Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:7])[CH3:6].[OH-].[Na+]>>[C:5]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:13][C:14]=1[N+:1]([O-:4])=[O:2])(=[O:7])[CH3:6]
Reactant: CC(=O)Nc1ccc(-c2ccncc2)cc1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(-c2ccncc2)cc1[N+](=O)[O-]

Procedure:
To 160 ml. of nitric acid (90%) cooled to less than 0°C. in an ice-ethanol bath was slowly added with stirring 42 g. of 4-(4-acetamidophenyl)pyridine over a period of about twenty minutes. The reaction mixture was then stirred for 45 minutes, keeping the reaction temperature below 0°C. The reaction mixture was then poured onto ice and the mixture treated with 35% aqueous sodium hydroxide solution, adding ice to keep the mixture cool. The resulting yellow solid was collected, washed with water and air-dried to yield 43.7 g. of 4-(4-acetamido-3-nitrophenyl)pyridine, which was used directly in Example 4 without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]([O:10][C:11]2[CH:16]=CC=C[CH:12]=2)=[O:9])[CH:4]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]=1.[CH3:22]C(C)([O-])C.[K+].CCOC(C)=O>C1COCC1>[C:11]([O:10][C:8]([N:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]1[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:9])([CH3:12])([CH3:16])[CH3:22]
Reactant: O=C(Oc1ccccc1)N1C=CC(Cl)=CC1C1CCCC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C=CC(Cl)=CC1C1CCCC1
Temperature: -42 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a stirred solution of 4-Chloro-1-(phenoxycarbonyl)-2-cyclopentyl-1,2-dihydropyridine (5.52 g, 17.3 mmol) in 200 ml of THF at −42° C. was added dropwise over 15 minutes a 1.0M solution of potassium t-butoxide (50 mL, 50 mmol). The resulting orange solution was stirred for 1 h at −42° C. The cooling bath was removed, and the reaction mixture was allowed to stir for 20 min while being slowly warmed to room temperature. Water (50 ml) and ether (70 ml) were added and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with cold 1.0 N NaOH (2×35 ml), and brine. The organic phase was dried over MgSO4, filtered through Celite, and concentrated in vacuo to give the crude product. Column chromatography with 5% EtOAc in hexanes afforded 3.71 g (75.7%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 6.89-6.67 (dd, 1H), 5.58 (br s, 1H), 5.27-5.23 (m, 1H), 4.92-4.62 (m, 1H), 2.21 (m, 1H), 1.892-1.25 (m, 17H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:14].[NH2:15][C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:19].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:20]2[C:18](=[O:19])[C:17]3[C:16](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=[C:9]2[C:8]2[CH:11]=[C:12]([CH3:13])[C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:6]([CH3:14])[CH:7]=2)=[CH:22][CH:23]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)cc(C)c1OCCO
Temperature: 155 °C

Procedure:
To a mixture of 4-(2-hydroxyethoxy)-3,5-dimethyl-benzaldehyde (0.420 g, 2.17 mmol) and 2-amino-N-(4-chloro-phenyl)-benzamide (0.500 g, 2.17 mmol) in N,N-dimethylacetamide (5 mL) was added sodium hydrogensulfite (0.350 g, 3.26 mmol) and p-toluenesulfonic acid (0.21 g, 0.11 mmol). The reaction mixture was heated at 155° C. for 14 hours, cooled to room temperature, and diluted with cold water (20 mL), to produce the precipitate. The yellow solid was filtered, washed with cold water, then methanol, and dried under vacuum to provide crude product, which was purified by preparative HPLC (0.1% TFA in CH3CN/H2O as eluent) to give the title compound as a white solid. Yield: 0.23 g (14%). MP 101-103° C. 1H-NMR (400 MHz, CDCl3): δ 8.38 (d, 1H), 7.81-7.78 (m, 2H), 7.59-7.51 (m, 1H), 7.31-7.20 (m, 2H), 7.15-7.12 (m, 2H), 7.01-6.98 (d, 2H), 3.98-3.80 (m, 4H), 2.20 (s, 6H), 2.01 (t, 1H). MS (ES+) m/z: 421.05 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15](=[O:29])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:7][O:6][C:4](=[O:5])[CH2:3][CH2:2][N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15](=[O:29])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13]1
Reactant: COC(=O)CCBr
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 50 °C
Yield: 70 %

Procedure:
Methyl 3-bromopropionate (553 μL, 5.07 mmol) was added to a stirred solution of biphenyl-2-ylcarbamic acid piperidin-4-yl ester (1.00 g, 3.38 mmol; prepared as described in Preparation 1) and DIPEA (1.76 mL, 10.1 mmol) in ACN (34 mL) at 50° C. and the reaction mixture was heated at 50° C. overnight. The solvent was then removed under reduced pressure, and the residue was dissolved in DCM (30 mL). The resulting solution was washed with saturated aqueous sodium bicarbonate solution (10 mL), dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography (5-10% MeOH/DCM) to give 905 mg of the title intermediate (70% yield).
Reaction SMILES: [Al](C)(C)C.C(O[C:8]([C:10]1[C:15]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][CH:13]=[C:12]([C:24](C)(C)[O:25][SiH2]C(C)(C)C)[N:11]=1)=[O:9])C.[NH2:33][C:34]1[S:35][CH:36]=[C:37]([CH3:39])[N:38]=1>>[C:20]([O:19][C:17](=[O:18])[NH:16][C:15]1[C:10]([C:8](=[O:9])[NH:33][C:34]2[S:35][CH:36]=[C:37]([CH3:39])[N:38]=2)=[N:11][C:12]([CH2:24][OH:25])=[CH:13][CH:14]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1nc(C(C)(C)O[SiH2]C(C)(C)C)ccc1NC(=O)OC(C)(C)C
Reactant: Cc1csc(N)n1
Agent: C[Al](C)C
Product: Cc1csc(NC(=O)c2nc(CO)ccc2NC(=O)OC(C)(C)C)n1

Procedure:
The Al(Me)3-catalyzed reaction of 0.53 g (1.29 mmol) of 3-tert-Butoxycarbonylamino-6-(tert-butyl-dimethyl-silanyloxymethyl)-pyridine-2-carboxylic acid ethyl ester and 2-amino-4-methyl thiazole in accordance with the general method of Example 78, step 2 yielded 0.58 g of crude [6-Hydroxymethyl-2-(4-methyl-thiazol-2-ylcarbamoyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (which also contains 2-amino-4-methyl thiazole) as a dark brown oil, MS (ISP): m/e=365.1 (M+H+). This crude material was dissolved in 4 ml of methylene chloride and 2.4 ml of trifluoroacetic acid. The solution was stirred overnight at room temperature. The pH of the solution was adjusted to 8 by addition of saturated sodium carbonate solution and extracted three times with methylene chloride. The combined organic phases were dried over magnesium sulfate and concentrated to yield 0.47 g of 3-Amino-6-hydroxymethyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide as a dark brown oil (containing 2-amino-4-methyl thiazole), MS (ISP): m/e=265.3 (M+H+). The crude material was reprotected with tert-butyldimethylchlorosilane/imidazole according to the general procedure described in step 4 to yield, after extraction and purification, 88 mg (0.23 mmol, 13%) of the pure title compound as a light yellow solid, MS (ISP): m/e=379.3 (M+H+).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.[C:27]1([CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:26][O:25][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]([O:19][CH3:20])=[C:17]2[C:12]=1[CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:37]1[CH2:38][CH2:39][N:34]([CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:35][CH2:36]1)[CH2:18]2
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN1CCN(C(c3ccccc3)c3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.6 %

Procedure:
The mixture of 2-(8-iodooctyl)-4,5,6,7-tetramethoxyindan (1.17 g), 1-diphenylmethylpiperazine (1.24 g) and potassium carbonate (1.70 g) in DMF (10 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=10:1) to yield the entitled compound (1.19 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[CH2:11]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:19]=[C:18]([C:7]2[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:10])[CH:6]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1F
Product: CCOc1cccc(-c2cc(F)c(N)c(F)c2)c1
Yield: 36.6 %

Procedure:
The title compound (0.219 g) was prepared from 2,6-difluoro-4-bromo aniline (0.5 g, 2.4 mmol) and 3-ethoxyphenylboronic acid (0.517 g, 3.12 mmol) as a pale-yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.30-7.24 (m, 3H), 7.14 (d, J 7.9, 1H), 7.11 (s, 1H), 6.82 (dd, J 2.1, 8.1, 1H), 5.31 (s, 2H), 4.07 (q, J 7, 2H), 1.32 (t, J 7, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2NCc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2NCc1ccc(Cl)cc1
Yield: 14 %

Procedure:
The title compound was synthesized from methyl 4-(4-chlorobenzylamino)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.023 g, 0.075 mmol) and lithium hydroxide (0.023 g, 0.55 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by reverse phase chromatography, eluting with MeOH in water (0.1% formic acid) a to afford a yellow solid: 3 mg, 14% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.47-2.58 (m, 1H), 2.71-2.83 (m, 1H), 2.87-3.06 (m, 2H), 4.23 (q, J=13.16 Hz, 2H), 4.54-4.67 (m, 1H), 6.81 (s, 1H), 7.38-7.56 (m, 4H), 8.49 (s, 1H); LCMS-MS (ESI−) 289.0 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:22][O:21][C:19](=[O:20])[CH:18]([O:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Br:1])=[CH:3][C:4]=2[F:16])=[CH:12][CH:11]=1)[CH3:23]
Reactant: COC(=O)C(C)Br
Reactant: Oc1ccc(Oc2ccc(Br)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the 4-(4-bromo-2-fluorophenoxy)phenol (5.66 g, 0.02 mol) from Step V, methyl 2-bromoproprionate (3.34 g, 0.02 mol) and potassium carbonate (3.06 g, 0.22 mol) in DMSO (30 ml) was stirred, under an atmosphere of nitrogen, at room temperature for 18 hours. The mixture was poured into water (300 ml), and the resulting mixture extracted with ether (2×100 ml). The ether extracts were combined, washed with water (100 ml), dried (MgSO4), and the solvent evaporated to give the desired 2-[4-(4-bromo-2-fluorophenoxy)phenoxy]propionic acid; methyl ester as a yellow oil (6.0 g, 81%); RI=1.5628; NMR (CDCl3) was consistent with the assigned structure. The carbon and hydrogen content was as follows:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: C1COCCN1
Product: C/C(=C\c1ccc(C(=O)N2CCOCC2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 11, from p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid and morpholine there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid morpholide of melting point 143°-144° C.
Reaction SMILES: Br[C:2]([CH3:31])([CH3:30])[C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1)=[O:4].C(N)C.[CH3:35][OH:36]>>[O:28]=[S:20]1(=[O:29])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH2:23][N:17]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([O:36][CH3:35])([CH3:31])[CH3:30])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[N:9]=2)[CH2:18][CH2:19]1
Reactant: CO
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C(C)(C)Br)c2c1
Agent: CCN
Product: COC(C)(C)C(=O)Nc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropanamide (80 mg, 0.159 mmol, prepared in Example 40-2) in methanol (5 mL) was added ethylamine (1 mL), the resulting mixture was heated under reflux overnight. After being cooled to room temperature, the resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (eluting with 33% ethyl acetate in hexanes) to afford 15 mg of the title compound as a light powder (yield was 21%). MS obsd. (ESI+) [(M+H)+] 454, 1H NMR (400 MHz, CD3OD) δ ppm 7.94-7.89 (m, 3 H), 7.58 (m, 2 H), 7.43-7.39 (m, 3 H), 5.17 (s, 2 H), 4.50 (brs, 2 H), 3.59 (m, 2 H), 3.50 (s, 3 H), 2.46 (s, 3 H), 1.56 (s, 6 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH:13]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[CH2:19][NH:20][O:21][CH3:22])([CH3:15])[CH3:14]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:20]([CH2:19][C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[O:16][CH:13]([CH3:15])[CH3:14])[O:21][CH3:22])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccccc1OC(C)C
Product: CON(Cc1ccccc1OC(C)C)C(=O)C=C1OC(C)(C)OC1=O
Yield: 93 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-isopropoxy-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (93% yield): mp 103° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.34 (6H, d, J=6.0 Hz, CH3), 1.75 (6H, s, CH3), 3.68 (3H, s, OCH3), 4.60 (1H, m, CH), 4.95 (2H, broad s, NCH2), 6.44 (1H, s, CH), 6.89 (2H, m, aromatics), 7.2-7.3 (2H, m, aromatics). Anal. calcd for C18H23NO6: C, 61.88; H, 6.64; N, 4.01. Found: C, 61.22; H, 6.33; N, 3.87.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([OH:13])=[O:12])[N:6]=[CH:5][C:4]=1[NH:14][C@@H:15]1[CH2:20][C@@H:19]2[CH2:21][C@@H:17]([C:18]2([CH3:23])[CH3:22])[C@H:16]1[CH3:24].[CH2:25](O)[CH3:26].C(OCC)(=O)C>O1CCCC1>[CH3:1][S:2][C:3]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][CH2:25][CH3:26])=[O:12])[N:6]=[CH:5][C:4]=1[NH:14][C@@H:15]1[CH2:20][C@@H:19]2[CH2:21][C@@H:17]([C:18]2([CH3:23])[CH3:22])[C@H:16]1[CH3:24]
Reactant: CSc1c(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)cnn(CC(=O)O)c1=O
Reactant: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(SC)c1=O
Yield: 82 %

Procedure:
2-{5-Methylthio-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid (105 mg, 0.299 mmol) in tetrahydrofuran (1 mL) was stirred with 1,1-carbonyldiimidazole (145 mg, 0.897 mmol) at room temperature for 1 hour and then with ethanol (0.2 mL) at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added, and the resulting organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate=1/1) to give the desired product (93 mg, 82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[N:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)[nH]c1cc(Br)ccc12
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c3ccc(Br)cc3n(-c3ccccc3)c2c1
Temperature: 130 °C
Yield: 78 %

Procedure:
A mixture of 32.5 g (100 mmole) 2,7-dibromo-9H-carbazole, 20.4 g (100 mmole) iodobenzene, 9.5 g (150 mmole) of copper powder, 27.6 g (200 mmole) of potassium carbonate, and 600 ml dimethylformamide were heated at 130° C. under nitrogen overnight, then cooled to room temperature, the solution was filtered. The filtrate was extracted three times with dichloromethane and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica(hexane-dichloromethane) afforded a white solid (31.3 g, 78 mmol, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([CH2:7][N+:8]([O-:10])=[O:9])[CH:14]([C:13]([O:20][CH3:21])=[O:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Reactant: COC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)C(C[N+](=O)[O-])c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-(pentamethylbenzenesulfonyl)-1,2-diphenyl-ethylenediamine](hexamethylbenzene)ruthenium (13.7 mg, 0.02 mmol, S/C=50), 4-chloro-β-nitrostyrene (1.0 mmol), dimethyl malonate (114 μl, 1.0 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at −20° C. for 48 hours. The reaction solution was purified by flash column chromatography (hexane/acetone=80/20, SiO2), showing that the isolation yield of the product was 24%. The optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 0.5 ml/min, detection by 210 nm), resulting to 95% ee.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:3]=1.[Br:18]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:15])[F:16])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(-c2ccccc2C(F)(F)F)n1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1-c1nccc(CBr)n1
Temperature: 25 °C

Procedure:
247 mg (1.04 mmol) of the compound from Example 67A together with 185 mg (1.04 mmol) of N-bromosuccinimide and 17 mg (0.10 mmol) of 2,2′-azobis-2-methylpropanenitrile in 3 ml of carbon tetrachloride were heated under reflux for 18 h. For work-up, the reaction mixture was cooled to RT, and 10 ml of dichloromethane were added. The mixture was washed with 5 ml of water, and the aqueous phase was re-extracted twice with in each case 5 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was briefly dried under high vacuum and reacted further without further purification. This gave 303 mg of product which contained the target compound in a purity of 20% (corresponds to 20% of theory). The main component of the crude product was unreacted starting material (Example 67A).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.O>CN1CCCC1=O>[N:10]1([C:2]2[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=2)[C:8]#[N:9])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: N#Cc1ccnc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccnc(N2CCOCC2)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 71.1 %

Procedure:
2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved in N-methylpyrrolidone (2.0 ml), and morpholine (0.7 ml, 8.0 mmol) was added thereto. The reaction mixture was stirred at 100° C. for 2.5 hrs and combined with water to give precipitates, which were collected by filtration and dried to give the titled compound (0.39 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:34]([CH3:35])=[CH:33][C:32]([CH2:36]OS(C)(=O)=O)=[N:31]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:36][C:32]2[CH:33]=[C:34]([CH3:35])[N:30]([CH3:29])[N:31]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(COS(C)(=O)=O)nn1C
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)nn1C

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid 1,5-dimethyl-1H-pyrazol-3-ylmethyl ester (prepared by mesylation of commercially available methanesulfonic acid 1,5-dimethyl-1H-pyrazol-3-ylmethyl ester) gave the title compound. ES-MS m/e (%): 507.2 (M+H+).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH2:14](I)[CH3:15]>>[CH2:14]([S:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)[CH3:15]
Reactant: CCI
Reactant: CCOC(=O)Cc1ccc(S)cc1
Product: CCOC(=O)Cc1ccc(SCC)cc1

Procedure:
Alkylation of ethyl (4-mercaptophenyl)acetate (20 g, 102 mmol) with EtI (9.8 mL, 122 mmol), using a similar procedure to that described in Preparation 39, furnished ethyl (4-ethylsulfanylphenyl)acetate: m/z (ES+)=225.2 [M+H]+. Oxidation of this compound (22.6 g, 101 mmol) with mCPBA (222 mmol), employing a protocol similar to that described in Preparation 22, provided the title compound: m/z (ES+)=298.2 [M+MeCN+H]+.