Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][NH:3][C:4]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])=[S:5].[CH3:17]O>>[ClH:1].[ClH:1].[CH3:2][NH:3][C:4](=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])[S:5][CH3:17]
Reactant: CO
Reactant: CNC(=S)NCCSCc1[nH]cnc1C
Agent: Cl
Product: CNC(=NCCSCc1[nH]cnc1C)SC

Procedure:
Dry hydrogen chloride gas was passed into a solution of N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl] thiourea (73.2 g) in methanol (600 ml) and the mixture was refluxed for 5 hours. Concentration and re-evaporation with isopropyl alcohol afforded a crystalline solid which was recrystallised from isopropyl alcohol-ether to give N,S-dimethyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]isothiourea dihydrochloride (96.2 g) m.p. 191°-192° (isopropyl alcohol-ether).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[C:4]([OH:24])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH:7]=1)[CH3:5].C(=O)(O)[O-].[Na+].[CH3:32][C:33]([CH3:35])=[O:34]>S(=O)(=O)(O)O>[CH3:32][C:33]1([CH3:35])[O:24][C:4]([CH3:5])([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)[CH:7]=2)[CH:3]([O:2][CH3:1])[O:34]1
Reactant: COC(OC)C(C)(O)c1cccc(OCc2ccc3ccccc3c2)c1
Reactant: CC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC1OC(C)(C)OC1(C)c1cccc(OCc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
Concentrated sulphuric acid (5 drops) was added to a solution of 2-hydroxy-2-[3-(naphth-2-ylmethoxy)phenyl]propionaldehyde dimethyl acetal (1.5 g) in acetone (30 ml) and the mixture was stirred at ambient temperature for 5 hours. A saturated aqueous sodium bicarbonate solution (30 ml) was added and the bulk of the acetone was evaporated. The residue was partitioned between diethyl ether and water. The organic phase was washed with water and with a saturated sodium chloride solution, dried (MgSO4) and evaporated. The residue, comprising a mixture of diastereoisomers, was purified by column chromatography using increasingly polar mixtures of petroleum ether (b.p. 40°-60° C.) and methylene chloride as eluent. There was thus obtained the less polar diastereoisomer, (4SR,5RS)-2,2,4-trimethyl-5-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]-1,3-dioxolane (0.39 g, 31%), m.p. 100°-103° C.; the 4-methyl and 5-methoxy groups being in a cis-relationship.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[S:29]
Reactant: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1oncc1C(=S)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A solution of 24 grams of 5-methyl-4-(4-trifluoromethylphenyl)aminocarbonylisoxazole and 39 grams of Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] in 400 ml of toluene was refluxed for three hours. Upon cooling of mixture to room temperature, all the solid was filtered off and the filtrate was concentrated. The resulting crude product from the filtrate was then purified on a silica gel column with 3% methanol in dichloromethane to yield 16.5 grams of 5-methyl-4-(4-trifluoromethylphenyl)aminothiocarbonylisoxazole.
Reaction SMILES: [C:1]1([C:7]2([OH:12])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[C:55]([C:56](O)=[O:57])=[CH:54][O:53][N:52]=2)=[CH:47][CH:46]=1>CN(C=O)C>[CH3:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]2[C:55]([C:56]([N:9]3[CH2:10][CH2:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([OH:12])[CH2:8]3)=[O:57])=[CH:54][O:53][N:52]=2)=[CH:49][CH:50]=1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: OC1(c2ccccc2)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
A solution of 3-phenylpyrrolidin-3-ol (8 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0,079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z Calcd for C21H20N2O3: 348.1474, found 348.1465.
Reaction SMILES: Br.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:17]=[C:18]([NH:21][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[S:19][CH:20]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc(-c2ccccc2OCc2ccccc2)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3OCc3ccccc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
A mixture of 0.5 g of 4-(2-benzyloxy-phenyl)-thiazol-2-ylamine hydrobromide with 0.29 g of p-toluenesulfonyl chloride was stirred for 2 hours with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. After neutralization with concentrated hydrochloric acid the mixture was concentrated and the aqueous residue was extracted twice with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and freed from solvent. The residue was chromatographed on 60 g of Kieselgel 60 with ethyl acetate/hexane (1:2) as the eluent. The product-containing fractions were concentrated and yielded 0.28 g of N-[4-(2-benzyloxy-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as a colorless, amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:17])[N:6]([CH2:13][C:14]([OH:16])=[O:15])[C:7]2=[O:12].[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:15][C:14](=[O:16])[CH2:13][N:6]1[C:5](=[O:17])[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[C:7]1=[O:12]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1cccc2c1C(=O)N(CC(=O)O)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cccc2c1C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Yield: 41.4 %

Procedure:
To a solution of 2-(4-methoxy-1,3-dioxoisoindolin-2-yl)acetic acid (30 mg, 0.128 mmol) in DCM (3 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (53.6 mg, 0.128 mmol), EDC (73.4 mg, 0.383 mmol) and DMAP (15.58 mg, 0.128 mmol) were added, and the mixture was reacted overnight at room temperature. The solvent was removed, and the resulting crude was purified by flash chromatography on silica gel (DCM:MeOH=98:2) recovering the title compound (33.7 mg, 0.053 mmol, 41% yield). MS/ESI+ 637.34 [MH]+; [αD]=−12.96, c=0.25 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.85 (dd, 1H), 7.54 (d, 1H), 7.46 (dd, 1H), 7.18 (d, 1H), 7.06 (d, 1H), 6.95 (dd, 1H), 7.08 (t, 1H), 5.99 (dd, 1H), 4.36 (s, 2H), 3.99 (s, 3H), 3.94 (dd, 1H), 3.90 (dd, 1H), 3.38 (dd, 1H), 3.22 (dd, 1H), 1.07-1.36 (m, 1H), 0.50-0.68 (m, 2H), 0.24-0.45 (m, 2H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[F:19][C:20]1([F:27])[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1>C1COCC1>[F:19][C:20]1([F:27])[CH2:25][CH2:24][C:23](=[CH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:22][CH2:21]1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=C1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (0.298 g, 7.46 mmol) in THF (10 mL) was cooled to 0° C. tert-Butyl diethylphosphonoacetate (1.751 mL, 7.46 mmol) diluted with THF (10 mL) was added dropwise. The reaction mixture was removed from the cooling bath and stirred at room temperature for 30 min. The reaction mixture was then cooled to 0° C. and 4,4-difluorocyclohexanone (1 g, 7.46 mmol) diluted with THF (2 mL) was added. The reaction mixture was stirred at room temperature under nitrogen over night. The reaction was quenched with sat NH4Cl (50 mL). The aqueous phase was extracted with diethyl ether (3×25 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 50% solvent A/B=hexanes/EtOAc, REDISEP® SiO2 40 g). Concentration of the appropriate fractions provided Intermediate S-3A (1.43 g, 83%). 1H NMR (400 MHz, chloroform-d) δ 5.68 (s, 1H), 3.02 (td, J=6.7, 0.9 Hz, 2H), 2.43-2.36 (m, 2H), 2.12-1.97 (m, 4H), 1.51 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH2:14][F:15])([CH2:12][F:13])[CH2:8][C@@H:7]2O.N12CCCN=C1CCCCC2.C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:42]([C@H:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[O:10][C:9]([CH2:14][F:15])([CH2:12][F:13])[CH2:8]1)=[N+:43]=[N-:44]
Reactant: O[C@H]1CC(CF)(CF)Oc2c(Cl)cccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H]1CC(CF)(CF)Oc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of Example 2B (7.75 g, 31.2 mmol) and THF (116 mL) was cooled to <5° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (7.91 mL, 53.0 mmol) and diphenylphosphoryl azide (10.09 mL, 46.8 mmol) were added. The yellow slurry was warmed slowly to ambient temperature, becoming a brown solution. After 14 hours, the mixture was concentrated, diluted with MTBE (200 mL), and washed with 2N NaOH (50 mL×2), brine (50 mL), 2N HCl (50 mL×2), and brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to give the title compound. This material was used without further purification in the next step.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)C.Cl>CC(C)=O.C(Cl)Cl>[CH:4]([C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)=[O:3]
Reactant: CCOC(OCC)c1nc(C(=O)OC)cs1
Agent: Cl
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)c1csc(C=O)n1
Reaction time: 2 h
Yield: 67.2 %

Procedure:
Thiazole-4-carboxylate 3 (30 g, 122 mmol) was dissolved in 300 mL of acetone, to which was added aqueous HCl (21 mL, 2M). After keeping the reaction mixture at RT for overnight, the reaction mixture was heated up and kept at 60° C. for 2 h. The reaction mixture was then cooled and evaporated under vacuum to give a residue which was taken up in 200 mL of DCM. DCM solution was then washed with saturated NaHCO3 solution and then brine and dried over anhydrous Na2SO4. DCM solution was filtered and concentrated under vacuum to give the concentrated solution which was triturated by ether to give methyl 2-formylthiazole-4-carboxylate 4 (14 g, 82 mmol, 54% for two steps) as a white solid. 1HNMR (400 MHz, CDCl3) δ 133-8-p110.16 (d, J=1.3 Hz, 1H), 8.53 (d, J=1.3 Hz, 1H), 4.01 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[N:10]=[CH:9][NH:8][C:7]2=O)[CH3:2].O=P(Cl)(Cl)[Cl:20]>C1(C)C=CC=CC=1>[Cl:20][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH2:15][CH3:16])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: CCOc1cc2nc[nH]c(=O)c2cc1OCC
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1cc2ncnc(Cl)c2cc1OCC
Temperature: 120 °C
Yield: 98 %

Procedure:
According to the procedure described in Example 6A Step 5, a mixture of 6,7-diethoxyquinazolin-4(3H)-one (1.70 g, 7.3 mmol) and POCl3 (3 mL) in toluene (10 mL) was heated at 120° C. for 5 hours to afford 4-chloro-6,7-diethoxyquinazoline as a solid (1.794 g, 98%). 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 1H), 7.45 (s, 1H), 7.39 (s, 1H), 4.31 (m, 4H), 1.58 (m, 6H); LC-MS (ESI) m/z 253 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]#[N:11]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: N#CCCc1ccccc1F
Solvent: C1CCOC1
Product: NCCCc1ccccc1F
Temperature: -15 °C
Yield: 38.7 %

Procedure:
A solution of 3-(2-fluorophenyl) propionitrile (9.11 g) in tetrahydrofuran (200 mL) was heated to reflux and treated with borane-methyl sulfide complex (6 mL of ˜10 M, 60 mmol). Approximately half of the volume of the reaction was then distilled off. The mixture was then cooled in a −15° C. bath and treated dropwise with ice water (100 mL). The mixture was then concentrated to a solid. The solid was then dissolved in water (100 mL) and treated with concentrated (12 N)HCl (50 mL). The mixture was heated at reflux for 1 h, cooled to ambient temperature, and equilibrated with diethyl ether (100 mL). The organic solution was removed and the resulting aqueous mixture, cooled by the addition of ice, and then basified (pH>10) by treatment with 10 N NaOH (70 mL). The resulting solution was extracted with diethyl ether (100 mL). The diethyl ether extract was removed, dried over anhydrous MgSO4, filtered and concentrated to afford 3-(2-fluorophenyl)propylamine (3.62 g (41% from 2-fluorobenzaldehyde)). GC/MS gave: m/z (rel.int.) 153 (M+, 10), 136 (100), 109 (50), and 83 (22).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH:4]([CH:1]1[CH2:3][CH2:2]1)[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)CC1CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(=O)C(Br)C1CC1

Procedure:
To a solution of ethyl 3-cyclopropyl-2-oxopropanoate (4.75 g, 30.44 mmol) in CCl4 (60 mL) at rt was added NBS (5.96 g 33.49 mmol). The resulting mixture was heated at reflux overnight, then cooled, filtered, and evaporated to provide ethyl 3-bromo-3-cyclopropyl-2-oxopropanoate; 1H NMR (CDCl3): δ 4.46-4.32 (3H, m), 1.41 (3H, t, J=8 Hz), 0.96-0.86 (1H, m), 0.55-0.50 (2H, m), 0.07-0.03 (2H, m). This compound was used without purification for the preparation of compounds of the invention such as 1-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(1-piperidinyl)-5-cyclopropyl-1H-imidazole-4-carboxamide hydrochloride (Table entry 22). In a similar manner, ethyl 3-bromo-3-cyclobutyl-2-oxopropanoate and ethyl 3-bromo-3-isobutyl-2-oxopropanoate were prepared.
Reaction SMILES: [C:1]([S:5][CH:6]1[N:9]([CH2:10][C:11](=[O:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8](=[O:21])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:30])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[C:1]([S:5]([CH:6]1[N:9]([CH2:10][C:11](=[O:20])[CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8](=[O:21])[CH2:7]1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)SC1CC(=O)N1CC(=O)CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)S(=O)C1CC(=O)N1CC(=O)CCc1ccccc1
Temperature: -50 °C
Reaction time: 3 h

Procedure:
4-tert-Butylthio-1-(4-phenyl-2-oxobutyl)azetidin-2-one (0.6 g, 2 mmol) was dissolved in dry dichloromethane (30 ml) and the solution cooled to -50° C. A solution of m-CPBA (0.32 g, 2 mmol) in dry dichloromethane (20 ml) was added dropwise and the resulting mixture stirred for an additional 3 h. The mixture was poured into an aqueous solution of sodium hydrogen carbonate and sodium sulphite. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with sodium hydrogen carbonate solution, dried (MgSO4) and evaporated to give a solid which was purified by flash hromatography using ethyl acetate/ether and ethyl acetate as the eluting solvents. Evaporation of the appropriate fractions gave the title compound as a colourless solid, 0.3 g, 48%, m.p. 79-81° C.
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][CH2:8][CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)(C)(C)C.Cl>O1CCOCC1>[CH2:23]([O:22][C:20](=[O:21])[NH:19][CH:9]([CH2:8][NH:7][C:6](=[O:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(OCC(CNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc(OCC(CNC(=O)c2ccccc2)NC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 180.1 %

Procedure:
To (2-benzyloxycarbonylamino-3-m-tolyloxypropyl)carbamic acid tert-butyl ester (220 mg) obtained in Step 2 was added 4N solution (2 ml) of hydrogen chloride in dioxane, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated, dichloromethane (7 ml), benzoyl chloride (96 μl) and triethylamine (265 μl) were added to the obtained solid, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and, after washing with water, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane) to give [1-(benzoylaminomethyl)-2-m-tolyloxyethyl]carbamic acid benzyl ester (200 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].F[C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:26])[NH:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[N:16]2)=[C:11]([O:27][CH3:28])[CH:10]=1>CS(C)=O.CCOCC>[CH3:28][O:27][C:11]1[CH:10]=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:18]=[C:17]2[C:12]=1[C:13](=[O:26])[NH:14][C:15]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1)=[N:16]2
Reactant: COCCO
Reactant: COc1cc(F)cc2nc(-c3ccnc(C)c3)[nH]c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COCCOc1cc(OC)c2c(=O)[nH]c(-c3ccnc(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-ethanol (0.64 g, 8.40 mmol) in anhydrous DMSO (4 mL) was added sodium hydride (60% suspension in mineral oil, 0.12 g, 5.00 mmol) in small portions and the reaction mixture was stirred at room temperature for 30 minutes. To this mixture was added a solution of 7-fluoro-5-methoxy-2-(2-methyl-pyridin-4-yl)-3H-quinazolin-4-one (0.24 g, 0.84 mmol) in anhydrous DMSO (12 mL). The reaction mixture was stirred at 80° C. for 3 hours, then cooled to room temperature, and diluted with ether (500 mL). The solid was filtered and washed with ether. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 4% methanol in dichloromethane). The compound was further purified by preparative HPLC to give the title compound as a white solid. Yield: 60 mg (21%). MP 260-262° C. 1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, J=5.07 Hz, 1H), 7.98 (s, 1H), 7.88 (d, J=5.07 Hz, 1H), 6.80 (d, J=2.34 Hz, 1H), 6.61 (d, J=2.34 Hz, 1H), 4.25 (t, J=4.68 Hz, 2H), 3.86 (s, 3H), 3.71 (t, J=3.90 Hz, 2H), 3.33 (s, 3H), 2.57 (s, 3H). MS (ES) m/z: 342.07 (M+1) (100%).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[H][H]>C(O)(C)C.O1CCCC1.[Pd]>[CH2:6]1[CH:1]([CH:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH:4]([OH:7])[CH2:5]1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: OC1CCC(C2CCC(O)CC2)CC1

Procedure:
In 1 l of isopropanol was dissolved 100 g (0.54 mol) of biphenyl-4,4'-diol, and 5 g of anhydrous sodium carbonate and 5 g of 5% palladium-on-carbon were added to the solution. The mixture was subjected to reduction reaction in an autoclave at 100° C. and at a hydrogen pressure of 5 kg/cm2 for 25 to 30 hours. After completion of the reaction, the reaction mixture was filtered, and the isopropanol was removed from the filtrate by distillation under reduced pressure to recover a part of dicyclohexyl-4,4'-diol. The crystals obtained as a filter cake were dissolved in 500 ml of tetrahydrofuran while hot and filtered. The tetrahydrofuran was removed from the filtrate by distillation under reduced pressure to obtain dicyclohexyl-4,4'-diol. Both crystals were combined, suspended in 1 l of n-hexane while hot, and allowed to stand at 5° to 6° C. for 1 hour. The precipitated crystals were colleoted by filtration and dried under reduced pressure to obtain 93 g (0.47 mol) of a compound of formula: ##STR28## Melting Point: 179°-181° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[N:13]=[CH:14][CH:15]=[C:6]3[NH:5][C:4]=2[CH:3]=1.[H][H]>C(N(CC)CC)C.[Pd].CN(C)C=O>[N:13]1[N:7]2[C:8](=[O:12])[C:9]3[CH:10]=[N:11][CH:2]=[CH:3][C:4]=3[NH:5][C:6]2=[CH:15][CH:14]=1
Reactant: O=c1c2cnc(Cl)cc2[nH]c2ccnn12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1c2cnccc2[nH]c2ccnn12
Temperature: 25 °C

Procedure:
22 g. of 6-chloropyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one of Example 1 are hydrogenated in 200 ml. of dimethylformamide in the presence of 15 g. of triethylamine and 10% palladium on charcoal as catalyst at 80° and 3 atmospheres hydrogen pressure. When the theoretical amount of hydrogen has been absorbed, the reaction is stopped and the mixture is filtered after cooling to room temperature. After evaporation of the solvent, the crystalline residue, pyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one, is recrystallized from dimethylformamide, yield: 13 g. (70%); m.p. >300°.
Reaction SMILES: S([O:5][CH3:6])(OC)=O.C(=O)([O-])[O-].[K+].[K+].[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1)(=[O:15])[CH3:14]>>[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:5][CH3:6])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: COS(=O)OC
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(NC(C)=O)cc1
Temperature: 70 °C
Yield: 36.7 %

Procedure:
To a three-necked 100 ml flask equipped for reflux and fitted with a mechanical stirrer was added 10 ml (0.12 mol) of dimethyl sulfite, 2.0 g (0.014 mol) of potassium carbonate, and 5.0 g (0.033 mol) of p-acetamidophenol. The mixture was heated to 70° C. for six hours then quenched while hot with 50 ml of water. The solution was made basic with dilute caustic and the organic materials were extracted into methylene chloride. The extracts were concentrated in vacuo to give 2.0 g of p-acetamidoanisole.