Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]([C:21]1[S:22][C:23]([S:36][CH3:37])=[C:24]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=2)(=[O:28])=[O:27])[CH:25]=1)=[NH:20])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.CCO>[C:12]([O:16][C:17](=[O:38])[NH:18][C:19](=[NH:20])[C:21]1[S:22][C:23]([S:36][CH3:37])=[C:24]([S:26]([C:29]2[CH:30]=[C:31]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=3)[CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH:25]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: C=Cc1ccc(B(O)O)cc1
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: CCO
Solvent: Cc1ccccc1
Product: C=Cc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)cc1
Yield: 44 %

Procedure:
Following the procedure outlined in Example 1, step c, reaction of 4-vinyl-phenyl-boronic acid (181 mg, 1.22 mmol), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (300 mg, 0.61 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosphine)palladium(0) (141 mg, 0.122 mmol, Strem Chemicals, Inc., Newburyport, Mass.), Na2CO3 (2.4 mL, 2M aqueous), and toluene/EtOH mixture (2:1, 7.2 mL) afforded 138 mg (45%) of the title compound as a white glassy solid after SiO2 flash chromatography (1:3 EtOAc/hexanes). 1H-NMR (CDCl3): δ 8.21 (t, 1H, 1.7 Hz), 8.00 (brs, 1H), 7.92–7.95 (m, 1H), 7.79–7.81 (m, 1H), 7.48–7.58 (m, 5H), 6.75 (dd, 1H, J=17.7, 10.9 Hz), 5.82 (d, 1H, J=17.5), 5.31 (d, 1H, J=10.9 Hz), 2.54 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.N[C:15](OCC)=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCO>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][C:15]1[NH:12][C:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[N:1]=1)[CH3:21]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: COC(=O)c1cccc(N)c1N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1nc2c(C(=O)OC)cccc2[nH]1
Yield: 106.2 %

Procedure:
A solution of methyl 2,3-diaminobenzoate (680 mg) and ethyl 3-amino-3-ethoxyacrylate hydrochloride (880 mg) in EtOH (12 mL) was stirred at 60° C. for 2 hours. EtOH was removed under reduced pressure, and the residue was purified on column chromatography to obtain the titled compound (1.14 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])CCC(OC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:36]O>C(O)(C)C>[CH2:1]([N:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[OH:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OO
Reactant: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)CCC(=O)OC
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCN(O)CCCCCCCCCCCCCC
Yield: 43.5 %

Procedure:
Using the general procedure of Example 2, 57.5 grams (0.116 mol) of the product of Example 7 in 450 ml of isopropanol is oxidized using 5.6 ml (0.15 mol) of 70% aqueous hydrogen peroxide solution to give 21.5 grams (44% yield) of the above-named product as a white solid melting at 94°-96° C.
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19]=[O:20])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].FC1C=C(C(NN)=O)C=CC=1C(OC)=O.[Cl-].[Na+]>C(O)(=O)C.O>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:19]=2[OH:20])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CNN=CC(C)=O
Reactant: CC(C)(C)c1ccc(C(=O)C=O)cc1
Agent: COC(=O)c1ccc(C(=O)NN)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
2-Oxopropanal methylhydrazone (46.375 mmol, 4.64 g) synthesized in Reference Synthetic Example 1 and (4-tert-butylphenyl)(oxo)acetaldehyde synthesized in Reference Synthetic Example 4 (46.375 mmol, 8.82 g) were dissolved in acetic acid (140 mL) and stirred at 100° C. for 2 hours. The reactor was cooled to room temperature, and after addition of water (100 mL) and saturated aqueous sodium chloride (50 mL), it was extracted with chloroform three times. The resulting organic layer was dried and filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the desired product as a yellow solid (5.79 g, yield 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:21][NH2:22].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH:22][N:21]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)C(=O)CC(=O)c1cc(Cl)cc(Cl)c1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1cc(-c2cc(Cl)cc(Cl)c2)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from step C (6.8 g, 21.7 mmol) in 125 mL of ethanol was added hydrazine (0.75 mL, 23.9 mmol) and 10 mL of glacial acetic acid. The reaction mixture was stirred at ambient temperature for 16 h then was concentrated in vacuo and the residue suspended in ethyl acetate. The organic layer was washed successively with two portions of saturated aqueous sodium bicarbonate solution and one portion of brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo to provide the title compound as a pale yellow solid which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[N:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:28]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:29])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(-c2cncc(CNC(=O)N3CCOCC3)c2)c(C#N)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e, 0.060 g, 0.202 mmol) in dichloromethane (2 mL) are added morpholine-4-carbonyl chloride (0.026 g, 0.222 mmol) and triethylamine (0.056 mL, 0.405 mmol) and the reaction is stirred at room temperature overnight. The mixture is then washed with water and extracted with dichloromethane twice. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford morpholine-4-carboxylic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide as a solid. 1H NMR (400 MHz, MeOD) δ ppm 3.41-3.47 (m, 4H), 3.66-3.72 (m, 4H), 3.84 (s, 3H), 4.55 (s, 2H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 8.11 (t, J=2.1 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H). MS (ESI) m/z 410.00 (M+H)+.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:18][O:19][CH3:20])[CH:9]=1)C>O1CCCC1.C(OCC)(=O)C>[C:24]([O:23][C:21](=[O:22])[N:16]([CH2:15][CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][CH2:6][OH:5])[CH:9]=1)[CH2:17][CH2:18][O:19][CH3:20])([CH3:25])([CH3:27])[CH3:26]
Reactant: CCOC(=O)Cc1cccc(CCN(CCOC)C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCN(CCc1cccc(CCO)c1)C(=O)OC(C)(C)C
Yield: 98.3 %

Procedure:
2M Lithium borohydride in tetrahydrofuran solution (0.7 mL) was added to a solution of (3-{2-[tert-butoxycarbonyl-(2-methoxy-ethyl)-amino]-ethyl}-phenyl)-acetic acid ethyl ester (230 mg) in tetrahydrofuran (10 mL) and heated to reflux for 1 hour. On cooling, the reaction was diluted with ethyl acetate and extracted sequentially, twice with saturated aqueous sodium bicarbonate solution, once with brine, dried over magnesium sulfate and evaporated, to give the subtitle compound as an oil (200 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH2:21][CH2:22][CH3:23])[CH:4]=1.[N-:24]=[N+:25]=[N-:26].[Li+]>CS(C)=O>[N:24]([CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH2:21][CH2:22][CH3:23])[CH:4]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1cc(CBr)ccc1OC(C(=O)OC)c1ccccc1
Agent: [Li+]
Solvent: CS(C)=O
Product: CCCc1cc(CN=[N+]=[N-])ccc1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 81 %

Procedure:
To a solution of 45 mg (0.12 mmol) of the product from Step H in 0.37 ml of dry DMSO was added 7.3 mg (0.15 mmol) of lithium azide. The solution was stirred at room temperature under N2 for 4.5 hours. After flash chromatography on silica gel (elution with 10:1 hexane-EtOAc), 33 mg (83%) of the title compound was obtained as a gum; satisfactory purity by TLC in 4:1 hexane-EtOAc.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]([B:12](O)O)[CH2:9][CH2:10][CH3:11]>C(Cl)Cl.CCOCC>[CH2:8]([B:12]1[O:7][CH2:6][CH2:5][NH:1][CH2:2][CH2:3][O:4]1)[CH2:9][CH2:10][CH3:11]
Reactant: OCCNCCO
Reactant: CCCCB(O)O
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCB1OCCNCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2′-azanediyldiethanol (26.12 g, 246 mmol) in DCM (250 ml) and ether (500 mL) was added n-butylboronic acid (25.4 g, 242 mmol) and molecular sieves (3 A, 4-6 mesh, 65 g). It was stirred at ambient temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting white solid was recrystallized with DCM/ether to provide white crystals as the title product. NMR (300 MHz, CDCl3): δ 0.47 (t, J=9 Hz, 2H), 0.88 (t, J=6 Hz, 3H), 1.20-1.37 (m, 4H), 2.82 (br, 2H), 3.24 (br, 2H), 3.95 (br, 4H), 4.27 (br, 1H). MS (DCI—NH3) m/z 172 (M+H)+.
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[Cs+].[Cs+].[OH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=2)[N:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:11]=1>CC(C)=O>[CH3:3][O:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=2)[N:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)n1nc(OC)c2cc([N+](=O)[O-])ccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
Iodomethane (10 ml) and cesium carbonate (4.89 g) were added to an acetone (20 ml) solution containing ethyl 3-hydroxy-5-nitro-1H-indazol-1-carboxylate (2.51 g) obtained in the 2nd step under ice cooling in a nitrogen atmosphere, followed by stirring at 80° C. for 0.5 hours. An insoluble precipitate was removed by filtration and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1). A white solid of ethyl 3-methoxy-5-nitro-1H-indazol-1-carboxylate (1.24 g) was thus obtained.
Reaction SMILES: [CH:1]([CH2:3][C:4]([CH3:12])([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].[CH2:13](O)[CH2:14][OH:15].O>C1(C)C=CC=CC=1>[O:8]1[CH2:9][CH2:10][O:7][CH:6]1[CH2:5][C:4]([CH3:11])([CH3:12])[CH2:3][C:1]([O:15][CH2:14][CH3:13])=[O:2]
Reactant: CCOC(=O)CC(C)(C)CC=O
Reactant: OCCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(C)(C)CC1OCCO1
Yield: 93.3 %

Procedure:
74 g of ethyl 4-formyl-3,3-dimethylbutanoate, prepared in Example 91, are dissolved in 450 ml of anhydrous toluene in the presence of 0.5 g of paratoluenesulfonic acid and 26.7 g of ethylene glycol. The mixture is heated to the reflux temperature and the water formed during the reaction is removed by means of a Dean-Stark apparatus. After refluxing for two hours, the solvent is evaporated off under vacuum and the residue is distilled to give 86.7 g of ethyl 4-(dioxolan-2-yl)-3,3-dimethylbutanoate in the form of a liquid with a boiling point b.p. of 138°-140° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@H:11]1[CH2:16][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[C:14](=[O:25])[CH2:13][N:12]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:29]([O:28][C:26]([N:12]1[C@@H:11]([CH2:10][CH2:9][OH:8])[CH2:16][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[C:14](=[O:25])[CH2:13]1)=[O:27])([CH3:31])([CH3:30])[CH3:32]
Reactant: [H][H]
Reactant: Cc1cccc(N2C[C@H](CCOCc3ccccc3)N(C(=O)OC(C)(C)C)CC2=O)c1C
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(N2C[C@H](CCO)N(C(=O)OC(C)(C)C)CC2=O)c1C

Procedure:
The product from Step D was dissolved in methanol (40 mL) and 10% Pd/C was added (0.160 g). The reaction was shaken under 60 psi hydrogen overnight. The catalyst was removed by filtration, and the solvent evaporated to give the title compound.
Reaction SMILES: [C:1]1([C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].[H-].[Na+].Cl>COCCOC.O>[C:1]1([C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH2:14][C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CC(=O)c1cccc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(=O)CC(=O)CC(=O)c1cccc2ccccc12

Procedure:
A solution of 1-(1-naphthalenyl)-1,3-butanedione (5.3 g) and diethyl oxalate (6.75 ml) in 1,2-dimethoxyethane (10 ml) was added dropwise to a stirred suspension of sodium hydride (3.6 g, 50% dispersion in mineral oil, washed with petrol 40°-60° C.) in 1,2-dimethoxyethane (40 ml) under nitrogen. The stirred mixture was heated under reflux for 5 minutes, cooled, acidified with 2 M hydrochloric acid (50 ml), diluted with water (50 ml) and filtered. The filtrate was extracted with ethyl acetate and the extract was dried and evaporated to yield ethyl 6-(1-naphthalenyl)-2,4,6-trioxohexanoate as a dark oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:22])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: O=C(O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CC(C)(C)OC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.1 %

Procedure:
3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid (0.20 g, 0.64 mmol) as dissolved in N,N-dimethylformamide (3 ml), and glycine tert-butyl ester (0.11 g, 0.67 mmol), WSC (0.25 g, 1.3 mmol) and HOBt (0.18 g, 1.3 mmol) were added successively thereto. The reaction mixture was stirred at room temperature for 17 hrs, concentrated under reduced pressure and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (15 g) column chromatography. The fractions eluted with hexane-ethyl acetate (1:1, v/v) were collected and concentrated to give the titled compound (0.27 g, 99%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N+:7]([O-])=[C:6]([C:11]2[O:12][C:13](=[O:17])[N:14]([CH3:16])[N:15]=2)[CH:5]=1)[CH3:2].C(OC1C=CN=C(C2OC(=O)N(C)N=2)C=1)C.C1C=C([Cl:40])C=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:40][C:8]1[N:7]=[C:6]([C:11]2[O:12][C:13](=[O:17])[N:14]([CH3:16])[N:15]=2)[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=1
Reactant: CCOc1cc[n+]([O-])c(-c2nn(C)c(=O)o2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CCOc1ccnc(-c2nn(C)c(=O)o2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1cc(Cl)nc(-c2nn(C)c(=O)o2)c1
Temperature: 0 °C
Yield: 75 %

Procedure:
Step-4: 4-Ethoxy-2-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridine1-oxide: A solution of 5-(4-ethoxypyridin-2-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (200 mg, 0.90 mmol) and mCPBA (156 mg, 0.90 mmol) in DCM (5 mL) was stirred at RT for 48 h. Ice water (10 mL) was added to the above reaction mixture, basified with aqueous saturated sodium bicarbonate solution (5 mL) and extracted with ethylacetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford 160 mg (75%) of title compound as a white solid. 1HNMR (400 MHz, DMSO) δ 8.29 (d, J=5.5 Hz, 1H), 7.32 (d, J=2.5 Hz, 1H), 7.13 (dd, J=5.5 & 2.5 Hz, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.42 (s, 3H), 1.32 (t, J=7.0 Hz, 3H); GC-MS (m/z) 237 (M)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][C:12]1[C:13]([N+:18]([O-:20])=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=1)(=O)=O.C(=O)(O)[O-].[Na+].C(Cl)Cl>CS(C)=O>[N:1]([CH2:10][CH2:11][C:12]1[C:13]([N+:18]([O-:20])=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCc1cccnc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: [N-]=[N+]=NCCc1cccnc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
Sodium azide (1.16 g, 17.8 mmol) was added to a solution of 3-(2-methansulfonyloxyethyl)-2-nitropyridine (0.44 g, 1.78 mmol) in dimethyl sulfoxide (5 mL), then stirred overnight at 50° C. The reaction was cooled and worked up with saturated sodium bicarbonate and methylene chloride. The organic phase was dried over sodium sulfate. This material was chromatographed (silica gel, 0-50% ethyl acetate in hexane, gradient elution) to produce the title compound (0.190 g) as a yellow oil. MS 194 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[C:4]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:52]([O:54][CH3:55])=[O:53]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:26]([O:25][C:23]([C:17]1[CH:16]=[N:15][N:14]([C:12]2[N:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=3[O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([CH:36]4[CH2:41][CH2:40][N:39]([C:52]([O:54][CH3:55])=[O:53])[CH2:38][CH2:37]4)=[CH:34][CH:35]=3)[CH:9]=[CH:10][CH:11]=2)[C:18]=1[C:19]([F:21])([F:22])[F:20])=[O:24])[CH3:27]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCNCC4)cc3)n2)c1C(F)(F)F
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCN(C(=O)OC)CC4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Example 5 Step C (194 mg, 0.34 mmol) in DCM (2 mL) were added diisopropyl ethyl amine (0.60 mL, 3.41 mmol) and methyl chloroformate (0.08 mL, 1.02 mmol). The reaction mixture was stirred for 1 h at ambient temperature, then was diluted with sat. aq. NaHCO3 and extracted with DCM. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was used in the subsequent step without further purification: LCMS m/z 626.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:41].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:41])[C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3cccnc3c2n1CCCC(=O)N1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CCCC(=O)N1CCOCC1

Procedure:
The method described in Part F of Example 37 was used to treat 2-(ethoxymethyl)-1-(4-morpholin-4-yl-4-oxobutyl)-1H-imidazo[4,5-c][1,5]naphthyridine (1.42 g, 3.70 mmol) with mCPBA (0.958 g, 5.55 mmol), ammonium hydroxide (4 mL), and p-toluenesulfonyl chloride (0.776 g, 4.07 mmol). Following the chromatographic purification, the resulting solid was dried for 48 hours under high vacuum at 120° C. to provide 0.614 g of 2-(ethoxymethyl)-1-(4-morpholin-4-yl-4-oxobutyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a tan powder, mp 156-157° C.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[C@@H:8]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:7][CH2:6][N:5]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C([BH-](CC)CC)C.[Li+]>C1COCC1>[C:20]([O:19][C:17]([N:5]1[CH2:6][CH2:7][C@H:8]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[C@H:4]1[CH2:3][OH:2])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of compound 1H (4.3 g, 12 mmol) in THF (75 mL) at −78° C. under nitrogen was added dropwise 1.0 M lithium triethylborohydride in THF (60 mL, 60 mmol). The reaction was allowed to warm to rt and stirred for 4 h. The reaction was quenched by pouring over ice (150 g) and stirring for 30 min. The product was extracted into EtOAc and washed with saturated aqueous NaHCO3. The organics were dried over MgSO4, filtered and concentrated. Purification by flash chromatography (silica gel, 0-15% EtOAc in hexanes) provided the title compound (3.3 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(I)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(I)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
4-Iodo-2-methylphenol (15.0 g, 64.1 mmol) was dissolved in N,N-dimethylformamide (250 ml), and imidazole (8.7 g, 128.2 mmol, 2.0 eq.) added to the mixture, tert-Butyldimethyl silyl chloride (10.6 g, 70.5 mmol, 1.1 eq.) was slowly added to the above mixture and stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was extracted with aqueous ammonium chloride solution and ethyl acetate, and dried over magnesium sulfate. The crude product was purified on silica flash column. The solvent was evaporated under reduced pressure to thereby yield 21.8 g of the title compound (yield: 97.5%).