrochloride (Astatech) (0.2 g, 0.8 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-methanesulfonylamino-2-methoxy-phenyl)-amide as a yellow solid (Yield 0.16 g, 47%).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12.C(N1C=CN=C1)([N:20]1C=CN=C1)=O>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:20])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2nc3cscc3c(=O)n2c1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2nc3cscc3c(=O)n2c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (6.0 g., 0.024 mol) and 1,1'-carbonyldiimidazole (4.0 g., 0.024 mol) in dimethylformamide (120 ml) is heated at 110° C. for 2.5 hours under nitrogen. The solution is cooled in an ice bath and anhydrous ammonia is bubbled through for 15 minutes. The mixture is stirred at ice bath temperature for 2 hours and at room temperature for one hour. The precipitate is filtered off, washed with tetrahydrofuran and dried to give the product (5.2 g.), mp 340° C. (dec).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]1([F:34])[CH2:30][CH:29]1[C:31](O)=[O:32]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31]([CH:29]3[CH2:30][C:28]3([F:34])[F:27])=[O:32])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)C1CC1(F)F
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CC1(F)F

Procedure:
The title compound, light brown solid (81 mg, 75%), MS (ISP) m/z=431.4 [(M+H)+], mp 189° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2,2-difluoro-cyclopropane-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH:11](OC)OC>ClC1C=CC=CC=1>[Br:1][C:2]1[C:3]2[O:9][CH:10]=[CH:11][C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(COc1ccc(C)cc1Br)OC
Solvent: Clc1ccccc1
Product: Cc1cc(Br)c2occc2c1
Yield: 65.6 %

Procedure:
To a 2 L round bottom flask was added PPA (3 g), anhydrous chlorobenzene (1.0 L) and the mixture was brought to reflux followed by the slow addition of 2-bromo-1-(2,2-dimethyoxy-ethoxy)-4-methyl benzene (22.9 g, 83.3 mmol) in chlorobenzene (200 ml) by addition funnel over a 2 h period. The reaction was then cooled and passed through a silica plug (washed with chlorobenzene) and concentrated to a mixture of product plus 4-iodo-2-methylphenol. Column chromatography (10% EtOAc/hexane) afforded 11.54 g (66%) of product as a clear oil: 1H NMR (300 MHz, DMSO-d6): δ 2.40 (3H, s), 7.02 (1H, d, J=2.2 Hz), 7.39 (1H, s), 7.45 (1H, s), 8.07 (1H, d, J=2.2 Hz).
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][N:17]2[CH2:20][C:21]2[CH:38]=[CH:37][C:24]([C:25]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[O:26])=[CH:23][C:22]=2[O:39][CH3:40])=[CH:13][CH:12]=1>>[CH:1]1([CH2:6][C:7]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[CH2:20][C:21]3[CH:38]=[CH:37][C:24]([C:25]([NH:27][S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:30])=[O:29])=[O:26])=[CH:23][C:22]=3[O:39][CH3:40])=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)NS(=O)(=O)c2ccccc2)ccc1Cn1ccc2ccc(N)cc21
Reactant: O=C(Cl)CC1CCCC1
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2)ccc1Cn1ccc2ccc(NC(=O)CC3CCCC3)cc21

Procedure:
Using a similar procedure to that described in Example 157, but starting with 2-cyclopentylacetyl chloride and N-(4-[6-aminoindol-1-ylmethyl]-3-methoxybenzoyl)benzenesulphonamide, there may be obtained N-(4-[6-(2-cyclopentylacetamido)indol-1-ylmethyl]-3-methoxybenzoyl)benzenesulphonamide as a solid essentially identical in physical properties to that obtained in Example 280.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: c1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1

Procedure:
The title compound was prepared from the product of Example 65A and phenylboronic acid according to General Method B: 1H NMR (500 MHz, CDCl3) δ ppm 6 ppm 8.14 (d, 2 H), 7.56 (d, 2 H), 7.46 (t, 2 H), 7.39 (t, 1 H), 7.10 (s, 1 H), 3.73-3.37 (m, 5 H), 3.05-2.97 (m, 3 H), 2.27-2.17 (m, 4 H), 1.88-1.77 (m, 3 H); LC-MS Method D (ESI+) m/z 306.0 (M+H)+, retention time 1.28 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4]([C:7]2[CH:8]=[C:9](OB(O)O)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)=[N:3]1.Cl.Br[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>C(=O)([O-])[O-].[Na+].[Na+].COCCOC.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>[CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4]([C:7]2[CH:8]=[C:9]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)=[N:3]1
Reactant: Brc1ccncc1
Reactant: CC1(C)COC(c2cc(OB(O)O)cc(C(F)(F)F)c2)=N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC1(C)COC(c2cc(-c3ccncc3)cc(C(F)(F)F)c2)=N1
Temperature: 80 °C
Reaction time: 12 h
Yield: 99.5 %

Procedure:
To a suspension of 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)phenylboroic acid (0.58 g) and 4-bromopyridine hydrochloride (0.39 g) in a mixture of sodium carbonate aqueous solution (2M, 6 ml) and 1,2-dimethoxyethane (4 ml) was added tetrakis(triphenylphosphine)palladium (0.116 g) under nitrogen atmosphere. After stirring at 80° C. for 12 hours, the mixture was quenched with water and extracted with ethyl acetate twice. The combined extracts were dried over magnesium sulfate, evaporated, and purified with column chromatography (silica gel, ethyl acetate:hexane=1:3–2:1–1:2) to give 4-[3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)phenyl]pyridine (0.61 g) as a syrup.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:12]2[C:16]3[C:17]([CH3:31])=[C:18]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O.C(OCC)(=O)C>[CH:2]([C:6]1[CH:7]=[C:8]([CH:12]2[C:16]3[C:17]([CH3:31])=[C:18]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1cccc(C3OCCO3)c1)CO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1cccc(C=O)c1)CO2
Yield: 96.1 %

Procedure:
A mixed solution of N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (910 mg, 2.15 mmol) obtained in Example 73 and pyridinium p-toluenesulfonic acid (25 mg) in acetone (20 mL)-water (1.5 mL) was refluxed with heating for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain 784 mg (yield: 96%) of the title compound. Melting point: 178-179° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]1([C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:13]1([C:19]2[N:20]=[CH:21][N:22]([C:2]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][CH:10]=[CH:11][N:12]=3)[CH:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1-n1cnc(-c2ccccc2)c1
Temperature: 160 °C
Yield: 28.9 %

Procedure:
A mixture of 5.0 g of ethyl 2-chloronicotinate (26.94 mmol), 3.4 g of 4-phenylimidazole (23.58 mmol), 7.6 g of K2CO3 and 80 mg of 18-crown-6 in 18 ml of N,N-dimethylformamide was heated in a microwave at 160° C. for about 1 hour. This was followed by concentrating, taking up the residue in dichloromethane, washing with water and sat. NaCl solution, drying over MgSO4, filtering and evaporating. Chromatography on silica gel (eluent: CH2Cl2/methanol 2%-5%) resulted in 2 g of a dark oil, which was immediately reacted further; ESI-MS [M+H]+=294.15.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=2[C:9]#[N:10])[CH:6]=1.[CH3:18][N+:19]([CH3:21])=[CH2:20].[I-]>CN(C=O)C>[CH3:18][N:19]([CH2:21][C:6]1[N:5]([C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=2[C:9]#[N:10])[CH:4]=[N:3][C:2]=1[CH3:1])[CH3:20]
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2C#N)cn1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2C#N)c1CN(C)C
Yield: 35 %

Procedure:
In analogy to example 5b, 2-(4-methyl-imidazol-1-yl)-5-nitro-benzonitrile (+regioisomer) was reacted with Eschenmoser's salt in DMF for 16 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography afforded the title compound as a yellow oil that was sufficiently pure to be used in the next step (yield: 35%). MS: m/e=286.1 [M+H]+.