Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:18](COCC[Si](C)(C)C)[C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl(O)(=O)(=O)=O>C(O)(=O)C.O>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(F)c(N)c(C(=O)O)c3)cc12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(F)c(N)c(C(=O)O)c3)cc12
Reaction time: 17 h
Yield: 105.9 %

Procedure:
175 mg (0.34 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid was dissolved in 5 mL of glacial acetic acid. 250 μL of 70% perchloric acid was added and the resulting mixture left at ambient temperature for 17 h. The resulting solution was diluted with 85 mL of water and the resulting precipitate filtered off and dried by suction to afford 137 mg (0.36 mmol, 106%) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid as a brown solid. MS: m/z 379.1 (M+H+).
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10]>>[Cl:1][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[C:5]=1[OH:10]
Reactant: Oc1ccccc1F
Reactant: ClCl
Product: Oc1c(F)cccc1Cl

Procedure:
4 g (56 mmol) of chlorine is introduced at this temperature. Then 60.5 g (540 mmol) of 2-fluorophenol are dropped in the solution over about 2 hours, while at the same rate 42 g (590 mmol) more chlorine is Introduced. After that 4 g more chlorine are introduced to complete the chlorination.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: OCCc1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Brc1ccccc1CCOC1CCCCO1
Yield: 81.5 %

Procedure:
A solution of 2-(2-bromophenyl)ethanol (3.10 g, 15.4 mmol), 3,4-dihydro-2H-pyran (1.70 ml, 18.6 mmol) and p-toluenesulfonic acid monohydrate (10.0 mg, 5.35 mmol) in chloroform (30 ml) was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium carbonate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=30:1-10:1) to give 2-[2-(2-bromophenyl)ethoxy]tetrahydropyran (3.58 g, yield 81.7%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][CH3:22])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(O)cc1OC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OC)c(OC)c1
Temperature: 50 °C
Yield: 496.4 %

Procedure:
To a solution of 4-hydroxy-2-methoxybenzoic acid methyl ester (4.17 g, 22 mmol) in DMF (50 ml) under argon was added potassium carbonate (6.33 g, 4.6 mmol) followed by iodoethane (7.15 g, 4.6 mmol). The mixture was then heated to 50° C. under argon for 12h. On cooling the mixture was poured into a large excess of water and extracted with ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a brown oil (4.8 g).
Reaction SMILES: [N:1]([CH:4]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[O:18]1[CH2:19][CH2:20][O:21][CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([CH:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH2:1])[CH:24]=[CH:23][CH:22]=1
Reactant: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Temperature: 0 °C

Procedure:
To a stirred solution of 2-(8-(3-(azido(phenyl)methyl)phenoxy)octyl)-1,3-dioxolane (1.11 g, 2.71 mmol) in THF (15 mL) at −78° C. under an atmosphere of nitrogen, a solution of lithium aluminium hydride (2.0M in THF, 2.8 mL, 5.60 mmol) was added drop wise. After stirring the reaction at −78° C. for 1 hour, the reaction mixture was warmed up to 0° C. for 1 hour. The reaction mixture was quenched with water (304 mL), 2M sodium hydroxide (304 mL) and water (304 mL×3). Anhydrous magnesium sulphate and ethyl acetate were added, and the reaction mixture filtered and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 100% iso-hexane to 100% DCM to 25:1 DCM:methanol (0.63 g, 39% based on (3-(8-(1,3-dioxolan-2-yl)octyloxy)phenyl)(phenyl)methanol).
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][CH:9]=[CH:10][C:5]=2[N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.[NH2:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]([O:44][CH3:45])[CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>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].C(Cl)Cl>[CH3:45][O:44][C:40]1[CH:39]=[C:38]([NH:37][C:2]2[C:6]3[C:7]([O:11][CH:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[N:8][CH:9]=[CH:10][C:5]=3[NH:4][N:3]=2)[CH:43]=[CH:42][N:41]=1
Reactant: COc1cc(N)ccn1
Reactant: Ic1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccnc(OC3CCOCC3)c12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Nc2n[nH]c3ccnc(OC4CCOCC4)c23)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 7.3 %

Procedure:
To a microwave tube was added 3-iodo-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (260 mg, 0.44 mmol), 4-amino-2-methoxy-pyridine (66 mg, 0.53 mmol), cesium carbonate (0.29 g, 0.88 mmol), XPhos (21 mg, 0.044 mmol), and tris(dibenzylideneacetone)dipalladium (20 mg, 0.022 mmol). The tube was then flushed with nitrogen for 1 minute before the addition of 1,4-dioxane (2.5 mL). The tube was sealed and irradiated in the microwave at 140° C. for 35 minutes. The reaction mixture was filtered through Celite® and concentrated. The crude material was filtered through a silica gel column (EtOAc) and concentrated. To the residue was added DCM (3 mL), triethylsilane (0.1 mL, 0.63 mmol) and trifluoroacetic acid (0.50 mL, 6.5 mmol). The mixture was stirred at room temperature for 15 minutes before concentrated under vacuum. The crude material was purified by reverse phase HPLC to give the title compound (11 mg, 7.3% over 2 steps). LC-MS (Method G): m/z=342.1 [M+H]+, 2.94 min. 1H-NMR (400 MHz, DMSO): δ 12.78 (s, 1H), 8.26 (s, 1H), 7.90 (d, J=5.6, 1H), 7.81 (d, J=6.0, 1H), 6.99 (d, J=6.0, 1H), 6.90 (d, J=5.4, 1H), 6.86 (s, 1H), 5.39 (m, 1H), 3.80 (m, 5H), 3.50 (m, 2H), 1.99 (m, 2H), 1.76 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[CH3:21][C:22](=O)[CH2:23][C:24](=O)[CH3:25].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:21])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Solvent: O
Solvent: CCO
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1
Yield: 84 %

Procedure:
(4-Chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)amine (4.15 g, 14.3 mmol) and 2,4-pentanedione (2.0 mL, 19.1 mmol) in ethanol (100 mL) were heated to reflux for 20 min. Water was added and the white crystalline compound was collected by filtration, washed with water and dried to give (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-amine (4.25 g, 84%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([O:14]CC)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CN1C(=O)CCC1>[C:1]([C:5]1[N:10]=[C:9]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1Cl
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2nc(C(C)(C)C)ncc2C(=O)O)CC1
Yield: 31.9 %

Procedure:
Using a procedure analogous to Example B40, ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate from Example B40 (0.30 g, 1.24 mmol) and 1-methylpiperazine (0.62 g, 6.18 mmol) in presence of NMP (catalytic amount) were combined to afford 2-tert-butyl-4-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid (0.11 g, 32% yield). MS (ESI) m/z: 279.0 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][CH3:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][CH3:37])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M139) (0.27 g, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (165 mg, 77%).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][C:17](=[C:20]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH2:24][CH2:23][N:22]4[C:31]([CH2:34][OH:35])=[CH:32][N:33]=[C:21]34)[CH2:16][CH2:15]2)[CH2:10][C@@H:9]1[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:7]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:49][C:46]([F:47])([F:48])[C:44]1[CH:43]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:51])[F:50])[CH:45]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][C:17](=[C:20]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH2:24][CH2:23][N:22]4[C:31]([CH:34]=[O:35])=[CH:32][N:33]=[C:21]34)[CH2:16][CH2:15]2)[CH2:10][C@@H:9]1[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCC(=C3c4ccccc4CCn4c(CO)cnc43)CC2)C[C@@H]1Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cnc2n1CCc1ccccc1C2=C1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3ccccc3)C2)CC1
Yield: 69.1 %

Procedure:
A mixture of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-[5,6-dihydro-3-(hydroxymethyl)-11H-imidazo[2,1-b][3]benzazepin-11-ylidene]-1-piperidinyl]-2-(phenylmethyl)piperidine (4.5 g) and manganese dioxide (20 g) in CHCl3 (200 ml) was stirred and refluxed for 1 hour. The mixture was filtered warm over dicalite and the filtrate was evaporated. The residue as purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was purified by HPLC (eluent: CH2Cl2/CH3OH 100/0 to 95/5). The pure fractions were collected and the solvent was evaporated, yielding 3.1 g (70%) of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(3-formyl-5,6-dihydro-11H-imidazo[2,1-b][3]benzazepin-11-ylidene)-1-piperidinyl]-2-(phenylmethyl)piperidine (comp. 11; mp. 125.8° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14](S(C)=O)[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][C@H:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14]([NH:21][C@H:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24])[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)c1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Reactant: CC(C)C[C@@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)C[C@H](CO)Nc1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Temperature: 100 °C
Reaction time: 18 h
Yield: 38.8 %

Procedure:
To the solution of 6-(2-chloropyridin-4-yloxy)-2-(methylsulfinyl)benzo[d]thiazole (26 mg, 80 μmol) in 400 μL of NMP was added (R)-2-amino-4-methylpentan-1-ol (33 μL, 250 μmol) and DIPEA (17 μL, 100 μmol). The reaction solution was stirred at 100° C. for 18 hours. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give (R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)-4-methylpentan-1-ol (12 mg, 31 μmol) as powder. ES/MS m/z 378.1 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3](=[O:31])[CH2:4][N:5]([C@@H:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1)[C:6]1[C:7]2[CH:14]=[CH:13][N:12]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:8]=2[N:9]=[CH:10][N:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:54][C:55]1[CH:56]=[C:57]([NH:62][CH2:63][C:64](O)=[O:65])[CH:58]=[C:59]([Cl:61])[CH:60]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:54][C:55]1[CH:56]=[C:57]([NH:62][CH2:63][C:64]([N:27]2[CH2:28][CH2:29][CH2:30][C@@H:25]([N:5]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([S:15]([C:18]5[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=5)(=[O:17])=[O:16])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:4][C:3]([N:2]([CH3:1])[CH3:32])=[O:31])[CH2:26]2)=[O:65])[CH:58]=[C:59]([Cl:61])[CH:60]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(CC(=O)N(C)C)[C@@H]4CCCNC4)ncnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(CC(=O)N(C)C)[C@@H]4CCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a solution of (R)—N, N-dimethyl-2-(piperidin-3-yl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) acetamide (100 mg, 0.24 mmol) in DMF (7 mL) was added EDCI (54 mg, 0.3 mmol), HOBt (39 mg, 0.3 mmol), 2-(3,5-dichlorophenylamino)acetic acid (53 mg, 0.24 mmol) and DIEA (0.50 mL, 0.36 mmol) at 0° C. The solution was stirred at rt overnight and the reaction mixture was diluted with water (50 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give a residue which was purified by column chromatography (silica gel, gradient 0-2% methanol in chloroform) to afford the titled compound (50 mg, 31%). LCMS [M+1]: 675.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.CCCCCC.CCOC(C)=O>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:13][CH2:14][N:15]([C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:27])[CH2:16][CH2:17]1
Reactant: Clc1ccc2nccc(N3CCNCC3)c2c1
Reactant: O=C=Nc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3ccc(Cl)cc23)CC1

Procedure:
6-Chloro-4-(piperazin-1-yl)quinoline (0.25 g, 1.0 mmol), 4-fluorophenyl isocyanate (170 μL, 1.5 mmol), and DMAP (2 mg) in THF (10 mL) are reacted according to method C yielding the product as a colorless solid after column chromatography with hexane-EtOAc. 1H NMR ([D]6-DMSO), δ 3.17 (m, 4H), 3.75 (m, 4H), 7.08 (t, 2H), 7.10 (d, 1H), 7.46 (dd, 2H), 7.72 (dd, 1H), 7.98 (d, 1H), 8.01 (d, 1H), 8.68 (br. s, 1H), 8.72 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36]Br)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCBr)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
2.0 g of 5-benzyloxy-3-[5-(2-bromoethoxy)-1-tert-butoxycarbonyl-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester are stirred in 90 ml of acetonitrile. 498 mg of potassium iodide are added and the suspension is heated to 80° C. After 7 h 20 min, the following reactants are successively added: 394 μl of morpholine, 1.24 g of potassium carbonate, 150 mg of potassium iodide. The suspension is heated at 80° C. overnight. The insoluble material is filtered off and the filtrate is concentrated under vacuum. The reaction crude is taken up in 50 ml of dichloromethane. The organic phase is washed with 2 times 25 ml of distilled water. The organic phase is dried over magnesium sulfate and filtered. The solvent is evaporated off in a rotary evaporator to obtain 1.90 g of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]-indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](Cl)[CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=1)=[O:5])[CH3:2].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:21]2[CH:20]=[C:19]([Cl:18])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])[CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: CCOC(=O)c1cc(Cl)cc(C(=O)OCC)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cc(-c2cc(Cl)ccc2OC)cc(C(=O)OCC)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a solution of 4-chloro-pyridine-2,6-dicarboxylic acid diethyl ester (700 mg, 2.8 mmol), 5-chloro-2-methoxy-phenylboronic acid (630 mg, 3.4 mmol), palladium acetate (105 mg, 0.47 mmol) in ethylene glycol dimethyl ether (50 ml), degassed with argon, was added a solution of sodium carbonate (868 mg, 8.2 mmol) in water (5 ml) followed by triphenylphosphine (220 mg, 0.84 mmol). The mixture was stirred at 80° C. for 3 hours and filtered through a pad of celite under suction. The filtrate was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3 followed by 1:2) to give 4-(5-chloro-2-methoxy-phenyl)-pyridine-2,6-dicarboxylic acid diethyl ester (755 mg, 74% yield) as a white solid. 1H NMR (acetone-d6) δ 1.42 (t, 6H, J=7.1 Hz CH3), 3.92 (s, 3H, CH3), 4.45 (q, 4H, J=7.1 Hz, CH2), 7.27 (d, 1H, J=8.9 Hz, Ar), 7.52 (dd, 1H J=8.8 Hz, J=2.7 Hz, Ar), 7.56 (d, 1H, J=2.7 Hz, Ar), 8.43 (s, 2H, Ar).
Reaction SMILES: [Li][C:2]([N-]C(C)C)(C)C.[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=[CH:19][C:18]=1[CH:32]1[CH2:37][C:36](=[O:38])[CH:35]=[C:34]([O:39][CH3:40])[CH2:33]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)P(N(C)C)(N(C)C)=O.CI>O1CCCC1>[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=[CH:19][C:18]=1[CH:32]1[CH:37]([CH3:2])[C:36](=[O:38])[CH:35]=[C:34]([O:39][CH3:40])[CH2:33]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [Li]C(C)(C)[N-]C(C)C
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)C=C(OC)C2)c(OCc2ccccc2)c1
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCC(C)(C)c1ccc(C2CC(OC)=CC(=O)C2C)c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a -78° C. solution of 0.5 mole of lithiodiisopropylamide in 500 ml of tetrahydrofuran (from 50.5 g, 0.5 mole diisopropylamine and 417 ml of 1.2 M n-butyllithium in hexane) is added dropwise (30 mm) a solution of 217 g (0.5 mole) of 5-(2-benzyloxy-4-(1,1-dimethylheptyl)phenyl)-3-methoxy-2-cyclohexen-1-one in 250 ml of tetrahydrofuran. The reaction is stirred 30 minutes longer at -78° C. followed by the addition of 179 g (1.0 mole) of hexamethylphosphoramide and 78.1 g (0.55 mole) of methyl iodide. The reaction is allowed to slowly warm to room temperature, stirred one hour and quenched by the addition of 10 ml of water. The reaction is evaporated under reduced pressure to remove the tetrahydrofuran and added to one liter ice water-one liter ether. The ether extract is washed with three one liter portions of water, dried over magnesium sulfate and evaporated to yield the title compound in nearly pure form. The title compound is purified via column chromatography on 2 kg of silica gel eluted with ether-pentane.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>CC(C)=O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCC2CO2)cc1
Yield: 67.2 %

Procedure:
A mixture of 15.2 gm (0.1 mole) of methyl 4-hydroxybenzoate, 27.6 gm (0.2 mole) potassium carbonate and 31 mL (0.4 mole) epichlorohydrin in 250 mL acetone was heated to reflux for 24 hours. The reaction medium was then filtered and evaporated. The residue was taken up in 100 mL toluene and washed with 100 mL 1.0N NaOH and 2×100 mL water. The toluene phase was then dried over magnesium sulfate and evaporated to provide the crude product as an oil. Purification was effected by vacuum distillation (66°-67°; 75 u pressure) and provided 14 gm (67%) of a clear oil when gradually crystallized at room temperature: mp 54°-55° C. The NMR and IR spectra and elemental analysis data were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([CH:8]=[CH:9]CCCCC)[C:2]1C=CC=C[CH:3]=1.CCOCC.[C:20]([OH:23])(=[O:22])[CH3:21].O>C1COCC1>[C:20]([OH:23])([OH:22])=[CH:21][CH2:3][CH2:2][CH2:1][CH2:8][CH3:9]
Reactant: CC(=O)O
Reactant: CCCCCC=CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCC=C(O)O

Procedure:
A solution of the benzyl ether 4, 80 ml of acetic acid and 20 ml of water in 50 ml of THF was stirred at 70° C. overnight. The solution was then concentrated under vacuum and the residue purified by chromatography over silica gel (3 EtOAc: 2 hexanes) to provide the title compound.