Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:21]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)[CH2:23][CH2:22]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c2ccccc21
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2CC2)c2ccccc21
Yield: 84.4 %

Procedure:
Dissolve 3-bromo-1-triisopropylsilanyl-1H-indole (1.02 g, 2.89 mmol), cyclopropylboronic acid (259 mg, 3.01 mmol) and K3PO4 (1.8 g, 8.5 mmol) in a mixture of toluene (20 mL) and water (0.8 mL). Add tricyclohexyl-phosphane (86 mg, 0.31 mmol) and palladium(II) acetate (50 mg, 0.22 mmol) and stir the mixture at 70° C. for 3 h. Filter the mixture through celite and wash the solids with EtOAc (30 mL). Collect and concentrate the filtrate and purify the residue by flash chromatography, using a linear gradient of 100% hexanes to 10% EtOAc/hexanes, to give the title compound as a clear oil 765 mg (84%): MS (ES) 314.1 (M+1)+.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH:30]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31]1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:30]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31]1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: O=C(O)C1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCC(C(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and pyrrolidine-3-carboxylic acid (22.81 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The crude material was purified via preparative LC/MS with the following conditions: Column. Waters XBridge C18, 19×100 mm, 5-μm particles; Guard Column: none; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5, acetonitrile:water with 0.05% TFA; Gradient: 25-100% B over 10 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl) pyrrolidine-3-carboxylic acid was 16.3 mg, and its purity was 96%. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.21 (2H, d, J=8.35 Hz), 7.81 (2H, dd, J=8.02, 1.65 Hz), 7.69 (2H, d, J=8.35 Hz), 7.54-7.66 (3H, m), 5.10-5.22 (1H, m), 3.39-3.54 (4H, m), 3.24-3.27 (3H, m), 3.00-3.10 (2H, m), 2.23-2.57 (2H, m), 1.70-1.83 (2H, m), 1.05 (3H, t, J=7.36 Hz). MS (m+1)=489. HPLC Peak RT=2.08 minutes. (Analytical Method C). Purity=96%.
Reaction SMILES: [CH2:1]([C@@H:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:33][C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30](O)=[S:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:33][C:34]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:30]([N:10]1[CH2:9][CH2:8][N:7]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])[CH2:6][C@@H:5]1[CH2:1][CH2:2][CH2:3][CH3:4])=[S:31])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCCC[C@H]1CN(C(=O)c2cccc(C)c2C)CCN1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCC[C@H]1CN(C(=O)c2cccc(C)c2C)CCN1C(=S)[C@@H](CC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
3(S)-n-Butyl-1-(2,3-dimethylbenzoyl)piperazine (0.240 g, 0.874 mmol) and 2(R)-tert-butoxycarbonylamino-3-triphenylmethylthiopropionic acid (0.405 g, 0.874 mmol) were dissolved in dimethylformamide. To this solution was added HOBT (0.114 g, 0.874 mmol), and EDC.HCl (0.184 g, 0.962 mmol). The reaction was stirred under nitrogen overnight. The dimethylformamide was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with several portions of water, saturated sodium chloride solution, and dried over magnesium sulfate. Filtration and evaporation of solvent gave the crude product, which was chromatographed on silica gel with 50% ethyl acetate in hexane. The title compound as a white foam (0.620 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([CH3:18])[C:11]=1Br)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][C:29]1([CH3:36])[C:33]([CH3:35])([CH3:34])[O:32][BH:31][O:30]1>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([CH3:18])[C:11]=1[B:31]1[O:32][C:33]([CH3:35])([CH3:34])[C:29]([CH3:36])([CH3:28])[O:30]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: COc1cc(C)c(Br)c(COCC(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)c(COCC(=O)OC(C)(C)C)c1
Temperature: 80 °C
Yield: 58.6 %

Procedure:
A solution of (2-bromo-5-methoxy-3-methyl-benzyloxy)-acetic acid tert-butyl ester ((Example 192: step d) 1.19 g, 3.45 mmol) in dioxane (10 mL) was treated with PdCl2(PPh3)2 (0.242 g, 0.345 mmol) and triethylamine (2.88 mL, 20.7 mmol). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.00 mL, 6.89 mmol) was added slowly and the mixture heated to 80° C. 15 h. The reaction was diluted with EtOAc and washed with brine (2×50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (25% EtOAc in hexanes) afforded the product [5-methoxy-3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-acetic acid tert-butyl ester (0.793 g, 58%) as a brown oil. The crude material was used directly in the next reaction.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=O.C([O-])(=O)C.[Na+].Cl.[NH2:25][OH:26]>C1COCC1>[OH:26][N:25]=[CH:1][C:3]1[CH:4]=[C:5]([CH:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: NO
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a solution of tert-butyl N-[1-(3-formylphenyl)ethyl]carbamate (4.0 g, 16.0 mmol) and sodium acetate (3.3 g, 40.1 mmol) in THF (69 mL) at 0° C. was added hydroxylamine hydrochloride (1.4 g, 20.9 mmol). The reaction was allowed to warm to ambient temperature and stirred for 16 hours. The reaction was concentrated in vacuo and the residue partitioned between EtOAc and water and the layers separated. The organic layer was washed with brine (×2), dried (Na2SO4), filtered and concentrated in vacuo to give the sub-title compound as a colourless gel (4.24 g, quantitative Yield). 1H NMR (400 MHz, DMSO) δ 1.30 (d, 3H), 1.33 (d, 9H), 4.61 (dd, 1H), 7.24-7.38 (m, 2H), 7.41 (q, 2H), 7.53 (s, 1H), 8.11 (s, 1H) and 11.20 (s, 1H) ppm; MS (ES+) 265.3.
Reaction SMILES: C([C:5](C(C)(C)C)([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:37])[CH2:17][N:18]([C:20](=[O:36])[CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH3:19])=[CH:12][C:11]=1[O:38][CH2:39][C:40]([O-:42])=[O:41])[C:6]([O-:8])=[O:7])(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[NH:26]1[CH2:27][CH2:28][CH:23]([CH2:22][CH2:21][C:20]([N:18]([CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:5][C:6]([OH:8])=[O:7])=[C:11]([O:38][CH2:39][C:40]([OH:42])=[O:41])[CH:12]=2)=[O:37])[CH3:19])=[O:36])[CH2:24][CH2:25]1
Reactant: CN(CC(=O)c1ccc(OC(C(=O)[O-])(C(C)(C)C)C(C)(C)C)c(OCC(=O)[O-])c1)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)c1ccc(OCC(=O)O)c(OCC(=O)O)c1)C(=O)CCC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The solution of 250 mg of the compound prepared in (a) in 2 ml of trifluoroacetic acid was stirred at room temperature for 3 hours. Afer the solvent was evaporated under reduced pressure, ether was added and deposited crystals were collected by filtration to give 168 mg of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH3:13])[CH:10]=[CH:9]2.Cl.Cl.[CH3:16][N:17]1[CH2:23][C:22]2[CH:24]=[C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:26]=[N:27][C:21]=2[NH:20][C:19](=[O:33])[CH2:18]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH3:13])[CH:10]=[CH:9]2)[C:30](=[O:31])/[CH:29]=[CH:28]/[C:25]1[CH:26]=[N:27][C:21]2[NH:20][C:19](=[O:33])[CH2:18][N:17]([CH3:16])[CH2:23][C:22]=2[CH:24]=1
Reactant: CNCc1cccc2ccn(C)c12
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(=O)Nc2ncc(/C=C/C(=O)N(C)Cc3cccc4ccn(C)c34)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of (methyl-(1-methyl-1H-indol-7-ylmethyl)amine (103 mg, 0.6 mmol), (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid dihydrochloride (160 mg, 0.5 mmol), HOBt (81 mg, 0.5 mmol) and diisopropylethylamine (0.41 mL, 2 mmol) in DMF (12 mL) was added EDC hydrochloride (114 mg, 0.6 mmol). The mixture was stirred overnight at room temperature. Water (75 mL) was added and the solution stirred for 1 hr. The precipitate was collected by filtration and triturated with hexanes to afford (E)-N-methyl-N-(1-methylindol-7-ylmethyl)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide (100 mg, 50%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 10.33 (m, 1H), 8.54-8.47 (m, 1H), 8.16-7.97 (m, 1H), 7.62-7.19 (m, 4H), 6.92-6.97 (m, 1H), 6.78-6.58 (m, 1H), 6.39 (d, J=3.1 Hz, 1H) 5.48-5.19 (2×s, 2H), 3.99-4.11 (2×s, 3H), 3.79-3.70 (2×s, 2H), 3.42-3.36 (m, 2H), 3.30-3.13 (2×s, 3H), 2.36-2.30 (2×s, 3H); ESI MS m/z 404 [C23H25N5O2+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][OH:24])=[C:9]2[CH3:25])=[CH:4][CH:3]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:57][C:58]1[CH:63]=[CH:62][C:61](O)=[CH:60][CH:59]=1>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][O:24][C:61]3[CH:62]=[CH:63][C:58]([I:57])=[CH:59][CH:60]=3)=[C:9]2[CH3:25])=[CH:6][CH:7]=1
Reactant: Cc1c(CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: Oc1ccc(I)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(COc2ccc(I)cc2)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1

Procedure:
Compound 6 (from Example A) (1 mmol) is added to a solution of diethylazodicarboxylate (1 mmol), triphenylphosphine (1 mmol) and 4-iodophenol (1 mmol) in dry THF (25 mL). The progress of the reaction is monitored by tlc. When the reaction is complete, water is added and the crude product is extracted in ethyl acetate. The extract is dried and evaporated and the title compound 25 is purified by HPLC.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[Cl:10][CH2:11][CH2:12]Cl.[OH-].[K+]>>[Cl:10][CH2:11][CH2:12][O:3][C:2]1[CH:4]=[CH:5][CH:6]=[CH:7][C:1]=1[O:8][CH3:9]
Reactant: ClCCCl
Reactant: COc1ccccc1O
Agent: [K+]
Agent: [OH-]
Product: COc1ccccc1OCCCl
Yield: 52.2 %

Procedure:
A mixture of 52.88 g (0.426 mol) of guaiacol (34), 50 ml (0.426 mol) of 1,2-dichloroethane, 88.3 g (0.639 mol) of potassium hydroxide and heated at reflux for 24 h. The mixture was concentrated and extracted into ethyl acetate and evaporate the solvent and purified by column chromatography to gave 41.47 g (52%) of 1-(2-Chloroethoxy)-2-methoxy benzene (35) as a white solid, mp 42-43° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:30]=[C:31]([CH2:42][O:43][CH2:44][CH3:45])[N:32]([CH2:33][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])([CH3:36])[CH3:35])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N+:26]([O-:9])=[CH:25][C:24]3[N:30]=[C:31]([CH2:42][O:43][CH2:44][CH3:45])[N:32]([CH2:33][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])([CH3:36])[CH3:35])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NS(C)(=O)=O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NS(C)(=O)=O
Reaction time: 2 h
Yield: 93.5 %

Procedure:
mCPBA (60% pure, 1.45 g,) was added to a solution of N-[2-(8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (2.37 g, 4.91 mmol) in chloroform (100 mL). The reaction was stirred for 2 hours and quenched by adding 50 mL of aqueous 2% sodium carbonate. The layers were separated and the aqueous fraction was extracted with two portions of chloroform. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 2.29 g of crude N-[2-(8-benzyloxy-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as an orange foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([C:7]([N:9](C(=O)C2C=CC(OC)=CC=2)[C:10]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:29]([CH3:31])[CH3:30])[CH:16]=3)[N:11]=2)=[O:8])=[CH:5][CH:4]=1.C(O)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C.[OH-].[K+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:29]([CH3:30])[CH3:31])[CH:16]=3)[N:11]=2)=[O:8])=[CH:42][CH:43]=1
Reactant: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N(C)C)cc3c(NCc3ccco3)c2C#N)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2nc3ccc(N(C)C)cc3c(NCc3ccco3)c2C#N)cc1

Procedure:
To the solution of 2.3 g of 4-methoxy-N-(4-methoxybenzoyl)-N-(6-dimethylamino-4-[2-furylmethylamino]-3-cyanoquinolin-2-yl)benzamide in 20 mL of acetonitrile, 5 mL of 1N methanolic potassium hydroxide solution is added. The reaction mixture is heated under reflux conditions for 10 minutes, 1.5 mL of glacial acetic acid is added to it, then it is neutralized with 15 mL of 1M sodium hydrogen carbonate solution. The precipitate is filtered off, the yellow crystalline material is recrystallized from the mixture of 5 ml of dimethylformamide and 40 mL of ethanol. After drying 1.1 g of the title compound is obtained, m.p.: 195° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[N:21][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(C#N)cn2)C1
Temperature: 140 °C

Procedure:
1.0 g (4.99 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate and 1.383 g (9.99 mmol) of 6-chloropyridine-3-carbonitrile and 1.29 g (9.99 mmol) of diisopropylethylamine were suspended in 40 ml of DMSO and heated in a microwave reactor at 140° C. for 45 min. Most of the DMSO was removed from the mixture by kugelrohr distillation, water was added and the resulting precipitate was filtered off. Drying under high vacuum gave 2.24 g (46% of theory) of the product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:23][C:22]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc(C(F)(F)F)cc2C1=O
Yield: 11.7 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-4-d: 120 mg, 0.558 mmol) was reacted with 3-iodo-4-methyl-pyridine (134 mg, 0.613 mmol), 1,4-dioxane (5 mL), copper iodide (10.6 mg, 0.0558 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (23.7 mg, 0.167 mmol) and potassium phosphate (354 mg, 1.674 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afforded 20 mg of the product (11.71% yield).
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1.O>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1ccc(F)c(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)ccc3F)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.9 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-4-fluorophenyl)propanoate (400 mg) in methanol (5.0 mL) and THF (10 mL) was added a solution of sodium hydroxide (305 mg) in water (10 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust to pH<4. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (350 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[O:14][CH3:15])#[N:2].[C:16]1([CH3:34])[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=[C:24]([C:30]([F:33])([F:32])[F:31])[N:23]=2)[CH:17]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([NH:29][CH2:28][C:27]2[C:22]([C:18]3[CH:17]=[C:16]([CH3:34])[CH:21]=[CH:20][CH:19]=3)=[N:23][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:25][CH:26]=2)=[O:12])=[CH:5][C:4]=1[O:14][CH3:15])#[N:2]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Reactant: COc1cc(C(C)C(=O)O)ccc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C(C)C(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)ccc1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.8 %

Procedure:
To a stirred solution of 2-(4-cyano-3-methoxyphenyl)propanoic acid (112 mg, 0.545 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (145 mg, 0.546 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (157 mg, 0.819 mmol), N-hydroxybenzotriazole (111 mg, 0.819 mmol) and triethylamine (0.19 mL, 1.36 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-Cyano-3-methoxyphenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (222 mg) was obtained as 90% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[CH:5]=O.[NH2:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([SH:17])([CH3:16])[CH3:15]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[NH:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([CH3:16])([CH3:15])[S:17]2)[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Solvent: CO
Product: CC1(C)SC(c2cc(Br)c(O)c(Br)c2)N[C@H]1C(=O)O
Reaction time: 16 h
Yield: 82.3 %

Procedure:
A solution containing 5.6 g (20 mmoles) of 3,5-dibromo-4-hydroxybenzaldehyde and 3 g (20 mmoles) of D-penicillamine in 100 ml of 30% methanol is stirred for 16 hours. The precipitated product is filtered and washed with aqueous methanol to give 6.77 g (82.3%) of the title acid which can be recrystallized from a mixture containing ethanol, dimethylformamide and water, m.p.: 154°-155° C., [α]D25 =+87° (c=1.362, dimethylsulphoxide).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=O)=[N:8][NH:9]2)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:23]=[C:22]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)[CH:21]=[CH:20][C:18]=1[NH2:19].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([NH:19][C:18]3[CH:20]=[CH:21][C:22]([B:24]4[O:25][C:26]([CH3:31])([CH3:32])[C:27]([CH3:30])([CH3:29])[O:28]4)=[CH:23][C:17]=3[O:16][CH3:15])=[O:14])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)O)n[nH]c2c1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(C(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3OC)n[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To 6-methoxy-1H-indazole-3-carboxylic acid (64 mg, 0.333 mmol) in dichloromethane (10 ml) was added 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (166 mg, 0.666 mmol), O-(7-azabenzotriazol-1-yl)1,1,3,3-tetramethyluronium hexafluorophosphate (190 mg, 0.500 mmol) and N,N-diisopropylethylamine (0.174 ml, 0.999 mmol). The reaction mixture was stirred overnight at room temperature. Then the reaction mixture was concentrated in vacuo and the residue was purified by column chromatograpy (silica gel; dichloromethane/methanol 99/1) and thereafter by column chromatograpy (silica gel; heptane/ethyl acetate 2/1) to give 6-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazole-3-carboxamide (54 mg).