Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O[C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1cc(O)cc(Cl)c1
Product: COC(=O)[C@H](C)Oc1cc(C)cc(Cl)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the 3-chloro-5-methylphenol instead of the m-cresol and the (R)-methyl 2-hydroxypropanoate instead of the (S)-methyl 2-hydroxypropanoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:11]([F:13])[F:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].P(OC)(OC)(O[CH3:17])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:11]([F:12])[F:13])=[N:8][N:9]([CH3:17])[CH:10]=1)=[O:5])[CH3:2]
Reactant: COP(=O)(OC)OC
Reactant: CCOC(=O)c1c[nH]nc1C(F)F
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: 180 °C
Reaction time: 18 h
Yield: 63.7 %

Procedure:
A mixture of 5.7 g of 3-difluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (30 mmol) and 25 ml of trimethyl phosphate (214 mmol) is stirred at a temperature of 180° C. for 18 hours. 250 ml of an ice-water mixture are then added. The resulting reaction product is filtered, washed with water and dissolved in 50 ml of ethyl acetate. The organic phase is washed with 50 ml of saturated sodium chloride solution and dried over sodium sulfate and concentrated by evaporation. 3.9 g (64% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester are obtained in the form of crystals (m.p. 59-60° C.).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:21])=[C:6]([C:18]([NH2:20])=[S:19])[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:9]=1)(=[O:3])[CH3:2].Cl[CH2:23][CH:24]=O>C(O)C>[C:1]([C:4]1[C:5]([CH3:21])=[C:6]([C:18]2[S:19][CH:23]=[CH:24][N:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=CCCl
Reactant: CC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c(C(N)=S)c1C
Solvent: CCO
Product: CC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c(-c2nccs2)c1C

Procedure:
To a suspension (5 ml) of 6-acetyl-4-(aminothioxomethyl)-2-(3-chlorophenyl)-5-methyl-3(2H)-pyridazinone (200 mg) in ethanol (5 ml) was added a 50% aqueous solution of chloroacetoaldehyde, followed by heating under reflux for 10 hours. After cooling on standing, the reaction mixture was extracted with ethyl acetate. After washing with a saturated sodium hydrogen carbonate aqueous solution and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2), and the resulting crude crystals was washed with hexane to obtain 6-acetyl-2-(3-chlorophenyl)-5-methyl-4-(1,3-thiazol-2-yl)-3(2H)-pyridazinone (90 mg) (Compound No. 1-155).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:12][NH2:13])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].O[Li].O>CO>[NH2:13][CH2:12][C:5]1([C:3]([OH:4])=[O:2])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1
Reactant: COC(=O)C1(CN)CC12CCCC2
Agent: [Li]O
Solvent: CO
Solvent: O
Product: NCC1(C(=O)O)CC12CCCC2
Yield: 38.8 %

Procedure:
To a solution of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid methyl ester (3.40 g, 18.6 mmol) was added methanol (75 mL) and LiOH—H2O (1.55 g, 37.1 mmol). The mixture was heated to reflux under nitrogen for 48 hours. The solvent was removed by evaporation under reduced pressure and the residue was dissolved in water (50 mL). With ice bath cooling, concentrated HCl (˜2.5 mL) was added until the pH was adjusted to 6. A white precipitate was isolated by filtration and dried under vacuum to yield 1.22 g (39%) of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid as an off-white solid: mp 231–235° C. (decomposition); 1H NMR (300 MHz, D2O) δ 0.78 (d, J=4.7 Hz, 1H), 1.32 (d, J=4.7 Hz, 1H), 1.40 (m, 1H), 1.54–1.77 (m, 7H), 2.86 (d, J=13.2 Hz, 1H), 3.43 (d, J=13.2 Hz, 1H); MS (APCI) m/z 170 [M+H]+. Anal. Calcd. For C9H15NO2 −1.1H2O: C, 57.18; H, 9.17; N, 7.41. Found: C, 57.38; H, 8.82; N, 7.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[CH:7][C:6]2=[O:15].Br[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: COc1cc2[nH]ccc(=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cn3)c2cc1OC
Yield: 34.1 %

Procedure:
6,7-Dimethoxy-1,4-dihydro-4-quinolinone (4.10 g, 20.0 mmol), 2-bromo-5-nitropyridine (4.46 g, 22.0 mmol) and potassium carbonate (5.53 g, 40.0 mmol) were heated and stirred at 70° C. for 3 hours in N,N-dimethylformamide (20 ml). The reaction solution was diluted with ethyl acetate, the insoluble portion was filtered off, and after washing with water and saturated saline and drying the organic layer over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent: ethyl acetate), and the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, after which the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (2.23 g, 6.81 mmol, 34%) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12](O)=[O:13])=[CH:9][CH:8]=[C:7]2[O:15][CH3:16].O=S(Cl)Cl.C[CH2:22][N:23](C(C)C)[CH:24](C)C.CNC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([N:23]([CH3:24])[CH3:22])=[O:13])=[CH:9][CH:8]=[C:7]2[O:15][CH3:16]
Reactant: COc1ccc(C(=O)O)c2c(Cl)cccc12
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)N(C)C)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a mixture of 8-chloro-4-methoxy-1-naphthoic acid (step-4 intermediate) (0.5 g, 2.11 mmol) in CH2Cl2 (5 mL) was added, SOCl2 (0.31 mL, 4.22 mmol, 2.0 eq.) and the mixture was stirred at RT for 3 h. The solvent was evaporated under reduced pressure and the crude product was dissolved in DCM (10 mL). To this, DIPEA (0.74 mL, 4.23 mmol) was added followed by dimethylamine (1.5 eq.) and the reaction mixture was stirred at RT for 3 h and then quenched with ice. The aqueous layer was extracted with dichloromethane and the combined organic layer was washed with sat. NaHCO3 solution, water, brine, dried over Na2SO4 and filtered. The solvent was evaporated to provide the desired amide derivative (528 mg, 95%) this was used in the next step without any further purification.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH:14]=[C:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25].N>O.CC(O)C.C1COCC1>[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH2:14][CH:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: FB(F)F
Agent: N
Agent: [BH4-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -12.5 °C
Reaction time: 2.5 h

Procedure:
In a 100 mL round bottom flask dry THF (50 mL) was taken. It was cooled to −15 to −10° C. and NaBH4 (1.1 g) was added. After that boron trifluoride etherate (10.9 g) was added dropwise at −15 to −5° C. over a period of 30 min. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (5.0 g) was mixed in a solvent mixture of dry THF (12.5 mL) and IPA (5.5 mL) and added into the reaction mixture over a period of 45-60 min. at −10 to −5° C. It was stirred for 2.5 h at −10 to −5° C. Reaction mixture was poured into cold water. It was basified by adding 25% aq. ammonia solution. Product was extracted in ethyl acetate. The organic layer was collected and combined. It was washed with water and brine solution. It was dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-4.81 g, % Y-95.8%, % Purity by HPLC-96.5%).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH:13]=[CH:14][N+:15]([O-])=O)[CH:11]=[CH:12][C:4]=2[O:3]1.S(=O)(=O)(O)O>[Pt](=O)=O.C(O)(=O)C>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][CH2:14][NH2:15])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1Oc2ccc(C=C[N+](=O)[O-])cc2NC1=O
Agent: O=[Pt]=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1Oc2ccc(CCN)cc2NC1=O
Yield: 52.7 %

Procedure:
2 g (8.5 mmol) of 2-methyl-3-oxo-6-(2-nitro-ethenyl)-3,4-dihydro-2H-1,4-benzoxazine is mixed with 80 ml of acetic acid and 1.6 ml of concentrated sulfuric acid and, after 200 mg of platinum dioxide is added, it is reduced in an autoclave. The catalyst is then suctioned off, and the batch is spun in until a dry state is reached. The remaining residue is chromatographed on silica gel (mobile solvent: isopropanol/ammonia). 923.5 mg (52.4%) of the described compound is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:23]([CH3:24])[CH:22]=[CH:21][C:5]2=[N:6][C:7]=1[C@@H:8]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:9].CC1(C)C(C)(C)OB([C:33]2[CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH:37]=2)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:13]([O:12][C:11]([NH:10][C@H:8]([C:7]1[N:6]=[C:5]2[CH:21]=[CH:22][N:23]([CH3:24])[C:4]2=[CH:3][C:2]=1[C:37]1[CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH:33]=1)[CH3:9])=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccn(C)c2cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccn(C)c2cc1C1=CCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 5 h
Yield: 86.2 %

Procedure:
A mixture of benzyl (S)-(1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (850 mg, 2.19 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (904 mg, 3.06 mmol), K2CO3 (605 mg, 4.38 mmol) and Pd(dppf)Cl2 (170 mg, 0.22 mmol) in anhydrous DMF (25 mL) was stirred at 100° C. for 5 hours under nitrogen. After the solvent was removed, the residue was purified by silica gel column chromatography (PE/EtOAc=7:1) to give the title compound as a yellow oil (900 mg, 87%). ESI-MS m/z [M+H]+ calc'd for C22H32N4O4, 477. found 477.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]([CH3:23])[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=2)/[C:6](=[C:24](/OCC)\[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)/[C:5]1=[O:34])(=O)C.[CH3:35][N:36]([CH3:51])[CH2:37][CH2:38][N:39]([C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1)[S:40]([CH3:43])(=[O:42])=[O:41].[OH-].[Na+]>CN(C=O)C>[CH3:35][N:36]([CH3:51])[CH2:37][CH2:38][N:39]([C:44]1[CH:45]=[CH:46][C:47]([NH:48]/[C:24](=[C:6]2\[C:5](=[O:34])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N:13]([CH3:23])[S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:10][CH:11]=3)/[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:49][CH:50]=1)[S:40]([CH3:43])(=[O:42])=[O:41]
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCO/C(=C1\C(=O)N(C(C)=O)c2ccc(N(C)S(=O)(=O)c3ccccc3)cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C)CCN(c1ccc(N/C(=C2\C(=O)Nc3ccc(N(C)S(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 1f from 350 mg (0.73 mmol) of (Z)-1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone and 257 mg (1 mmol) of 4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline in DMF and subsequent treatment with sodium hydroxide solution.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:10]([O:12][CH3:13])=[O:11])=[O:6])[CH2:3][CH2:2]1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)c(C(=O)CC2CC2)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)c(C(=O)C(Br)C2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 3-(2-cyclopropylacetyl)-4-methylbenzoate (compound 4.5, 150 mg, 0.65 mmol) in chloroform (15 mL). Bromine (40 μL, 0.78 mmol) in chloroform (2 mL) was added drop-wise to the reaction mixture. The resulting solution was stirred for 2 h at room temperature, then concentrated under reduced pressure to yield the title compound as a yellow oil (200 mg, crude), which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([S:14][CH3:15])[C:5]=1[CH2:16][S:17][CH2:18][CH3:19].C1(C(C)=O)CC1>CO.O1CCCC1>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:14][CH3:15])[C:5]=1[CH2:16][S:17][CH2:18][CH3:19]
Reactant: CCSCc1c(Cl)ccc(C(=O)OC)c1SC
Agent: CC(=O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCSCc1c(Cl)ccc(C(=O)O)c1SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Methanol (2 drops) was added to a mixture of sodium hydride (0.9 g) and tetrahydrofuran heated under reflux conditions. A mixture of methyl 4-chloro-3-ethylsulphenylmethyl-2-methylsulphenylbenzoate (4.0 g) and methyl cyclopropyl ketone (2.5 g) in tetrahydrofuran (36 ml) was added during 0.5 hours whilst maintaining at reflux. The mixture was stirred overnight at ambient temperature, and then quenched with methanol. Ether and water were added and the aqueous layer acidified (dilute hydrochloric acid), extracted (ether) and the ethereal solution extracted (sodium carbonate solution). This basic extract was re-acidified (hydrochloric acid), extracted (ether) and evaporated to give 4-chloro-3-ethylsulphenylmethyl-2-methylsulphenylbenzoic acid (3.0 g), NMR (CDCl3) 1.35 (t,3H), 2.5 (s,3H), 2.7 (q,2H), 4.3 (s,2H), 7.5 (d,1H), 7.8 (d,1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1>CN(C)C=O>[CH2:23]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:10]1=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCC1CC1
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1N(Cc1ccccc1)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cc(F)c(F)cc2n(CC2CC2)c(=O)n1N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 3-dibenzylamino-6,7-difluoro-1H-quinazoline-2,4-dione (Example 16) (0.43 g, 1.1 mmol) in 10 mL of N,N-dimethylformamide is added to a suspension of sodium hydride (0.05 g, 1.3 mmol) in 10 mL of N,N-dimethylformamide and stirred for 30 minutes. Bromomethylcyclopropane (0.16 mL, 1.6 mmol) is added, and the mixture is stirred at 25° C. for 18 hours. The reaction is quenched with 1 mL of water and concentrated in vacuo. The residue is dissolved in chloroform, washed with water, brine, and dried over magnesium sulfate. The solution is concentrated and purified via chromatography (SiO2, CHCl3) to give 0.33 g of the title compound as a solid. MS CI: m/z 448 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([N+:12]([O-])=O)=[CH:7][C:6]=2[Br:15].[OH-].[Na+].CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1.C(OCC)(=O)C>Cl.[Fe]>[NH2:12][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([Br:15])[CH:7]=1)[N:4]=[CH:3][C:2]([Br:1])=[CH:11]2
Reactant: O=[N+]([O-])c1cc(Br)c2ncc(Br)cc2c1
Agent: [Fe]
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1cc(Br)c2ncc(Br)cc2c1

Procedure:
3,8-Dibromo-6-nitroquinoline (48.5 g, prepared as described in J Am Chem Soc (1955), 77, 4175-4176) was suspended in concentrated hydrochloric acid (400 ml) at ambient temperature and iron powder (27 g, reduced by hydrogen) was added in portions allowing the reaction temperature to rise to 73° C. during the additions. The bright yellow suspension that was initially produced became dark brown during the final stages of the reaction. The mixture was cooled to 0° C. and basified with aqueous sodium hydroxide (10M) until the reaction was at pH10. Ethyl acetate was added to the suspension and the mixture was thoroughly mixed then filtered through a bed of kieselguhr. The organic fraction was separated and the aqueous fraction re-extracted with further ethyl acetate. The insoluble material that was filtered from solution was further extracted with hot acetone and the organic fractions combined, washed with aqueous sodium hydrogen carbonate, dried over sodium sulphate and evaporated under reduced pressure to give 6-amino-3,8-dibromoquinoline as a brown solid, 34.7 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([Br:24])[CH:17]=1)[C:10]([CH3:26])([CH3:25])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([Br:24])[CH:17]=1)[C:10]([CH3:25])([CH3:26])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Br)cc(OC)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Br)cc(OC)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a mixture of 2-(3-bromo-5-methoxy-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (5.4 g, 12.4 mmol) and triethylsilane (10 mL) at 25° C. was added trifluoroacetic acid (10 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium bicarbonate solution (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-(3-bromo-5-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.7 g, 52%) as a white solid: LC/MS m/e calcd for C21H24BrNO3 M+: 418.3, observed: 418.1, 420.1.
Reaction SMILES: Cl.[CH2:2]([NH:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8])[CH2:3][CH3:4].[OH-].[Na+]>CO>[CH2:2]([NH:5][CH:6]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:28][CH:29]=2)=[CH:17][CH:18]=1)[C:7]([OH:9])=[O:8])[CH2:3][CH3:4]
Reactant: CCCNC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCNC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O

Procedure:
Ethyl 2-propylamino-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate hydrochloride, which is the product of Example 183(b) is hydrolyzed by sodium hydroxide in methanol to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([OH:24])[C:21]([F:25])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[C:26](OC(=O)C)(=O)C.C([O-])([O-])OCC.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCOCC1.C(OCC)C.O.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:11](=[CH:20][C:21]([F:25])=[C:22]([OH:24])[N:23]=2)[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:26]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Reactant: CC(=O)OC(C)=O
Agent: CCOC([O-])[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(O)c(F)cc2c1=O
Yield: 52.3 %

Procedure:
In 1 ml of dioxane were dissolved 80 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]acetate, 46 mg of acetic anhydride and 50 mg of ethyl ortho-formate, and the resulting solution was subjected to reaction under reflux for 7 hours, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved 10 ml of methanol and 5 ml of water, and the pH thereof was adjusted to 8.5 with a 10% by weight aqueous sodium carbonate solution. The resulting mixture was subjected to reaction at room temperature for 30 minutes, and the pH of the reaction mixture was adjusted to 2.0 with 2N hydrochloric acid, after which 20 ml of ethyl acetate and 10 ml of water were added thereto. The organic layer was separated, washed successively with 15 ml of water and 15 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained was added 1 ml of diethyl ether, after which the crystals thus deposited were collected by filtration to obtain 43 mg (yield 52.3%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 40.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CC(C)=O>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:43]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)CCCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCCOc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 137.4 %

Procedure:
To a solution of 60.1 (0.7 g, 7.5 mmol) in dry acetone (50 mL), under a nitrogen atmosphere, was added 18-crown-6 (1.584 g, 6 mmol), anhydrous potassium carbonate (2.07 g, 15 mmol), and ethyl 7-bromoheptanoate (1.18 g, 5 mmol) successively. The mixture was stirred at 50° C. overnight and then it was cooled to room temperature and the solvent removed in vacuo. The residue obtained was partitioned between diethyl ether (50 mL), and water (10 mL). The organic phase was separated and the aqueous layer extracted with diethyl ether. The combined organic layer was washed with brine, dried (MgSO4) and the solvent was removed under reduced pressure. Purification by flash column chromatography (20% diethyl ether-hexane) afforded 61.1 (1.72 g, 92% yield) as a colorless liquid.