Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:38])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:27]CC4C=CC(OC)=CC=4)=[CH:22][C:23]=3[O:24][CH2:25][CH3:26])=[CH:14][C:13]=2[F:37])=[CH:5][C:4]=1[C:39]([F:42])([F:41])[F:40])#[N:2].C(O)(C(F)(F)F)=O.[NH4+].[OH-]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:38])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([O:24][CH2:25][CH3:26])=[CH:22][C:21](=[O:27])[NH:20][CH:19]=3)=[CH:14][C:13]=2[F:37])=[CH:5][C:4]=1[C:39]([F:41])([F:42])[F:40])#[N:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c(F)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3-yl)-2-fluorophenyl)acetamide (870 mg, 1.501 mmol) in DCM (10 mL) was added TFA (1.157 mL, 15.01 mmol) at 0° C. The mixture was stirred at rt for 1 h. The mixture was basified with NH4OH (5 mL, 20%) to pH=8, filtered to give a solid, which was washed with H2O (5 mL) and dried to afford the product N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (462.91 mg, 0.973 mmol, 64.8% yield): 1H NMR (400 MHz, CD3OD): δ 8.24 (s, 1H), 7.96-8.05 (m, 1H), 7.90-7.96 (m, 1H), 7.36-7.40 (m, 2H), 7.20-7.28 (m, 2H), 6.00 (s, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.85 (s, 2H), 1.38 (t, J=7.2 Hz, 3H): LCMS (m/z): 459.9 (M+H).
Reaction SMILES: O.[CH2:2]([CH:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:17](O)[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:2]([CH:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCO
Reactant: CCCCCCC1C(=O)CCC1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCC1C(=O)CCC1C(=O)OCC

Procedure:
In a 1 L flask, to which is attached a water separator under a reflux condenser, is placed a solution of 20 g of 2-n-hexyl-3-oxocyclopentanecarboxylic acid, 9.5 g of absolute ethanol and 1 g of p-toluenesulphonic acid in 500 ml of benzene. The reaction mixture is refluxed until no more water separates. The reaction mixture is then cooled and washed successively with water and sodium carbonate solution and dried over anhydrous sodium sulphate. The solvent is removed by distillation at atmospheric pressure and the residue is distilled through a short Vigreux column. Ethyl 2-n-hexyl-3-oxocyclopentanecarboxylate is collected at 102° C/0.25 mm, yield 19,5 g (86%), nD20 1.4535.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18][CH3:19])=[O:17])=[N:9]2)=[CH:4][CH:3]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.C1(C)C=CC=CC=1>[O:28]=[C:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18][CH3:19])=[O:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(-c2ncn(-c3ccc(Br)cc3)n2)c1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2ncn(-c3ccc(N4CCCC4=O)cc3)n2)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
A 50 mL culture tube containing methyl 3-[1-(4-bromophenyl)-1H-[1,2,4]triazol-3-yl]benzoate (407 mg, 1.14 mmol), copper (I) iodide (10.8 mg, 0.057 mmol), pyrrolidin-2-one (121 mg, 1.42 mmol) and potassium carbonate (138 mg, 2.28 mmol) is evacuated and back charged with nitrogen. N,N′-Dimethylethylenediamine (10 mg, 0.12 mmol) and toluene (5 mL) are added, the tube is sealed with a PTFE cap, and the reaction mixture is heated to 110° C. with stirring for 12 h. The cooled reaction mixture is partitioned between water and ethyl acetate, and the organic extract is washed with water, dried over MgSO4, filtered and evaporated. The residual material is separated by column chromatography (silica gel, 1:20 methanol-dichloromethane) to provide methyl 3-{1-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-1H-[1,2,4]triazol-3-yl}-benzoate as a tan solid (380 mg, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)[CH:34]=[N:33][CH:32]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:35]6[CH:36]=[N:31][CH:32]=[N:33][CH:34]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: NC1(c2cncnc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cncnc5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.1 g, 0.25 mmol, 1 eq), 1-(pyrimidin-5-yl)cyclopropanamine (0.041 g, 0.3 mmol, 1.2 eq) (60% purity), HOBT (0.057 g, 0.42 mmol, 1.7 eq), EDC.HCl (0086 g, 0.44 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added Diisopropylethylamine (0.162 g, 1.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for overnight. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer is further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally it was purified by preparative HPLC. Yield: 0.02 g (20%). 1H NMR (400 MHz, DMSO-d6): δ 1.34-1.35 (m, 2H), 1.41-1.42 (m, 2H), 2.29 (s, 3H), 2.81-2.82 (d, 3H, J=4.56 Hz), 738-7.45 (m, 4H), 7.58 (d, 1H, J=0.96 Hz), 7.75 (d, 1H, J=8.4 Hz), 7.81 (s, 1H), 7.83 (m, 1H), 7.98-8.01 (m, 2H), 8.46-8.47 (d, 1H, J=4.6 Hz), 8.64 (s, 2H), 9.01 (s, 1H), 9.31 (s, 1H). LCMS: (ES+) m/z=521.2 (M+H). LCMS Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% ACN-98% H2O-10 mM NH4COOH Mphase B: 98% ACN-2% H2O-10 mM NH4COOH
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:19]=[N:20][N:21]([CH2:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:22]=4)=[CH:16][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]3=[N:13][CH:14]=2)=[CH:5][C:4]=1[NH:41][S:42]([CH3:45])(=[O:44])=[O:43].[OH-].[Li+]>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:19]=[N:20][N:21]([CH2:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:22]=4)=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)=[CH:5][C:4]=1[NH:41][S:42]([CH3:45])(=[O:44])=[O:43]
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(CCc4ccccc4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(CCc5ccccc5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 17.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(2-methoxy-5-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (100 mg, 0.155 mmol) was hydrolyzed by lithium hydroxide (13 mg, 0.311 mmol) in THF/methanol/water (5/1/2 mL) to afford 13 mg of the titled compound. 1H NMR (DMSO-d6, 400 MHz): δ 9.07 (s, 1H), 8.45-8.44 (d, 1H), 8.186-8.182 (d, 1H), 8.13, s 1H), 7.89 (s, 1H), 7.716-7.710 (d, 1H), 7.60-7.59 (m, 2H), 7.31-7.28 (m, 2H), 7.24-7.19 (m, 4H), 4.43-4.39 (t, 2H), 3.91 (s, 3H), 3.20-3.16 (t, 2H), 3.02 (s, 3H). MS: m/z=487.8 (M+1), HPLC: 95.48% in method A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:5]2.S(Cl)([Cl:21])=O>O1CCCC1>[Cl:21][C:5]1[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: Clc1ccc(-c2cc3cc(Cl)cc(Cl)c3[nH]2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(-c2[nH]c3c(Cl)cc(Cl)cc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
(1.0 g, 3.38 mmole) A solution of 5,7-dichloro-2-(p-chlorophenyl)-indole(in tetrahydrofuran is treated dropwise with 1.0 mL of thionyl chloride, stirred for 16 hours at room temperature, poured over ice and filtered. The filtercake is air-dried to afford the title product as a yellow solid, 0.85 g (76% yield), mp 148°-149° C., identified by IR, 1HNMR and elemental analyses.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:34])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24]>>[CH3:34][N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN(C)C
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(-c4ccccc4)cc32)c(C)c1C(=O)NCCCN(C)C
Yield: 28.2 %

Procedure:
5-Phenyl-1,3-dihydroindol-2-one (67 mg, 0.32 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-dimethylaminopropyl)amide (81 mg) to give 40 mg (28%) of the title compound as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:29]1[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccccn2)CC1
Yield: 80 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-pyridyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 80%). 1H NMR (200 MHz, CDCl3): δ 3.72-3.76 (m, 8H), 4.16 (s, 3H), 6.66-6.70 (m, 2H), 7.24-7.52 (m, 4H), 7.80-7.81 (m, 1H), 8.21 (dd, J=5.4 and 1.8 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.O1CCCC1.[H-].[Na+].C([O:15][C:16](=[O:19])[CH2:17]Br)C>C(O)C>[N:1]1([CH2:17][C:16]([OH:19])=[O:15])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cn1cccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 g of pyrazole in 250 ml of abs. tetrahydrofuran is added dropwise in a nitrogen atmosphere within 1/2 hour at 20°-30°, with stirring and cooling, to 38.7 g of sodium hydride in 100 ml of abs. tetrahydrofuran. The reaction mixture is stirred for a further 3 hours at 40°; it is then cooled towards 5° and, with good cooling, 160.7 g of bromoacetic acid ethyl ester in 100 ml of abs. tetrahydrofuran is added dropwise at 0°-10° during 1 hour. Stirring is maintained overnight at room temperature; there is then added dropwise 150 ml of ethanol; stirring is continued for 1 hour, and the suspension is subsequently concentrated by evaporation. To the residue is added a solution of 74 g of NaOH tablets in 600 ml of 60% methanol (aqueous), and refluxing is carried out for 40 minutes. The solution is then cooled, and washed twice with 200 ml of ether. The aqueous phase is made acid to a congo-red indicator (about pH 2) with conc. hydrochloric acid at 5° with cooling, and the solution is continuously extracted during 24 hours with methylene chloride. The extract is concentrated by evaporation, and recrystallised from ether/tetrahydrofuran. The crystals melt at 167°-169°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH:10]([CH3:14])[CH2:9][NH:8][C:7]=2[N:15]=1.[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:16]([CH3:17])=[N:19][N:20]=[C:11]3[CH:10]([CH3:14])[CH2:9][NH:8][C:7]=2[N:15]=1
Reactant: CC(=O)NN
Reactant: COc1ccc2c(n1)NCC(C)C(=S)N2
Solvent: CCCCO
Product: COc1ccc2c(n1)NCC(C)c1nnc(C)n1-2
Temperature: 130 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To a solution of 7-methoxy-3-methyl-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepine-2(3H)-thione (1.8 g, 8.06 mmol) in n-butanol (25 mL) was added acetohydrazide (5.97 g, 80.61 mmol). The mixture was stirred at 130° C. for 3 hours. The reaction mixture was concentrated in vacuo and washed with brine (20 mL), and then the mixture was filtered through a celite pad. The filtrate was extracted with acetic ester (20 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph silica gel (elute: dichloro methane/Methanol: 80:1→35:1→20:1) to give 8-methoxy-1,4-dimethyl-5,6-dihydro-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepine (1.2 g, 61%) as a yellow solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].N#N>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.O.COCCOC>[CH2:13]([CH:12]([CH2:15][CH3:16])[CH:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[CH:2][SH:3]([C:29]3[CH:30]=[CH:31][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][CH:28]=3)[C:4]=2[CH:10]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH3:14]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCC(CC)C(c1ccc2nc(Br)sc2c1)n1ccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCC(CC)C(c1ccc2c(c1)[SH](c1ccc(C(=O)OC)cc1)C=N2)n1ccnc1
Temperature: 80 °C

Procedure:
A solution of 2-bromo-6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole (93 mg, 0.255 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (50.6 mg, 0.281 mmol), tetrakis(triphenylphosphine)palladium (29.5 mg, 0.0255 mmol), potassium carbonate (106 mg, 0.765 mmol), DME (5 mL) and water (0.8 mL) was degassed, filled with N2, and heated to 80° C. for 6 h. The reaction mixture was evaporated. The crude product was purified by column chromatography using 5 MeOH in DCM as eluent to afford to methyl 4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-1-yl)benzoate as white solid. MS (ES+): m/z 420.28 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([CH3:36])[CH:35]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:32]4[CH:33]=[C:34]([CH3:36])[CH:35]=[C:30]([CH3:29])[CH:31]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Product: Cc1cc(C)cc(-c2ccc3c(c2)CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)c1
Reaction time: 0.33 h
Yield: 46 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3,5-dimethylphenyl boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (46%).
Reaction SMILES: [Na].[NH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH2:14].CO[C:17](=[O:35])[C@H:18]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[NH:19][CH2:20][C:21]([O:23]C)=O>CO>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH:18]2[NH:19][CH2:20][C:21](=[O:23])[NH:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:17]2=[O:35])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: COC(=O)CN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Reactant: NCCNCCNCCNCCN
Agent: [Na]
Solvent: CO
Product: O=C1CNC(Cc2ccc([N+](=O)[O-])cc2)C(=O)NCCNCCNCCNCCN1
Yield: 50 %

Procedure:
Sodium (20 mmol) was dissolved in dry methanol (100 ml) at room temperature under nitrogen atmosphere and to this solution was added tetraethylenepentamine (18 mmol) and N-((Methoxycarbonyl)methyl)-4-Nitrophenylaianine methyl ester (3) (18 mmol). This solution was refluxed for 72 hours after which the solvent was removed and the residue was purified on silica gel chromatography with chloroformelmethanol/NH3 (aq) (75:20:5), affording a yellow powder. The yield was 50%.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=O)[CH2:8]2)([CH3:3])[CH3:2].[CH3:14][Mg]Br.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:14][C:7]1[CH2:8][C:9]2[C:5]([CH:6]=1)=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:12]=[CH:11][CH:10]=2
Reactant: CC(C)c1cccc2c1CC(=O)C2
Reactant: C[Mg]Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1=Cc2c(cccc2C(C)C)C1
Reaction time: 17 h
Yield: 36 %

Procedure:
11.1 g (63.8 mmol) of indanone b3 were reacted with 2.5 equivalents of methylmagnesium bromide analogously to instructions I.3. The reaction time was 17 hours at room temperature. The mixture was then refluxed with p-toluenesulfonic acid hydrate for 25 minutes. Chromatography gave 3.9 g (36%) of indene b4 as a colorless oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](=[O:16])[N:14]=[N:15][C:11]3=[CH:10][C:9](=[O:17])[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1.I([O-])(=O)(=O)=[O:26].[Na+]>CO>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](=[O:16])[N:14]=[N:15][C:11]3=[CH:10][C:9](=[O:17])[N:8]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:7]=2[CH:24]=1)=[O:26]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc2c(c1)n(-c1ccccc1)c(=O)cc1nnc(=O)n2-1
Agent: [Na+]
Solvent: CO
Product: CS(=O)c1ccc2c(c1)n(-c1ccccc1)c(=O)cc1nnc(=O)n2-1

Procedure:
3.22 g of 8-(methylthio)-6-phenyl-1H-s-triazolo [4,3-a][1,5]benzodiazepine-1,5-dione and 2.14 g of sodium metaperiodate in 500 ml methanol is stirred at +5° C for 24 hours. The reaction is evaporated; the residue dissolved in methylene chloride, washed with water, dried and concentrated. The concentrate is chromatographed on twenty silica gel (1000μ plates, 20 × 20 cm) using acetone-methanol (9:1) as eluting solvent. The band containing the product is removed, stirred with acetone-methanol (4:1) and the silica gel filtered off. The filtrate is evaporated to give the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].[CH2:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]([CH3:31])[CH3:30]>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][S:32]([CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: Cc1cc(NCc2ccc(Cl)cc2Cl)c2cccc(OCCN)c2n1
Reactant: CC(C)CS(=O)(=O)Cl
Agent: Cl
Product: Cc1cc(NCc2ccc(Cl)cc2Cl)c2cccc(OCCNS(=O)(=O)CC(C)C)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(2,4-dichlorobenzyl)-amine dihydrochloride (example 36) and isobutanesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([CH:19]=1)[C:7]([C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][C:10]=1[OH:18])=O>C(O)=O.[Zn]>[F:20][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][C:6]=1[CH2:7][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][C:10]=1[OH:18]
Reactant: O=C(O)c1cncc(O)c1C(=O)c1cc(Cl)ccc1F
Agent: [Zn]
Solvent: O=CO
Product: O=C(O)c1cncc(O)c1Cc1cc(Cl)ccc1F
Reaction time: 0.17 h

Procedure:
To a stirred suspension of zinc dust (>230 mesh; 100 mg) in 75% formic acid (1.3 mL), at 80° C. (external bath temperature), 4-(5'-chloro-2'-fluorobenzoyl)-5-hydroxynicotinic acid of Preparative Example 26 (100 mg) is added portionwise during 5 minutes. Three further portions of zinc dust (3×50 mg) are subsequently added every 30 min. Stirring is continued for further 10 minutes after the last addition of zinc dust and the reaction mixture is then partitioned between ethyl acetate (10 mL) and 0.5N HCl (10 mL). The aqueous phase is extracted three times with ethyl acetate (3×10 mL), saturated with NaCl and further extracted with ethyl acetate (10 mL). The combined organic phases are washed with brine (10 mL), dried over Na2SO4 and concentrated to dryness. The residue is triturated in acetone (2 mL) and allowed to crystallize overnight. The white solid is collected by filtration, washed with methyl tert-butyl ether and dried under vacuum at 100° C. 4-(2'-fluoro-5'-chlorobenzyl)-5-hydroxynicotinic acid is obtained as a white solid (47 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[C:17](=[S:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:24]=1.[C:25](=O)(O)[O-].[Na+].CI>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[C:17]([S:23][CH3:25])=[N:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:24]=1
Reactant: O=C([O-])O
Reactant: Cc1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1c[nH]c(=O)[nH]c1=S
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CI
Product: CSc1nc(=O)[nH]cc1C1c2ccc(Cl)cc2C=Cc2sc(C)nc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A suspension of the product from example 38, step (v) (1.8 g) in ethanol (200 ml) and sodium bicarbonate (0.5 g) in water (15 ml) was heated until a complete solution formed. After cooling to room temperature methyl iodide (0.33 ml) was added and the whole stirred for 18 h. Another aliquot of methyl iodide was added (0.2 ml) followed by heating at 50° C. for 4 h. The reaction mixture was concentrated under reduced pressure and then partitioned between dichloromethane and brine. The organic phase was collected, dried (MgSO4) and evaporated under reduced pressure to leave a beige foam. Purification was by chromatography eluting with ethyl acetate/methanol mixtures to give the subtitle product as colourless solid.