Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:12][CH3:13])=[CH:7][C:6]=1[F:14])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[N:24]=[C:25]=[S:26]>CO.C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([NH:11][C:25]([NH:24][C:18]2[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])=[S:26])[C:8]([NH:12][CH3:13])=[CH:7][C:6]=1[F:14])[CH3:2]
Reactant: CCOC(=O)c1cc(N)c(NC)cc1F
Reactant: S=C=Nc1c(Cl)cccc1Cl
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)c1cc(NC(=S)Nc2c(Cl)cccc2Cl)c(NC)cc1F

Procedure:
Prepared analogously to example 131d from 5-amino-2-fluoro-4-methylamino-benzoic acid ethyl ester and 1,3-dichloro-2-isothiocyanato-benzene in methanol and acetonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:39])=[O:15])[CH2:10][CH:9]1[CH2:40][C:41]([O:43]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45][NH2:46].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:31][C:32]2[C:33]([CH3:39])=[CH:34][CH:35]=[CH:36][C:37]=2[CH3:38])=[O:15])[CH2:10][CH:9]1[CH2:40][C:41](=[O:43])[NH:46][CH3:45])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CC1CN(C(=O)c2c(Oc3c(C)cccc3C)n(-c3ccccc3)c3cccnc23)CCN1C(=O)OC(C)(C)C
Reactant: CN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CNC(=O)CC1CN(C(=O)c2c(Oc3c(C)cccc3C)n(-c3ccccc3)c3cccnc23)CCN1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 168 h
Yield: 32.2 %

Procedure:
A solution of the crude compound of example 58, step 2, (140 mg, 234 μmol) in MOH (1 ml) was mixed with a 2 M methanolic solution of methylamine (2.60 ml, 5.19 mmol). The reaction mixture was stirred at 40° C. for 7 days. After cooling to room temperature, the mixture was neutralized with an aqueous solution of citric acid and extracted with EA. The combined organic phases were dried over sodium sulfate and evaporated. 45 mg of crude title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:11])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Br
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Br

Procedure:
Yet another process, described in Scheme 3, comprises reacting 3-bromo-4-methyl-aniline with 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester to obtain N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide. The latter is reacted with 4-(3-pyridyl)-2-pyrimidine amine (which is obtained by reacting cyanamide with 3-dimethylamino-1-pyridin-3-yl-propenone) to obtain Imatinib
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]=[C:25]=[O:26])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:26]
Reactant: O=C=Nc1ccccc1-c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1-c1ccccc1
Yield: 19.4 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-phenyl phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.22 g, 19%). EI-MS m/z 350 (M+H)+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.C(OCC)C>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:16][CH:17]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-c3ccc(F)cc3)cn2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Fc1ccc(-c2ccc(OC3CCNCC3)nc2)cc1
Reaction time: 24 h
Yield: 80.8 %

Procedure:
4-[5-(4-fluorophenyl)pyridin-2-yloxy]piperidine-1-carboxylic acid tert-butyl ester (0.88 g) was dissolved in methanol (20 ml) and treated dropwise with a 1.0 M solution of HCl in diethyl ether (24 ml). After stirring for 24 h, the resultant mixture was evaporated. The residue was dissolved in 2% citric acid (30 ml) and washed with diethyl ether (2×15 ml). The aqueous phase was then basified with sodium hydroxide to pH 13 and extracted with ethyl acetate (3×30 ml). The combined ethyl acetate extracts were then washed with water (3×10 ml), saturated brine (10 ml), dried (Na2SO4) and evaporated to furnish the title compound as a white solid (0.52 g, 81%)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1>C1(C)C=CC=CC=1>[C:1]([NH:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1cccc(N)c1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 ml of acetic anhydride are added in the cold to a suspension of 30 g (0.22 mole) of 1-(3-aminophenyl)ethanone in 200 ml of toluene, and the mixture is stirred for 1 h at room temperature, then heated for 1 h to 60° C. and left to stand overnight. The precipitate obtained is drained, ground in ether and dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1B(O)O>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:19])[CH2:3][C:2]2([CH3:20])[CH3:1]
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3cc(Cl)ccc3Cl)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 2,5-dichlorophenyl boronic acid according to the procedure described in example 21. MS m/z 305; HRMS: calcd for C17H14Cl2O+H+, 305.04944; found (ESI, [M+H]+), 305.0502.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:27])=[C:23]([Cl:26])[C:24]=3[Cl:25])=[O:19])[CH2:13][CH2:12]2)[N:10]=1)[C:5](O)=[O:6].Cl.[O:29]([NH2:31])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:27])=[C:23]([Cl:26])[C:24]=3[Cl:25])=[O:19])[CH2:15][CH2:16]2)[N:10]=1)[C:5]([NH:31][O:29][CH3:30])=[O:6]
Reactant: CON
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)cc(Cl)n3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CONC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1

Procedure:
The title compound was synthesised by an analogous method to Example 45 starting from 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isonicotinic acid (Example 153) and methoxylamine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@H:15]([CH2:16][C@@H:17]([O:28]S(C)(=O)=O)[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:33])[CH2:10][CH2:9]1)[CH3:7].[CH2:35](O)[CH2:36][OH:37].N1C=CC=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:35][CH2:36][OH:37])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:33])[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: OCCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 120 °C
Yield: 37 %

Procedure:
A pressure vessel (250 mL flask) containing the compound of Example 1A (10.0 g, 20 mmol) was charged with ethylene glycol (20 mL) and pyridine (4 mL) at ambient temperature, sealed and then heated at 120° C. for 4 hours. The reaction was cooled to ambient temperature, diluted with EtOAc (50 mL), and quenched with 1N HCl (30 mL). The layers were separated and the organic layer was washed with 1N HCl (2×30 mL), dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10%—>40% acetone/hexanes) provided the title compound (3.5 g, 37%). MS (ESI) m/e 484 (M+NH4)+
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21].Cl>ClCCl>[Br:16][CH2:17][CH2:18][CH2:19][C:20]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)CCCBr
Reactant: OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl alcohol (1 mL) and triethylamine (2.69 mL) in dichloromethane (15 mL) was added 4-bromobutyryl chloride (1.68 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=8/1) to give benzyl 4-bromobutyrate (2.45 g). To a solution of 3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (0.17 g) in acetone (3 mL) were added cesium carbonate (0.16 g), benzyl 4-bromobutyrate (0.1 g) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature for 2 days. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1−3/1) to give 1-(3-benzyloxycarbonylpropyl)-3-(β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (0.14 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2-dichloromethane/methanol=15/1) to give the title compound (95 mg).
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:31][O:32][C:33](=[O:42])[CH2:34][C:35]1([CH2:38][CH2:39][CH2:40][NH2:41])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:41][CH2:40][CH2:39][CH2:38][C:35]2([CH2:34][C:33]([O:32][CH3:31])=[O:42])[CH2:36][CH2:37]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reactant: COC(=O)CC1(CCCN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1(CCCNC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)CC1
Temperature: 0 °C

Procedure:
A solution of 591 mg (1.51 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxa-diazin-4-yl)methyl]phenyl}acetic acid (enantiomer 2), 376 mg (1.81 mmol) of methyl[1-(3-amino-propyl)cyclopropyl]acetate hydrochloride, 859 mg (2.26 mmol) of HATU and 1 ml of N,N-diiso-propylethylamine in 10 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the mixture was poured into ice-water, the phases were separated and the aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, and, after filtration, the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by preparative RP-HPLC. This gave 233 mg (0.43 mmol, 28.5% of theory) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][CH2:17][CH2:16][C:15](=[O:22])[C:14]=3[C:13]=2[C:23]([OH:25])=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][Mg]Br>C(OCC)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][CH2:17][CH2:16][C:15]([OH:22])([CH3:26])[C:14]=3[C:13]=2[C:23]([OH:25])=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=C1CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(C(=O)O)c21
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(C(=O)O)c21
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A mixture of Example 103B (40 mg, 0.11 mmol) in diethyl ether (3 mL) and THF (2 mL) was treated with methylmagnesium bromide (3M solution in diethyl ether, 0.11 mL), stirred at 45° C. for 2 hours, quenched with saturated NH4Cl, and partitioned between diethyl ether and brine. The organic phase was dried (Na2SO4), filtered, concentrated, and purified by reverse-phase HPLC to provide the desired product. MS (ESI) m/e 378 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 12.18 (br s, 1H), 8.5 (s, 1H), 7.75 (m, 2H), 7.52 (m, 2H), 7.32 (d, 1H), 6.85 (d, 1H), 2.56 (m, 2H), 1.82-1.73 (m, 1H), 1.72-1.61 (m, 1H), 1.53-1.37 (m, 2H), 1.33 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[S:16]([C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][N:27]=1)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:32][C:31]4[C:26]([S:16]([C:19]5[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=5)(=[O:18])=[O:17])=[N:27][CH:28]=[CH:29][CH:30]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)c2ncccc2N)cc1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)c2ncccc2NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 2-tosylpyridin-3-amine (50 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 436.5. Found 437.1 (M+1)+. Retention time 3.16 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:18](Cl)(=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22]>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCNCC2)c2ccccc2n1
Reactant: CC/C=C/C(=O)Cl
Solvent: ClCCl
Product: CC/C=C/C(=O)N1CCN(c2cc(C)nc3ccccc23)CC1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
2-Methyl-4-piperazin-1-yl-quinoline (113.7 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (1 ml), TEA (77 μl, 0.5 mmol) followed by (E)-pent-2-enoyl chloride (65 mg, 0.55 mmol dissolved in 1 ml anhydrous dichloromethane) were added and the mixture was shaken for 15 minutes. The mixture was diluted with dichloromethane, washed with 5% sodium bicarbonate solution and water and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 143 mg of a solid (0.44 mmol, 88%). MS (ES): m/z=354.2 [M+1]+.
Reaction SMILES: C([C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])=[O:8])=[CH:5][C:4]=1[O:21][CH2:22][O:23][CH3:24])=O.[CH:25]([O:30][CH3:31])([O:28][CH3:29])OC.C(=O)([O-])O.[Na+].O>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:24][O:23][CH2:22][O:21][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:3]=1[CH:25]([O:28][CH3:29])[O:30][CH3:31])[C:7]([NH:9][C:10]([CH3:18])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:11])=[O:8]
Reactant: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C(OC)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
4-Formyl-3-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (3.12 g, 9.53 mmol) was dissolved in methanol (30 mL), and the solution was added with trimethyl orthoformate (2.09 mL, 19.1 mmol) and p-toluenesulfonic acid monohydrate (16.4 mg, 0.0952 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 3-methoxymethoxy-4-dimethoxymethyl-N-(1-methyl-1-phenylethyl)benzamide (3.61 g, yield 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH:9]([C:11](=[O:32])[NH:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]([C:20]#[C:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[N:14]=1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:34]N1C(=O)CCC1=O>C(#N)C>[C:1]([O:5][C:6](=[O:33])[N:7]([CH:9]([C:11](=[O:32])[NH:12][C:13]1[CH:18]=[C:17]([Br:19])[C:16]([Cl:34])=[C:15]([C:20]#[C:21][Si:22]([CH:23]([CH3:24])[CH3:25])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[N:14]=1)[CH3:10])[CH3:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C(=O)Nc1cc(Br)cc(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Solvent: CC#N
Product: CC(C(=O)Nc1cc(Br)c(Cl)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A mixture of (1-{4-Bromo-6-[(triisopropylsilanyl)-ethynyl]-pyridin-2-ylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester C1 (50 mg, 930 μmol), N-chlorosuccinimide (12 mg, 0.90 mmol) and ACN (1 ml) is stirred at 50° C. for 17 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 11 mg (21%). HPLC-MS: M+H=574/572; tR=2.04 min (METHOD—1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:3]=1.[CH3:28][O:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].C(NC(C)C)(C)C>O1CCOCC1>[CH3:28][O:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1Cl
Reactant: COc1ccc(CN)c(OC)c1
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: COc1ccc(CNc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2[N+](=O)[O-])c(OC)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
15.00 g (38.99 mmol) of the compound from example 79A were dissolved in 200 ml of dioxane, 6.98 g (40.94 mmol) of 2,4-dimethoxybenzylamine and 5.54 g (42.88 mmol) of N,N-diisopropylamine were added and the mixture was stirred at 85° C. for 1 h. After cooling, the mixture was filtered and the filtrate was concentrated on a rotary evaporator and the residue was dried under high vacuum. The residue was crushed with a mortar and pestle, stirred with 250 ml of water, filtered off with suction and dried under high vacuum. 19.96 g (89% of theory) of the title compound were obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH:22]=[CH:23][O:24][CH3:25])C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:25][O:24][CH2:23][CH2:22][CH2:21][C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: COC=CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COCCC[C@H]1CNCCN1

Procedure:
Add 20% Pd(OH)2/C (2.15 g) to (S)-1,4-dibenzyl-2-(3-methoxy-allyl)-piperazine (3.382 g, 10.05 mmol) in ethanol (100 mL) and under hydrogen atmosphere at 40° C. over night. Filter to give the title compound: mass spectrum (m/e):159.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[C:5]2[N:6]=[C:7]([CH3:31])[C:8]([C@H:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=[C:9]([C:10]3[C:11]([CH3:21])=[C:12]4[C:17](=[C:18]([F:20])[CH:19]=3)[O:16][CH2:15][CH2:14][CH2:13]4)[N:4]2[N:3]=1.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)=[C:34]=[O:35].CCN(C(C)C)C(C)C>C1COCC1>[C:27]([O:26][C@@H:22]([C:8]1[C:7]([CH3:31])=[N:6][C:5]2[N:4]([N:3]=[C:2]([NH:1][C:34]([NH:33][C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)=[O:35])[CH:32]=2)[C:9]=1[C:10]1[C:11]([CH3:21])=[C:12]2[C:17](=[C:18]([F:20])[CH:19]=1)[O:16][CH2:15][CH2:14][CH2:13]2)[C:23]([OH:25])=[O:24])([CH3:28])([CH3:29])[CH3:30]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Cc1nc2cc(N)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c4cc(F)c5c(c4C)CCCO5)n3n2)cc1

Procedure:
A mixture of Example 1 (22 mg, 0.050 mmol), 1-isocyanato-4-methylbenzene (7.28 mg, 0.055 mmol), Hunig's base (0.026 mL, 0.149 mmol) in THF (2 mL) was stirred at rt for 16 h. It was then concentrated and purified by prep HPLC (TFA/MeOH). The fractions were combined and adjusted pH=6 using 1N NaOH. The residue was adjusted pH=3-4 by adding 1-2 drops of 1N HCl. It was then extracted with EtOAc, dried, filtered and concentrated to obtained Example (18 mg, 60%) as light yellow solid. LCMS (M+H)=576.31.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][NH2:13]>O>[NH:12]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[NH2:13]
Reactant: NN
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Solvent: O
Product: NNc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A stirred solution of 4-chlorobenzenesulfonamide (38.33 g, 200 mmol) and anhydrous hydrazine (31.4 mL, 1.0 mol) was heated at reflux for 30 hours. After cooling to room temperature, the mixture was poured into water (500 mL) with swirling. The resulting precipitate was collected by filtration, washed thoroughly with water several times, air-dried, and dried under vacuum to give the title compound (35.5 g, 95% yield) as a white solid. Mp 169-171° C. 1H NMR (300 MHz, THF-d8) δ 7.59 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 6.62 (br, 1H), 5.99 (br, 2H), 3.87 (br, 2H). Mass spectrum (API-TIS) m/z 188 (MH+).