Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.Cl.[CH3:29][N:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:2]([N:40]3[CH2:39][CH2:38][N:37]([C:35]([C:31]4[N:30]([CH3:29])[CH:34]=[CH:33][CH:32]=4)=[O:36])[CH2:42][CH2:41]3)=[O:3])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(N2CCC(O)CC2)cc1
Reactant: Cn1cccc1C(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1cccc1C(=O)N1CCN(C(=O)Nc2ccc(N3CCC(O)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-nitrophenyl chloroformate (242 mg, 1.2 mmol) was dissolved in tetrahydrofuran (3 ml), and a tetrahydrofuran (4 ml) solution of the 4-hydroxy-N-(4-aminophenyl)piperidine (211 mg, 1.0 mmol) obtained in Example 1(2) was added dropwise at −30° C. After stirring for 30 minutes at the same temperature, 1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperazine hydrochloride (252 mg, 1.1 mmol) and triethylamine (0.49 ml, 3.5 mmol) were added to the mixture, followed by stirring at room temperature for 17 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (NH silica gel, methanol:chloroform=0:1 to 1:50), thereby obtaining N-(4-(4-hydroxypiperidin-1-yl)-phenyl)-4-((1-methylpyrrol-2-yl)-carbonyl)-1-piperazinecarboxamide (256 mg, 62%) as a milky-white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][C:27]=1[C:36](O)=[O:37]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:27]4[CH:28]=[N:29][C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:26]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cnc5ccccc5n4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoxaline-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:38])[CH:5]=[C:6]([Cl:37])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.Cl.[C:40](Cl)(=[O:50])[O:41][C@@H:42]1[CH:47]2[CH2:48][CH2:49][N:44]([CH2:45][CH2:46]2)[CH2:43]1>C(#N)C>[CH:21]([OH:22])=[O:20].[Cl:1][C:2]1[CH:3]=[N+:4]([O-:38])[CH:5]=[C:6]([Cl:37])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][N:29]([C:40]([O:41][C@@H:42]2[CH:47]3[CH2:48][CH2:49][N:44]([CH2:45][CH2:46]3)[CH2:43]2)=[O:50])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNc3ccccc3F)s2)cc1OC
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: CC#N
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3F)s2)cc1OC
Product: O=CO
Temperature: 80 °C
Yield: 74.4 %

Procedure:
A microwave tube was charged with [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[(2-fluoroanilino)methyl]thiophene-2-carboxylate (50 mg, 0.09 mmol), (R)-quinuclidin-3-yl carbonochloridate hydrochloride (81 mg, 0.36 mmol) and anhydrous acetonitrile (0.8 mL). The mixture was heated at 80° C. for 3 minutes under microwave irradiation. The reaction was evaporated to dryness. The residue was dissolved in DMSO (1.5 mL) and purified by preparative HPLC to afford [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-thiophene-2-carboxylate formate salt as a white solid (26 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)(=[O:15])[CH2:11][C:12]([CH3:14])=O.[NH2:38]/[C:39](/[CH3:46])=[CH:40]\[C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:39]([CH3:46])[NH:38][C:12]([CH3:14])=[C:11]2[C:10]([O:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][N:22]([CH:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:23][CH2:24]2)=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc(Cl)c1
Yield: 43.3 %

Procedure:
A mixture of m-chlorobenzaldehyde, 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate and ethyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-(4-benzhydryl-1-piperazinyl)ethyl ethyl 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 72°-75° C. (sintering). Yield 43.3%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:18]=1.C(N(CC)CC)C>O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:17]3[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[N:18]=3)[CH2:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc([C@H]2CNCCO2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1
Yield: 94.3 %

Procedure:
A solution of (S)-2-(4-methoxyphenyl)morpholine hydrochloride (1.02 g, 4.44 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (0.76 g, 3.42 mmol) and triethylamine (1.42 ml, 10.3 mmol) in tetrahydrofuran (20 ml) was refluxed for several hours. The precipitate was filtered off after cooling and solvent was removed in vacuo. The residue was washed with refluxing diethyl ether to give the title compound (1.22 g, 95%).
Reaction SMILES: I[C:2]1[S:3][C:4]2[NH:5][C:6](=[O:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[CH2:16](C([SnH3])=C(CCCC)CCCC)[CH2:17]CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH:16]([C:2]1[S:3][C:4]2[NH:5][C:6](=[O:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1)=[CH2:17]
Reactant: O=c1[nH]c2sc(I)nc2c2ccccc12
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=Cc1nc2c([nH]c(=O)c3ccccc32)s1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
Bis(triphenylphosphine)palladium dichloride (0.005 g, 0.007 mmol) was added to a solution of 2-iodo-4H-1,3-thiazolo[5,4-c]isoquinolin-5-one (0.115 g, 0.35 mmol) and DMF (5 ml) at 23° C. After 30 minutes, tributylvinylstannane (0.11 ml, 0.37 mmol) was added, and the reaction mixture was stirred overnight at 45° C. All volatiles were evaporated, and the resulting oil was purified by flash-chromatography (CH2Cl2/methanol, 99/1) to afford the title compound as a yellow solid (a quantitative yield). m.p 235-239° C. (dec.); 1H NMR (200 MHz, DMSO) δ 5.55 (d, 1H, CHH, J=11 Hz), 5.95 (d, 1H, CHH, J=17 Hz), 6.85-7.00 (m, 1H, CH), 7.47-7.54 (m, 1H, Ar), 7.74-7.82 (m, 1H, Ar), 8.09-8.20 (m, 2H, Ar), 12.43 (bs, 1H, NH).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Mg]Br.[CH3:9][CH:10]([CH3:14])[CH2:11]C#C.O1CCCC1.C1OC1.[Cl-].[NH4+]>O1CCCC1>[CH3:9][CH:10]([CH3:14])[CH2:11][C:5]#[C:4][CH2:3][CH2:2][OH:1]
Reactant: C1CCOC1
Reactant: C#CCC(C)C
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CO1
Product: CC(C)CC#CCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
22 ml of dry tetrahydrofuran and 25 ml of a 1 Methyl magnesium bromide tetrahydrofuran solution were added to a nitrogen-substituted flask, and thereafter, 2.9 ml of 4-methylpentine was slowly added dropwise to the mixed solution. The obtained solution was stirred at a room temperature for 1 hour, and thereafter, 25 ml of a 1.1 M ethylene oxide tetrahydrofuran solution was slowly added dropwise to the reaction solution at a room temperature. The obtained solution was further stirred at a room temperature overnight. Thereafter, 100 ml of a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained solution was then extracted with 100 ml of diethyl ether twice. It was dried over magnesium sulfate. The magnesium sulfate was filtrated, and the organic layer was then concentrated. The generated alcohol was directly used in the subsequent reaction (yield: 3.78 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=O)[CH2:20][CH3:21].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:4]1[C:3]2[C:2](=[CH:10][C:9]([F:11])=[CH:8][CH:7]=2)[N:1]=[C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])[C:20]=1[CH3:21]
Reactant: CCC(=O)c1ccccc1F
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Cl

Procedure:
Prepared according to Procedure J using 2-amino-4-fluorobenzoic acid (4.90 g, 31.6 mmol) and 1-(2-fluorophenyl)propan-1-one (3.70 g, 24.3 mmol) in phosphorous oxychloride (45.00 mL, 483 mmol) to afford product as a white solid upon purification by chromatography on silica gel. Mass Spectrum (ESI) m/e=290.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[OH-:12].[Na+]>O>[F:9][C:8]([F:11])([F:10])[C:5]1[N:6]=[N:7][C:2]([OH:12])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(C(F)(F)F)nn1

Procedure:
A mixture of 6-chloro-3-trifluoromethylpyridazine (10 g, 54. 9 mmol) (prepared by following the procedure described in Goodman, A. J.; Stanforth, S. P.; Tarbit B. Tetrahedron 1999, 55, 15067-15070) and sodium hydroxide (8 g, 0.7 mmol) in water (150 ml) was stirred at reflux for 5 h. After this period, the solvent was evaporated in vacuo and the crude product dried at 60° C. under vacuum for 16 h. to yield D3, mixed with sodium chloride, (16.2 g,>100%) as a solid. C5H3F3N2O requires 164; Found 165 (MH+).
Reaction SMILES: [CH3:1][N:2]([C:4]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:6])[CH3:5])[CH3:3].[CH3:12][Br:13]>ClCCl>[Br-:13].[CH3:3][N+:2]([C:4]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:5])[CH3:6])([CH3:12])[CH3:1]
Reactant: CN(C)C(C)(C)CC(C)(C)C
Reactant: CBr
Solvent: ClCCl
Product: CC(C)(C)CC(C)(C)[N+](C)(C)C
Product: [Br-]

Procedure:
The procedure given in the previous example was followed. Starting with a solution of N,N-dimethyl t-octylamine (5 g, 31.8 mmol) in dichloromethane (5 mL) and methyl bromide (2.0 M solution in t-butyl methyl ether, 42.8 mL, 85.6 mmol), product was obtained as a white solid (7.2 g (90%)). 1H NMR (CDCl3): δ3.35 (s, 9H, —N+(CH3)3), 1.79 (s, 2H, —CH2—), 1.60 (bt, 6H, —C(CH3)2—), 1.11 (s, 9H, —C(CH3)3) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[C:13]1([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[S:27](Cl)(=[O:29])=[O:28])=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:27](/[CH:26]=[CH:25]/[C:22]2[CH:23]=[CH:24][C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][CH:21]=2)(=[O:29])=[O:28])[C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)/C=C/c1ccc(-c2ccccc2)cc1
Reactant: Nc1cccc(F)c1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1c(F)cccc1NS(=O)(=O)/C=C/c1ccc(-c2ccccc2)cc1
Reaction time: 12 h
Yield: 19.2 %

Procedure:
2-Amino-6-fluoro-benzenesulfonamide (38 mg, 200 μmol) and (E)-2-(4-phenylphenyl)ethenesulfonyl chloride (56 mg, 200 μmol) were dissolved in pyridine (1.5 mL) and the reaction mixture was shaken for 12 h. The solvent was removed in vacuum and the residues were purified by HPLC to give the product (16.6 mg, 19%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:15][CH3:16].Cl>CCO.O.[Fe]>[NH2:12][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:15][CH3:16])[C:2]=1[Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(OC)c(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(N)c(Cl)c(OC)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 103.9 %

Procedure:
A suspension of methyl 4-chloro-3-methoxy-5-nitrobenzoate (3) (900 mg, 3.66 mmol) and iron powder (614 mg, 11.0 mmol) in a mixture of EtOH (15 mL) and water (15 mL) was heated to 70° C. and degassed with nitrogen for 20 min. Conc. HCl (44.5 μL, 1.47 mmol) was added and the reaction mixture was stirred at 70° C. for 3 h. Celite (1 g) was added and the suspension stirred for 10 min then filtered through a celite pad. The solvent was removed in vacuo and the residue was partitioned between EtOAc (15 mL) and water (15 mL). The phases were separated and the organic solution was washed with brine (2×15 mL). The solvent was removed in vacuo to afford methyl 3-amino-4-chloro-5-methoxybenzoate (0.82 g, 100% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ: 7.10 (1H, d), 6.78 (1H, d), 5.68 (2H, s), 3.81 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].N.Cl[N:15]1C(C)(C)C(=O)N(Cl)C1=O>>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH2:15]
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Agent: N
Product: COC(=O)c1cccc(Cl)c1N
Yield: 49.6 %

Procedure:
Pure 3-chloroanthranilic alkyl esters have previously been prepared only in a 5-step synthesis starting from anthranilic esters (U.S. Pat. No. 5,068,392). According to U.S. Pat. No. 5,068,392, (pure) 3-chloroanthranilic alkyl esters can be prepared starting from anthranilic esters by means of a 5-step synthesis. The amino group of the anthranilic alkyl ester is first acetylated, bromination then takes place in the para position to the acetylated amino group, and this is then followed by chlorination in the ortho position to the acetylated amino group. Subsequently, the bromine is removed by reduction and the acetamino group is de-acetylated. The process is fairly elaborate and is found to be problematical owing to the use of bromine chloride or elemental bromine and chlorine. In addition to this, a series of unwanted waste products is inevitably formed. Apart from this, the preparation of 3-chloroanthranilic alkyl esters has only been described in the form of a mixture together with chloroanthranilic alkyl esters substituted in the 5 or 6 positions. Thus, according to EP 20 969, 3-chlorophthalic anhydride is reacted with ammonia, alkali metal hydroxide and alkali metal hypochlorite, and the resulting mixture of 5-chloroisatoic and 8-chloroisatoic anhydrides is esterified with alkanols to give a mixture of 3-chloroanthranilic and 6-chloroanthranilic alkyl esters. 5-Chloroanthranilic and 3,5-dichloroanthranilic alkyl esters arise as by-products in the amounts of from 23 to 48% and from 2 to 6%, respectively, when 3-chloroanthranilic alkyl esters are prepared in accordance with U.S. Pat. No. 5,118,832 by the reaction of anthranilic esters with 1,3-dichloro-5,5-dimethylhydantoin. After complicated removal of the by-products, methyl 3-chloroanthranilate is obtained in 49.6% yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([CH3:13])[SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:14][CH2:15][CH2:16][OH:17]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([S:12][S:14][CH2:15][CH2:16][OH:17])[CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(S)Cc1ccc2c(c1)OCO2
Reactant: OCCS
Product: CC(Cc1ccc2c(c1)OCO2)SSCCO

Procedure:
5.0 g of the title compound was prepared from 8.4 g of 2-(1,3-benzodioxol-5-yl)-1-methylethanethiol and 2.24 g of.2-mercaptoethanol as a colorless oil according to the same procedure as that described in Example 1.
Reaction SMILES: C([Mg][CH2:4][CH3:5])C.[CH2:6]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)[CH:7]=[CH2:8].[O:22]=O>C(OCC)C.C1COCC1>[OH:22][CH2:8][CH:7]([CH2:4][CH3:5])[CH2:6][N:9]1[CH2:10][CH2:11][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:14]1
Reactant: O=O
Reactant: C=CCN1CCC(Cc2ccccc2)CC1
Reactant: CC[Mg]CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CO)CN1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of diethylmagnesium (5 ml of a 0.8 M solution in diethyl ether, 4 mmol) was placed in a Schlenk tube and the solvent removed. The residue was dissolved in THF (1 ml). (Cyclopentadienyl)(1-[(1'S,2'S,5'R)-2'-isopropyl-5'-methylcyclohexyl]-4,5,6,7-tetrahydroindenyl)zirconium dichloride (prepared as in Example 1, 24 mg, 0.05 mmol) was added under positive argon flow followed by N-allyl-4-benzylpiperidine (0.215 g, 1 mmol) in THF (1 ml). The reaction mixture was stirred at room temperature overnight. The mixture was cooled to 0° C. and a balloon of oxygen gas added. The tube was flushed through with a small amount of oxygen and the reaction mixture was stirred overnight. The reaction mixture was poured into aqueous ammonium chloride solution (100 ml) and the aqueous was extracted with diethyl ether (3×50 ml). The organic extracts were combined, dried and evaporated to leave a residue which was purified by column chromatography (eluant 20% diethyl ether in petroleum ether) followed by Kugelrohr distillation (170° C., 1.0 mbar) to give the title compound as a clear oil which crystallised on standing (0.096 g, 37%, 42% ee).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: CCCCCN1CCC(CN)CC1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: CCCCCN1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 49.6 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-pentyl-piperidine (0.368 g, 2.0 mmol) according to the procedure used for Example 2 to give 0.210 g of the title compound as a white solid (Et2O).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19]>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:23]2[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2ccc(C=O)cc2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-formylbenzene-boronic acid gives “A75”; method 1: HPLC/MS: 1.29 min, [M+H]=319;
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:17][NH:18][CH3:19].C(O)C>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:18]([CH3:19])[CH3:17])=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(C)c2CCCl)C1
Reactant: CNC
Solvent: CCO
Product: CC(=O)N1CCc2c(sc(C)c2CCN(C)C)C1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 0.8 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 20 ml of 16.8% dimethylamine-ethanol solution in a pressure bottle was stirred at 80° C. for 5 hours and then the solvent was distilled away. To the residue was added water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated in vacuo to give 0.4 g of 6-acetyl-3-(2-dimethylaminoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=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>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(COc1ccc(Br)nn1)N1CCCCC1
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: COCCOC
Product: O=C(COc1ccc(-c2ccc(F)cc2)nn1)N1CCCCC1

Procedure:
95 mg (0.326 mmol) of 2-(6-bromo-pyridazin-3-yloxy)-(1-piperidin-1-yl)-ethanone, 46.7 mg (0.334 mmol) 4-fluoro-phenylboronic acid, 11 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium and 0.5 ml of a 1 M aqueous sodium carbonate solution in 15 ml of DME were heated under reflux for 3 h. After cooling, the mixture was poured onto water and extracted with ethyl acetate. The combined organic phases were dried and evaporated, and the product was purified by RP18 chromatography. Yield: 73 mg.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>>[CH2:31]([N:33]([CH2:34][CH3:35])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:11]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:15][C:16]=2[CH:12]=1)[CH3:32]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: CCNCC
Product: CCN(CC)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and diethylamine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.74 (d, J=8.1, 2H), 7.54 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.80(s, 1H), 3.32-3.8 (m, 16H), 1.38 (t, J=7.5 Hz, 6H); MS (DCI) m/z 407 (M+H)+;