Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.Cl.[NH2:14][OH:15]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])/[CH:5]=[N:14]/[OH:15]
Reactant: Cc1cc(C=O)ccc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1cc(/C=N/O)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a warm solution of 3-methyl-4-nitrobenzaldehyde (1.0 equiv.) in methanol was added hydroxylamine hydrochloride (2.0 equiv.) and the mixture was stirred at 65° C. for 2 hours. Methanol was evaporated and the residue was diluted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then recrystallized from ethyl acetate and petroleum ether 60-80, to provide the title compound as a creamish solid (81%); 1H NMR (300 MHz, CDCl3) δ: 2.62 (s, 3H), 7.54-7.56 (m, 2H), 7.89 (s, 1H), 7.98-8.01 (d, J=9.0 Hz, 1H), 8.14 (s, 1H); IR (KBr) 3375, 3207, 3087, 2994, 1607, 1585, 1506, 1384, 1319, 1161, 986, 841, 755 cm−1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([NH:12][C@H:13]2[CH2:17][C:16](=[O:18])[N:15]([CH:19]([CH3:21])[CH3:20])[CH2:14]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30]>CN(C=O)C>[Cl:3][C:4]1[CH:11]=[C:10]([N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[C@H:13]2[CH2:17][C:16](=[O:18])[N:15]([CH:19]([CH3:21])[CH3:20])[CH2:14]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)N1C[C@@H](Nc2ccc(C#N)c(Cl)c2)CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C[C@@H](N(Cc2ccccc2F)c2ccc(C#N)c(Cl)c2)CC1=O
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
NaH (60% in mineral oil, 0.026 g, 0.65 mmol) was washed free of mineral oil and then suspended in DMF (3 mL) and cooled to −20° C. To this suspension was added a solution of 2-chloro-4-{[(3S)-1-(1-methylethyl)-5-oxo-3-pyrrolidinyl]amino}benzonitrile (0.120 g, 0.43 mmol). After stirring at −20° C. for 20 min, 1-(bromomethyl)-2-fluorobenzene (0.12 g, 0.65 mmol) in DMF (2 mL) was added and the reaction was stirred at −20° C. for 5 min and then at 0° C. for 5 min. The reaction was quenched with aqueous NH4Cl, diluted with H2O, and extracted with Et2O (2×). The organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography with 25% EtOAc in hexane grading to 100% EtOAc in hexane to afford the product (0.13 g, 79%) as a white solid. 1H-NMR (CDCl3) δ: 1.137 (6H, dd, J=16.8 Hz, 6.8 Hz), 2.547 (1H, m), 2.842 (1H, m), 3.349 (1H, m), 3.749 (1H, m), 4.465 (1H, m), 4.588 (2H, m), 4.755 (1H, m), 6.566 (1H, d, J=8.8 Hz), 6.747 (1H, s), 7.031 (1H, m), 7.130 (2H, m), 7.325 (1H, m), 7.455 (1H, d, J=8.8 Hz). LC-MS (ES) m/e 386.4 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(OC)cccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(OC)cccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-methoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([O:31][CH2:32][CH3:33])[C:29]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH2:24][OH:25])[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].C(OC1C=C(C=O)C=C(OCC)C=1[C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:32]([O:31][C:28]1[CH:27]=[C:6]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH2:24][OH:25])[CH:17]=3)[CH2:12][CH2:13]2)[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:29]=1[C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1)[CH3:33]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1F
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 50k), 3-hydroxymethyl-5-methoxy-N-piperidin-4-yl-benzamide (example 217) was reacted with 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (example 102), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless amorphous solid. MS: 537.3 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1.C(OC(=O)C)(=O)C.[CH2:25]([OH:27])[CH3:26]>O>[C:25]([C:15]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[C:3]([CH2:2][NH2:1])[C:16]=31)[C:9]1[C:8]2=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:27])[CH3:26]
Reactant: CCO
Reactant: NCC12CC(c3ccccc31)c1ccccc12
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)C12CC(c3ccccc31)c1cccc(CN)c12

Procedure:
A solution of 9-aminomethyl-9,10-dihydro-9,10-methanoanthracene (235 mg) and acetic anhydride (217 mg) in ethanol (5.0 ml) was refluxed for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-acetyl-aminomethyl-9,10-dihydro-9,10-methanoanthracene. M.P. 184°-185.5° C.
Reaction SMILES: [OH:1][C@@H:2]([CH3:21])[CH2:3][C@@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)C>[C:22]([O:1][C@@H:2]([CH3:21])[CH2:3][C@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:24])[CH3:23]
Reactant: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(=O)O[C@@H](C)C[C@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 47.4 %

Procedure:
0.50 g of the (R,S) -4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]benzonitrile obtained in the above Example 1 was mixed with 0.12 g of acetic anhydride, 0.51 g of triphenylphosphine and 5 ml of ethyl ether. To the obtained mixture, was added dropwise 0.34 g of diethyl azodicarboxylate under stirring. The obtained mixture was stirred at room temperature for three hours. The triphenylphosphine oxide thus precipitated was filtered and desolvated to thereby give a crude product which was purified by silica gel column chromatography with the use of a mixture of ethyl acetate and n-hexane (1:3) as a developing solvent. Thus 0.18 g of the title compound as obtained. The obtained product showed the following characteristic absorptions in infrared spectroscopy, which proved that it was the aimed compound.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[CH:36]([C@H:38]1[CH2:43][CH2:42][C@H:41]([C:44]#[N:45])[CH2:40][CH2:39]1)=O.C(=O)([O-])O.[Na+]>C(OCC)C>[F:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:36][C@H:38]3[CH2:43][CH2:42][C@H:41]([C:44]#[N:45])[CH2:40][CH2:39]3)=[CH:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Fc1ccc(-c2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Reactant: N#C[C@H]1CC[C@H](C=O)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: N#C[C@H]1CC[C@H](C=Cc2ccc(-c3ccc(F)c(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 12.05 g of [2-(3,4-difluorophenyl)-5-pyridyl]methyltriphenylphosphonium chloride in 70 ml of diethyl ether is treated with 2.67 g of potassium tert.-butylate in a nitrogen atmosphere. The dark yellow suspension is stirred at room temperature for a further 30 minutes. A solution of 2.74 g of -trans-4-formylcyclohexanecarbonitrile in 30 ml of diethyl ether is then added dropwise at 0° C. The reaction mixture is stirred at 0° C. for a further 1 hour, then stirred with 40 ml of 1N sodium hydrogen carbonate solution and diluted with diethyl ether. The organic phase is separated, washed neutral with water, dried over sodium sulphate and concentrated. The residue is chromatographed on silica gel with hexane/ethyl acetate 3:1 (v/v). There is obtained trans-4-[2-[2-(3,4-difluorophenyl)-5-pyridyl]vinyl]cyclohexanecarbonitrile.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH3:15][C:16]1[CH:21]=[C:20]([C:22]([OH:24])=O)[CH:19]=[CH:18][N:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:22]([C:20]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:15])[CH:21]=1)=[O:24]
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCNC[C@@H]2C)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.7 %

Procedure:
A mixture of 1,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (146 mg, 0.73 mmol), 2-methyl-4-pyridinecarboxylic acid (100 mg, 0.73 mmol), HBTU (277 mg, 0.73 mmol) HOBT (112 mg, 0.72 mmol) and DIPEA (0.38 mL, 2.19 mmol) in DMF (20 mL) was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM and extracted with saturated sodium bicarbonate. The organic layer was collected and the solvent was evaporated off using the rotary evaporator. The solvent was difficult to remove so it was azeotroped twice with toluene. The residual solid was dissolved in DCM and purified using SP4. The fractions containing product were combined and evaporated to dryness on the rotary evaporator. The product was dissolved in 1,4-dioxane (7.5 mL) and 4M HCl in dioxane (2.5 mL) was added and the reaction stirred for 3 h. A few drops of water were then added and the mixture stirred for a further 45 min. The solvent was then evaporated off on the rotary evaporator. To remove the water, the residue was azeotroped twice with toluene. The residual solid was dissolved in methanol and transfered to an SCX column. Once loaded, the material was washed with 2 column volumes of methanol. The product was eluted from the column with 2M ammonia in methanol and the solvent removed under vacuum to give the title compound (70 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)COC(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: CC(C)COC(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using isobutyl chloroformate (72 μL, 0.55 mmol) to provide isobutyl[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]carbamate (0.046 g).
Reaction SMILES: Br[CH2:2][CH:3]1[CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:5]([C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4]1.[CH2:19]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][C:3]2[C:4]3[CH:5]4[CH2:6][CH2:7][CH:8]([C:13]5[C:18]4=[CH:17][CH:16]=[CH:15][CH:14]=5)[C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCC1CC2c3ccccc3C1c1ccccc12
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: c1ccc(CC2CCN(Cc3cccc4c3C3CCC4c4ccccc43)CC2)cc1
Temperature: 90 °C

Procedure:
11-Bromomethyl-9,10-dihydro-9,10-ethanoanthracene (1.2 gm), 4-benzylpiperidine (7.0 gm) and potassium carbonate (0.40 gm) were combined in hexamethylphosphoramide (8 ml) in a sealed tube and heated to 90° C. for 48 hours. The mixture was extracted between water (50 ml) and ether (50 ml). The aqueous layer was extracted with ether (2×50 ml) and the combined ether solutions were washed with water (2×50 ml), then extracted with 3.6 N sulfuric acid (3×50 ml). The combined acid solutions were made basic with the addition of concentrated aqueous ammonia and the resulting mixture was extracted with ether (3×50 ml). The combined ether solutions were dried over magnesium sulfate and the ether and excess 4-benzylpiperidine were removed on a rotary evaporator. The residue was dissolved in methylene chloride (15 ml) and purified by preparative centrifugally accelerated radial thin layer chromatography on silica gel using 90:9:1 methylene chloride/ethanol/triethylamine as the eluant. The crude product was dissolved in isopropyl alcohol (10 ml) and treated with 6 N hydrochloric acid in isopropyl alcohol (0.5 ml). The solution was added dropwise to ether (150 ml) and the resulting solid was filtered. The solid was recrystallized from isopropyl alcohol to provide the product as a white solid. Analytical data are reported in Table I.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:17]([C:13]1[S:14][CH:15]=[CH:16][C:12]=1[CH3:11])=[O:18]
Reactant: Cc1ccsc1C(=O)Cl
Reactant: Nc1nc2ccccc2s1
Solvent: c1ccncc1
Product: Cc1ccsc1C(=O)Nc1nc2ccccc2s1

Procedure:
Using 2-amino-benzothiazole and 3-methyl-thiophene-2-carboxylic acid chloride in pyridine the title compound was obtained as a yellow solid (69% yield), MS: m/e=275.1 (M+H+).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[C:9]([C:14]#[N:15])[CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:29]([O-])=O)=[N+]=[N-]>C1COCC1.C(O)C.[Pd]>[NH2:29][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[NH2:1])[N:11]=[CH:10][C:9]([C:14]#[N:15])=[C:8]2[NH:16][C:17]1[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(N=[N+]=[N-])c([N+](=O)[O-])cc23)cc(OC)c1OC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(N)c(N)cc23)cc(OC)c1OC
Yield: 98.7 %

Procedure:
A solution of 493.4 mg (1.17 mmol) of 7-azido-6-nitro-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile in 15 mL of THF and 5 mL of ethanol is hydrogenated at 30 psi for 1 hour in the presence of 100.0 mg of 10% palladium-on-carbon. The catalyst is removed by filtration and the solvent removed in vacuo to give 422.1 mg (98.8%) of 6,7-diamino-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile as a deep yellow solid which is used directly in the next step.
Reaction SMILES: [CH3:1][CH:2]([CH:8]([OH:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:11]1([C:24](Cl)=[O:25])[C:23]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1>>[CH3:1][CH:2]([CH:8]([O:10][C:24]([C:11]1[C:23]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:25])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)C(C)O
Reactant: O=C(Cl)c1cccc2c1Cc1ccccc1-2
Product: CCOC(=O)C(C)C(C)OC(=O)c1cccc2c1Cc1ccccc1-2
Yield: 25 %

Procedure:
0.01 Mole of ethyl 2-methyl-3-fluorenoyloxybutyrate was prepared from 0.04 mol of ethyl 2-methyl-3-hydroxybutyrate and 0.05 mol of fluorenoyl chloride (9-fluorenyl carbonyl chloride) following the procedure as described in step 3) of the Preparation Example 3. Yield 25%.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=O)[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C(Cl)(Cl)Cl>[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[S:19])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN1CC(CCCl)Oc2ncccc2C1=S

Procedure:
To a solution of 59 g (0.25 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)one hydrochloride in 1500 ml of chloroform was added 41.5 g (0.19 mole) of phosphorus pentasulfide and the mixture was heated to reflux for 18 hr. The mixture was filtered and the filtrate was extracted with dilute sodium hydroxide. The chloroform layer was concentrated and the residue was dissolved in 250 ml of boiling isopropyl alcohol. On cooling, 28 g (44%) of yellow solid precipitated. A portion was recrystallized from isopropyl alcohol, m.p. 134°-136° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH+:10]([O-:16])[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)([O-:3])=[O:2].[H-].[Na+].S(OC)(O[CH3:23])(=O)=O.O>CN(C)C=O>[CH3:23][N+:10]([O-:16])([N:11]1[CH:12]=[CH:13][CH:14]=[CH:15]1)[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccncc1[NH+]([O-])n1cccc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[N+]([O-])(c1cnccc1[N+](=O)[O-])n1cccc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
A solution of 4-nitro-N-(1H-pyrrol-1-yl)-3-pyridinamine-N-oxide (3.9 g) in 50 ml of dimethylformamide was added to a cooled suspension of sodium hydride (60% oil dispersion, 0.8 g, washed with hexanes) in 5 ml of dimethylformamide. After the anion formation, a solution of dimethyl sulfate (2.7 g) in 5 ml of dimethylformamide was added. After stirring twenty hours at ambient temperature, the reaction mixture was stirred with water and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to 4.5 g of oil. This oil was purified by flash chromatography (silica, 10% ethyl acetate in dichloromethane) to give 4 g of solid, mp 135°-140°. This material was purified by HPLC (silica, 20% ethyl acetate in dichloromethane) to give 3.5 g of solid, mp 140°-144°. This material was recrystallized from absolute ethanol to give 2.1 g of needles, mp 150°-151°.
Reaction SMILES: Cl[C:2]1[C:3]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1.[CH3:21][NH:22][CH:23]1[CH2:25][CH2:24]1.C(N(CC)CC)C>CO>[CH:23]1([N:22]([CH3:21])[C:2]2[C:3]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:4]=3[N:5]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=2)[CH2:25][CH2:24]1
Reactant: CNC1CC1
Reactant: CCOC(=O)Cc1nc(Cl)c2c3c(sc2n1)CCCC3
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The ethyl 2-(4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetate (7.0 g, 0.0225 mol) and N-methyl cyclopropyl amine (4.8 g, 0.0675 mol) was dissolved in methanol (200 ml). To this reaction mixture, triethyl amine (13.66 g, 0.135 mol) was added slowly at room temperature. The resulting reaction mixture was stirred at room temperature for 18 h. After completion of reaction it was concentrated under reduced pressure. The residue was dissolved in DCM (250 ml) and it was washed with water. Aqueous layer was extracted with DCM (250 ml). Organic extracts were combined and washed with brine. Separated organic layer was dried over anhydrous Na2SO4 and concentrated to get crude compound. It was purified by column chromatography by using 100-200 mesh silica gel and 10% EtOAc:hexane as eluent to give ethyl 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetate as a yellow solid. Yield—(6 g, 77.12%); 1H-NMR: (400 MHz, CDCl3); δ=4.20-4.10 (q, 2H), 3.88 (s, 2H), 3.1 (s, 3H), 2.90-2.86 (m, 3H), 2.84-2.83 (m, 2H), 1.93-1.87 (m, 2H), 1.77-1.71 (m, 2H), 1.41 (s, 1H), 1.26-1.23 (t, 3H), 0.72-0.68 (m, 2H), 0.45-0.41 (m, 2H); LC-MS [M+H]=345.9.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:15]([C:14](=[O:19])[CH3:13])[C:16](=[O:18])[CH3:17])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)CC(C)=O
Product: CC(=O)C(=Cc1ccc(Cl)c([N+](=O)[O-])c1)C(C)=O

Procedure:
The procedure described in Example 1 was repeated by using 1.85 g of 4-chloro-3-nitrobenzaldehyde and 1.5 g of 2,4-pentanedione. Yield 1.32 g, mp 110°-111° C.
Reaction SMILES: CO.C(=O)([O-])[O-].[K+].[K+].C([O:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[C:16]([NH:18][C:19]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])=[O:17])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[OH:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[C:16]([NH:18][C:19]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])=[O:17]
Reactant: CC(=O)Oc1cccc(C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(Oc2ccccc2)ccc1C(=O)O)c1cccc(O)c1
Reaction time: 2 h
Yield: 61.6 %

Procedure:
0.50 mL of methanol, 0.50 mL of tetrahydrofuran and 4.2 mg of potassium carbonate were added sequentially to 8.0 mg of 2-(3-acetoxybenzamido)-4-phenoxybenzoic acid at room temperature and stirred at the same temperature for 2 hours. 10% citric acid aqueous solution was added to the reaction mixture and a solid substance was separated by filtration to obtain 4.4 mg of 2-(3-hydroxybenzamido)-4-phenoxybenzoic acid as whine solid.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26][C:27]2[S:28][CH:29]=[C:30]([Br:32])[CH:31]=2)[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>ClCCl>[ClH:1].[Br:32][C:30]1[CH:31]=[C:27]([CH2:26][O:25][CH:23]2[CH2:22][NH:21][CH2:24]2)[S:28][CH:29]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Brc1csc(COC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Solvent: CCO
Solvent: ClCCl
Product: Brc1csc(COC2CNC2)c1
Product: Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
1-Chloroethyl chloroformate (218 μL, 2.0 mmol) was added to a solution of 1-benzhydryl-3-((4-bromothiophen-2-yl)methoxy)-azetidine (793 mg, 1.91 mmol) in dichloromethane (10 mL). The reaction mixture was stirred for 1 hour at 0° C. and for an additional 1 hour at room temperature. Ethanol (10 mL) was then added and the reaction mixture was stirred overnight. After concentration to dryness, the crude mixture was precipitated from a mixture dichloromethane/diethyl ether to afford a white solid (417 mg, 77%) which was used in the next step whitout further purification.