Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].[OH-].[Na+]>O1CCCC1.O>[CH3:22][S:23]([NH:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-amino-4-nitrobenzoate (600 mg) and triethylamine (2.9 mL) were dissolved in tetrahydrofuran (11 mL), methanesulfonyl chloride (0.51 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. Methanol (18 mL) and 1N aqueous sodium hydroxide solution (9.1 mL) were added to the obtained residue, and the mixture was stirred at 50° C.-60° C. After completion of the reaction, to the reaction mixture was added aqueous sodium hydroxide solution, and the mixture was partitioned with ethyl acetate. The aqueous layer was neutralized with diluted hydrochloric acid, and the precipitated solid was collected by filtration to give 2-methanesulfonylamino-4-nitrobenzoic acid (358 mg). Using the obtained 2-methanesulfonylamino-4-nitrobenzoic acid (358 mg) and 1-(2,4-dimethylphenyl)piperazine (262 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, N-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-nitrophenyl}methanesulfonamide (330 mg) was obtained. Then, to a solution of ethanol (5.4 mL) and water (1.8 mL) were added ammonium chloride (528 mg) and iron (379 mg), and the obtained N-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-nitrophenyl}methanesulfonamide (267 mg) was added while stirring at 60° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (268 mg).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:16]([O:18]C)=[O:17].[I-].[Li+].O>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1cnc2c3ccccc3ncn2c1=O
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnc2c3ccccc3ncn2c1=O
Temperature: 150 °C
Reaction time: 2 h
Yield: 15.1 %

Procedure:
A mixture of methyl 4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (6.3 g) and lithium iodide (15.8 g) in N,N-dimethylformamide (100 ml) was stirred for 2 hours and a half at 150° C. and then cooled to ambient temperature. To the reaction mixture was added water separated by filtration, washed with water (600 ml) and dried to give crystalline 4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylic acid (0.9 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:7]=1[CH3:8].Br[C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[C:24]([NH2:29])[N:25]=[CH:26]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.O>C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:1][C:2]1[C:7]([CH3:8])=[C:6]([C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[C:24]([NH2:29])[N:25]=[CH:26]3)=[CH:21][CH:20]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1c(F)cncc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1cc2ccc(Br)cc2cn1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(F)cncc1-c1ccc2cc(N)ncc2c1
Temperature: 120 °C
Yield: 83.2 %

Procedure:
A mixture of 3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (261 mg; 0.7706 mmol), 7-bromoisoquinolin-3-amine (233.1 mg; 1.045 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (52.8 mg; 0.0746 mmol), potassium carbonate (338 mg; 2.44566 mmol), acetonitrile (3.0 mL; 57 mmol) and water (0.30 mL; 17 mmol) was heated at 120° C. for 40 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (25 g silica, solvent gradient: 0-5% methanol in dichloromethane) to yield 162.4 mg (83%) of the title compound. LCMS (ESI): M+H=254.2; 1H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.50 (s, 1H), 8.37 (s, 1H), 7.86 (s, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.51 (dd, J=8.6, 1.6 Hz, 1H), 6.67 (s, 1H), 6.04 (s, 2H), 2.25 (d, J=2.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:32])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: Cc1ccccc1B(O)O
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccccc1-c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 78.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), o-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.054 g (79%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:39]([CH2:38][CH2:37][C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:13])=[O:14]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: NCCc1ccc(F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(CCc2ccc(F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(4-Fluoro-phenyl)-ethylamine. MS (ESI): 451.3 (MH+).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])[CH:2]=[CH2:3].B1C2CCCC1CCC2.C([O-])([O-])=O.[K+].[K+].Br[C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][N:32]=1>CN(C=O)C.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:3][CH2:2][CH2:1][N:4]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:14])=[N:32][CH:33]=1
Reactant: C=CCN1C(=O)c2ccccc2C1=O
Reactant: Brc1ccc(Br)nc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.3 %

Procedure:
To a stirred solution of 2-allyl-isoindole-1,3-dione (3-1) (18.9 g, 101 mmol) in degassed TBF (100 mL) at 0° C. was added dropwise a solution of 9-BBN (243 mL of 0.5M in THF, 121 mmol) and the mixture stirred for 18 hours at ambient temperature. K2CO3 (24 g, 172 mmol) and 2,5-dibromopyridine (30 g, 126 mmol) were added, followed by a premixed and aged (70° C. for 30 min) suspension of Pd(OAc)2 (2.6 g, 11.5 mmol) and DPPF (7 g, 12.6 mmol) in degassed DMF (100 mL). The resulting mixture was stirred for 18 hours at 70° C., cooled, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated. To the stirring residue dissolved in TUF (500 mL) were added water (150 mL) and NaHCO3 (33 g) and after 10 minutes, NaBO3•H2O (55 g). After vigorous stirring for 30 minutes, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated to an oil. The residue was chromatographed on silica gel (10-20% EtOAc/hexane) to give 13 g of 3-2 as a colorless oil.
Reaction SMILES: C[C@H]1[C@]2(C)C[C@H](C(C)=C)CCC2=CCC1.ON1C(=O)C2=CC=CC=C2C1=O.[CH3:28][C@H:29]1[C@:35]2([CH3:43])[CH2:36][C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C:34]2=[CH:33][C:31](=[O:32])[CH2:30]1>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.CC(CC(C)=O)=O.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Co].C(#N)C>[CH3:28][C@H:29]1[C@:35]2([CH3:43])[CH2:36][C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C:34]2=[CH:33][C@@H:31]([OH:32])[CH2:30]1
Reactant: C=C(C)[C@@H]1CCC2=CC(=O)C[C@@H](C)[C@]2(C)C1
Agent: [Co+2]
Agent: [Co]
Agent: C=C(C)[C@@H]1CCC2=CCC[C@@H](C)[C@]2(C)C1
Solvent: CC#N
Solvent: CC(=O)CC(C)=O
Solvent: O
Product: C=C(C)[C@@H]1CCC2=C[C@@H](O)C[C@@H](C)[C@]2(C)C1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
In a flask 316.1 g (1.1 mol) of valencene with a purity of 71% by weight, 22.28 g (0.14 mol) of N-hydroxyphthalimide, 6.97 g (0.028 mol) of cobalt(II) acetate tetrahydrate, 29.93 g (0.084 mol) of tris(acetylacetonato)cobalt(III), and 3230 g of acetonitrile were placed and were stirred at 40° C. at a pressure of 13 kgf/cm2 (=1.3 MPa) for 2 hours under flow of air at a rate of 150 L (under standard conditions) per hour. The resulting mixture was further treated with 22.84 g (0.14 mol) of N-hydroxyphthalimide with stirring at 40° C. for 2 hours. The reaction mixture was analyzed by gas chromatography and was found that a target compound nootkatone and nootkatol were produced in yields of 53.7% and 1.4%, respectively, with a conversion from valencene of 100%. The reaction mixture was further analyzed by high-performance liquid chromatography and was found to contain 4.4 g of N-hydroxyphthalimide, 0.7 g of phthalimide, and 18.8 g of tris(acetylacetonato)cobalt(III).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:14]=[C:12]([CH3:13])[CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1cccc(C=O)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3.05 g of 3-hydroxybenzaldehyde, 2.3 ml of bromoacetone and 30 ml of dimethylformamide was added 4.15 g of potassium carbonate, and this was heated and stirred at 70° C. for 30 minutes. After cooled to room temperature, insolubles were filtered and the filtrate was concentrated under reduced pressure. Water was added to the resulting residue, and then extracted with ethyl acetate. The organic layer was washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to obtain 0.76 g of oily 3-(2-oxo-propoxy)benzaldehyde [Compound No. (o)].
Reaction SMILES: [NH2:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])(=[O:4])=[O:3].C(Cl)CCl.[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:61])[C@@H:33]1[CH2:40][N:39]2[C:41]3[CH:42]=[C:43]([C:54](O)=[O:55])[CH:44]=[CH:45][C:46]=3[C:47]([CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)=[C:38]2[C:37]2[CH:57]=[CH:58][CH:59]=[CH:60][C:36]=2[O:35][CH2:34]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:61])[C@@H:33]1[CH2:40][N:39]2[C:41]3[CH:42]=[C:43]([C:54]([NH:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[O:9])(=[O:3])=[O:4])=[O:55])[CH:44]=[CH:45][C:46]=3[C:47]([CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)=[C:38]2[C:37]2[CH:57]=[CH:58][CH:59]=[CH:60][C:36]=2[O:35][CH2:34]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: NS(=O)(=O)CCCC(=O)OCc1ccccc1
Reactant: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)CCCC(=O)OCc4ccccc4)cc3n2C1
Yield: 37 %

Procedure:
Benzyl 4-(aminosulfonyl)butanoate (1.3 eq)(prepared as described in step 1), DMAP (2.5 eq) and EDC (1.5 eq), were added to a solution of (7R)-7-[{2-[(tert -butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (0.03 M) in DCM. The reaction was stirred under N2 at RT for 24h, before volatiles were removed in vacuo to leave the crude product as a yellow gum, which was purified by automated RP-HPLC (WATERS XTERRA column; MeCN/H2O/0.1% TFA gradient). Fractions containing the pure compound were combined and lyophilized to afford the product as a white powder (37%). (ES+) m/z 787 (M+H)+
Reaction SMILES: FC(F)(F)C(C(O)=O)=O.[NH2:10][CH:11]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)[CH2:16][CH2:15]1)=[O:13].[CH:40]([N:43]1[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]1[CH2:52][C:53](O)=[O:54])([CH3:42])[CH3:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH:11]([NH:10][C:53](=[O:54])[CH2:52][C@@H:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:51][N:43]2[CH:40]([CH3:41])[CH3:42])[C:12](=[O:13])[N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:26][N:27]3[CH:31]=[N:30][CH:29]=[N:28]3)[CH2:16][CH2:15]2)=[CH:38][CH:37]=1
Reactant: CC(C)N1Cc2ccccc2C1CC(=O)O
Reactant: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2Cn2cncn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1Cc2ccccc2[C@H]1CC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2Cn2cncn2)CC1
Reaction time: 3 h
Yield: 17.4 %

Procedure:
To a solution of 2-amino-3-(4-chloro-phenyl)-1-[4-(2-[1,2,4]triazol-1-ylmethyl-phenyl)-piperazin-1-yl]-propan-1-one trifluoroacetyl carboxylate salt(0.30 g, 0.55 mmol), (2-isopropyl-2,3-dihydro-1H-isoindol-1-yl)-acetic acid (0.12 g, 0.55 mmol), HATU (0.21 g, 0.55 mmol) in DCM was added DIPEA (0.19 mL, 1.13 mmol). After about 3 hours, the solution was purified by silica gel chromatography (eluent: 3% 2.0M NH3 in MeOH/DCM). The purified fractions were combined and concentrated under reduced pressure to give the final compound as white foam (0.06 g, 18%). ES MS 626.3 (M+H)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C(#N)C.Br[CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]>O>[CH2:25]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH2:24][CH2:23][CH:22]=[CH2:21]
Reactant: C=CCCCBr
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C=CCCCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a mixture of 15 g (0.105 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 15.93 g (0.115 mol) of K2CO3, and 100 ml of acetonitrile is added dropwise 14.41 ml (0.105 mol) of 5-bromopentene. The mixture is stirred overnight at room temperature and then at 65° C. for 2 hours. After cooling, the mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to furnish 18.62 g (84%) of title compound as an oil: IR (neat) 2940 and 1090 cm-1 ; NMR (CDCl3) δ5.84 (m, 1H), 5.02 (m, 2H), 3.96 (s, 4H), 2.70-1.40 (m, 14H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].O=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6](/[N:7]=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=O
Reactant: COc1ccc(N)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=N\c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
To a round bottom flask was added 4-methoxyaniline (10 g, 81 mmol), toluene (100 mL) and Na2SO4 (40 gm). Then a solution of ethyl 2-oxoacetate (8.29 gm, 81 mmol) in toluene (20 mL) was slowly added to the reaction over 45 min. The reaction was stirred at rt for an additional 30 min. Then, the Na2SO4 was filtered off and the filtrate was concentrated to give (Z)-ethyl 2-(4-methoxyphenylimino)acetate (5.0 g, 24 mmol, 30% yield) as a clear oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16].CC(C)([O-])C.[K+].O>CC(N(C)C)=O>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(C)c21
Temperature: 97.5 °C
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
A solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (20.4 g, 96.55 mmol) in DMA (117 mL) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (26.0 g, 96.55 mmol) and potassium tert-butoxide (11.4 g) in DMA (96 mL) at room temperature. The mixture was stirred at 95-100° C. for 1.5 h. Water (221 mL) was added at 80-100° C. The precipitate was collected at room temperature and dried over under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (35.8 g) as crude product. The obtained crude 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (10.0 g) was dissolved in DMSO (150 mL) at 90-100° C. The solution was filtered through filter paper and washed with DMSO (10 mL). The combined filtrate was slowly added to a mixture of crystals (Form G: 100 mg) obtained in 120p) (as seed crystals) in AcOEt (100 mL) at 5-30° C. After stirring at room temperature for 17 h, the mixture was stirred at 70° C. for 1 h. The mixture was gradually cooled to 25° C. and stirred for 2 h. The mixture was stirred at 0-10° C. for 1 h and at room temperature for 1 h. The solids were collected by filtration and dried at 50° C. under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8.0 g) as white crystals (Form G).
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[CH:10]=[O:11].Cl[Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].O>CN(C=O)C.C(OCC)C>[CH3:15][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([O:6][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:14]=1)[CH:10]=[O:11]
Reactant: Cc1cc(O)cc(C=O)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
After adding 1.11 g of imidazole to a solution of 2.02 g of 3-hydroxy-5-methylbenzaldehyde [CAS No. 60549-26-0] in 20 ml of DMF, the reaction mixture was cooled to 0° C. Next, 3.56 ml of chlorotriisopropylsilane was added and the mixture was stirred at room temperature for 19 hours and 10 minutes. Water was added to the reaction mixture, and extraction was performed twice with diethyl ether. The organic layer was washed twice with water and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-diethyl ether) to give the title compound (3.86 g) as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([CH:29]=[O:30])[CH:23]=[CH:22]2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[C:9]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([CH:29]=[O:30])[CH:23]=[CH:22]4)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(B(O)O)cc1-c1ccccc1
Reactant: O=Cc1ccc2cc(Br)ccc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc3cc(C=O)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A mixture of 3-phenyl-4-methoxyphenyl boronic acid (0.465 g, 2.04 mmol), 6-bromo-2-naphthaldehyde (0.400 g, 1.70 mmol) and sodium carbonate (0.541 g, 5.10 mmol) in 10 mL of toluene:ethanol (4:1) and water (1 mL) was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine) palladium(0) (0.059 g, 0.05 mmol) was added and the mixture heated at reflux for 17 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:EtOAc, 9:1) to give 0.50 g of 6-(3-phenyl-4-methoxyphenyl)-2-naphthaldehyde (86%) as a solid. 1H NMR (300 MHz; DMSO-d6, 300 MHz): δ 3.90 (s, 3H), 7.12 (d, J=9.0 Hz, 1H), 7.33–7.50 (m, 3H), 7.55-7.65 (m, 2H), 7.68–7.75 (m, 2H), 7.87 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H), 7.97 (brs, 2H), 8.06 (d, J=9.0 Hz, 1H), 8.09 (d, J=1.0 Hz, 1H), 8.35 (s, 1H), 10.16 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.S(Cl)(Cl)=O.C(Cl)Cl.[N-:22]=[N+:23]=[N-:24].[Na+]>O.CN(C=O)C>[CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([N:22]=[N+:23]=[N-:24])=[O:14])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C(=O)O)cc2oc(=O)[nH]c12
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)N=[N+]=[N-])cc2oc(=O)[nH]c12
Temperature: 40 °C
Reaction time: 4 h

Procedure:
1.00 g (5.20 mmol) 4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carboxylic acid, 3.00 ml (41.1 mmol) thionyl chloride, 20 mL DCM and 1.0 mL DMF were combined and stirred for 4 h at 40° C. The reaction mixture was evaporated to dryness and co-evaporated with toluene. The residue was dissolved in acetone, combined with 340 mg (5.20 mmol) sodium azide and stirred for 1 h at RT. Then water was added, the precipitate formed was suction filtered and dried.