Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]3[N:20]([N:22]=[CH:23][C:24]=3B3OC(C)(C)C(C)(C)O3)[CH:21]=2)=[CH:12][CH:11]=1.Cl[C:35]1[CH:40]=[C:39]([NH:41][C:42]([NH:44][CH2:45][CH3:46])=[O:43])[CH:38]=[CH:37][N:36]=1.N#N>O.O1CCOCC1>[CH2:45]([NH:44][C:42]([NH:41][C:39]1[CH:38]=[CH:37][N:36]=[C:35]([C:24]2[CH:23]=[N:22][N:20]3[CH:21]=[C:16]([C:13]4[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=4)[CH:17]=[N:18][C:19]=23)[CH:40]=1)=[O:43])[CH3:46]
Reactant: CC1(C)OB(c2cnn3cc(-c4ccc(F)cc4)cnc23)OC1(C)C
Reactant: CCNC(=O)Nc1ccnc(Cl)c1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccnc(-c2cnn3cc(-c4ccc(F)cc4)cnc23)c1
Temperature: 90 °C
Yield: 18.6 %

Procedure:
A solution of K3PO4 (640 mg, 3 mmol) in H2O (2 ml) was added to a stirred mixture of 6-(4-fluoro-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[1,5-a]pyrimidine (330 mg, 0.97 mmol) and 1-(2-chloro-pyridin-4-yl)-3-ethyl-urea (procedure U4, 420 mg, 2.1 mmol) in dioxane (8 ml) at RT under N2. The mixture was deoxygenated by evacuate/fill N2 (×2), PdCl2dppf (40 mg, 0.05 mmol) was added and the mixture was deoxygenated again (×3). The reaction was stirred and heated at 90° C. for 18 h. After cooling to RT the reaction was partitioned between CH2Cl2/H2O. The aqueous layer was extracted with CH2Cl2 (×1). The combined extracts were dried, then evaporated. The residue was purified by preparative HPLC to give the title compound (68 mg) as a yellow solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][CH:28]([CH2:32][CH3:33])[C:29](O)=[O:30]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:29](=[O:30])[CH:28]([CH3:27])[CH2:32][CH3:33])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CCC(C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CCC(C)C(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (77 mg, 75%), MS (ISP) m/z=411.4 [(M+H)+], mp 172° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (RS)-2-methyl-butyric acid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([NH:46][CH2:47][CH3:48])=[O:45])=[CH:40][CH:39]=3)[C:11]=2/[CH:12]=[CH:13]/[C:14]2[N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=[CH:17][N:18]=2)=[O:6])[CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:38]3[CH:39]=[CH:40][C:41]([C:44]([NH:46][CH2:47][CH3:48])=[O:45])=[CH:42][CH:43]=3)[C:11]=2/[CH:12]=[CH:13]/[C:14]2[NH:18][CH:17]=[CH:16][N:15]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-[(E)-2-(1-trityl-1H-imidazol-2-yl)vinyl]-1H-1,2,3-triazole-4-carboxamide (670 mg) obtained in Example 322a) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in chloroform. This chloroform solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column (ethyl acetate to ethyl acetate/methanol=4/1) to give the title compound as a white powder (220 mg).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=[N:18][NH2:19])[CH3:17])[C:11]=3[OH:20])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[C:22]=[S:23].O>CN(C)C=O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=[N:18][NH:19][C:22](=[S:23])[NH:21][C:24]4[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=4)[CH3:17])[C:11]=3[OH:20])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(N=C=S)cc1
Reactant: CC(=NN)c1nn(C)c(-c2ccc3c(c2)CCC3)c1O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc3c(c2)CCC3)c1O
Yield: 79.3 %

Procedure:
5-(2,3-Dihydro-1H-inden-5-yl)-3-(1-hydrazonoethyl)-1-methyl-1H-pyrazol-4-ol (47 mg, 0.174 mmol) in N,N-dimethylformamide (0.94 mL) was stirred with 4-isothiocyanatobenzoic acid (33 mg, 0.184 mmol) at room temperature for 4 hours and 40 minutes. After the reaction, 0.94 mL of water was added, and the resulting pale yellow solid was collected by filtration, washed with water and dried under reduced pressure to obtain the desired product (62 mg, 79% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH2:39][OH:40].O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: OCCCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1OCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 345) (45 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (50 mg) and 4-bromo-1-butanol (55 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (19 mg, yield 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Cl:1][C:2]1[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(Cl)c(C(=O)O)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(Cl)cc(C(=O)O)c(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
41 g of 2,5-dichloro-4-methylbenzoic acid are added in portions to a mixture of 100 ml of concentrated H2SO4 and 20 ml of 68% strength HNO3. The mixture is kept at 50° for 3 hours and then poured onto 600 g of ice. The solid which has precipitated is isolated, dried and stirred with a little toluene. Melting point: 210°-18°, yield: 43.8 g.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.CCCCCC.[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1.[N+]([O-])(O)=O.C(I)C>C1COCC1>[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:22][CH2:2][CH3:3])[CH:17]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cc(Cl)ccn1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O=[N+]([O-])O
Product: CCCc1cc(Cl)ccn1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A 1.5M solution of LDA in hexane (100 mL, 150 mmol) was cooled to -60° C. in an isopropyl alcohol/dry ice bath. To the stirred LDA solution, under nitrogen, was added, dropwise over a 0.5 hours period, a solution of 17.466 g (137 mmol) of 4-chloro-2-picoline (the product of Step 1 of Example 58) in 80 mL of dry THF. The reaction mixture was stirred for 0.5 hours at -60° C. and then a solution of 10.95 mL (137 mmol) of ethyl iodide in 30 mL of dry THF was added, dropwise over a 20 minute period. After the reaction mixture was stirred at -60° C. for 0.5 hours, the cooling bath was allowed to slowly (1.5 hours) warm to -30° C. According to TLC analysis on silica gel eluted with 5% methanol in methylene chloride, the reaction had gone to completion. The reaction mixture was poured into cold brine and the aqueous mixture was extracted with methylene chloride. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was distilled to afford 12.667 g (60% yield of the title compound, b.p. 77°-80° C. (10 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:14]2[S:15][C:16]([N:19]([CH:27]([CH3:29])[CH3:28])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][N:18]=2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:31][CH:32]=O>CCO>[CH:27]([N:19]([C:16]1[S:15][C:14]([C:5]2[N:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[N:3]([CH:31]=[CH:32][N:1]=3)[CH:4]=2)=[N:18][CH:17]=1)[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:29])[CH3:28]
Reactant: O=CCCl
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1cnc(-c2cnc(N)c(-c3ccccc3)n2)s1
Solvent: CCO
Product: CC(C)N(C(=O)OC(C)(C)C)c1cnc(-c2cn3ccnc3c(-c3ccccc3)n2)s1
Temperature: 60 °C

Procedure:
A solution of tert-butyl 2-(5-amino-6-phenylpyrazin-2-yl)thiazol-5-yl(isopropyl)carbamate (23.7 mg, 0.06 mmol) in EtOH (0.25 mL) was added chloroacetaldehyde (11.8 μL, 50% in water) and the reaction mixture was then heated to 60° C. for 24 h and then concentrated to dryness. The crude product was dried under high vacuum and used without further purification.
Reaction SMILES: [Na][Na].[OH:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].S(OC)(O[CH3:19])(=O)=O.[OH-].[Na+].C>O>[CH3:19][O:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(C)c(O)c(C(=O)O)c1
Agent: [Na+]
Agent: [Na][Na]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cc(C)cc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The disodium salt of 2-hydroxy-3,5-dimethylbenzoic acid (21 g.) and dimethyl sulphate (92 ml.) were stirred together at 140°-150° C. for 2.5 hours. After standing overnight, the mixture was added to a solution of sodium hydroxide (40 g.) in water (250 ml.), and the mixture stirred and heated on the steam-bath for 1 hour. Charcoal was added, the mixture was filtered and the filtrate was cooled, acidified with concentrated hydrochloric acid, and maintained at 0° C. The solid which separated was filtered off and recrystallised from aqueous ethanol to give 2-methoxy-3,5-dimethylbenzoic acid (14.7 g.), m.p. 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:19][C:20]1[CH:45]=[CH:44][C:23]2[CH2:24][CH2:25][C:26]3[C:27]([C:41]([NH2:43])=[O:42])=[N:28][N:29]([C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=4)[C:30]=3[C:22]=2[CH:21]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH:19][C:20]1[CH:45]=[CH:44][C:23]2[CH2:24][CH2:25][C:26]3[C:27]([C:41]([NH2:43])=[O:42])=[N:28][N:29]([C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=4)[C:30]=3[C:22]=2[CH:21]=1)=[O:6]
Reactant: CN1CCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(N)ccc2CC3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Cl)c(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc(S(C)(=O)=O)cc3)CC4)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a mixture of 2-chloro-5-(4-methylpiperazin-1-yl)benzoic acid (0.9 g, 0.0035 mol), the title compound of Example 92 (0.0024 mol) and 1 mL of diisopropylethylamine in 25 mL of DMF was added HATU (1.3 g, 0.0035 mol) in one portion. The reaction mixture was stirred at room temperature for 16 h. Solvent was removed and the residue was purified on preparative HPLC to give the product as a pale white solid (89% yield); mp: 194-195° C.; 1HNMR (DMSO+TFA-d, 400 MHz) δ: 10.29 (s, 1H), 8.10 (d, J=8.7 Hz, 2H), 7.86 (d, J=8.7 Hz, 2H), 7.64 (s, 1H), 7.43 (dd, J=2.1, 8.2 Hz, 1H), 7.41 (s, 1H), 7.37 (dd, J=2.0, 8.2 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.08 (dd, J=3.0, 8.9 Hz, 1H), 7.04 (d, J=3.0 Hz, 1H), 3.89 (d, J=12.8 Hz, 2H), 3.51 (d, J=12.8 Hz, 2H), 3.23(s, 3H), 3.11 (m, 2H), 2.95 (m, 4H), 2.86 (m, 2H). The bioactivity in the IKK 2 Resin assay for the compound of Example 126 is shown in Table 2.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[CH:13]1[C:26]2[C:17](=[N:18][C:19]([CH2:27][NH2:28])=[C:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:8][CH2:9][C:10]([NH:28][CH2:27][C:19]1[N:18]=[C:17]2[C:26](=[C:25]3[C:20]=1[CH:21]=[CH:22][CH:23]=[CH:24]3)[CH:13]=[CH:14][CH:15]=[CH:16]2)=[O:11]
Reactant: O=C(Cl)CCl
Reactant: NCc1nc2ccccc2c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)NCc1nc2ccccc2c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (460 μL, 3.30 mmol), followed by a solution of chloroacetyl chloride (175 μL, 2.20 mmol) in CH2Cl2 (5 mL) were added dropwise over 5 minutes to a solution of the amine 8 (229 mg, 1.10 mmol) dissolved in CH2Cl2 (15 mL) at 0° C. The reaction mixture was then allowed to warm to ambient temperature and stirred for 2 hours. The solvent was removed under reduced pressure and the reaction crude purified via flash chromatography over silica eluting with a gradient of CH2Cl2 to 1% MeOH/99% CH2Cl2. Evaporation of the solvents under reduced pressure yielded the chloro 9 as an off-white solid (177 mg, 56.5% over three steps).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33](Br)[CH:32]=2)([C:19]2[CH:23]=[C:22]([C:24](=[O:27])[CH2:25][CH3:26])[N:21]([CH2:28][CH2:29][CH3:30])[CH:20]=2)[N:13]=1>>[NH2:11][C:12]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:36]=2)([C:19]2[CH:23]=[C:22]([C:24](=[O:27])[CH2:25][CH3:26])[N:21]([CH2:28][CH2:29][CH3:30])[CH:20]=2)[N:13]=1
Reactant: OB(O)c1cccnc1F
Reactant: CCCn1cc(C2(c3cccc(Br)c3)N=C(N)N(C)C2=O)cc1C(=O)CC
Product: CCCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C(=O)CC

Procedure:
Using essentially the same procedure described in Example 43, step e, and employing 2-fluoro-pyridin-3-yl boronic acid and 2-amino-5-(3-bromophenyl)-3-methyl-5-(5-propionyl-1-propyl-1H-pyrrol-3-yl)-3,5-dihydro-imidazol-4-one as reactants, the title product was obtained as a white solid, mp 118° C., 1H NMR (400 MHZ, DMSO-d6) δ 0.73 (t, 3H), 0.96 (t, 3H), 1.54 (m, 2H), 2.67 (m, 2H), 2.92 (s, 3H), 4.13 (m, 2H), 6.60 (bs, 2H), 6.92 (s, 1H), 7.01 (s, 1H), 7.41 (m, 3H), 7.53 (m, 1H), 7.67 (m, 1H), 7.97 (m, 1H), 8.19, (m, 1H), m/e (M−H)− 446.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[F:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>N1C=CC=CC=1>[F:12][C:13]1[CH:14]=[C:15]([S:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[I:11])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Nc1ccc2[nH]nc(I)c2c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2[nH]nc(I)c2c1)c1cccc(F)c1
Yield: 10.8 %

Procedure:
3-Fluoro-N-(3-iodo-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 2 from 230 mg of 5-amino-3-iodo-1H-indazole, 5 ml of pyridine and 173 mg of 3-fluorobenzenesulfonyl chloride. 40 mg of 3-fluoro-N-(3-iodo-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a cream solid melting at 189° C.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][NH:4]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[CH2:32]([N-:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]/[CH:57]=[CH:58]\[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].C(NCC)C>ClCCl>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][NH2:4].[CH2:32]([N-:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]/[CH:57]=[CH:58]\[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC[N-]CCCCCCCCCCCCCCCC
Solvent: CCNCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Temperature: 25 °C

Procedure:
1 g Boc-Dap(Fmoc)-N-palmityl-N-oleyl-amide raw product were dissolved in 8 ml anhydrous dichloromethane in a 50 ml round-bottom flask. 3 ml diethylamine was added and stirred at room temperature (FIG. 4). Thin layer chromatography control of the reaction showed that after 4.5 hours the reaction of the starting product was completed. The volatile components were removed by a rotary evaporator and the residue is chromatography purified using 40 g silica gel 60 (Merck) using hexane/ethylacetate 5:1. The product was eluted using a step gradient consisting of ethylacetate, ethylacetate/methanol 4:1 and dichloromethane/methanol 4:1. 576 mg (0.85 mmol) Boc-Dap-N-palmityl-N-oleyl-amide were obtained as a yellow viscous oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:9](Cl)=[O:10])[CH2:8][CH2:7][CH2:6]1.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:5]1([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH2:8][CH2:7][CH2:6]1
Reactant: c1ccccc1
Reactant: O=C(Cl)C1CCC1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)C1CCC1
Temperature: 25 °C

Procedure:
In a 5-L round bottomed flask equipped with an overhead stirrer and a pressure equalizing additional funnel was placed 1500 mL of benzene and 1150 g (8.65 mole) of anhydrous aluminum chloride. The reaction vessel was cooled in an ice-salt bath. To this mixture was added very carefully over a 1.5 hour period 920 g (7.7 mole) of cyclobutanecarbonyl chloride. Following the addition, the cooling bath was removed and the mixture allowed to warm to room temperature overnight and cautiously poured onto ice. The phases were separated and the aqueous layer extracted three times with ethyl acetate. The organic layers were combined washed three times with saturated sodium bicarbonate three times with water, and once with brine. The solution was dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was distilled to give 1126 g of phenyl cyclobutyl ketone, bp 97°-102° C. at 0.1 mm Hg. NMR (CDCl3) 1.8-2.6 (m, 6 H), 4.0 (q, 1 H), 7.4-7.6 (m, 3 H), 7.8-8.0 (m, 2 H); IR (neat film) 2950, 1675, 1450, 1350, 1225, 960, and 700 cm-1.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[CH2:38]([N:42]([CH3:47])[C:43](=O)[CH2:44]Cl)[CH2:39][CH2:40][CH3:41]>>[CH2:38]([N:42]([CH3:47])[CH2:43][CH2:44][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCCCN(C)CCOc1ccc(CCCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 53.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and N-butyl-2-chloro-N-methylacetamide (9.5 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.1 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([CH2:9][C:10]1[C:11]([O:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])=[N:12][C:13]([CH3:22])=[CH:14][C:15]=1[NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:5]([O:7]C)=O>C(O)(=O)C>[CH3:1][O:2][C:3]([CH:4]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH3:22])=[N:12][C:11]=2[O:23][C:24]2[C:25]([CH3:32])=[CH:26][C:27]([CH3:31])=[CH:28][C:29]=2[CH3:30])[N:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:5]1=[O:7])=[O:33]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1CC(C(=O)OC)C(=O)OC
Solvent: CC(=O)O
Product: CCC(CC)N1C(=O)C(C(=O)OC)Cc2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Temperature: 130 °C
Yield: 34.4 %

Procedure:
A mixture of 2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-malonic acid dimethyl ester (22 mg, 0.048 mmol) and 2 ml of acetic acid and bubbled through HCl (g) was heated at 130° C. for 30 hours. The reaction was cooled and concentrated to dryness. The residue was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 7 mg of the title compound. 1H NMR (CDCl3) δ 6.89(s,2H), 6.59(s,1H), 4.4(m,1H), 3.72(s,3H), 3.6-3.8(m,1H), 3.4-3.6(m,1H), 3.1-3.2(dd,1 H), 2.31(s,3H), 2.28(s,3H), 2.06(s,6H), 1.8-2.2(m,4H), 0.92(t,6H) ppm.
Reaction SMILES: C([N:5]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)CCC.[CH2:31]([O:33][C:34]1[CH:35]=[C:36](N)[CH:37]=[CH:38][CH:39]=1)[CH3:32]>CN1CCCC1=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:16]2[C:15]([NH:5][C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([O:33][CH2:31][CH3:32])[CH:39]=3)=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[N:17]2)=[CH:25][CH:26]=1
Reactant: CCOc1cccc(N)c1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Product: CCOc1cccc(Nc2c3ccccc3nn2-c2ccc(Cl)cc2)c1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with 3-ethoxy-phenylamine ([621-33-0]) in N-methyl 2-pyrrolidone for 4 d at 175° C. in a sealed tube to give the title compound as yellow solid. MS: m/e=364.3 [M+H+].
Reaction SMILES: [CH2:1]([C:13]1[NH:17][N:16]=[N:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1NN=NN=1)CCCCCCCCC.[CH2:33]([O:35][C:36](=[O:41])[C:37](Br)([CH3:39])[CH3:38])[CH3:34].BrC1C=CC=CC=1CC(OCC)=O>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([C:37]([CH3:39])([CH3:38])[C:36]([O:35][CH2:33][CH3:34])=[O:41])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCCCCCCCCCCc1nnn[nH]1
Agent: CCCCCCCCCCc1nnn[nH]1
Agent: CCOC(=O)Cc1ccccc1Br
Product: CCCCCCCCCCCCc1nnn(C(C)(C)C(=O)OCC)n1

Procedure:
When in the general procedure of Example 71 an appropriate amount of 5-dodecyl-1H-tetrazole was substituted for 5-decyl-1H-tetrazole and an appropriate amount of ethyl-2-bromoisobutyrate was substituted for ethyl 2-bromophenylacetate, the title compound was obtained.