Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@:6]12[CH2:24][C@H:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[C@@H:9]([CH2:10][CH2:11][CH2:12]1)[C:8](=[O:34])[NH:7]2)=[O:5])C.CO.O[Li].O.Cl>C1COCC1.O>[C:29]([O:28][C:26]([NH:25][C@@H:15]1[C:14](=[O:33])[N:13]2[C@@H:9]([CH2:10][CH2:11][CH2:12]2)[C:8](=[O:34])[NH:7][C@@:6]2([C:4]([OH:5])=[O:3])[C@@H:23]([CH2:24]2)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N2
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2CCCN2C1=O
Reaction time: 4 h
Yield: 98.5 %

Procedure:
The macrocyclic ester 1e from Step C (1.0 g, 2.1 mmol) was first dissolved in THF (3.0 mL), then methanol (3.0 mL) and water (1.5 mL) were added, followed by addition of LiOH—H2O (3 equiv). The resulted mixture was stirred for 4 h and concentrated to dryness. The residue was first re-dissolved in water (10 mL), then acidified with aqueous HCl (3.0 N, 2.2 mL, 6.6 mmol). The aqueous was extracted with EtOAc (3×15 mL). The combined organic layers was dried with sodium sulfate and concentrated to give the acid product 1f (0.93 g, 99%). MS (ESI+): 450 [M+1] (5) and 350 [M+1−100] (100).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:26][C:27]4[C:35]5[O:34][CH:33]=[CH:32][C:31]=5[CH:30]=[CH:29][C:28]=4[Cl:36])=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:37][CH3:38])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:36][C:28]1[CH:29]=[CH:30][C:31]2[CH:32]=[CH:33][O:34][C:35]=2[C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[C:17]([O:37][CH3:38])[CH:18]=2)[N:23]=[CH:22][N:21]=1
Reactant: COc1cc2c(Nc3c(Cl)ccc4ccoc34)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3c(Cl)ccc4ccoc34)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
A mixture of 7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(6-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline (0.4 g), trifluoroacetic acid (3 ml) and methylene chloride (12 ml) was stirred at ambient temperature for 3 hours. The mixture was evaporated and the residue was diluted with water. The mixture was basified to pH11 by the addition of 1 N aqueous sodium hydroxide solution and methylene chloride was added. The precipitate which was formed was collected by filtration, washed with water and dried under vacuum to give the title compound (0.195 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.55 (m, 2H), 2.0 (m, 2H), 2.25 (m, 1H), 2.95 (m, 2H), 3.4 (m, 2H), 4.05 (s, 3H), 4.2 (d, 2H), 7.1 (d, 1H), 7.4 (s, 1H), 7.55 (d, 1H), 7.8 (d, 1H), 8.05 (d, 1H), 8.2 (s, 1H), 8.85 (s, 1H), Mass Spectrum: M−H− 437.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1([F:32])[O:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([CH:30]=O)[C:23]=2[O:22]1>>[F:32][C:21]1([F:20])[O:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)[C:23]=2[O:22]1
Reactant: O=Cc1cccc2c1OC(F)(F)O2
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC1(F)Oc2cccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2O1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2,2-difluoro-1,3-benzodioxole-4-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2,2-difluoro-1,3-benzodioxol-4-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C([Li])CCC.[CH:6](N1CCCCC1)=[O:7].Br[C:15]1[C:24]([CH3:25])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1.[Cl-].[NH4+]>O1CCCC1>[CH:6]([C:15]1[C:24]([CH3:25])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)=[O:7]
Reactant: O=CN1CCCCC1
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
22.2 mL (35.2 mmol) of n-butyl lithium (1.6 M in hexanes) was added. After 1 hours, a solution of 3.95 mL (35.5 mmol) of N-formylpiperidine was added to a solution of 5 g (17.8 mmol) of 2-bromo-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 50 mL of tetrahydrofuran, cooled in a dry ice/acetone bath. After 30 minutes 30 mL of saturated aqueous ammonium chloride was added to the reaction mixture. The reaction mixture was warmed to room temperature and extracted with ethyl acetate. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with gradient elution (hexane-10% ethyl acetate/hexane) to provide 3.5 g (85%) of 2-formyl-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (m.p.: 82.4-84.1° C.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=1.CCN(CC)CC.[CH2:30]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41](=[O:53])[C@@H:42]([NH2:52])[CH2:43][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:37][CH2:36]1)=[O:34])[CH3:31]>C(#N)C.O>[CH2:30]([O:32][C:33]([N:35]1[CH2:36][CH2:37][N:38]([C:41](=[O:53])[C@@H:42]([NH:52][C:20]([C:10]2[CH:9]=[C:8]([Cl:7])[N:13]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:11]=2)=[O:22])[CH2:43][CH2:44][C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:39][CH2:40]1)=[O:34])[CH3:31]
Reactant: O=C(O)c1cc(Cl)nc(-c2ccccc2)n1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under argon, oxalyl chloride (0.843 ml) was added to a solution of 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid (1.17 g) in acetonitrile (50 ml) and it was refluxed for 3 h. The reaction mixture was cooled down to 0° C. and NEt3 (2.07 ml) was added, followed by 4-((S)-2-amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester (1.7 g) in 10 ml acetonitrile. It was stirred at RT under argon for 1 h. Water was added and the reaction mixture was extracted with EA. The org. layers were dried (Na2SO4) and evaporated off. Purification by column chromatography (EA/Hept 1/3 to 1/2) offered 1.61 g of the desired compound.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:26]2[N:27]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:25]=2[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccccc2F)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(2-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester by the procedure of Example 26. 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, 1H, J=3.52 Hz, 1.17 Hz), 7.36 (dd, 1H, J=5.08 Hz, 1.17 Hz), 7.21 (d, 3H, J=8.60 Hz), 7.12-6.95 (m, 3H), 6.83 (d, 3H, J=8.60 Hz), 4.19 (t, 2H, J=6.65 Hz), 3.27 (d, 1H, J=14.08 Hz), 3.17 (d, 1H, J=14.08 Hz), 2.95 (t, 2H, J=6.65 Hz), 2.35 (s, 3H), 1.41 (s, 3H). HRMS (ES+) m/z exact mass calcd for C26H25FNO5S 482.1437, found 482.1454.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([OH:11])[CH:8]([OH:10])[CH3:9].[C:12]([O:16][O:17][C:18]([CH2:20][CH2:21][C:22](Cl)=[O:23])=[O:19])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:18]([O:17][O:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:19])[CH2:20][CH2:21][C:22]([O:11][CH2:7][CH:8]([OH:10])[CH3:9])=[O:23]
Reactant: CC(C)(C)OOC(=O)CCC(=O)Cl
Reactant: CC(O)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(O)COC(=O)CCC(=O)OOC(C)(C)C
Temperature: 10 °C
Reaction time: 3.5 h
Yield: 97.5 %

Procedure:
A 250 mL 3-neck round-bottom flask, equipped with a magnetic stirrer, a thermometer, a cold water condenser and an addition funnel, was charged with 50 mL of methylene chloride, 4.2 g (0.052 mole) of pyridine and 19.0 g (0.25 mole) of 1,2-propanediol. The resulting vigorously stirred solution was cooled to 10° C.. and to it was slowly added a solution of 11.5 g (0.050 mole) of 94% 3-(t-butylperoxycarbonyl)propionyl chloride in 10 mL of methylene chloride over a period of 20 minutes. The reaction mass was warmed to 20° C.. and stirred at 20° C.. for 210 minutes. The reaction mixture was washed at 10°-15° C.. with 50 mL of aqueous 5% HCl solution and then twice with 100 mL portions of 5% aqueous NaHCO3 solution. The methylene chloride solution was then dried over 10% by weight of anhydrous MgSO4 and, after separation of the spent desiccant by filtration, the solvent was removed in vacuo leaving 12.4 g (100% of theory, uncorrected) of a straw-color liquid. An infrared spectrum of the product showed a strong OH band, a strong and broad carbonyl band at ca. 1720-1780 cm-1 and a strong --OO-- band at ca. 850 cm-1. The product had a peroxyester Act[O] content of 6.29%. Based on a theoretical Act[O] of 6.45% for the desired title product, the assay was 97.5% and the corrected yield was 97.5%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2)([O-])=O.O1CCCC1.O.NN>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.CO>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:4]=2[NH2:1]
Reactant: O=[N+]([O-])c1cccc2cc(-c3nccs3)[nH]c12
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc2cc(-c3nccs3)[nH]c12
Yield: 90.7 %

Procedure:
A mixture of 7-nitro-2-(1,3-thiazol-2-yl)-1H-indole (2.21 g), iron(III) chloride hexahydrate (0.12 g), activated carbon (1.20 g), tetrahydrofuran (10 mL) and methanol (10 mL) was heated under reflux for 20 min. To the reaction mixture was added hydrazine monohydrate (2.70 g) over 15 min while heating under reflux. The reaction mixture was heated under reflux for 2 hr, filtrated, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (1.76 g, yield 90%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). melting point 173-174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:20])[CH:9]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[C:4]([CH3:21])[CH:3]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:20])[CH:9]2[CH2:12][NH:11][CH2:10]2)=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(F)ccc1N(C)C1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: Cc1cc(F)ccc1N(C)C1CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To an ice cooled solution of tert-butyl 3-((4-fluoro-2-methylphenyl)(methyl)amino)azetidine-1-carboxylate (D33) 8170 mg, 0.577 mmol) in dichloromethane (1 ml) trifluoroacetic acid/dichloromethane (3/1 ml) was added and the resulting mixture was stirred at room temperature for 1 h. Solvents were evaporated under vacuo and the residue was purified by SPE-SCX cartridge (10 g) eluting with methanol and 2N ammonia in methanol. Ammonia fractions were evaporated in vacuo to afford the title compound (D56) (110 mg)
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)C.[C].[Pd]>[NH2:11][C:10]1[C:2]([CH3:1])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)cccc1C(=O)O
Yield: 105.5 %

Procedure:
2-Methyl-3-nitrobenzoic acid (5 g) is dissolved in ethanol (50 ml) and the mixture is subjected to catalytic reduction with 5% palladium carbon (0.25 g) at room temperature for 5 hours. The catalyst is removed by filtration, and the filtrate is concentrated to give 3-amino-2-methylbenzoic acid (4.4 g).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][N:4]=[C:5]([NH2:33])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:32])[CH2:20][NH:21][C:22](OCC2C=CC=CC=2)=[O:23])[N:8]=1.[OH-].[K+].[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42]>CCO>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42].[OH:23][C:22]1[N:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:9]2[N:8]=[C:7]([NH:6][C:5]([NH2:33])=[N:4][CH2:3][C:2]([F:35])([F:34])[F:1])[CH:12]=[CH:11][N:10]=2)[C:19]([OH:32])=[CH:20][N:21]=1
Reactant: NC(=NCC(F)(F)F)Nc1ccnc(CCCCCNC(=O)CNC(=O)OCc2ccccc2)n1
Agent: O=C(O)/C=C\C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=NCC(F)(F)F)Nc1ccnc(CCCCCn2c(O)cnc2O)n1
Yield: 64 %

Procedure:
To 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[5-(2-benzyloxycarbonylaminoacetylamino)pentyl]pyrimidine (0.2 g.) was added 13 ml. of a solution of potassium hydroxide (0.096 g.) in EtOH (50 ml.), and the mixture was heated under reflux for 35 minutes. The mixture was evaporated in vacuo, a few drops of aqueous HOAc was added to the residue, followed by sodium bicarbonate solution until pH 7 was obtained. The mixture was extracted with EtOAc, the extract dried and evaporated to give a pale yellow solid. This was dissolved in a small volume of hot EtOH and a solution of maleic acid (0.05 g.) in EtOH (0.5 ml.) added. There was obtained 2,4-dihydroxy-3-(5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]pentyl)imidazole maleate (0.13 g.), m.p. 172°-174°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:21])=[CH:8][CH:9]=2)[N:4]=1.[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:21])=[CH:8][CH:9]=2)[N:4]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=c1c2ccc(F)cc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2cc(F)ccc2c(=O)n1-c1ccccc1Cl
Yield: 43.6 %

Procedure:
Prepared according to Procedure C using Intermediate 2c (100 mg, 0.310 mmol), adenine (46 mg, 0.340 mmol), K2CO3 (47 mg, 0.340 mmol), and DMF (1 mL). The crude product was recrystallized from EtOH to provide 57 mg of a beige solid (44%), mp 216.8-217.2° C. 1H NMR (DMSO-d6) δ: 8.22 (dd, J=6.3, 8.7 Hz, 1H); 8.05 (s. 1H); 8.03 (s, 1H); 7.78-7.80 (m, 2H); 7.61-7.64 (m, 2H); 7.46 (dt, J=2.1, 8.6 Hz, 1H); 7.32 (d, J=9.8 Hz, 1H); 7.22 (s, 2H); 5.13 (d, J=17 Hz, 1H); 4.95 (d, J=17 Hz, 1H). 13C NMR (DMSOd6) ppm: 166.1 (d, J=253 Hz), 159.6, 155.8, 152.5, 149.7, 148.6 (d, J=14 Hz), 141.4, 132.8, 131.8, 131.6, 130.8, 130.5, 129.8 (d, J=11 Hz), 129.0, 118.1, 117.4, 116.2 (d, J=24 Hz), 112.7 (d, J=22 Hz), 44.6. MS (ES): m/z 422.0 (M+). Anal. calcd. for C20H13ClFN7O.0.1H2O(0.15KCl: C, 55.25; H, 3.06; Cl, 9.38; N, 22.55. Found: C, 55.13; H, 2.92; Cl, 9.12; N, 22.30.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][O:6][CH2:5][C@:4]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[N:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][C:25](Br)=[CH:24]4)[CH:14]=[CH:15][C:16]=2[F:17])([CH:8]([F:10])[F:9])[N:3]=1.O.[CH3:31][N:32](C=O)C>[Zn].[C-]#N.[C-]#N.[Zn+2].[Zn](OC(C)=O)OC(C)=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[CH2:7][O:6][CH2:5][C@:4]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[N:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][C:25]([C:31]#[N:32])=[CH:24]4)[CH:14]=[CH:15][C:16]=2[F:17])([CH:8]([F:10])[F:9])[N:3]=1
Reactant: NC1=N[C@@](c2cc(Nc3nccc4cc(Br)cnc34)ccc2F)(C(F)F)COC1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)O[Zn]OC(C)=O
Solvent: O
Product: N#Cc1cnc2c(Nc3ccc(F)c([C@]4(C(F)F)COCC(N)=N4)c3)nccc2c1
Temperature: 25 °C

Procedure:
[3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-(3-bromo-[1,7]naphthyridin-8-yl)-amine (150 mg, 0.32 mmol), Zn powder (0.842 mg, 0.013 mmol), Zn(CN)2 (22.7 mg, 0.193 mmol), Zn(OAc)2 (2.36 mg 0.013 mmol), 1,1′-Bis-(diphenylphosphino)-ferrocene (0.54 mg, 0.001 mmol) and Tris(dibenzylideneacetone)-dipalladium (0) (0.29 mg 0.0003 mmol) were dissolved in DMF (4 ml) and water (0.04 ml) and heated under inert conditions to 95° C. for 2 h and then allowed to cool to rt. The reaction was quenched with water (10 ml) and NH3 (25%, 1 ml) and extracted with EtOAc (25 ml). The aq phase was extracted another 3× with EtOAc. The combined organic layer was washed with NaHCO3 solution and brine, treated with MgSO4 and filtered. The filtrated was concentrated and purified by column chromatography (silica gel; hexane/0-15% EtOAc) to give the desired product as a yellow solid.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH3:59][O:60][C:61]1[CH:62]=[C:63]([CH:67]=[CH:68][C:69]=1[O:70][CH3:71])[C:64](Cl)=[O:65]>>[CH3:59][O:60][C:61]1[CH:62]=[C:63]([CH:67]=[CH:68][C:69]=1[O:70][CH3:71])[C:64]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:65]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC)c(OC)c4)cc3)cc2C1=O
Yield: 87 %

Procedure:
The compound of example 141 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3,4-dimethoxy benzoyl chloride.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=2)[CH:9]=[CH:8][CH:7]=1.[C:22]([C:24](=[CH2:28])[C:25](O)=[O:26])#[N:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][C:10]2[N:11]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:25](=[O:26])[C:24]([C:22]#[N:23])=[CH2:28])[CH:7]=[CH:8][CH:9]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: Cn1cc(Br)cc(Nc2cccc(OCCN)n2)c1=O
Reactant: C=C(C#N)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C#N)C(=O)NCCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
A mixture of 3-(6-(2-aminoethoxyl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 103a (480 mg, 1.42 mmol), 2-cyanoacrylic acid (790 mg, 2.84 mmol), DIPEA (1.2 mL, 7.12 mmol) and HATU (810 mg, 2.13 mmol) in DCM (10 mL) was stirred at rt for 16 h. The reaction mixture was concentrated and purified by silica gel chromatography (PE/EA=1/2) to give N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethyl)-2-cyanoacrylamide 117a (400 mg, 67%) as green solid. ESI-LCMS: m/z=420.0
Reaction SMILES: [CH3:1][C:2]1([C:5]#[C:6][C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[NH:16]C(=O)CCC)[CH2:4][CH2:3]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][C:2]1([C:5]2[NH:16][C:8]3[C:7]([CH:6]=2)=[CH:12][C:11]([N+:13]([O-:15])=[O:14])=[CH:10][CH:9]=3)[CH2:4][CH2:3]1
Reactant: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1C#CC1(C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(c2cc3cc([N+](=O)[O-])ccc3[nH]2)CC1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A mixture of N-[2-(1-methyl-cyclopropylethynyl)-4-nitro-phenyl]-butyramide (1.3 g, 4.6 mmol) and TBAF (2.4 g, 9.2 mmol) in THF (20 mL) was heated at reflux for 24 h. The mixture was cooled to room temperature and poured into ice water. The mixture was extracted with CH2Cl2 (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to afford 2-(1-methylcyclopropyl)-5-nitro-1H-indole (0.70 g, 71%). 1H NMR (400 MHz, CDCl3) δ 8.56 (brs, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.01 (dd, J=2.4, 8.8 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 6.34 (d, J=1.6 Hz, 1H), 1.52 (s, 3H), 1.03-0.97 (m, 2H), 0.89-0.83 (m, 2H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([CH3:9])[CH3:8].[OH-].[Na+]>C1COCC1>[CH:7]([N:10]1[CH2:11][CH2:12][N:13]([C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:14][CH2:15]1)([CH3:9])[CH3:8]
Reactant: CC(C)N1CCN(c2ccc(-c3ccc(C#N)cc3)cn2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2ccc(-c3ccc(CN)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A mixture of a 1 M solution of LiAlH4 in THF (1.1 mL, 1.1 mmol) and dry THF (10 mL) was placed under an atmosphere of nitrogen. A solution of 4-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)benzonitrile (306 mg, 1.0 mmol, prepared as described in Example 10) in dry THF (5 mL) was added dropwise. The reaction mixture was then stirred at rt for 3 h and quenced with 1 N NaOH. The mixture was filtered and the volatiles were removed. The residue was re-evaporated with THF to give 310 mg (100%) of 4-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl]benzylamine.
Reaction SMILES: NC1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1.[H-].[Li+].IC.[CH3:24][N:25]([CH:27]=O)[CH3:26]>>[CH3:26][N:25]([CH3:24])[C:27]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1
Agent: [H-]
Agent: [Li+]
Solvent: CI
Product: CCOC(=O)c1cc(N(C)C)n(Cc2ccccc2F)n1
Reaction time: 1 h

Procedure:
1.96 g of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate 1-8-1 (7.46 mmol, 1.0 eq.) were dissolved in 9.8 mL of dry DMF. Under nitrogen atmosphere 237 mg of lithium hydride (29.8 mmol, 4.0 eq.) were added at 0° C. bath temperature. The mixture was stirred for one hour at this temperature. Then 3.7 mL of iodomethane (59.6 mmol, 8.0 eq.) were added at 0° C. bath temperature. The reaction mixture was stirred then for three days at rt. After the addition of ice it was stirred for 30 minutes and then extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to provided 1.35 g (4.49 mmol, 60%) of analytically pure target compound.