Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]3[NH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=4)=[CH:18][N:19]=3)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4].[CH3:27][O:28][C:29](=[O:62])[NH:30][CH:31]([C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42]1[NH:43][C:44]([C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][CH:48]=2)=[CH:45][N:46]=1)=[O:36])[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]3[NH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:50]5[CH:51]=[CH:52][C:47]([C:44]6[NH:43][C:42]([CH:38]7[CH2:39][CH2:40][CH2:41][N:37]7[C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH3:27])=[O:62])[CH:32]([CH3:34])[CH3:33])=[N:46][CH:45]=6)=[CH:48][CH:49]=5)=[CH:22][CH:21]=4)=[CH:18][N:19]=3)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: COC(=O)N1CC(=O)N2C(CCC2c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCC6CN(C(=O)OC)CC(=O)N65)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 16 %

Procedure:
A mixture of 6-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (65 mg, 0.15 mmol), [2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (77 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol), potassium carbonate (42.8 mg, 0.31 mmol), 1,2-dimethoxyethane (4 mL) and water (1 mL) was heated in a microwave reactor at 120° C. for 20 minutes. The mixture was cooled and all volatiles were removed under reduced pressure. The resulting residue was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1% TFA in water and 0.1% TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide 6-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (16.8 mg, 0.024 mmol, 15%). C38H44BrN8O6 calculated 708.3 observed [M+1]+ 709.4; rt=1.39 min. 1H (DMSO-d6): δ=8.10 (s, 2H), 7.89 (m, 7H), 7.33 (d, J=9 Hz, 1H), 5.03 (t, J=7.8 Hz, 1H), 5.12 (m, 1H), 4.30 (m, 1H), 4.23 (m, 1H), 4.11 (t, J=8.1 Hz, 1H), 3.99 (m, 2H), 3.83 (m, 1H), 3.67 (s, 3H), 3.54 (m, 3H), 2.90 (m, 1H), 2.41 (m, 1H), 2.18 (m, 2H), 2.01 (m, 4H), 1.67 (m, 1H), 0.82 (m, 6H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([CH2:18][C:19]([OH:21])=O)[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[NH3:33].O>C1C=CC=CC=1.C(OC(=O)C)C>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([CH2:18][C:19]([NH2:33])=[O:21])[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C(O)Cc1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1
Solvent: c1ccccc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: NC(=O)Cc1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1
Yield: 91 %

Procedure:
3.54 grams 1,3,5-triphenyl-pyrazol-4-acetic acid, 1.68 gram phosphorus oxychloride and 30 milliliters benzene were mixed and the mixture heated to the boiling temperature under reflux for 2 hours. The reaction mixture, containing in benzene solution the correspondingly substituted acetyl chloride was then added dropwise at 0° C. to 30 milliliters 25% aqueous ammonia solution. The mixture was permitted to stand over night at room temperature. Thereafter, 30 milliliteres water and enough ethylacetate were added to cause dissolution of the crystalline mass formed in the reaction mixture. The organic phase was separated, dried with magnesium sulfate, evaporated and the residue was recrystallized from a mixture of ethanol and water. 3.2 grams 1,3,5-triphenyl-pyrazol-4-acetamide, melting at 207°-207.5° C., were obtained, representing a yield of 91%.
Reaction SMILES: NCC(N)C.[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH:15]([NH2:18])[CH2:16][NH2:17])[CH:10]=[C:11]([F:13])[CH:12]=1.[C:19]([NH:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=1)[C:31](O)=O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH2:14][CH:15]1[CH2:16][NH:17][C:31]([C:30]2[CH:34]=[CH:35][N:36]=[C:28]([NH:27][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:29]=2)=[N:18]1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: NCC(N)Cc1cc(F)cc(F)c1
Agent: CC(N)CN
Product: O=C(Nc1cc(C2=NC(Cc3cc(F)cc(F)c3)CN2)ccn1)c1ccccc1
Yield: 24 %

Procedure:
Following the procedure as described in Example 9, making variations as required to replace 1,2-diaminopropane with 3-(3,5-difluorophenyl)propane-1,2-diamine to react with 2-benzamidoisonicotinic acid, N-(4-(4-(3,5-difluorobenzyl)-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide was obtained in 24% yield: MS (ES+) m/z 393.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9](I)=[C:8]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:7]=1)[CH3:2].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[F-].[Cs+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9]([C:31]2[CH:32]=[CH:33][C:28]([C:27]([F:38])([F:37])[F:26])=[CH:29][CH:30]=2)=[C:8]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:7]=1)[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1cc(OCC(F)(F)F)c(I)c(OCC(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Cc1cc(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c(OCC(F)(F)F)c1
Temperature: 100 °C
Yield: 64.9 %

Procedure:
To a solution of [4-iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester (0.8 g, 1.65 mmol) in DME (anhydrous, 15 mL) under argon atmosphere were added 4-trifluoromethylphenylboronic acid (0.4 g, 2.10 mmol), CsF (0.6 g, 3.95 mmol), and Pd(PPh3)4 (0.3 g, 0.26 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give [2,6-bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-acetic acid ethyl ester (0.54 g, 70%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.64 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 6.68 (s, 2H), 4.28-4.16 (6H), 3.63 (s, 2H), 1.29 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ 170.6, 155.3, 136.1, 135.5, 131.0, 129.4, 129.0, 124.4 (q, 3JCF=3.9 Hz), 124.2, 122.9, 119.0, 109.2 (two signals), 66.5 (q, 2JCF=35.5 Hz), 61.3, 41.5, 14.2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C@@H:22]3[O:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)=[CH:18][CH:17]=2)=[O:14])=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[ClH:35]>O1CCOCC1>[ClH:35].[CH3:1][C:2]1[C:3]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C@@H:22]3[O:27][CH2:26][CH2:25][NH:24][CH2:23]3)=[CH:18][CH:17]=2)=[O:14])=[N:4][N:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)Nc1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nn(-c2ccccc2)nc1C(=O)Nc1ccc([C@H]2CNCCO2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Step b): To a solution of (S)-tert-butyl 2-(4-(5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxamido)phenyl)morpholine-4-carboxylate (106 mg, 229 μmol, Eq: 1.00) in dioxane (298 μl) was added 4 M HCl in dioxane (858 μl, 3.43 mmol, Eq: 15). The reaction mixture was stirred at 60° C. overnight. To the mixture was added 2 ml of dioxane and stirred for 15 min at room temperature. The mixture was filtered and concentrated under high vacuum to give the expected HCl salt as a white solid (82 mg, 90%)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[N+:8]([C:7]1[C:2]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Oc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
To a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1280 mg) in dimethylformamide (18 mL) were added phenol (800 mg) and cesium carbonate (5530 mg). The reaction mixture was stirred at 60° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and a saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified on silica gel column chromatography (hexane:ethyl acetate=1:19) to give the titled compound (370 mg) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH:24]=[CH2:25])(=[O:23])=[O:22])[CH2:17][C:16]2=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30]([OH:36])[C:31](=[CH:34][CH:35]=1)[CH:32]=O.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH2:25][O:36][C:30]4[CH:29]=[C:28]([Cl:27])[CH:35]=[CH:34][C:31]=4[CH:32]=3)(=[O:22])=[O:23])[CH2:17][C:16]2=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1O
Reactant: C=CS(=O)(=O)N1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CC1
Yield: 34.3 %

Procedure:
To a solution of the obtained 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-vinylsulfonyl-2-piperazinone (3.99 g) and 4-chlorosalicylaldehyde (1.61 g) in tert-butanol (35 ml) was added potassium t-butoxide (446 mg), and the mixture was refluxed for 4 days. The reaction solution was concentrated, and the residue was partitioned with ethyl acetate/water. The organic layer was washed with brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:4) to give colorless solid of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone (1.856 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH2:23])=[CH:21][N:22]=2)[N:19]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:21][N:22]=2)[N:19]=1
Reactant: Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a DCM (0.1 mL) solution of (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-amine (Preparation B; 6 mg, 0.019 mmol) cooled in an ice bath was added acetic anhydride (2.1 mg, 0.021 mmol), followed by pyridine (2 mg, 0.025 mmol). The reaction was warmed to ambient temperature and stirred for 1 hour before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield (R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)acetamide as an off-white solid (6 mg, 81% yield). MS (apci) m/z=358.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH+:10]([O-:16])[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)([O-:3])=[O:2].[H-].[Na+].S(OC)(O[CH3:23])(=O)=O.O>CN(C)C=O>[CH3:23][N+:10]([O-:16])([N:11]1[CH:12]=[CH:13][CH:14]=[CH:15]1)[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1ccncc1[NH+]([O-])n1cccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[N+]([O-])(c1cnccc1[N+](=O)[O-])n1cccc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
A solution of 4-nitro-N-(1H-pyrrol-1-yl)-3-pyridinamine- N-oxide (3.9 g) in 50 ml of dimethylformamide was added to a cooled suspension of sodium hydride (60% oil dispersion, 0.8 g, washed with hexanes) in 5 ml of dimethylformamide. After the anion formation, a solution of dimethyl sulfate (2.7 g) in 5 ml of dimethylformamide was added. After stirring twenty hours at ambient temperature, the reaction mixture was stirred with water and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to 4.5 g of oil. This oil was purified by flash chromatography (silica, 10% ethyl acetate in dichloromethane) to give 4 g of solid, mp 135°-140°. This material was purified by HPLC (silica, 20% ethyl acetate in dichloromethane) to give 3.5 g of solid, mp 140°-144°. This material was recrystallized from absolute ethanol to give 2.1 g of needles, mp 150°-151°.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:19][CH2:20][C:21]1([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[OH:27][C:21]1([CH2:20][NH:19][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Reactant: NCC1(O)CCCCC1
Agent: Cl
Product: O=C(NCC1(O)CCCCC1)c1cc(OCC2CC2)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 54, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 1-(aminomethyl)cyclohexanol hydrochloride (CAN 19968-85-5) as starting materials and isolated (70.5 mg, 58%) as a white solid; MS (ESI, m/z): 345.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([CH2:23][CH2:24][CH2:25][OH:26])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([O:26][CH2:25][CH2:24][CH2:23][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:27])[CH:8]=2)[NH:12][C:11]1=[O:16])(=[O:40])=[O:39]
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(CCCO)(c1ccccc1)C(=O)N2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1noc(C)c1-c1ccc2c(c1)C(CCCOS(C)(=O)=O)(c1ccccc1)C(=O)N2
Temperature: 0 °C
Yield: 65.3 %

Procedure:
A mixture of compound 5-(3,5-dimethylisoxazol-4-yl)-3-(3-hydroxypropyl)-3-phenylindolin-2-one (0.72 g, 2.0 mmol), DIPEA (1.05 mL, 6.0 mmol), MsCl (250 mg, 2.2 mmol) in CH2Cl2 (20 mL) was stirred at 0° C. then gradually raised to RT overnight. The contents were diluted with CH2Cl2, washed with water (2×10 mL), and concentrated. The crude was purified with flash chromatography to afford compound 3-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)propyl methanesulfonate (575 mg, 65.3%). 1H NMR (400 MHz, DMSO-d6): δH 10.73 (s, 1H), 7.24-7.38 (m, 7H), 7.02 (d, J=8.0 Hz, 1H), 4.13-4.16 (m, 2H), 3.12 (s, 3H), 2.37 (s, 3H), 2.30-2.34 (m, 2H), 2.20 (s, 3H), 1.30-1.48 (m, 2H). To a stirred solution of 3-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)propyl methanesulfonate (440 mg, 1.0 mmol) in dry THF (10 mL) was successively added triethylamine (280 μl, 2.0 mmol) and morpholine (174 mg, 2.0 mmol) at room temperature. The reaction mixture was heated at 80° C. for 15 h and then water (10 mL) was added. The aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate and filtered. After concentration of the filtrate in vacuo, the residue was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH: 95/5) to afford compound (385 mg, 89.3%) as a white solid. 1H NMR (400 MHz, CDCl3): δH 7.88 (s, 1H), 7.28-7.39 (m, 5H), 7.14-7.16 (m, 1H), 7.08 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 3.76 (m, 4H), 2.45-2.55 (m, 5H), 2.37-2.39 (m, 4H), 2.22-2.29 (m, 5H), 1.54-1.55 (m, 2H). MS (ESI) m/e [M+1]+ 432.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5]2.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5]3)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc2cc(O)ccc12
Reactant: COc1ccc(B(O)O)cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cccc2cc(Oc3ccc(OC)nc3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution/suspension of methyl 6-hydroxy-1-naphthoate (2.49 g, 12.3 mmol), 6-methoxypyridin-3-ylboronic acid (2.26 g, 14.8 mmol), copper acetate (2.46 g, 13.6 mmol), triethylamine (6.24 g, 61.7 mmol) and 4Å molecular sieves (2.00 g) in acetonitrile (120 mL) was stirred at RT for 16 h. The solids were filtered off. The filtrate was concentrated in vacuo. Water was added and extracted with EtOAc. The organic layer was washed with 1M aqueous NaOH solution, water, brine and dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography afforded the title compound.
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5](=[O:13])[NH:6][C@H:7]1[CH2:12][CH2:11][O:10][C:8]1=[O:9].[OH-:22].[Li+]>CO>[OH:10][CH2:11][CH2:12][C@H:7]([NH:6][C:5]([N:4]([CH2:3][CH2:2][SH:1])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:8]([OH:22])=[O:9]
Reactant: [OH-]
Reactant: O=C1OCC[C@@H]1NC(=O)N(CCS)CCc1ccccc1
Agent: [Li+]
Solvent: CO
Product: O=C(O)[C@H](CCO)NC(=O)N(CCS)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 48 %

Procedure:
(2S)-2-[3-(2-Mercaptoethyl)-3-phenethylureido]-4-butanolide (Compound No. 1-69, 2.9 g) is dissolved in methanol (19 ml) under a nitrogen atmosphere. A 2 N aqueous lithium hydroxide solution (5.6 ml) is added thereto under ice cooling, and the mixture is stirred under ice cooling for 50 minutes and further at room temperature for 35 minutes. The reaction mixture is concentrated under reduced pressure, a 10% aqueous citric acid solution is added to the concentrate, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.5 g (48%) of the titled compound (Compound No. 8-1).
Reaction SMILES: CN1CCOCC1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH2:20]([NH:24][CH:25]1[CH2:29][CH2:28][S:27][C:26]1=[O:30])[CH:21]([CH3:23])[CH3:22].O>ClCCl>[CH2:20]([N:24]([CH:25]1[CH2:29][CH2:28][S:27][C:26]1=[O:30])[S:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH:21]([CH3:23])[CH3:22]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CNC1CCSC1=O
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)N(CC(C)C)C2CCSC2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5 mmol of N-methylmorpholine and 2.5 mmol of 4-methoxyphenylsulphonyl chloride are added at 0° C. to a solution of 2.5 mmol of the compound obtained in Step A in 15 ml of dichloromethane. After stirring for 12 hours at ambient temperature, the reaction mixture is poured into water and then extracted with dichloromethane. The combined organic phases are washed with a 2N hydrochloric acid solution, then with a 5% solution of NaHCO3, and then with water. After drying over sodium sulphate, filtration and evaporation, chromatography on silica gel (dichloromethane/methanol: 20/1) allows the expected product to be isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[C:5]([CH3:20])[CH:4]=1.C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:15]1[C:16]2[C:11](=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:20])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[OH:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(-c2ccc3cc(O)ccc3c2)c(C)c1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)c(C)c1

Procedure:
The title compound was prepared by reacting 6-(4-methoxy-2-methylphenyl)-2-naphthol (800 mg, 3.03 mmol) and NCS (485 mg, 3.61 mmol) in THF (30 mL) according to method A to yield 640 mg (71%) of yellow solid: 1H NMR (DMDO-d6): δ 2.26 (3H, s), 3.79 (3H, s), 6.86 (1H, dd, J=8.36 Hz, J=2.63 Hz), 6.91 (1H, d, J=2.51 Hz), 7.22 (1H, d, J=8.34 Hz), 7.31 (1H, d, J=8.89 Hz), 7.56 (1H, dd, J=8.71 Hz, J=1.71 Hz), 7.79–7.83(2H, m), 8.04 (1H, J=8.91 Hz), 10.46 (1H, s); 13C NMR (DMDO-d6): δ 20.54, 55.07, 111.48, 112.21, 115.71, 118.73, 121.94, 127.92, 128.15, 128.35, 129.34, 130.12. 130.87, 133.26, 136.14, 136.36, 150.99, 158.49; MS (ESI) m/z 297/299 (M−H)−.
Reaction SMILES: [Na].[C:2]([O:8]CC)(=O)[CH2:3][C:4]([O-:6])=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])[CH:16]=[CH:17][CH:18]=1>CCO>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][N:21]2[C:2](=[O:8])[CH2:3][C:4](=[O:6])[NH:24][C:22]2=[O:23])[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(CCNC(N)=O)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: COc1cccc(CCN2C(=O)CC(=O)NC2=O)c1

Procedure:
Sodium (236 mg, 10.2 mmol, 2 eq.) was added to degassed EtOH (18 mL), when sodium dissolved completely, ethyl malonate (1.56 mL, 10.2 mmol, 2 eq.) was added and the reaction was refluxed for 1 h. Intermediate 1 (995 mg, 5.12 mmol, 1 eq.) in EtOH (4 mL) was then added and the reaction was refluxed for 1 day. The desired intermediate 37 1-[2-(3-methoxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione precipitated upon addition of 2N aqueous HCl, it was filtered and washed with H2O and finally dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8](O)=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[CH:14]1([NH:17][CH2:8][CH2:7][O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:16][CH2:15]1
Reactant: COc1cccc(OCC(=O)O)c1
Reactant: NC1CC1
Product: COc1cccc(OCCNC2CC2)c1

Procedure:
Synthesized according to typical procedures C and D from (3-methoxyphenoxy)-acetic acid and cyclopropylamine.