Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[CH3:27][C:28]([O-])=O.[K+]>CC#N.O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:28]4[CH:27]=[CH:18][N:17]=[CH:15][CH:13]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3ccncc3)cc1OCC2)c1ccccc1Cl
Temperature: 140 °C

Procedure:
A suspension of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 (50 mg, 0.11 mmol) in 1.0 mL MeCN and 1.0 mL 1M KOAc in water in a 10 mL microwave vial was degassed with bubbling nitrogen for approximately 10 min. 4-pyridineboronic acid (16 mg) was added followed by Pd(PPh3)4 (13 mg). The vessel was sealed and heated in a microwave at 140° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethylacetate. The combined organics were concentrated and the residue purified by reverse phase HPLC to give 134. 1H NMR (DMSO-d6) δ 8.77 (m, 2H), 8.05 (m, 2H), 7.70-7.53 (m, 7H), 6.65 (br s, 1H), 4.25 (m, 2H), 3.31 (s, 3H), 3.02 (m, 2H). MS: (ESI+) 447.1
Reaction SMILES: [CH:1]1([O:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[S:25]([CH3:28])(=[O:27])=[O:26])[C:12]([C:14]1[NH:19][C:18](=[O:20])[C:17]([CH3:21])=[CH:16][CH:15]=1)=O.O>C(O)CCC>[Cl:8][C:9]1[CH:10]=[C:11](/[C:12](=[N:7]\[O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:14]2[NH:19][C:18](=[O:20])[C:17]([CH3:21])=[CH:16][CH:15]=2)[CH:22]=[CH:23][C:24]=1[S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: Cc1ccc(C(=O)c2ccc(S(C)(=O)=O)c(Cl)c2)[nH]c1=O
Reactant: NOC1CCCC1
Solvent: O
Solvent: CCCCO
Product: Cc1ccc(/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)[nH]c1=O
Temperature: 200 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
O-cyclopentylhydroxylamine (0.3 mL) was added to a solution of 6-[3-chloro-4-(methylsulfonyl)benzoyl]-3-methylpyridin-2(1H)-one (220 mg) in n-butanol (2 mL) at room temperature, and the mixture was stirred under microwave irradiation at 200° C. for two hours. O-cyclopentylhydroxylamine (0.3 mL) was further added at room temperature, and the mixture was stirred under microwave irradiation at 200° C. for three hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:1) and further purified by silica gel column chromatography (chloroform:ethyl acetate=50:1→25:1). The resulting less polar product was powdered with an ethyl acetate/hexane solution, and filtration operation gave (E)-6-{[3-chloro-4-(methylsulfonyl)phenyl](cyclopentyloxyimino)methyl}-3-methylpyridin-2(1H)-one as a white solid (95 mg, 34%). The more polar product was powdered with an ethyl acetate/hexane solution, and filtration operation gave (Z)-6-{[3-chloro-4-(methylsulfonyl)phenyl](cyclopentyloxyimino)methyl}-3-methylpyridin-2(1H)-one as a white solid (36 mg, 13%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][N:5](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:6]2.C1(O)C=CC=CC=1.Br>O.C(O)(=O)CC>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3c(F)ccc(F)c3C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: O
Solvent: CCC(=O)O
Product: Fc1ccc(F)c2c1CNC2
Yield: 49.4 %

Procedure:
A mixture of 4,7-difluoro-2-(toluene-4-sulfonyl)isoindoline (2.36 g, 7.64 mmol), phenol (2.36 g, 25.11 mmol), 48% hydrogen bromide in water (20 ml) and propionic acid (4 ml) was stirred and held at reflux for 6 hours. Upon cooling to room temperature water (50 ml) was added and the mixture extracted with diethyl ether (2×100 ml). The aqueous layer was basified by the addition of 2M sodium hydroxide and was extracted with diethyl ether (3×100 ml). The combined extracts were evaporated to dryness in vacuo to afford 4,7-difluoroisoindoline (586 mg, 50%) as a brown oil that solidified upon standing. 1H NMR (DMSO-d6) 7.06 (2H, dd), 4.12 (4H, s). MS: [M+H]+ 156.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].[OH2:12].Cl.[CH3:14]O>>[Cl:1][C:2]1[N:9]=[C:8]([O:12][CH3:14])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: O
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Reactant: CO
Agent: Cl
Product: COc1cc(C)c(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
2,6-dichloro-4-methyl-nicotinonitrile (3.70 g, 19.83 mmol) was dissolved in 30 mL of methanol, added with 4.28 mL of methanol containing 25% sodium methoxide and then stirred for about 3 hours at room temperature. The mixture was added to cool water, adjusted to have a pH of about 6 to 7 with 10% HCl and extracted using methylene chloride. The extract was dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure. A silica gel column chromatography (10% EtOAc/Hexane) was performed to obtain 1.8 g (50%) of 2-chloro-6-methoxy-4-methyl-nicotinonitrile in pale yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][O:39][CH3:40])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:15]([CH:17]1[CH2:19][CH:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])(C)(C)C.ClCCl.Cl>O1CCOCC1>[NH2:7][C@@H:8]([C@@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][C:35]([CH2:38][O:39][CH3:40])=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:16]
Reactant: CC[C@H](C)[C@@H](CN(C(=O)C1CC1c1ccccn1)c1ccc(-c2ccc(COC)cc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](N)CN(C(=O)[C@@H]1C[C@H]1c1ccccn1)c1ccc(-c2ccc(COC)cc2)cc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A solution of ((1S,2S)-1-{[(4′-methoxymethyl-biphenyl-4-yl)-(2-pyridin-2-yl-cyclopropanecarbonyl)-amino]-methyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (25 mg, 0.045 mmol) and dichloromethane (4 mL) was treated with a solution of HCl in dioxane (4 N, 0.5 mL) and the resulting reaction mixture was maintained at room temperature for 12 h. The reaction was then concentrated to dryness to afford (1R,2R)-2-pyridin-2-yl-cyclopropanecarboxylic acid ((2S,3S)-2-amino-3-methyl-pentyl)-(4′-methoxymethyl-biphenyl-4-yl)-amide (18 mg, 95% yield) as a white solid: 1H NMR (400 MHz, MeOD) δ 8.49 (d, J=5.8 Hz, 1H), 8.23 (t, J=7.8 Hz, 1H), 7.61-7.71 (m, 3H), 7.44-7.54 (m, 5H), 7.34 (d, J=8.1 Hz, 2H), 4.40 (s, 2H), 4.22 (dd, J=14.9, 9.1 Hz, 1H), 3.70 (dd, J=14.9, 2.5 Hz, 1H), 3.62-3.66 (m, 1H), 3.54-3.59 (m, 1H), 3.46-3.50 (m, 1H), 3.31 (s, 3H), 2.83-2.90 (m, 1H), 2.07-2.13 (m, 1H), 1.84-1.92 (m, 1H), 1.64-1.74 (m, 1H), 1.60 (dt, J=8.7, 5.5 Hz, 1H), 1.24-1.36 (m, 1H), 1.06-1.22 (m, 1H), 0.88 (d, J=6.8 Hz, 3H), 0.76 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 458.1 [(M+H)+, calcd for C29H36N3O2 458.3].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(N(CC)CC)C.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.Cl.[CH3:50][C:51]1[S:52][CH:53]=[C:54]([CH2:56][O:57][NH2:58])[N:55]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:58][O:57][CH2:56][C:54]1[N:55]=[C:51]([CH3:50])[S:52][CH:53]=1)=[O:8]
Reactant: Cc1nc(CON)cs1
Reactant: COc1cccc(C(=O)O)c1NCc1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)NOCc2csc(C)n2)c1NCc1ccncc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
3-Methoxy-2-[(pyridin-4-ylmethyl)-amino]-benzoic acid (200 mg, see preparation 1D) was dissolved in DMF (20 ml) and triethylamine (0.65 ml) at 50-60° C. N,N,N′,N′-Tetramethyl-O-(benzotriazole-1-yl)uronium-tetrafluoroborate (250 mg) was added and after 5 minutes O-(2-methyl-thiazol-4-ylmethyl)-hydroxylamine hydrochloride (209 mg, see preparation 12) was added. The reaction mixture was heated to 90° C. and stirred at this temperature for 2 hours. The mixture was cooled to room temperature and water was added. The mixture was extracted several times with EtOAc and the combined organic layers were washed with water, saturated aqueous sodium bicarbonate, water, and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The remaining material was purified by column chromatography on silica gel (elution with 1 to 4% methanol in EtOAc) and gave the title compound as an yellow oil. 13C-NMR (DMSO-d6) δ 165.3, 150.4, 150.0, 149.8, 149.3, 137.8, 122.2, 120.5, 118.8, 117.9, 114.0, 71.8, 55.7, 48.3, 18.6.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[C:15]([O-])([O-])=O.[K+].[K+].ClCCC[C:25]#[N:26]>C(#N)C>[C:25]([CH:2]([CH3:15])[CH2:3][NH:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])#[N:26]
Reactant: O=C([O-])[O-]
Reactant: CCOP(=O)(CCNCCO)OCC
Reactant: N#CCCCCl
Agent: [K+]
Solvent: CC#N
Product: CCOP(=O)(CCNCC(C)C#N)OCC
Temperature: -10 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
The mixture of diethyl 2-(2-hydroxyethylamino)ethylphosphonate (6 g, 26.7 mmol) and K2CO3 (3.7 g, 26.7 mmol) in dry acetonitrile (80 ml) was cooled to −10° C. and 4-chlorobutyronitrile (4.16 g, 40 mmol) was added. The reaction mixture was stirred at −10° C. for 1 h and then heated at 80° C. for 70 h. The solvent was then removed by evaporatation. Water and CHCl3 were added, the organic layer separated, washed with brine and dried over anhydrous MgSO4. After filtration, solvent was evaporated and the residue was purified by column chromatography on silica gel (CHCl3-MeOH), the diethyl 2-(2-cyanopropylamino)ethylphosphonate was obtained in 69% yield (5.38 g).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>C(C1C(O)=CC=C(CCCC)C=1C)CCC.C1(C)C=CC=CC=1>[C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:22]=[CH2:23])=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccccc1-c1cccc(Nc2ccc(Br)cc2)c1
Agent: CCCCc1ccc(O)c(CCCC)c1C
Solvent: Cc1ccccc1
Product: C=Cc1ccc(Nc2cccc(-c3ccccc3C)c2)cc1
Temperature: 100 °C
Reaction time: 76 h
Yield: 83.1 %

Procedure:
In a reactor equipped with a stirrer and a reflux condenser, 2.0 g (0.0059 mol) of m-tolyl(p-bromophenyl)phenylamine, 0.18 g (0.00015 mol) of tetrakistriphenylphosphine palladium (0), 0.005 g of 2,6-dibutylhydroxytoluene and 20 ml of toluene were added and dissolved, and then 2.1 ml (0.0071 mol) of tributyl(vinyl)tin was added to the mixture in an argon gas atmosphere at room temperature. The mixture was heated to 100° C. and continuously stirred for 76 hours. After air cooling, the solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent: hexane) to yield 1.4 g of m-tolyl(p-vinylphenyl)phenylamine as a colorless liquid at a yield of 81%.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].Cl[C:27]1[S:28][C:29]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:30]=2[N:31]=1.Cl>C(O)CCC.O1CCOCC1>[F:36][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([NH:22][C:19]3[CH:20]=[CH:21][C:16]([C:14]4[N:15]=[C:11]([C:9]([NH:8][CH:3]([CH:2]([CH3:25])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])[S:12][CH:13]=4)=[CH:17][CH:18]=3)[S:28][C:29]=2[CH:35]=1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: Fc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cs1)C(C)C
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
To methyl-2-(4-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 3, 300 mg) in n-butanol (5 ml), 2-chloro-6-fluorobenzo[d]thiazole (202 mg) was added and the reaction mixture was heated at 70° C. and stirred for 10 minutes. 4M HCl in dioxane (0.131 gm) was added and the reaction mixture was stirred for 16 hours at 90° C. Organic solvent was concentrated to obtain a sticky solid, which was purified by column chromatography (silica gel, EtOAc-petroleum ether) to obtain title compound as solid. Yield: 130 mg (29%). 1H NMR (CDCl3; 300 MHz): δ 7.97 (d, 2H), 7.83 (d, 1H), 7.67 (s, 1H), 7.64 (m, 4H), 7.38 (dd, 1H), 7.13 (td, 1H), 4.77 (q, 1H), 3.80 (s, 3H), 2.37 (m, 1H), 0.97 (dd, 6H).
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:9])[NH:7][C:6]([NH2:8])=[N:5][CH2:4]1.[N:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18](OCC)=[O:19])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:2][C:3]1([CH3:9])[CH2:4][N:5]2[C:18](=[O:19])[CH:17]=[C:16]([C:13]3[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=3)[N:8]=[C:6]2[NH:7]1
Reactant: CC1(C)CN=C(N)N1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1(C)Cn2c(nc(-c3ccncc3)cc2=O)N1

Procedure:
A suspension of 4.5 g (23.2 mmol) of 5,5-dimethyl-4,5-dihydro-1H-imidazol-2-ylamine hydrobromide, 2.99 g (15.46 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate and 4.27 g (30.89 mmol) of potassium carbonate in 100 ml of ethanol was heated at reflux temperature for 18 h.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl.[C:24](Cl)(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O.ClCCl>[C:24]([NH:6][C@@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[C:4]([O:3][CH3:2])=[O:15])(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Yield: 90.6 %

Procedure:
300 ml of dichloro methane (DCM) was added to (L)-tyrosine methyl ester HCl salt (23.16 g, 0.1 mol) and 28 ml of triethyl amine (TEA, 0.2 mol) was added thereto, thereby dissolving HCl salt. The reactor was temperature-lowered to 0° C. by using an ice bath, and 21.88 g of dodecanoyl chloride (0.1 mol) was slowly added, following by stirring for 3˜4 hours. 200 ml of water was added to the reacted material, followed by extraction with 500 ml of ethyl acetate. Drying over sodium sulfate followed by filtering was carried out. The solvent was removed from the filtrate by rotary evaporation, followed by separation by column chromatograph using hexane and ethyl acetate (Hex:EA=2:1), thereby obtaining a white solid (34.2 g, 90.5% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@@H:16]1Br)(=[O:13])[CH3:12]>[O-2].[Zn+2]>[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:16]1[S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc([N+](=O)[O-])cc2)SC[C@H]1OC(C)=O
Yield: 79 %

Procedure:
If the procedure described in Preparation IV is followed starting from 6 g (38.10-3 mol) of 4-nitrobenzenethiol, 15.1 g (42.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 3.2 g (39.10-3 mol) of zinc oxide (ZnO), 13 g (yield: 79%) of the expected product are obtained after precipitation in ether.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:19].[CH2:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:26]1[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH2:20][CH3:21])[CH2:25]1)[N:9]1[CH2:12][CH2:13][S:14][C:8]1=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: O=C(O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Reactant: CCNCC1CCNC1
Solvent: c1ccncc1
Product: CCNCC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)c2n3CCS2)C1

Procedure:
A mixture of 3.0 g (10 mmol) of 8-chloro-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid, 1.93 g (15 mmol) of N-ethyl-3-pyrrolidinemethanamine and 50 ml of pyridine is heated at reflux for 18 hours. The solvent is removed in vacuo and the residue triturated with water. The solid which separates is removed by filtration, washed with water and dried in vacuo to give 7-fluoro-8-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-5-oxo-1,2-dihydro-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)([CH3:20])[CH3:19].O>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH:8]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=1
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(C)C)cc1)C(=O)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (4-fluorobenzoyl)acetate (23.21 g, 110.4 mmol) in 1,2-dimethoxyethane (150 ml) was added a suspension (4.42 g, 110 mmol) of 60% sodium hydride in liquid paraffin under ice-cooling and the mixture was stirred as it was for 0.5 hr. A solution of 4-isopropylbenzyl chloride (18.6 g 110 mmol) in 1,2-dimethoxyethane (50 ml) was added at room temperature and the mixture was stirred at 70° C. overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1-9/1) to give the objective substance.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])=[CH:8][C:7]=1[NH:23][C:24](=[O:26])[CH3:25].C(OCC)(=O)C>[Fe].O>[NH2:12][C:10]1[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])=[CH:8][C:7]([NH:23][C:24](=[O:26])[CH3:25])=[C:6]([F:5])[CH:11]=1
Reactant: CC(=O)Nc1cc(Oc2ccccc2O)c([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Oc2ccccc2O)c(N)cc1F
Temperature: 80 °C
Yield: 82.3 %

Procedure:
Into a mixture of 25 ml of acetic acid and 25 ml of water was added 9.5 g of an iron powder, and the mixture was heated to 80° C. Into the mixture was added dropwise a solution composed of 10.0 g of N-[2-fluoro-5-(2-hydroxyphenoxy)-4-nitrophenyl]acetamide and 100 ml of ethyl acetate. The mixture was heated for 1 hour under reflux, then, poured into water, extracted with ethyl acetate, the organic layer was washed with water, and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated to obtain 7.42 g of N-[4-amino-2-fluoro-5-(2-hydroxyphenoxy)phenyl]acetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Cl)cc1N
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a solution of methyl 2-amino-4-chlorobenzoate (20.0 g, 108 mmol) in DMF (200 mL) was added N-bromosuccinimide (19.2 g, 108 mmol) in one portion and stirred overnight at room temperature. The resulting solids were filtered off and dissolved in toluene, dried with Na2SO4, and concentrated to give methyl 2-amino-5-bromo-4-chlorobenzoate (26.47 g, 93%)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu](I)I>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: c1c[nH]nn1
Reactant: Brc1ccccn1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-n2ccnn2)nc1
Temperature: 110 °C

Procedure:
1,2,3-Triazole (5 g), 2-bromo pyridine (8.5 ml) and copper iodide (0.68 g) was taken in dry DMF under Nitrogen atmosphere. 1,2-(N,N-dimethyl)cyclohexyl diamine (1.02 g) and potassium phosphate (30.73 g) was added into above mixture. The reaction mixture was reflux at 110° C. for over night. TLC was checked no starting material and the reaction mixture was filtered through celite. The filtrate was diluted with water and product was extracted with dichloromethane. The organic layer was evaporated and the crude product was purified by column chromatography using 60-120 silica gel and pet ether\ethyl acetate as eluent to give compound 2-(1H-1,2,3-triazol-1-yl)pyridine as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:5]([NH:7][C@H:8]([CH2:26][CH2:27][OH:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C:22](=NO)[CH3:23])[N:19]([CH3:21])[CH:20]=2)=[CH:12][CH:11]=1)=[O:6].[C:36]([O-:39])([O-])=O.[K+].[K+].ICC.CN([CH:48]=[O:49])C>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:34])[CH3:35])[C:5]([NH:7][C@H:8]([CH2:26][CH2:27][OH:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C:22]3([CH3:23])[O:39][CH2:36][CH2:48][O:49]3)[N:19]([CH3:21])[CH:20]=2)=[CH:12][CH:11]=1)=[O:6]
Reactant: CN(C)C=O
Reactant: CC(=NO)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: O
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn(C)c(C4(C)OCCO4)n3)cc2)cc1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of compound 3 (5.307 g, 18 mmol) in DMF (15 mL) was added K2CO3 (3.73 g, 27 mmol) and iodoethane (3.5 mL, 43.2 mmol). The resulting mixture was stirred at 60° C. for three hours. The mixture was diluted with water and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, and concentrated. Purification with column chromatography (Hexanes/EtOAc 50:50) gave the product 4 (3.2 g, 55%) as white solid.