Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1)CCC>C1(C)C=CC=CC=1.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(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]4[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccn2C)c(F)c2oc(C3CC3)nc2c1C#N
Yield: 78.7 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (200 mg, 0.68 mmol) was dissolved in toluene (4 ml), then 2-tributylstannyl-1-methylpyrrole (300 mg, 0.81 mmol) and 2,6-di-tert-butylcresol (2 mg) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) were added, followed by heating under reflux for 19 hours under nitrogen atmosphere. The reaction liquid was cooled, the insoluble matter was separated by filtration through Celite, the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, followed by removing tin-derived side products with n-hexane and by elution with a mixed solvent of n-hexane/ethyl acetate (10:1, v/v) to obtain 2-cyclopropyl-7-fluoro-5-methyl-6-(1-methyl-1H-pyrrol-2-yl)-1,3-benzoxazole-4-carbonitrile (158 mg, 79%) as a pale yellow transparent oily substance. Apart of this (157 mg, 0.53 mmol) was dissolved in dimethyl sulfoxide (3 ml), triethylamine (187 μl, 1.33 mmol) and (3S)-3-(dimethylamino)pyrrolidine (101 μl, 0.80 mmol) were added, followed by stirring at 90° C. under nitrogen atmosphere for 13 hours. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away, the resulting residue was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform/methanol (20:1, v/v). The resulting residue was recrystallized and purified with a mixed solvent of diethyl ether-n to obtain the entitled compound (104 mg, 50%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH2:24][NH:23][CH2:22][CH2:21]2)[S:9]([C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](O)(=[O:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:28]([N:23]1[CH2:22][CH2:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]([N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[S:9]([C:12]3[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=3)(=[O:11])=[O:10])[CH:19]=2)[CH2:24]1)(=[O:30])[CH3:29]
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccc3c(c2)CCNC3)n1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2cc(N(Cc3ccccc3)S(=O)(=O)c3ccn(C)n3)ccc2C1
Yield: 66.7 %

Procedure:
To a stirred solution of 1-methyl-1H-pyrazole-3-sulfonic acid benzyl-(1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide (24 mg, 0.06 mmol) and acetic acid (3.6 μl, 0.06 mmol) in dry acetonitrile (2 ml) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (24 mg, 0.06 mmol), then diisopropylethylamine (33 μl, 0.20 mmol) and the solution was stirred at 50° C. for 16 hrs. The reaction mixture was concentrated in vacuo and the residue purified using preparative HPLC to afford the title compound as a white solid (17 mg, 67% yield), HPLC retention time 3.97 min. Mass spectrum (ES+) m/z 425 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[O:10][C:11]([C:13]#[C:14][C:15](OC)=[O:16])=[O:12]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[C:15](=[O:16])[CH:14]=[C:13]([C:11]([OH:12])=[O:10])[NH:5]2
Reactant: Nc1cccc(F)c1
Reactant: COC(=O)C#CC(=O)OC
Product: O=C(O)c1cc(=O)c2c(F)cccc2[nH]1

Procedure:
Using the method described in Example 15 with 3-fluoroaniline (8.7 ml) and dimethylacetylene dicarboxylate (5.46 ml) gave 5-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.022 g), m.p. 285°-286° C. (dec), δ (360 MHz, NAOD) 6.86 (1H, s, 3-H), 7.04 (1H, m, 7-H) and 7.52-7.68 (2H. m, 6-H, 8-H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([C:5]1[S:4][C:3]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([CH3:1])[CH:6]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)Cl
Reactant: COC(=O)c1sccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1sc(C(C)(C)C)cc1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 42.4 %

Procedure:
A solution of methyl 3-methylthiophene-2-carboxylate 109a (33 g, 0.211 mol) in dry CH2Cl2 (30 mL) was added dropwise to a mixture of aluminum chloride (40 g, 0.297 mol) and dry CH2Cl2 (200 mL) at −78° C., under nitrogen. The reaction mixture was stirred for 10 min at −78° C., and a solution of tert-butyl chloride (23 mL, 0.211 mol) in dry CH2Cl2 (30 mL) was added dropwise at −78° C. The reaction mixture was stirred for 1 h at −78° C., gradually allowed to warm to room temperature and stirred for 16 h at room temperature. It was poured on ice and extracted with CH2Cl2 (2×200 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent evaporated under vacuum. The obtained residue was purified by fractional distillation to yield methyl 5-tert-butyl-3-methylthiophene-2-carboxylate 109b (19 g, 43%) as a light yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>CC(O)C.Cl.[NH4+].[Cl-].CS(C)=O>[C:17]([O:16][C:15](=[O:21])[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCCCNc1cc(Cl)ncn1
Temperature: 100 °C
Yield: 41 %

Procedure:
4,6-Dichloropyrimidine (4.14 mmol) and tert-butyl 4-aminobutylcarbamate (4.14 mmol) were dissolved in 13 ml of 2-propanol, and 3 drops of 3M aq. HCl were added. The mixture was heated in a Personal Chemistry Optimizer microwave system at 100° C. for 900 s. The reaction mixture was diluted with sat. aq. NH4Cl-solution (50 ml) and extracted with EtOAc (2×). Drying of the organic layer (Na2SO4) and evaporation of the solvent under reduced pressure yielded the crude product, which was taken up in DMSO (2.5 ml) and purified via prep.-HPLC (XTerra Prep. MS C18 5 μm, 19×150 mm, gradient from water to MeCN over 14 min), yielding 41% of a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:16](OC)=[N:15][S:14](=[O:20])(=[O:19])[N:13]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.CC1NC=NC=1CSCCN.[NH:46]([C:50]1[S:51][CH:52]=[C:53]([CH2:55][S:56][CH2:57][CH2:58][NH2:59])[N:54]=1)[C:47]([NH2:49])=[NH:48]>CO>[NH:46]([C:50]1[S:51][CH:52]=[C:53]([CH2:55][S:56][CH2:57][CH2:58][NH:59][C:16]2[C:12]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]3[N:4]=[CH:5][NH:6][C:2]=3[CH3:1])=[N:13][S:14](=[O:20])(=[O:19])[N:15]=2)[N:54]=1)[C:47]([NH2:49])=[NH:48]
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1C
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: Cc1[nH]cnc1CSCCN
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: Cc1[nH]cnc1CSCCNC1=NS(=O)(=O)N=C1NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a well stirred solution at -10° of 3-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide [prepared from the dihydrochloride of 2-{(5-methyl-1H-imidazol-4-yl)methylthio}ethylamine (2.73 g; 11.2 mmole) by the procedure of Step A of Example 1] was rapidly added a solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 3.41 g; 11.2 mmoles) [prepared according to the procedure described in South African Pat. No. 78/2129] in 35 ml of methanol. After stirring at -10° for 30 minutes, the solution was allowed to warm to ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was placed on 45 g of silica gel and chromatographed using 1 liter of methylene chloride-methanol (4:1). The appropriate fractions were combined and evaporated, and the residue (5.82 g) was placed on 80 g of aluminum oxide and chromatographed using a gradient elution of ethyl acetate-methanol. The appropriate fractions were combined, filtered through Celite and evaporated under high vacuum to yield the title compound (2.5 g) as an amorphous solid containing approximately 2/3 mole of ethyl acetate, as ascertained by the NMR spectrum (100 MHz) in d6 dimethyl sulfoxide.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH3:16])[CH2:6]1)[CH2:2][CH3:3].[O:17]([CH2:24][C:25](O)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[B-][N+](C)(C)C>>[CH3:16][O:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][CH:5]([N:4]([CH2:25][CH2:24][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:1][CH2:2][CH3:3])[CH2:6]2
Reactant: CCCNC1CCc2c(cccc2OC)C1
Reactant: O=C(O)COc1ccccc1
Agent: [B-][N+](C)(C)C
Product: CCCN(CCOc1ccccc1)C1CCc2c(cccc2OC)C1

Procedure:
A mixture of (-)-2-(N-n-propylamino)-5-methoxytetralin (80 mg, 31.9 mmol; prepared according to J. Chem. Soc., 1965, pp 26-36), phenoxyacetic acid (166 mg, 109.4 mmol) and borane trimethylamine complex (80 mg, 109.4 mmol) was refluxed in xylenes overnight. The cooled reaction mixture was extracted with NaHCO3 and the organic layer was dried over MgSo4, filtered and concentrated. The resulting oil was subjected to flash chromatography (Silica: 9:1 pet ether/EtOAc) and product was isolated with characteristic peaks at: NMR (300 MHz, CDCl3); δ7.3-6.6 (m, 8H), 4.0(t,2H), 3.7(S,3H), 3.1-2.5(m,9H), 2.1(m, 1H), 1.7-1.4 (m, 3H) 0.9 (t, 3H) .
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:18][CH2:17][C@@H:16]([NH:19]C4C5C(=CC(Cl)=CC=5)N=CC=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([F:41])[CH:40]=1)[C:35]([OH:37])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[Br:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([F:41])[CH:40]=1)[C:35]([NH:19][CH:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:18][CH2:17]1)=[O:37]
Reactant: Clc1ccc2c(N[C@H]3CC[C@@H](Nc4ccnc5cc(Cl)ccc45)CC3)ccnc2c1
Reactant: O=C(O)c1cc(F)cc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1)c1cc(F)cc(Br)c1
Reaction time: 3 h
Yield: 40.8 %

Procedure:
A mixture of 23A cis-N,N′-bis(7-chloroquinolin-4-yl)cyclohexane-1,4-diamine (500 mg, 3.6 mmol), 3-bromo-5-fluorobenzoic acid (600 mg, 5.4 mmol), 1-hydroxybenzotriazole (245 mg, 3.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(348 mg, 3.6 mmol) in 30 mL dichloromethane was stirred for 3 hours. The reaction was incomplete. 3-bromo-5-fluorobenzoic acid (160 mg, 0.9 mmol), 1-hydroxybenzotriazole (61 mg, 0.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (87 mg, 0.9 mmol) was added and the solution was allowed to stir overnight. The solution was then washed with 1N NaOH, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (10% methanol in dichloromethane) to provide 700 mg of pure compound, an 81% yield. MS (ESI(+)Q1MS m/z 477 (M+2 H)+; 1H NMR (300 MHz, MeOH) δ ppm 8.36-8.42 (m, 3 H), 7.95 (t, 1 H), 7.69-7.79 (m, 3 H), 7.45 (dd, 1 H), 6.83 (d, 1 H), 6.54 (d, 1 H), 3.95 (m, 1 H), 3.68 (m, 1 H), 1.66-1.98 (m, 8 H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH2:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1.[OH-].[Na+]>CC#N.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:10][C@@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]2)[N:7]=1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(O)[C@H]1CC[C@@H](Nc2nc(Cl)nc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of cyanuric chloride (493.65 mg, 2.7 mmol, 1 equivalent) in CH3CN/H2O (1/1, 20 ml) was cooled to 0° C. cis-4-aminocyclohexylcarboxylic acid (283.26 mg, 2.7 mmol, 1 equivalent) was added, followed by 1N NaOH (10.7 ml, 2 equivalents). The reaction was stirred at 0° C. for 15 min. LCMS analysis showed the complete consumption of the 2,4,6-trichloro-1,3,5-triazine. The crude product was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C.[CH2:47]([Si:49]([C:54]#[CH:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH3:48]>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.CN(C)C=O>[Cl:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[C:48]#[C:47][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51]
Reactant: C[Si](C)(C)CCOCn1c(Cl)c(I)c2c(=O)[nH]ncc21
Reactant: C#C[Si](CC)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC[Si](C#Cc1c(Cl)n(COCC[Si](C)(C)C)c2cn[nH]c(=O)c12)(CC)CC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To 61 mg (0.14 mmol) of 2-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 30-(b) were added 5 mg of bis(triphenylphosphine)palladium dichloride, 4 mg of cuprous iodide, 8 mg of triphenylphosphine, 1 ml of diisopropylamine, 0.04 ml of triethylsilylacetylene and 0.4 ml of N,N-dimethylformamide, the mixture was degassed under reduced pressure and replaced with argon, and the mixture was stirred at 80° C. for 1.5 hours. After completion of the reaction, toluene was added to the reaction mixture, and the mixture was washed successively with 5% aqueous sodium hydrogen sulfite solution, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. The organic layer after separation was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3→1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 47 mg of the title compound as a yellowish solid. (Yield: 75%)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=[O:8].[H-].[Na+].O.[CH3:13]N(C)C=O>>[CH3:13][O:8][C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: Cn1cccc1C(=O)O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cccn1C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The solution of 28 g of 1-methylpyrrole-2-carboxylic acid in 20 ml of dimethylformamide is added to the suspension prepared from 12 g of 50% sodium hydride in mineral oil, washed with petroleum ether and suspended in 50 ml of dimethylformamide, while stirring and cooling. Thereupon 30 ml of methyl iodide are added and stirring is continued at ambient temperature. Another 10 ml of methyl iodide are added after the initial exothermic reaction has subsided. After standing overnight, the mixture is treated with water, extracted with diethyl ether, the extract washed with aqueous sodium carbonate and water, dried and evaporated, to yield the 1-methylpyrrole-2-carboxylic acid methyl ester as an oil.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[C:3](=[O:13])[C:4]1[C:9]([C:10]2=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:14]1([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[N:14]1[CH2:15][CH2:16][N:17]([C:2]2[C:3](=[O:13])[C:4]3[C:9]([C:10](=[O:12])[C:11]=2[OH:1])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:18][CH2:19]1
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Reactant: O=C1c2ccccc2C(=O)C2OC12
Solvent: CCO
Product: O=C1C(O)=C(N2CCN(c3nc4ccccc4o3)CC2)C(=O)c2ccccc21
Reaction time: 18 h
Yield: 14.2 %

Procedure:
A mixture of 3.48 g of 2,3-epoxy-2,3-dihydro-1,4-naphthoquinone, 2.03 g of 2-(1-piperazinyl)benzoxazole and 200 ml of absolute ethanol was stirred 18 hours and then filtered. The filtrate was concentrated to dryness and the residue flash chromatographed, eluting with dichloromethane, then 1% methanol in dichloromethane. The desired fraction was evaporated, then recrystallized twice from dichloromethane/ethanol, giving 533 mg of the desired product, mp 190°C. (dec.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[N:32]1[CH:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=1>>[N:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:22][C:21]([C:20]2[N:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[C:12](=[O:31])[C:13]3[C:18]([C:19]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=3)=[O:23])=[CH:34][CH:33]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: OCc1ccncc1
Product: O=C(OCc1ccncc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg) and 4-pyridinemethanol. Colorless crystals (246 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([CH:31]=O)[CH:22]=2)=[CH:17][CH:16]=1>COCCOC>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[C:23]([CH:31]=[C:5]3[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]3=[O:7])[CH:22]=2)=[CH:19][CH:20]=1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)ccc1C(F)(F)F
Reactant: CC1(C)CC(=O)C(C)(C)O1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3)ccc2C(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (0.887 g, 6.25 mmoles) in 1,2-dimethoxyethane (10 ml) is added sodium methoxide (0.405 g, 7.50 mmoles) in one portion. The reaction mixture is stirred at 0° C. for 30 minutes, followed by the dropwise addition of 4′-chloro-4-trifluoromethylbiphenyl-3-carbaldehyde (1.779 g, 6.25 mmoles) as a solution in 1,2-dimethoxyethane (10 ml). The reaction mixture is stirred at 0° C. for 30 minutes and then at ambient temperature for a further 1 hour after which it is partitioned between 1M hydrochloric acid and dichloromethane. The aqueous phase is extracted again with dichloromethane, than all organics are combined and evaporated to afford 4-[1-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (2.50 g) as a yellow gum. This material is used directly in the next step.
Reaction SMILES: CO[C:3]([CH:5]([CH:12]1[NH:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=O.ClC1C=CC=C[N:20]=1.C1(CC#N)C=CC=CC=1>>[N:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:3]#[N:20]
Reactant: Clc1ccccn1
Reactant: COC(=O)C(c1ccccc1)C1CCCCN1
Solvent: N#CCc1ccccc1
Product: N#CC(c1ccccc1)c1ccccn1

Procedure:
U.S. Pat. No. Nos. 2,507,631 and 2,957,880 disclose synthetic procedures wherein methylphenidate, alternatively known as methyl α-piperid-2-ylphenylacetate, is prepared through a multi-step process in which 2-chloropyridine and phenylacetonitrile initially are coupled to form α-pyrid-2-ylphenylacetonitrile. The resulting α-pyrid-2-ylphenylacetonitrile then is hydrated in the presence of acid to yield α-pyrid-2-ylphenylacetamide which, in turn, is either: (a) catalytically hydrogenated to yield α-piperid-2-ylphenylacetamide and then converted to methyl α-piperid-2-ylphenylacetate, or (b) converted to methyl α-pyrid-2-ylphenylacetate which, in turn, is hydrogenated to yield methyl α-piperid-2-ylphenylacetate.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH2:9][CH2:10][C:11]3[C:12]4[C:17]([S:18][C:19]=3[C:7]=2[CH:6]=[N:5]1)=[N:16][CH:15]=[N:14][C:13]=4[O:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][N:4]2[C:8]3[CH2:9][CH2:10][C:11]4[C:12]5[C:17]([S:18][C:19]=4[C:7]=3[CH:6]=[N:5]2)=[N:16][CH:15]=[N:14][C:13]=5[O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:35][CH2:34]1
Reactant: O=[N+]([O-])c1ccc(CCOc2ncnc3sc4c(c23)CCc2c-4cnn2CCBr)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(CCn2ncc3c2CCc2c-3sc3ncnc(OCCc4ccc([N+](=O)[O-])cc4)c23)CC1
Yield: 100 %

Procedure:
This compound was prepared in a similar fashion as described in Example 48 step 6 starting from 3-(2-bromo-ethyl)-6-[2-(4-nitro-phenyl)-ethoxy]-4,5-dihydro-3H-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluorene (2.6 g, 5.2 mmol) and N-methyl piperazine (1.56 g, 15.59 mmol). The crude desired product was obtained as a light yellow solid (2.7 g) in 100% yield.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[S:12]([OH:15])(=O)=[O:13].P(Cl)(Cl)(Cl)(Cl)[Cl:17].Cl>>[Br:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[S:12]([Cl:17])(=[O:15])=[O:13]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1c(F)c(F)c(F)c(F)c1Br
Agent: Cl
Product: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1Br
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
1Bromo-2,3,4,5-tetrafluorobenzene (5.0 g, 21.8 mmol) was mixed at ambient temperature with 20% fuming sulfuric acid (20 ml). The mixture was heated at 40° C. for 3 h and at 110° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature and poured onto 12 g of crushed ice. The mixture was acidified dropwise with concentrated HCl (2 ml) until a solid, consisting mostly of 2-bromo-3,4,5,6-tetrafluorophenylsulfonic acid was formed. The solid was filtered, washed with 12N HCl, and dried under high vacuum to afford 5.3 g of 2-bromo-3,4,5,6-tetrafluorophenylsulfonic acid as a white hygroscopic solid that was used without further purification. To the sulfonic acid (3.0 g, 9.7 mmol) was then added phosphorous pentachloride (8.0 g, 38.4 mmol) in small portions, at ambient temperature (Caution: exothermic reaction with significant evolution of HCl). The reaction was allowed to stir for 20 minutes after the final addition of phosphorous pentachloride. The reaction mixture was then poured onto crushed ice and the white solid that formed was filtered and dried to afford 2.8 g of the title compound, which was used without further purification. MS (EI): 328 (30, M+), 293 (70), 229 (30), 148 (100).