Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:16]([O-])=[CH:15][C:14]=2[N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:30].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:30])[C:14]=2[N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CC(C)(F)Cn1c(CCOCc2ccccc2)nc2c[n+]([O-])c3cccnc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(F)Cn1c(CCOCc2ccccc2)nc2c(N)nc3cccnc3c21
Reaction time: 1 h

Procedure:
2-[2-(Benzyloxy)ethyl]-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine 5-oxide (1.97 g, 5.00 mmol) was dissolved in 50 mL of CH2Cl2 and treated with 5 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (1.00 g, 5.33 mmol) was carefully added. Rapid stirring was continued for 1 hour. The reaction mixture was then treated with 20 mL of H2O. The layers were separated and the organic portion was washed successively with 5% Na2CO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered, and concentrated under reduced pressure. Chromatography (SiO2, 10% CMA/CHCl3) gave 0.90 g of 2-[2-(benzyloxy)ethyl]-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:4]=1.[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@H:27]([OH:35])[CH2:28][N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:21][C:19]=2[N:20]=1.C(N(C(C)C)CC)(C)C>CCO>[F:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[C:3]([CH2:2][N:32]3[CH2:33][CH2:34][N:29]([CH2:28][C@@H:27]([OH:35])[CH2:26][O:25][C:22]4[CH:23]=[CH:24][C:18]5[S:17][C:16]([CH3:15])=[N:20][C:19]=5[CH:21]=4)[CH2:30][CH2:31]3)[O:7][N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: Fc1cccc(-c2noc(CCl)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(Cc4nc(-c5cccc(F)c5)no4)CC3)ccc2s1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 5-(chloromethyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole (300 mg, 1.41 mmol) and (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-yl-propan-2-ol, a compound of formula (6) (291 mg, 0.94 mmol) in EtOH (20 mL, anhydrous) was added diisopropylethylamine (0.329 m, 1.89 mmol), and the reaction was shaken on a J-Kem™ block overnight at 90° C. Upon cooling to room temperature, the solution was concentrated to an oil and purified on an Isco™ Combi Flash Si 10X, using Redi Sep columns (10 g), eluting with ethyl acetate, then gradient to 4:1 ethyl acetate/methanol, to yield (2R)-3-(4-{[3-(3-fluorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol, a compound of Formula I.
Reaction SMILES: [S:1](OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].C(OC=C)(=O)C.[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1C=CC(O)=[CH:32][CH:33]=1>O>[CH2:32]([SH:1])[CH2:33][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: C=COC(C)=O
Solvent: O
Product: CCCCCCCCCCCCS

Procedure:
As soon as the mixture has reached 80° C., a solution of 2 g of ammonium persulfate in 10 cm3 of water is added thereto. A mixture containing 1,251 g of vinyl acetate and 450 g of "Versatate VEOVA 10", and a solution containing 100 g of deionized water, 2 g of ammonium persulfate and 82.5 g of a 22% strength aqueous solution of polyoxyethyleneated nonylphenol (30 units of ethylene oxide), are then introduced simultaneously at a constant rate over 3 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)[CH:38]=[CH2:39]
Reactant: C=CCOC(=O)Cl
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCOC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Compound 494 (0.06 g, 0.16 mmol) was suspended in dry CH2Cl2 (1.5 mL) under an argon atmosphere in a screw cap vessel. K2CO3 (0.044 g, 0.32 mmol) was added followed by allyl chloroformate (0.034 mL, 0.032 mmol). The suspension was stirred for 48 h at room temperature. Work up as described in the preparation of compound 277. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 5:95→30:70 as the eluent. This afforded the title compound as yellow oil. 13C NMR (CDCl3) δ 195.8, 159.1 (dd), 155.5 (dd), 153.2, 147.7, 139.6, 135.4, 135.2, 133.6, 132.9, 132.3, 132.0, 129.3, 124.4 (dd), 124.2 (dd), 121.3, 119.7, 118.3, 116.3, 112.8, 111.6 (dd), 105.0 (dd), 65.9, 19.7
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.Br[CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C[Si](Cl)(C)C>C1COCC1>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2]1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=C1C=CCCC1
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
Into a 1 L round-bottom flask was placed a solution of cyclohex-2-en-1-one (15.00 g, 156.04 mmol, 1.00 equiv) in anhydrous THF (300 mL). 1,3-diethyl 2-bromopropanedioate (56.00 g, 234.25 mmol, 1.50 equiv), In powder (18.00 g, 1.00 equiv) and TMSCl (87.00 g, 800.81 mmol, 5.00 equiv) were added under nitrogen. The resulting solution was stirred for 30 min at room temperature and quenched by the addition of 200 mL of saturated aqueous sodium carbonate, extracted with 3×300 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give 1,3-diethyl 2-(3-oxocyclohexyl)propanedioate (28.50 g, 71%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[Na+]>>[NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([S:11][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1cc(C(=O)O)cc(S)c1Oc1ccccc1
Reactant: CCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: CCCCCSc1cc(C(=O)O)cc(N)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 5-amino-3-mercapto-4-phenoxybenzoic acid (5.2 g), n-pentyl bromide (5 ml), and 0.5 N sodium hydroxide is stirred at room temperature for 5 days. 5-Amino-3-n-pentylthio-4-phenxoybenzoic acid is precipitated by addition of 4 N hydrochloric acid (30 ml). After collection by filtration, recrystallisation from cyclohexane and drying, the compound is obtained with a melting point of 98°C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.S(Cl)([Cl:30])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH2:16][Cl:30])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(CCl)c(C)c23)cc1
Temperature: 0 °C
Yield: 59.5 %

Procedure:
To a cold (ice bath) solution of acetic acid 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (4.00 g, 9.4 mmol) in anhydrous methylene chloride (41 mL) was added sulfuryl chloride (0.76 mL, 10.3 mmol) dropwise over a period of 10 minutes. After stirring 1 hour in the ice bath the reaction was quenched with water (100 mL) and diluted with diethyl ether. After filtering, the layers were separated. Silica gel was added to the organic layer and the solvents were removed. The adsorbate was flash chromatographed (gradient 90/10-80/20 petroleum ether/ethyl acetate) to give the title compound as a white solid (2.57 g, 59%): NMR (DMSO-d6); δ 8.23 (d, J=8 Hz, 1H), 7.71 (dd, J=8,1 Hz, 1H), 7.55-7.43 (m, 4H), 7.33-7.30 (m, 2H), 5.09 (s, 2H), 2.34 (s, 3H), 1.66 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:13][CH3:14])[CH:8]=[C:9]([F:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.CCOC(C)=O>[F:15][C:2]1[C:11]2[C:6](=[C:7]([O:13][CH3:14])[CH:8]=[C:9]([F:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(F)cc2c(Cl)nccc12
Reactant: [F-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(F)cc2c(F)nccc12
Temperature: 140 °C
Yield: 105.3 %

Procedure:
To a solution of 1-chloro-7-fluoro-5-methoxyisoquinoline (350 mg, 1.654 mmol) in DMSO (3 mL), was added CsF (502 mg, 3.31 mmol) and the mixture was heated to 140° C. for 4 h. The reaction was diluted with EtOAc and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give 1,7-difluoro-5-methoxyisoquinoline (340 mg, 105% yield) which was not purified further. MS m/z 196.1 (M++1).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:12]([C:14]([C:20]#[N:21])=[C:15](C#N)[C:16]#[N:17])#[N:13].CCCCCC>CN(C=O)C.C(=O)([O-])O.[Na+]>[CH2:10]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:15]([C:16]#[N:17])=[C:14]([C:20]#[N:21])[C:12]#[N:13])=[CH:6][CH:5]=1)[CH3:11]
Reactant: N#CC(C#N)=C(C#N)C#N
Reactant: CCN(CC)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCN(CC)c1ccc(C(C#N)=C(C#N)C#N)cc1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 73.8 %

Procedure:
In an atmosphere of argon, 42.3 g (0.28 mol) of N,N-diethylaniline was dissolved in 570 ml of anhydrous DMF, and the solution obtained was cooled to 0° C., and then 46.3 g (1.25-fold equivalent weight) of tetracyanoethylene was added thereto. Then, the solution obtained was restored to room temperature, and stirred for 4.5 hours, which was thereafter poured in 1 liter of a saturated aqueous sodium hydrogencarbonate solution. The solid thus deposited was filtered to obtain a residue, and the residue was subjected to azeotropic distillation twice with 300 ml of toluene to remove the water content. Thereafter, 300 ml of ethyl acetate was added, and the atmosphere was replaced with argon, followed by heating at 80° C. for 1 hour to effect dissolution. To the mixture obtained, 800 ml of hexane was added with stirring, and the solution obtained was cooled to room temperature. The solid thus deposited was collected by filtration, and the residue obtained was vacuum-dried to obtain 51.7 g of N,N-diethyl-4-tricyanovinylaniline (yield: 74%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3ccc4ccccc4n3)CC2)cc1
Yield: 18 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (150 mg, 0.53 mmol) was reacted with 2-chloroquinoline (175 mg, 1.06 mmol), DIEA (0.37 ml, 2.12) and 1,4-dioxane (0.2 ml) at 185° C. to afford the title compound (39 mg), a white solid, in 18% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=1[N+:15]([O-])=O)[CH3:2].[H][H]>CCO>[CH2:1]([O:3][C:4]([C:5]1[NH:15][C:8]2[C:7]([CH:6]=1)=[CH:12][CH:11]=[C:10]([C:13]#[N:14])[CH:9]=2)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)c1cc2ccc(C#N)cc2[nH]1
Yield: 65.3 %

Procedure:
Add to 1.5 g of 3-(4-cyano-2-nitrophenyl)-2-oxopropionic acid ethyl ester, in EtOH (40 mL) 10% Pd/C (0.45 g) and stir under a hydrogen atmosphere until the theoretical amount of hydrogen is absorbed. Filter the mixture and concentrate the filtrate to afford 1.1 g of crude product. Purify by chromatography on SiO2 and elute with CH2Cl2. Concentrate the desired fractions and vacuum dry the residue over night (40° C.) to afford the title compound (0.8 g) as white crystals, mp 176° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=2[CH:29]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1>>[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=3[CH:29]=2)=[CH:33][CH:32]=1
Reactant: Cc1ccc(S)cc1
Reactant: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCSc3ccc(C)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-di-n-hexyl-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][NH:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(C(C)C)CC)(C)C.[C:27](Cl)([O:29][CH2:30][CH:31]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28].OS([O-])(=O)=O.[K+]>ClCCl>[CH3:17][O:16][CH:3]([O:2][CH3:1])[CH2:4][N:5]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:27]([O:29][CH2:30][CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[C:43]1=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:28]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCC/C=C/CCCNCC(OC)OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC/C=C/CCCN(CC(OC)OC)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
2-(trans-Dec-4-en-1-ylamino)acetaldehyde dimethyl acetal (10.5 g, 43.2 mmol) was mixed with dichloromethane (300 mL) and 7.5 mL (43.2 mmol) diisopropylethyl amine and 11.2 g (43.2 mmol) of FMOC-Cl was added portionwise. The reaction was stirred at room temperature for 3 hours and then poured into a solution of 10% KHSO4 (200 mL). The organic layer was washed with water (200 mL), dried over MgSO4, and concentrated under reduced pressure. The resulting oil was chromatographed on silica gel in 10% EtOAc/Hexanes to give 16.1 g (34.6 mmol) of N-Fmoc-2-(trans-dec-4-en-1-ylamino)acetaldehyde dimethyl acetal as a clear oil that was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21](F)[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:21]3[CH:20]=[N:19][CH:18]=[C:17]([F:16])[CH:22]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Fc1cncc(F)c1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cncc(F)c1

Procedure:
The title compound, MS: m/e=312.1 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 3,5-difluoro-pyridine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1O
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1OCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
4-Hydroxy-3-methylbenzaldehyde (365 mg, 2.68 mmol), 3,4-dichlorobenzyl alcohol (665 mg, 3.76 mmol), and triphenylphosphine (980 mg, 3.74 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.71 mL, 3.76 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a white solid (542 mg, yield: 69%).
Reaction SMILES: Br[CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.N1C=CN=C1C(C(C(C1NC=CN=1)=O)=O)=O.O>C(#N)C>[CH3:5][C:4]([C:3]([CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[N:17]1[CH:18]=[N:19][CH:20]=[CH:21]1)=[O:8])([CH3:7])[CH3:6]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Agent: O=C(C(=O)c1ncc[nH]1)C(=O)c1ncc[nH]1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1

Procedure:
The antigingivitis agent utilized in present invention is 1-imidazoyl-(p-chlorophenoxy)3-3-dimethyl 2-butanone having the structural formula: ##STR2## which is prepared by reacting 1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-2-butanone with imidazole dissolved in acetonitrile as disclosed in U.S. Pat. Nos. 3,812,142 and 3,903,287, which is made a part of this specification. This imidazoyl ketone is a water insoluble crystalline powder having a melting point of 94.5°-97.8° C. which may be obtained from the Bayer Company as Climbazole. Due to the water insolubility of this imidazole compound, it must first be solubilized in a nonionic compound prior to the addition of ionic materials in an aqueous medium.
Reaction SMILES: C(N)(=N)C1C=CC=CC=1.[CH3:10][C@H:11]1[CH2:94]O[C@@:14]2(O[C@H:17]3[C@@H:19](O)[C@H:20]4[C@@H:25]5[CH2:26][CH2:27][C@H:28]6[CH2:33][C@@H:32]([O:34][C@@H]7O[C@H](CO)[C@H](O[C@@H]8O[C@H](CO)C(O)[C@H](O[C@@H]9OC[C@@H](O)[C@H](O)[C@H]9O)[C@H]8O[C@@H]8O[C@H](CO)[C@H](O)[C@H](O[C@@H]9O[C@H](CO)[C@@H](O)[C@H](O)[C@H]9O)[C@H]8O)[C@H](O)[C@H]7O)[C@H:31](O)[CH2:30][C@:29]6([CH3:89])[C@H:24]5[CH2:23][CH2:22][C@:21]4([CH3:90])[C@H:16]3[C@@H:15]2[CH3:92])[CH2:13][CH2:12]1>P([O-])([O-])([O-])=O>[CH3:94][CH:11]([CH2:12][CH2:13][CH2:14][C@H:15]([C@@H:16]1[C@:21]2([CH3:90])[C@H:20]([C@H:25]3[C@H:24]([CH2:23][CH2:22]2)[C@:29]2([CH3:89])[C:28]([CH2:33][C@H:32]([CH2:31][CH2:30]2)[OH:34])=[CH:27][CH2:26]3)[CH2:19][CH2:17]1)[CH3:92])[CH3:10]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1[C@@H](O)[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[C@@H]6O[C@H](CO)[C@H](O[C@@H]7O[C@H](CO)C(O)[C@H](O[C@@H]8OC[C@@H](O)[C@H](O)[C@H]8O)[C@H]7O[C@@H]7O[C@H](CO)[C@H](O)[C@H](O[C@@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@H]8O)[C@H]7O)[C@H](O)[C@H]6O)[C@H](O)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: N=C(N)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Human pancreas was received at autopsy. About 30 g of tissue in 10 mM phosphate, pH 6.0, 50 mM benzamidine, 0.5% digitonin were homogenized with a polytron, centrifugally pelleted (48,000×g, 30 min.) and the supernatant collected. The supernatant was centrifugally pelleted (100,000×g, 60 min.) again and the second supernatant was passed through glass wool and dialized overnight against 50 mM benzamidine, 10 mM phosphate, pH 6.8. The dialysate was loaded onto a hydroxylapatite column (2.6×10 cm) equilibrated with 50 mM benzamidine, 10 mM phosphate, pH 6.8. The column was washed with identical buffer, then developed with a linear gradient of 50 mM to 350 mM phosphate, pH 6.8, 50 mM benzamidine. The cholesterol esterase activity eluted at a conductivity of 20-22 mS/cm. These fractions were pooled and loaded onto an AcA34 column (Bio-Rad Laboratories, Inc., 2200 Wright Avenue, Richmond, Calif. 94804) (2.6×90 cm) equilibrated with 500 mM NaCl, 10 mM phosphate, pH 6.0. The fraction emerging at an apparent molecular weight of 350 kDa contained cholesterol esterase activity and was dialyzed against 10 mM phosphate, pH 6.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH3:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(=O)C>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@H:14]([CH3:31])[C@:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 70 °C
Yield: 38.4 %

Procedure:
Racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (44 g) and (1R)-10-camphorsulfonic acid (20 g) were suspended in methanol (ca. 300 ml), the slurry was stirred intensively, warmed up to ca. 70° C. and a small addition of acetic acid was added to obtain a clear solution. After cooling of the solution to rt and then to 0° C., the mixture was seeded with enantiomerically pure salt and stirred for another 2 hrs. The crystalline solid was collected by filtration, washed with cooled methanol and dried under reduced pressure. The crystals were partitioned between methylenechloride (300 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic layer was washed twice with water (50 ml), dried with magnesium sulphate, filtrated and evaporated under reduced pressure to give the title compound (16.9 g, 38% yield, 95% ee). The analytical data were identical with published (U.S. Pat. No. 5,648,372 or Chem. Pharm. Bull. 1998, 46, 623).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]([NH:35][NH2:36])=[O:34]>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:36][NH:35][CH:33]=[O:34])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC=O
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (1.0 g, 6.0 mmol) in THF (30 mL) was added 1,1′-carbonyldiimidazole (1.6 g, 7.2 mmol) at 0° C. The reaction mixture was stirred at rt for 1 h, then, formohydrazide (1.1 μg, 18.1 mmol) was added rapidly at rt. The reaction mixture was stirred at rt for 3 hrs and then diluted with EtOAc (100 mL). The combined organic layer was washed with saturated sodium chloride (10 mL), dried over Na2SO4, and concentrated to afford (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide (1.6 g), which was used directly in the next step. ESI-MS (EI+, m/z): 319.1 [M+H]+.