Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20](OC)=[O:21].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:21]
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C)c2ccc(Oc3ccccc3)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Oc3ccccc3)ccc12
Temperature: 110 °C

Procedure:
A pressure glass reaction flask which included top threads for a screw cap lid can be fitted with a magnetic stirrer, charged with 2e, glycine (about 3 molar equivalents), methanol, and a sodium methoxide solution (with 1.2 molar eqivalents NaOCH3) and sealed. The reaction can then be heated to 110° C. for at least 6 h during which time the reaction forms a yellow suspension. The reaction can then be cooled to 20-25° C. and evaluated by HPLC. The reaction can be continued until less than 1% 2e remains as determined by HPLC, filtered, washed with methanol, dried under vacuum, dissolved in water and extracted with ethyl acetate to remove impurities to below 0.1%. The ethyl acetate can be removed and an acetic acid solution (with 3 molar eqivalents acetic acid) can be added over one hour. The suspension can be stirred at room temperature for at least 3 hours, filtered, and the solid washed with water (3×), cold acetone (5-10° C., 2×) and evaluated for impurities by HPLC. If acetone removable impurities are present, the flask can be charged with acetone and refluxed for at least 8 h, slowly cooled to 5-10° C., stirred for at least 2-3 h, filtered, washed with cold acetone (5-10° C., 3×) and dried under vacuum to obtain 2-(4-hydroxy-1-methyl-6-phenoxyisoquinoline-3-carboxamido)acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:38][C:39]1[C:44]([F:45])=[C:43]([F:46])[CH:42]=[CH:41][C:40]=1B(O)O.[F-].[Cs+]>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(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:18][CH:19]=1)=[O:29])=[C:8]([C:42]1[CH:41]=[CH:40][C:39]([F:38])=[C:44]([F:45])[C:43]=1[F:46])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1ccc(F)c(F)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)c(F)c3F)ccc2c1
Temperature: 80 °C

Procedure:
Charge a round bottom flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.13 g, 4.0 mmol), 2,3,4-trifluorophenyl boronic acid (1.0 g, 5.7 mmol), trans-dichlorobis(triphenylphosphine)palladium II, (561 mg, 0.8 mmol) and cesium fluoride (5.5 g, 36 mmol) and add 50 mL of acetonitrile. Heat the mixture at 80° C. for 4 hours. Cool and filter the mixture and purify on an SCX column, eluting with 2N ammonia/methanol. Purify further on a silica column eluting with 2% 2N ammonia/methanol/methylene chloride. The yield is 880 mg (43%): 1H-NMR (CD3OD, 400 MHz) δ7.93 (d, J=8.8 Hz, 1H); 7.50 (d, J=8.4 Hz, 3H); 7.39 (d, J=8.8 Hz, 1H); 7.35 (d, J=2.4 Hz, 1H); 7.07 (dd, J=9.2, 2.8 Hz, 1H); 6.96-6.87 (m, 2H); 6.80 (d, J=9.6 Hz, 2H); 4.10-4.07 (t, 2H); 3.91 (s, 3H); 2.72-2.69 (t, 2H); 2.48-2.48 (m, 4H); 1.61-1.55 (m, 4H); 1.46-1.43 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(CBr)cc1
Yield: 65.1 %

Procedure:
39.7 g (287 mmmol) of p-toluylic acid, 51.2 g (287 mmmol) of N-bromosuccinimide and 2.8 g (11.5 mmol) of dibenzoyl peroxide were suspended in 350 ml of carbon tetrachloride. Then, the resultant mixture was heated with vigorously stirring to perform a reaction under reflux for 2 hours. After completion of the reaction, the reaction mixture was cooled in ice bath. The deposited crystalline product was collected by filtration, which was then washed with hexane and water, followed by drying. The resultant crystalline product was recrystallized from ethanol to obtain 40.3 g of 4-bromomethylbenzoic acid as a white needle crystal (isolated yield: 65%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(C=O)cn1
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C=C2N=C(c3cccs3)OC2=O)cn1
Temperature: 90 °C
Yield: 65.2 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 6-methoxy-3-pyridinecarboxaldehyde (45 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 56 mg of the above-captioned compound.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13])=[CH:3][Cl:4].[CH3:16][N:17]=[C:18]=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:18]([NH:17][CH3:16])=[O:19])(=[O:13])=[O:14])=[CH:3][Cl:4]
Reactant: CN=C=O
Reactant: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)NS(=O)(=O)c1ccccc1OC(Cl)=CCl

Procedure:
A suspension of 6.7 g of 2-(1,2-dichlorovinyloxy)phenylsulfonamide in 50 ml of methylene chloride is treated with 1.9 g of methyl isocyanate. 3.3 g of triethylamine are added dropwise to this mixture at a temperature of 20°-25° C. within 10 minutes resulting in a clear solution. The solution is stirred for a further hour and evaporated to dryness. The residue is solved in 5% aqueous sodium carbonate and acidified with a 10% solution of hydrochloric acid yielding 7.8 g of N-[2-(1,2-dichlorovinyloxy)-phenylsulfonyl]-N'-methyl urea, m.p. 225°-226° C.
Reaction SMILES: CNN.[Si:4]([O:11][CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[O:27][N:28]1C(=O)C2=CC=CC=C2C1=O)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]>C(Cl)Cl>[NH2:28][O:27][C@@H:14]1[C@@H:13]([CH2:12][O:11][Si:4]([C:7]([CH3:10])([CH3:8])[CH3:9])([CH3:5])[CH3:6])[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15]1
Reactant: Cc1cn([C@H]2C[C@H](ON3C(=O)c4ccccc4C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: CNN
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](ON)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Cold methylhydrazine (1.6 ml, 30 mmol) was added to a stirred solution of 5'-O-(t-butyldimethylsilyl)-3'-O-phthalimidothymidine (2, 4.6 g, 9.18 mmol) in dry CH2Cl2 (60 ml) at 5°-10° C. After 10 minutes white precipitation of 1,2-dihydro-4-hydroxy-2-methyl-1-oxophthalizine occured. The suspension was stirred at room temperature for 1 h. The suspension was filtered and precipitate washed with CH2Cl2 (2×20 ml). The combined filtrates were concentrated and the residue purified by silica gel column chromatography. Elution with CH2Cl2 :MeOH (100:0→97:3, v/v) furnished the title compound (3.40 g, 100%) as white solid. Crystallization from CH2Cl2 gave white needles, m.p. 171° C.; 1H NMR (CDCl3) δ0.05 [s, 6, (CH3)2 ], 0.90 [s, 9, (CH3)3 ], 2.22-2.58 (2 m, 2, 2'CH2), 3.9-4.08 (m, 3, 5'CH2, and 3'H) 4.30 (m, 1, 4'H) 5.5 (br s, 2, NH2) 6.2 (m, 1, 1'H) 7.45 (s, 1, C6H) 8.9 (br s, 1, NH). Anal. Calcd. for C16H29N3O5Si: C, 51.72; H, 7.87; N, 11.32. found: C, 51.87, H. 7.81; N, 11.32.
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[C:7]([Cl:13])[CH:6]=1>O.CS(C)=O>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[C:7]([Cl:13])[CH:6]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(Br)cc1Cl
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Potassium cyanide (587 g) was dissolved in a mixed solution of water (1408 mL) and dimethyl sulfoxide (767 g), and a solution of 4-bromo-2-chlorobenzyl bromide (512 g) of Reference Example 13 in dimethylsulfoxide (1663 g) was added dropwise at an inside temperature of 90° C. After stirring at the same temperature for 1 hr, the reaction mixture was poured into water. After partitioning and extraction with ethyl acetate, the organic layer was washed 4 times with 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (383 g) as a brown oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@@H:22]([O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reaction time: 0.5 h

Procedure:
16.91 ml of triethylamine and 9.36 ml of methanesulfonyl chloride were added, in that order, whilst ice-cooling, to a solution of 25 g of (3R)-1-t-butoxycarbonyl-3-hydroxypyrrolidine dissolved in 250 ml of dry tetrahydrofuran, and the mixture was stirred at 0° to 5° C. for 30 minutes and then at 15° C. for 30 minutes. At the end of this time, the mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 3.10 g of the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].[CH2:12](Br)[C:13]#[CH:14].O>O1CCCC1>[CH2:14]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7])[C:13]#[CH:12]
Reactant: COC(=O)c1ccc[nH]1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCn1cccc1C(=O)OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
3.302 g of methyl 1H-pyrrole-2-carboxylate were dissolved in 40 ml of tetrahydrofuran and then, at 0° C., 1.422 g of sodium hydride in suspension at 50% in vaseline oil were added. The mixture stirred for 1 hour at 20° C. and a solution of 2 ml of propargyl bromide in 10 ml of tetrahydrofuran was introduced dropwise. The mixture was stirred for 1 hour at 50° C. and after having added 5 ml of propargyl bromide, the reaction mixture was poured into water. The mixture was extracted with methylene chloride and the extracts were concentrated to dryness by distilling under reduced pressure. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (9-1) to obtain 2.993 g of methyl 1-(2-propynyl)-1H-pyrrol-2-carboxylate.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].O1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:3]1([C:2]2[NH:9][CH:15]=[C:16]([C:17]3[CH:18]=[CH:5][C:4]4[C:16](=[CH:17][CH:18]=[CH:2][CH:3]=4)[CH:15]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccccc1
Reactant: C1CCOC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: c1ccc(-c2nc(-c3ccc4ccccc4c3)c[nH]2)cc1

Procedure:
Benzamidine hydrochloride and an equimolar amount of sodium methylate were heated under reflux in tetrahydrofuran for 1 hour. After cooling, a tetrahydrofuran solution of an equimolar amount of ω-bromo-2-acetonaphthone was added dropwise thereto so that the temperature did not exceed 30° C., and then an equimolar amount of sodium methylate was further added, followed by heating under reflux for 1 hour. After removal of the solvent by distillation under reduced pressure, the residue was washed with water and subjected to recrystallization from acetonitrile to obtain grayish blue crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=[O:4].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][NH2:19].O>C(O)(=O)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][N:19]=[C:3]([OH:4])/[C:2](/[Cl:1])=[CH:7]\[C:6]([OH:5])=[O:8]
Reactant: COc1ccccc1CCN
Reactant: O=C1C=C(Cl)C(=O)O1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1CCN=C(O)/C(Cl)=C\C(=O)O
Yield: 73.3 %

Procedure:
13.25 g (0.1 mol) of chloromaleic anhydride and 15.2 g (0.1 mol) of 2-(2-methoxyphenyl)-ethylamine are heated to the boiling point in 100 ml of glacial acetic acid for 4 hours. 100 ml of water are then added and the oil which has precipitated is extracted with methylene chloride. The methylene chloride phase is separated off, washed with water, dried and evaporated. The oil which remains crystallizes. 20.8 g (78% of theory) of chloromaleic acid N-[2-(2-methoxyphenyl)-ethyl]-imide are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH2:10][O:11][CH3:12])[CH:3]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:42]([O:46][CH2:47][CH3:48])(=[O:45])[CH:43]=[CH2:44]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][O:11][CH2:10][O:9][CH2:8][C:4]1[CH:3]=[C:2](/[CH:44]=[CH:43]/[C:42]([O:46][CH2:47][CH3:48])=[O:45])[CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(=O)OCC
Reactant: COCOCc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cccc(COCOC)c1

Procedure:
Under a nitrogen atmosphere, a crude product of 1-bromo-3-((methoxymethoxy)methyl)benzene (3.60 g), triethylamine (6.50 mL), palladium acetate (175 mg), tri-o-tolylphosphine (711 mg) and ethyl acrylate (8.4 mL) were stirred in DMF (30 mL) at 110° C. for 1 hr. The solvent of the reaction mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (3.41 g) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.C(O)C.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCOCC>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: C1CNCCN1
Solvent: CCO
Solvent: CCOCC
Product: Fc1ccc(CN2CCNCC2)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
A solution of 29 g of p-fluorobenzyl chloride in 50 g of reagent ethanol was added dropwise to a stirred solution of 34.5 g of piperazine in 150 g of reagent ethanol. A cold water bath was used to maintain the reaction temperature at 20° C. during the addition. The reaction mixture was stirred for an additional 11/2 hours and then added to 2 liters of ether. Precipitated piperazine hydrochloride was filtered off. The filtrate was concentrated to an oil, which was chromatographed on a silica column, the eluant being a mixture of CH2Cl2 /methanol/ammonium hydroxide in the ratio of 45:5:1. After concentration of appropriate fractions, 21.7 g of 1-(4-fluorobenzyl)piperazine were isolated as a colorless liquid (56% of theory).
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][S:10][CH2:11][N:5]2[CH2:4]1.[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([OH:40])=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][C:25]=1[Cl:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:40][CH2:2][CH:3]4[O:8][CH2:7][C@@H:6]5[CH2:9][S:10][CH2:11][N:5]5[CH2:4]4)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Reactant: ClCC1CN2CSC[C@H]2CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CN2CSC[C@H]2CO1
Yield: 9.6 %

Procedure:
A solution of (8aR)-6-(chloromethyl)tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazine (11.6 mg, 0.0599 mmol), 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetate (salt) (30.0 mg, 0.0644 mmol), and potassium carbonate (45.0 mg, 0.326 mmol) in N,N-dimethylacetamide (1.0 mL) was heated in a sealed tube to 150° C. for 12 h. The crude reaction mixture was directly purified via reverse-phase preparative HPLC (acetonitrile/water/0.1%-TFA). Lyophillization of the pure fractions yielded 3.5 mg (8.9%) of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(8aR)-tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazin-6-ylmethyl]oxy} quinazolin-4-amine trifluoroacetate. 1H NMR (400 MHz, d6-DMSO): 8.80 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.74 (s, 2H), 7.29 (s, 1H), 4.29 (d, 2H), 4.11 (m, 2H), 4.00 (s, 3H), 3.96 (m, 1H), 2.99 (m, 2H), 2.56 (t, 1H), 2.367 (m, 1H); MS (EI) for C22H22N4O3SCl2: 492 (MH+).
Reaction SMILES: Cl[CH:2]=[C:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].C[Si]([C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)(C)C>C1(C)C=CC=CC=1>[N:23]1([CH:2]=[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:24]=[CH:25][N:26]=[CH:22]1
Reactant: C[Si](C)(C)c1ncc[nH]1
Reactant: CC(C)(C)C(=O)C(=CCl)Oc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)C(=Cn1ccnc1)Oc1ccc(Cl)cc1
Yield: 59.1 %

Procedure:
13 g (0.05 mols) of 1-chloro-2-(4-chlorophenoxy)-4,4-dimethyl-1-penten-3-one and 7 g (0.05 mole) of trimethylsilylimidazole in 50 ml of toluene were heated under reflux for 5 hours. Thereafter, the reaction mixture was concentrated by distilling off the solvent in vacuo and the oily residue was separated by column chromatography (silica gel; ethyl acetate: chloroform=1:2). 9 g (58% of theory) of 1-(imidazol-1-yl)-2-(4-chlorophenoxy)-4,4-dimethyl-1-penten-3-one of melting point 94°-95° C. were obtained. ##STR54##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:13][Mg]I.S(=O)(=O)(O)O>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([CH3:13])([OH:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(=O)CCc1ccc(F)cc1
Reactant: C[Mg]I
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)(O)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.7 %

Procedure:
4-(4-Fluorophenyl)-2-butanone (10.0 g) in ether (30 ml) was added over 20 min. to a stirred solution of methyl magnesium iodide (0.086 mole) in ether (80 ml). The mixture was stirred at room temperature over 5 hr, then cooled and 2 M sulphuric acid (30 ml) added. The mixture was extracted with ether (5×50 ml), washed with saturated sodium bicarbonate solution, saturated brine and dried (MgSO4). The solvent was removed and the residue was distilled. The alcohol (9.4 g) b.p. 83°-85°/0.1 mm was obtained as a colourless liquid.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23](I)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH2:29]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1[CH:36]=[O:37])[CH3:30]>C(Cl)Cl.C(OCC)C.ClCl>[CH2:29]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1[CH:36]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[OH:37])[CH3:30]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCc1sccc1C=O
Agent: C[Mg+]
Agent: ClCl
Agent: [Br-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1sccc1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 3 h

Procedure:
To a solution of N-trityl-4-iodo-imidazole (4.1 g, 0.0095 mol) in dry CH2Cl2 (75 mL) was added a solution of MeMgBr (4.0 mL, 3.0M) in diethyl ether and the solution was stirred for 3 hrs. Then a solution of 2-ethylthiophene-3-carboxaldehyde, B7, (1.66 g, 0.0087 mol) in CH2 Cl2 (20 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous NH4Cl and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with a second portion of CH2Cl2. The extracts were combined and washed with a small portion of water, dried (Na2 SO4), and filtered. The solvent was evaporated in vacuo, and the residue was triturated with Et2O to give (2-ethylthien-3-yl)-1-trityl-imidazol-4-yl-methanol, C7, as a beige solid which was taken on to the next step directly. ##STR56##
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][CH2:2][CH2:3][S:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCSc1ccc(CCC(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCc1ccc(SCCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-[4-(2-aminoethylthio)phenyl]propionic acid (0.8 g), triethylamine (1.6 ml) and methylene chloride (50 ml) was added 4-chlorophenylsulfonyl chloride (0.79 g), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed successively with 3% hydrochloric acid and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave a residue, which was then crystallized from ethyl acetate - n-hexane to give 3-{4-[2-(4-chlorophenylsulfonylamino)ethylthio]phenyl}propionic acid (Compound No. 52) (1.07 g).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:16](O)=O)#[N:12].N>>[F:22][C:20]1[CH:21]=[C:13]([CH:14]=[C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:19]=1)[C:11]#[N:12]
Reactant: NC(=NO)c1cccnc1
Reactant: N#Cc1cc(F)cc(C(=O)O)c1
Agent: N
Product: N#Cc1cc(F)cc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-cyano-5-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.65 (ddd, J=8.0, 5.1, 0.8 Hz, 1H), 7.95 (ddd, J=8.1, 2.6, 1.6 Hz, 1H), 8.32 (ddd, J=8.7, 2.6, 1.4 Hz, 1H), 8.46 (t, J=1.4 Hz, 1H), 8.58 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 8.76 (dd, J=5.2, 1.6 Hz, 1H), 9.31 (dd, J=2.0, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 267 (M+H)+.