Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:34].ClC([O-])=O>C1COCC1>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:10]2)[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)COC(=O)Cl
Agent: O=C([O-])Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: -60 °C
Yield: 89.2 %

Procedure:
At RT, triethylamine (260 μL, 1.86 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (300 mg, 0.93 mmol) in THF (6 mL), and the reaction was cooled to −60° C. external temperature. Neopentyl chloroformate (132 μL in 1.0 mL THF, 0.89 mmol) was added dropwise over a period of 5 minutes. Once the addition of the chloroformate was complete, the reaction mixture was warmed to RT, quenched with H2O, and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-10% EtOAc in CH2Cl2 to give (R)-neopentyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 9) (345 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.44-8.42 (m, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.59 (d, J=0.5 Hz, 2H), 7.38-7.32 (m, 2H), 6.94-6.90 (m, 2H), 4.28-4.19 (m, 3H), 4.12-4.01 (m, 1H), 3.89 (d, J=9.0 Hz, 1H), 3.71-3.64 (m, 2H), 2.49 (s, 3H), 2.25-2.20 (m, 1H), 2.06-2.00 (m, 1H), 0.89 (s, 9H) ppm. LC/MS: m/z 435.5 (M+H)+ at 2.73 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:16])=O>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
After heating and refluxing 1.4 g (8.0 mmol) of 4-acetoxybenzoic acid and 6 ml of thionyl chloride, surplus thionyl chloride was removed, and 4-acetoxybenzoic acid chloride was obtained. Then, a mixed solution of 1.7 g of the hydrazide obtained in Step 1, 1 ml of pyridine and 15 ml of dioxane was added to the 4-acetoxybenzoic acid chloride and the mixture was heated and refluxed for two hours. After the reaction was completed, 2.6 g (7.0 mmol) of dihydrazide was obtained by pouring a 50 ml solution of salt, filtering and cleaning the crystals which had deposited, by water and methanol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[F:1])[CH3:16]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F

Procedure:
To a solution of 2-fluoro-4-nitrobenzoic acid (1.15 g, 6.22 mmol) in absolute ethyl alcohol (20 mL) was added p-toluenesulfonic acid monohydrate (100 mg). After 16 h at reflux, the reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel (eluted with 5% ethyl acetate in hexane) to give 770 mg (Y: 58%) of the title product; 1H-NMR (CDCl3): δ 8.16-8.00 (m, 3H), 4.45 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). MS (DCI) m/e: 214 (MH+).
Reaction SMILES: [O-2].[Mg+2].[CH:3](O)=[O:4].C(OC(=O)C)(=O)C.[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][C:16]([OH:18])=O.C(O)(C)C>>[CH:3]([NH:13][C@@H:14]1[C:19](=[O:20])[O:21][C:16](=[O:18])[CH2:15]1)=[O:4]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: O=CO
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Product: O=CN[C@H]1CC(=O)OC1=O
Reaction time: 2.5 h

Procedure:
0.12 grams (0.003 mole) of magnesium oxide, a catalyst, was dissolved in 16 milliliters (ml) (0.405 mole) of 95% formic acid. 60.2 ml of acetic anhydride was then added to the aforementioned solution which was heated to 35°-40° C. for 10-15 minutes. Subsequently, 39.93 grams (0.3 mole) of L-aspartic acid was added and this mixture was stirred for 2.5 hours at 50°±2° C. At this point, an additional 8.6 ml of acetic anhydride was added and the reaction continued for an additional 2.5 hours at 50°±2° C. 9.2 ml (0.120 mole) of isopropyl alcohol was then added to the reaction mixture and heating was continued for an additional two hours. N-formyl-L-aspartic anhydride was formed at this point as shown by high performance liquid chromatography (HPLC).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10])=[O:4].I[C@@:14]1([N:23]2[CH:30]=[CH:29][C:27](=[O:28])[NH:26][C:24]2=[O:25])[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17](O)[C@H:15]1O.CO>ClCCl>[F:1][C:2]([F:11])([F:12])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:29]1[C:27](=[O:28])[NH:26][C:24](=[O:25])[N:23]([CH:30]=1)[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[CH2:17][CH2:15]1)=[O:4]
Reactant: C#CCCCNC(=O)C(F)(F)F
Reactant: O=c1ccn([C@]2(I)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: CO
Solvent: ClCCl
Product: O=C(NCCCC#Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F

Procedure:
5-Trifluroacetamido-1-pentyne (59) was coupled for 4 h to 5-iodo-2',3'-dideoxyuridine (47, prepared as described in Example 2A) according to the general procedure described in Example 1C. Chromatography on silica gel (100 g) with a 0-5% methanol in dichloromethane gradient afforded 647.7 mg of alkynylamino nucleoside 58 as a light tan foam. This material was homogeneous by TLC and NMR except for the presence of about 16 mole % of dimethylformamide. Correcting for the presence of dimethylformamide, the yield of desired product was 80%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.[CH:20]([Mg]Br)=[CH2:21]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]2[C:3]=1[NH:17][CH:21]=[CH:20]2
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)c(F)cc1Br
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Fc1cc(Br)c2[nH]ccc2c1OCc1ccccc1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 34.7 %

Procedure:
A solution of 1-bromo-5-fluoro-2-nitro-4-[(phenylmethyl)oxy]benzene (D4) (10.58 g, 32.4 mmol) in THF was cooled to −40° C. under argon and vinylmagnesium bromide (97 mL of 1M solution in THF, 97 mmol) was added quickly via syringe. The temperature reached ˜−30° C. before cooling down to −40° C. The mixture was stirred at −40° C. for 40 mins and then quenched by the addition of NH4Cl solution. The mixture was allowed to reach room temperature and the layers were separated. The aqueous layer was reextracted with ethyl acetate and the combined organic layers were dried (Na2SO4) and evaporated. Chromatography on silica gel (elution with 0-50% ethyl acetate in hexane) gave the title compound as an orange oil (D5), (3.6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1N.[C-:10]#[N:11].[K+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[C:10]#[N:11]
Reactant: Cc1cccc(C)c1N
Reactant: [C-]#N
Agent: [K+]
Product: Cc1cccc(C)c1C#N

Procedure:
The preparation of 2,6-dimethyl DL-phenylalanines is disclosed by R. R. Herr, T. Enkoji & J. P. Dailey, J. Amer. Chem. Soc., 79, 4229(1957). The method involves the conversion of 2,6-dimethyl aniline into its diazonium salt, followed by treatment with potassium cyanide and cuprous cyanide to produce 2,6-dimethylbenzonitrile. The benzonitrile is reduced with lithium aluminum hydride to provide 2,6-dimethylbenzylamine, which is reacted with excess methyl iodide producing 2,6dimethylbenzyltrimethylammonium iodide. The trimethylammonium group is displaced with diethyl-2acetamidomalonate to form the amido diester, which is subsequently acidolysed to form the racemic mixture of 2,6-dimethylphenylalanine.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:20][F:21])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]1.S(=O)(=O)(O)O.[N+:27]([O-])([O-:29])=[O:28].[Na+]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:27]([O-:29])=[O:28])=[CH:4][C:3]=1[C@:9]1([CH2:20][F:21])[CH2:14][C@@H:13]([C:15]([F:16])([F:17])[F:18])[O:12][C:11]([NH2:19])=[N:10]1
Reactant: NC1=N[C@](CF)(c2cccc(F)c2F)C[C@@H](C(F)(F)F)O1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC1=N[C@](CF)(c2cc([N+](=O)[O-])cc(F)c2F)C[C@@H](C(F)(F)F)O1
Reaction time: 0.25 h

Procedure:
To a cooled (ice bath) solution of (4S,6S)-4-(2,3-difluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.62 g, 5.19 mmol) in sulfuric acid (24 mL, 450 mmol) was added sodium nitrate (0.573 g, 6.75 mmol) in one portion. After stirred for 15 min, The ice bath was removed and the mixture was stirred for 3 h at room temperature. Reaction was cooled with ice bath, quenched with ice water and basified by addition of potassium carbonate (50 g) in small portion. The resulted suspension was extracted with EtOAc (2×). The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and dried in vacuum to afford crude (4S,6S)-4-(2,3-difluoro-5-nitrophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine as yellow oil. It was carried to next step without purification. Assume theoretical yield. MS m/z=358.1 [M+H]+. Calculated for C12H9F6N3O3: 357.2
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH2:15][CH2:16][CH2:17][CH2:18]I)[C:4]=1[CH3:20].O1CCCCC1[O:27][CH2:28][C:29]#[C:30][CH2:31][CH2:32][CH2:33][C:34]#[CH:35]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH2:15][CH2:16][CH2:17][CH2:18][C:35]#[C:34][CH2:33][CH2:32][CH2:31][C:30]#[C:29][CH2:28][OH:27])[C:4]=1[CH3:20]
Reactant: COc1c(C)c(CCCCI)c(OC)c2ccccc12
Reactant: C#CCCCC#CCOC1CCCCO1
Product: COc1c(C)c(CCCCC#CCCCC#CCO)c(OC)c2ccccc12
Yield: 73.4 %

Procedure:
By condensing 1,4-dimethoxy-2-methyl-3-(4-iodobutyl)naphthalene (3.84 g, 10 mmole) with 1-(2-tetrahydropyranyloxy)-2,7-octadiyne (2.10 g, 10 mmole) in accordance with the procedure of the above Reference Example 46, there was produced 1,4-dimethoxy-2-methyl-3-(12-hydroxy-5,10-dodecadiynyl)naphthalene (2.78 g, 73.5%, oily product). 1,4-Dimethoxy-2-methyl-3-(4-iodobutyl)naphthalene [δ1.5 to 2.2(4H), 2.40(3H), 2.82(2H), 3.23(2H), 3.84(3H), 3.87 (3H), 7.3 to 7.5(2H), 7.8 to 8.1(2H)] as utilized in this Reference Example was produced from 1,4-dimethoxy-2-methyl-3-(4-hydroxybutyl)naphthalene [oily substance, NMR (CDCl3), δ1.5 to 1.8(5H), 2.39(3H), 2.81(2H), 3.67(2H), 3.84(3H), 3.87(3H), 7.3 to 7.5(2H), 7.9 to 8.1(2H)] in accordance with the procedure described in Japanese Patent Application No. 49433/'80.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[O:3]1.[CH2:19]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH2:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)COCCO>[CH2:19]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH:32][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=1)=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCC1CCCN1Cc1ccccc1
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Solvent: O
Solvent: OCCOCCO
Product: CC1Cc2cc(S(N)(=O)=O)cc(C(=O)NCC3CCCN3Cc3ccccc3)c2O1
Temperature: 25 °C
Reaction time: 30.5 h

Procedure:
A suspension of 4.0 g of methyl 2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylate and 3.37 g of 1-benzyl-2-aminomethyl-pyrrolidine in 15 ml of diethylene glycol is heated at 120°-130° C. and stirred for 30-31 hours. The reaction solution is cooled to room temperature, poured into 150-200 ml of water, and extracted with ethyl acetate three times. The ethyl acetate extract is washed with water followed by sodium chloride saturated water. The product is dried over magnesium sulfate and the solvent is distilled off under diminished pressure. The resulting residue is recrystallized from isopropanol by the use of decolorizing charcoal to give crystals of N-(1-benzyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 161°-167° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])(=O)[CH3:2].Cl.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([O:28][NH2:29])[CH:25]=[CH:26][CH:27]=1.CC([O-])=O.[Na+]>CCO>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:4]([C:1](=[N:29][O:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:31])[F:30])[CH:23]=2)[CH3:2])[CH:9]=1
Reactant: NOc1cccc(C(F)(F)F)c1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NOc1cccc(C(F)(F)F)c1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 90.6 %

Procedure:
A solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (310 mg, 1.03 mmol), O-(3-trifluoromethylphenyl)hydroxylamine hydrochloride (220 mg, 1.03 mmol) and anhydrous NaOAc (93 mg, 1.13 mmol) in EtOH (18 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:5) afforded N-{4-chloro-2-[1-(3-trifluoromethylphenoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 134 (430 mg, 91%), as a pale yellow solid. M.p. 63-64° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.00, br S, 1H, 7.71, d, J=9.0 Hz, 1H, 7.60, d, J=2.2 Hz, 1H, 7.56-7.35, m, 5H, 2.58, s, 3H. O-(3-Trifluoromethylphenyl)hydroxylamine hydrochloride was prepared in two steps by the procedure of Petrassi, M. H.; Sharpless, K. B.; Kelly, J. W. Org. Lett., 2001, 3, 139-142.
Reaction SMILES: [CH:1]1([C@@H:7]([OH:20])/[CH:8]=[CH:9]/[C@@H:10]2[C@@H:17]3[C@@H:13]([O:14][C:15](=[O:18])[CH2:16]3)[CH2:12][C@H:11]2[OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C>[Pd].C(Cl)Cl>[CH:1]1([C@@H:7]([OH:20])[CH2:8][CH2:9][C@@H:10]2[C@@H:17]3[C@@H:13]([O:14][C:15](=[O:18])[CH2:16]3)[CH2:12][C@H:11]2[OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@H](O)C3CCCCC3)[C@H](O)C[C@@H]2O1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1C[C@@H]2[C@@H](CC[C@H](O)C3CCCCC3)[C@H](O)C[C@@H]2O1
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixture of 43 (5.3 g, 18.9 mmol), 10% w/w Pd/C (320 mg), ethyl acetate (30 mL), and CH2Cl2 (10 mL) was hydrogenated in a Parr hydrogenation apparatus for 3 h at 45 psi. The mixture was filtered through Celite and concentrated, and the residue was chromatographed on silica gel (ethyl acetate) to afford 44 (4.3 g, 80%). 13C NMR (CDCl3) δ 177.64 (C), 83.87 (CH), 77.21 (CH), 76.02 (CH), 53.45 (CH), 43.84 (CH), 42.96 (CH), 40.46 (CH2), 35.88 (CH), 31.37 (CH2), 29.23 (CH2), 29.10 (CH2), 27.85 (CH2), 26.41 (CH), 26.22 (CH2), 26.08 (CH2).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH2:18]([NH2:23])[CH2:19][CH2:20][CH2:21][CH3:22]>C(O)CO.CCOC(C)=O>[CH2:18]([NH:23][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCN
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Solvent: CCOC(C)=O
Solvent: OCCO
Product: CCCCCNc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 120 °C
Yield: 93.5 %

Procedure:
To a solution of 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (500 mg) in dry ethylene glycol (2.3 mL) was added 1-pentylamine (689 mg). The solution was stirred at reflux (120° C.) overnight. The reaction was cooled, taken up in EtOAc (30 mL) and washed with water (2×20 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a viscous brown oil (561 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1.C(C(CCCC)C([O-])=O)C.[Na+:36]>C(OC(=O)C)C.C(Cl)(Cl)Cl>[Na+:36].[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:24]3[CH2:23][CH2:22][NH:21][CH:20]([CH3:19])[CH2:25]3)[CH:11]=2)[C:6](=[O:17])[C:7]([C:14]([O-:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCn1cc(C(=O)[O-])c(=O)c2cc(F)c(N3CCNC(C)C3)cc21
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
A mixture of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [J. Med. Chem., 23, 1358 (1980)] (0.52 g, 2 mmol) and 2-methylpiperazine (0.8 g, 8 mmol) was heated at 175° for 5 hours. The residue was dissolved in ethylacetate (10 mL) and chloroform (10 mL), and a solution of sodium-2-ethyl- hexanoate (0.33 g, 2 mmol) in ethyl acetate (20 mL) was added. The mixture was stirred for 30 minutes and the precipitate was collected. The crude product was purified by preparative liquid chromatography (C-18 reverse phase, gradient 0-40% acetonitrile in water) to give a pale yellow lyophilized solid (0.5 g, 75% yield).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]([O:11][C:12](=O)[O:13]C(C)(C)C)([CH3:10])([CH3:9])[CH3:8].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[C:7]([O:11][C:12]([NH:6][CH2:5][CH2:4][CH2:3][Cl:2])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: NCCCCl
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCl
Temperature: 0 °C

Procedure:
The compound of the title, employed as the starting material in example 1, is prepared by slowly adding a solution of 3-chloro-propylamine hydrochloride (12.98 g, 0.1 mol) in dioxane/water (100 ml 2/1 v/v) to a vigorously stirred mixture of di-(tert-butyl)carbonate (24 g, 0.11 mol), 1N Na2CO3 (100 ml) and dioxane/water (200 ml, 2/1 v/v) cooled to 0° C. When the addition is over, the reaction mixture is stirred at room temperature for an additional hour, dioxane is removed under vacuum and the aqueous phase is extracted a few times with ethyl acetate.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH2:20])=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>CN(C)C=O>[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=2)=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:14]=1
Reactant: CCOC(=O)C(N)c1ncc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(OC)c(OC)c1)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.75 h

Procedure:
Triethylamine (0.28 ml) was added to a solution of ethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate (1 g; prepared in a similar manner to the starting material for Example 3) in dimethylformamide (10 ml) with stiring followed by 3,4-dimethoxybenzoyl chloride (0.70 g). the mixture was stirred for 45 minutes and evaporated. The residue was extracted with ethyl acetate and the extracts worked up to give the title product, m.p. 40-3° C. (Compound 601)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH2:15]1)[C:6]([O:8][CH3:9])=[O:7].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]2[O:17][CH2:16][CH2:15][N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])[C:19]=2[CH:20]=1
Reactant: COC(=O)c1ccc(CN2CCOc3ccc([N+](=O)[O-])cc32)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2CCOc3ccc(N)cc32)c(OC)c1
Yield: 98.9 %

Procedure:
Palladium-on-carbon (10% w/w, 0.2 g.) was added to a solution of (G) (0.69 g.) in ethyl acetate (50 ml.) in a hydrogenation bottle and the mixture hydrogenated at a pressure of 3.17 bars of hydrogen. When the uptake of hydrogen had ceased, catalyst was removed by filtration through diatomaceous earth. The filter pad was washed with ethyl acetate and the filtrate and washings were evaporated to give methyl 4-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)-3-methoxybenzoate (0.625 g., 91%) as a foam; NMR 3.1(br s,2H, NH2), 3.3(t,2H, OCH2CH2N), 3.85(m,6H, OCH +CO2CH3), 4.2(t,2H, OCH2CH2N), 4.45(s, 2H, C H2 --Ar), 6.0(m,2H), 6.55(d,1H), 7.3(d,1H), 7.55(m, 2H).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([C:12]2[C:17]3[S:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N+:16]=3[CH2:15][CH2:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I-].C1(S[C:33]2[S:34][C:35]3[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=3[N+:37]=2[CH2:38][CH3:39])C=CC=CC=1.N1C=CC=CC=1>C(OCC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:38]([N:37]1[C:36]2[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=2[S:34][C:33]1=[C:14]1[CH2:15][N+:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:17]=2[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:13]1)[CH3:39]
Reactant: C1=C(c2ccccc2)c2sc3ccccc3[n+]2CC1
Reactant: CC[n+]1c(Sc2ccccc2)sc2ccccc21
Agent: [I-]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCN1C(=C2C=C(c3ccccc3)c3sc4ccccc4[n+]3C2)Sc2ccccc21
Yield: 35 %

Procedure:
1,2-Dihydro-4-phenylpyrido[2,1-b]benzothiazolium perchlorate (2.0 g., 0.0055 mole), 2-phenylthio-3-ethylbenzothiazolium iodide (2.19 g., 0.0055 mole) and pyridine (30 ml.) are heated to reflux for 3 minutes, the solution is cooled, diethyl ether (30 ml.) is added and the green solution is decanted off from the oily dye. Water is added and the dye solidifies upon cooling. The solid dye is boiled out with isopropyl alcohol. The yield of dye is 1.0 g. (35% yield). The product has a melting point of 120°-128° C with an absorption maximum at 629 nm.