Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[Br:13]NC(=O)CCC(N)=O>C(#N)C>[Br:1][C:2]1[S:3][C:4]2[C:10]([Br:13])=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1
Reactant: COc1cccc2sc(Br)nc12
Reactant: NC(=O)CCC(=O)NBr
Solvent: CC#N
Product: COc1ccc(Br)c2sc(Br)nc12
Yield: 119.4 %

Procedure:
Starting from 2-bromo-4-methoxybenzothiazole (1.6 g), N-bromosuccinamide (0.91 g) and acetonitrile (100 ml). Purification by flash chromatography (eluent 20% ethylacetate/hexane) yielded the title compound as an off-white solid (1.8 g). TLC Rf 0.31 (20% ethyl acetate in heptane).
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([NH:21][C@H:22]([C:27](O)=[O:28])[C@H:23]([CH2:25][CH3:26])[CH3:24])=[O:20])[C:11]2=[O:30])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C1N=[CH:34][N:33](C(N2C=NC=C2)=O)[CH:32]=1.CNC.O>CN(C=O)C>[CH3:32][N:33]([CH3:34])[C:27]([C@@H:22]([NH:21][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][CH2:8][N:2]2[CH2:3][CH2:4][O:5][CH2:6][CH2:7]2)[C:11]1=[O:30])=[O:20])[C@@H:23]([CH3:24])[CH2:25][CH3:26])=[O:28]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC[C@H](C)[C@H](NC(=O)n1c(=O)n(CCN2CCOCC2)c2ccccc21)C(=O)O
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)n1c(=O)n(CCN2CCOCC2)c2ccccc21)C(=O)N(C)C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a solution of N-{[3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-isoleucine hydrochloride (Step 1, 62 mg, 0.14 mmol) in DMF (1 mL) was added CDI (27 mg, 0.17 mol) at rt. After 2 h, to the mixture was added aq. dimethylamine (40%, 20 μL) and stirred for further 14 h. Then to the mixture was added water (10 mL). The mixture was extracted with ethyl acetate (20 mL×2) and the combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC eluting with dichloromethane/methanol (10/1) to afford 33 mg (54%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CC(C)([O-])C.[Na+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:10][C:3]1[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(Br)cc1C
Reactant: C1CNCCN1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Cc1cc(C)c(N2CCNCC2)cc1C

Procedure:
A target compound (1.03 g, 5.041 mmol, 40.2%) was yielded in the same manner as Reference Example 10 by reacting 5-bromo-1,2,4-trimethylbenzene (2.5 g, 12.556 mmol) with piperazine (4.32 g, 50.224 mmol), sodium t-butoxide (1.75 g, 18.206 mmol) and dichlorobis(tri-o-tolylphosphine)palladium(II) (295.5 mg, 0.37 mmol) and purifying by separation through column chromatography (CH2Cl2/MeOH, 1:1).
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:32][C@H:33]([C:39]([NH:41][C:42]1[CH:51]=[C:50]2[C:45]([C:46]([CH3:53])=[CH:47][C:48](=[O:52])[O:49]2)=[CH:44][CH:43]=1)=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37].FC(C(O)=O)(F)F>>[NH:1]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:32][C@H:33]([C:39]([NH:41][C:42]1[CH:51]=[C:50]2[C:45]([C:46]([CH3:53])=[CH:47][C:48](=[O:52])[O:49]2)=[CH:44][CH:43]=1)=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@@H](N)CCC(N)=O)ccc12
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)ccc12

Procedure:
Boc-Phe-Gly-Leu-Gln-AMC was prepared by coupling Boc-Phe-Gly-Leu-OH (0.39 g, 0.90 mmol) to H-Gln-AMC trifluoroacetate (0.41 g, 0.99 mmol) by a mixed anhydride coupling procedure to yield 0.49 g crude product. Product was recrystallized from ethyl acetate to provide 0.27 g of Boc-Phe-Gly-Leu-Gln-AMC, mp 234°-236° with decomposition. TLC with methanol:chloroform (1:9) showed a single spot, Rf 0.20.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.C([O:19][C:20]1[CH:28]=[C:27]([NH:29]C(=O)C)[C:26]([Cl:33])=[CH:25][C:21]=1[C:22](O)=[O:23])(=O)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:29][C:27]1[C:26]([Cl:33])=[CH:25][C:21]([C:22]([NH:1][CH2:2][CH:3]2[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:4]2)=[O:23])=[C:20]([OH:19])[CH:28]=1
Reactant: CC(=O)Nc1cc(OC(C)=O)c(C(=O)O)cc1Cl
Reactant: NCC1CN(Cc2ccccc2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1cc(O)c(C(=O)NCC2CN(Cc3ccccc3)CCO2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.2 %

Procedure:
To a mixture of 2-aminomethyl-4-benzylmorpholine (3.1 g), 2-acetoxy-4-acetylamino-5-chlorobenzoic acid (4.0 g), and dichloromethane (40 ml) is added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.9 g), and the mixture is stirred at 25° C. for 4 hours. The reaction mixture is washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is dissolved in ethanol (80 ml), and 10% hydrochloric acid (30 ml) is added. The mixture is refluxed with stirring for 2 hours and concentrated under reduced pressure. The residue is neutralized with aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is recrystallized from isopropyl alcohol to give the monohydrate of the title compound (3.0 g), mp 153°-155° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.[CH3:17]OC(=O)C1C=CC(C(F)(F)F)=CC=1I.[Br-].C1([Zn+])CCC1>>[CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2][CH2:17]1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1I
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Agent: [Br-]
Agent: [Zn+]C1CCC1
Product: O=C(O)c1ccc(C(F)(F)F)cc1C1CCC1

Procedure:
The title compound, white solid, MS: m/e=243.0 [(M−H)−], was prepared in accordance with the general method of intermediate K from 2-iodo-4-trifluoromethyl-benzoic acid methyl Ester and cyclobutylzincbromide followed by saponification with sodium hydroxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1
Reactant: COc1cccc(O)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: COc1cccc(Oc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-methoxy-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-methoxy-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:17]3[CH2:22][CH2:21][CH2:20][C:19]([F:24])([F:23])[CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:25]>>[ClH:25].[F:24][C:19]1([F:23])[CH2:20][CH2:21][CH2:22][N:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N3CCCC(F)(F)C3)cc2C1
Agent: Cl
Product: FC1(F)CCCN(c2ccc3c(c2)CNC3)C1

Procedure:
Prepared in analogy to Example A3(e) from 5-(3,3-difluoro-piperidin-1-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 239.3 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([C:15]([O:17]C)=[O:16])=[CH:5][CH:4]=1>[OH-].[Na+].CO>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(OC)c(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.6 %

Procedure:
Methyl 6-(methyloxy)-3-biphenylcarboxylate (D39) (194 mg, 0.8 mmol) dissolved in 2N NaOH aq. (3 ml) and methanol (3 ml). Stirred at room temperature overnight and then the organic solvent was evaporated in vacuo. Added EtOAc/water separated and then acidified the aqueous and re-extracted. The organic extracts were dried and evaporated to afford 202 mg of the title compound as a white solid. δH (d6-DMSO, 400 MHz) 3.84 (3H, s), 7.22 (1H, d), 7.33-7.49 (5H, m), 7.82 (1H, d), 7.95 (1H, dd), MS (ES+): C14H12O3 requires 228; found 229 (M+H+).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[S:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.Cl>CCOC(C)=O>[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:14]2[C:15](=[O:18])[CH2:16][CH2:17][S:12][CH2:13]2)=[CH:6][CH:5]=1
Reactant: O=C1CCSCC1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1CCSCC1=Cc1ccc(F)cc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Aqueous KOH (0.3 g in 250 mL water) was added to 4-fluoro-benzaldehyde Compound 12a (4.82 g, 38.9 mmol) and tetrahydro-4H-thiopyran-4-one Compound 1a (4.5 g, 38.8 mmol), and the mixture was heated to about 65° C. for 24 hrs, then cooled to r.t. and stirred for 2 hrs. The mixture was acidified to pH 7 with 1.0N HCl (2 mL) and diluted with EtOAc (200 mL). The organic layer was separated, washed with brine and dried with anhydrous Na2SO4, then filtered and concentrated to provide a crude product, which was purified by silica gel column (eluted with 8% EtOAc in hexane) to give 3-(4-fluoro-benzylidene)-tetrahydro-4H-thiopyran-4-one Compound 12b (4.8 g, 48.5%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.O.C([C@@H]([C@H](C(OCC)=O)O)O)(OCC)=[O:26].C(N(C(C)C)CC)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1>C(OCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(CC(C)(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[O:26])=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [O-]O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(C)CC(C)(C)C
Product: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
1.6 kg (5.0 mol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole was dissolved in 7.51 of ethyl acetate. To the solution was added 31 ml (1.7 mol) water. To the mixture was added 856 ml (5.0 mol) of (+)-diethyl L-tartrate, 744 ml (2.5 mol) of titanium(IV) isopropoxide and 436 ml (2.5 mol) diisopropylethylamine at room temperature. The addition of 830 ml (4.5 mol) cumene hydroperoxide was then performed at 30° C. After stirring for one hour at 30° C. the reaction was complete. Chiral and achiral chromatographic analyses showed that the mixture consited of 75% sulphoxide with an enantiomeric excess (e.e.) of 80%. The mixture was cooled to 10° C. and after addition of 1.5 l of isooctane and ethyl acetate (0.5 l), the product was extracted three times with an aqueous ammonia (12%) solution with a total volume of 14 l. The combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (4 l). The phases were separated and the aqueous phase was extracted with ethyl acetate (4 l). The solvent of the combined organic solutions was removed. Acetone (3.0 l) was added to precipitate the racemate of omeprazole which was filtered off. HPLC--analyses (achiral and chiral columns) of the filtrate showed that this solution consisted of 90% sulphoxide with an optical purity of 95% e.e. and thus the optical purity has been improved from 80% e.e. to 95% e.e. simply by one precipitation of racemic omeprazole. Further, a content analysis (HPLC) of the filtrate showed that the yield was 1.0 kg (58%). The (+)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole was not isolated in its neutral form but further processed to corresponding sodium salt.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:21]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:3]2[CH2:2][CH2:1][C@@H:10]3[C@H:5]([CH2:6][CH2:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)[CH2:4]2)=[CH:31][CH:32]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN2CC[C@H]3c4ccccc4CC[C@@H]3C2)cc1
Yield: 26.6 %

Procedure:
Following the procedure of Example 3, step 4, 0.300 g (1.60 mmol) of crude trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in 10 ml of anhydrous DMF was reacted with 0.243 g (1.76 mmol) of anhydrous potassium carbonate and 0.310 ml (1.60 mmol) of 4-(tert-butyl)benzyl chloride. Chromatography on flash silica, eluting with 10-30% ethyl acetate/petroleum ether and 30-90% ether/petroleum ether, gave 0.142 g (27%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent the title product hydrochloride was obtained as a white solid, m.p. 229°-230° C. (dec). NMR δ(D2O) 1.33 (9H, s), 1.52 (1H, m), 1.65 (1H, m), 1.72-1.84 (2H, m), 2.60-2.72 (2H, m), 2.88-2.94 (2H, m), 3.20 (1H, t of d), 3.51 (1H, m), 3.70 (1H, m), 4.33 (2H, m), 7.21-7.25 (3H, m), 7.30-7.32 (1H, m), 7.47 (2H, d, J=8.4 Hz), 7.61 (2H, d, J=8.3 Hz). m/z (CI+, NH3) 334 (M+H)+, 233, 186 (M-CH2C6H4CMe3)+, 113.
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[CH:14]=[N:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]#[CH:24].[Cl-].C(N(CC)CC)C>C(#N)C.[Cu]I.O>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]#[C:24][C:2]1[S:15][C:5]2[C:6]3[CH:14]=[N:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: C#Cc1ccccc1Cl
Reactant: Brc1cc2c(s1)-c1cnccc1OCC2
Agent: [Cu]I
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Clc1ccccc1C#Cc1cc2c(s1)-c1cnccc1OCC2
Temperature: 85 °C
Yield: 81 %

Procedure:
A mixture of 2-bromo-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine (140 mg, 0.5 mmol) from Example 72, 1-chloro-2-ethynylbenzene, 18 mg (0.025 mmol) of bistriphenylphosphinepalladium(II) chloride and 1 ml (7.17 mmol) of triethylamine in 4 ml of acetonitrile was degassed. Copper (I) iodide (2.4 mg, 0.012 mmol) was then added and the mixture was heated at 85° C. for 3 hours. The mixture was mixed with 20 ml of water and extracted with 10 ml of ethyl acetate twice. The combined extracts were washed with 1% aqueous ammonia, water, brine and dried over sodium sulfate. The solution was concentrated in vacuum, the residue purified by flash chromatography eluting with 30% ethyl acetate in hexane to give 2-((2-chlorophenyl)ethynyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine (137 mg, 81%). MS: (ESI+) 338.1
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[C:2]1=[O:11].[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl>[N:12]1[CH:17]=[CH:16][C:15]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:10])[C:2]2=[O:11])=[CH:14][CH:13]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: OB(O)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(=O)N(c2ccncc2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1H-indole-2,3-dione (isatin, 552 mg, 3.75 mmol), pyridine-4-boronic acid (922 mg, 7.5 mmol), anhyd cupric acetate (1.36 mg, 7.5 mmol), activated 4A molecular sieve (2.0 g), triethylamine (1.05 mL, 7.5 mmol), pyridine (607 μL, 7.5 mmol) and dichloromethane (50 mL) is stirred for 24 hr at room temperature. The mixture is filtered through a pad of hyflo and evaporated. The residue is stirred with ethyl acetate, the insoluble copper salts removed by filtration and the filtrate is evaporated. The residue is purified by flash chromatography eluting with pentane-30 to 80% ethyl acetate to give the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:24][C:25]1[N:26]=[C:27]([CH:30]=[CH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([F:39])[CH:33]=2)[O:28][CH:29]=1.[I-].[K+]>CC(=O)CC>[Cl:38][C:35]1[CH:36]=[CH:37][C:32](/[CH:31]=[CH:30]/[C:27]2[O:28][CH:29]=[C:25]([CH2:24][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[N:26]=2)=[CH:33][C:34]=1[F:39]
Reactant: Fc1cc(C=Cc2nc(CCl)co2)ccc1Cl
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: Fc1cc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)ccc1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
A mixture of 0.16 g (0.74 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol and 0.14 g cesium carbonate in 20 ml 2-butanone was stirred at 60° C. for 30 min, then 0.20 g (0.74 mmol) 4-chloromethyl-2-[2-(4-chloro-3-fluoro-phenyl)-vinyl]-oxazole and 0.123 g (0.74 mmol) potassium iodide were added and stirring at 60° C. continued over night. After evaporation, 15 ml water was added and the mixture extracted thrice with 15 ml ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide and water, dried over sodium sulfate and evaporated to give 350 mg raw material which was purified on silica gel. Elution with heptane/ethyl acetate 1:1 yielded 167 mg (50%) 1-[4-(4-{2-[2-(E)-(4-chloro-3-fluoro-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole as white solid melting at 146-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH2:15][OH:16])([CH3:14])[NH:10][C:9]2=[O:17])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH2:15][O:16][S:23]([CH3:22])(=[O:25])=[O:24])([CH3:14])[NH:10][C:9]2=[O:17])=[CH:4][C:3]=1[C:18]([F:19])([F:21])[F:20]
Reactant: CC1(CO)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC1(COS(C)(=O)=O)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
3-(4-Chloro-3-trifluoromethyl-phenyl)-5-hydroxymethyl-5-methyl-imidazolidine-2,4-dione from Example 10 (1.01 g, 3.14 mmoL) in DCM (10 mL) was treated with TEA (0.66 mL, 4.70 mmoL) followed by MsCl (360 mg, 3.14 mmoL) at 0° C., The reaction was slowly warmed to room temperature and stirring for another 2 hrs. The crude product was partitioned between DCM and water. The organic layer was washed with sat. NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated, then purified by silica gel column chromatography using heptane and ethyl acetate as eluent to afford the title compound as a white solid (1.05 g, yield 85%).
Reaction SMILES: [C:1](=O)([O:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[C:7]([Cl:13])[N:6]=1)OC.ClC[C:17]([O:19][CH3:20])=[O:18]>>[Cl:11][C:10]1[C:5]([O:4][CH2:1][C:17]([O:19][CH3:20])=[O:18])=[N:6][C:7]([Cl:13])=[C:8]([Cl:12])[CH:9]=1
Reactant: COC(=O)Oc1nc(Cl)c(Cl)cc1Cl
Reactant: COC(=O)CCl
Product: COC(=O)COc1nc(Cl)c(Cl)cc1Cl

Procedure:
Mixtures of 2.56 g (0.01 g mole) of methyl 3,5,6-trichloro-2-pyridyl carbonate, 0.01 to 0.1 g mole of methyl chloroacetate, and initiator as noted were heated at 100° C. until gas evolution had stopped. Unreacted methyl chloroacetate was then removed from the reaction mixture using a rotary evaporator. The crude product remaining was analyzed by gas chromatography. In each case, a good yield (about 2.8 g of crude product) of the expected 3,5,6-trichloro-2-pyridoxyacetic acid, methyl ester (III) was found with only small amounts of by-products IV, V, and VI as shown schematically below. ##STR2## The reaction conditions and results are listed in detail in Table II.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([O:30][CH3:31])=[CH:25][C:24]=1[Cl:32].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:22][C:23]3[C:24]([Cl:32])=[CH:25][C:26]([O:30][CH3:31])=[CH:27][C:28]=3[Cl:29])[C:8]2=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Reactant: O=C1CCCN1C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
Dissolve commercially available 1-cyclohexyl-pyrrolidin-2-one (88.2 g, 527.9 mmol) in 2500 mL tetrahydrofuran and cool to −78° C. Add 176 mL 2 M LDA and stir for ˜5 min. Add 2-bromomethyl-1,3-dichloro-5-methoxy-benzene (95 g, 351.9 mmol) and allow the reaction to warm to room temperature. Pour the mixture into saturated ammonium chloride and extract twice with dichloromethane. Dry over sodium sulfate, filter and concentrate under vacuum to obtain a tan solid. Add hexanes and stir rapidly before filtering. Wash the filter cake several times with cold hexane to obtain 86 g (69%) of a light-tan solid: MS (m/z): 356 (M+).
Reaction SMILES: [C-:1]#[N:2].[Na+].[C-]#N.CO[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1.Cl>CO.C1(C)C=CC=CC=1>[OH:19][C:12]1[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:14][C:9]([CH2:8][C:1]#[N:2])=[CH:10][C:11]=1[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: [C-]#N
Reactant: COCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)c1cc(CC#N)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Sodium cyanide (2.94 g; 50 mmol) was slurried in methanol (20 mLs) in a 100 mL round bottom flask and the slurry was heated to a gentle reflux. To the cyanide slurry, a solution of 4-methoxymethyl-2,6-di-t-butyl phenol (12.5 g; 50 mmol), toluene (20 mLs) and methanol (25 mLs) was added dropwise over a period of time of 55 minutes. The resultant black reaction mixture was refluxed an additional 35 minutes after complete addition of the 4-methoxymethyl-2,6-di-t-butyl phenol. Upon cooling to ambient temperature, 2N hydrochloric acid (40 mLs) was added to the reaction flask. A yellow slurry which resulted was extracted with diethyl ether. The ether extract was dried (MgSO4) and concentrated in vacuo to afford 11.74 grams of 4-hydroxy-3,5-di-t-butylphenylacetonitrile as identified by NMR. Analysis by VPC indicated a 95% yield of 4-hydroxy-2,6-di-t-butylphenylacetonitrile.