Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:20][C:21]1[N:26]=[C:25]([CH2:27][CH2:28][CH2:29]O)[CH:24]=[CH:23][CH:22]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:20][C:21]1[N:26]=[C:25]([CH2:27][CH2:28][CH2:29][O:17][C:16]([C@@H:11]2[CH2:12][S:13][CH2:14][CH2:15][N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[O:18])[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: Cc1cccc(CCCO)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCCCc2cccc(C)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.9 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.230 g (1.5 mmol) of 3-(6-methyl-pyridin-2-yl)-propanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:1) to obtain the product as a oil (0.23 g).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1B(O)O)[CH3:13]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:20]3[CH:19]=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=3[O:14][CH2:12][CH3:13])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CCOc1ccc(Cl)cc1B(O)O
Product: CCOc1ccc(Cl)cc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-ethoxy-5-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-ethoxy-5-chloro-phenylboronic acid in a manner analogous to Example 2c (0.46 g, 66%). MS=322 (MH)+.
Reaction SMILES: CC1C(=CC(=CC=1)N=C=O)[N:4]=C=O.[CH3:14][S:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([NH2:23])=[C:18]([S:24][CH3:25])[C:17]=1N>>[CH3:22][C:20]1[C:21]([NH2:4])=[C:16]([S:15][CH3:14])[CH:17]=[C:18]([S:24][CH3:25])[C:19]=1[NH2:23]
Reactant: CSc1cc(C)c(N)c(SC)c1N
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: *O[Si](*)(C)C
Product: CSc1cc(SC)c(N)c(C)c1N

Procedure:
To a glass kettle there were added 80.76 g of a polytetramethylene glycol/polypropylene glycol based resin end-capped with an excess of toluene diisocyanate, obtained from Dow Chemical Company, 18.0 g of bis[oxydiethylenebis(polycaprolactone)yl]-5-methyltriphenylphosphoniumsulfo-1,3-benzenedicarboxylate, three drops of a polydimethylsiloxane anti-foam agent obtained from Union Carbide Company as SAG 47™, and 21.5 g of di(methylthio)-2,4-toluenediamine, an aromatic diamine sold by and obtained from Ethyl Corporation under the tradename Ethacure 300. The reaction mixture was stirred at room temperature, under nitrogen, for four minutes, degassed under reduced pressure (0.01 mm Hg) and poured into a stainless steel mold. The polymer was cured at 100° C. for sixteen hours and demolded. The slab was then cooled to room temperature and the resistiviities of the slab molded to a thickness of 0.25 in (0.635 cm) were measured as described above at the two designated relative humidities and the relative humidity sensitivity was determined after an equilibration time of fourteen days in a relative humidity chamber. The results are shown in Table I, Example 5 below.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[C:4]([CH:16]([OH:18])[CH3:17])[CH:3]=1.C(Cl)Cl.FC(F)(F)C(O)=O>>[NH2:8][C:5]1[C:4]([CH:16]([OH:18])[CH3:17])=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1
Reactant: CC(O)c1cc(Cl)ncc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)c1cc(Cl)ncc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.3 %

Procedure:
To a solution of tert-butyl 6-chloro-4-(1-hydroxyethyl)pyridin-3-ylcarbamate (823 mg, 3.02 mmol) in methylene chloride (40 mL, 500 mmol) was added trifluoroacetic acid (2 mL, 20 mmol). The reaction mixture was stirred at room temperature for 5 hours and then evaporated in vacuo. The resulting residue was dissolved in dichloromethane and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated in vacuo to yield 455.2 mg (87%) of 1-(5-amino-2-chloropyridin-4-yl)ethanol which was carried forward without purification.
Reaction SMILES: [Si:1]([CH3:5])([CH3:4])(Cl)[Cl:2].N(CC)(CC)CC.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>CCCCC>[Cl:2][Si:1]([NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:5])[CH3:4]
Reactant: CC(C)(C)N
Reactant: C[Si](C)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC(C)(C)N[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Me2SiCl2 (151.50 g, 1.17 moles) was stirred in pentane (2 L) as N(C2H5)3 (119.62 g, 1.18 moles) was added slowly. t-Butylamine (85.85 g, 1.17 moles) in pentane (100 mL) was then added dropwise and the reaction allowed to stir at room temperature for 16 hours. After the reaction period the mixture was filtered and concentrated to 600 mL at which time more salts began to precipitate. The mixture was then refiltered and concentrated to 250 mL and then transferred to a 250 mL roundbottom flask equipped with a microdistillation apparatus and a thermometer. Distillation was performed until the reflux temperature reached 50° C. The clear, colorless liquid remaining was then determined to be pure by NMR and the yield to be essentially quantitative.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].Br[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:16]([O:17][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CCBr
Reactant: CCCCOc1c(O)c2cccc(O)c2oc1=O
Product: CCCCOc1c(O)c2cccc(OCCC(=O)OCC)c2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-butoxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-butoxy-4-hydroxy-8-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:13]([O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(O)C>[ClH:1].[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:26][CH:27]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: Clc1ncnc2ccc(Br)cc12
Solvent: CC(C)O
Product: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Product: Cl
Temperature: 25 °C
Yield: 88.1 %

Procedure:
4-Chloro-6-bromoquinazoline (0.25 g, 1.0 mmol) and 4-benzyloxyaniline (0.25 g, 1.3 mmol) were mixed in 2-propanol (6 ml) and heated at reflux for 10 mins (Procedure A). The solution was allowed to cool at room temperature and the 2-propanol removed in vacuo. The resulting solid was triturated with acetone to give the product as a yellow solid (0.39 g, 88%); δH [2H6]-DMSO 11.60 (1H, b, NH), 9.21 (1H, s, 5-H), 8.86 (1H, s, 2-H), 8.20 (1H, d, 7-H), 7.90 (1H, d, 8-H), 7.65 (2H, d, 2′-H, 6′-H), 7.50-7.25 (5H, m, Ph—H), 7.10 (2H, d, 3′-H, 5′-H), 5.15 (2H, s, CH2); m/z 405/407 (M+).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[CH2:4].Cl[F:12].[Al].[F:14][C:15]([F:22])([F:21])[C:16](F)=[C:17]([F:19])[F:18]>[Ni]>[C:3]([CH2:4][C:16](=[C:17]([F:19])[F:18])[C:15]([F:22])([F:21])[F:14])([C:5]([F:8])([F:7])[F:6])([C:2]([F:10])([F:9])[F:1])[F:12]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: C=C(C(F)(F)F)C(F)(F)F
Reactant: FCl
Agent: [Ni]
Agent: [Al]
Product: FC(F)=C(CC(F)(C(F)(F)F)C(F)(F)F)C(F)(F)F
Temperature: 50 °C
Reaction time: 12 h
Yield: 34 %

Procedure:
Hexafluoroisobutene (HFIB) (32 g, 0.2 mol), aluminum chlorofluoride AlClxFy (5 g) and hexafluoropropene (30 g, 0.2 mol) were charged into a 400 mL Hastelloy™ nickel alloy reactor and agitated at 50° C. for 12 hours. The reaction mixture was poured onto ice, the organic (lower) layer was separated, dried over P2O5 and distilled to give 21 g (34% yield) of (CF3)2CFCH2C(CF3)=CF2, b.p. 80.5-81.5 (see Table 1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]2[C:8](=[C:9]([F:12])[C:10]=1[F:11])[C:7](=[NH:13])[NH:6][C:5]2=N.Cl.[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24]1[S:25][CH2:26][C:27](=[NH:29])[N:28]=1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:1].[NH:13]=[C:7]1[C:8]2[C:4](=[C:3]([F:15])[C:2]([Cl:1])=[C:10]([F:11])[C:9]=2[F:12])[C:5](=[C:26]2[S:25][C:24]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]3[CH3:17])=[N:28][C:27]2=[NH:29])[NH:6]1
Reactant: CC1CCCCN1C1=NC(=N)CS1
Reactant: N=C1NC(=N)c2c(F)c(Cl)c(F)c(F)c21
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Product: CC1CCCCN1C1=NC(=N)C(=C2NC(=N)c3c(F)c(F)c(Cl)c(F)c32)S1

Procedure:
Following the procedure described in Example 9, part B above but using equivalent amounts of 5-chloro-4,6,7-trifluoro-1,3-diiminoisoindoline and 2-(2-methylpiperidino)-4-imino-2-thiazoline hydrochoride in place of 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, there is obtained as the product 1-imino-5-chloro-4,6,7-trifluoro-3-[2-(2-methylpiperidino)-4-imino-2-thiazolin-5-ylidene]isoindoline hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14](O)=O)=[CH:12][N:11]=[C:10]([CH2:17][N:18]2[N:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19]2)[N:9]=1.N1C(C)=CC=CC=1C.CS(Cl)(=O)=O.[NH2:40][C:41]1[C:49]([CH3:50])=[CH:48][C:47]([Cl:51])=[CH:46][C:42]=1[C:43]([OH:45])=[O:44]>C(#N)C>[Cl:51][C:47]1[CH:48]=[C:49]([CH3:50])[C:41]2[N:40]=[C:14]([C:13]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:9][C:10]([CH2:17][N:18]4[N:22]=[N:21][C:20]([C:23]([F:24])([F:26])[F:25])=[N:19]4)=[N:11][CH:12]=3)[O:44][C:43](=[O:45])[C:42]=2[CH:46]=1
Reactant: O=C(O)c1cnc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cnc(Cn4nnc(C(F)(F)F)n4)nc3-c3ccccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
At RT, 385 mg (1.30 mmol) of 4-(2-chlorophenyl)-2-{[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl}pyrimidine-5-carboxylic acid was initially charged in 5 ml of acetonitrile, and 0.27 ml (2.33 mmol) of lutidine was added. With stirring, the solution was then cooled to 0° C., 0.14 ml (1.78 mmol) of methanesulphonyl chloride, dissolved in 2 ml of acetonitrile, was added dropwise and the mixture was stirred at 0° C. for another 15 min. A little at a time, an acetonitrile suspension (3 ml) of 0.53 ml (4.54 mmol) of lutidine and 289 mg (1.56 mmol) of 2-amino-5-chloro-3-methylbenzoic acid was then added to this reaction mixture, and stirring was continued for another 15 min. 0.14 ml (1.78 mmol) of methanesulphonyl chloride, dissolved in 2 ml of acetonitrile, was then added dropwise. The reaction was stirred overnight, with the temperature increasing to RT. The solvent was removed under reduced pressure. The residue was then poured into ice-water and mixed in an ultrasonic bath. The residue was filtered off, again taken up in water and sonicated once more. The residue is filtered off, washed with water and dried under reduced pressure. 708 mg (88% of theory; content 86%) of the desired product were isolated. There was not further purification.
Reaction SMILES: [Br:1][C:2]1[C:3](O[C:6](=[O:8])[CH:7]=1)=[O:4].[CH3:9][NH2:10].C1COCC1.C([O-])(=O)C.[Na+]>C(OCC)C>[CH3:9][N:10]1[C:6](=[O:8])[CH:7]=[C:2]([Br:1])[C:3]1=[O:4]
Reactant: CN
Reactant: O=C1C=C(Br)C(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1C(=O)C=C(Br)C1=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Pursuant to steps a and b of Reaction Scheme 14, a solution of bromomaleic anhydride (52.8 g, 0.298 mol) in diethyl ether (250 mL) was cooled to 5° C. A 2 M solution of methylamine in THF (298 mL, 0.596 mol, 2 eq.) was added dropwise over 1 hour and the reaction stirred for a further 30 minutes, maintaining the temperature below 10° C. The resulting precipitate was filtered, washed with diethyl ether (2×100 mL) and air-dried for 30 minutes, then suspended in acetic anhydride (368 mL) and sodium acetate (12.2 g, 0.149 mol, 0.5 eq.) added. The reaction was heated to 60° C. for 2 hours and solvent was then removed in vacuo. The residue was taken up in DCM (500 mL) and washed with saturated sodium bicarbonate solution (2×500 mL) and water (2×300 mL). Organics were dried over MgSO4 (89 g), filtered and reduced in vacuo. The resulting oil was azeotroped with toluene (4×100 mL) to give N-methyl bromomaleimide as a beige solid. Yield=41.4 g (73%); 1H NMR (300 MHz, CDCl3) δ 6.95 (1H, s, CH), 3.07 (3H, s, NCH3).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:19][C:20](=[O:23])[CH2:21]Br)[CH3:18]>CC(C)=O>[CH2:17]([O:19][C:20]([CH2:21][O:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])=[O:23])[CH3:18]
Reactant: O=C(CO)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a solution of 10 g of 2-hydroxyacetophenone in 40 ml of acetone, 12 g of potassium carbonate was added, and after the mixture was agitated for 1 hour at room temperature, 14 g of bromoacetic acid ethyl ester was added dropwise while stirring, and the resultant mixture was agitated for 3 hours. The reaction mixture was filtered and acetone was evaporated, leaving a residue which was extracted with ether. Evaporation of ether left a residue, which was recrystallized from petroleum ether to give 9.7 g of 2-(ethoxycarbonylmethoxy)-acetophenone, m.p. 33°-35° C.
Reaction SMILES: [CH2:1]([O:19][C@@H:20]1[C@H:24]([OH:25])[C@@H:23]([CH2:26][OH:27])[O:22][C@H:21]1[N:28]1[C:38]2[N:37]=[C:35]([NH2:36])[NH:34][C:32](=[O:33])[C:31]=2[N:30]=[CH:29]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[Si](Cl)(C)C.[C:44](Cl)(=[O:48])[CH:45]([CH3:47])[CH3:46].[OH-].[NH4+:51]>N1C=CC=CC=1.O>[N:51]#[N:28].[C:44]([C@@:21]1([N:28]2[C:38]3[N:37]=[C:35]([NH2:36])[NH:34][C:32](=[O:33])[C:31]=3[N:30]=[CH:29]2)[O:22][C@H:23]([CH2:26][OH:27])[C@@H:24]([OH:25])[C@H:20]1[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:48])[CH:45]([CH3:47])[CH3:46]
Reactant: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Reactant: CC(C)C(=O)Cl
Reactant: [NH4+]
Agent: C[Si](C)(C)Cl
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@@]1(C(=O)C(C)C)n1cnc2c(=O)[nH]c(N)nc21
Product: N#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2'-O-Octadecylguanosine (1.9 g) in pyridine (150 ml) was cooled in an ice bath, and treated with trimethylsilyl chloride (2 g, 5 eq) and isobutyryl chloride (2 g, 5 eq). The reaction mixture was stirred for 4 hours, during which time it was allowed to warm to room temperature. The solution was cooled, water added (10 mL) and stirred for an additional 30 minutes. Concentrated ammonium hydroxide (10 mL) was added and the solution concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with 3% MeOH/EtOAc) to yield 1.2 g of product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.Cl.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CC>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:28]([C:4]3[N:3]=[C:2]([NH2:1])[C:7]([NH2:8])=[CH:6][CH:5]=3)[CH2:29][CH2:30]2)=[CH:17][CH:16]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(CCCN1CCNCC1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: Nc1ccc(N2CCN(CCCC(=O)c3ccc(F)cc3)CC2)nc1N
Reaction time: 0.17 h

Procedure:
6 g 2-amino-6-chloro-3-nitropyridine, 12.6 g 1-(4-fluorophenyl)-4-(1-piperazinyl)-1-butanone dihydrochloride and 20 g potassium carbonate in 120 ml n-propanol are stirred under reflux for 21/2 hours. The mixture is then treated with 400 ml water, stirred for further 10 minutes and cooled in an ice bath. The resulting precipitate is filtered off, washed with water, dissolved in methylene chloride, dried over sodium sulphate and evaporated. The resulting 1-(4-fluorophenyl)-4-[4-(2-amino-3-nitro-pyridin-6-yl)-1-piperazinyl]-1-butanone, m.p. 128°-130°, is without further purification dissolved in 400 ml methanol. 3 g palladium on charcoal (5%) are added to the solution and the mixture is hydrogenated under normal conditions. The catalyst is filtered off and the solvent distilled off to give 1-(4-fluorophenyl)-4-[4-(2,3-diaminopyridin-6-yl)-1-piperazinyl]-1-butanone which is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO.C(Cl)(Cl)Cl.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccnc(F)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of methyl 2-(2-fluoropyridin-4-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (125.0 mg, 0.35 mmol) in methanol (25 mL) and chloroform (10 mL) was added sodium hydroxide (56.0 mg, 1.40 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (20 mL) and adjusted to pH 6 with hydrochloric acid (1N). The product was precipitated and collected by filtration to afford 2-(2-fluoropyridin-4-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (50 mg, 42%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=O)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].Cl.[NH2:28][OH:29].N1C=CC=CC=1>C(O)C.O>[C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[N:28][OH:29])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=NO)=CC[C@@H]32)C1
Reaction time: 2 h
Yield: 83.4 %

Procedure:
56 Parts of 3β-acetoxy-5β-pregn-16-en-20-one is mixed with 315 parts of ethanol and heated to reflux to effect solution. Then, 11.6 parts of hydroxylamine hydrochloride, 14.7 parts of pyridine, 11.2 parts of water and 395 parts of ethanol is added and the refluxing continued for 2 hours. Distillation is initiated and continued until the pot volume is about 200 parts. The pot residue is then chilled to afford a precipitate that is washed first with 150 parts by volume chilled distillate and then with 200 parts of water. Further cooling of the mother liquor affords a second crop. The first and second crops are combined to give 3β-acetoxy-5β-pregn-16-en-20-one oxime, in a yield of 83.4%. This compound melts at about 180°-183° C. and is represented by the following structural formula. ##STR3##
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[Cl:17][CH2:18][C:19](Cl)=O.[NH:22]1[CH2:27][CH2:26][C:25]2([C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28]2)[CH2:24][CH2:23]1>>[ClH:17].[CH:12]1[C:7]2[CH2:6][CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=3[CH:2]([NH:1][CH2:18][CH2:19][N:22]3[CH2:27][CH2:26][C:25]4([C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28]4)[CH2:24][CH2:23]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: O=C(Cl)CCl
Reactant: NC1c2ccccc2CCc2ccccc21
Product: C1=CC2(CCN(CCNC3c4ccccc4CCc4ccccc43)CC2)c2ccccc21
Product: Cl

Procedure:
The title compound, m.p. 186° C. and MS: m/e=421.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-amino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, chloroacetyl chloride, spiro[1H-indene-1,4'-piperidine] and Hcl.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[OH:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(B(O)O)c1O
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Product: Cc1ccc(-c2cccc(-c3cccc(-c4cccc(C)c4O)n3)n2)c(O)c1
Yield: 84 %

Procedure:
6-(2-Hydroxy-3-methylphenyl)-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 2-hydroxy-3-methylphenylboronic acid in 84% yield using method F; δH [2H6]-DMSO 13.38,(1H, b), 8.41-8.22,(4H, m), 8.13,(1H, d), 8.09-8.01,(2H, m), 7.96,(1H, d), 7.28,(1H, d), 6.90,(1H, t), 6.80,(2H, m), 2.33,(3H, s), 2.26,(3H s); MS 369 (MH)+; HPLC retention time (system 1) 4.53 minutes.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=O.C(Cl)Cl.[CH2:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:22].S(Cl)(Cl)=O>C(N(CC)CC)C>[CH3:22][CH2:21][N:23]([C:15]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:12])[C:11]=2[C:2]=1[OH:1])=[O:17])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Cl)cccc21
Reactant: CCNc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 7.5 °C
Reaction time: 4 h
Yield: 55.1 %

Procedure:
The mixture of 1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid (1 gm) and methylene chloride (20 ml) was cooled to 5-10° C. under nitrogen atmosphere. Triethylamine (1.15 gm) was added to the resulting mass at 5-10° C. to form a clear solution. The solution was followed by addition of N-ethyl aniline (0.45 gm) in one portion at 5-10° C. and then thionyl chloride (0.48 gm) was added at 5-10° C. The resulting mixture was stirred for 4 hours followed by evaporation of methylene chloride under vacuum. The resulting residue was dissolved in ethyl acetate (100 ml) followed by washings with 5% sodium hydroxide solution (30 ml) at 25-30° C. The resulting aqueous layer was cooled to 10-15° C. and pH was adjusted to 2 by using 18% aqueous hydrochloric acid solution (20 ml). The resulting mass was stirred for 2 hours at 15-20° C. The resulting white colored solid was filtered and dried at 55-60° C. to yield 0.73 gm of laquinimod (HPLC Purity: 84.31%).