Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6].Br[CH2:15][C:16]([CH3:18])=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[O:1][CH2:17][C:16]([CH3:18])=[CH2:15]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=C(C)COc1cc(C(=O)O)ccc1OC

Procedure:
The reaction of methyl 3-hydroxyl-4-methoxybenzoate and 3-Bromo-2-methyl-propene in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 4-Methoxy-3-(2-methyl-allyloxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.63 (s, —CO2H); 7.56 (d-like, 1 arom. H); 7.43 (m, 1 arom. H); 7.04 (m, 1 arom. H); 5.04, 4.90 (2 s, —C(CH3)═CH2); 4.48 (s, CH2—C(CH3)═CH2); 3.79 (s, OCH3); 1.75 (s, C(CH3)═CH2). 13C-NMR (100 MHz, d6-DMSO): 167.02 (—C═O); 152.90; 147.18; 140.76; 123.39; 122.84; 113.76; 112.33; 111.28; 71.56; 55.75; 19.16.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20][C:19]2=[O:25])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].[C:26]1(=[O:36])[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>ClCCl>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]([CH2:23][O:24][C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]([OH:31])=[O:30])[CH2:20][C:19]2=[O:25])=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1ccc(N2CC(CO)CC2=O)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(N2CC(COC(=O)c3ccccc3C(=O)O)CC2=O)cc1
Yield: 100.1 %

Procedure:
A 8.3 ml (60 mmol) quantity of triethylamine was added to a solution of 12.35 g (50 mmol) of [1-(4-t-butylphenyl)-2-pyrrolidone-4-yl)methyl alcohol (III) and 7.4 g (50 mmol) of phthalic anhydride in dichloromethane (150 ml), and the mixture was refluxed with heating for 24 hours. The reaction mixture was washed with a dilute hydrochloric acid, dried over magnesium sulfate and concentrated under reduced pressure to give 19.8 g (quantitative yield) of the title compound.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8][CH2:7]1)=[O:5].[CH3:21][Mg]I>C1COCC1>[C:4]([C@@H:6]1[CH2:7][CH2:8][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:10][CH2:11]1)(=[O:5])[CH3:21]
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of tert-butyl cis-4-(methoxy(methyl)carbamoyl)cyclohexylcarbamate (4.7 g, 16.41 mmol) in THF (109 mL) was cooled to 0° C. under nitrogen atmosphere. To this was added methylmagnesium iodide (3M in ether solution)(10.94 mL, 32.8 mmol) dropwise via syringe, and the mixture was stirred at 0° C. for 1 hour. The ice bath was removed, and the reaction mixture was stirred for 18 hours at RT. The reaction mixture was again cooled to 0° C. under nitrogen atmosphere and quenched with aqueous NH4Cl (100 mL). DCM (200 mL) was added, and the layers were separated. The organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated to afford a yellow oil which was purified by silica gel chromatography (5-30% MeOH/DCM) to afford tert-butyl cis-4-acetylcyclohexylcarbamate as an off-white solid (1.8 g, 45.4% yield).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:23]3[CH:24]=[C:25]4[O:30][CH2:29][O:28][C:26]4=[CH:27][C:22]=3[CH2:21][C:20]([CH3:31])=[N:19][N:18]=2)=[CH:13][CH:12]=1>C(OCC)C>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:23]4[CH:24]=[C:25]5[O:30][CH2:29][O:28][C:26]5=[CH:27][C:22]=4[CH2:21][C:20]([CH3:31])=[N:19][N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Product: CC1=NN=C(c2ccc(NC(=O)Nc3ccccc3)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
0.22 ml (2.04 mmol) of phenyl isocyanate was added to solution of 0.50 g (1.7=mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 4 ml of dimethylformamideand the reaction mixture was stirred at 25° C. for one hour. Then it was diluted with 20 ml of diethyl ether and filtered at 5 ° C. The crystals were washed with 2×5 ml of diethyl ether and dried at 60°-100° C. The resulting 0.70 g of raw product, m.p. 239°-240° C. (sintering at 180 ° C.) was refluxed in 15 ml of ethanol, filtered after cooling, washed with 3×1 ml of ethanol and dried at 100 ° C. to yield 0.55 g (78.6%) of the aimed product, m.p. 240°-241° C. (decomp.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O)#[N:2].S([O-])([O-])(=O)=O.[Mg+2].[C:24]1([CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:31][CH:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)#[N:2]
Reactant: N#Cc1cccc(Cc2ccccc2C=O)c1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: N#Cc1cccc(Cc2ccccc2C=NC(c2ccccc2)c2ccccc2)c1
Temperature: 4 °C

Procedure:
To a stirred suspension of 3.58 g of 2-(3-cyanobenzyl)benzaldehyde and 10.4 g of anhydrous magnesium sulfate was added 3.6 ml of diphenylmethanamine, and the stirring continued overnight. The reaction was filtered through dicalite and the filtrate evaporated to give an oil that crystallised on addition of diethyl ether and cooling to 4° C., to give 4.11 g of N-[2-(3-cyanobenzyl)benzylidene]-1,1-diphenylmethanamine, melting at 113-115° C. A stirred solution of 1.0 g of N-[2-(3-cyanobenzyl)benzylidene]-1,1-diphenylmethanamine in 15 ml of tetrahydrofuran was cooled to -78° C. and 6.7 ml of a 1 M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise. The purple coloured solution was stirred for 20 min then 0.9 ml of propargyl bromide was added rapidly and the reaction allowed to slowly warm to room temperature. The reaction mixture was diluted with 25 ml of saturated aqueous ammonium chloride and extracted into dichloromethane. The combined organic extracts were dried over sodium sulfate the evaporated to give crude N-(diphenylmethylidene)-2-(3-cyanobenzyl)-a-2-propynyl-benzenemethanamine which was not characterised due to instability. The crude product was dissolved in 20 ml of acetone and 5 ml of 1 M hydrochloric acid added. The solution was stirred at room temperature for 3 h then cooled to 4° C. overnight. The acetone was removed by evaporation and the crude product redissolved in 20 ml of dichloromethane. The solution was extracted with two 20 ml portions of 2N hydrochloric acid. The combined acid extracts were washed with 10 ml of dichloromethane and then basified with 4N sodium hydroxide solution. The basic extracts were combined and re-extracted with three 20 ml portions of dichloromethane, the combined organic extracts were dried over sodium sulfate and evaporated to give 120 mg of product. The product was dissolved in 1 ml of methanol and 57 mg of fumaric acid was added. The product was crystallised by trituation with ether and cooling to 4° C. to yield 120 mg of 2-(3-cyanobenzyl)-a-2-propynyl-benzenemethanamine (E)-butenedioate, melting at 182-184° C.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(N(CC)CC)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([C:24]#[C:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: C#Cc1ccccc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
4-Fluoro-4'-phenylethynylbenzophenone was synthesized by the cuprous iodide catalyzed coupling of 4-bromo-4'-fluorobenzophenone. More specifically, 4-bromo-4'-fluorobenzophenone (30 grams, 0.11 mol), phenylacetylene (11 grams, 0.11 mol), triphenylphosphine (0.2 gram), cuprous iodide (0.1 gram), bis(triphenylphosphine) palladium dichloride (0.1 gram) and 450 milliliters of triethylamine were charged to a 500 milliliter flask equipped with a mechanical stirrer, N2 inlet, and reflux condenser. The mixture was heated to reflux for 4 hours, cooled to 23° C., and stirred for an additional 16 hours. The mixture was then poured into water acidified with HCl and the precipitate was collected by filtration. Recrystallization from acetone gave 23 grams (75 percent yield) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][SH:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([S:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:7]=1
Reactant: COc1ccc(CS)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(CSc2cc(F)ccc2[N+](=O)[O-])cc1
Product: COc1ccc(CSc2ccc([N+](=O)[O-])c(F)c2)cc1

Procedure:
A mixture of 2,4-difluoronitrobenzene (2.6 ml, 23.3 mmol), p-methoxybenzyl mercaptan (2.00 g, 11.7 mmol), K2CO3 (6.47 g, 46.8 mmol) in acetone (50 ml) was refluxed for 20 h. The reaction mixture was poured into cold water. The whole was extracted with CH2Cl2 (3×100 ml), and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (1:30→1:20 EtOAc/hexanes) to give the desired 2-fluoro-4-(4′-methoxybenzylmercapto)nitrobenzene containing a small amount of 4-fluoro-2-(4′-methoxybenzylmercapto)nitrobenzene. MS (Cl) m/e 294 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:17]1([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.N1(C2C3CCCCC=3N=CC=2)CCNCC1>C(#N)C>[N:26]1[C:27]2[CH2:28][CH2:29][CH2:30][CH2:31][C:32]=2[C:23]([N:17]2[CH2:18][CH2:19][N:20]([CH2:2][C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:21][CH2:22]2)=[CH:24][CH:25]=1
Reactant: COC(=O)COc1ccc(C(=O)CBr)cc1
Reactant: c1ccc2c(N3CCNCC3)ccnc2c1
Agent: c1cc(N2CCNCC2)c2c(n1)CCCC2
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccnc4c3CCCC4)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a similar manner to Example 1, methyl 4-bromoacetylphenoxyacetate (1.23 g), a 1:1 mixture containing 4-(1-piperazinyl)quinoline and 4-(1-piperazinyl)-5,6,7,8-tetrahydroquinoline (1.84 g) and acetonitrile (56 ml) yielded, after stirring at room temperature overnight, filtration and evaporation of the filtrate, an orange/brown oily residue which was purified by flash chromatography, first on neutral alumina by elution with 5% v/v methanol/dichloromethane, then on silica by elution with methanol/dichloromethane (0.5% v/v to 5% v/v), and finally by crystallisation of the lower Rf material from methanol/water, to yield the title compound (298 mg) as a cream solid: NMR (CDCl3) δ1.76 (2H, m), 1.89 (2H, m), 2.64 (2H, m), 2.76 (4H, m), 2.95 (2H, m), 3.07 (4H, m), 3.80 (2H, s), 3.81 (3H, s), 4.71 (2H, s), 6.68 (1H, d), 6.95 (2H, d), 8.03 (2H, d) 8.28 (1H, d); m/Z 424 (M+H)+ ; calculated for C24H29N3O4. 1.0 H2O: C, 65.3%; H, 7.08%; N, 9.52%; found: C, 65.6%; H, 6.7%; N, 9.3%.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:14])[C:12](=[O:15])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1.C(O)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]3([CH2:11][CH2:10]3)[C:12](=[O:15])[N:13]([CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 48.7 %

Procedure:
A mixture of 0.0449 g (0.000146 mole) of 2-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VII-53), 0.0222 g (0.00016 mole) of 4-amino-benzoic acid, 0.8 mL of ethanol, 3.2 mL of water and 3 drops of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the precipitate which formed was collected by filtration to give 0.029 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-benzoic acid (I-62a) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[C@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[O:9]2)=[CH:4][CH:3]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:12])=[O:13])=[CH:4][CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)C[C@@H]1OC(c2ccc(Br)cc2)OC1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(Br)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Zinc chloride (1.12 l of 1M solution in ether, 1120 mmol) was added to 500 ml ether at −40° C. (5S)-2-(4-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one (3:2 mixture of cis/trans) (56 g, 187 mmol) was then added dropwise in 200 ml ether (over 15 min), followed by phenylmagnesium bromide (125 ml of a 3M solution in ether, 374 mmol) (dropwise over 45 min). The solution was stirred at 0° C. for 2 hours. The reaction was quenched at 0° C. with 800 ml of a saturated solution of NH4Cl, the phases were separated and the aqueous layer extracted with 800 ml ether. The organic layers were combined, washed with brine, dried with MgSO4 and the solvent was removed. (2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid (de=86%) was obtained after purification on silica gel (5% ethyl acetate/toluene).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](O)[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([O:15][CH2:18][CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(benzyloxycarbonylamino)-2-methyl-propanoic acid (which may be prepared as described in Description 24) (5000 mg, 21.08 mmol) in toluene (50 mL) was added ethanol (5 mL) and p-toluenesulfonic acid (400.89 mg, 2.11 mmol). The solution was stirred at 80° C. overnight. The reaction mixture was evaporated and the residues dissolved in EtOAc and washed with saturated aqueous sodium bicarbonate. The aqueous phase was back extracted into EtOAc. The combined organics were dried over magnesium sulphate, filtered and evaporated to yield the title compound as a light yellow oil (4.667 g);
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[C:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])[CH3:36]>COCCO>[C:35]([N:38]1[CH2:43][CH2:42][N:41]([CH2:33][CH2:32][CH2:31][O:30][C:24]2[CH:23]=[C:22]3[C:27]([C:18]([NH:17][C:3]4[C:4]5[O:8][CH2:7][O:6][C:5]=5[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:10][C:2]=4[Cl:1])=[N:19][CH:20]=[N:21]3)=[CH:26][C:25]=2[O:28][CH3:29])[CH2:40][CH2:39]1)(=[O:37])[CH3:36]
Reactant: CC(=O)N1CCNCC1
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C(C)=O)CC4)c(OC)cc23)c2c1OCO2
Yield: 82.6 %

Procedure:
N-[5-Chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (192 mg, 0.38 mmol) and 1-acetylpiperazine (244 mg, 1.9 mmol) in 2-methoxyethanol (4 ml) were stirred and heated at 100° for 12 hr. then quenched in water and extracted with dichloromethane. The combined extracts were washed with saturated brine, dried over magnesium sulphate and evaporated to an orange oil. This was then purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (187 mg, 82%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 1.98 (quintet, 2H), 1.99 (s, 3H), 2.33 (m, 2H), 2.40 (m, 2H), 2.48 (t, 2H), 2.72 (t, 2H), 3.31 (s, 3H), 3.43 (m, 4H), 3.53 (t, 2H), 3.93 (s, 3H), 4.21 (t, 2H), 6.13 (s, 2H), 7.07 (s, 1H), 7.18 (s, 1H), 7.81 (s, 1H), 8.32 (s, 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 596/598.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:22][C@H:23]([C:25]([OH:27])=[O:26])[CH3:24].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:22][C@@H:23]([CH3:24])[C:25]([OH:27])=[O:26])=[O:10]
Reactant: CCOC(=O)c1ncc2c(-c3ccccc3)noc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)c1ncc2c(-c3ccccc3)noc2c1O)C(=O)O
Temperature: 25 °C
Yield: 79.4 %

Procedure:
Ethyl 7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (0.1 g, 0.35 mmol) was dissolved in 10 mL of DMF. L-Alanine (0.627 g, 7.04 mmol) and sodium ethoxide (0.36 g, 5.28 mmol) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 2. The resulting suspension was filtered and the solid dried under vacuum to give 91 mg of the title compound. MS: (+) m/z 328.00 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Br>CC(C)=O>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:26][CH:28]3[O:30][CH2:29]3)[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(C(c2ccccc2)N2CCN(CC3CO3)CC2)cc1

Procedure:
In acetone, 1-(diphenylmethyl)piperazine (6.0 g) was dissolved (20 v/w), and potassium carbonate (1.5 eq.) and epibromohydrin (2.0 eq.) were added thereto, and the obtained mixture was heated to reflux for 3.5 hours. The salt produced by the reaction was separated by filtration, and the filtrate was then concentrated in vacuo to obtain a crude product of 1-(diphenylmethyl)-4-(1-(2,3-epoxy)propyl)piperazine.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Si]([C:15]#[N:16])(C)(C)C.CN(C)C(Cl)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:15]#[N:16])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)c1cc[n+]([O-])cc1
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 139 mg (1.01 mmol) of 4-isopropylpyridine N-oxide in 10 mL of CH2Cl2 at r.t. was added 160 μL (1.20 mmol) of TMSCN. After 5 min., 100 μL (1.09 mmol) of dimethylcarbamyl chloride was added, and the solution was stirred at r.t. for 16 h. The solution was diluted with chloroform and washed with 20 mL of 10% aqueous K2CO3. The layers were separated, and the aqueous layer was extracted 3 times with CHCl3. The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (30% EtOAc/hexanes) provided 4-isopropylpicolinonitrile with some impurity as a liquid.
Reaction SMILES: [CH2:1]([C:6](Cl)=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:9]1([C@H:15]2[NH:18][C:17](=[O:19])[C@@H:16]2[O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:1]([C:6]([N:18]1[C@H:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:16]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[C:17]1=[O:19])=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@@H]1c1ccccc1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC[Si](CC)(CC)O[C@H]1C(=O)N(C(=O)CC(C)(C)C)[C@@H]1c1ccccc1

Procedure:
By following the above procedure and using neopentylcarbonyl chloride, and (3R,4R)-4-phenyl-3-triethylsilyloxy-azetidin-2-one were converted to the title product: 1H NMR (CDCl3) δ 0.19-0.62 (m, 15H), 0.88 (s, 3H), 2.43 (d, 1H, J=13.8 Hz), 2.62 (d, 1H, J=14.1 Hz), 4.90 (d, 1H, J=5.7 Hz), 4.95 (d, 1H, J=6.0 Hz), 7.05-7.17 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([F:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1>COCCOC>[F:16][C:5]1[C:6]([NH:32][CH2:31][CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c(F)c(-c2ccco2)n1
Reactant: COc1ccc(CCN)cc1
Solvent: COCCOC
Product: COc1ccc(CCNc2nc(N)nc(-c3ccco3)c2F)cc1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-fluoro-6-furan-2-yl-pyrimidin-4-yl ester and 2-(4-methoxyphenyl)ethylamine in DME. ES-MS m/e (%): 329 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:11][CH2:12][CH2:13][OH:14]>C(OCC)(=O)C>[Br-:11].[OH:14][CH2:13][CH2:12][N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]=1[CH3:1]
Reactant: OCCBr
Reactant: Cc1nc2ccccc2s1
Solvent: CCOC(C)=O
Product: Cc1sc2ccccc2[n+]1CCO
Product: [Br-]
Temperature: 110 °C
Yield: 39 %

Procedure:
A solution of 2-methylbenzothiazole (5.87 g) and 2-bromoethanol (49.2 g) was stirred and heated in an oil bath at 110° C. for 18 hours. After cooling the reaction mixture to room temperature, adding ethyl acetate (100 ml), and decanting, the resultant solid was then dissolved in methanol (50 ml) and precipitated with ethyl acetate (300 ml). The solid was again recrystallized from a mixture of methanol and ethyl acetate, washed with ethyl acetate (2×25 ml) and dried in an oven under high vacuum at 50° C. overnight to obtain 4.21 g (39%) of 4a.