Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:13])[CH2:10][C:11]#[N:12].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:33][C:32](=[O:34])[N:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:30]=2)=[CH:25][CH:24]=1>C(O)C>[NH2:12][C:11]1[O:34][C:32]2[N:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:30]=[C:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=3)[C:33]=2[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[C:9]#[N:13]
Reactant: N#CCC#N
Reactant: COc1ccc(C2=NN(c3ccccc3)C(=O)C2)cc1
Reactant: O=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-c2nn(-c3ccccc3)c3c2C(c2ccccc2)C(C#N)=C(N)O3)cc1
Reaction time: 0.02 h
Yield: 57.5 %

Procedure:
A mixture of benzaldehyde (290 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-5(4H)-one (764 mg, 2.87 mmol, 1 equ.). The reaction mixture was concentrated after 19 h and washed with ethanol and hexanes, re-crystallized from ethanol, and washed with hexanes and ethanol to give 6-amino-3-(4-methoxyphenyl)-1,4-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (695 mg, 1.65 mmol, 58%) as a white solid. 1H-NMR (400 MHz) DMSO: 7.94-7.92 (d, 2H), 7.58-7.53 (m, 2H), 7.41-7.37 (t, 1H), 7.27-7.16 (m, 7H), 6.83-6.81 (d, 2H), 5.04 (s, 1H), 3.71 (s, 3H), 13C-NMR (100 MHz) DMSO: 159.5, 159.0, 146.6, 145.6, 144.5, 137.9, 129.8, 128.9, 128.3, 128.0, 127.3, 127.1, 125.1, 121.1, 120.3, 114.1, 97.5, 59.8, 55.5, 37.9; LC/MS-MS: 421.2→355.0 m/z; GS1 and GS2 at 30, DP=71, CE=33, CXP=24, tR=4.28 min.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[NH2:15][C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1.O=[C:24]([CH3:33])[CH2:25][C:26]([O:28][CH2:29][CH2:30][C:31]#[N:32])=[O:27]>C(O)C>[CH3:33][C:24]1[NH:15][C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=2[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:25]=1[C:26]([O:28][CH2:29][CH2:30][C:31]#[N:32])=[O:27]
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: Nc1cc[nH]c(=O)c1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: CCO
Product: CC1=C(C(=O)OCCC#N)C(c2cccc3c(=O)cc(C)oc23)c2c(cc[nH]c2=O)N1
Reaction time: 8 h

Procedure:
3.00 g (15.94 mmol) of the compound from Example 5A, 1.75 g (15.94 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] and 2.47 g (15.94 mmol) of 2-cyanoethyl 3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16, 798-802 (2006)] are dissolved in 60 ml of ethanol and stirred at the reflux temperature under argon overnight. The precipitated product is then filtered off, washed with ethanol and diethyl ether and dried under high vacuum. 2.30 g (35% of theory) of the title compound are obtained in the form of beige-colored crystals.
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]3[C:19](=[N:21][OH:22])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([CH2:23][C:24]([O:26]CC)=[O:25])[C:13]=2[CH3:29])=[CH:7][CH:6]=1.C(O)(=O)C>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]3[C:19](=[N:21][OH:22])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([CH2:23][C:24]([OH:26])=[O:25])[C:13]=2[CH3:29])=[CH:7][CH:6]=1
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c1CCCC2=NO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(Sc2ccc(Cl)cc2)c2c(n1CC(=O)O)CCCC2=NO
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
Aqueous sodium hydroxide (1M, 10 mL, 10 mmol) and water (20 mL) were added to a stirred suspension of ethyl [3-(4-chloro-phenylsulfanyl)-4-(hydroxyimino)-2-methyl-4,5,6,7-tetrahydro-1H-indol-1-yl]acetate (4.0 g, 10.2 mmol) and ethanol 40 mL) and the mixture was warmed up to 40° C. After 1.5 h at this temperature, the reaction mixture was allowed to cool to r.t. and held overnight. The suspension was reheated to 33° C. and acetic acid (1.7 mL, 29.7 mmol) added to the resulting solution. The mixture was allowed to cool to r.t., the solid product was collected by filtration, washed with water (2×20 mL), then dried under vacuum at 30° C. to provide the title compound as a solid; 2.94 g (79%); purity by HPLC 98.9 area %
Reaction SMILES: Br[C:2]1[C:3]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:4][N:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[C:6]=1[NH2:7].[CH3:21]B1OBOBO1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:17]([C:3]1[C:2]([CH3:21])=[C:6]([NH2:7])[N:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:4]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1cccc(C)c1-n1nc(C(C)(C)C)c(Br)c1N
Reactant: CB1OBOBO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C)c1-n1nc(C(C)(C)C)c(C)c1N
Temperature: 155 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of 4-bromo-3-tert-butyl-1-(2-methoxy-6-methylphenyl)-1H-pyrazol-5-amine (2.6 g, 7.68 mmol) in DMF (15 mL) was added methylboroxine (6.66 mL, 46.08 mmol), [1,1′-bis(diphenylphosphino)-butane]palladium (II) dichloride (481.97 mg, 0.80 mmol), and potassium carbonate (3.3 g, 23.04 mmol). The reaction mixture was stirred for 18 h at 155° C. The reaction was diluted with water (100 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 90% hexane/EtOAc, to afford the product (1.7 g, 77%) as a pure white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.24 (s, 9H), 1.96 (s, 3H), 1.99 (s, 3H), 3.71 (s, 3H), 4.25 (s, 2H), 6.85 (d, 1H), 6.94 (d, 1H), 7.23-7.29 (m, 1H). ES-MS m/z 274.2 (MH+); HPLC RT (min.) 1.78.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:20]3[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26]C(C)([O-])C.[K+].CI>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:20]3[CH2:24][CH2:23][C@@H:22]([O:25][CH3:26])[CH2:21]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N2CC[C@@H](O)C2)c2ccc(OCc3ccccc3)cc2n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CO[C@@H]1CCN(c2cc(C)nc3cc(OCc4ccccc4)ccc23)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
A suspension of 3.2 g (9.5 mmol) of (R)-1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-3-ol, product of example 86, in THF (275 ml) was treated at RT under nitrogen with 1.42 g (12.4 mmol) of potassium tert-butoxide. The suspension was stirred for 20 minutes at RT then 0.72 ml (11.4 mmol) of methyl iodide were added. After 25 minutes of stirring further 0.284 g (2.48 mmol) of potassium tert-butoxide were added followed by 0.144 ml (2.28 mol) of methyl iodide (10 minutes later) for completion of the reaction. Stirring was continued for 20 minutes, the reaction mixture was then concentrated in vacuo and the residue partitioned between water and AcOEt. The layers were separated the aqueous layer once extracted with AcOEt, the combined organic layers washed with brine, dried over magnesium sulphate and concentrated in vacuo to give 3.33 g (94.5%) (R)-7-benzyloxy-4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinoline as an orange viscous oil. ISP mass spectrum, m/e: 349.5 (M+1 calculated for C22H24FN2O2: 349).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10](O)=[O:11])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][CH:62]=1)[CH2:58][NH2:59]>C1COCC1>[CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:59][CH2:58][C:57]2[CH:60]=[CH:61][CH:62]=[C:55]([F:54])[CH:56]=2)=[O:11])=[C:8]([C:13]([F:15])([F:14])[F:16])[CH:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]=1)[CH3:2]
Reactant: NCc1cccc(F)c1
Reactant: CCSc1nc(N2CCOCC2)cc(C(F)(F)F)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSc1nc(N2CCOCC2)cc(C(F)(F)F)c1C(=O)NCc1cccc(F)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 26 %

Procedure:
To a solution of 170 mg (0.5 mmol) 2-(ethylsulfanyl)-6-morpholin-4-yl-4-(trifluoromethyl)-pyridine-3-carboxylic acid in THF (3 ml) were added 192 mg (0.5 mmol) HATU and 210 μl (1.5 mmol) NEt3 and the RM was stirred at 50° C. for 90 min. Then 69 μl (0.6 mmol) 3-fluorobenzylamine were added and stirring was continued at 50° C. for 5d. After cooling to RT the mixture was partitioned between water and EtOAc. The organic layer was separated, washed with a 4N aq. NH4Cl sol. and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexae/EtOAc 3:1) provided 57 mg (0.13 mmol, 26%) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-morpholin-4-yl-4-(trifluoromethyl)-pyridine-3-carboxylic acid amide (example 11). [M+H]+444.1.
Reaction SMILES: FC(F)(F)C(O)=O.C([Si](C)(C)[O:13][CH:14]([CH2:35][N:36]1[C:44](=[O:45])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]1=[O:46])[CH2:15][N:16]1[C:24]([C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[C:23]2[C:18]([N:19]([CH3:34])[C:20](=[O:33])[N:21]([CH3:32])[C:22]2=[O:31])=[CH:17]1)(C)(C)C.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[Cl:74][C:75]1[O:79][C:78]([CH:80]=O)=[CH:77][CH:76]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:74][C:75]1[O:79][C:78]([CH:80]2[C:17]3=[C:18]4[N:19]([CH3:34])[C:20](=[O:33])[N:21]([CH3:32])[C:22](=[O:31])[C:23]4=[C:24]([C:25]4[S:26][CH:27]=[C:28]([CH3:30])[N:29]=4)[N:16]3[CH2:15][CH:14]([CH2:35][N:36]3[C:37](=[O:46])[C:38]4[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:44]3=[O:45])[O:13]2)=[CH:77][CH:76]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CC(CN2C(=O)c3ccccc3C2=O)O[Si](C)(C)C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN2C(=O)c4ccccc4C2=O)OC3c2ccc(Cl)o2)n1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (0.032 ml, 0.421 mmol) was added to a solution of 6-(2-((tert-butyldimethyl silyl)oxy)-3-(1,3-dioxoisoindolin-2-yl)propyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (50 mg, 0.084 mmol) in toluene (1 ml) and the mixture was stirred for 30 mins. Bismuth triflate (27.6 mg, 0.042 mmol) and 5-chlorofuran-2-carbaldehyde (16.49 mg, 0.126 mmol) were added and the mixture stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml), saturated NaHCO3(aq) (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane, afforded the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][C:15]1[N:19]([CH2:20][CH3:21])[N:18]=[CH:17][CH:16]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[CH2:20]([N:19]1[C:15]([NH:14][C:2]2[C:3](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:16][CH:17]=[N:18]1)[CH3:21]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCn1nccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCn1nccc1Nc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A mixture of 2-chloro-5-nitrobenzoic acid (4.03 g, 0.02 mol), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol), DMF (25 ml), K2CO3 (2.76 g, 0.02 mol) and Cu(OAc)2H2O (0.5 g) is refluxed for 24 hours. The reaction mixture is cooled to room temperature, poured into ice waterl and acidified with acetic acid to a pH of 5. A solid forms which is collected by filtration and dried to afford 3.8 g (68%) of N-(1-ethylpyrazol-5-yl)-5-nitroanthranilic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([NH2:23])=[C:16]3[N:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1N=CN([C:29]([N:31]2[CH:35]=N[CH:33]=[CH:32]2)=[O:30])C=1.N1CC[C@H:38]([OH:41])C1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([NH:23][C:29]([N:31]4[CH2:32][CH2:33][C@H:38]([OH:41])[CH2:35]4)=[O:30])=[C:16]3[N:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)cc(Cl)c3)nc12
Reactant: O[C@H]1CCNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)cc(Cl)c3)nc12)N1CC[C@H](O)C1
Reaction time: 2 h
Yield: 187.3 %

Procedure:
To a DCM (0.6 mL) solution of (R)-5-(2-(3-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 11, Step A; 20 mg, 0.06 mmol), was added CDI (20 mg, 0.12 mmol) at ambient temperature in one portion. After stirring two hours, (S)-pyrrolidin-3-ol (16 mg, 0.18 mmol) was added in one portion. The reaction was stirred overnight before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a solid (50 mg, 83% yield). MS (apci) m/z=445.2 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:17]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)Br
Reactant: CCc1cnc(NCCc2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1ccc(CCNc2ncc(CC)cn2)cc1
Yield: 74.4 %

Procedure:
Alkylation of 4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}phenol (135 mg; 0.56 mmol) with ethyl 2-bromopropionate (0.18 ml; 1.39 mmol) as per general procedure C (conditions: 2 eq Cs2CO3, MeCN, 60C, 4 hr). provided ethyl 2-(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)propanoate (143 mg; 75% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH:15]([CH3:20])[C:16](=O)[O:17]C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][NH2:23]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:23][NH:22][C:16](=[O:17])[C:15]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NN
Solvent: Cc1ccccc1
Product: Cc1c(C2CCN(C(=O)OC(C)(C)C)CC2)[nH][nH]c1=O
Temperature: 25 °C

Procedure:
A solution of 419 mg (1.4 mmol) of 1-(tert-butoxycarbonyl)-4-(1,3-dioxo-3-methoxy-2-methyl-prop-1-yl)piperidine (from Step B) and 0.26 mL (8.4 mmol) of hydrazine in 5 mL of toluene was refluxed for 50 minutes. The reaction was cooled to rt and placed in the freezer overnight. After decanting the solvent, the white solid was triturated with Et2O to provide the title compound, which was used without further purification. 1H-NMR (500 MHz) δ 1.49 (s, 9H), 1.55–1.63 (m, 2H), 1.77–1.79 (m, 2H), 1.90 (s, 3H), 2.69–2.77 (m, 3H), 4.22 (m, 2H), 5.15–5.79 (br m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:46][CH3:47])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[C:20](/[CH:25]=[C:26](\[CH3:35])/[C:27]([NH:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])=[O:28])[CH:21]=[CH:22][C:23]=4[F:24])[CH:16]=3)[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.O.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[C:3]([O:46][CH3:47])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[C:20](/[CH:25]=[C:26](\[CH3:35])/[C:27]([NH:29][C:30]([CH3:33])([CH3:34])[CH2:31][OH:32])=[O:28])[CH:21]=[CH:22][C:23]=4[F:24])[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1c(F)cc(F)cc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(/C=C(\C)C(=O)NC(C)(C)CO)ccc3F)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cc(/C=C(\C)C(=O)NC(C)(C)CO)ccc3F)cc12
Temperature: 60 °C

Procedure:
A solution of 163 (40 mg) was taken in methanol (7 mL) and water (3 mL) was added potassium carbonate (20 mg). The reaction was heated to 60° C. for overnight. The methanol was completely distilled and diluted with water. The organic phase was extracted with ethyl acetate (50 ml) twice. The organic layer was dried over sodium sulphate and filtered and concentrated to get the crude. The crude was triturated with hexane to afford the half white colour solid (E)-3-(3-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-fluorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-2-methylacrylamide 164. MS-ES+486.19, 1H NMR (400 MHz, CDCl3): 9.6 (s, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 7.52 (s, 1H) 7.44 (s, 3H), 7.22 (m, 1H), 7.1 (d, 1H), 6.8(m, 1H), 5.91 (s, 1H), 3.74 (s, 3H), 2.116 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2].[CH3:10][CH2:11][CH2:12][CH2:13][CH2:14]C.[CH2:16]([O:22][CH2:23]Cl)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CS(C)=O>[C:1]([O-:4])(=[O:3])[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:1]([O:4][CH2:5][CH2:6][N+:7]([CH2:23][O:22][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:10])([CH3:9])[CH3:8])(=[O:3])[CH3:2]
Reactant: CCCCCCOCCl
Reactant: CCCCCC
Reactant: CC(=O)OCCN(C)C
Solvent: CS(C)=O
Product: CCCCCCCOC[N+](C)(C)CCOC(C)=O
Product: O=C([O-])c1ccccc1
Temperature: 18 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
In a two-necked, round bottomed flask, equipped with a condenser and addition funnel, 2-(dimethylamino)ethyl acetate (0.1 mol) was mixed with 150 mL of anhydrous hexane. Chloromethyl hexyl ether (0.1 mol) was slowly added over 15 minutes. After 30 minutes, the reaction mixture was cooled to the temperature of minus 18° C. and the crude product was separated. The crude product was washed with 100 mL of hexane and used in the next step without further purification. The material was dissolved in 100 mL of water and aqueous solution of sodium benzoate was added in stoichiometric amount. After 30 minutes, two phases were separated. The water phase was removed and 100 mL of anhydrous acetone was added to the residue. Precipitated NaCl was filtered off and the obtained liquid product, (2-acetoxyethyl)heptyloxymethyldimethylammonium benzoate, was dried for 12 h at 60° C. in vacuum. The product was obtained as viscous liquid in 65% yield. Thermogravimetric analysis: Tonset=120° C. 1H and 13C NMR (DMSO) were obtained.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[CH2:8]([N:15]([Si](C)(C)C)[CH2:16]OC)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1/[CH:31]=[CH:32]/[C:33]([O:35][CH3:36])=[O:34]>ClCCl>[CH2:8]([N:15]1[CH2:16][C@@H:31]([C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[F:23])[C@H:32]([C:33]([O:35][CH3:36])=[O:34])[CH2:2]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COCN(Cc1ccccc1)[Si](C)(C)C
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)/C=C/c1ccc(F)cc1F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A solution of trifluoroacetic acid (2.42 mL, 31.5 mmol) in dichloromethane (5 mL) was added at 0-5° C. to a stirred solution of N-benzyl-N-(methoxymethyl)trimethylsilylamine (45.1 g, 190 mmol) and methyl (2E)-3-(2,4-difluorophenyl)acrylate (from preparation 3) (25.1 g, 126 mmol) in dichloromethane (100 mL). After stirring overnight at room temperature, the organic solution was washed with saturated sodium bicarbonate solution and then brine. The resulting organic solution was dried over anhydrous sodium sulfate, filtered and then evaporated. The residue was purified by flash chromatography on silica gel eluting with toluene:tetrahydrofuran mixture (11:1) to afford the title compound (31.6 mL, 71%) as a colourless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[CH:10][C:2]1=2.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([Br:31])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].C(N(CC)CC)C>ClCCl>[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([Br:31])[C:28]=1[O:29][CH3:30])[C:23]([N:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[CH:10][C:2]1=2)=[O:24]
Reactant: N#Cc1ccc(-c2cnc3c(c2)NCCO3)cc1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccc(C#N)cc4)cc32)cc1Br
Yield: 75.6 %

Procedure:
By the same method as in the step c) of Example 45, 4-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-benzonitrile (71.4 mg, 0.30 mmol), 3,5-dibromo-4-methoxy-benzoyl chloride (148 mg, 0.45 mmol) and triethylamine (84 μl, 0.60 mmol) were dissolved in dichloromethane (3 ml) and reacted at room temperature for 3 hours to obtain 4-[1-(3,5-dibromo-4-methoxy-benzoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-benzonitrile as white solid (120 mg, 75.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CO>C1COCC1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4](=[O:20])[N:5]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]2=[O:19])[C:6]3=[O:11])=[O:27])=[CH:24][CH:23]=1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(Cl)cc4)c3C2=O)C(=O)N1
Yield: 80.9 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.2 g, 4.5 mmol) and 4-chlorobenzoyl chloride (1.1 mL, 8.8 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with ether (2×10 mL) then methanol (5 mL) to give 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-benzamide as a white solid (1.5 g, 81% yield): mp, 261–263° C.; 1H NMR (DMSO-d6) δ 2.05–2.09 (m, 1H, CHH), 2.49–2.65 (m, 2H, CH2), 2.83–2.98 (m, 1H, CHH), 5.18 (dd, J=5.5, 12.8 Hz, 1H, NCH), 7.68–7.72 (m, 3H, Ar), 7.89–8.01 (m, 3H, Ar), 8.52 (d, J=8.2, Hz, 1H, Ar), 10.47 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 48.98, 118.48, 119.06, 126.76, 129.10, 129.29, 131.46, 132.13, 136.28, 137.47, 164.08, 166.60, 167.86, 169.67, 172.72; Anal Calcd for C20H14N3O5Cl+0.2 H2O: C, 57.83; H, 3.49; N, 10.12; Cl, 8.53; H2O, 0.87. Found: C, 57.88; H, 3.33; N, 9.93; Cl, 8.53; H2O, 0.73.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5].[CH3:15][NH:16][CH3:17]>C(O)C.Cl>[CH3:15][N:16]([CH3:17])[CH2:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5]
Reactant: CCCCCCCCNC(=O)CCBr
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CCCCCCCCNC(=O)CCN(C)C
Reaction time: 72 h
Yield: 83 %

Procedure:
3-Bromo-N-octylpropanamide (21.3 g) was dissolved in ethanol (50 ml) and a 33% solution of dimethylamine in IMS (100 ml) was added. The solution was allowed to stand at 20° for 72 hours then evaporated to give a yellow oil. This oil was dissolved in dilute HCl to give a solution of pH 4 which was washed twice with dichloromethane, basified with dilute aqueous sodium hydroxide solution and extracted with dichloromethane three times. The latter dichloromethane extracts were dried and evaporated to a pale yellow oil. Distillation of the residue gave 3-dimethylamino-N-octylpropanamide as a colourless oil (15.1 g, 83% yield) (bp 135°-8°/0.15mm).