Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:11]([CH3:12])[N:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH3:21])[CH:14]=2)[CH:8]=1.CN(C)[CH:24]=[O:25]>>[Cl:3][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH3:21])[CH:14]=2)[C:8]=1[CH:24]=[O:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc(O)n(C)n2)cc1C
Reactant: CN(C)C=O
Product: COc1ccc(-c2nn(C)c(Cl)c2C=O)cc1C
Yield: 55.9 %

Procedure:
At 0° C., to phosphorus oxychloride 56 g was added N,N-dimethylformamide 4.0 g and the resulting mixture was stirred for a half hour. Thereto was added 5-hydroxy-3-(4-methoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole (described in Reference preparation example 90) 9.3 g. The resulting mixture was stirred for seven hours and the reaction solvent was distilled off under reduced pressure. To the reaction mixture was added ice water 100 ml and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 5-chloro-4-formyl-3-(4-methoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole 6.3 g.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:9]([OH:18])=[C:10]([C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][C:13]=1[OH:14].[Br:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1.Cl>CC(C)=O.CCOC(C)=O>[Br:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:14][C:13]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH3:16])=[C:9]([OH:18])[C:8]=2[Cl:7])=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Reactant: BrCc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccc(CBr)cc2)c(Cl)c1O

Procedure:
Add K2CO3 (1.48 g, 10.7 mmol) to a solution of 1-(3-chloro-2,4-dihydroxy-phenyl)ethanone (2.00 g, 10.7 mmol) and 1,4-bis(bromomethyl)benzene (2.83 g, 10.7 mmol) in acetone (100 mL). Cool and work up with a 10% HCl solution and EtOAc. Triturate in acetone to remove insoluble material. Dry, filter, and concentrate. Purify the residue by flash chromatography on silica gel (731 mg, 18%): MS (esi negative) m/z 368.9 (rel intensity) (M−H, 55%), 367.0 (45%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]#N)[CH2:2][CH:3]=[CH2:4].[OH-:15].[Na+].[OH2:17]>CCO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([OH:17])=[O:15])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOc1ccccc1CC#N
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: C=CCCOc1ccccc1CC(=O)O
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 2-(2-(but-3-en-1-yloxy)phenyl)acetonitrile (1.0 g, 5.34 mmol, 1 equiv) in EtOH (27 mL) was added 10 N NaOH (27 mL). The reaction was heated at reflux for 18 h. Upon cooling to ambient temperature, the reaction was diluted with water and washed with ether. The aqueous layer was acidified with concentrated HCl and extracted with DCM (×3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to provide the product (0.98 g, 89%) as a viscous pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 11.15-9.85 (m, 1H), 7.30-7.25 (m, 1H), 7.21 (dd, J=7.3, 1.5 Hz, 1H), 6.97-6.91 (m, 1H), 6.89 (d, J=8.3 Hz, 1H), 5.98-5.82 (m, 1H), 5.21-5.14 (m, 1H), 5.10 (dd, J=10.3, 1.5 Hz, 1H), 4.06 (t, J=6.5 Hz, 2H), 3.68 (s, 2H), 2.55 (q, J=6.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:30])[CH:14]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:15](=O)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O)[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:30])[CH:14]([C:15]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:17]2[C:16]=1[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:11]
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C(=O)C1CCCCC1=O)C1CCCCC1
Solvent: CCO
Product: CCOC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Yield: 46 %

Procedure:
(4-Chloro-phenyl)-hydrazine (100 mg, 700 μmol; CAS Reg. No. 1073-69-4) was added to a solution of 2-cyclohexyl-3-oxo-3-(2-oxo-cyclohexyl)-propionic acid ethyl ester (206 mg, 700 μmol) in ethanol (4.7 ml). The reaction mixture was heated under reflux conditions for 6 h. The solvent was removed under reduced pressure. The residue was taken up in ice water/brine 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a brown oil which was purified by preparative thick layer chromatography (silica gel, iPrOAc/heptane) to give the title compound (130 mg, 324 μmol; 46%) as orange solid. MS: m/e=401.2 [M+H+].
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1S(O)(=O)=O.C(NCCNC1C=CC(N)=CC=1S(O)(=O)=O)(=O)C.Cl>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1c(S(=O)(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: CC(=O)NCCNc1ccc(N)cc1S(=O)(=O)O
Agent: Cl
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-4-bromoanthraquinone-2-sulfonic acid and 4-(β-acetylaminoethylamino)aniline 3-sulfonic acid were subjected to Ullmann condensation in the presence of cuprous chloride as a catalyst, followed by hydrolysis of the acetyl group under an acid condition of hydrochloric acid, thereby obtaining an anthraquinone intermediate compound of the following formula (2) in the free acid form ##STR493##
Reaction SMILES: O[CH:2]([C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=[CH2:4].S(Cl)([Cl:13])=O>CCCCCC.CN(C)C=O>[Cl:13][CH2:4][CH:3]=[CH:2][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C=CC(O)C#CC(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)C#CC=CCCl
Yield: 88.7 %

Procedure:
Ten grams (0.072 mole) of 3-hydroxy-6,6-dimethylhept-1-ene-4-yne was dissolved in 100 ml of hexane, and to the resulting solution were added 50 mg (6.8×10-4 mole) of N,N-dimethylformamide and 12.80 g (0.108 mole) of thionyl chloride. The mixture was reacted overnight at room temperature with stirring with a hydrogen chloride gas trap mounted on the reactor. The reaction mixture was concentrated under reduced pressure to obtain 10 g of a crude 1-chloro-6,6-dimethylhept-2-ene-4-yne.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH2:17].[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:17][CH2:16][C:18]3[CH:19]=[N:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cnc2ccccc2c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc3ccccc3c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 3-vinylquinoline and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:13]([CH3:18])=[N:14][CH:15]=[CH:16][CH:17]=1)[C:8]([CH:19](O)[CH3:20])=[CH:7]2.C(Cl)(Cl)[Cl:23].S(Cl)(Cl)=O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:13]([CH3:18])=[N:14][CH:15]=[CH:16][CH:17]=1)[C:8]([CH:19]([Cl:23])[CH3:20])=[CH:7]2
Reactant: ClC(Cl)Cl
Reactant: Cc1ncccc1-c1nc2c(Cl)cccc2cc1C(C)O
Solvent: O=S(Cl)Cl
Product: Cc1ncccc1-c1nc2c(Cl)cccc2cc1C(C)Cl
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-(8-chloro-2-(2-methylpyridin-3-yl)quinolin-3-yl)ethanol (1.1090 g, 3.712 mmol) in chloroform (12.37 mL, 3.712 mmol) was treated with thionyl chloride (1.350 mL, 18.56 mmol) dropwise, and the reaction mixture was stirred at room temperature. After 3 h, the mixture was concentrated under reduced pressure and co-evaporated three times with CH2Cl2 to give 8-chloro-3-(1-chloroethyl)-2-(2-methylpyridin-3-yl)quinoline hydrochloride as an off-white syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (1 H, s), 8.94 (1 H, dd, J=5.7, 1.4 Hz), 8.56 (1 H, d, J=7.4 Hz), 8.19 (1 H, dd, J=8.2, 1.2 Hz), 8.07 (1 H, dd, J=7.4, 1.2 Hz), 8.02 (1 H, dd, J=7.6, 5.7 Hz), 7.71-7.77 (1 H, m), 5.25 (1 H, d, J=6.3 Hz), 2.52 (3 H, s), 1.92 (3 H, d, J=6.7 Hz); LC-MS (ESI) m/z 317.0 [M+H]+ (Exact Mass of neutral form: 316.053). The crude product was carried on crude without purification for the next step.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][NH:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:21]1[O:22][C:23]2[C:24](=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][CH:29]=2)[N:25]=1>COCCOC>[C:14]([O:13][C:11]([N:9]1[CH2:10][C:5]2([CH2:1][CH2:2][CH2:3][CH2:4]2)[N:6]([C:21]2[O:22][C:23]3[C:24](=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][CH:29]=3)[N:25]=2)[CH2:7][CH2:8]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCNC2(CCCC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cccc2oc(N3CCN(C(=O)OC(C)(C)C)CC34CCCC4)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.5 %

Procedure:
To a solution of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (192 mg, 0.80 mmol) in DME (10 mL) was added NaH (60%, 96 mg, 2.4 mmol). The reaction mixture was stirred at room temperature for 10 min, followed by addition of methyl 2-chlorobenzoxazole-4-carboxylate (186 mg, 0.88 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction was quenched by adding 5 mL of H2O and extracted with EtOAc (2×30 mL). The organic layer was washed by brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 50-100% chloroform in hexane) to afford methyl 2-(9-(tert-butoxycarbonyl)-6,9-diazaspiro[4.5]decan-6-yl)benzoxazole-4-carboxylate (61.4 mg, 18.5%) as yellow oil. MS consistent.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].O>CN(C)C=O>[C:21]1(=[O:30])[N:20]([CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][C:9]3=[O:12])=[CH:4][CH:3]=2)[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C1CCCc2ccc(O)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCc2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc21
Reaction time: 0.05 h

Procedure:
7-Hydroxy-1-tetralone (33.3 g) is dissolved in dimethylformamide (325 ml) and the mixture is cooled in an ice bath. Sodium methoxide (11.07 g) is added to the mixture. After the mixture is stirred for 3 min., N-(3-bromopropyl) phthalimide (54.96 g) is added to the mixture; stirring is continued and the reaction mixture stirred overnight. The resulting mixture is poured into H2O (650 ml), stirred for 1 hour, filtered, washed with H2O and air dried. The resulting fluffy near-white solid (62.8 g) is crystallized from ethyl acetate to give the desired product, a fluffy white solid (M.P. 149°-150° C. )
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:17])[C:9]=1[SH:18].I[CH2:20][CH3:21].Cl>C(#N)C.O>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:17])[C:9]=1[S:18][CH2:20][CH3:21]
Reactant: Cc1c(C(=O)O)ccc(Cl)c1S
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCSc1c(Cl)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
3.71 g (11.3 mmol) of cesium carbonate were added to 1.10 g (5.42 mmol) of 4-chloro-3-mercapto-2-methylbenzoic acid in 20 ml of acetonitrile. The reaction mixture was stirred at RT for 10 min, and 1.02 g (6.51 mmol) of iodoethane were then slowly added dropwise. The reaction mixture was then stirred at RT for 16 h. The solvent was then removed, and a mixture of 20 ml of methanol and 2 ml of 20% strength aqueous sodium hydroxide solution was then added to the reaction mixture. For the hydrolysis of the ethyl ester formed, the mixture was stirred at RT for 16 h and then freed from the solvents. The residue was taken up in water and acidified with diluted HCl, and the mixture was stirred at RT for 10 min and then filtered. The residue was washed with water and sucked dry. 1.15 g of clean product were isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:27](=[O:28])[CH2:26][C:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:31])[CH3:30])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (prepared in a similar manner as described in International Patent Application No. WO 04/043965, 0.949 g, 3.96 mmol), 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid (0.86 g, 3.96 mmol), HOBt (1.334 g, 8.71 mmol), and Hunig's base (2.074 mL, 11.88 mmol) in methylene chloride (20 mL) was treated with EDC (1.669 g, 8.71 mmol), and the reaction was allowed to stir for about 16 h at room temperature. The mixture was concentrated in vacuo, and the residue was taken up in ethyl acetate. The organic phase was washed 3× with 1M NaOH, 3× with 1M HCl, once with water, and once with brine, dried over sodium sulfate, and concentrated in vacuo to yield an amber solid which was used as-is in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.ClC[C:13](=O)[CH2:14][CH2:15][CH2:16][C:17]#[N:18].[C:20]1(C)C=CC=CC=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:13]=[C:14]([CH:15]([CH3:20])[CH2:16][C:17]#[N:18])[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(Br)cc1
Reactant: N#CCCCC(=O)CCl
Reactant: Cc1ccccc1
Product: CC(CC#N)c1csc(-c2ccc(Br)cc2)n1

Procedure:
A mixture of 4-bromothiobenzamide (2.16 g., 0.01 mole) and 6-chloro-5-oxohexanenitrile (2.28 g., 0.012 mole) is heated at 60° C. in toluene for 12 hours. On cooling and partial evaporation, there is obtained 3-[2-(4-bromophenyl)thiazol-4-yl]butanenitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[C:11]([CH:15]=[O:16])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[CH:17]1([CH:15]([C:11]2[C:12]([CH3:14])=[CH:13][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:10]=2)[OH:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cccc(-n2cc(C)c(C=O)n2)c1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: COc1cccc(-n2cc(C)c(C(O)C3CCCCC3)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To a solution (10 mL) of 1-(3-methoxyphenyl)-4-methyl-1H-pyrazole-3-carbaldehyde (0.84 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (7.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.62 g, 52%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](N)=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10].[OH2:13]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:3](=[O:13])[NH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=1
Reactant: O
Reactant: O=[N+]([O-])O
Reactant: Cc1cccnc1N
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c[nH]c1=O
Temperature: 30 °C
Yield: 35 %

Procedure:
A solution of (3-methylpyridin-2-yl)amine (10 g, 90 mmol) in 50 ml of concentrated sulfuric acid was cooled to 5° C. in ice-salt bath. A mixture of 7 ml each of concentrated sulfuric acid and concentrated nitric acid was added slowly with stirring while maintaining the reaction temperature below 10° C. This mixture was then allowed to warm to 30° C. overnight. The solution was stirred rapidly while 7 ml of concentrated nitric acid was added at such a rate as to keep the temperature below 40° C. Approximately 10 ml of the solution was then poured into 20 ml of water and heated to 100° C.; large quantities of gas were evolved. When gas evolution ceased, the remainder of the nitrating mixture was added in 10 ml portions with heating. When the last of the nitrating mixture had been added, the solution was cooled rapidly by placing the flask in an ice bath and by adding ice directly to the solution. The light brown precipitate was filtered and dried to afford 5.0 g (35%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:27][S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[CH3:19][C:15]1[CH:14]=[C:13](/[C:10](=[N:11]/[OH:12])/[CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([N:34]3[CH2:35][CH2:36][N:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:32][CH2:33]3)=[CH:7][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:18]=[CH:17][N:16]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cc1cc(/C(C[C@H](c2ccc(Br)cc2)c2ccccc2C)=N/O)ccn1
Product: Cc1cc(/C(C[C@H](c2ccc(N3CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 39, from (E,R)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one oxime (example 142, step 1) and 1-methanesulfonyl-piperazine (CAS RN: [55276-43-2]) was prepared the title compound as a yellow solid, MS (ESI+): m/z=493.3 ([M+H]+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].P(C#N)(=O)(OCC)OCC.Cl>CN(C)C=O.O.C(N(CC)CC)C>[O:8]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]#[N:10]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CCOC(=O)CC#N
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)C(=O)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A solution of 2.2 g of pyrrole-2-carboxylic acid, 8.4 ml of anhydrous triethylamine and 2.1 ml of ethyl cyanoacetate in dimethylformamide is treated with 2.9 ml of diethyl phosphorocyanidate at room temperature. After stirring for 80 minutes at room temperature, the reaction mixture is cooled in an ice bath, treated with about 50 ml of water and acidified with 6N hydrochloric acid. The crude precipitate is collected, washed with water, dried and recrystallized from ether to yield β-oxo-α-ethoxycarbonyl-β-(2-pyrrolyl)-propionitrile, m.p. 138°-9°.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)=O.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:14]=1C([O-])=O.[Li+].COC1C=CC=C(OC)C=1[Li]>CCCCCC>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:14]=1
Reactant: COc1cccc(OC)c1C(=O)[O-]
Agent: O=C=O
Agent: [Li+]
Agent: [Li]c1c(OC)cccc1OC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature solution of 0.24 moles DMR in 55 ml hexane is added dropwise over a 45 minute period a solution of 0.2 mole of the complex solution of Example 1. After stirring 18 hours, the resulting yellow to orange colored mixture of DMPL is slowly drained into a slurry of 80 ml hexane, 70 ml toluene, and approximately 600 g dry ice (large excess of CO2). The carbonylation is continued at approximately -50° C. or 12 hours, then gradually allowed to warm to room temperature. The tan colored mixture of lithium 2,6-dimethoxybenzoate is slowly quenched by pouring into 400 ml of tap water. The resulting mixture is stirred with a magnetic stirrer for 30 minutes. The pale yellow aqueous layer is separated and decolorized with 1 g activated charcoal. The nearly colorless solution is acidified (Ph~1) with 6 N HCl to cause precipitation of DMBA. The crystalline product is filtered and dried. Then the melting point is determined followed by calculation of percent yield based on moles of the complex of Example 1 used. Analysis of the yield of 2,6-dimethoxyphenyllithium resulting from the metalation step is determined by proton NMR. Using this method, a sample of the mixture resulting from the reaction of complex metalating agent and 1,3-dimethoxybenzene is quenched with deuterium oxide. The proton NMR spectrum reveals greater than 95%±5% deuterium incorporation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.Cl.[NH2:17][OH:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=[N:17][OH:18])[CH2:8][CH2:7]1
Reactant: O=C1CCN(Cc2cccc(Cl)c2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(Cc2cccc(Cl)c2)CC1

Procedure:
1-(3-Chlorobenzyl)-4-piperidone oxime is prepared from 1-(3-chlorobenzyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.Cl.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH2:21])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH:21][C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[C:8]=1[CH3:14])=[O:13])[CH3:17]
Reactant: Cc1c(C(=O)O)nc2ccc(Cl)nn12
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
3.9 g of ethyl 6-chloro-3-methylimidazo[1,2-b]pyridazine-2-carboxylate was suspended in 40 ml of tetrahydrofuran; 30 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The residue was adjusted to pH 4 by the addition of 50 ml of water and 1 N hydrochloric acid; the crystal precipitated was collected by filtration and dried to yield 2.55 g of 6-chloro-3-methylimidazo[1,2-b]pyridazine-2-carboxylic acid. 1.27 g of this carboxylic acid was dissolved in 20 ml of N,N-dimethylformamide; 1.07 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To this mixture, 0.922 g of glycine ethyl ester hydrochloride and 0.915 ml of triethylamine were added, followed by further stirring for 3 hours. 60 ml of ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 1.18 g of the title compound.