Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[OH:2]C1C=CC(S([O-])(=O)=O)=CC=1[N+]([O-])=O.[CH:16]1([N:22]=[C:23]=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[CH:25]1([NH:24][C:23](=[O:2])[NH:22][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)[O-])ccc1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
One molar equivalent (2.24 g) of 4-hydroxy-3-nitro-benzene sulfonic acid sodium salt (HNSA) is mixed together with one molar equivalent (2.06 g) of dicyclohexylcarbodiimide and one molar equivalent (2.10 g) of N-maleimido-6-aminocarpoic acid in 25 ml of dimethylformamide (DMF) at room temperature overnight. A white precipitate of dicyclohexyl urea is formed. The precipitate is filtered and 300 ml diethyl ether is added to the mother liquor. After about 10 minutes to 4 hours a gummy solid precipitated from the mother liquor is formed. This solid will contain 58% of active HNSA ester and 42% of free HNSA.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.C1(C)C=CC=CC=1>CO>[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)([O-:31])(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Clopidogrel base was dissolved in methanol. p-Toluene sulphonic acid was added to the solution at 20° C. The reaction mixture was heated to reflux temperature for 2 hrs. The solution was cooled to room temperature and the methanolic solution was added dropwise to hot toluene. The resulting solution was refluxed for an additional 20 minutes. The solution was cooled to room temperature and was stirred for 24 hrs. The solvent was evaporated under reduced pressure to dryness to obtain Clopidogrel tosylate, similar to that obtained above.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>CO>[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)([O-:31])(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Clopidogrel base was dissolved in methanol to obtain a clear solution. To it was added p-toluenesulfonic acid at 20° C. The reaction mixture was heated to reflux temperature for 2 to 10 hrs. The solvent was evaporated to dryness under reduced pressure to obtain a powder.
Reaction SMILES: C(=O)([O-])[O-].[Ba+2].O.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]1[C:57](=[O:58])[O:56][CH:55]([CH:59]([CH:61]([OH:69])[CH2:62][CH2:63][CH2:64][NH:65][C:66]([NH2:68])=[NH:67])[CH3:60])[CH:54]([CH3:70])[CH:53]=[C:52]([CH3:71])[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]([OH:72])[CH2:46][CH:45]([OH:73])[CH2:44][CH:43]([OH:74])[CH2:42][CH:41]([OH:75])[CH2:40][CH:39]([OH:76])[CH:38]([O:77][C@H:78]2[O:82][C@H:81]([CH2:83][OH:84])[C@@H:80]([OH:85])[C@@H:79]2[OH:86])[CH:37]=[C:36]([CH3:87])[CH:35]([OH:88])[CH2:34][CH2:33][CH2:32][CH:31]([OH:89])[CH2:30][CH2:29][CH2:28][CH:27]([OH:90])[CH2:26][CH2:25][CH:24]([CH3:91])[CH:23]1[OH:92].S([O-])([O-])(=O)=O>CO>[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]1[C:57](=[O:58])[O:56][CH:55]([CH:59]([CH:61]([OH:69])[CH2:62][CH2:63][CH2:64][NH:65][C:66]([NH2:68])=[NH:67])[CH3:60])[CH:54]([CH3:70])[CH:53]=[C:52]([CH3:71])[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]([OH:72])[CH2:46][CH:45]([OH:73])[CH2:44][CH:43]([OH:74])[CH2:42][CH:41]([OH:75])[CH2:40][CH:39]([OH:76])[CH:38]([O:77][C@H:78]2[O:82][C@H:81]([CH2:83][OH:84])[C@@H:80]([OH:85])[C@@H:79]2[OH:86])[CH:37]=[C:36]([CH3:87])[CH:35]([OH:88])[CH2:34][CH2:33][CH2:32][CH:31]([OH:89])[CH2:30][CH2:29][CH2:28][CH:27]([OH:90])[CH2:26][CH2:25][CH:24]([CH3:91])[CH:23]1[OH:92].[S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)([O-:16])(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCCCC1C(=O)OC(C(C)C(O)CCCNC(=N)N)C(C)/C=C(\C)CCCCC(O)CC(O)CC(O)CC(O)CC(O)C(O[C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)/C=C(\C)C(O)CCCC(O)CCCC(O)CCC(C)C1O
Agent: CCCCC1C(=O)OC(C(C)C(O)CCCNC(=N)N)C(C)C=C(C)CCCCC(O)CC(O)CC(O)CC(O)CC(O)C(O[C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)C=C(C)C(O)CCCC(O)CCCC(O)CCC(C)C1O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
0.088 g (0.446 millimoles) of barium carbonate and 0.169 g (0.892 millimoles) of p-toluene sulfonic acid monohydrate are heated to boiling in 20 ml of methanol until all the substance goes into solution. The colorless hot solution thus obtained is poured into a suspension of 0.1 g (0.887 millimoles) of primycin sulfate and 80 ml of methanol. The reaction mixture is heated to boiling for 15 minutes under constant stirring. The hot mixture is filtered through Celite. The filtrate is evaporated in vacuo. The residue is suspended in a 2:1 mixture of acetone and water, filtered and washed with the above solvent mixture. Thus 1.05 g of white primycin tosylate are obtained, yield 93.3%. The salt decomposes on heating, /α/D25 =-3.9°.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>CCO.O>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(Oc1ccccc1)C(=O)O
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a solution of ethyl 2-methyl-2-phenoxypropanoate (2.0 g, 9.6 mmol) in EtOH (16 ml) was added a solution of NaOH (0.46 g, 11.5 mmol) in H2O (4 ml) at 26° C. The mixture was stirred for 30 min then concentrated. Water was added (20 mL) and washed with ethyl acetate (2×20 mL). The aqueous layer was acidified with 2N HCL until pH 3 and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound (1.6 g, 94.1%) as a white solid which was used in next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:19])[C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1)([O-])=O.O>C(O)C.O1CCOCC1>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:19])[C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2Oc2cc(O)cc(O)c21
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CC(=O)c1c(O)cc(O)cc1O2
Yield: 51 %

Procedure:
1.40 g of 2-nitro-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10,11-one (Compound 70) and 4.40 g of tin (II) chloride·2H═O were suspended in 20 ml of ethanol and 20 ml of 1,4-dioxane, followed by reflux under heating for 3 hours. Water was added to the reaction solution, which was then extracted in ethyl acetate. The extracted solution was sequentially washed in water and then an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (elution solvent; dichloromethane:methanol=95:5), to recover the entitled Compound 71 represented by the formula (0.64 g; yield of 51%). The melting point of the amorphous powder recovered by recrystallization in hexane and ethyl acetate was 227-229° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[OH-].[Na+].O.Br[CH2:16][CH2:17][CH2:18][Cl:19]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.CC1C=CC=CC=1>[Cl:19][CH2:18][CH2:17][CH2:16][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: ClCCCBr
Reactant: O=C1COc2ccccc2N1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1COc2ccccc2N1CCCCl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of 9 parts of 2H-1,4-benzoxazin-3(4H)-one, 0.9 parts of N,N,N-triethylbenzenemethanaminium chloride, 9 parts of sodium hydroxide solution 50% and 24 parts of water are added 10.4 parts of 1-bromo-3-chloropropane at 30° C. The whole is heated to 90° C. and stirring is continued for 3 hours at this temperature. The reaction mixture is cooled to about 70° C., methylbenzene is added and the whole is stirred overnight at room temperature. The organic phase is separated, dried, filtered and evaporated, yielding 10 parts of 4-(3-chloropropyl)-2H-1,4-benzoxazin-3(4H)-one as a residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[S:10](Cl)([CH3:13])(=[O:12])=[O:11]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccnc(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
(2-Fluoropyridin-4-yl) methanol (1 g) was dissolved in DCM (40 ml), added with TEA (3.3 ml) and mesyl chloride (0.67 ml), and the mixture was stirred at 0° C. for 1 hr. The mixture was concentrated and then purified by silica gel column (n-hexane/ethyl acetate=4/1) to obtain the title compound (1.18 g, 77%).
Reaction SMILES: [Cl-:1].[Cl-].[CH3:3][O:4][P:5]([OH:7])[OH:6].[CH:8]([NH:11][CH:12]([CH3:14])[CH3:13])([CH3:10])[CH3:9]>CCOCC.CCCCC>[CH3:3][O:4][P:5]([OH:7])[OH:6].[Cl-:1].[CH:8]([N-:11][CH:12]([CH3:14])[CH3:13])([CH3:10])[CH3:9]
Reactant: CC(C)NC(C)C
Agent: COP(O)O
Agent: [Cl-]
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)[N-]C(C)C
Temperature: 25 °C

Procedure:
127 g (0.96 mol) of phosphorous acid methyl ester-dichloride are initially taken in a mixture of 250 ml of absolute ether and 250 ml of absolute pentane, and a solution of 270 ml (1.92 mol) of diisopropylamine in 100 ml of absolute ether and 100 ml of absolute pentane is added dropwise in the course of 2 hours at -15° C., with vigorous stirring and nitrogen blanketing. The reaction mixture is allowed to heat up to room temperature while being stirred, and is then stirred for a further 2 hours. It is then cooled to -15° C. again, and the hydrochloride is removed from the reaction solution by filtration under an inert gas. The filter cake is rinsed with 750 ml of a cold mixture of equal volumes of absolute ether and absolute pentane. The filtrates are combined, and the solvents are removed under a water pump vacuum. The residue is subjected twice to a high-vacuum distillation through an 80 cm Vigreux column. This gives 80 g of a main fraction (boiling point 38 to 41° C. at 0.1 mbar) which, according to 31P-NMR, is composed of 99% of a single substance (δ=185 ppm).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C=O)C>[Cl:24][CH2:23][CH2:22][CH2:21][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OCCCCl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To DMF (80 mL) was added potassium carbonate (5.7 g, 41.1 mmol) and methyl 3-hydroxy-4-methoxybenzoate (5.0 g, 27.4 mmol). The mixture was cooled to 0° C. and 1-bromo-3-chloropropane (8.64 g, 57.9 mmol) in DMF (10 mL) was added dropwise over 30 minutes. The mixture was allowed to warm to r.t overnight. After removing most of the DMF in vacuo, the remaining oil was diluted with H2O and filtered to give methyl 3-(3-chloropropoxy)-4-methoxybenzoate (6.65 g, 25.8 mmol, 94%). 1H NMR (300 MHz, DMSO-d6) δ 7.61 (d, 1H), 7.47 (s, 1H), 7.09 (d, 1H), 4.12 (t, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.78 (t, 2H), 2.23-2.15 (m, 2H); LC-MS (ESI) m/z 259 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[CH3:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][N+:12]=1[O-:19].[OH-].[Na+]>O>[N+:1]([C:15]1[C:14]([CH3:18])=[CH:13][N+:12]([O-:19])=[C:11]([CH3:10])[C:16]=1[CH3:17])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a cooled solution of fuming HNO3 (50 ml) and conc. H2SO4 (50 ml) in an ice bath was added 2,3,5-trimethylpyridine-N-oxide (35.67 g) and the reaction mixture was stirred at 40°-50° C. for 18 h. After which time, the reaction was cooled to rt, poured into water/crushed ice (250 ml), alkalized with NaOH pellets and extracted with CH2 Cl2 (3×100 ml). The extracts were combined and washed with sat. NaCl (1×50 ml), dried (MgSO4) and the solvent removed in vacuo to give 4-nitro-2,3,5-trimethyl-pyridine-N-oxide (45.5 g, 96%) as an orange solid; mp 69°-71° C. (ether), orange plates.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][N+:7]=1[O-:14].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:5][C:6]1[C:11]([CH3:12])=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([CH3:13])=[CH:8][N+:7]=1[O-:14]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
65 ml of fuming nitric acid (d=1.5) were added dropwise while cooling to 210 ml of concentrated sulfuric acid. 96.5 g of 2,3,5-trimethylpyridine 1-oxide were subsequently added portionwise at 0°-5°, whereupon the mixture was stirred at room temperature for 1 hour, then heated to 90° within 3 hours and left at this temperature overnight. After cooling the solution was poured on to 1.5 kg of ice, whereupon the mixture was adjusted to pH 3 with concentrated sodium hydroxide solution and extracted three times with 500 ml of methylene chloride. The combined organic phases were washed with 1 l of water, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from ether/petroleum ether and there was obtained 2,3,5-trimethyl-4-nitropyridine 1-oxide of melting point 76°-78°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A solution of (5R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyl-oxazolidin-2-one (1019, 269.6 g, 0.8 mol) in methylene chloride (CH2Cl2, 1200 mL) was treated with N,N-diisopropylethylamine (Hunig's base, DIEA, 206.8 g, 279 mL, 1.6 mol, 2.0 equiv) at 25° C., and the resulting mixture was cooled down to 0-5° C. before methanesulfonyl chloride (MsCl, 109.97 g, 74.3 mL, 0.96 mol, 1.2 equiv) was dropwise introduced into the reaction mixture at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 1 h and then gradually warmed up to room temperature for 4 h under N2. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (500 mL). The resulting mixture was then stirred at room temperature for 30 min. before being concentrated in vacuo to remove methylene chloride. When almost all of methylene chloride was removed in vacuo, the residue was then treated with H2O (1000 mL). The resulting slurry was stirred at room temperature for an additional 1 h. The solids were then collected by filtration, washed with H2O (2×500 mL), and dried in vacuo at 40° C. for 24 h to afford the crude, desired (5R)-methanesulfonic acid 3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020, 290.0 g, 332.0 g theoretical, 87.3%) as off-white powders, which was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1020: 1H NMR (300 MHz, DMSO-d6) δ 3.26 (s, 3H, OSO2CH3), 3.83 (dd, 1H, J=6.4, 9.2 Hz), 4.19 (t, 1H, J=5.4 Hz), 4.44-4.54 (m, 2H), 5.01-5.06 (m, 1H), 7.22 (dd, 1H, J=2.4, 8.7 Hz), 7.56 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (dd, 1H, J=7.5, 8.7 Hz); C11H11FINO5S, LCMS (EI) m/e 416 (M++H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([O:12][B:13](OCC)[O:14]CC)C.S(=O)(=O)(O)O.O>C(OCC)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:13]([OH:14])[OH:12])=[CH:3][CH:4]=1
Reactant: CCOB(OCC)OCC
Reactant: COc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: COc1ccc(B(O)O)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
100 ml of a solution of 10 g of p-bromoanisole in anhydrous diethyl ether were added dropwise at reflux under an inert gas atmosphere to a suspension of 1.3 g of Mg turnings in 5 ml of anhydrous diethyl ether, and the mixture was refluxed for 2 hours. The mixture was then poured into a solution of 9.02 ml of triethylborate in 60 ml of anhydrous ether cooled to -70° C. After stirring for one hour at -70° C., then for one hour at ambient temperature, the solution was poured into a mixture of 11 ml of sulfuric acid and 50 g of ice and water and stirring was carried out for one hour. The organic phase was extracted with 100 ml of a saturated aqueous solution of sodium bicarbonate and the aqueous phases were combined and reacidified with 6N hydrochloric acid, followed by extraction with ether, drying and evaporating under reduced pressure to obtain 3.9 g of the expected product.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:9]1(=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[N:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: COc1ccc(CN2CCc3ccncc3C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NCCc2ccncc21
Temperature: 0 °C

Procedure:
2-(4-methoxy-benzyl)-3,4-dihydro-2H-[2,7]naphtyridine-1-on (1.63 g, 6.075 mmol) was suspended in 30 mL of anhydrous toluene, added with p-toluene sulfonic acid monohydrate (4.62 g, 24.30 mmol) and heated to reflux for about 6 hours under the nitrogen atmosphere. The mixture, while being stirred at 0° C., neutralized by adding a saturated solution of sodium carbonate and extracted seven times with 150 mL of 15% MeOH/MC. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated. A silica gel column chromatography (7% MeOH/MC) was performed on the resulting residue an dobtained 550 mg (61%) of 3,4-dihydro-2H-[2,7]naphtyridine-1-on in white solid.
Reaction SMILES: [CH3:1][C:2](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[CH:3][C:4](OCC)=[O:5]>C1(C)C=CC=CC=1>[CH3:1]/[C:2](/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1)=[CH:3]\[CH2:4][OH:5]
Reactant: CCOC(=O)C=C(C)/C=C/c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: CC(/C=C/c1ccc(C(F)(F)F)cc1)=C\CO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 70.1 %

Procedure:
After a solution in which 150 mg (0.53 mmol) of ethyl (4E)-3-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienoate ((2E)/(2Z)=5/1) as described in Reference example 8 were dissolved in 2 ml of toluene was stirred at 0° C. 0.7 ml (1.06 mmol) of a 1.5M diisobutyl aluminum hybride-toluene solution were added to the solution. After 20 minutes, ice-water was added to the reaction mixture and the mixture was stirred for 10 minutes. The insolubles were removed by filtration using Celite and the filtrate was extracted with ethyl acetate and dried, followed by evaporation of the solvent to obtain an oil. The oil was subjected to column chromatography using 5 g of silica gel and eluted with a mixed solvent of 30 to 40% ethyl acetate-hexane to obtain 90 mg of the title compound as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>[OH-].[Na+].C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:14])([F:15])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCn1ccc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(O)CCn1ccc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21
Temperature: 50 °C
Yield: 8.4 %

Procedure:
D3 (38 mg) was dissolved in 2M aqueous NaOH (0.5 ml) and MeOH (0.5 ml) then stirred at RT overnight. LCMS analysis showed 41% product so the reaction mixture was heated to 50° C. and stirred over the weekend. LCMS showed the reaction to be complete. The reaction mixture was evaporated then partitioned between H2O and DCM. The organic layer was extracted with H2O. The combined aqueous extracts were acidified to pH=1 and extracted with DCM. These DCM extracts were dried over MgSO4, filtered and evaporated to give the crude product MF105672-149A1 (30 mg). The crude product was purified on a silica cartridge (12+S), eluting with a 0 to 10% mixture of MeOH in DCM to give the purified product. This was dissolved in CHCl3 and evaporated to give the title compound (3 mg) as a white solid. δH (CDCl3, 400 MHz): 2.92 (2H, t), 4.50 (2H, t), 6.51 (1H, d), 7.24 (1H, d), 7.40-7.53 (6H, m), 7.90 (1H, s), 8.00 (1H, d), 8.45 (1H, s). MS (ES+): C24H16F3N3O3S requires 483; found 484 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(Cl)Cl.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:4][O:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)O1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To 1.3 g, 1.2 ml (10 mmol) of Dimethyl-1,3-dioxolane-4-methanol, 3.7 g (3.0 mmol, 3.0 eq) of 4-Dimethyl amino pyridine dried for one hour was added and dissolved with 100 mL of CH2Cl2. Thereafter, 2.3 g (12 mmol, 1.2 eq) of p-Toluenesulfonyl chloride was added, then, [the solution] was stirred for the first 30 minutes dipped in cold water at room temperature under argon atmosphere (colorless transparent). After stirring for 18 hours, the disappearance of the raw materials was checked by TLC, liquid separation was carried out with a separating funnel (organic solvent: CDCl3) and the oil layer was dried with anhydrous Na sulfate. An hour later, cotton plug-filtered and concentrated with an evaporator, [the solution] was the target compound was isolated by silica gel column chromatography (CHCl3→CHCl3:MeOH=100 to 10:1) to obtain an oily liquid (2) (pale yellow transparent to colorless transparent). The obtained liquid was dried overnight and an NMR measurement was carried out. (yield: 1.85 g, 8.3 mmol; yield 83%)