Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH2:5])[CH2:3][OH:4].[C:6](Cl)(=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(Cl)Cl>[C:6]([NH:5][CH:2]([CH3:1])[CH2:3][OH:4])(=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(N)CO
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NC(C)CO
Yield: 51 %

Procedure:
A solution of 4.00 g (53.2 mmol) of commercially obtained dl-2-amino-1-propanol b and 8.0 g (8.8 ml, 29.3 mmol) of hexadecanoyl chloride in 100 ml of CH2Cl2 was stirred at room temperature for hours. The solution was concentrated and the residue was boiled with 200 ml acetone and decanted. The solution was concentrated and the residue was chromatographed on silica gel using 50% ethylacetate in hexane to afford 4.15 g (51%) of the title compound as white needles, m.p. 75-76° C. Using the same procedure as in Example 19, the following compounds were prepared:
Reaction SMILES: Cl[P:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH2:6][C:5]2[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:4]=2[O:3]1.[OH2:34].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:34]=[PH:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH2:6][C:5]2[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:4]=2[O:3]1
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(Cl)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Reactant: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[PH](=O)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.8 %

Procedure:
To a solution of 8.9 g (0.019 mol) of the compound of Example 4 in 150 mL of toluene at ambient temperature is added dropwise a solution of 0.34 mL (0.019 mol) of distilled water in 4.0 mL (0.029 mol) of triethylamine. After the addition is complete, the reaction mixture is stirred at ambient temperature for 15 minutes. The reaction solvent is removed under vacuum and the residue is recrystallized twice with 50 mL of acetonitrile. The acetonitrile is then removed in vacuo and the residue is dried under vacuum to give 2.4 g (79.5% yield) of the title compound as an off-white solid melting at 164° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[C:18]([F:28])=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[C:18]([F:28])[C:17]=3[Cl:16])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(COC)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc2c(c(Cl)c1F)NCC2
Product: CCC(COC)n1cc(Cl)nc(N2CCc3cc(OC)c(F)c(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 140-142° C.; 1H NMR (300 MHz, CDCl3): δ 7.00 (s, 1 H), 6.79 (d, J=7.3 Hz, 1 H), 4.97-4.85 (m, 1 H), 4.34 (t, J=7.6 Hz, 2 H), 3.86 (s, 3 H), 3.65 (dd, J=10.6, 5.8 Hz, 1 H), 3.54 (dd, J=10.6, 3.7 Hz, 1 H), 3.33 (s, 3 H), 3.07 (t, J=7.5 Hz, 2 H), 1.90-1.72 (m, 2 H), 0.92 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C18H21N3O3Cl2F (M+H)+: 416.0944; found m/z 416.0955.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]>C(OC(=O)C)(=O)C>[N+:1]([C:26]1[C:17]([NH:16][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCCCC(=O)Nc1ccccc1C(=O)OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCC(=O)Nc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
Fuming nitric acid (7.0 ml) was added dropwise to acetic anhydride (60 ml) under ice-cooling and there was added conc. sulfuric acid (0.2 ml). To the mixture was added methyl 2-valerylaminobenzoate (12 g), which was stirred for one hour at room temperature. To the resultant mixture was added ice-water and the mixture was then extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The concentrate was purified by column chromatography on silica gel to give crude crystals, followed by recrystallization from isopropyl ether to afford colorless needles (3.9 g, 28%), m.p. 61°-62° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:13]([C:20]#[N:21])[CH2:14][C:15]([O:17]CC)=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.Cl[Co]Cl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:20][NH:21][C:15](=[O:17])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CCOC(=O)CC(C#N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1
Temperature: 20 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
Ethyl 3-(3,5-bis(trifluoromethyl)phenyl)-3-cyanopropanoate (1.2 g, 1.0 eq.) was dissolved in MeOH (48 mL). Dichlorocobalt hexahydrate (1.68 g, 2.0 eq.) was added and the reaction mixture was cooled to 20° C. NaBH4 (1.98 g, 15 eq.) was added portion wise by maintaining temperature below 30° C. After completion of addition, this reaction mixture was stirred for 18 h at 25° C. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (25 mL) and water (25 mL). The reaction mixture was filtered through Celite™ and the organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 0.65 g of crude product, which after trituration with petroleum ether gave 0.5 g of 4-(3,5-bis(trifluoromethyl)phenyl)pyrrolidin-2-one (Yield 47.61%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[BrH:14]>>[Br:14][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C(=O)O)n1
Reactant: Br
Product: Cc1cc(Br)cc(C(=O)O)n1
Temperature: 25 °C

Procedure:
A solution of 3.6 g (19.6 mmol) of 6-Methyl-4-nitro-pyridine-2-carboxylic acid in 40 ml of 48% hydrobromic acid was heated at 100° C. overnight and then allowed to cool to room temperature. The solution was then evaporated to dryness in vaccuo. The crude material (10.5 g) containing inorganic salts was directly used in the next step.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:33])[C:14]=2[NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=2)[C:9]1=[O:34])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[Cl:33][C:13]1[C:14]([NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[C:23]([F:31])[CH:22]=2)=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:34])[N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[CH:17]=[CH:16]2
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@H](CO)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with (R)-2-(6-chloro-5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-1-oxoisoquinolin-2(1H)-yl)propyl acetate (1.200 g, 0.002406 mol), potassium carbonate (0.997 g, 0.00722 mol) and methanol (20 mL, 0.5 mol) and 2 drops of water. The reaction was stirred at room temperature for 1 hour and was filtered over sodium sulfate and washed with methanol. the solvent was removed under reduced pressureunder reduced pressure and the residue purified by flash chromatography to afford the product as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][CH2:17]/[C:18](=[CH:19]\[CH:20]=[C:21]3\[CH2:22][C@@H:23]([OH:28])[CH2:24][CH2:25][C:26]\3=[CH2:27])/[C@@H:13]2[CH2:12][CH2:11]1)[CH2:3][CH2:4][CH2:5][C:6]([OH:9])([CH3:8])[CH3:7].C(Cl)(=O)C1C=CC=CC=1.[CH3:39][Si:40]([CH3:43])([CH3:42])Cl.[OH2:44]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][CH2:17]/[C:18](=[CH:19]\[CH:20]=[C:21]3\[CH2:22][C@@H:23]([OH:28])[CH2:24][CH2:25][C:26]\3=[CH2:27])/[C@@H:13]2[CH2:12][CH2:11]1)[CH2:3][CH2:4][CH2:5][C:6]([OH:9])([CH3:7])[CH3:8].[CH3:39][Si:40]([O:44][Si:40]([CH3:43])([CH3:42])[CH3:39])([CH3:43])[CH3:42]
Reactant: O
Reactant: C[Si](C)(C)Cl
Agent: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C[Si](C)(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 25-hydroxycholecalciferol (5.0 g.) in pyridine (25 ml.) at -15°, under an atmosphere of argon, is added 4-(N,N-dimethylamino)-pyridine (50 mg) followed by benzoyl chloride (2.10 ml.). The solution is warmed to 0° and kept at this temperature for 1.5 hours. After cooling to -15°, trimethylchlorosilane (1.75 ml.) is added and then the mixture is heated to room temperature for 10 minutes, before pouring into water. The mixture is extracted with hexane (500 ml.) and the extracts washed with brine, dilute hydrochloric acid, brine, sodium bicarbonate solution, brine and then dried over sodium sulfate. Evaporation of the solution yields 25-hydroxycholecalciferol, 3-benzoate, trimethylsilylether as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH:16]([OH:18])[CH3:17])=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([C:16](=[O:18])[CH3:17])=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)c1nc(Cl)ccc1OCc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CC(=O)c1nc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a mixture of 1-[3-(benzyloxy)-6-chloropyridin-2-yl]ethanol (7.04 g) synthesized above, 4-methylmorpholine N-oxide (6.26 g) and acetonitrile (140 mL) was added tetrapropylammonium perruthenate (938 mg), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% ethyl acetate/hexane) to give the title object compound (6.26 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:13])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.B.C1COCC1>C1COCC1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2>[CH3:1][C:2]1[C@@H:3]([OH:13])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CC1=C(c2ccccn2)CCC1=O
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Product: CC1=C(c2ccccn2)CC[C@@H]1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
To a solution of ketone 13 (0.2 g, 1.16 mmol) in THF (2 ml) was added (R)-2-methyl-CBS-oxazaborolidine (0.35 ml of 1.0 M solution in toluene, 0.35 nmol, 0.3 equiv) at room temperature. To this solution was added borane-THF (0.755 ml of 1.0 M solution in THF, 0.755 mmol 0.65 equiv) dropwise. The reaction mixture was stirred at room temperature for 30 min after which time another portion of borane-THF (0.8 ml) was added and the mixture was stirred for an additional 3 hours. It was then cooled to 0° C. and quenched carefully by slow addition of water (2 ml). The mixture was extracted with ethyl acetate (3×4 ml). The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a yellow color oil that was purified by flash column chromatography (EtOAc-hexanes, 1:7) to give the alcohol 9 (0.174 g, 86%) as a light yellow solid: [α]22D=−16.2 (c=0.9, CHCl3); TLC Rf=0.47 (silica gel, 25% hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ 8.6-8.59 (d, 3J=4.8 Hz, 1H), 7.66-7.62 (m, 1H), 7.28-7.26 (d, 3J=7.8 Hz, 1H), 7.13-7.10 (m, 1H), 4.75-4.74 (m, 1H), 2.89-2.83 (m, 1H), 2.73-2.67 (m, 1H), 2.42-2.36 (m, 1H), 2.05 (s, 3H), 2.01-1.99 (d, 3J=7.8 Hz, 1H), 1.77-1.71 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 156.750, 149.405, 140.980, 137.494, 136.153, 122.930, 121.717, 82.459, 32.923, 32.771, 13.301; HRMS calcd for C11H13NO+H+ 176.1075; found 176.1080 [M+H+].
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].Br[CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[O:26][CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31]
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: CCC(Br)CC
Product: CCC(CC)Oc1cc(-c2nc(CNC(=O)c3ncccc3C)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 97 and 3-bromopentane, colorless oily N-{2-[4-difluoromethoxy-3-(1-ethylpropoxy)phenyl]oxazol-4-ylmethyl}-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:8]=[CH:9][C:10]=1I)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>[Cu].CCCCCC.C(OCC)(=O)C.C(O)(=O)C.CN(C)C=O>[C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:8]=[CH:9][C:10]=1[S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:3])=[O:2]
Reactant: CC(C(=O)O)c1ccc(I)c(CC(=O)O)c1
Reactant: Sc1ccccc1
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C(=O)O)c1ccc(Sc2ccccc2)c(CC(=O)O)c1
Temperature: 115 °C
Yield: 49 %

Procedure:
2-(3-Carboxymethyl-4-iodophenyl)propionic acid (prepared in the manner as described in Example 12, 202 mg, 0.605 mol.), potassium carbonate (380 mg, 2.8 mmol.), N,N-dimethylformamide (DMF, 10 mL), and thiophenol (95 wt. %, 92 mg, 0.79 mmol.) were mixed. The resulting mixture was heated for 19 hours under reflux (temperature: approx. 115° C.) after addition of 20 mg of powdery copper. The reaction mixture was cooled, made acidic by addition of hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated to leave a residue. The residue was subjected to silica gel column chromatography (Wako gel C-200, Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/1, v/v/v) to obtain 94 mg (0.30 mmol., yield: 49%) of the desired compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[CH2:29][OH:30])[CH2:6][NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:25])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:24])[CH:13]=1.[CH2:31]([Mg]Br)[CH3:32]>C1COCC1>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:11]([CH3:25])=[CH:10][CH:9]=[C:8]([NH:7][CH2:6][C:5]3[CH:26]=[CH:27][C:28]([CH2:29][OH:30])=[C:3]([CH2:2][OH:1])[CH:4]=3)[CH:13]=2)=[C:15]([CH3:24])[CH:16]=1)([OH:23])[CH2:31][CH3:32])[CH3:22]
Reactant: CCC(=O)c1ccc(-c2cc(NCc3ccc(CO)c(CO)c3)ccc2C)c(C)c1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)(CC)c1ccc(-c2cc(NCc3ccc(CO)c(CO)c3)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
450 mg (1.1 mmol) of 1-{5′-[3,4-bis(hydroxymethyl)benzylamino]-2,2′-dimethylbiphenyl-4-yl}-1-propanone are dissolved in 30 ml of THF. 1.5 ml (4.5 mmol) of ethylmagnesium bromide are added and the medium is stirred at room temperature for 1 hour. After the usual work-up, the residue is purified by chromatography on silica gel (eluent: 1 heptane/1 ethyl acetate). A white solid is obtained (m=130 mg; Y=27%).
Reaction SMILES: C([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13][CH2:12]2)[N:9]=1)(=O)C>C(O)C.Cl>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13][CH2:12]2)[N:9]=1
Reactant: CC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Agent: Cl
Solvent: CCO
Product: Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 38.8 %

Procedure:
2-Acetylamino-4-[4-(3-indolyl)piperidinomethyl]thiazole (1.2 g) in a mixture of ethanol (3 ml) and 10% hydrochloric acid (9 ml) was stirred at 80° C. for 2.5 hours. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added dropwise 10% aqueous sodium hydroxide solution (12 ml) under ice-cooling. The resulting crystals were collected, washed with water, dried and recrystallized from ethanol to give 2-amino-4-[4-(3-indolyl)piperidinomethyl]thiazole (410 mg).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=2[CH2:7][O:6][C:5]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:4]1=2.[N:20]1([CH2:26][CH2:27][N:28]2[C:32]3[CH:33]=[CH:34][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:31]=3[NH:30][C:29]2=[O:46])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[F:19][C:16]1[CH:17]=[CH:18][C:4]2[C:3](=[CH:2][C:35]3[CH:34]=[CH:33][C:32]4[N:28]([CH2:27][CH2:26][N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:29](=[O:46])[NH:30][C:31]=4[CH:36]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=3[CH2:7][O:6][C:5]=2[CH:15]=1
Reactant: Fc1ccc2c(c1)OCc1c(F)cccc1C2=CBr
Reactant: CC1(C)OB(c2ccc3c(c2)[nH]c(=O)n3CCN2CCOCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(C=C3c4ccc(F)cc4OCc4c(F)cccc43)ccc2n1CCN1CCOCC1
Yield: 66.2 %

Procedure:
Following procedures essentially as described in Example 219, mix 11-bromomethylene-3,7-difluoro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 200 mg, 0.619 mmol) (prepared essentially as described in Preparation 55), 1-(2-morpholin-4-yl-ethyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (220 mg, 0.589 mmol), Na2CO3 (2M in water, 736 □L, 1.47 mmol), dioxane (4 mL), and Pd(PPh3)4 (36 mg, 0.031 mmol). Purify the crude product on silica gel (64 g) eluting with 2% (2M NH3/MeOH)/CH2Cl2 to afford 191 mg (66%) of the title compound as a white foam. HPLC (ISO80-10) t=1.95 min, 98%; MS [ES] 488 (M−H), 490 (M+H); 1H-NMR (DMSO-d6) δ 10.69 (s, 1H), 7.58 (dd, 1H, J=8.8, 7.0 Hz), 7.24 (m, 2H), 7.02 (s, 1H), 6.96 (d, 1H, J=8.4 Hz), 6.80 (m, 3H), 6.64 (m, 2H), 5.56-5.20 (br d, 2H), 3.81 (t, 2H, J=6.4 Hz), 3.46 (t, 4H, 4.4 Hz), 2.48 (m, 2H), 2.37 (s, 4H).
Reaction SMILES: O.[C:2]([C:4]1[C:5](=[O:17])[O:6][C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[C:9]([CH3:15])[C:8]=2[CH3:16])#[N:3].CC1C(C)=CC=CC=1[OH:26].CC1C(C)=CC=C(C(O)=O)C=1O.C(OC1C(C)=C(C)C=CC=1C(O)=O)(=O)C.C(OC1C(C)=C(C)C=CC=1C(Cl)=O)(=O)C>>[OH2:6].[C:2]([C:4]1([OH:26])[CH2:13][C:12]2[C:7](=[C:8]([CH3:16])[C:9]([CH3:15])=[CH:10][CH:11]=2)[O:6][C:5]1=[O:17])#[N:3]
Reactant: Cc1cccc(O)c1C
Reactant: Cc1ccc2c(O)c(C#N)c(=O)oc2c1C
Agent: CC(=O)Oc1c(C(=O)Cl)ccc(C)c1C
Agent: CC(=O)Oc1c(C(=O)O)ccc(C)c1C
Agent: Cc1ccc(C(=O)O)c(O)c1C
Solvent: O
Product: Cc1ccc2c(c1C)OC(=O)C(O)(C#N)C2

Procedure:
3-Cyano-7,8-dimethyl-4-hydroxycoumarin monohydrate, m.p. (EtOH - pet. ether) 255°-6°, (Found; C, 62.04; H, 4.80; N, 6.04. C12H9NO3.H 2 O requires C, 61.79; H, 4.76; N, 6.01) was prepared from 2,3-dimethylphenol via 3,4-dimethylsalicylic acid (m.p. 192°-3°), 2-acetoxy-3,4-dimethylbenzoic acid (m.p. 142°-4°) and 2 -acetoxy-3,4-dimethylbenzoyl chloride by an analogous procedure to that described in Example 10.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.C(OCC)C.[CH3:15][Sn:16](Cl)([CH3:18])[CH3:17].[Cl-].[NH4+].CC1C=CC(C2C=CC(C)=CC=2)=CC=1>O1CCCC1.O>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([Sn:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][CH:2]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1ccc([Mg]Br)cc1
Agent: Cc1ccc(-c2ccc(C)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc([Sn](C)(C)C)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
41.4 L of 1.0 M p-tolylmagnesium bromide in diethyl ether (41.4 mol) was added dropwise, maintaining the temperature below -5° C., over 4 hours to a solution of 546 g (2.79 mol) of trimethyltin chloride in tetrahydrofuran (4 L) under nitrogen at -10° C. The suspension was allowed to warm slowly to room temperature over 12 hours then saturated ammonium chloride solution (1 L) was added followed by sufficient water (approximately 1 L) to dissolve the precipitate. The solution was extracted with ether-hexane (1:1) (1×4 L, 3×2 L). The combined organic phases were washed with brine, dried over magnesium sulfate and the solvents removed under vacuum. Purification by flash chromatography on silica gel eluting with hexanethyl acetate (95:5) gave a pale yellow oil containing white crystals of 4,4'-dimethylbiphenyl which were removed by filtration to leave 711.3 g (100%) of product. 1H NMR (300 MHz, CDCl3): δ 0.30 (s, 9H), 2.34 (s, 3H), 7.19 (d, 7.7 Hz, 2H), 7.40 (d, 7.7 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:18]([CH2:21][C:22](Cl)=[O:23])=[N+:19]=[N-:20]>CC(C)=O>[N:18]([CH2:21][C:22]([NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=NCC(=O)Cl
Reactant: NCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC(=O)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-benzyloxyethylamine (15 g) and potassium carbonate (40 g) in acetone (400 ml) was treated dropwise with azidoacetyl chloride at 20° C. After stirring for 3 h at room temperature, the mixture was filtered and concentrated in vacuo. Dichloromethane (800 ml) was added, and the solution was washed with aq. sodium bicarbonate. The organic phase was dried over magnesium sulfate. Removal of solvent in vacuo gave a yellow oil which was filtered through silica gel with ethyl acetate. Removal of the solvent in vacuo gave 6a as a colorless oil. Yield: 22 g.