Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH2:5][O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[ClH:14].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[CH2:22](O)C>Cl>[ClH:14].[O:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([C:1](=[O:3])[CH2:2][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:5]1
Reactant: CN1CCNCC1
Reactant: CCO
Reactant: CC(=O)C1=Cc2ccccc2OC1
Agent: Cl
Product: CN1CCN(CCC(=O)C2=Cc3ccccc3OC2)CC1

Procedure:
3-Acetyl-2H-chromene (0.5 mole) is dissolved in 250 ml ethanol, while warming. N-methyl-piperazine hydrochloride (0.4 mole) in ethanol (250 ml) and concentrated hydrochloric acid (1 ml) are added thereto. Trioxymethylene (3 moles) is added portionwise over 2 hours, and the resulting material is refluxed overnight. A pale yellow precipitate forms gradually. After cooling, the precipitate is filtered off, washed with ethanol and then with ether, after which it is dried in a desiccator at 90° C. and recrystallized from the minimum amount of water. M.p.=228° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[CH2:12][CH2:11][NH:10][C:8]3=[CH:9][C:4]=2[N:3]=[C:2]1[SH:13].[OH-].[Na+].[ClH:16].[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>O>[ClH:17].[ClH:16].[ClH:17].[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:13][C:2]1[NH:1][C:5]2[CH:6]=[C:7]3[CH2:12][CH2:11][NH:10][C:8]3=[CH:9][C:4]=2[N:3]=1
Reactant: Sc1nc2cc3c(cc2[nH]1)CCN3
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CSc2nc3cc4c(cc3[nH]2)CCN4)nc1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To 2.5 g of 1,5,6,7-tetrahydropyrrolo-(2,3-f)benzimidazole-2-thiol, suspended in 40 ml of alcohol, were added dropwise while stirring 1.2 g of sodium hydroxide in 20 ml of water and, after 30 minutes, there were added 2.4 g of 2-chloromethyl-pyridine hydrochloride. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in methylene chloride. The solution obtained was washed with 100 ml of 3 N sodium hydroxide and three times with 100 ml of water, dried over sodium sulfate and evaporated in vacuo. The crude product, dissolved in methanol, was treated with 30 ml of hydrochloric acid in ethyl acetate and the precipitated crystals were removed by filtration under suction. There were obtained 1.6 g (31.3% of theory) of 1,5,6,7-tetrahydro-2-[(2-pyridylmethyl)thio]pyrrolo(2,3-f)benzimidazole trihydrochloride of melting point 207°-209° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])[CH:3]=1.[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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.C(Cl)Cl>[F:12][C:11]([F:14])([F:13])[S:8]([C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(c1cccc(Br)c1)C(F)(F)F
Reactant: OB(O)c1ccncc1
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: Cc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: O=S(=O)(c1cccc(-c2ccncc2)c1)C(F)(F)F
Temperature: 90 °C

Procedure:
1-Bromo-3-trifluoromethylsulfonyl benzene (580 mg) and 4-pyridine-boronic acid (275 mg) was dissolved in toluene (5 ml) and abs EtOH (5 ml). To the mixture was then added Na2CO3 (424 mg) and Pd(PPh3)4 (119 mg) under an atmosphere of Argon. The resulting mixture was heated to 90° C. for 18 h. Then CH2Cl2 was added and the organic phase was washed with water and dried (MgSO4), filtered and evaporated to dryness. The residue was then used without any further purification. (MS m/z (rel. intensity, 70 eV) 287 (M+, 33), 218 (22), 154 (bp), 127 (56), 69 (27).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][CH:7]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[CH:12]=1)[C:8]([OH:10])=[O:9]>CCCCCC>[CH2:1]([NH2+:3][CH2:4][CH3:5])[CH3:2].[Cl:6][CH:7]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[CH:12]=1)[C:8]([O-:10])=[O:9]
Reactant: CCNCC
Reactant: COc1ccc2cc(C(Cl)C(=O)O)ccc2c1
Solvent: CCCCCC
Product: CC[NH2+]CC
Product: COc1ccc2cc(C(Cl)C(=O)[O-])ccc2c1

Procedure:
Anhydrous diethylamine (0.11 moles) is added dropwise to a stirred solution of α-chloro-6-methoxy-2-naphthylacetic acid (0.10 moles) in 100 ml. of n-hexane at 0°C. The precipitate is collected on a filter, washed with n-hexane, and dried in a vacuum desiccator to obtain α-chloro-6-methoxy-2-naphthylacetic acid, diethylammonium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH:7]=1.ClC1CCC(C(OCC)=O)=C(C2C=CC=CC=2)C=1.C(O[K])(C)(C)C.O>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CCOC(=O)C1CC=C(Cl)C=C1c1ccccc1
Agent: CC(C)(C)O[K]
Agent: CCOC(=O)C1=C(c2ccccc2)C=C(Cl)CC1
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1ccc(Cl)cc1-c1ccccc1
Reaction time: 48 h

Procedure:
To a stirred solution of ethyl 4-chloro-2-phenylcyclohexa-2,4-dienecarboxylate and ethyl 4-chloro-2-phenylcyclohexa-1,3-dienecarboxylate(200 mg, 0.762 mmol) in tert-BuOH(3 ml), tert-BuOK(103 mg, 0.914 mmol) was added by portion on a water bath. After stirring for 2 days, water was added to the reaction mixture and it was acidified with dil. HCI aq., extracted with AcOEt. The organic layer was washed with brine and dried over MgSO4. Concentration of the organic layer afford a mixture(200 mg) of ethyl 4-chloro-2-phenylbenzoate and 4-chloro-2-phenylbenzoic acid. 1H-NMR(ppm, 300 MHz, CDCl3) δ ester 7.79(1H, d, J=8.0 Hz), 7.10-7.50(7H), 4.07(2H, d, J=6.9 Hz), 0.98(3H, t, J=6.9 Hz); acid 7.91(1H, d, J=8.7 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C(Cl)Cl.CCN(C(C)C)C(C)C.[Cl:28][C:29]1[C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]([Cl:38])=[CH:31][N:30]=1>CN(C1C=CN=CC=1)C.CC(O)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:35]([C:34]2[C:29]([Cl:28])=[N:30][CH:31]=[C:32]([Cl:38])[CH:33]=2)=[O:36])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)C1(NC(=O)c2cc(Cl)cnc2Cl)Cc2ccccc2C1
Reaction time: 1368 h
Yield: 107.7 %

Procedure:
A 30 mL reaction vial is charged with 2-aminoindan-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and dry DCM (5 mL). A stirring bar is added and stirring is initiated. DIPEA (1.35 mL, 7.8 mmol) is added. 2,5-dichloro-pyridine-3-carbonyl chloride (1.23 g, 5.85 mmol) and DMAP (8 mg, cat.) are added. The reaction is capped. After 57 days, tlc analysis (silica, 10% iPrOH/DCM) indicates that the starting has been completely consumed. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (60 mL). This is washed with water (2×25 mL), saturated aqueous NaHCO3 (2×25 mL), and brine (25 mL), and then dried over MgSO4, filtered and evaporated by pumping to constant weight yields 1.99 g of off-white solid. This is diluted with DCM (20 mL) and applied to a silica column ((80 g) on an ISCO Companion. The column is eluted with 5% EtOAc in heptanes for 3 column volumes followed by a linear gradient to 75% EtOAc in heptanes over 12 column volumes. 17 mL fractions of UV positive eluent are collected. Fraction 12-16 are combined and evaporated by pumping to constant weight to give light yellow solid (1.39 g, 75%).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].C(N(CC)CC)C.[C:13]1([C:19]2[C:28]([CH3:29])=[CH:27][C:26]3[C:21](=[C:22]([C@H:30]([OH:40])[CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(OCC)C>[C:13]1([C:19]2[C:28]([CH3:29])=[CH:27][C:26]3[C:21](=[C:22]([C@H:30]([O:40][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:31][O:32][Si:33]([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:34])[CH3:35])[CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2cccc([C@H](O)CO[Si](C)(C)C(C)(C)C)c2nc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: Cc1cc2cccc([C@@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)c2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2 ml (26 mmol) of mesyl chloride and 4 ml (27 mmol) of triethylamine are added sequentially, at 0° C., to a solution of 7 g (17.8 mmol) of 2-phenyl-3-methyl-8-(1-(S)-hydroxy-2-[tert-butyldimethylsilyloxy]ethyl)quinoline in 200 ml of ethyl ether. The solution rapidly turns cloudy and a white precipitate is formed. After stirring for one hour at ambient temperature, 150 ml of distilled water are added to the reaction medium and the aqueous phase is extracted with 3×200 ml of ethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum to provide 8.4 g of 2-phenyl-3-methyl-8-(1-(S)-methanesulfonyloxy-2-[tert-butyldimethylsilyloxy]ethyl)quinoline in the form of a colorless oil, used without purification in the following stage. (Yield: quantitative)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-])(=[O:3])[CH3:2].[CH3:11][N:12](C)C(Cl)=O.C([Si](C)(C)C)#N.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CN(C)C(=O)Cl
Reactant: CC(=O)c1cccc[n+]1[O-]
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)c1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-acetylpyridine-N-oxide (0.098 mol) in 200 ml of methylene chloride was added dimethylcarbamyl chloride (0.1 mol) and the reaction mixture was allowed to react at room temperature under nitrogen for 24 h. Additional dimethylcarbamyl chloride (0.1 mol) was added followed by cyanotrimethylsilane (0.22 mol), and the resulting mixture was allowed to react at 20° C. for 2 days. An additional 4 ml (0.03 mol) of cyanotrimethylsilane was then added, and the mixture was stirred at room temperature for another 24 hours. A solution of 200 ml of 10% K2CO3 was added to the reaction mixture and the resulting mixture was stirred for 45 min. The aqueous layer was extracted with 100 ml methylene chloride twice, the organic layers were combined and dried (K2CO3). After stripping the solvent, 16.9 g of crude product was isolated. The crude product obtained was chromatographed over Florisil" to isolate the desired products and the by-products with elution by the series of solvents: 2-acetyl-6-cyanopyridine (3a) (2 g, 50% CH2Cl2 /hexane), 2-cyano-6-(1-cyano-1-trimethysilyloxy)ethylpyridine (3b) (0.81 g, CH2Cl2), 2-cyano-6-(1-cyano-1-dimethylcarbamoyloxy)ethylpyridine (3c) (1.67 g, 25:72 EtOAc/CH2Cl2), 2-(1-cyano-1-hydroxy)ethylpyridine (3d) (0.42 g, 50:50 EtOAc/CH2Cl2), and 2-(1-cyano-1-dimethylcarbamoyloxy)ethylpyridine-1-N-oxide (3e) (1.8 g, EtOAc). The products exhibited the following properties.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:45])[N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[CH:26]=[C:25]([NH:27][C:28]5[CH:33]=[CH:32][C:31]([C:34]([N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)=[O:35])=[CH:30][N:29]=5)[C:24](=[O:42])[N:23]([CH3:43])[N:22]=4)[C:16]=3[CH3:44])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>CO.Cl>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:45])[N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[CH:26]=[C:25]([NH:27][C:28]5[CH:33]=[CH:32][C:31]([C:34]([N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)=[O:35])=[CH:30][N:29]=5)[C:24](=[O:42])[N:23]([CH3:43])[N:22]=4)[C:16]=3[CH3:44])[CH2:11][NH:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)cccc1-n1cnc2cc(C(C)(C)C)ccc2c1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)cccc1N1CNc2cc(C(C)(C)C)ccc2C1=O
Reaction time: 0.75 h
Yield: 61.1 %

Procedure:
To a mixture of 7-tert-Butyl-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-3H-quinazolin-4-one (11 mg, 0.018 mmol) and sodium cyanoborohydride (1.3 mg, 0.019 mmol) in 1 mL methanol was added 1 drop of 2M hydrochloric acid in methanol to bring the pH to 3. After stirring for 45 minutes, the resulting mixture was partitioned between ethylacetate and dilute aqueous NaHCO3. The ethylacetate layer was washed with brine, dried over anhydrous MgSO4, concentrated in vacuo, and purified by preparative TLC (5% MeOH/CH2Cl2) to yield 7-tert-Butyl-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2,3-dihydro-1H-quinazolin-4-one (6.5 mg, 0.011 mmol). MS (EST) 608 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29]>ClCCl.C(OCC)(=O)C>[C:14]([O:13][C:11]([N:8]1[CH2:7][CH2:6][CH:5]([NH:4][CH2:1][CH:2]=[CH:3][C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=2)=[O:29])[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCC=CC(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
A portion of the crude 4-(allylamino)-1-(tert-butoxycarbonyl)piperidine (400 mg, 1.66 mmol) was dissolved in 10 mL of dichloromethane and treated with N,N-diisopropylethylamine (0.700 mL, 519 mg, 4.0 mmol) and 4-nitrobenzyl chloroformate (392 mg, 1.82 mmol). After stirring 3 h at RT, the mixture was diluted with 30 mL of ethyl acetate and washed with 15 mL each of 2 N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with 30% ethyl acetate in hexane, to give 572 mg of the title compound as a colorless syrup. 1H NMR (400 MHz, CDCl3): δ8.22 (d, 2H, J=8 Hz), 7.50 (d, 2H, J=8 Hz), 5.80 (ddt, 1H, J=17, 10, 5 Hz), 5.23 (s, 2H), 5.18-5.09 (m, 2H), 4.27-4.08 (m, 3H), 3.89-3.79 (m, 2H), 2.79-2.66 (m, 2H), 1.74-1.52 (m, 4H), 1.46 (s, 9H). Mass spectrum (ESI): m/z=420 (M+1, 27%), 437 (M+1+NH3, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](C)[C:3]=1[C:4]#[N:5].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[S:21])#[N:5]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1cccc(N)c1C#N
Product: N#Cc1ccccc1NC(=S)NC(=O)c1ccccc1

Procedure:
Prepared as in example 1a from 2-amino-6-methylbenzonitrile and benzoyl isothiocyanate as a pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.40 (m, 1H), 7.52-7.69 (m, 5H), 7.98-8.01 (m, 2H), 11.99 (s, 1H), 12.54 (s, 1H). MS 296 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)=[O:7].C(N(CC)C(C)C)(C)C.[Cl:36][C:37]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C(Cl)Cl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:25]([NH:26][C:39](=[O:40])[C:38]4[CH:42]=[CH:43][C:44]([Cl:46])=[CH:45][C:37]=4[Cl:36])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
A mixture of 1.0 g of 5-(3-methoxy-4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.47 g of N,N-diisopropylethylamine and 0.76 g of 2,4-dichlorobenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water and saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to give 1.39 g of the desired product as a crystalline solid, m.p. 212°-214° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=3)[O:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[CH:17]=O)[C:3]=12.[CH:39]([CH:41]=O)=O.C(=O)([O-])[O-].[NH4+:47].[NH4+:48]>CO>[NH:47]1[CH:41]=[CH:39][N:48]=[C:17]1[C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=CC=O
Reactant: [NH4+]
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(Oc5ccccc5C=O)c4)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Solvent: CO
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(Oc5ccccc5-c5ncc[nH]5)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
A mixture of cis-2-(3-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzaldehyde (0.102 g, 0.199 mmol, 1 equiv), glyoxal (0.12 mL, 0.99 mmol, 5 equiv), and ammonium carbonate (0.078 g, 0.99 mmol, 5 equiv) in methanol (1 mL) was stirred at ambient temperature for 16 h. Additional glyoxal (0.20 mL, 1.6 mmol, 8.3 equiv) and ammonium carbonate (0.130 g, 1.66 mmol, 8.4 equiv) were added and the reaction mixture was stirred at ambient temperature for 24 h. The crude reaction mixture was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give cis-3-{3-[2-(1H-2-imidazolyl)phenoxy]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a brown solid (0.010 g, 0.018 mmol): 1H NMR (d6 DMSO, 400 MHz): 6H 8.23 (1H, s), 8.11-8.13 (1H, dd, J=7.7, 1.9 Hz), 7.95 (1H, s), 7.66 (2H, d, J=8.5 Hz), 7.34-7.39 (1H, m), 7.23-7.27 (3H, m), 7.07-7.19 (3H, m), 4.77-4.82 (1H, m), 2.16-2.56 (11H, m), 2.14 (3H, s), 2.05-2.11 (2H, m), 1.55-1.71 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 10.43 min. MS: MH+ 550.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1>CN(C=O)C.C(OCC)(=O)C>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:6]2[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cnc(Cl)nc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,4-dichloro-5-methyl-pyrimidine (3.61 g, 22.15 mmol), triethylamine (7.02 mL, 50.34 mmol) in DMF (15 mL) was slowly added benzyl-4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1, 5.00 g, 20.13 mmol). The resulting reaction solution was stirred at rt for 2 h, then diluted with ethyl acetate (400 mL), washed with water (3×30 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (20–80% ethyl acetate in hexane) to give 4-[(2-Chloro-5-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S. (M+1): 375.36
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[OH-:14].[Na+]>CCO.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]([NH2:10])=[O:14]
Reactant: [OH-]
Reactant: N#Cc1cccc(C2OCCO2)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1cccc(C2OCCO2)c1
Yield: 69.6 %

Procedure:
To a solution of 3-(1,3-dioxolan-2-yl)-benzonitrile (5.86 g) in a mixture of EtOH (140 mL) and H2O (60 mL) was added sodium hydroxide (6.46 g) and the mixture was heated under reflux for 2 hours. The solvent was evaporated under reduced pressure and the aqueous layer was extracted with CH2Cl2. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated to give the title compound (4.5 g) as a white solid.
Reaction SMILES: C(OC(N1C2SC(C(O)=O)=CC=2C([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=N1)C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C1(NN)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([NH2:17])=[O:27])=[CH:20][CH:21]=1
Reactant: CCOC(C)n1nc(NC(=O)c2ccc(OC)cc2)c2cc(C(=O)O)sc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: NNc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(N)=O)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 28 %

Procedure:
1-(1-Ethoxyethyl)-3-(4-methoxybenzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (0.3 g, 0.77 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (0.247 g, 0.77 mmol, 1 eq.), dimethylformamide (3.85 mL) and phenylhydrazine (0.151 mL, 1.54 mmol, 2 eq.) are successively introduced into a 20 mL round-bottomed flask under argon. Triethylamine (0.322 mL, 2.31 mmol, 3 eq.) is added to the reaction mixture. The mixture is stirred at a temperature in the region of 60° C. for 15 hours. The solvent is then evaporated off under vacuum and the residual oil is diluted with 15 mL of ethyl acetate and 10 mL of water. The aqueous phase is isolated and then acidified to pH 4-5, after which it is extracted with ethyl acetate (3×15 mL). The combined organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography on silica gel, eluting with a 1:1 ethyl acetate/heptane mixture. The product obtained in oil form (0.310 g, 84%, Rf=0.47 (1:9 MeOH/dichloromethane)) is placed without further purification in 5 mL of tetrahydrofuran and 2.5 mL of 2.5 N hydrochloric acid. The reaction mixture is then heated at a temperature in the region of 50° C. for 2 hours and is then cooled to room temperature. 15 mL of water are then added to the mixture. A precipitate forms. The tetrahydrofuran is evaporated off and the aqueous phase is neutralized with 5 N NaOH. The precipitate formed is filtered off and then washed with water. The beige-colored solid is dried in an oven at a temperature in the region of 60° C. under vacuum. The dry solid is then dissolved in acetone and precipitated from heptane. The 5-(N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-methoxybenzamide thus obtained (86 mg, 33%) has a purity of 95%. Overall yield=28%. 1H NMR (400 MHz, (CD3)2SO-d6, δ in ppm): 3.85 (s, 3H); 6.72 (broad t, J=7.5 Hz, 1H); 6.76 (broad d, J=8.0 Hz, 2H); 7.05 (broad d, J=8.0 Hz, 2H); 7.15 (broad t, J=7.5 Hz, 2H); 7.85 (broad s, 1H); 8.09 (broad d, J=8.0 Hz, 2H); 8.19 (broad s, 1H); 10.45 (broad m, 1H); 11.0 (broad m, 1H); 12.9 (broad m, 1H). LC/MS: m=407. ES m/z=408 MH+