Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Br:12]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:12][C:6]1[CH:7]=[C:8]([CH:10]=[O:11])[S:9][C:5]=1[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C=O)s1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Cc1sc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.2 %

Procedure:
To a solution of 5-isobutylthiophene-2-carbaldehyde (192 mg, 1.14 mmol) in 3 mL acetic acid at room temperature was added bromine (0.07 mL, 1.36 mmol). The resulting solution was stirred at room temperature in the dark for 48 h before being poured into 35 mL saturated sodium bicarbonate. Organics were extracted with ether (2×30 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel (5% ethyl acetate in hexanes) to give 4-bromo-5-isobutylthiophene-2-carbaldehyde (147 mg, 52%). Used without further purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:14]([NH2:17])[CH2:15][CH3:16].C(O)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:17][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN
Reactant: COc1ccc2c(c1)CC(=O)CC2
Solvent: CCO
Solvent: CC(=O)O
Product: CCCNC1CCc2ccc(OC)cc2C1
Yield: 61 %

Procedure:
A solution of 7-methoxy-2-tetralone (32 mmol. 5 g), n-propylamine (60 mmol. 5 mL), acetic acid (60 mmol. 4 mL), molecular sieves 3A (5 g) in ethanol (25 mL) was stirred at room temperature for 2.5 hrs. The solution was filtered on paper in a Paar bottle and the reduction was carried out with PtO2 (100 mg) as the catalyst, under 30 PSI of hydrogen. When the pressure dropped to 6 PSI (30 min.), the catalyst was removed by elution onto a column (celite 545) with chloroform. The eluent was concentrated under vacuum. The residue, a brown oil, was converted to solid by formation of hydrogen chloride salt in ether/HCl. Several recrystallizations in ether/methanol (60/40) afforded the final product (1) as white crystals (4.28 g, 61% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:4]([S:11][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(Oc2c(N)cc(C(=O)O)cc2S)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Oc2c(N)cc(C(=O)O)cc2SCc2ccccc2)cc1
Reaction time: 17 h

Procedure:
5-Amino-4-(p-methoxyphenoxy)-3-mercaptobenzoic acid (2 g) is dissolved in 1 N sodium hydrogen carbonate (50 ml), and after addition of benzyl bromide (0.85 ml), the reaction mixture is stirred for 17 hours. After extraction twice with diethyl ether (25 ml), the aqueous layer is adjusted to pH 2 by addition of 4 N hydrochloric acid. The precipitated 5-amino-3-benzylthio-4-(p-methoxyphenoxy)-benzoic acid is collected and recrystallized from aqueous ethanol. After drying in vacuo at 80° C, the compound is obtained with a melting point of 158°-161° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:12]=[C:13](/[C:16](=O)[CH3:17])\[C:14]#[N:15].[NH2:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][C:22]#[N:23]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:12]1[C:21]([C:22]#[N:23])=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:16]([CH3:17])=[C:13]1[C:14]#[N:15]
Reactant: CC(=O)/C(C#N)=C/c1cc2c(C)n[nH]c2cc1F
Reactant: N#CC=C(N)C(F)(F)F
Product: CC1=C(C#N)C(c2cc3c(C)n[nH]c3cc2F)C(C#N)=C(C(F)(F)F)N1

Procedure:
Following the procedure described for Example 4, 250 mg (0.411 mmol) (2E)-2-[(6-fluoro-3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 4A) were treated with 3-amino-4,4,4-trifluorobut-2-enenitrile. The crude product was purified by preparative RP-HPLC (aceto-nitrile/water gradient, final mixture 90:10 v/v) to yield 159 mg (42% of th.) of the racemic title compound.
Reaction SMILES: [CH:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=1
Reactant: N#Cc1ccc(OCc2c(-c3ccccn3)noc2C=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Reaction time: 72 h
Yield: 94.7 %

Procedure:
A suspension of 6-(5-formyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinonitrile (0.77 g, 2.5 mmol) in methanol (20 mL) was cooled in an ice bath and treated with sodium borohydride (0.29 g, 7.7 mmol). The reaction mixture was allowed to reach room temperature and was stirred for 72 h. Additional sodium borohydride (0.29 g, 7.7 mmol) was added and stirring at room temperature was continued for 3 h. After quenching with methanol all volatile components were evaporated. The residue was partitioned (ethyl acetate/brine). The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound (0.73 g, 94%) as a brown solid. MS: m/e=309.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:13]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:13]
Reactant: COc1ccc(Br)cc1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(Br)cc1C#N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 5-Bromo-o-anisaldehyde (6.45 g), hydroxylamine hydrochloride (2.2 g), sodium acetate (4.1 g) and acetic acid (20 mL) was heated at 100 ° C. with stirring for 1 h. Acetic anhydride was added (20 mL) and the mixture was refluxed for 8 h. The reaction mixture was poured onto ice water and the mixture was made basic by the careful addition of 50% sodium hydroxide. The product was extracted with ether, the ether extracts were dried over magnesium sulfate and the sovent was removed in vacuo. The residue was crystallized from ether/hexane to afford 5-Bromo-2-methoxy-benzonitrile.
Reaction SMILES: [ClH:1].[O:2]1[CH2:7][CH2:6][N:5]([N:8]=[CH:9][C:10]2[CH:32]=[CH:31][C:13]([C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[O:23][CH2:22][CH:21]([CH2:27][C:28]([OH:30])=[O:29])[CH2:20]4)=[O:15])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.S(=O)(=O)(O)O>C(O)CCC>[ClH:1].[O:2]1[CH2:7][CH2:6][N:5]([N:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[O:23][CH2:22][CH:21]([CH2:27][C:28]([O:30][CH2:9][CH2:10][CH2:11][CH3:12])=[O:29])[CH2:20]4)=[O:15])=[CH:31][CH:32]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)CC1COc2ccc(NC(=O)c3ccc(C=NN4CCOCC4)cc3)cc2C1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)CC1COc2ccc(NC(=O)c3ccc(C=NN4CCOCC4)cc3)cc2C1
Temperature: 100 °C
Yield: 142.6 %

Procedure:
The compound (0.2 g) obtained in Example 5, was suspended in n-butanol. Concentrated sulfuric acid (0.1 ml) was dropwise added to the suspension and heated at 100° C. for an hour. The solvent was distilled off under reduced pressure and the concentrated residue was purified by reversed C18 column chromatography using a mixture, water:acetonitrile:trifluoroacetic acid=30:70:0.1, as a developer. The desired fraction was concentrated under reduced pressure. The concentrated residue was treated with a hydrochloric acid/dioxane solution to obtain the entitled compound (0.16 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][N:16]2[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[F:29][C:26]([F:27])([F:28])[C:25]([N:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]1[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)=[O:30]
Reactant: O=C(N1CCc2ccccc2C1c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(N1CCc2ccccc2C1c1ccc(O)cc1)C(F)(F)F
Yield: 102.3 %

Procedure:
A mixture of 1-[1-(4-benzyloxyphenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoroethanone (0.144 g, 0.35 mmol), ammonium formate (0.441 g, 7.00 mmol), and 20% Pd(OH)2/C (0.100 g) in MeOH (50 ml) was refluxed under N2 for 1.5 hr, then filtered through Celite. The filtrate was evaporated in vacuo to a yellow residue that was suspended in a mixture of H2O (15 ml) and saturated NaHCO3 solution (15 ml), then extracted with CHCl3 (4×15 ml). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give 0.115 g of colorless oil. Purification by flash chromatography, eluting with hexane:EtOAc (8:2) gave 0.100 g (89% yield) of colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:13]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])[CH3:14].C(OC1C=CC(C(O)=O)=CC=1OC)C>N1C=CC=CC=1>[CH2:13]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]([OH:12])[CH2:11][CH:2]2[CH3:1])=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])[CH3:14]
Reactant: CCOc1ccc(C(=O)Cl)cc1OC
Reactant: CC1CC(O)c2ccccc2N1
Agent: CCOc1ccc(C(=O)O)cc1OC
Solvent: c1ccncc1
Product: CCOc1ccc(C(=O)N2c3ccccc3C(O)CC2C)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
2-Methyl-1,2,3,4-tetrahydro-4-quinolinol (7.1 g, 43.5 mmol) synthesized in the published manner was dissolved in pyridine (50 ml), followed by addition of 4-ethoxy-3-methoxybenzoyl chloride prepared from 4-ethoxy-3-methoxybenzoic acid (9.2 g, 46.4 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated and extracted by addition of ethyl acetate and water. After the organic layer was dried and concentrated, the residue was applied to silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/1) and the resulting eluate was recrystallized from ethyl acetate-hexane to give the titled compound (4.4 g, yield: 30%) as a white crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]([O:23][CH2:24]Cl)=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:26].[Na+]>CC(C)=O>[I:26][CH2:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][O:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCC(=O)OCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCC(=O)OCI
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-propionate (2.05 g, 5.51 mmole) in dry acetone (50 ml) was added sodium iodide (4.12 g, 27.5 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl acetate water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield: 2.35 g=92%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][O:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C@@H:5]23)[CH:10]=1.[F:26][C:27]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C(O)(=O)C>[F:26][C:27]1[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][CH:14]1[N:7]2[C:8]3[C:4]([CH:5]4[CH2:18][NH:17][CH2:16][CH2:15][CH:6]42)=[CH:3][C:2]([NH2:1])=[CH:10][C:9]=3[CH2:11][O:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: Nc1cc2c3c(c1)C1CNCCC1N3C(Cc1cccc(C(F)(F)F)c1F)COC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B (35 mg, 0.10 mmol) in 5 mL of acetonitrile was added 2-fluoro-3-(trifluoromethyl)benzaldehyde (38 mg, 0.20 mmol) and three drops of glacial acetic acid. The reaction was stirred at ambient temperature for 1 h and then there was added sodium triacetoxyborohydride (64 mg, 0.30 mmol). The reaction was stirred at ambient temperature for 3 h and then was quenched by the addition of aq ammonium hydroxide. The mixture was extracted with methylene chloride, washed with brine, dried (K2CO3) and concentrated. The residue was taken up in 10 mL of methylene chloride and then there was added 5 mL of trifluoroacetic acid. The reaction was allowed to stir at ambient temperature for 3 h and then was concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and the product containing fractions were concentrated, free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 126. 1H NMR (CDCl3) δ: 7.55-7.40 (m, 2H), 7.12 (t, 1H, J=7.7 Hz), 6.31 (d, 1H, J=2.0 Hz), 6.15 (d, 1H, J=1.9 Hz), 4.48 (ABq, 2H, JAB 14.3 Hz), 4.32 (s, 2H), 4.12 (app d, 1H), 3.63 (app t, 1H), 3.30-3.20 (m, 2H), 3.18-2.98 (m, 4H), 2.56 (app t, 1H), 2.43 (app t, 1H), 2.05-1.92 (m, 2H). LRMS (ES)+: 422.3 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:4]1.C(=O)(O)[O-].[Na+].[Br-].[K+].Cl[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>CC1(C)N([O])C(C)(C)CCC1.C(OCC)(=O)C>[CH:2]([C@H:3]1[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:4]1)=[O:1]
Reactant: CON(C)C(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1
Reaction time: 2 h
Yield: 93.1 %

Procedure:
2-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (30.0 g), ethyl acetate (240.0 mL), sodium bicarbonate (28.5 g), potassium bromide (3.0 g), and TEMPO (0.06 g) were added to a reactor. The temperature of the reaction mixture was adjusted to 0˜5° C. 10% Sodium hypochlorite solution (96.0 mL) was slowly added to the reaction mixture, which was then stirred at 0˜5° C. for 2 hours. 5% Sodium sulfite solution (150.0 mL) was added to the reaction mixture. The separated organic layer was washed with 10% sodium chloride solution (150.0 mL). The organic layer was concentrated under reduced pressure to obtain 2-[(4R,6S)-6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide as a light brown solid (27.7 g, yield 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:27]([NH:29][CH2:30][CH2:31][OH:32])=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+:35]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([O-:33])=[C:14]([C:27]([NH:29][CH2:30][CH2:31][OH:32])=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[Na+:35]
Reactant: Cn1ccnc1Cn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccnc1Cn1c(=O)c(C(=O)NCCO)c([O-])c2ncc(Cc3ccc(F)cc3)cc21
Yield: 92 %

Procedure:
In a manner similar to that described in example 474, from 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-1-[(1-methyl-1H-imidazol-2-yl)methyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (336 mg, 0.744 mmol described in example 468) and 1 N sodium hydroxide was prepared sodium 7-[(4-fluorophenyl)methyl]-3-{[(2-hydroxyethyl)amino]carbonyl}-1-[(1-methyl-1H-imidazol-2-yl)methyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-4-olate (324 mg, 92% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.61 (s, 1 H), 8.16 (s, 1 H), 7.95 (s, 1 H), 7.27 (m, 2 H), 7.08 (m, 2 H), 6.98 (s, 1 H), 6.73 (s, 1 H), 5.36 (s, 2 H), 4.76 (br s, 1 H), 3.95 (s, 2 H), 3.62 (s, 3 H), 3.46 (br s, 2 H), 3.30 (br s, 2 H); MS m/z 452 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N+:3]=1[O-:20]
Reactant: CC(C)(C)c1ccnc(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc[n+]([O-])c(Cl)c1
Yield: 90 %

Procedure:
2-Chloro-4-t-butylpyridine (5.0 g, 30 mmol) was dissolved in chloroform (75 mL), treated with MCPBA, ca. 75% (8.3 g, 36 mmol, 1.2 equivalents) and heated to reflux for 19 h. The mixture was stirred with sodium bisulfite solution until testing with starch-iodide paper indicated consumption of oxidant. The pH was adjusted to 7 with saturated aqueous NaHCO3 solution, the phases separated and the aqueous phase extracted once with CH2Cl2. The organic phases were pooled and washed twice with H2O, once with brine, dried (Na2SO4) and concentrated in vacuo to afford 2-chloro-4-t-butylpyridine-N-oxide (5.0 g, 90%), which crystallized to long white needles on standing.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:11]=[C:9]1[CH2:10][C:4]2[CH:3]=[C:2](/[CH:16]=[CH:15]/[C:14]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C1CCCc2ccc(Br)cc2C1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc2c(c1)CC(=O)CCC2
Temperature: 100 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
A mixture of 3-bromo-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (2.00 g), ethyl acrylate (1.26 g), palladium acetate (94 mg), tris(2-methylphenyl)phosphine (764 mg), triethylamine (1.69 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 20 hours under nitrogen atmosphere. After cooling, ice water (20 ml) was added to the mixture. The resulting precipitates were collected by filtration and the powder was dissolved in ethyl acetate (20 ml). The solution was washed with water (20 ml) three times, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform as an eluent to give ethyl (E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)acrylate (1.34 g).
Reaction SMILES: O.[NH2:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(=O)([O-])O.[Na+].[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32](ON2C(=O)CCC2=O)=[O:33])[CH:27]=[CH:28][CH:29]=1)#[N:23]>O1CCOCC1>[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]([NH:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:33])[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: N#Cc1cccc(C=CC(=O)ON2C(=O)CCC2=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccc(C=CC(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To water (80 mL)-dioxane (80 mL) solution of L-tryptophan (3.0 g) was added sodium hydrogencarbonate (1.3 g) at 0° C., and the mixture was stirred for 30 minutes at room temperature. Next, dioxane (80 mL) solution of the compound obtained in Example 117 (4.2 g) was added to the mixture solution at 0° C., the mixture was stirred for 17 hours at room temperature. The reaction mixture was concentrated to a ⅓ volume under a reduced pressure, thereafter the solution was made acidic with a 10% aqueous citric acid solution, and the crystals precipitated were filtered. The crystals were washed with water, to give the captioned compound (4.6 g, 87%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:4])=[O:3].Cl[C:19]1[NH:27][C:26]2[C:21](=[N:22][C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:24][CH:25]=2)[N:20]=1>>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][N:15]([C:19]2[NH:27][C:26]3[C:21](=[N:22][C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:24][CH:25]=3)[N:20]=2)[CH2:14][CH2:13]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccccc1N1CCNCC1
Reactant: Clc1nc2nc(-c3ccccc3)ncc2[nH]1
Product: CS(=O)(=O)Nc1ccccc1N1CCN(c2nc3nc(-c4ccccc4)ncc3[nH]2)CC1

Procedure:
By following the same reaction as described in Example 19 except that 1-(2-methylsulfonylaminophenyl)piperazine was used in place of 3-tert-butoxycarbonyl-cis-3,7-diazabicyclo[3.3.0]octane, and 8-chloro-2-phenylpurine was used in place of 2-chloro-5-phenylbenzimidazole, the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:4][C:3]=1[CH:15]=[CH2:16].Cl.[CH3:18]O>CCOCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:18])=[CH:4][C:3]=1[CH:15]=[CH2:16]
Reactant: C=Cc1cc(OC[C@H]2CCCN2)cnc1Cl
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: C=Cc1cc(OC[C@H]2CCCN2C)cnc1Cl

Procedure:
To a solution of 6-chloro-5-ethenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine in Et2O was added hydrogen chloride (1.0 M in Et2O) carefully to afford the tittle compound: mp 173-175° C.; 1H NMR (D2O) δ 2.04-2.18 (m, 2H), 2.23 (m, 1H), 2.40 (m, 1H), 3.04 (s, 3H), 3.29 (m, 1H), 3.73 (m, 1H), 3.95 (m, 1H), 4.37 (dd, 1, J=6.0, 11.0 Hz), 4.53 (dd, 1H, J=3.0, 11.0 Hz), 5.61 (d, 1H, J=11.0 Hz), 5.94 (d, 1H, J=17.5 Hz), 7.02 (dd, 1H, J=11.0, 17.5 Hz), 7.73 (d, 1H, J=3.0 Hz), 8.04 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 253 (M+H)+. Anal. Calcd for C13H17ClN2O.1.1 HCl: C, 53.32; H, 6.23; N, 9.57. Found: C, 53.51; H, 6.48; N, 9.20. [α]25D +7.4 (c 0.66 MeOH).