Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C@@:11]([CH2:17][CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:17]([C@@:11]1([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:25]3[CH:24]=[C:23]([C:22]([F:36])([F:21])[F:35])[CH:28]=[CH:27][N:26]=3)[CH2:30][CH2:31]2)=[O:16])[CH2:12][CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)[CH3:18]
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Reactant: CC[C@@]1(C(=O)O)CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of (1R,3S)-3-[(tert-butoxycarbonyl)amino]-1-ethylcyclopentanecarboxylic acid (0.30 g, 1.2 mmol) and 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine dihydrochloride (0.39 g, 1.3 mmol) in DMF (10 mL) under N2 was added triethylamine (0.65 mL, 4.7 mmol) and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.663 g, 1.75 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3 and extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, concentrated and purified by flash column chromatography to yield the desired product (400 mg, 72.9%). MS calculated for C23H34F3N4O3:(M+H) 471.3; found 371.2 (M+H-Boc).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([N:9]([CH2:13][CH3:14])[CH2:10][CH2:11][NH2:12])[CH3:8].Cl.[Cl:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=3)=[CH:22][N:23]=[N:24]2)=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([S:34]([NH:12][CH2:11][CH2:10][N:9]([CH2:13][CH3:14])[CH2:7][CH3:8])(=[O:35])=[O:36])=[CH:32][CH:33]=3)=[CH:22][N:23]=[N:24]2)=[CH:19][CH:18]=1
Reactant: CCN(CC)CCN
Reactant: O=S(=O)(Cl)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Temperature: 5 °C

Procedure:
A mixture of anhydrous sodium carbonate (3.08 g) and N,N-diethylethylenediamine (0.43 ml) in chloroform (30 ml) was vigorously stirred at 5° C. and treated with 4-(7-Chloro-4-cinnolinylamino)benzenesulphonyl chloride hydrochloride (1.0 g). The mixture was stirred at room temperature for 11/2 hours and then filtered. The filtrate was evaporated to give a residue that crystallised from ethanol to give the title compound (0.456 g), m.p. 175°-76° C.
Reaction SMILES: C1(NC(=O)NC2C=CC(OC3C=CN=C4C=C(C5N=CN(CCN6CCN(C(OC(C)(C)C)=O)CC6)C=5)SC=34)=C(F)C=2)CC1.C1(NC(NC2C=CC(OC3C=CN=C4C=C(C5C=CC(CN6CCNCC6)=CN=5)SC=34)=C(F)C=2)=O)CC1.C(OCC(O)=O)(=O)C.C([O:93][CH2:94][C:95]([N:97]([CH2:102][C:103]1[CH:104]=[N:105][C:106]([C:109]2[S:117][C:116]3[C:111](=[N:112][CH:113]=[CH:114][C:115]=3[O:118][C:119]3[CH:120]=[N:121][C:122]([NH:125][C:126]([NH:128][CH:129]4[CH2:131][CH2:130]4)=[O:127])=[CH:123][CH:124]=3)[CH:110]=2)=[CH:107][CH:108]=1)[CH2:98][CH2:99][O:100][CH3:101])=[O:96])(=O)C>>[CH:129]1([NH:128][C:126](=[O:127])[NH:125][C:122]2[N:121]=[CH:120][C:119]([O:118][C:115]3[CH:114]=[CH:113][N:112]=[C:111]4[CH:110]=[C:109]([C:106]5[N:105]=[CH:104][C:103]([CH2:102][N:97]([CH2:98][CH2:99][O:100][CH3:101])[C:95](=[O:96])[CH2:94][OH:93])=[CH:108][CH:107]=5)[S:117][C:116]=34)=[CH:124][CH:123]=2)[CH2:130][CH2:131]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)nc4)c3s2)nc1)C(=O)COC(C)=O
Agent: CC(=O)OCC(=O)O
Agent: CC(C)(C)OC(=O)N1CCN(CCn2cnc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)c2)CC1
Agent: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)nc4)c3s2)nc1)C(=O)CO

Procedure:
Compounds 309 (example 167) and 310 (example 168) were prepared by reacting compounds 307 (scheme 68) and compound 49 (scheme 15) with acetoxyacetic acid, similarly to compound 30 (scheme 13). Compound 311 (example 169) was synthesized by following the procedures described above for the synthesis of compound 49 (scheme 15). Compounds 312 (example 170) and 313 (example 171) were obtained similarly to compound 31 (scheme 13). Compound 314 (example 172) was synthesized by following the procedures described above for the synthesis of compound 75 (scheme 20).
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[CH:11]=1.ICC>C1COCC1.[Cl-].[Na+].O>[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH2:2][CH3:3])[CH:11]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCI
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(Cl)ccn1
Temperature: -60 °C
Reaction time: 1.5 h
Yield: 67.5 %

Procedure:
To a solution of LDA (0.13 moles) in THF/hexanes (40 mL/40 mL) at −60° C. under argon was added a solution of 4-chloro-2-picoline (15 g) in THF (250 mL) over 20 min. After a further 30 min at −60° C. iodoethane (10.4 mL) in THF (60 mL) was added over 20 min, the reaction stirred at −60° C. for 1.5 h and then allowed to warm to −30° C. The mixture was poured into brine and extracted with dichloromethane. After drying (MgSO4) and purification by chromatography eluting with dichloromethane in petroleum ether (70-100%) followed by dichloromethane containing methanol (0 to 5%) the title compound was obtained as a brown oil (12.35 g). 1H NMR δ (CDCl3) 0.97 (3H, t), 1.75 (2H, m), 2.75 (2H, t), 7.12 (1H, m), 7.16 (1H, d), 8.42 (1H, d).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].OCC([C@H]([C@@H]([C@H](CO)O)O)O)=O.[Na+].[Cl-].C([O-])([O-])=O.[Ca+2]>>[OH:8][C:7]1[C@@H:5]([C@@H:3]([OH:4])[CH2:2][OH:1])[O:6][C:11](=[O:12])[C:9]=1[OH:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 20 h

Procedure:
A series of resting cell reactions (0.5 ml reaction mixture in 5 ml reaction tube) was carried out with 2% D-sorbitol or with 2% L-sorbose, and all reaction mixtures further contained 0.3% NaCl, 1% CaCO3 and cells at a final concentration of 5 absorbance units at 600 nanometers (OD600). After 20 h incubation time, G. oxydans DSM 17078 produced 270 mg/l or 670 mg/l of Vitamin C, respectively from 2% D-sorbitol or 2% L-sorbose, respectively. In comparison, strain G. oxydans DSM 17078-dSMS 05 produced 1540 mg/l or 1990 mg/l of Vitamin C, respectively.
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8](C3C=CC=CC=3)=[C:9]3[N:32]=[C:12]([C:13](Br)=[C:14]4[NH:30][C:17](=[C:18](C5C=CC=CC=5)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.C([C@@H]1COC(=O)N1)C1C=CC=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.C(Cl)Cl>[C:3]12[CH:2]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:17]3[NH:30][C:14]([CH:15]=[CH:16]3)=[CH:13][C:12]3=[N:32][C:9]([CH:10]=[CH:11]3)=[CH:8][C:6]([NH:7]1)=[CH:5][CH:4]=2
Reactant: Brc1c2nc(c(-c3ccccc3)c3ccc([nH]3)c(Br)c3nc(c(-c4ccccc4)c4ccc1[nH]4)C=C3)C=C2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
The general procedure described by Gao et al., (2004) Org. Lett., 6:1837, was used to couple 5,15-dibromo-10,20-diphenylporphyrin (31.0 mg, 0.05 mmol) with (R)-(+)-4-benzyl-2-oxazolidinone (70.8 mg, 0.4 mmol), using Pd2(dba)3 (2.3 mg, 0.0025 mmol) and Xantphos (5.78 mg, 0.01 mmol) in the presence of Cs2CO3 (65.2 mg, 0.2 mmol). The reaction was conducted in THF at 68° C. for 22 h., The title compound was isolated by flash chromatography (silica gel, methylene chloride:ethyl acetate (v/v)=9:1) as a purple mixture of two atropic isomers (25 mg, 62%, α,α/α,β=50%/50%). 1H NMR (300 MHz, CDCl3): δ 9.46 (d, J=5.1 Hz, 4H), 9.42 (d, J=4.8 Hz, 4H), 9.24 (t, J=4.2 Hz, 4H), 9.00 (d, J=4.8 Hz, 2H), 8.96 (d, J=4.2 Hz, 4H), 8.93 (d, J=4.8 Hz, 2H), 8.32 (d, J=4.8 Hz, 2H), 8.20 (t, J=7.2 Hz, 4H), 8.06 (d, J=4.8 Hz, 2H), 7.79 (m, 12H), 7.07 (m, 6H), 7.02 (m, 6H), 6.83 (m, 8H), 5.35 (m, 2H), 5.23 (m, 2H), 5.00 (dd, J=9.0 Hz, 4H), 4.82 (dd, J=9.0 Hz, 4H), 3.13-3.30 (m, 4H), 2.94 (dd, J=13.2, 3.3 Hz, 2H), 2.70 (dd, J=13.2, 3.3 Hz, 2H), −2.84 (s, 2H), −2.89 (s, 2H); 13C NMR (75 MHz, CDCl3): δ 147.1, 140.1, 140.9, 135.0, 134.6, 128.8, 128.7, 128.2, 127.1, 126.9, 126.8, 121.4, 111.5, 68.3, 66.4, 40.4, 40.3. UV-vis (CH2Cl2, λmax, nm): 412, 526, 558. HRMS-MALDI ([M+H]+): calcd for C52H41N6O4, 813.3184, found 813.3194 with an isotope distribution pattern that is the same as calculated one.
Reaction SMILES: [NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CO.[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 0.5 h

Procedure:
The title compound of Example 3 (12.6 g., 26 mmoles) is dissolved in 78 ml. of methanol and 78 ml of 1 N sodium hydroxide is added dropwise with stirring to give a clear solution. After 1/2 hour, the tlc (5 percent methanol-chloroform) showed that saponification was complete.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=O)=O.Cl>C1C=CC=CC=1.[Zn]>[SH:2][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: [Zn]
Solvent: c1ccccc1
Product: O=C(O)c1cccc(S)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-(chlorosulfonyl)benzoic acid (22.0 g, 0.10 mol) and zinc powder (87.5 g, 1.3 mol) in benzene (150 mL) was added at 0° C., in a dropwise manner, concentrated hydrochloric acid (150 mL, 10 M). The mixture was heated at reflux, stirred for 1 hour, cooled to room temperature, and filtered through a pad of celite, which was subsequently washed with benzene (3×50 mL). The organic layer was separated and washed with water (100 mL), and brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a white solid which was recrystallised from aqueous ethanol (9.5 g, 62%) to give the title compound as a solid, mp 147° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A solution of 3.90 g of ethyl 1,2-dihydro-2-oxoquinoxaline-3-carboxylate in 25 ml of N,N-dimethylformamide was added dropwise to a suspension of 0.79 g of 60% sodium hydride/oil in 10 ml of N,N-dimethylformamide at room temperature over 30 minutes. After stirring at room temperature for 30 minutes, 3.36 g of benzyl bromide was added dropwise over 10 minutes, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue, after addition of ethyl acetate, was washed with water, 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; hexane—ethyl acetate=10:1−2:1) and recrystallized from ethyl acetate—hexane to give 3.77 g of ethyl 1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=3)=[CH:21][CH:20]=1)[C:13]([CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([OH:37])=[O:36])=[C:12]2[S:40][C:41]([CH3:44])([CH3:43])[CH3:42].[OH-].[Na+:46]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=3)=[CH:23][CH:24]=1)[C:13]([CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([O-:37])=[O:36])=[C:12]2[S:40][C:41]([CH3:44])([CH3:43])[CH3:42].[Na+:46]
Reactant: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)O)c(SC(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)[O-])c(SC(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1
Yield: 100.4 %

Procedure:
3-[5-(Pyrid-2-ylmethoxy)-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyrid-5-yl)benzyl]indol-2-yl]-2,2-dimethylpropionic acid (444 g, 0.729 mol) was added to a reactor containing 2.1 L of EtOH and stirred. A NaOH solution (29 g in 218 mL of water; 1.00 equivalents) was added to the reactor and stirred at ambient temperature for about 30 minutes. The reaction was concentrated under vacuum at a temperature of about 40 to about 50° C. under a reduced pressure of about 10 mm Hg to about 30 mm Hg. The compound was subsequently dried under vacuum at a temperature of between 40 and 45° C. under a reduced pressure of between 5 and 10 mm Hg to afford 460 g of desired product in near quantitative yield. The sodium salt had a detectable amount of palladium less than about 10 ppm.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].ClP(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[OH:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2[Cl:42])[N:35]([CH3:43])[C:34](=[O:44])[C:33]=1[C:45](O)=[O:46]>C(Cl)(Cl)Cl>[CH3:2][CH2:1][N:3]([C:45]([C:33]1[C:34](=[O:44])[N:35]([CH3:43])[C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([Cl:42])[C:41]=2[C:32]=1[OH:31])=[O:46])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Cl)cccc21
Reactant: CCNc1ccccc1
Agent: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 27.5 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
N-Ethyl aniline (5.2 gm) was taken in chloroform (100 ml) and stirred for 10 minutes at 25-30° C. under nitrogen atmosphere. The resulting mass was followed by the addition of dichlorotriphenyl phosphorane (26.6 gm) at 25-30° C. and the reaction mixture was stirred for 15 minutes. 1,2-Dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid (10 gm) was added to the resulting mass at 25-30° C. followed by heating to reflux (40-45° C.) and then stirred for 3 hours at reflux. Chloroform was distilled out from the reaction mass under vacuum at below 55° C. The resulting residue was cooled to 25-30° C., followed by the addition of ethyl acetate (50 ml) and water (50 ml) at 25-30° C. and the resulting mixture was stirred for 30 minutes at 25-30° C. The separated solid was filtered, washed with water and then dried to yield 12.95 gm of laquinimod (HPLC purity: 99.24%).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][N:30]=4)[N:25]=[CH:24][C:23]=3[N+:32]([O-])=O)[O:17][N:16]=2)=[CH:11][CH:10]=1>[Pt].C(O)(C)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][N:30]=4)[N:25]=[CH:24][C:23]=3[NH2:32])[O:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Nc1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1

Procedure:
A Parr vessel was charged with 5% platinum on carbon (0.12 g), purged with nitrogen, and then charged sequentially with toluene (2 mL), N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-3-nitro[1,5]naphthyridin-4-amine (6.00 g, 16.4 mmol), toluene (73 mL), and isopropanol (5 mL). The vessel was purged with hydrogen three times and then placed under hydrogen pressure (50 psi, 3.4×105 Pa) for 16 hours. An analysis by high-performance liquid chromatography (HPLC) indicated the presence of starting material. The catalyst was removed by filtration and washed with hot dichloromethane and methanol. The filtrate was concentrated under reduced pressure, and the residue was dissolved in hot methanol (100 mL) and added to a Parr vessel. Catalytic 5% platinum on carbon (0.12 g) was added, and the reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for four hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to provide N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}[1,5]naphthyridine-3,4-diamine.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].N1C=CN=C1.Cl>CN(C=O)C>[O:4]([CH2:3][CH2:2][CH2:1][OH:5])[Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: OCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1,3-propanediol (10 mmol), tert-butyldimethylchlorosilane (11 mmol), and imidazole (22 mmol) dissolved in 5 mL of DMF was stirred at room temperature for 16 hours. The mixture was poured into 0.1 M HCl (100 mL) and extracted with ether (3×100 mL). The organic phases were washed with brine (100 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The mixture was purified by flash chromatography to give the product as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[CH3:6][C:7](=[N:9][OH:10])[CH3:8]>[OH-].[Na+]>[C:7](=[N:9][O:10][CH2:2][C:3]([OH:5])=[O:4])([CH3:8])[CH3:6]
Reactant: CC(C)=NO
Reactant: O=C(O)CCl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=NOCC(=O)O
Temperature: 30 °C

Procedure:
47.3 Grams (0.5 moles) of chloroacetic acid was dissolved in 55 g (0.55 moles) of an aqueous solution of 40% sodium hydroxide. To the solution, 36.5 g (0.5 moles) of acetone oxime was added, and then 55 g (0.55 moles) of an aqueous solution of 40% sodium hydroxide was added dropwise to the mixture while maintaining a temperature at not higher than 30° C. Reaction was subsequently performed with the solution being allowed to flow at a rate of 4 ml/min into a glass tube (10 mm in diameter and 100 mm in length) that was heated at 90°-100° C. The unreacted acetone oxime was removed from the reaction solution by two extractions with 100 ml of ether. The pH of the remaining aqueous solution was adjusted to 1 with concentrated HCl. The solution was subsequently saturated with sodium chloride. The resulting aqueous solution was subjected to two extractions with 100 ml of ether and the extract was dried with magnesium sulfate. Ether was distilled off under vacuum and the residue was distilled under vacuum to obtain isopropylidene aminooxyacetic acid (m.p. 76° C.) in an amount of 16.3 g (yield, 25 mol %).
Reaction SMILES: [CH3:1][C:2]1([S:12][CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].Cl[CH2:15][CH2:16][O:17]C1CCCCO1.CC1(C)C2C(=CC=CC=2)N(CCO)C1=O>>[OH:17][CH2:16][CH2:15][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])([S:12][CH3:13])[C:3]1=[O:11]
Reactant: ClCCOC1CCCCO1
Reactant: CSC1(C)C(=O)Nc2ccccc21
Agent: CC1(C)C(=O)N(CCO)c2ccccc21
Product: CSC1(C)C(=O)N(CCO)c2ccccc21

Procedure:
Prepared from 3-methyl-3-methylthioindol-2(3H)-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described for 3,3-dimethyl-1-(2-hydroxy-1-ethyl)-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C(O)(=O)/C=C\C(O)=O.[F:19][C:20]1[CH:21]=[C:22]([CH:26]2[S:40][C:33]3([CH2:38][CH2:37][N:36](C)[CH2:35][CH2:34]3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=3)[CH:23]=[CH:24][CH:25]=1>ClCCl>[F:19][C:20]1[CH:21]=[C:22]([CH:26]2[S:40][C:33]3([CH2:34][CH2:35][N:36]([C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[CH2:37][CH2:38]3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=3)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC2(CC1)SC(c1cccc(F)c1)c1ccccc12
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)SC(c1cccc(F)c1)c1ccccc12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To 5.0 g of phenyl chloroformate in 80 ml of dichloromethane is added 7.89 g of the free base, 3-(3-fluorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine] of Example 55, in 10 ml of dichloromethane over 20 minutes. The reaction mixture is stirred at room temperature for 21 hours, then diluted with 200 ml of dichloromethane. The resultant mixture is washed with two 175 ml portions of 10% aqueous sodium hydroxide solution, two 150 ml portions of water and one 70 ml portion of saturated aqueous sodium chloride solution, and dried over magnesium sulfate to give an oil. The oil is chromatographed on silica gel with dichloromethane to give an oil, which crystallizes to yield 3-(3-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine], m.p. 134°-142° C. A portion is recrystallized twice from toluene:hexane, m.p. 144°-146° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.[I:21]I.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.C(OCC)C>[F:13][C:14]1[C:19]([I:21])=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1
Reactant: Fc1cccc(F)n1
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1ccc(I)c(F)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of butyllithium (38.8 ml, 97 mmol) in tetrahydrofuran (194 ml) at −78° C. was added diisopropylamine (13.8 ml, 97 mmol) dropwise. After 15 minutes at −78° C., 2,6-difluoropyridine (8.8 ml, 97 mmol) was added slowly. After 1 hour slowly, a solution of iodine (24.6 g, 97 mmol) in tetrahydrofuran (50 ml) was carefully added, keeping the internal temperature at −78° C. Sodium sulfite (3.0 g, 24 mmol) was added and the temperature was allowed to gradually increase to ambient temperature. The reaction mixture was diluted with ethyl ether, washed with water, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting (ethyl acetate/isohexane gradient) to give 2,6-difluoro-3-iodopyridine.