Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl.O>[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:23][CH2:24][N:25]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:26][CH2:27]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32]
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(S(C)(=O)=O)CC4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.1 g, 0.215 mmol, Preparation #K.1) and TEA (0.141 g, 1.4 mmol, Sd Fine Chem) in DCM (10 mL) was added methane sulfonyl chloride (0.032 g, 0.28 mmol, Spectrochem). The reaction mixture was slowly warmed to RT and stirred for about 0.5 h. The reaction mixture was diluted with water (10 mL) and the product extracted with DCM (2×20 mL). The combined organic layers were washed with water (1×25 mL) followed by brine (1×50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude material obtained was purified using silica gel column chromatography eluted in 60% EtOAc-hexane. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(methylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide as light pale yellow solid 0.065 g (55%): 1H NMR (400 MHz, DMSO): δ 9.501-9.469 (t, J=6.4 Hz, 1H), 8.144 (s, 1H), 7.179-7.135 (m, 2H), 6.901-6.890 (m, 1H), 4.730-4.692 (m, 1H), 4.483-4.467 (d, J=6.4 Hz, 2H), 3.815 (s, 3H), 3.617-3.587 (d, J=12 Hz, 2H), 3.517-3.489 (m, 2H), 2.848 (s, 3H) 2.755 (s, 3H), 2.699-2.639 (m, 2H), 1.896-1.864 (m, 1H), 1.740-1.711 (m, 2H), 1.323-1.236 (m, 2H). LC/MS (Table 1, Method c) Rt=4.71 min MS m/z: 506 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:12]/[C:13](/[CH3:17])=[CH:14]\[C:15]#[N:16].C([O-])(O)=O.[Na+]>CC(O)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[NH:12][C:7]([CH3:6])=[C:8]3[C:9]#[N:1])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: C/C(N)=C/C#N
Reactant: O=Cc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc3[nH]ncc3c2)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
A mixture of 1H-indazole-5-carboxaldehyde from Synthetic Preparation 1 (447 mg, 3.1 mmol) and 3-aminocrotononitrile (526.4 mg, 6.41 mmol) in HOAc (10 mL) was kept at 110° C. for 1.5 hr, after which it was cooled to rt. The reaction was treated with NaHCO3 (sat.) to pH 10, and extracted with EtOAc. The organic phases were combined, washed with brine, and dried. Concentration followed by purification with flash chromatography afforded 1,4-dihydro-4-(1H-indazol-5-yl)-2,6-dimethyl-3,5-pyridinedicarbonitrile (370 mg, 44%) (Cpd. No. 80, Table 2). 1H-NMR (400 MHz, CDCl3): δ=8.07 (s, 1H), 7.64 (s, 1H), 7.53 (d, 1H), 7.35 (d, 1H), 4.48 (s, 1H), 2.03 (s, 6H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]3/[C:16](=[O:25])[NH:17][C:18]4[C:23]/3=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)/[CH:9]=2)=[CH:4][CH:3]=1.[CH:26]([B-](F)(F)F)=[CH2:27].[K+].C(N(CC)CC)C.O>C(O)(C)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]1([CH3:14])[O:11]/[C:10](=[C:15]2/[C:16](=[O:25])[NH:17][C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)/[CH:9]=[C:8]1[C:5]1[CH:6]=[N:7][C:2]([CH:26]=[CH2:27])=[CH:3][CH:4]=1
Reactant: C=C[B-](F)(F)F
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: C=Cc1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)ccc43)OC2(C)C)cn1
Temperature: 76 °C

Procedure:
A mixture of 3-[4-(6-chloro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-6-fluoro-1.3-dihydro-indol-2-one (60 mg, 0.17 mmol), potassium vinyltrifluoroborate (40 mg, 0.30 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with CH2Cl2, mg, 0.012 mmol) and triethylamine (60 mg, 0.59 mmol) in isopropanol/water (10 mL/5 mL) solution was heated at 76° C. under nitrogen for 2.5 hours. The reaction was cooled to room temperature and poured into 100 mL of water. The resulting precipitates were filtered, washed with water and dried in vacuo to give (3E)-3-[5,5-dimethyl-4-(6-vinylpyridin-3-yl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 50 mg, 85%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[C:15]([C:22]([NH2:24])=[O:23])=[N:16][CH:17]=[CH:18][C:19]=1[C:20]#[N:21]>>[C:20]([C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:22]([NH2:24])=[O:23])[C:14]=1[NH:13][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[O:3][CH2:1][CH3:2])#[N:21]
Reactant: N#Cc1ccnc(C(N)=O)c1N
Reactant: CCOc1ccccc1C(=O)Cl
Product: CCOc1ccccc1C(=O)Nc1c(C#N)ccnc1C(N)=O

Procedure:
The title compound was prepared from 2-ethoxybenzoyl chloride and 3-amino-4-cyanopyridine-2-carboxamide (Preparation 12), following the procedure of Preparation 7, and was obtained as a colourless solid (6.2%), m.p. 150-152° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[C:5]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[S:8][C:6]=2[N:7]=1.S(=O)(=O)(O)O.O.[CH2:29](O)[CH3:30]>>[CH2:29]([O:12][C:11]([C:9]1[S:8][C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[C:5]=2[CH:10]=1)=[O:13])[CH3:30]
Reactant: CCO
Reactant: Nc1nc(-c2c[nH]c3ccccc23)c2cc(C(=O)O)sc2n1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1cc2c(-c3c[nH]c4ccccc34)nc(N)nc2s1

Procedure:
The crude 2-amino-4-(1H-indol-3-yl)-thieno[2,3-d]pyrimidine-6-carboxylic acid was dissolved in ethanol (2 ml) and conc. sulphuric acid was added (5 drops). The solution was refluxed overnight before water was added and the volatiles were removed in vacuo. The aqueous solution was partitioned with 1M sodium hydrogen carbonate solution and ethyl acetate. The organics were combined, dried over sodium sulphate and evaporated to dryness. The pure compounds was obtained after preparative TLC as an off white coloured powder.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[Na+:6].[C:7]([OH:11])(=[O:10])C=C.C1(=O)OC(=O)C=C1.[OH-].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[Na]>>[C:7]([O-:11])(=[O:10])/[CH:3]=[CH:2]\[C:1]([O-:5])=[O:4].[Na+:6].[Na+:6]
Reactant: C=CC(=O)[O-]
Reactant: C=CC(=O)O
Agent: O=C1C=CC(=O)O1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
An aqueous sodium acrylate solution and an aqueous sodium maleate solution were prepared by neutralizing acrylic acid and maleic anhydride, respectively, with an aqueous sodium hydroxide solution. The aqueous solution polymerization of the two solutions was effected in the presence of ammonium persulfate at 100° C. for 5 h to obtain a dyeability-improving agent comprising sodium salt of the copolymer.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:10][N:11]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[O:2]=[C:3]1[C:8]2[C:9]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)=[N:10][N:11]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCOCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2nn(C3CCOCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a solution of 4-(4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (106 mg) in acetonitrile (10 mL) were added sodium iodide (82.0 mg) and chloro(trimethyl)silane (0.276 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (99.0 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C([Sn](CCCC)(CCCC)[C:59]([O:61][CH2:62][CH3:63])=[CH2:60])CCC.C(N(CC)CC)C>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]>[CH2:62]([O:61][C:59]([C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)=[CH2:60])[CH3:63]
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Product: C=C(OCC)c1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
A flask equipped with a reflux condenser and a nitrogen line was charged with 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 50, Steps A-B; 74.8 mg, 0.157 mmol), tri-O-tolylphosphine (9.6 mg, 0.031 mmol), and tris(dibenzylideneacetone)dipalladium (0) (14.4 mg, 0.015 mmol) Anhydrous DMF (2 mL), tributyl(1-ethoxyvinyl)tin (0.07 mL, 0.22 mmol) and triethylamine (0.03 mL, 0.22 mmol) were added to the flask, and the reaction mixture was degassed under nitrogen and stirred at 100° C. for 6 hours. The reaction mixture was cooled, diluted with excess water and extracted with DCM and EtOAc. The combined organics were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative thin-layer chromatography (silica, 5% MeOH/DCM as eluent) to afford 56.4 mg of desired product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N+:21]([O-])=O)=[CH:16][C:3]=1[C:4]([O:6][CH:7]([C:13]([CH3:15])=[CH2:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5].[NH4+].[Cl-]>O1CCCC1.[Zn]>[Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([NH2:21])=[CH:16][C:3]=1[C:4]([O:6][CH:7]([C:13]([CH3:15])=[CH2:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5]
Reactant: C=C(C)C(OC(=O)c1cc([N+](=O)[O-])c(F)cc1Cl)C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C(C)C(OC(=O)c1cc(N)c(F)cc1Cl)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 2-(2-chloro-4-fluoro-5-nitrobenzoyl)oxy-3-methyl-3-butenoate (3.5 g, 10.13 mmoles) was added to a mixture of 2N NH4Cl (80 mL) in tetrahydrofuran (THF) (100 mL) at room temperature. The above mixture was cooled in an ice cold water bath and zinc dust (1.4 g, 21.4 mmoles) was added. The mixture was then stirred at room temperature for 2 hrs. The solid was removed by suction-filtration and the filtrate was concentrated under reduced pressure to give a black oily product. The crude product was subjected to a column silica gel chromatography and eluted with EtOAc/hexane (1:4) to give ethyl 2-(2-chloro-4-fluoro-5-aminobenzoyl)oxy-3-methyl-3-butenoate, 0.5 g (yield =45.6%), as an oily product. An 1H nmr (CDCl3) showed the desired product: δ 7.42 (d, 1H), 7.11 (d, 1H), 5.60 (s, 1H), 5.29 (s, 1H), 5.17 (s, 1H), 4.25 (q, 2H), 3.90 (br, 2H), 1.91 (s, 3H), 1.29 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[C:27]12[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:32]C(=O)O[C:28]2=[O:29]>CN(C)C1C=CN=CC=1.CN(C)C=O>[NH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=1[C:28]([O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1)=[O:29]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COc1ccc(S(=O)(=O)Nc2cccnc2Nc2ccc(O)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)Nc2cccnc2Nc2ccc(OC(=O)c3ccccc3N)cc2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 75.5 %

Procedure:
500 mg (1.35 mmol) of the compound of Example 6, 260 mg (1.59 mmol) of isatoic anhydride and 170 mg (1.39 mmol) of 4-dimethylaminopyridine were dissolved in 5 ml of dimethylformamide and the solution was stirred at 80° C. for 5 h. The solvent was distilled off under reduced pressure and ethyl acetate was added to the residue. A precipitate thus formed was recrystallized from ethanol to obtain 500 mg of the title compound.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[Cl:7][C:8]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])[CH:11]=[C:10]([N:24]2[CH2:29][CH2:28]S[CH2:26][CH2:25]2)[N:9]=1.N#N>CN1C(=O)CCC1.O>[Cl:7][C:8]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])[CH:11]=[C:10]([N:24]2[CH2:25][CH2:26][S:3](=[O:5])(=[O:2])[CH2:28][CH2:29]2)[N:9]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCSCC2)nc(Cl)c1C#N
Reactant: O=S([O-])OO
Agent: N#N
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(F)ccc1-c1cc(N2CCS(=O)(=O)CC2)nc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.1 %

Procedure:
Oxone® (56.18 g, 91.4 mmol) was added to a solution of 2-chloro-3-cyano-4-(4-fluoro-2-methylphenyl)-6-(thiomorpholino)pyridine (26.54 g, 76.3 mmol) in 200 mL of NMP in a 1000-mL, 3-necked flask (equipped with a teflon paddle stirrer, septum with teflon-coated thermocouple, dry N2 adapter). The mixture was stirred at 25° C. for 20 hours, and diluted with 800 mL of water. The resulting mixture was stirred at 25° C. for 30 minutes. The precipitate was filtered, washed several times with H2O, and dried to afford 29.30 g (101.1%) of 2-chloro-3-cyano-4-(4-fluoro-2-methylphenyl)-6-(1,1-dioxo-thiomorpholin-4-yl)pyridine as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]([CH2:16][CH2:17][O:18]COC)[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2].Cl.O>C(O)C>[C:1]([C:3]1[CH:15]=[C:14]([CH2:16][CH2:17][OH:18])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2]
Reactant: CCOC(=O)COc1ccc(CCOCOC)cc1C#N
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)COc1ccc(CCO)cc1C#N
Temperature: 70 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
To a solution of 2-hydroxy-5-(2-methoxymethoxyethyl)benzonitrile (496 mg) in N,N-dimethylformamide (5 ml) were added potassium carbonate (435 mg) and ethyl bromoacetate (292 μl), and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, and removal of the solvent under reduced pressure gave ethyl 2-[2-cyano-4-(2-methoxymethoxyethyl)phenoxy]acetate (619 mg). To a solution of the obtained ethyl 2-[2-cyano-4-(2-methoxymethoxyethyl)phenoxy]acetate (522 mg) in ethanol (5 ml) was added concentrated hydrochloric acid (20 μl), and the mixture was stirred for 2 hours at 70° C. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, and removal of the solvent under reduced pressure gave ethyl 2-[2-cyano-4-(2-hydroxyethyl)phenoxy]acetate (449 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([I:22])[CH:21]=1)[C:5]([NH:7][NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)=O>O=P(Cl)(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[O:18][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)=[N:8][N:7]=2)[CH:19]=[C:20]([I:22])[CH:21]=1
Reactant: COc1cccc(C(=O)NNC(=O)c2cc(I)cc(I)c2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2nnc(-c3cc(I)cc(I)c3)o2)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
3,5-Diiodo-N′-(3-methoxybenzoyl)benzohydrazide (5.0 g, 9.58 mmol) was suspended in POCl3 (50.0 ml) and heating was started. During heating white solid of starting materials dissolved into a clear solution (130° C.). The reaction was kept at 100° C. and the reaction was monitor by thin layer chromatography. After 5 h, the reaction mixture was brought to room temperature and was carefully dropped into ice-water (1000.0 ml). White solid precipitated out was collected by filtration and washed with water. After dried, the crude product was purified by silica gel column chromatography eluting with dichloromethane and ethyl acetate in 9.5:0.5 ratio. After evaporating solvent the white solid was recrystallized from acetone/water and finally dried under vacuum. Pure product was obtained as white solid in 3.4 g (70.8%) yield. 1H NMR (400 MHz, CDCl3, δ): 8.43 (dd, J1=1.6 Hz, J2=0.8 Hz, 2H), 8.23 (t, J=1.6 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.66 (m, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.12 (dd, J1=8.0 Hz, J2=2.4 Hz, 1H), 3.92 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3, δ): 165.06, 161.67, 159.98, 148.05, 134.63, 130.31, 126.95, 124.44, 119.44, 118.56, 111.66, 94.98, 55.59.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](O)[CH2:3][CH2:2]1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1.ClC1C=CC=CC=1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1
Reactant: OC1CCOc2ccccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: Clc1ccccc1
Solvent: c1ccccc1
Product: C1=Cc2ccccc2OC1

Procedure:
The compound 4 is refluxed under heating in a solvent such as benzene, chlorobenzene, toluene and xylene, in the presence of an acid catalyst such as p-toluenesulfonic acid and camphor sulfonic acid, using a Dean-Stark apparatus, while removing liberated water, or the hydroxyl group of compound 4 is activated into acetyl, trifluoroacetyl, methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl using acetic anhydride, trifluoroacetic acid, methanesulfonyl chloride, trifluoromethanesulfonyl chloride or p-toluenesulfonyl chloride and removing the activated hydroxy using a base such as triethylamine, N-methylmorpholine and diazabicycloundecene, particularly preferably diazabicycloundecene, to give a chromene (compound 5 wherein R1, R2 and R3 are as defined above).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[CH:12]([C:23]#[N:24])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[O:21][CH3:22].[BH4-].[Na+].Cl.N>CO.O.O.O.O.O.O.[Co](Cl)Cl>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[CH2:4][C:3](=[O:2])[NH:24][CH2:23][CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[O:21][CH3:22])[C:6]=2[CH:7]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1C(C#N)c1cccc(OC)c1OC
Agent: Cl[Co]Cl
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: COc1cccc(C2CNC(=O)Cc3ccc(Cl)cc32)c1OC
Temperature: 0 °C

Procedure:
118 mg of the compound from Example 27A (0.33 mol) are dissolved in 2.3 ml of methanol, and 156 mg of cobalt(II) chloride hexahydrate (0.66 mol) are added. While stirring at 0° C., 133 mg of sodium borohydride (3.51 mol) are added in portions over the course of 10 min. The reaction mixture is stirred at 0° C. for 30 min and at room temperature for 1 h. For working up, 7 ml of 1 N hydrochloric acid are added, and the mixture is stirred until a homogeneous solution results. The solution is made basic with concentrated ammonia solution and extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated in a rotary evaporator. The residue is dissolved in 10 ml of toluene and heated under reflux for 16 h. The solvent is removed in a rotary evaporator, and the residue is purified by preparative HPLC (eluent: acetonitrile/water, gradient 20:80→95:5). 42 mg (40% of theory) of the title compound are obtained.
Reaction SMILES: [ClH:1].NC(=O)[C@@H:4]([NH:11][C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])[C:5]1[CH:10]=CC=C[CH:6]=1.[CH3:34]C(C)(C)CN>>[ClH:1].[NH2:30][C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:11][CH2:4][C:5]([CH3:10])([CH3:34])[CH3:6])=[O:32])=[CH:18][C:19]=2[F:31])[CH:29]=[CH:28][N:27]=1
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Reactant: CC(C)(C)CN
Agent: Cl
Product: CC(C)(C)CNC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Yield: 31.6 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with 2,2-dimethylpropan-1-amine (Aldrich, 12 mg, 0.2 mmol) in a manner similar to that which is described in Step C of Example 1 to give N1-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-N3-neopentylmalonamide, hydrochloride salt (13 mg, 32% yield). 1H NMR (DMSO-d6) δ 13.34 (s, 1H), 10.69 (s, 1H), 8.08 (m, 1H), 7.96 (d, 1H, J=7.0 Hz), 7.87 (m, 3H), 7.44 (m, 2H), 6.70 (m, 1H), 6.13 (d, 1H, J=2.0 Hz), 3.34 (s, 2H), 2.91 (d, 2H, J=6.5 Hz), 0.84 (s, 9H); MS (ESI+) m/z 375.32 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C@H:10]([OH:32])[CH2:11][CH2:12][N:13]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][CH:25]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:33]1[C:43]2[CH:42]=[C:41]([C:44](O)=[O:45])[C:40]3[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=3[O:38][C:37]=2[CH:36]=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>>[CH2:3]([C@H:2]([NH:1][C:44]([C:41]1[C:40]2[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=2[O:38][C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:43]=2[CH:42]=1)=[O:45])[C@H:10]([OH:32])[CH2:11][CH2:12][N:13]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH3:31])=[CH:28][CH:29]=1)[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCc1ccc(CN(CC[C@@H](O)[C@@H](N)Cc2ccccc2)Cc2ccc(CC)cc2)cc1
Reactant: O=C(O)C1=Cc2ccccc2Oc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(CN(CC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)C2=Cc3ccccc3Oc3ccccc32)Cc2ccc(CC)cc2)cc1
Yield: 34.4 %

Procedure:
A solution of (2S,3R)-2-Amino-5-[bis-(4-ethyl-benzyl)-amino]-1-phenyl-pentan-3-ol (13 mg), salt with two trifluoroacetic acids, Dibenzo[b,f]oxepine-10-carboxylic acid (5 mg), HBTU (11 mg) and N-Ethyl-diisopropylamine (0.007 ml in 2 ml DCM) is stirred for 16 h at rt. The reaction mixture is evaporated and purified by flash chromatography with hexane/EtOAc/NH3=3/1/0.01. 4.7 mg of desired product are obtained.