Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH:11](B(O)O)=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[Cl:8][C:6]1[CH:7]=[C:2]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3](=[O:10])[N:4]([CH3:9])[N:5]=1
Reactant: OB(O)C=Cc1ccccc1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(C=Cc2ccccc2)c1=O
Temperature: 85 °C
Yield: 67.9 %

Procedure:
A mixture of 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (8 g, 35.8 mmol, Preparation #28), styrylboronic acid (6.62 g, 44.8 mmol, Combiblocks), bis(triphenylphosphine)palladium(II) chloride (2.51 g, 3.58 mmol, Hindustan Platiniums) and potassium phosphate (11.40 g, 53.7 mmol, Aldrich) in aqueous dioxane (75%: 100 mL) was heated to about 85° C. for 6 h. The reaction mixture was cooled to RT and then concentrated on the rotovapor to 25 mL. The oily residue obtained was partitioned between EtOAc (100 mL) and water (50 mL). The layers were separated and then the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over sodium sulphate and evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography by eluting with 10-20% ETOAc in hexane. The relevant fractions containing the product were combined and evaporated under reduced pressure to afford 6-chloro-2-methyl-4-styrylpyridazin-3(2H)-one 6 g (67.9%) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.878-7.838 (d, J=17 Hz, 1H), 7.620-7.560 (m, 2H) 7.412-7.344 (m, 3H) 7.279 (s, 1H) 7.177-7.136 (d, J=16 Hz, 1H) 3.809 (s, 3H); MS m/z: 247.1 (M+H)+
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][S:19](CC2C=CC=CC=2)(=[O:21])=[O:20])[CH:12]=[CH:11][C:10]=1[N:29]1[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]1)C1C=CC=CC=1.O>CCO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][S:19]([OH:21])=[O:20])[CH:12]=[CH:11][C:10]=1[N:29]1[CH2:30][C:31](=[O:36])[NH:32][S:33]1(=[O:35])=[O:34]
Reactant: O=C1CN(c2ccc(CCCCS(=O)(=O)Cc3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: O=C1CN(c2ccc(CCCCS(=O)O)cc2O)S(=O)(=O)N1
Reaction time: 2 h

Procedure:
A mixture of 5-[2-benzyloxy-4-(4-phenylmethanesulfonylbutyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (450 mg), 10% Pd/C (400 mg) and KHCO3 (1.6 mL of 0.52M) in EtOH (1 mL)/water (10 mL) is hydrogenated at 1 atm for 2 h. The catalyst is filtered and the filtrate evaporated. The residue is treated with 1N HCl and extracted with EtOAc. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to give the title compound: (M−1)−=347 1H NMR (400 MHz, DMSO-D6) δ ppm 1.38-1.48 (m, 2 H) 1.49-1.58 (m, J=7.67, 7.67, 7.52, 7.20 Hz, 3 H) 1.79-1.85 (m, 2 H) 2.43 (t, J=7.45 Hz, 2 H) 4.01 (s, 2 H) 6.56 (dd, J=8.08, 1.77 Hz, 1 H) 6.67 (d, J=1.77 Hz, 1 H) 7.25 (d, J=8.08 Hz, 1 H)
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:26]4[CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1cccc(-c2ccc(-c3cccnc3N)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 35.5 mg) in THF (dry). (5 mL) was added 2-chloroethanesulfonyl chloride (0.056 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(3′-methoxybiphenyl-4-yl)pyridin-2-amine (49 mg) in THF (dry) (5 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water. Water and EtOAc were added and the extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with EtOAc and dried in vacuo to give the title compound (18 mg) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:21])[NH:12][CH2:13][CH2:14][CH2:15][C:16](=[O:20])[NH:17][CH2:18][CH3:19])(C)(C)C.[C:23]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=O)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CO.Cl>[C:26]([O:25][C:23](=[O:24])[NH:30][CH2:31][CH2:32][CH2:33][C:34](=[O:36])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:21])[NH:12][CH2:13][CH2:14][CH2:15][C:16](=[O:20])[NH:17][CH2:18][CH3:19])([CH3:27])([CH3:28])[CH3:29]
Reactant: CCNC(=O)CCCNC(=O)CCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: Cl
Solvent: CO
Product: CCNC(=O)CCCNC(=O)CCCNC(=O)CCCNC(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
Boc-Protected derivative 4 (22.3 g, 70.7 mmol) was stirred in a mixture of MeOH (200 ml) and HCl (12%, 81 ml) for 48 h, concentrated to dryness in vacuo, dissolved in H2O, and washed 3 times with CHCl3. Water was removed on a rotary evaporator at 45° C. The resulting hydrochloride was dissolved in a mixture of CH2Cl2 (600 ml) and aq. Na2CO3 (20%, 100 ml), cooled on an ice bath, and Bt-derivative 2 (22.47 g, 70.15 mmol) was added. The cooling bath was removed and the mixture was stirred for 18 h with a mechanical stirrer. The main part of the CH2Cl2 was removed on a rotary evaporator, the reaction mixture was suspended in water and filtered. The product was triturated in EtOAc, filtered, washed with petr. ether and dried in vacuo. Yield 25.46 g (90%). mp: 170-171° C. 1H NMR (CDCl3/CD3OD): 1.14 (t, J=7.30, 3H), 1.44 (s, 9H), 1.72-1.85 (m, 6H), 2.10-2.23 (m, 6H), 3.06-3.12 (m, 2H), 3.18-3.26 (m, 6H), 5.57 (bs, 1H), 7.32 (bs, 1H), 7.46 (bs, 1H), 7.60 (bs, 1H). 13C NMR (CDCl3/CD3OD): 14.22, 24.73, 25.32, 25.39, 25.96, 28.15, 33.33, 33.59, 34.12, 34.25, 38.60, 39.64, 79.29, 156.68, 173.39, 173.88. ESI-MS: 423.4 (MNa+), 401.4 (MH+).
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]3[NH:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[O:30][CH3:31])=[CH:24][CH:23]=4)=[CH:20][N:21]=3)[CH2:13]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.[CH3:62][C:63]([O:66][C:67]([NH:69][C:70]([N:79]1[CH2:84][CH2:83][CH:82]([C:85](O)=[O:86])[CH2:81][CH2:80]1)=[N:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])=[O:68])([CH3:65])[CH3:64]>ClCCl.CN(C)C=O>[CH3:78][C:75]([O:74][C:72](=[O:73])[NH:71][C:70]([N:79]1[CH2:80][CH2:81][CH:82]([C:85]([N:15]2[CH2:16][C@@H:12]([CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH2:13][C@H:14]2[C:17]2[NH:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([O:30][CH3:31])=[O:32])=[CH:26][CH:27]=3)=[CH:20][N:21]=2)=[O:86])[CH2:83][CH2:84]1)=[N:69][C:67](=[O:68])[O:66][C:63]([CH3:62])([CH3:64])[CH3:65])([CH3:76])[CH3:77]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(C(=O)O)CC1
Reactant: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)C3CCN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
To a solution of the compound prepared in Example 66 (0.11 g, 0.25 mmol) in dichloromethane (5.0 mL) and N,N-dimethylformamide (2.0 mL) was added 1-hydroxy-7-azabenzotriazole (0.034 g, 0.25 mmol), followed by N-methyl morpholine (0.075 g, 0.74 mmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.095 g, 0.50 mmol) and the compound prepared in Example 7 (0.10 g, 0.27 mmol). The reaction was stirred at room temperature under nitrogen overnight whereupon it was concentrated under reduced pressure. The resultant residue was diluted with dichloromethane (20 mL), washed with brine (10 mL), dried and concentrated. Purification by flash chromatography (silica gel, 12 g, 0-5% methanol/dichloromethane) and trituration from methanol and methyl tert-butyl ether afforded the title compound (0.067 g, 38%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6]O.C(Br)(Br)(Br)[Br:12]>ClCCl>[Br:12][CH2:6][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1cccc(Cl)c1
Solvent: ClCCl
Product: Clc1cccc(CCBr)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.8 %

Procedure:
Add triphenylphoshpine (3.90 g, 14.9 mmol) to a stirred solution of 3-chlorophenethyl alcohol (2.0 mL, 14.8 mmol), carbon tetrabromide (4.91 g, 14.8 mmol) and anhydrous dichloromethane (100 mL). Stir for 5 h under nitrogen at room temperature, and then wash with water (100 mL) and brine (100 mL). Dry the dichloromethane layer over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 100% hexanes to yield 2.30 g (71%) of 1-(2-bromo-ethyl)-3-chloro-benzene: TLC: Rf in 100% hexanes: 0.27; 1H NMR (CDCl3): 7.26-7.11 (m, 3H), 7.09-7.07 (m, 1H), 3.54 (t, 2H), 3.12 (t, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:24](=[O:26])=[O:25]>C1COCC1.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C>[C:1]([O:5][C:6]([NH:7][C:8]1[N:9]=[C:10]([CH2:14][C:24]([OH:26])=[O:25])[CH:11]=[CH:12][CH:13]=1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)n1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(CC(=O)O)n1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
(6-Methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.04 g, Pitts, J. Med. Chem., 43, 2000, 27) under an argon atmosphere in THF (40 mL) was cooled to −20° C. and treated dropwise at −20° C. with 5.5 mL of a 2 M solution of lithium diisopropylamide in THF/heptane/ethylbenzene (Fluka). The solution was stirred 1 h at −20° C., cooled to −70° C. and then treated with an access of dry ice. The mixture was allowed to warm to 10° C. and partitioned between aqueous 1N HCl and AcOEt, the layers were separated, the organic layer dried over Na2SO4, filtered, evaporated and the residue was purified by flash chromatography (MeOH/CH2Cl2 0-15%). The obtained material was triturated with ether, the crystalline solid obtained was filtered off by suction and dried in vacuo to give (6-tert-butoxycarbonylamino-pyridin-2-yl)-acetic acid as an off-white solid (0.3 g). MS (ESI−): 251.1 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[CH:6][N:5]2[CH:18]=1.C=O.Cl>CO>[CH3:4][N:5]([CH2:18][C:18]1[N:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][C:4]2=[N:3][C:2]=1[CH3:1])[CH3:6]
Reactant: Cc1cn2ccc(CCc3ccccc3)cc2n1
Agent: C=O
Agent: Cl
Solvent: CO
Product: Cc1nc2cc(CCc3ccccc3)ccn2c1CN(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Into a one-liter flask there was placed 2-methyl-7-(2-phenylethyl)-imidazo[1,2-a]pyridine (112 g) dimethylamine hydrochloride (41.6 g), paraformaldehyde (15.23 g) and methanol (450 ml) and the mixture was refluxed with stirring for 1.5 hours. Thereafter the mixture was boiled, open to the air, for 3/4 hours. After cooling to room temperature and treatment with concentrated hydrochloric acid (45 ml) the mixture was stirred for 18 hours, filtered and the thick white solid mass formed was washed with methanol and 200 ml of anhydrous ether and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:45][CH3:46])[C:41]=1[O:42][CH2:43][CH3:44])[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:36](=[O:37])[C:35]4[CH:34]=[C:33]([O:32][CH3:31])[C:41]([O:42][CH2:43][CH3:44])=[C:40]([O:45][CH3:46])[CH:39]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCNCC1)=C2
Reactant: CCOc1c(OC)cc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1c(OC)cc(C(=O)N2CCN(C(=O)C3=Cc4cc(OC)c(OC)cc4CCC3)CC2)cc1OC
Temperature: 0 °C
Yield: 45.2 %

Procedure:
To a mixture of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)piperazine (1.2 g), triethylamine (0.5 g) and methylene chloride (20 ml) is added dropwise, with stirring under ice-cooling, a solution of 3,5-dimethoxy-4-ethoxybenzoyl chloride (1.0 g) in methylene chloride (20 ml). The reaction mixture is then stirred for one hour at room temperature, and then poured into ice-water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (hexane:ethyl acetate:acetone=1:2:1) to afford 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,5-dimethoxy-4-ethoxy-benzoyl)piperazine (0.9 g). This product is recrystallized from ethyl acetatehexane to give colorless needles, m.p. 171°-172° C.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].[CH3:28][O:29][CH2:30][CH2:31][NH2:32].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CN(C)C=O.ClCCl>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[C:3]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: COCCN
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCNc1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 5-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonylpyrazole (2.5 g, 4.8 mmol) in 1,4-dioxane and N,N-dimethylformamide was added 2-methoxyethylamine (0.74 g, 9.7 mmol) and potassium carbonate (1.35 g, 9.7 mmol). The resulting mixture was stirred at 50° C. for 4 hours, left to stand overnight, then poured into a mixture of water and dichloromethane. The organic phase was washed with water, dried (sodium sulfate), evaporated. The crude product was recrystallised from diisopropylether to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-(2-methoxyethylamino)4-trifluoromethylsulfonylpyrazole as a white solid (Compound number 1-3, 1.30 g), mp 164° C.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:23])[CH:7]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([CH3:22])[CH:14]=1)C(OCC)=O)C>CO.O>[CH3:22][C:15]1[CH:14]=[C:13]([CH2:7][C:6]([OH:23])=[O:5])[CH:18]=[CH:17][C:16]=1[N+:19]([O-:21])=[O:20]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Potassium hydroxide (0.168 g) was dissolved in 7 mL of methanol and 1 mL of water, and the 2-(3-methyl-4-nitrophenyl)malonic acid diethyl ester (0.250 g) obtained in Example 1-3a) was dissolved in the solution. The solution was stirred at 100° C. for 2 hours and concentrated. The residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate and concentrated to give the title compound (0.143 g) as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[NH:7][C:8](=[O:12])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].[CH3:13][Si:14]([CH3:20])([C:16]([CH3:19])([CH3:18])[CH3:17])Cl>>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][Si:14]([CH3:20])([CH3:13])[C:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1cccc(=O)[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CNS(=O)(=O)c1cccc(O[Si](C)(C)C(C)(C)C)n1

Procedure:
2-(N-methylsulphamoyl)pyrid-6-one was silylated with dimethyl-(1,1-dimethylethyl)chlorosilane in the presence of imadazole under standard conditions to give 2-[N-methylsulphamoyl]-6-[dimethyl-(1,1-dimethylethyl)silyloxy]pyridine
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]1[C:15]2([CH2:20][CH2:19][CH:18]([C:21]#[N:22])[CH2:17][CH2:16]2)OCC1.Br[C:24]1[C:29]([CH3:30])=[CH:28][C:27]([Br:31])=[CH:26][N:25]=1>O>[Br:31][C:27]1[CH:28]=[C:29]([CH3:30])[C:24]([C:18]2([C:21]#[N:22])[CH2:17][CH2:16][C:15](=[O:11])[CH2:20][CH2:19]2)=[N:25][CH:26]=1
Reactant: N#CC1CCC2(CC1)OCCO2
Reactant: Cc1cc(Br)cnc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cnc1C1(C#N)CCC(=O)CC1
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
1M Solution of sodium bis(trimethylsilyl)amide (77 ml) was added under ice cooling to 1,4-dioxaspiro[4,5]decane-8-carbonitrile (11.0 g) described in Reference Example 82(1) and stirred for 30 minutes. Then, 2,5-dibromo-3-methylpyridine (15 g) was added, stirred for 30 minutes and further stirred at room temperature for an hour. The reaction solution was treated with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated in vacuo. To the residue, were added trifluoroacetic acid (20 ml) and water (5 ml), and the mixture was stirred at 40° C. for two hours. The reaction solution was treated with an aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and the residue was purified with silica gel column chromatography (ethyl acetate:n-hexane=5:1) to give 1-(5-bromo-3-methylpyridin-2-yl)-4-oxocyclohexanecarbonitrile (17.1 g).
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[N:5]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.O>[CH2:12]([S:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[N:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(O)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Oc1cc(O)nc(SCc2ccccc2)n1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium hydroxide (3.30 g) in ethanol/H2O (60 ml/60 ml) was added to 2-mercaptopyrimidine-4,6-diol (10.00 g) and the mixture stirred for 10 min. Benzyl bromide (13.45 g) was then added dropwise and the mixture heated at 60° C. for 2 h. The reaction was cooled to 0° C. for 1 h before the precipitate was filtered and washed with H2O (100 ml) and then dried in vacuo to afford the subtitle compound as a cream solid. Yield: 15.0 g.
Reaction SMILES: [Br:1]Br.[CH:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[C:5]([OH:11])[CH:4]=1>C1C=CC=CC=1>[OH:11][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][Br:1])=[CH:3][CH:4]=1
Reactant: BrBr
Reactant: OCc1ccc(O)cc1
Solvent: c1ccccc1
Product: Oc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Dried bromine gas (Br2) was blown through a mixed solution of 33 g of p-hydroxybenzyl alcohol ##STR133## and 900 ml of benzene for 2 hours while cooling the solution with ice water. Thereafter, the solution was stirred for 2 hours, and then distilled to obtain p-hydroxybenzyl bromide ##STR134## The boiling point of this compound was 125°-126° C./15 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]OS(OC)(=O)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:25])[C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)c2ccccc2)c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cccc(C(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
N-tert-butoxycarbonyl-3-aminobenzophenone (2 g, 6.7 mmol) in DMF (15 mL) was added to a suspension of sodium hydride (0.54 g, 13.5 mmol) in DMF (70 mL) and the mixture was stirred at 0° C. for 40 minutes. Dimethylsulfate (1.3 mL, 13.5 mmol) was added and the mixture stirred at room temperature for 15 hours. The mixture was partitioned between ethyl acetate and saturated NaCl. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired material as an orange oil.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=CC=C[CH:9]=1.[CH3:21]C(C)C(=O)C(=NO)C.CC1C=C(C=CC=1C)C=O>>[CH3:21][C:18]1[CH:19]=[C:14]([C:5]2[O:6][C:7]([CH:8]([CH3:9])[CH3:13])=[C:3]([CH2:2][I:1])[N:4]=2)[CH:15]=[CH:16][C:17]=1[CH3:20]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: CC(=NO)C(=O)C(C)C
Agent: Cc1ccc(C=O)cc1C
Product: Cc1ccc(-c2nc(CI)c(C(C)C)o2)cc1C

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 4-methylpentane-2,3-dione-2-oxime and 3,4-dimethylbenzaldehyde gave 2-(3,4-dimethylphenyl)-4-iodomethyl-5-isopropyloxazole.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19][CH3:20])=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=O)=O.[CH2:21]([S-:23])[CH3:22].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:21]([S:23][CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19][CH3:20])=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)[CH3:22]
Reactant: COC(=O)C12CCC(CCCOS(C)(=O)=O)(CC1)CC2
Reactant: CC[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSCCCC12CCC(C(=O)OC)(CC1)CC2
Temperature: 45 °C
Reaction time: 3 h

Procedure:
Mesylate 2-5 (3.30 g, 10.9 mmol) was dissolved in DMF (20 mL) and treated with sodium ethanethiolate (1.82 g, 21.7 mmol). The solution was stirred at 45° C. for 3 h, then the mixture was diluted with 100 mL of ethyl acetate and washed twice with 1N aqueous HCl, then with saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to afford methyl 4-[3-(ethylthio)propyl]bicyclo[2.2.2]octane-1-carboxylate (2-6) as a crude oil which was used without purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[O:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[C:12]([C:6]1[O:5][C:4](=[O:7])[NH:3][C:2]=1[CH3:1])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=O)Cl
Reactant: Cc1coc(=O)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(=O)c1oc(=O)[nH]c1C
Temperature: 0 °C
Yield: 39.1 %

Procedure:
Six grams (0.06 mol) of 4-methyl-2(3H)-oxazolone and 24.2 g (0.182 mol) aluminum chloride were suspended in 250 ml methylene chloride. To this mixture was added dropwise 8.3 g (0.069 mol) n-pentanoyl chloride. The mixture was stirred and refluxed 15 hours, cooled and poured into ice water. The methylene chloride layer was isolated, washed with sodium bicarbonate solution and water. The methylene chloride solution was dried and solvent evaporated to give a residue which was recrystallized two times from ethyletherpentane to give 4.3 g (39%) of title compound; m.p. 92°-94°.