Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][O:35][CH3:36])=[N:11][C:12]([N:16]2C(C)=CC=C2C)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO.[OH-].[K+].[OH-].[Na+]>C(O)C.O.O>[CH2:1]([O:8][C:9]1[C:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][O:35][CH3:36])=[N:11][C:12]([NH2:16])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOCCCCCCCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COCOCCCCCCCCCCc1nc(N)nc(C)c1OCc1ccccc1

Procedure:
To a stirred solution containing 230 mg (0.47 mmol) of 5-(benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-(10-(methoxymethoxy)decyl)-6-methylpyrimidine in 15 mL of 9:1 ethanol-water was added 327 mg (4.70 mmol) of hydroxylamine hydrochloride followed by 263 mg (4.70 mmol) of KOH. The reaction mixture was then heated and stirred at reflux for 5 h. A second portion of 327 mg (4.70 mmol) of hydroxylamine hydrochloride followed by 263 mg (4.70 mmol) of KOH was added and the reaction mixture was heated and stirred at reflux for 12 h. The reaction mixture was poured into 70 mL of water and then treated with 1N NaOH until pH 9-10 was reached. The reaction mixture was extracted with two 70-mL portions of ethyl acetate. The combined organic layer was washed with 70 mL of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (10×3 cm). Elution with 2:1 hexanes-ethyl acetate afforded the expected product as a colorless oil: yield 133 mg (76%); silica gel TLC Rf 0.76 (9:1 dichloromethane-methanol); 1H NMR (CDCl3) δ1.27 (m, 12H), 1.53-1.63 (m, 4H), 2.26 (s, 3H), 2.54 (dd, 2H, J=7.6, 7.6 Hz), 3.31 (s, 3H), 3.46 (t, 2H, J=6.8 Hz), 4.57 (s, 2H), 4.69 (s, 2H), 5.19 (br s, 2H) and 7.35-7.37 (m, 5H); 13C NMR (CDCl3) δ 18.9, 26.2, 28.4, 29.36, 29.40, 29.5, 29.67, 29.70, 31.9, 55.0, 67.8, 75.9, 96.3, 127.9, 128.3, 128.3, 128.6, 128.6, 136.8, 142.8, 158.9, 161.1, 161.1 and 164.8; mass spectrum (APCI), m/z 416.2908 (M+H)+ (C24H38N3O3 requires 416.2913).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>[Zn]>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Agent: [Zn]
Product: Clc1cc(Cl)c(Cl)nc1Cl
Yield: 93.1 %

Procedure:
On reaction of 12.76 g (0.05 mol) of pentachloropyridine with 4.1 g (0.063 gram atom) of zinc dust and 11.6 g (0.08 mol) of ammonium sulfate using the method described in Example 1, there is obtained 10.1 g (92% of theory) of crude 2,3,5,6-tetrachloropyridine, which contains, according to gas-chromatographical analysis, 92% of 2,3,5,6-tetrachloropyridine, 3.3% of 2,3,5-trichloropyridine, 1.3% of 2,3,6-trichloropyridine and 2.9% of pentachloropyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N[C:10]1[CH:11]=[CH:12][C:13](C)=[C:14]([OH:16])[CH:15]=1>[OH-].[Na+]>[CH:7]1[C:2](=[N:1][C:11]2[CH:10]=[CH:15][C:14]([OH:16])=[CH:13][CH:12]=2)[CH:3]=[CH:4][C:5](=[O:8])[CH:6]=1
Reactant: Cc1ccc(N)cc1O
Reactant: Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1C=CC(=Nc2ccc(O)cc2)C=C1
Yield: 60.2 %

Procedure:
0.01 mole (1.09 g) of paraaminophenol is dissolved in 100 cm3 of a 0.1 N NaOH solution. A second solution of 0.01 mole (1.23 g) of 5-amino-2-methyl phenol in 100 cm3 of a 0.1N NaOH solution is also prepared. The two solutions are then mixed and air is bubbled in the resulting mixture for about 5 hours at ambient temperature. The reaction medium is then acidified with sufficient HCl to pH 5 to produce 1.2 g of said indophenol which is then filtered off and which, after recrystallization from a dimethylformamide-water mixture, melts at 215°.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[F:5][C:6]([F:16])([F:15])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[F:5][C:6]([F:15])([F:16])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:1](=[O:4])[CH3:2])=[CH:9][CH:8]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
Acetic acid (1.321 g, 22.000 mmol) was dissolved in DMF (10 ml), 1-[4-(trifluoromethyl)phenyl]methanamine (3.468 g, 19.800 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (7.770 g, 24.200 mmol) and N-ethyl-N,N-diisopropylamine (5.971 g, 46.200 mmol) was added. The solution was stirred for two hours at room temperature. EtOAc (20 ml) was added and the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×, 10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation and gave 3.085 g of N-[4-(trifluoromethyl)benzyl]acetamide (yield 64.6%).
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8].[CH:20]([NH2:23])([CH3:22])[CH3:21]>>[OH:1][CH:2]([CH2:19][NH:23][CH:20]([CH3:22])[CH3:21])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8]
Reactant: CC(C)N
Reactant: COC(=O)CCC(=O)c1ccccc1OCC1CO1
Product: COC(=O)CCC(=O)c1ccccc1OCC(O)CNC(C)C
Yield: 101.7 %

Procedure:
A stirred mixture of methyl 3-[2-(2,3-epoxypropoxy)benzoyl]propionate (8.3 g, 0.031 mole), and isopropylamine (16.4 ml, 0.19 mole) was heated under reflux for 90 minutes. Evaporation of the solution under reduced pressure gave methyl 3-[2-(2-hydroxy-3-isopropylaminopropoxy)benzoyl]-propionate (10.2 g, 100%) as a pale brown oil.
Reaction SMILES: [BH4-].[Na+].C(O)C.[CH3:6][O:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[CH3:20])[C:13]([CH:21]=[O:22])=[CH:12][CH:11]=1>O>[OH:22][CH2:21][C:13]1[C:14]2[C:19](=[C:18]([CH3:20])[CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH2:8][O:7][CH3:6])=[CH:11][CH:12]=1
Reactant: COCOc1ccc(C=O)c2cccc(C)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCOc1ccc(CO)c2cccc(C)c12
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
1.23 g of sodium borohydride was added to an ethanol (100 ml) solution of 15 g of 4-methoxymethoxy-5-methyl-1-naphthalenecarbaldehyde at room temperature and agitated for 30 minutes. Water was added to the reaction solution and the resultant crystals were collected by filtration and dried to obtain 14 g of the captioned compound as light brown crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2].[CH2:17]([O:19][CH:20]=[CH:21][Sn](CCCC)(CCCC)CCCC)[CH3:18].[F-].[Cs+].CCOCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[CH2:18])[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(Cl)cc(NC(C)=O)c1Cl
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: C=C(OCC)c1cc(NC(C)=O)c(Cl)c(C(=O)OC)n1
Temperature: 100 °C
Yield: 65 %

Procedure:
A solution of methyl 4-acetamido-3,6-dichloropyridine-2-carboxylate (0.988 g, 4.0 mmol), ethoxyvinyltributyltin (2.70 mL, 8.0 mmol) and cesium fluoride (1.34 g, 8.8 mmol) in dioxane (20 mL) was sparged with nitrogen for 15 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.140 g, 0.2 mmol) was then added and the mixture was heated at 100° C. for 5 hours. After cooling, ether was added and the reaction mixture filtered through a silica plug. The solvents were removed and the crude product was purified by chromatography (ethyl acetate:hexane (1:2)) to give methyl 4-acetamido-3-chloro-6-(1-ethoxyvinyl)pryidine-2-carboxylate (0.780 g, 2.6 mmol). 1H NMR (CDCl3): δ 8.85 (s, 1H), 7.90 (br.s, 1H), 5.47 (d, J=2.0 Hz, 1H), 4.44 (d, J=2.0 Hz, 1H), 4.01 (s, 3H), 3.98 (q, J=7.0 Hz, 2H), 2.32 (s, 3H), 1.46 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH:13]=2)=[CH:4][C:3]1=[O:21].[ClH:22].O1CCOCC1>CCOC(C)=O>[ClH:22].[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][C:3]1=[O:21].[ClH:22]
Reactant: Cn1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1ccc(C2=CCNCC2)cc1=O
Temperature: 25 °C

Procedure:
A solution of tert-Butyl 1′-methyl-2′-oxo-1′,2′,3,6-tetrahydro-4,4′-bipyridine-1(2H)-carboxylate (100 mg, 0.3 mmol) in AcOEt (2 mL) was treated with 4 M of hydrogen chloride in 1,4-dioxane (0.1722 mL, 0.6888 mmol). The mixture was stirred at r.t. 2 h., and concentrated under reduced pressure to afford the desired compound as HCl salt which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=191.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH:33]=[CH:32][N:31]([CH:34]7[CH2:39][CH2:38][N:37](C([O-])=O)[CH2:36][CH2:35]7)[N:30]=6)=[CH:25][N:24]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[ClH:43]>C(Cl)Cl.O1CCOCC1>[ClH:43].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH:33]=[CH:32][N:31]([CH:34]7[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]7)[N:30]=6)=[CH:25][N:24]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(-c6ccn(C7CCN(C(=O)[O-])CC7)n6)cn5)C4)c3n2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(-c6ccn(C7CCNCC7)n6)cn5)C4)c3n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
4-(3-(2-(3-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (25 mg, 0.04 mmol) was dissolved in CH2Cl2(5 ml), and then 4 N HCl in dioxane (1 ml) was added, followed by stirring at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and then purified with ether, to give 6-(1-methyl-1H-pyrazol-4-yl)-1-((1-(5-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)pyrimidin-2-yl)piperidin-3-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine hydrochloride (18 mg, 75%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=2)O1>>[OH:19][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:7]=2)[C:2]=1[C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=1
Reactant: Oc1cccc(-c2ccc3c(Br)c(O)ccc3c2)c1
Reactant: CC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: CC(=O)Nc1cccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)c1
Reaction time: 2 h
Yield: 77 %

Procedure:
The compound is prepared by the reaction of 1-bromo-6-(3-hydroxyphenyl)naphthalene-2-ol (150 mg, 0.48 mmol, 1 eq) with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (124.3 mg, 0.48 mmol, 1 eq) according to method A in 2 h. Purification by column chromatography with hexane/ethyl acetate 8/2 yields the desired compound in a yield of 77%, 136 mg.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:15])=O>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([Cl:15])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)OCC(C)(C)C(=O)Cl
Yield: 91 %

Procedure:
Under an argon atmosphere a stirred solution of 1.2 grams (0.008 mole) of 3-acetoxy-2,2-dimethylpropionic acid in 30 ml of toluene was heated to 80° and a solution of 1.9 grams (0.015 mole) of oxalyl chloride in 20 ml of toluene was added dropwise. Upon completion of addition the reaction mixture was heated at 80° for 18 hours. The reaction mixture was concentrated under reduced pressure to give 1.3 grams of 3-acetoxy-2,2-dimethylpropionyl chloride as an oil.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[N:22]=[C:21]([C:4]2=[CH:3][CH:2]=1)[N:20]=[C:19]1[C:23]2[C:28]([C:17](=[N:18]1)[N:16]=[C:15]1[C:29]4[C:34]([C:13](=[N:14]1)[N:12]=[C:11]1[C:35]5[C:40]([C:9](=[N:10]1)[N:8]=3)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][CH:26]=[CH:25][CH:24]=2.[Cu:41].[Cl-].[Na+].S(=O)(=O)(O)O>C(O)COCCO>[CH:25]1[CH:24]=[C:23]2[C:19]3[N-:18][C:17]([C:28]2=[CH:27][CH:26]=1)=[N:16][C:15]1=[N:14][C:13]([C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:12][C:11]1[N-:10][C:9](=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[CH:39]2)[N:8]=[C:7]1[C:5]2[C:4]([C:21](=[N:22]1)[N:20]=3)=[CH:3][CH:2]=[CH:1][CH:6]=2.[Cu:41]
Reactant: c1ccc2c(c1)C1=NC2=NC2=NC(=NC3=NC(=NC4=NC(=N1)c1ccccc14)c1ccccc13)c1ccccc12
Agent: [Cu]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: OCCOCCO
Product: c1ccc2c(c1)-c1nc-2nc2[n-]c(nc3nc(nc4[n-]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A conventional Baker-Perkins sigma blade mixer having a capacity of two cubic inches (32.8 cubic centimeters) is charged with 4.5 g of crude copper phthalocyanine, 1.5 of anhydrous FeCl3, 29.0 g of micropulverized sodium chloride, and 4.42 g of diethylene glycol. The charge is milled at 54 r.p.m. for three hours. The temperature during milling is maintained from 80°C. to 90°C. by passing steam through the mill jacket. The milled charge is then added to 500 cc of an acidic aqueous solution containing 5 cc of 98% sulfuric acid. The resulting slurry is heated to 95°C. and maintained at that temperature for one hour and thirty minutes. The pigment is isolated by filtering, washing with water to remove any residual sulfate and drying overnight at 180°F. (82°C.) to give a substantially quantitative yield of β-copper phthalocyanine exhibiting the bright green-shade blue color.
Reaction SMILES: [I-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][N:7]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.C(N(CC)CC)C.[NH:28]1[CH2:33][CH2:32][CH:31]([O:34][CH2:35][CH2:36][OH:37])[CH2:30][CH2:29]1.Cl>C(C(C)=O)C.CCOCC>[ClH:3].[OH:37][CH2:36][CH2:35][O:34][CH:31]1[CH2:32][CH2:33][N:28]([CH2:4][CH2:5][CH2:6][N:7]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:29][CH2:30]1
Reactant: ClCCCN1c2ccccc2Sc2ccccc21
Reactant: OCCOC1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: OCCOC1CCN(CCCN2c3ccccc3Sc3ccccc32)CC1
Reaction time: 20 h
Yield: 55.4 %

Procedure:
22.5 g (0.15 mole) of sodium iodide was added to a solution of 41.5 g (0.15 mole) of 10-(3-chloropropyl)-phenothiazine in 400 ml of methyl ethyl ketone and then 15.2 g (0.15 mole) of triethylamine followed by 21.7 g (0.15 mole) of 2-(4-piperidyloxy)-ethanol were added to the reaction mixture. The solution was refluxed with stirring for 20 hours and after cooling, the precipitate formed was removed by vacuum filtration. The filtrate was evaporated to dryness and the oily residue was extracted with aqueous hydrochloric acid. The acidic extract was washed with ether, made alkaline and was extracted with benzene. The benzene phase was repeatedly washed with water, dried and concentrated to obtain an oil. The oil was dissolved in ether and hydrogen chloride in ether was added thereto. The precipitate was recoved by vacuum filtration and was crystallized from a 95% ethanol-ether mixture to obtain 35 g (55% yield) of 10-[3-(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine hydrochloride in the form of white crystals melting at 183° C on a heated microscopic stage. The product was identical to that of Example XI.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])[NH2:5].N1C=CC=CC=1.Cl[C:20](OCC)=[O:21]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]1[NH:5][C:20](=[O:21])[O:7][N:6]=1
Reactant: Cc1ccc(C(N)=NO)c(C)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2noc(=O)[nH]2)c(C)c1

Procedure:
Under an inert atmosphere, 10.5 g of 2,4-dimethyl benzamidoxime are dissolved in 40 ml of anhydrous toluene; 6.5 ml of pyridine and 7.6 g of ethyl chloroformate are added.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]([CH3:41])=[C:16]([N:24]([CH2:39][CH3:40])[CH:25]2[CH2:30][CH2:29][CH:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27][CH2:26]2)[CH:17]=[C:18]([O:20][CH2:21][CH2:22][OH:23])[CH:19]=1)=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:31][CH:28]1[CH2:27][CH2:26][CH:25]([N:24]([CH2:39][CH3:40])[C:16]2[C:15]([CH3:41])=[C:14]([CH:19]=[C:18]([O:20][CH2:21][CH2:22][OH:23])[CH:17]=2)[C:12]([NH:11][CH2:10][C:3]2[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:13])[CH2:30][CH2:29]1
Reactant: CCN(c1cc(OCCO)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(c1cc(OCCO)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of tert-butyl (4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(2-hydroxyethoxy)-2-methylphenyl)-(ethyl)-amino)cyclohexyl)carbamate (0.80 g, 1.40 mmol) in DCM (5 mL) was added TFA (2 mL) and the reaction mixture was stirred at rt for 1 h. After completion of reaction, the solvent was removed under reduced pressure and saturated NaHCO3 solution was added. Extraction was carried out using 10% MeOH/DCM; the combined organic layers were washed with water and brine; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to give the title compound (0.5 g, 76%).
Reaction SMILES: [OH-].[Na+].O.[CH3:4][C:5]([CH3:17])([CH:11](Cl)[CH:12]=[C:13]([Cl:15])[Cl:14])[CH2:6][C:7]([O:9]C)=[O:8]>CO>[CH3:4][C:5]1([CH3:17])[CH:11]([CH:12]=[C:13]([Cl:15])[Cl:14])[O:9][C:7](=[O:8])[CH2:6]1
Reactant: COC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CC(=O)OC1C=C(Cl)Cl
Yield: 93 %

Procedure:
To a mixed solution of 6.0 parts of sodium hydroxide, 40 parts of water and 60 parts of methanol was added dropwise under reflux 26.0 parts of methyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate and, after the dropwise addition had been completed, the mixture was further stirred under reflux for 2 hours. The reaction mixture was then treated in the same manner as Reference Example 1 to obtain 19.5 parts of 3,3-dimethyl-4-(2',2'-dichlorovinyl)-4-butanolide (yield 93%).
Reaction SMILES: C(OC([C:6]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:26])[C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])=O)C>C(O)C.[OH-].[K+]>[O:12]=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:26])[C:21]([OH:23])=[O:22])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(C)c1ccc(CC2(C(=O)OCC)CCCCC2=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(CC2CCCCC2=O)cc1
Reaction time: 1 h
Yield: 43.7 %

Procedure:
Thirteen grams of ethyl 2-[4-(1-ethoxycarbonyl-2-oxocyclohexan-1-ylmethyl)phenyl]propionate was dissolved in 200 ml of 80% ethanol containing 5 g of potassium hydroxide and the solution was refluxed for 2 hours. Ethanol was removed by distillation from the reaction mixture, 100 ml of water was added to the residue and the mixture was extracted with ether. The aqueous layer was heated at 50°-60° C. with stirring for 1 hour after addition of 100 ml of conc. hydrochloric acid, extracted with ether, the extract was washed with water, dried and the solvent removed by distillation to give an yellow oily substance, which was chromatographed on a column of silica gel affording a colorless oily substance from an eluate with a mixture of benzene:ethyl acetate = 5:1. The substance was subjected to a vacuum distillation to give 4.1 g of the desired compound as a colorless oily substance, b.p. 190°-195° C. at 0.4 mm Hg (bath temp.). The compound solidified as it was cooled to crystals, m.p. 84°-86° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][N:6]=1.CN(C)C=O.[CH3:14][N:15]1[C:20](=[N:21][N+:22]([O-:24])=[O:23])[NH:19][CH2:18][O:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:19]2[CH2:18][O:17][CH2:16][N:15]([CH3:14])[C:20]2=[N:21][N+:22]([O-:24])=[O:23])=[CH:5][N:6]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: CN1COCNC1=N[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 5 h

Procedure:
2.5 g of 2-chloro-5-chloromethyl-thiazole, 12 ml of dimethylformamide, 2 g of 3-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine and 3.8 g of potassium carbonate are combined and the mixture is stirred for 5 hours at 50° C. The mixture is cooled to room temperature and 50 ml of water and 50 ml of dichloromethane are added. The organic phase is separated off and dried over magnesium sulfate; the solvent is evaporated off in vacuo. Purification is carried out by column chromatography on silica gel using hexane/ethyl acetate (1:1), yielding the title compound (compound 2-2).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[C:12]2[Cl:17].CN([CH:21]=[O:22])C>>[Cl:17][C:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:7]([CH:21]=[O:22])[C:8]=2[CH:9]=[CH:10][N:11]=1
Reactant: Clc1nccc2c(Br)cccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: O=Cc1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.1 %

Procedure:
A solution of n-BuLi (1.76 mL, 2.5 M in hexanes, 4.4 mmol) was added to a stirred solution of 5-bromo-1-chloroisoquinoline (Braye, E.; Eloy, F.; Hoogzand, C.; Lenaers, R. Eur. J. Med. Chem., Chim. Therap. 1974, 9, 197) (1.0 g, 4.12 mmol) in THF-ether (36 mL, 1:1) at −78° C. under N2. After 20 minutes, DMF (0.66 mL, 8.5 mmol) was added and after an additional 30 minutes at −78° C. the reaction was quenched with EtOH (3 mL) and warmed to room temperature. The mixture was diluted with ether (150 mL), washed with saturated NH4Cl (50 mL), brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using hexanes-EtOAc (95:5 to 50:50) as eluant to give 1-chloro-5-isoquinolinecarboxaldehyde (308 mg, 1.61 mmol) as a white solid.