Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[NH:17][C:16](=O)[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:16]1[N:15]=[C:14]([C:6]2[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc(-c2cc(C(F)(F)F)[nH]c(=O)n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (3.74 g, 10.6 mmol) and phosphoryl chloride (35 mL) according to the general procedure I. Obtained as a light brown solid. MS (EI) 370.0 [(M)+]; mp 89° C.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12](I)[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:12][CH2:13][CH3:14]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared by reaction of isovanillin with propyl iodide in DMF with K2CO3 as base as described in M. J. Ashton, D. C. Cook, G. Fenton, J.-A. Karlsson, M. N. Palfreyman, D. Raeburn, A. J. Ratcliffe, J. E. Souness, S. Thurairatnam, N. Vicker J. Med. Chem. 1994, 37, 1696-1703.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:18]=[C:17]([C:19](=[N:21]O)[NH2:20])[CH:16]=[CH:15][CH:14]=1)[C:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:6]2.[C:29](N1C=CN=C1)(N1C=CN=C1)=[S:30].[OH2:41]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:18]=[C:17]([C:19]3[NH:20][C:29](=[O:41])[S:30][N:21]=3)[CH:16]=[CH:15][CH:14]=1)[C:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:6]2
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C(N)=NO)n1
Reactant: O
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(-c2nsc(=O)[nH]2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(5-methoxy-2-phenylindol-1-ylmethyl)pyridine-2-carboxamidoxime (123 mg) in tetrahydrofuran (2 mL) was added 1,1′-thiocarbonyldiimidazole (71 mg). This mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the residue was added tetrahydrofuran (2 mL), and subsequently boron trifluoride ethyl ether complex (0.21 mL) was added thereto under ice-cooling. The mixture was stirred at room temperature for 3 days. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid and water successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: dichloromethane-methanol) to obtain the title compound (24 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 5.55 (2H, s), 6.45-6.55 (1H, m), 6.60-6.70 (1H, m), 6.77 (1H, dd, J=2.5, 8.9 Hz), 7.14 (1H, d, J=2.5 Hz), 7.28 (1H, d, J=8.9 Hz), 7.35-7.60 (5H, m), 7.75-7.95 (2H, m), 13.35 (1H, br s). ESI-MS (m/z): 415 (M+H)+
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([OH:8])=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C@@H:28]2[CH2:33][NH:32][C:31](=[O:34])[CH2:30][NH:29]2)=[CH:19]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl.O>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:29]1[C@H:28]([CH2:27][C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:18][CH:19]=2)[CH2:33][NH:32][C:31](=[O:34])[CH2:30]1)=[O:8]
Reactant: O=C1CN[C@H](Cc2c[nH]c3ccccc23)CN1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)CN1
Reaction time: 1.5 h
Yield: 26.1 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)benzoic acid (2.63 g) and (5R)-5-(1H-indol-3-ylmethyl)piperazin-2-one (2.34 g) in dichloromethane (50 ml) were added successively triethylamine (3.56 ml) and 2-chloro-1-methylpyridinium iodide (3.13 g) at room temperature. The resulting mixture was stirred for 1.5 hours at the same temperature. Dichloromethane and water were added into the mixture and the organic layer was separated. The organic layer was washed successively with 0.5N hydrochloric acid, water, aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After evaporation in vacuo, the residue was purified by column chromatography on silica gel (75 g) eluting with a mixture of dichloromethane-methanol (from 0% to 5% gradient elution) to give (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-5-(1H-indol-3-ylmethyl)piperazin-2-one (1.25 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2([CH:15]([NH2:17])[CH3:16])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](Cl)=[O:29].O>ClCCl>[Cl:1][C:2]1[C:3]([C:12]2([CH:15]([NH:17][C:28](=[O:29])[C:27]3[C:26]([F:25])=[CH:34][CH:33]=[CH:32][C:31]=3[F:35])[CH3:16])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC(N)C1(c2ncc(C(F)(F)F)cc2Cl)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(NC(=O)c1c(F)cccc1F)C1(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
100 mg of 1-[1-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropyl]-ethylamine (step 4) was dissolved in 4 ml of dichloromethane and cooled to 0° C. Then 76 mg of triethylamine was added, followed by dropwise addition of a solution of 67 mg of 2,6-difluorobenzoyl chloride in 1 ml of dichloromethane. The reaction mixture was stirred at ambient temperature for 2 hours. Then 20 ml of water were added and the mixture was extracted with 20 ml dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. Thus, 162 mg of crude material was obtained as a pale yellow oil. This residue was purified by chromatography on silica gel, with cyclohexane/ethyl acetate (85:15) as a eluent. Thus, 149 mg of N-{1-[1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropyl]-ethyl}-2,6-difluoro-benzamide was obtained as a colourless sticky oil. 1H-NMR (CDCl3): 8.67 ppm (s, 1H), 7.93 ppm (s, 1H), 7.33 ppm (m, 1H), 6.93 ppm (t, 2H), 6.69 ppm (d, 1H, broad), 4.37 ppm (m, 1H), 1.25 ppm (d, 3H), 1.20 ppm (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:17][CH2:18][CH3:19])[C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][CH2:7]2.[N+:20](C)([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-:22])=[O:21])=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:17][CH2:18][CH3:19])[C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][CH2:7]2
Reactant: C[N+](=O)[O-]
Reactant: CCCN(C(=O)CC)C1CCc2cccc(Cl)c2C1
Product: CCCN(C(=O)CC)C1CCc2c([N+](=O)[O-])ccc(Cl)c2C1
Temperature: 0 °C
Yield: 31 %

Procedure:
To an ice-cold solution of compound 6(12.5 g, 44.5 mmol) in nitromethane (100 ml) was added (dropwise) "nitrating acid" (32.6 ml) (see synthesis of compound 3) until all starting material was consumed (monitored with gas chromatography after basification of analytical samples and extraction with Et2O). Ice-water/Et2O was added, shaken and extracted one additional time (Et2O). The combined organic extracts were dried (Na2SO4), filtered and the solvent was evaporated (12.5 g, 87%). The resulting residue was chromatographed using flash chromatography on a silica column, using petroleum ether/E2O (1:2) as eluant, yielding 4.5 g (31%) of 8-chloro-5-nitro-2-(N-n-propyl-N-propionylamino)tetralin (7a) and 3.5 g (24% of 8-chloro-7-nitro-2-(N-n-propyl-N-propionylamino)tetralin (7b). Unseparated material could be recycled in second chromatography.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:13])[CH2:10][CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH2:18])[C:15](=[CH2:17])[CH3:16].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[CH2:14]([NH:18][CH2:11][CH2:10][C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13])[C:15](=[CH2:16])[CH3:17]
Reactant: O=C(CCBr)NCc1ccccc1
Reactant: C=C(C)CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=C(C)CNCCC(=O)NCc1ccccc1
Yield: 17 %

Procedure:
N-Benzyl-3-bromopropanamide (6 g), methallylamine (1.9 g) and triethylamine (3.5 ml) in dimethylformamide (12 ml) were heated together under reflux for 21/4 hr, then poured into ethyl actate (100 ml). The organic phase was washed with water (2×100 ml), saturated brine (100 ml) and dried over magnesium sulphate. Removal of the solvent under reduced pressure gave a yellow oil which produced the title compound in 17% yield after column chromatography using ethyl acetate:ethanol (1:1) as eluent.
Reaction SMILES: Br[NH-].Br[CH2:4][C@@:5]([OH:22])([CH3:21])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1)=[O:7].C([O-])([O-])=O.[K+].[K+].[F:29][C:30]1[CH:37]=[C:36]([OH:38])[CH:35]=[CH:34][C:31]=1[C:32]#[N:33]>CC(C)=O.CC(O)C.O>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C@:5]([OH:22])([CH3:21])[CH2:4][O:38][C:36]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([F:29])[CH:37]=2)=[CH:10][C:11]=1[C:17]([F:20])([F:19])[F:18])#[N:16]
Reactant: C[C@](O)(CBr)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH-]Br
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: C[C@](O)(COc1ccc(C#N)c(F)c1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Yield: 23 %

Procedure:
A mixture of bromoamide ((2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide, R-19 (2.0 g, 5.70 mmol) and anhydrous K2CO3 (2.4 g, 17.1 mmol) in 50 mL of acetone was heated to reflux for 2 h and then concentrated under reduced pressure to give a solid. The resulting solid was treated with 2-fluoro-4-hydroxybenzonitrile (1.2 g, 8.5 mmol) and anhydrous K2CO3 (1.6 g, 11.4 mmol) in 50 mL of 2-propanol and was heated to reflux for 3 h, then concentrated under reduced pressure to give a solid. The residue was was treated with 100 mL of H2O and then extracted with EtOAc (2×100 mL). The combined EtOAc extracts were washed with 10% NaOH (4×100 mL) and brine, successively. The organic layer was dried over MgSO4 and then concentrated under reduced pressure to give an oil which was crystallized from CH2Cl2/hexane to give 0.5 g (23%) of (S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropanamide as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[CH2:7][C:6]=2[CH:12]=1.[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3([O:15][CH2:14][CH2:13][O:11]3)[CH2:7][C:6]=2[CH:12]=1
Reactant: OCCO
Reactant: O=C1COc2ccc(Br)cc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)CC1(CO2)OCCO1
Temperature: 100 °C
Yield: 94.7 %

Procedure:
To a solution of 6-bromo-2H-1-benzopyran-3(4H)-one (300 mg, 1.13 mmol) in toluene (2 mL) was added ethyleneglycol (163 mg 2.64 mmol) and para-toluenesulfonic acid (27 mg, 0.13 mmol). The reaction mixture was heated at 100° C. for 6 hrs. The reaction mixture was cooled and the solvent concentrated. The resultant residue was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried over Na2SO4 and concentrated under vacuum to give the title compound (290 mg, 79% yield) as a solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH2:36][CH3:37])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:38]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:38])=[O:26])=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH2:36][CH3:37])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: N
Reactant: CCc1ccccc1COc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(=O)OC
Solvent: CO
Product: CCc1ccccc1COc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O

Procedure:
In a similar manner as described for example A5, 1.0 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[(2-ethylbenzyl)oxy]thiophene-2-carboxylate and 60 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[CH2:3][C:4]#[N:5].[N+:7]([CH3:10])([O-:9])=[O:8].C1CCN2C(=NCCC2)CC1>ClCCl>[CH3:1][C:2]([CH3:6])([CH2:10][N+:7]([O-:9])=[O:8])[CH2:3][C:4]#[N:5]
Reactant: C=C(C)CC#N
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(CC#N)C[N+](=O)[O-]
Temperature: 103 °C
Yield: 93.6 %

Procedure:
In a one liter glass reactor equipped with a thermometer, a cooling apparatus and a stirrer, 3-methyl-3-butenenitrile (37.0 g, 0.456 mol) and nitromethane (557.0 g, 9.125 mol) were charged. Then, 1,8-diazabicyclo[5.4.0]-7-undecene (13.9 g, 0.091 mol) was dropwise added over a period of 5 minutes at room temperature while stirring. After the dropwise addition, the mixture was heated and refluxed at 103° C. for 13.5 hours. After cooling the mixture to room temperature, unreacted nitromethane was evaporated off under reduced pressure. To the residue, dichloromethane (300 g) and 5% sulfuric acid (300 g) were added and stirred. Thereafter, the mixture was phase separated to obtain a dichloromethane layer. To the aqueous layer, dichloromethane (300 g) was added and the mixture was phase separated to obtain a dichloromethane layer. Two dichloromethane layers were combined and washed with water (300 g). After drying the dichloromethane solution over anhydrous sodium sulfate, dichloromethane was evaporated off under reduced pressure to obtain brown crystal 3,3-dimethyl-4-nitrobutanenitrile (60.7 g), a purity of which was 92.0%. Its yield was 86.1% based on 3-methyl-3-butenenitrile.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:18](=O)[CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][OH:23].CO.C([BH3-])#N.[Na+]>C(Cl)Cl>[OH:23][CH2:22][CH2:21][NH:20][CH:18]1[C:13]2[C:14]3[C:15](=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:16][CH2:17]1
Reactant: O=C1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: NCCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCCNC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 13 h
Yield: 32 %

Procedure:
A portion (0.20 g) of the compound obtained in Example 41 and 2-aminoethanol (0.49 ml) were suspended in a mixed solvent of methanol (3 ml) and methylene chloride (2 ml) and to the suspension was added sodium cyanoborohydride (61 mg). The mixture was stirred for 13 hours at room temperature and heated to reflux for further 8 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, followed by extraction with three portions of methylene chloride. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride/methanol=19:1) and further crystallized from ether to yield 75 mg (32%) of the titled compound as yellowish brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:24]=1)=[O:4].[H][H]>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:24]=1)=[O:4]
Reactant: COC(=O)Nc1cn2cc(Sc3ccc([N+](=O)[O-])cc3)ccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)Nc1cn2cc(Sc3ccc(N)cc3)ccc2n1

Procedure:
A suspension of 0.130 gms. of 2-(methoxycarbonylamino) 6-(p-nitrophenylthio) imidazo [1,2-a] pyridine in 30 ml. of glacial acetic acid is reduced at 40 psi. of hydrogen with 0.130 gm. of 5% palladium on carbon. When the uptake of hydrogen is complete, the catalyst is removed by filtration and the filtrate is evaporated to dryness in vacuo. The residue is stirred with saturated qqueous sodium bicarbonate and the resultant solids are collected by filtration, washed with water and dried in vacuo. The product melts 120°-175° C. Mass spectral data confirms the molecular ion of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27][C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36](O)[CH2:37][CH2:38][CH2:39][CH2:40]C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:27][CH2:25][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CCCCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCOC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Yield: 77.9 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-hexanol (24 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (54 mg, yield 68%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][CH2:13][O-:14].[Na+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:14][CH2:13][CH3:12])[CH:3]=1
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(Br)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (3 g, 13.6 mmol) and EtOH (50 mL) was added NaOEt (21% w/w, 50 mL). The mixture stirred for 2 h before concentrating in vacuo. The residue purified by flash chromatography (0-100% EtoAc/Hexane) to afford 62A (3 g, 90%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (t, 3 H) 4.19 (q, 2 H) 7.22 (dd, 2 H) 7.71-7.81 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[N:12][OH:13])=[CH:7][CH:6]=1)=[O:4].[CH2:15]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>O1CCCC1.ClCCl>[CH2:15]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:28]=2)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1
Reactant: C#Cc1ccc(OCCCCC)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)no2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of 4-Methoxycarbonylphenylhydroxyiminomethyl chloride (16.98 g) and 4-n-pentyloxyphenylacetylene (18.96 g) in tetrahydrofuran (170 ml) was added triethylamine (14.4 ml) in tetrahydrofuran (140 ml) over a period of 2 hours at 40° C. and the mixture was stirred at 40° C. for 30 minutes. The mixture was diluted with dichloromethane and washed with water and brine. The separated organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with acetonitrile. The precipitate was collected by filtration and dried to give Methyl 4-[5-(4-n-pentyloxyphenyl)isoxazol-3-yl]benzoate (24.56 g).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([OH:15])[C:7]=1[CH2:16][CH2:17][CH3:18])=[O:4].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[C:12]([C:9]1[C:8]([O:15][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:7]([CH2:16][CH2:17][CH3:18])[C:6]([S:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:19])=[CH:11][CH:10]=1)(=[O:14])[CH3:13]
Reactant: CCCc1c(SC(=O)N(C)C)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(SC(=O)N(C)C)ccc(C(C)=O)c1OCCCC(=O)OCC
Reaction time: 9 h
Yield: 84.2 %

Procedure:
A mixture of (4-(N,N-dimethylcarbamoylthio)-2-hydroxy-3-propylphenyl)ethanone (26.6 g), ethyl 4-bromobutyrate (92.9 g), potassium iodide (1 g) and potassium carbonate (26.1 g) in acetone (200 ml) was heated and refluxed with stirring. Each of potassium carbonate (13 g) was added thereto after 9 hours and 14 hours, and the mixture was heated and refluxed with stirring for total 29 hours. Then, inorganic materials were separated and the solution was concentrated under a reduced pressure. The resultant residue was purified through silica-gel column chromatography (eluting with hexane, then benzene and finally benzene:ethyl acetate=9:1) to give ethyl 4-(6-acetyl-3-(N,N-dimethylcarbamoylthio) -2-propylphenoxy)butyrate (31.5 g, 84.2%) as light brown crystal, mp 60-63° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:12])[CH:8]=[C:9]([CH3:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:11][C:9]1([CH3:10])[O:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:12])[CH2:8]1
Reactant: CC(C)=CC(=O)c1sccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2sccc2O1

Procedure:
A solution of 3-hydroxy-2-(3-methyl-1-oxo-2-buten-1-yl) thiophene (39.0 g, 0.214 mol) and p-toluenesulfonic acid (3.5 g, 18 mmol) in toluene (400 mL) was heated to reflux for 3.5 d. The resultant solution was washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. The solvent was evaporated in vacuo to give a brown oil, 38.62 g (99%). A portion of the resultant oil was purified for analysis by distillation in a Kugelrohr oven at 145° to 155° C. at 0.35 mm Hg to give the product as an amber oil: IR (neat): 2979, 1664, 1530 and 1442 cm-1 ; MS: m/z 183 (MH+); 1H NMR (CDCl3): δ1.51(s, 6H); 2.67(s, 2H); 6.67(d, J=5.4 Hz, 1H) and 7.60(d, J=5.4 Hz, 1H).