Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH2:15]1[NH:20][CH2:19][CH2:18][N:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C@H:16]12.C(N(C(C)C)CC)(C)C.Cl[C:35]1[N:36]=[N:37][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1>ClCCl.CS(C)=O>[F:50][C:47]([F:48])([F:49])[C:44]1[CH:43]=[CH:42][C:41]([C:38]2[N:37]=[N:36][C:35]([N:20]3[CH2:19][CH2:18][N:17]4[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:16]4[CH2:15]3)=[CH:40][CH:39]=2)=[CH:46][CH:45]=1
Reactant: C1CCN2CCNC[C@H]2C1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(-c2ccc(N3CCN4CCCC[C@@H]4C3)nn2)cc1
Temperature: 160 °C
Yield: 98.1 %

Procedure:
A mixture of the dihydrochloride salt of (R)-octahydropyrido[1,2-a]pyrazine (649 mg, 3.05 mmol), diisopropylethylamine (1.17 ml, 6.72 mmol), 3-chloro-6-(4-trifluoromethylphenyl)-pyridazine (290 mg, 1.12 mmol) and dimethylsulfoxide (1 ml) was heated in a closed vessel at 160° C. for 40 min. The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 ml) and washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulphate. The solvent was removed in vacuo to give 398 mg of the title compound as the free base.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]#[N:12])=[C:5]2[NH:6][CH2:7][CH2:8][CH2:9][N:4]2[N:3]=1.[OH-:13].[NH4+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:10]([C:11]([NH2:12])=[O:13])=[C:5]2[NH:6][CH2:7][CH2:8][CH2:9][N:4]2[N:3]=1
Reactant: Cc1nn2c(c1C#N)NCCC2
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1nn2c(c1C(N)=O)NCCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 1.0 g portion of 4,5,6,7-tetrahydro-2-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile was dissolved with stirring in 5.0 ml of concentrated sulfuric acid. The mixture was stirred for 6 hours at room temperature then poured onto ice. This mixture was made basic with concentrated ammonium hydroxide and then was filtered to give the product of the example as a colorless solid, mp 234°-236° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(O)=[O:2].C(Cl)(=O)C>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:12]2[CH:13]=[C:5]3[C:6](=[CH:10][CH:11]=2)[C:7](=[O:9])[O:8][C:1](=[O:2])[CH2:4]3)=[CH:17][CH:18]=1
Reactant: O=C(O)Cc1cc(OCc2ccc(F)cc2)ccc1C(=O)O
Solvent: CC(=O)Cl
Product: O=C1Cc2cc(OCc3ccc(F)cc3)ccc2C(=O)O1

Procedure:
The 2-Carboxymethyl-4-(4-fluoro-benzyloxy)-benzoic acid (3.4 g, 11.1 mmol) is suspended in acetylchloride (23.8 mL, 33.5 mmol) and refluxed for 4 h. Then the light brown precipitate is filtered off and washed with ether. The mother liquid is concentrated and suspended in cold diethylether and the rest of the compound is filtered again (2.85 g, 90%). MS: m/e=286.1 (M+).
Reaction SMILES: O.[CH:2]1([CH2:8][C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23]CC)=[O:22])[C:15]=3[N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+]>CO>[CH:2]1([CH2:8][C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:23])=[O:22])[C:15]=3[N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCCc2sc(NC(=O)CC3CCCCC3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(CC1CCCCC1)Nc1nc2c(s1)CCCC2C(=O)O

Procedure:
Water (20 mL) and MeOH (80 mL) were added to ethyl 2-(2-cyclohexylacetylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylate (F) (4.9 g, 14 mmol) and NaOH (5.6 g, 0.14 mol), and the resultant mixture was stirred at RT under a blanket of nitrogen as inert gas until completion of the reaction. Following removal of MeOH, 2N hydrochloric acid solution in water (250 mL) and DCM (250 mL) was added. The phases were separated, and the aqueous phase was extracted a number of times with DCM. Following drying of the combined organic phases over Na2SO4 and filtration, there was obtained the product 2-(2-cyclohexylacetylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid (G) in a yield of 3.9 g (corresponding to 87% of theory).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH:9][C:10]1[CH:31]=[CH:30][C:13]2[C:14]3[N:18]([CH2:19][CH2:20][O:21][C:12]=2[CH:11]=1)[CH:17]=[C:16]([C:22]1[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][N:26]=1)[N:15]=3)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:32])[C@@H:7]([N:9]([C:10]1[CH:31]=[CH:30][C:13]2[C:14]3[N:18]([CH2:19][CH2:20][O:21][C:12]=2[CH:11]=1)[CH:17]=[C:16]([C:22]1[N:23]([CH:27]([CH3:28])[CH3:29])[N:24]=[CH:25][N:26]=1)[N:15]=3)[CH3:35])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N[C@@H](C)C(=O)OC(C)(C)C)cc1OCC2
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N(C)[C@@H](C)C(=O)OC(C)(C)C)cc1OCC2
Yield: 96.4 %

Procedure:
To a solution of (S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-propionic acid tert-butyl ester (0.24 g, 0.55 mmol) in DCE (7 mL) was added aqueous formaldehyde (4.4 mL, 55.4 mmol, 37% solution) and sodium triacetoxyborohydride (7.2 g, 34.0 mmol) portion wise over 58 h. The resulting mixture was then washed with saturated aqueous sodium carbonate and the aqueous phase extracted with further DCM. The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give (S)-2-{[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-methyl-amino}-propionic acid tert-butyl ester (0.24 g, 97%). LCMS: RT=3.81 min, [M+H]+=453.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][C@@H:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=[O:21].[Na+].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[Na+]>C(Cl)Cl.CCOCC.O>[CH2:1]([O:8][CH2:9][O:10][CH2:11][C@@H:12]([CH3:19])[CH2:13][CH2:14][CH:15]1[O:21][C:16]1([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=CCC[C@H](C)COCOCc1ccccc1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](CCC1OC1(C)C)COCOCc1ccccc1
Reaction time: 24 h
Yield: 73.6 %

Procedure:
Olefin 5 (3.2 g, 12.2 mmol) was dissolved in anhydrous CH2Cl2 (60 mL), and NaHCO3 (1.6 g, 18.4 mmol) was added. Then, 3-chloroperoxybenzoic acid (60%, 12.8 g, 36.6 mmol) was added at room temperature with stirring. The stirring was continued for 24 hours, and the mixture was diluted with ether, and shaken with water and 2M NaOH. The organic layer was washed with water and saturated NH4Cl, dried over Na2SO4, and evaporated. The residue was chromatographed on silica gel using hexane/EtOAc (9:1) as an eluent to give the oily product 6 (2.5 g, 74%).
Reaction SMILES: NC1C=CC(OC)=CC=1C(O)=O.[OH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:24]=[CH:25][C:26]([O:28][CH3:29])=[O:27])[CH:22]=2)[N:17]=[C:16]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[N:15]=1>>[OH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:22]=2)[N:17]=[C:16]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[N:15]=1
Reactant: COC(=O)C=Cc1ccc2nc(-c3cccnc3)nc(O)c2c1
Agent: COc1ccc(N)c(C(=O)O)c1
Product: COC(=O)CCc1ccc2nc(-c3cccnc3)nc(O)c2c1

Procedure:
Methyl 3-(4-hydroxy-2-(pyridin-3-yl)quinazolin-6-yl)propanoate was prepared in a manner analogous to that described for 2-amino-5-methoxybenzoic acid in Method K, replacing 5-methoxy-2-nitrobenzoic acid with methyl 3-(4-hydroxy-2-(pyridin-3-yl)quinazolin-6-yl)acrylate to afford 1.40 g of xxvii-a in quantitative yield as a yellow solid. LCMS m/z=310.0 (M+1) (Method B) (retention time=1.42 min).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:24][CH2:25][CH3:26])[C:13](I)=[C:14]([O:16][S:17]([CH:20]3[CH2:22][CH2:21]3)(=[O:19])=[O:18])[CH:15]=2)=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([NH:34]C(=O)C(F)(F)F)=[C:30]([CH3:41])[CH:29]=1.C(O)C>O1CCOCC1.C(COC)OC>[NH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:13]2[C:12]([O:24][CH2:25][CH3:26])=[CH:11][C:10]([CH2:9][C:5]3[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[CH:15][C:14]=2[O:16][S:17]([CH:20]2[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:29][C:30]=1[CH3:41]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C2CC2)c1I
Reactant: Cc1cc(Br)ccc1NC(=O)C(F)(F)F
Solvent: CCO
Solvent: C1COCCO1
Solvent: COCCOC
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C2CC2)c1-c1ccc(N)c(C)c1
Yield: 30 %

Procedure:
Starting from cyclopropanesulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester (294 mg; 0.6 mmol) and N-(4-bromo-2-methyl-phenyl)-2,2,2-trifluoroacetamide (282 mg; 1.0 mmol) (first step in 12 ml dioxane instead of dimethylformamide with bis-triphenylphosphine-palladium dichloride (56 mg; 0.08 mmol) and second step in dimethoxyethane (8 ml) and ethanol (2 ml) with tetrakis-triphenylphosphine-palladium (69 mg; 0.06 mmol)), 151 mg (30%) cyclopropanesulphonic acid 4′-amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-3′-methyl-biphenyl-2-yl ester are obtained as a colourless powder.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([O:28][CH2:29][CH3:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[S:17][CH:18]=2)=[CH:8][C:7]=1[CH2:26][CH3:27].[Li+].[OH-]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[S:17][CH:18]=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([O:28][CH2:29][CH3:30])[C:3]([OH:31])=[O:2])=[C:7]([CH2:26][CH3:27])[CH:8]=3)[N:15]=2)=[CH:20][CH:21]=1
Reactant: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1CC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1CC)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], (2S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-ethyl-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (2S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-ethyl-phenyl}-2-ethoxy-propionic acid as light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[OH:9].[C:10](Cl)(Cl)=[S:11].[OH-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]2[O:9][C:10](=[S:11])[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: Oc1cccc(F)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Fc1cccc2oc(=S)oc12
Temperature: 10 °C
Reaction time: 2 h
Yield: 22.6 %

Procedure:
3-Fluorobenzene-1,2-diol (5.0 g, 39 mmol) and thiophosgene (3.3 mL, 5.0 g, 42 mmol) were combined in chloroform (50 mL), cooled to 10° C. and treated dropwise over 30 min with sodium hydroxide (10% solution; 36 g, 90 mmol) with vigorous stirring. After stirring for 2 h at ambient temperature, the chloroform was removed under vacuum, and the solid formed was collected by filtration and washed with water. The solid was dissolved in ethyl acetate (100 mL), the solution was washed with water (30 mL) and saturated NaCl (30 mL), dried (Na2SO4) and evaporated. The crude solid was purified by chromatography on silica with 0-30% ethyl acetate-hexane to give the title compound (1.5 g, 77%): mp 58-59° C.; 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 1H), 7.12 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −131.32; EIMS m/z 170.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:19][C:20]1([CH3:32])[C:24]([CH3:26])([CH3:25])[O:23][B:22]([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)[O:21]1.O[CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:19][C:20]1([CH3:32])[C:24]([CH3:25])([CH3:26])[O:23][B:22]([C:27]2[CH:31]=[N:30][N:29]([CH2:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:37][CH2:36]3)[CH:28]=2)[O:21]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reaction time: 18 h
Yield: 54.9 %

Procedure:
A solution of 630.8 mg (2.5 mmol) of 1,1′-(azodicarbonyl)-dipiperidine in 5 ml of THF was added dropwise to a mixture of 388 mg (2.0 mmol) of 4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane, 538 mg (2.5 mmol) of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate and 0.62 ml (2.5 mmol) of tributylphosphine in 6 ml of tetrahydrofuran at 0° C. The mixture was stirred for 18 hours. The precipitate was filtered out and washed with ethyl ether. The filtrate was mixed with 50 ml of water and extracted with ethyl ether. The organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified on 24 g silica column eluting with MeOH 0-4% gradient in DCM to afford 0.43 g (55%) of tert-Butyl 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate. ESI MS m/z 392.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:24]1[C:25]([C:31]([OH:33])=[O:32])=[N:26][CH:27]=[C:28]([Cl:30])[N:29]=1>C1COCC1>[Cl:30][C:28]1[N:29]=[C:24]([NH:12][C:3]2[CH:4]=[CH:5][C:6]([Si:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=2[F:1])[C:25]([C:31]([OH:33])=[O:32])=[N:26][CH:27]=1
Reactant: O=C(O)c1ncc(Cl)nc1Cl
Reactant: C[Si](C)(C)c1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(Nc2nc(Cl)cnc2C(=O)O)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of 2-fluoro-4-trimethylsilanyl-phenylamine (3.8 g, 20.7 mmol, 2.0 eq) in anhydrous THF (150 mL) at −78° C. under N2 was added dropwise a solution of 1.0 M LHMDS in THF (33.2 mL, 30 mmol, 3.2 eq) over 20 minutes. After 1 hour at −78° C., a solution of 3,5-dichloro-pyrazine-2-carboxylic acid (2.0 g, 10.3 mmol) in anhydrous THF (30 mL) was added. The mixture was stirred at −78° C. for 30 minutes, and then stirred at ambient temperature for 18 hours. The mixture was quenched with water and the pH adjusted to pH 2 by the addition of 2 N HCl. The reaction mixture was extracted with ethyl acetate, and the organic layer washed with water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 20 to 50% ethyl acetate in hexane, followed by 0% to 30%, methanol in dichloromethane) to give the desired compound as a yellow solid (2.95 g, 83.8%). 1H NMR (CDCl3, 400 MHz) δ ppm 10.41 (s, 1H), 8.28 (t, J=7.79 Hz, 1H), 7.93 (s, 1H), 7.40-7.23 (m, 2H), 0.27 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12]C)=[CH:2]1.Cl.[NH+]1C=CC=CC=1>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[CH:2]1
Reactant: COc1ccccc1-c1ccsc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1ccccc1-c1ccsc1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
An intimate mixture of 2-(thien-3-yl)anisole (1.2 g, 4 mmol) and 6.0 g (50 mmol) of pyridinium hydrochloride is heated for 20 minutes to 200° C. (1000 W MW, microwave). The mixture is allowed to cool to room temperature then is extracted with ethyl acetate and dichloromethane. The organic extracts are washed with water, dried over sodium sulfate and evaporated. The residue is purified via flash column on silica (eluent: 100% hexane>hexane/ethyl acetate 9:1 gradient) to give 700 mg of 2-(thien-3-yl)phenol (97%). M+=176.
Reaction SMILES: [CH:1]([S:4][CH:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18]C(=O)C)[C:6]([Cl:9])([Cl:8])[Cl:7])([CH3:3])[CH3:2].Cl>C(O)C>[CH:1]([S:4][CH:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[C:6]([Cl:8])([Cl:7])[Cl:9])([CH3:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)NC(SC(C)C)C(Cl)(Cl)Cl
Agent: Cl
Solvent: CCO
Product: CC(C)SC(NC(=O)c1ccccc1O)C(Cl)(Cl)Cl
Yield: 94.7 %

Procedure:
3.2 g of N-(1-iso-propylthio-2,2,2-trichloroethyl)-2-acetoxybenzamide, 30 ml of ethanol and 0.5 ml of 35% hydrochloric acid were mixed together and the reaction was effected while stirring under reflux for two hours. The solvent was distilled off, and the contents were washed with water and dried to obtain 2.7 g of N-(1-iso-propylthio-2,2,2-trichloroethyl)-2-hydroxybenzamide as white crystals.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.Cl.[F:7][C:8]1[C:13]([OH:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:9]=1[F:18]>>[CH3:1][Si:2]([CH3:5])([CH3:4])[O:14][C:13]1[C:12]([F:15])=[C:11]([F:16])[C:10]([F:17])=[C:9]([F:18])[C:8]=1[F:7]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C[Si](C)(C)Cl
Agent: Cl
Product: C[Si](C)(C)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 0.5 h

Procedure:
In a manner similar to Example 1, 2.5 mol of boiling trimethylchlorosilane was placed without solvent in a 2-liter reactor which contained, instead of the packed column, a reflux condenser (nitrogen gas flooded, with hydrogen chloride exhaust), and about 2 mol (370 g) of pentafluorophenol (m.p. 39° C.) in molten form was fed into it over a period of 30 minutes. The reactor temperature then rose to about 124° C. As boiling continued the temperature rose to about 160° C. in 90 minutes. Then a distillation was performed at about 300 mbar and 118° C. The yield of trimethylpentafluorophenoxysilane was virtually quantitative.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@H:7]([C:9]#[N:10])[CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O[Li].O>CO>[C:14]([O:13][C:11]([N:5]1[CH2:6][C@@H:7]([C:9]#[N:10])[CH2:8][C@H:4]1[C:3]([OH:18])=[O:2])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)[C@@H]1C[C@H](C#N)CN1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)O
Reaction time: 4 h

Procedure:
A solution of N-boc-cis-4-cyano-L-proline methyl ester (800 mg, 3.15 mmol) in MeOH (27 mL) was cooled to 0° C. and LiOH.H2O (792 mg, 18.9 mmol) was added. The colorless solution was allowed to reach RT and stirred for 4 h. LiOH.H2O (792 mg, 18.9 mmol) was added and the reaction further stirred at for 1 hour to complete the reaction. MeOH was concentrated and the residue diluted in CH2Cl2 and treated with aqueous 1M HCl adjusting the pH to 1. The layers were separated and the aqueous one re-extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the desired compound which was used in the next step without further purification. MS (LC/MS): 263.0 [M+Na]+, 503.2 [2M+Na]+, 239.1 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1cc(Br)cc(C(=O)O)c1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(=O)O)cc(-c2ccccc2Cl)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of 3-bromo-5-methoxybenzoic acid (1 g, 4.06 mmol) and 2-chlorophenylboronic acid (1.27 g, 8.13 mmol) in 1,4-dioxane (10 mL) and water (2 mL), Pd(PPh3)4 (468 mg, 0.40 mmol) and Na2CO3 (2.15 g, 20.3 mmol) were added and the resulting mixture was stirred at 80° C. for 16 h. The mixture was allowed to cool to room temperature and acidified with aqueous HCl (1.0 M) to adjust the pH to 3-4. The mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford the desired product (800 mg, 75% yield) without further purification. ESI-MS m/z: 361.2 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.Cl.[F:11][C:12]1([F:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:15]1[CH2:16][CH2:17][C:12]([F:18])([F:11])[CH2:13][CH2:14]1
Reactant: FC1(F)CCNCC1
Reactant: BrCc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC1(F)CCN(Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
A mixture of 3-bromobenzyl bromide (3.43 g, 13.73 mmol), 4,4-difluoro-piperidine hydrochloride (2.20 g, 13.97 mmol), and potassium carbonate (4.82 g, 34.86 mmol) in acetonitrile (50 mL) was stirred at RT for 16 h. The mixture was filtered and evaporated, and the residue partitioned between water (30 mL) and EtOAc (3×30 mL). The combined organic extracts were washed with water (2×50 mL) and dried (Na2SO4). The solvent was evaporated to give the title compound as a colourless oil (3.96 g, 99%). LCMS (Method 1): Rt 1.89 min, m/z 290/292 [MH+].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:11]=O)[CH:4]=[CH:3][CH:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2/[CH:11]=[CH:21]/[CH:22]=[O:23])[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2cccnc12
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1cccc2cccnc12

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 8-quinolinecarboxaldehyde (prepared as described in J. Am. Chem. Soc. 1997, 119, 8891) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.CC1(C)CCCC(C)(C)N1.[Li]CCCC.[C:25](=[O:27])=[O:26].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:25]([OH:27])=[O:26]
Reactant: O=C=O
Reactant: COc1ccc(F)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)c(C(=O)O)c1
Temperature: 0 °C
Yield: 40 %

Procedure:
Alternatively, a solution of 4-fluoroanisole (500 mg, 4.0 mmol) in THF (10 mL) was added to a cooled solution (−78° C.) of 2,2,6,6-tetramethylpiperidine (1.1 g, 7.9 mmol) and BuLi (5 mL, 1.6 M in hexanes, 7.9 mmol) in THF (10 mL) at a slow rate to maintain the temperature below −70° C. The mixture was maintained at this temperature for 12 h, and then dry CO2 gas was passed into the solution. The resulting mixture was allowed to warm up to 0° C. and then HCl (1 M, 10 mL) was added and the product was extracted with diethyl ether. The combined organic extracts were then dried over sodium sulfate, washed with water and brine, filtered and evaporated. The crude solid was then partioned between sodium hydroxide (1 M, 10 mL) and diethyl ether. The aqueous phase was then acidified with HCl (1 M) and the product extracted with diethyl ether. Evaporation afforded the title compound (268 mg, 40%) as a white solid. MS m/e=168.9 (M−H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[CH2:12]([C:14]1[NH:15][CH:16]=[CH:17][N:18]=1)[CH3:13]>O1CCOCC1>[Br:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH2:12][CH3:13])[CH:10]=[CH:9][CH:8]=1
Reactant: CCc1ncc[nH]1
Reactant: O=C(CBr)c1cccc(Br)c1
Solvent: C1COCCO1
Product: CCc1nccn1CC(=O)c1cccc(Br)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 2-bromo-1-(3-bromophenyl)ethanone (120 mg, 0.432 mmol) in dioxane (2 mL) was added 2-ethylimidazole (83.0 mg, 0.864 mmol) and the reaction mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the sub-title compound in 51% yield (65 mg, 0.22 mmol).