Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=O.[CH3:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][NH2:26])[CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[CH3:16][O:15][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH3:14])[C:6]([NH:26][CH2:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[CH:19]=1)=[O:8]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1
Reactant: Cc1cccc(CCN)c1
Solvent: ClCCl
Product: COc1cc(C(=O)NCCc2cccc(C)c2)cc(OC)c1OC

Procedure:
A solution of methyl 3,4,5-trimethoxybenzoate (31.1 g, 0.138 mol) and 2-(3-methylphenyl)ethylamine (18.6 g, 0.138 mol) was heated at 180° for 6 h. The dark reaction mixture was taken up in methylene chloride and washed with dilute HCl. The solvent was evaporated and the residue was chromatographed on 150 g of neutral alumina. Elution with methyl chloride/hexane (3:1) removed some by-products and elution with methylene chloride gave nearly pure amide F1 which was recrystallized from i-PrOH to give pure F1 (5.2 g, 11%), mp 105-108°.
Reaction SMILES: O1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:28][CH3:29])=[C:8]([C:14]([CH2:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3C)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:9]([O:11][CH2:12]C)=[O:10])=[CH:2]1.C1([S:36](CC2C(C(OC)=O)=C(OC)C(Br)=CC=2)(=O)=O)C=CC=CC=1.S1C=CC(B(O)O)=C1>>[C:21]1([S:18]([CH2:17][C:14]2[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:28][CH3:29])[C:6]([C:3]3[CH:4]=[CH:5][S:36][CH:2]=3)=[CH:16][CH:15]=2)(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2C)ccc(-c2ccoc2)c1OC
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: OB(O)c1ccsc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccsc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 28, starting from methyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 65) and thiophene-3-boronic acid.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:19]=[O:20])=[CH:15][NH:16]3)=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:25][C:24]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:19]=[O:20])=[CH:15][N:16]3[CH2:22][C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])=[CH:25][C:24]=3[O:36][CH3:37])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1c[nH]c2cc(C(=O)NCC3CCCC3)ccc12
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)OC(C)(C)C)ccc1Cn1cc(C=O)c2ccc(C(=O)NCC3CCCC3)cc21
Reaction time: 48 h
Yield: 71.9 %

Procedure:
A mixture of 6-(N-cyclopentylmethylcarbamoyl)-3-formylindole (0.92 g), t-butyl 4-bromomethyl-3-methoxybenzoate (1.2 g), and potassium carbonate (0.7 g) in N,N-dimethylformamide (17 ml) was stirred for 48 hours under a nitrogen atmosphere. Water was added to give a precipitate which was collected by filtration and dried to yield t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-formylindol-1-ylmethyl]-3-methoxybenzoate (1.2 g, 71%) as an ivory powder; mp 134°-135°.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=C[CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[Cl-].[NH4+:15]>C1COCC1.[Zn]>[Br:11][C:8]1[CH:9]=[C:10]2[C:5](=[N:15][CH:7]=1)[NH:4][C:3](=[O:12])[CH2:2]2
Reactant: O=C1Nc2ccc(Br)cc2C1(Br)Br
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Zn]
Solvent: C1CCOC1
Product: O=C1Cc2cc(Br)cnc2N1
Reaction time: 0.33 h

Procedure:
A solution of 3,3,5-tribromooxindole (5.0 g, 13.4 mmol) in fresh THF (100 mL) is stirred at room temperature and a saturated aqueous solution of ammonium chloride (100 mL) is added. The flask is placed in a water bath and activated zinc dust (15.0 g, 230 mmol) is added. The mixture is stirred for 20 min and the zinc is removed by filtration through a pad of diatomaceous earth. The organic layer is separated and the aqueous layer is extracted with THF (20 mL). The combined organic layers were washed with saturated brine solution, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The brown residue is triturated with water (20 mL) and the tan solid is collected by filtration and dried under vacuum to give 5-bromo-7-azaoxindole as a tan solid, 2.02 g (71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=2[Cl:41])[CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[CH:43]([N-]C(C)C)(C)[CH3:44].[Li+].I[CH2:52][CH3:53]>C1COCC1>[CH3:1][O:2][C:3](=[O:42])[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[C:32]=2[Cl:41])[CH2:16][CH:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)([CH2:52][CH3:53])[CH2:43][CH3:44]
Reactant: CCI
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)(C(=O)OC)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of (3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-acetic acid methyl ester (70 mg, 0.12 mmol) in dry THF (50 mL) was added lithium diisopropylamide (1.7 mL, 1.2 mmol) dropwise with cooling to −78° C. After the reaction mixture was stirred at −78° C. for an additional 1 h, iodoethane (0.4 mL) was added. The reaction was warmed to RT over 4 h followed by quenching with saturated ammonium chloride (10 mL). Solvent was removed and the residue was partitioned between water and ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil (37 mg, 50%). MS m/e 652.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:20])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[NH2:10])=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[CH:34]=[CH:33][C:27]([C:28](=N)OCC)=[CH:26][CH:25]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:10][C:28]([C:27]3[CH:33]=[CH:34][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)=[N:20]2)=[CH:6][CH:7]=1
Reactant: CCOC(=N)c1ccc(OC)cc1
Reactant: NC(c1ccc(Cl)cc1)C(N)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc([N+](=O)[O-])cc3)N2)cc1
Yield: 36.9 %

Procedure:
To a solution of 1-(4-chloro-phenyl)-2-(4-nitro-phenyl)-ethane-1,2-diamine (200 mg, 0.685 mmol) and ethyl 4-methoxy-benzimidate hydrochloride (148 mg, 0.686 mmol) in ethanol (5 mL) was added triethylamine (0.11 mL, 0.79 mmol). The reaction mixture was heated at reflux for 12 h. The solvent was removed to give a clear oil. It was then taken in methylene chloride (2 mL) and aqueous sodium carbonate. The product was extracted with methylene chloride (2×20 mL). The organic layers were washed with brine (1×5 mL), dried (Na2SO4) and concentrated. Purification of the crude residue by Biotage flash chromatography eluting with 70% ethyl acetate in hexanes gave 4-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-4,5-dihydro-1H-imidazole (103 mg, 37%).
Reaction SMILES: BrCBr.Cl[Si](C)(C)C.[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18](I)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][N:23]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C=O)C.[Zn]>[Cl:21][C:22]1[N:23]=[CH:24][C:25]([CH:18]2[CH2:19][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17]2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Clc1cc(I)ccn1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN(C)C=O
Solvent: BrCBr
Product: CC(C)(C)OC(=O)N1CC(c2ccc(Cl)nc2)C1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with zinc (2.54 g, 38.9 mmol), DMF (32 mL), and dibromomethane (736 mg, 4.24 mmol). After stirring at 70° C. for 10 min, the reaction mixture was cooled to room temperature, and chlorotrimethylsilane (423 mg, 3.89 mmol) was added. The resulting mixture was stirred at room temperature for 30 min, and a solution of 1-(tert-butoxycarbonyl)-3-iodoazetidine (9.31 g, 38.9 mmol) in DMF (32 mL) was added. After stirring at 40° C. for 1 h, a solution of 2-chloro-4-iodo-pyridine (10.0 g, 35.3 mmol) in DMF (16 mL) was added, followed by a solution of (dibenzylideneacetone)dipalladium(0) (1.62 g, 1.77 mmol) and tri(2-furyl)-phosphine (820 mg, 3.53 mmol) in DMF (16 mL). After stirring at 70° C. for 16, the reaction mixture was partitioned between saturated aqueous ammonium chloride (200 mL) and diethyl ether (200 mL). The layers were separated, and the aqueous phase was extracted with diethyl ether (200 mL). The organic extracts were combined, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford a 54% yield (5.42 g) of 117a as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.29 (d, 1H, J=2.5 Hz), 7.70 (dd, 1H, J=8.5, 2.5 Hz), 7.35 (d, 1H, J=8.5 Hz), 4.37 (t, 2H, J=8.5 Hz), 3.91 (dd, 2H, J=8.5, 4.5 Hz), 3.73 (m, 1H), 1.46 (s, 9H); MS (ESI+) m/z 269.0 (M+H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2].C(C1CC([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(C#N)CCC1=O)(OC)=O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][C:24]=1[C:3]1([C:1]#[N:2])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: N#CC1CCC(=O)CC1
Reactant: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: N#CC1(c2ccccc2Cl)CCC(=O)CC1
Yield: 80 %

Procedure:
Following the procedure of Example 1, Part C, but substituting 33.4 gm. (0.115 mole) of 2-carbomethoxy-4-chlorophenyl)-4-cyanocyclohexanone (prepared in Part B, above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone, using 730 ml. glacial acetic acid and 365 ml. 10 percent aqueous sulfuric acid instead of the 660 ml. and 330 ml., respectively, and heating for 48 hours instead of 24 hours there is obtained a residual solid that is recrystallized from a mixture of methylene chloride and technical hexane thus affording 20.54 gm. (80% yield) of 4-(o-chlorophenyl)-4-cyanocyclohexanone having a melting point at 106° to 108° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: ClCCCCOc1cccnc1
Reactant: CN
Solvent: CO
Product: CNCCCCOc1cccnc1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
The 4-chloro-1-(3-pyridyloxy)butane (2.00 g, 10.8 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 100% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.47 g (75.5%) of an oil.
Reaction SMILES: Cl.[C:2]([CH:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=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>[C:2]([CH:10]1[O:15][CH2:14][CH2:13][N:12]([C:17]2[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[N:18]=2)[CH2:11]1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(c1ccccc1)C1CNCCO1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCOC(C(=O)c3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 101.5 %

Procedure:
A solution of 2-benzoylmorpholine hydrochloride (269 mg, 1.17 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (320 mg, 1.41 mmol) and triethylamine (0.49 ml, 3.51 mmol) in tetrahydrofuran (10 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 ethyl acetate and diethyl ether to give the title compound (447 mg, quant.).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O>CCOCC>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=3[O:28][CH3:29])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Solvent: CCOCC
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)ccc3OC)c(F)ccc2c1N
Yield: 71.5 %

Procedure:
The title compound was prepared from 4-amino7-fluoro-8-iodo-N-propylcinnoline-3-carboxamide (200 mg, 0.535 mmol) and 2,5-dimethoxyphenyl boronic acid (194 mg, 1.07 mmol) according to Method A. The off-white solid from chromatography was slurried in ether, filtered and dried under vacuum at room temperature to afford the desired product (147 mg, 71%). 1H NMR (300.132 MHz, CDCl3) δ 8.50 (t, J=4.7 Hz, 1H), 7.89 (dd, J=9.3, 5.1 Hz, 1H), 7.52 (t, J=8.8 Hz, 1H), 6.98 (m, 2H), 6.91 (dd, J=2.4, 0.9 Hz, 1H), 3.79 (s, 3H), 3.67 (s, 3H), 3.44 (q, J=6.7 Hz, 2H), 1.64 (sextet, J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). MS APCI, m/z=385 (M+H). HPLC 2.62 min.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([N:9]([C:11]1[C:12]([Cl:31])=[C:13]([C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:26])[CH:22]=[CH:21]2)[CH3:10])=[O:8])=[O:4].[CH2:32]([P:36]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35]>O1CCCC1>[Br-:1].[CH2:41]([P+:36]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:2][C:3]([NH:5][CH2:6][C:7]([N:9]([C:11]1[C:12]([Cl:31])=[C:13]([C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:26])[CH:22]=[CH:21]2)[CH3:10])=[O:8])=[O:4])[CH2:42][CH2:43][CH3:44]
Reactant: CCCCP(CCCC)CCCC
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CBr)c3Cl)c2n1
Solvent: C1CCOC1
Product: CCCC[P+](CCCC)(CCCC)CC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Product: [Br-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 8-[3-[N-(bromoacetylglycyl)-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (200 mg) and tri-n-butylphosphine (140 μl) in tetrahydrofuran (4 ml) was stirred for 2 hours at ambient temperature. The mixture was concentrated, and the residue was purified by flash chromatography (dichloromethane - methanol) to give 8-[3-[N-[2-(tri-n-butylphosphonio)acetylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline bromide (128 mg) as an amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:6][N:7]=1.[NH2:20][OH:21]>C(O)C.O>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:20][OH:21])=[NH:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: NO
Reactant: CNC(=O)c1nc(-c2cccc(C#N)c2)cnc1N
Solvent: CCO
Solvent: O
Product: CNC(=O)c1nc(-c2cccc(C(=N)NO)c2)cnc1N
Temperature: 25 °C
Yield: 71.6 %

Procedure:
3-Amino-6-(3-cyanophenyl)-N-methylpyrazine-2-carboxamide (155 mg, 0.61 mmol) was suspended in ethanol (2 mL) followed by addition of 50% aqueous hydroxylamine (250 uL, 4.1 mmol) and the mixture was heated to reflux for 30 minutes then allowed to cool to room temperature. The suspension was diluted with water (2 mL) and the solid product collected by filtration and dried in vacuo to give crude 3-amino-N-methyl-6-{3-[(hydroxyamino)(imino)methyl]phenyl}pyrazine-2-carboxamide (125 mg, 72% yield) as a yellow solid which was carried forward without further purification: MS (EI) for C13H15N6O2: 287 (MH+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:7]=2N)=[N:2]1.N(OCCCC)=O.[CH3:21][S:22]SC>[Cu]>[CH3:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:7]([S:22][CH3:21])[C:6]=1[C:3]1[CH2:4][CH2:5][O:1][N:2]=1
Reactant: Cc1cccc(N)c1C1=NOCC1
Reactant: CSSC
Agent: [Cu]
Agent: CCCCON=O
Product: CSc1cccc(C)c1C1=NOCC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
40 g (0.22 mol) of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline and 1.5 g of copper powder are initially charged in 300 ml of dimethyl disulfide, and 26.1 g of n-butyl nitrite (0.23 mol) are added dropwise at 55-66° C. The mixture is then stirred at 60° C. for 1.5 hours. For work-up, the hot mixture is filtered through activated carbon and then washed with dilute hydrochloric acid and water and then concentrated under reduced pressure. This gives 44.5 g (88%) of a dark oil which solidifies after a while (content according to HPLC (95%). The product can be purified further by trituration with methyl tert-butyl ether.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:11]=2[CH2:10][CH2:9]1.O1CCOCC1CN1CCC2C=C(OC)C(N)=CC=2CC1.Cl[C:42]1[N:47]=[C:46]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[S:55]([N:58]([CH3:60])[CH3:59])(=[O:57])=[O:56])[C:45]([Cl:61])=[CH:44][N:43]=1>>[Cl:61][C:45]1[C:46]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[S:55]([N:58]([CH3:60])[CH3:59])(=[O:57])=[O:56])=[N:47][C:42]([NH:19][C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([CH2:7][CH:2]4[CH2:3][O:4][CH2:5][CH2:6][O:1]4)[CH2:9][CH2:10][C:11]=3[CH:18]=2)=[N:43][CH:44]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCN(CC1COCCO1)CC2
Agent: COc1cc2c(cc1N)CCN(CC1COCCO1)CC2
Product: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CC2COCCO2)CC3)ncc1Cl

Procedure:
3-1,4-Dioxinan-2-ylmethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine, prepared in a similar manner as 3-1,4-Dioxinan-2-ylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine of Example 636b, was reacted with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide, in a similar manner as Example 601b, to yield desired product 2-[5-Chloro-2-(3-[1,4]dioxan-2-ylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N,N-dimethyl-benzenesulfonamide as a lyophylate (38%); 1H NMR (400 MHz, DMSO-d6) δ 9.82 (bs, 1H), 9.56 (s, 1H), 9.29 (s, 1H), 8.51 (bs, 1H), 8.29 (s, 1H), 7.84 (d, J=8.08 Hz, 1H), 7.71 (m, 1H), 7.46-7.37 (m, 3H), 7.08 (d, J=6.57 Hz, 1H), 4.07 (m, 1H), 3.82-3.60 (m, 6H), 3.48 (bs, H2O), 3.3-2.9 (m, 9H), 2.75 (m, 1H), 2.65 (s, 6H); MS (m/e) 573.16 (M+H).
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1.[CH3:14][CH:15]([CH3:19])[C:16](=[O:18])[CH3:17].Cl>C1COCC1>[I:13][C:10]1[CH:11]=[CH:12][C:7]([C:16]([OH:18])([CH:15]([CH3:19])[CH3:14])[CH3:17])=[CH:8][CH:9]=1
Reactant: Ic1ccc(I)cc1
Reactant: CC(=O)C(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)C(C)(O)c1ccc(I)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (37.0 mL of a 2.5 M solution in hexanes, 92.8 mmol) was added to a stirred solution of 1,4-diiodobenzene (30.0 g, 90.9 mmol) in THF (200 mL) at −78° C. After approximately 20 min, 3-methyl-2-butanone (10.2 mL, 95.5 mmol) was added, and the resulting mixture was allowed to stir at −78° C. for about 1 h. The reaction mixture was poured into aqueous 1N HCl and extracted twice with diethyl ether. The combined organic extracts were washed water, brine, dried (magnesium sulfate) and concentrated in vacuo to afford the title compound i-3a. m/z (ES) 273 (M-OH)+. 1HNMR (500 MHz, CDCl3): δ 7.67 (d, 2H, J=8.5 Hz), 7.20 (d, 2H, J=8.7 Hz), 2.00 (m, 1H, J=6.7 Hz), 1.52 (s, 3H), 0.92 (d, 3H, J=6.7 Hz), 0.81 (d, 3H, J=6.9 Hz).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]([CH3:27])[C:15]1[CH:16]=[CH:17][C:18]([CH3:26])=[C:19]([CH:25]=1)[C:20]([N:22]([CH3:24])C)=[O:21].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)C#N>C1COCC1>[CH3:27][N:14]([CH3:13])[C:15]1[CH:25]=[C:19]2[C:18]([CH:26]=[C:24]([C:36]3[CH:35]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:37]=3)[NH:22][C:20]2=[O:21])=[CH:17][CH:16]=1
Reactant: COc1cccc(C#N)c1
Reactant: Cc1ccc(N(C)C)cc1C(=O)N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cccc(-c2cc3ccc(N(C)C)cc3c(=O)[nH]2)c1
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
To a solution of diisopropylamine (1.5 g, 15 mmol) in dry THF (10 mL) was added n-BuLi (6 mL of 2.5 M in hexane, 15 mmol) at −78° C. After 30 min, a solution of 5-dimethylamino-2,N,N-trimethylbenzamide (2.06 g, 10 mmol) in THF (15 mL) was added dropwise at −78° C., the red orange solution was stirred at the same temperature for 1 h. The solution of 3-methoxybenzonitrile (1.7 g, 13 mmol) in dry THF (10 mL) were added and the reaction mixture was stirred at −78° C. for 2 h. The reaction solution was quenched with water and extracted with ethyl acetate and dried over sodium sulfate. After removing the solvent, the residue was purified by column chromatography with n-hexane-ethyl acetate (3:1) to afford compound I as yellow solid (596 mg, 20%). 1H NMR (300 MHz, CDCl3) δ: 9.73 (s, 1H), 7.61 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.38 (m, 1H), 7.23-7.22 (m, 3H), 6.96 (m, 1H), 6.74 (s, 1H), 3.90 (s, 3H), 3.09 (s, 6H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:8][CH:9]=2)[N:4]([CH3:20])[N:3]=1.[C:21]([O:25][C:26](=[O:28])[NH2:27])([CH3:24])([CH3:23])[CH3:22].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([CH:45]=[CH:46][CH:47]=2)[CH2:40]NC(=O)O)O1>>[C:21]([O:25][C:26](=[O:28])[NH:27][CH2:40][C:39]1[CH:45]=[CH:46][CH:47]=[C:37]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[N:8][CH:9]=3)[N:4]([CH3:20])[N:3]=2)[CH:38]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(N)=O
Reactant: Cn1nc(Br)c2cnc(NCCN3CCOCC3)nc21
Reactant: CC1(C)OB(c2cccc(CNC(=O)O)c2)OC1(C)C
Product: Cn1nc(-c2cccc(CNC(=O)OC(C)(C)C)c2)c2cnc(NCCN3CCOCC3)nc21

Procedure:
Prepared as described above in Example 15 starting from (3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-(2-morpholin-4-yl-ethyl)-amine and [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-carbamic acid carbamic acid tert-butyl ester to give the title compound {3-[1-methyl-6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3yl]-benzyl}-carbamic acid tert-butyl ester; LC/MS (m/e)=468.4 (MH+), Rt=1.39 min
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15]>Cl>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)CCCc1ccc2c(n1)NCCC2
Agent: Cl
Product: O=C(O)CCCc1ccc2c(n1)NCCC2
Temperature: 55 °C

Procedure:
The ester obtained in Step b (0.36 g; 1.45 mmol) is dissolved in 10 ml of 6N HCl. The reaction mixture is heated at 55° C. for 4 hours. The reaction mixture is then concentrated, and the residue is taken up in AcOEt. The resulting precipitate, corresponding to the title product, is suction-filtered off over a frit and isolated in the form of a pale yellow solid.