Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:37]=[C:38]=[O:39])[CH2:35][CH3:36]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:38]([NH:37][CH2:34][CH2:35][CH3:36])=[O:39])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCN=C=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCNC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 18.9 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, propyl isocyanate (0.24 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 100:3) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(propylamino)carboxamide (0.13 g, 20%) as a white solid: mp 160-162° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.86-7.69 (m, 3H), 6.44 (t, J=5.9 Hz, 1H), 6.16 (t, J=1H), 5.18-5.11 (dd, J=5.3 and 12.4 Hz, 1H), 4.63 (d, J=5.9 Hz, 2H), 2.99-2.83 (m, 3H), 2.64-2.50 (m, 2H), 2.08-2.04 (m, 1H), 1.42-1.32 (m, 2H), 0.83 (t, J=7.3 Hz, 3H); 13C NMR (DMSO-d6) δ 172.78, 169.84, 167.59, 167.05, 158.03, 141.16, 134.62, 133.34, 131.51, 126.96, 121.63, 48.82, 41.18, 30.94, 23.15, 21.99, 11.33; Anal. Calcd. For C18H20N4O5: C, 58.06; H, 5.41; N, 15.05. Found: C, 57.94; H, 5.31; N, 14.90.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.Cl.[NH2:14][OH:15].CC([O-])=O.[Na+]>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[N:14][OH:15])[CH2:6][CH2:5]2
Reactant: NO
Reactant: O=C1CCc2cc(Br)ccc2C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCc2cc(Br)ccc2C1
Temperature: 25 °C

Procedure:
To a mixture of 6-bromo-3,4-dihydro-1H-naphthalen-2-one (5.370 g, 23.86 mmol) and hydroxylamine hydrochloride (2.487 g, 35.79 mmol) in EtOH (80 mL) was added a solution of NaOAc (5.871 g, 71.57 mmol) in H2O (20 mL). The mixture was heated to reflux for 2 h. The reaction was cooled to RT and concentrated in vacuo. The residue was suspended in H2O and filtered. The pad was washed with H2O (2×50 mL) and Et2O (2×50 mL) and the solids were dried in vacuo to furnish the title compound, which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH:9]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:22])([CH3:21])[CH2:10]2)[CH:3]=1.[CH3:23][O-:24].[Na+].[Na]>CO>[C:19]([C:16]1[CH:17]=[CH:18][C:13]2[O:12][C:11]([CH3:22])([CH3:21])[CH2:10][CH:9]([C:4]3[CH:3]=[C:2]([O:24][CH3:23])[CH:7]=[CH:6][N+:5]=3[O-:8])[C:14]=2[CH:15]=1)#[N:20]
Reactant: CC1(C)CC(c2cc(Cl)cc[n+]2[O-])c2cc(C#N)ccc2O1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc[n+]([O-])c(C2CC(C)(C)Oc3ccc(C#N)cc32)c1
Temperature: 25 °C

Procedure:
250 mg of 4-chloro-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide were dissolved in 6 ml of methanol and added to a solution of sodium methoxide prepared from 0.5 g of metallic sodium in 50 ml of methanol. The mixture was heated at reflux for 2 hours under a nitrogen atmosphere and then allowed to cool to room temperature. The solution was evaporated and the residue was taken up in ethyl acetate and water, the organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 20% (v/v) methanol/ethyl acetate for the elution to give a solid which was recrystallized from ethyl acetate. There were obtained 65 mg of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4 -yl)-4-methoxypyridine N-oxide of melting point 196°-198° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.C1(C(C2C=CC(Cl)=CC=2)O)CC1>O1CCCC1>[CH:11]1([CH:4]([C:3]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=2[Cl:1])[OH:5])[CH2:13][CH2:12]1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: OC(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1Cl)C1CC1

Procedure:
The title compound was prepared starting from 1.50 g (9.46 mmol) of 2-chloro-4-fluorobenzaldehyde and 28.4 ml (14.19 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 153A. 1.51 g (80% of theory) of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([OH:26])([CH3:25])[C:22]([OH:24])=O)[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:44])([C:40]([F:43])([F:42])[F:41])[CH2:38][NH2:39]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([OH:26])([CH3:25])[C:22]([NH:39][CH2:38][C:37]([F:44])([F:36])[C:40]([F:43])([F:42])[F:41])=[O:24])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Product: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-hydroxy-2-methyl-malonamic acid and 2,2,3,3,3-pentafluoro-propylamine, the title compound was prepared in the same manner as example 1c (59%). White solid. MS: m/e=606(M+H+).
Reaction SMILES: [CH2:1]([S:13][C:14]1[S:18][C:17]([SH:19])=[N:16][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].Cl[C:23]1[C:24]([C:29]#[N:30])=[N:25][CH:26]=[CH:27][N:28]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([S:13][C:14]1[S:18][C:17]([S:19][C:23]2[C:24]([C:29]#[N:30])=[N:25][CH:26]=[CH:27][N:28]=2)=[N:16][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: N#Cc1nccnc1Cl
Reactant: CCCCCCCCCCCCSc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCSc1nnc(Sc2nccnc2C#N)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to Example 1 by using 5-(dodecylthio)-1,3,4-thiadiazole-2-thiol (319 mg, 1.00 mmol), NaH (60% dispersion in mineral oil, 44 mg, 1.10 mmol), and 3-chloropyrazine-2-carbonitrile (140 mg, 1.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere overnight.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]([NH:22][CH:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)[CH3:21]>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:25]3[CH2:26][CH2:27][CH:23]([NH:22][CH2:20][CH3:21])[CH2:24]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CCNC1CCNC1
Solvent: CC#N
Product: CCNC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)C1
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To 1.0 g (3.7 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.56 g (3.7 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.44 g (3.7 mmol) of 3-(ethylamino)pyrrolidine. The mixture was refluxed for one hour, kept overnight at room temperature, filtered, and the solid washed with ether to give 0.81 g of 1-ethyl-7-[3-(ethylamino)-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, mp 227°-229° C.
Reaction SMILES: [C:1]1([C@@H:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:14]([NH:13][C@H:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:12])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](N)c1cccc2ccccc12
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N[C@@H](C)c1cccc2ccccc12
Temperature: 38 °C
Reaction time: 12 h
Yield: 59479.9 %

Procedure:
5 g of (S)-(-)-α-(1-naphthyl)ethylamine (manufactured by Hydras Kagaku) was dissolved in 20 ml of pyridine, and 5.07 mg of acetic anhydride was added thereto under cooling with ice. The mixture was stirred at 38° C. for 12 hours. The reaction solution was diluted with 500 ml of chloroform, and the organic layer was sequentially washed with a dilute hydrochloric acid aqueous solution, a dilute sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The reaction mixture thus obtained was recrystallized from dried ethanol to obtain 6.3 g of N-acetyl-(S)-α-(1-naphthyl)ethylamine. This substance is a known compound, and the measured values of various physical properties agreed to the values disclosed in literatures.
Reaction SMILES: CO[C:3](=[O:13])[CH2:4][CH2:5][O:6][N:7]=[C:8]([O:10][CH2:11][CH3:12])[CH3:9].[CH3:14][NH2:15].[CH3:16]O>>[CH2:11]([O:10][C:8](=[N:7][O:6][CH2:5][CH2:4][C:3](=[O:13])[NH:15][CH2:14][CH3:16])[CH3:9])[CH3:12]
Reactant: CCOC(C)=NOCCC(=O)OC
Reactant: CO
Reactant: CN
Product: CCNC(=O)CCON=C(C)OCC
Temperature: 60 °C
Reaction time: 13 h
Yield: 57 %

Procedure:
To a known compound, 3-(1-ethoxyethylideneaminooxy)-propanoic acid methyl ester (CAS No. 97164-30-2, 300 mg, 1.585 mmol) was added a 2 M solution of methylamine in methanol (7 ml), and the mixture was stirred at 60° C. for 13 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give N-(2-ethylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (182 mg, 57% yield).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([C:33]([O:35]C)=[O:34])=[O:32])=[CH:21][CH:20]=2)[C:7]([C:16]#[N:17])=[C:8]([CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-:37].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([C:33]([OH:35])=[O:34])=[O:32])=[CH:21][CH:20]=2)[C:7]([C:16]([NH2:17])=[O:37])=[C:8]([CH:10]([OH:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Agent: [Na+]
Product: CCCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1

Procedure:
335 mg of 2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]imidazole-5-carbonitrile [prepared as described in step (a) above] were subjected to hydrolysis using 7 ml of a 1N aqueous solution of sodium hydroxide in the same manner as described in Example 10(b), to give 256 mg of the title compound as a crystalline powder, melting at 192°-194° C. (with decomposition).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]>CC(C)=O>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH3:1])=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
Potassium carbonate (149 g, 1.08 mol) and iodomethane (252 mL, 4.05 mol) were added to a solution of 4-fluoro-3-nitrobenzoic acid (50 g, 0.27 mol) in dry acetone (700 mL) under argon. Overhead mechanical stirring was carried out for 16 hours. The reaction mixture was filtered, and acetone was removed under vacuum. The residue was partitioned between ethyl acetate and saturated potassium carbonate solution, the aqueous layer was washed with ethyl acetate, the combined organic layers were washed with saturated potassium carbonate solution, brine, dried over sodium sulfate, and concentrated to yield the title compound as a light yellow solid; m.p. 58.5°-59.50° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([C:12]([O:14]C)=[O:13])[N:8]=[CH:7][C:6]=2[C:5]([CH3:16])=[CH:4]1)[CH3:2].[OH-].[Na+]>C1COCC1>[CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[N:8]=[CH:7][C:6]=2[C:5]([CH3:16])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C)c2cnc(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCn1cc(C)c2cnc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 200-ml round bottom flask, methyl 1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1N, 6.0 g, 28 mmol) was dissolved in THF (50 ml). To the mixture was added a 2M NaOH (28 ml, 55 mmol) solution. The reaction was stirred at room temperature for 3 hrs. After completion, volatiles were removed and the residue was cooled in an ice bath and neutralized with dilute HCl to pH=4.0-4.5. The aqueous mixture washed with ethyl acetate (2×100 ml) and then lyophilized to give the crude product 1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid (10) which is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([NH2:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CC[O:23][CH2:22]C1.Cl[C:27](OCC(C)C)=O.CONC.Cl>C(Cl)Cl>[CH3:22][O:23][N:18]([CH3:27])[C:16](=[O:17])[CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(N)=O)CC1
Reactant: CN1CCOCC1
Agent: CNOC
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A mixture of 1.29 g (5.0 mmol) of 3-(1-(t-butoxycarbonyl)piperidin-4-yl)propionamide (from EXAMPLE 98, Step B) and 1.65 mL (15.0 mmol) of 4-methylmorpholine in 25 mL of CH2Cl2 at 0° C. was treated with 0.70 mL of isobutyl chloroformate. The resulting mixture was stirred cold for 15 min, then treated with 0.78 g (8.0 mmol) of O,N-dimethylhydroxylamine×HCl. The resulting mixture was stirred cold for 3.5 h, quenched with 100 mL of 0.5 N KHSO4, then extracted with 200 mL of ether. The extract was washed with 100 mL of 1.0 N NaOH, 50 mL of sat'd NaCM, dried and concentrated. Flash chromatography on 60 g of silica gel using 10:1 v/v, then 3:1 v/v CH2Cl2/EtOAc as the eluant afforded 1.31 g (91%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 1.07-1.18 (m, 2H), 1.38-1.69 (5H), 1.45 (s, 9H), 2.45 (t, J=7.6, 2H), 2.68 (app t, J=12.4, 2H), 3.18 (s, 3H), 3.69 (s, 3H), 4.05-4.11 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([O-])(O)=[O:11].[Na+].OOS([O-])=O.[K+]>CO.O>[NH:1]1[C:5]2=[N+:6]([O-:11])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C([O-])O
Reactant: c1cnc2[nH]ccc2c1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 1H-pyrrolo[2,3-b]pyridine (10.0 g) and NaHCO3 (45.2 g) in 1:1 MeOH/H2O (1000 mL) was added Oxone® (106 g) in portions during 40 min period. The mixture was stirred at RT for 5 h. The sold was removed by filtration and the filtrate was concentrated to 200 mL in volume. This aqueous phase was extracted with CH2Cl2 (200 mL×7) to afford 1H-pyrrolo[2,3-b]pyridine 7-oxide.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:24][S:25]([N:28]1[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[NH:31][CH2:30][CH2:29]1)(=[O:27])=[O:26]>N1C=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:31]3[CH2:30][CH2:29][N:28]([S:25]([CH3:24])(=[O:26])=[O:27])[CH2:34][CH2:33][S:32]3(=[O:36])=[O:35])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)N1CCNS(=O)(=O)CC1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)S(=O)(=O)CC1
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.147 g, 0.39 mmol), 5-(methylsulfonyl)-1,2,5-thiadiazepane 1,1-dioxide (0.081 g, 0.355 mmol) and Cu2O (0.056 g, 0.39 mmol) in pyridine (2.4 mL) were heated at reflux for 16 hr. The reaction was filtered and the solids washed with CHCl3 (100 mL). The filtrate was stirred for 1 hr with disodium ethylenediamine tetraacetate (0.2 g in water 10 mL) in the presence of air. The organic extracts were stirred for 1 hr with disodium ethylenediamine tetraacetate (0.2 g in water 10mL) in the presence of air. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[S:8][C:9]([Br:20])=[CH:10][C:11]=1[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].Cl>C1COCC1.O>[Br:20][C:9]1[S:8][C:7]([C:5]([OH:6])=[O:4])=[C:11]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]=1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(Br)sc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous 2 M lithium hydroxide solution (1 mL) was added to a solution of 5-bromo-3-tert-butoxycarbonylaminothiophene-2-carboxylic acid methyl ester (330.0 mg) in THF/water (1.6 mL/1.6 mL). The solution was stirred at room temperature overnight and was then neutralized with diluted HCl solution, and the solvent was removed in vacuo. The product with the molecular weight of 322.18 (C10H12BrNO4S) was obtained in this way; MS (ESI): 221, 223 (M-Boc+H+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:25]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:26][CH2:27][CH2:28]/[C:29](=[N:31]/[OH:32])/[NH2:30])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[CH:22][N:23]=4)[C:8]=3[CH:24]=2)[CH2:3][CH2:2]1.[C:37](N1C=CN=C1)([N:39]1[CH:43]=[CH:42][N:41]=[CH:40]1)=[S:38].C(OCC)(=O)C>O1CCCC1>[N:39]1([C:37]([O:32]/[N:31]=[C:29](\[NH2:30])/[CH2:28][CH2:27][CH2:26][N:25]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:24][C:8]3[C:9]([C:19]4[NH:20][CH:21]=[CH:22][N:23]=4)=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:33]([CH3:36])(=[O:35])=[O:34])=[S:38])[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: CS(=O)(=O)N(CCC/C(N)=N/O)c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CCC/C(N)=N/OC(=S)n1ccnc1)c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1
Yield: 100 %

Procedure:
A solution of Example 176 (69.3 mg, 0.135 mmol) and 1,1′-thiocarbonyldiimidazole (38.1 mg, 0.203 mmol) in anhydrous tetrahydrofuran (1.3 mL) was stirred under nitrogen at 25° C. for 1.5 hours. Ethyl acetate (25 mL) was added, the mixture was washed with H2O (2×10 mL) and brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation to provide the title compound as a yellow foam (84 mg, 0.135 mmol, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([C:14](O)=[O:15])=[C:12]([Br:17])[N:11]([CH:18]([CH3:20])[CH3:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][OH:15])=[C:12]([Br:17])[N:11]([CH:18]([CH3:20])[CH3:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1nc(OCc2ccccc2)c(C(=O)O)c1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1nc(OCc2ccccc2)c(CO)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
3-Benzyloxy-5-bromo-1-isopropylpyrazole-4-carboxylic acid (4.6 g) was dissolved in tetrahydrofuran (30 mL), and borane-tetrahydrofuran complex, 1M tetrahydrofuran solution (21 mL) was delivered by drops into the stirred solution under ice cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled with ice bath, and water (50 mL) was delivered by drops into the mixture. Hydrochloric acid (1 mol/L, 20 mL) was delivered by drops into the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent:ethyl acetate/hexane =1/5) to give the title compound (3.0 g).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:15]([O:16][CH3:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[O:18][CH3:19].[CH3:20]O>>[CH3:6][C:7]1[C:8]([O:18][CH3:19])=[CH:9][C:10]([C:11]([O:13][CH3:20])=[O:12])=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: CO
Reactant: COc1cc(C(=O)O)cc(OC)c1C
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)c(C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Concentrated sulphuric acid (1 mL), was added dropwise to a solution of 4-methyl-3,5-dimethoxybenzoic acid (186) (5.01 g, 25.56 mmol) in refluxing methanol (20 mL). The reaction mixture was heated at reflux for a further 5 hours and then cooled to room temperature and concentrated to a third of its original volume. The concentrate was poured onto crushed ice (c. 150 mL) and allowed to stand for 30 minutes. The aqueous mixture was extracted with ethyl acetate (3×100 mL) and the combined organic phase washed with distilled water (3×100 mL), brine (2×100 mL) and dried over anhydrous MgSO4. Removal of excess solvent under reduced pressure afforded the product as a beige solid (187) (4.865 g, 23.17 mmol, 91%); 1H NMR (270 MHz, CDCl3) δ7.21 (s, 2H), 3.91 (s, 3H), 3.86 (s, 6H), 2.13 (s, 3H); 13C NMR (67.8 MHz, CDCl3) δ171.57, 167.28, 158.16, 158.10, 128.23, 120.39, 105.20, 104.70, 55.85, 52.13, 8.77, 8.66.