Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:16][C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc(C(F)(F)F)n[nH]1
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1[nH]nc(C(F)(F)F)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Dissolve 5-methyl-3-(trifluoromethyl)pyrazole (1.00 g, 6.66 mmol) in 60% aqueous acetic acid (13 mL). Add sodium acetate (0.819 g, 9.99 mmol) and cool to 0° C. Add bromine (1.17 g, 7.33 mmol) dropwise over 10 min. Stir at 0° C. for 3 hr, then at room temperature for 18 hr. Add ethyl acetate and saturated aqueous sodium sulfite solution. Separate organics and wash one time with saturated aqueous sodium bicarbonate solution followed by saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate to give 4-bromo-5-methyl-3-trifluoromethyl-1H-pyrazole (1.50 g, 100%). GC-MS: m/z=229 [M+].
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C@@H:13]([CH2:18][OH:19])[CH2:14][CH:15]([CH3:17])[CH3:16].O>C1COCC1>[OH:19][CH2:18][C@H:13]([N:12]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C[C@@H](N)CO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](CO)N1C(=O)c2ccccc2C1=O
Temperature: 85 °C
Yield: 47.1 %

Procedure:
Phthalic anhydride (10.30 g, 69.55 mmol) and D-Leucinol (8.15 g, 69.55 mmol) were mixed in THF (100 mL), the reaction mixture was heated at 85° C. and refluxed for 18 hours. After cooling to room temperature, water was added and the solution was extracted with EtOAC, the extracts were washed with 1 N HCl, water, aq. NaHCO3, water and brine, dried over MgSO4, filtered and evaporated to give 8.1 g of (R)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (47%). 1H NMR (500 MHz, CDCl3): δ 0.94 (m, 6H); 1.54 (m, 2H); 1.99 (m, 1H); 3.86 (m, 1H); 4.04 (m, 1H); 4.47 (m, 1H); 7.72 (m, 2H); 7.83 (m, 2H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[CH:11]([C@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:27])=[CH2:26])([CH3:13])[CH3:12].I[CH3:30]>C1COCC1>[CH3:30][C@@H:21]([CH2:22][CH2:23][CH2:24][C:25]([CH3:27])=[CH2:26])[C:20]([N:15]1[C@@H:14]([CH:11]([CH3:13])[CH3:12])[CH2:18][O:17][C:16]1=[O:19])=[O:28]
Reactant: CI
Reactant: C=C(C)CCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: C=C(C)CCC[C@H](C)C(=O)N1C(=O)OC[C@@H]1C(C)C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
As reported by Schinzer et al.104 Sodium hexamethyldisilazane (13 ml of 1.0 M in THF, 13 mmol, 1.1 equiv) was added dropwise to a solution of imide 73 (3.0 g, 11.9 mmol, 1 equiv) in THF (15 ml) at −78° C. The reaction mixture was stirred for 30 min and a solution of iodomethane (3.74 ml, 60 mmol, 5 equiv) in THF (2 ml) was added dropwise. After stirring for 10 h at −78° C., the reaction was quenched with saturated aqueous ammonium chloride (10 ml), and extracted with ether (4×50 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product 74 (12:1 ratio of diastereomers by 1H NMR). Purification by flash column chromatography (10% EtOAc/hexanes) afforded compound 74 (2.69 g, 85%) as a colorless oil: [α]22D=+ 87.2 (c=0.5, CHCl3); TLC Rf=0.47 (silica gel, 25% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 4.674 (s, 1H), 4.642 (s, 1H), 4.45-4.42 (m, 1H), 4.265-4.23 (t, 2J=9 Hz, 1H), 4.2-4.17 (dd, 2J=9.6 Hz, 3J=3 Hz, 1H), 3.75-3.69 (m, 1H), 2.36-2.29 (m, 1H), 2.01-1.97 (t, 2J=7.2 Hz, 2H), 1.68 (s, 3H), 1.57-1.30 (m, 4H), 1.195-1.183 (d, 3J=7.2 Hz, 3H), 0.9-0.888 (d, 3J=7.2 Hz, 3H), 0.861-0.85 (d, 3J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 177.338, 153.886, 145.779, 110.214, 63.414, 58.628, 37.903, 37.866, 32.833, 28.632, 25.381, 22.538, 18.165, 18.132, 14.901.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:14]([O:15][CH3:16])=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>ClCCl>[C:24]([N:10]1[CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([O:3][CH3:2])[C:14]([O:15][CH3:16])=[CH:13][C:7]=2[CH2:8][CH2:9]1)(=[O:27])[CH:25]=[CH2:26]
Reactant: COc1cc2c(cc1OC)CCNCC2
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCc2cc(OC)c(OC)cc2CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At ambient temperature, 70 g (287.2 mmol) of the product obtained in Step 2 are dissolved in 1200 mL of dichloromethane, and then 100 mL (718 mmol/2.5 eq.) of triethylamine are added all at once. The mixture is brought to 0° C. and a solution of 25.8 mL (315.9 mmol/1.1 eq.) of acryloyl chloride in 270 mL of dichloromethane is poured in dropwise, maintaining the temperature at about 0° C. After 2 hours at 0° C., the mixture is stirred at ambient temperature overnight. Washing with 750 mL of water, 750 mL of 1N hydrochloric acid and 750 mL of water and then drying over magnesium sulphate are then carried out. After filtration and evaporation, the residue is chromatographed over 3.2 kg of silica (eluant: dichloromethane/ethanol: 95/5), followed by recrystallisation from isopropanol. After filtration over a frit and drying in vacuo at 50° C., the desired product is obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=O)=[CH:8][C:7]([O:22][CH3:23])=[CH:6][CH:5]=2.[CH3:24][N:25]([CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=1.C(OC(=O)C)(=O)C>>[CH3:33][N:32]([CH3:34])[C:28]1[CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=[CH:30][C:29]=1[C:11]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=3)[NH:3][C:2]=2[CH3:1])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:17]1
Reactant: COc1ccc2[nH]c(C)c(C(=O)c3ccccc3C(=O)O)c2c1
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2[nH]c(C)c(C3(c4ccc(N(C)C)cc4N(C)C)OC(=O)c4ccccc43)c2c1
Yield: 91.5 %

Procedure:
A mixture of 2.0 g (0.006 mole) of 2-[(2-methyl-5-methoxy-3-indolyl)carbonyl]benzoic acid, obtained as described in part A above, 1.1 g (0.0067 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and six ml of acetic anhydride were interacted at 50°-55° C. in a manner similar to that described in Example 2, part B to obtain 2.5 g of 3-[2,4-bis(dimethylamino)-phenyl]-3-(2-methyl-5-methoxy-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =R6 =H; R=R5 =CH3 ; R4 =N(CH3)2 ; Y1 =OCH3), as a light pink-colored solid melting at 196°-198° C. with decomposition. The infrared spectrum, showing a significant maximum at 1740 cm-1 (C=O; s) and the nuclear magnetic resonance spectrum were in accord with the structure. A toluene solution of this product spotted on a phenolic resin coated paper developed an intense violet-colored image.
Reaction SMILES: [N:1]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[CH:4][N:3]=[CH:2]1.C(O[CH:15](OCC)[N:16]([CH3:18])[CH3:17])C>>[CH3:15][N:16]([CH:18]=[C:6]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:17]
Reactant: CCOC(=O)Cn1ccnc1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)n1ccnc1

Procedure:
38.0 g (244.9 mmol) of the compound from Example 3A are stirred in 126 ml (108.1 g, 734.7 mmol) of N,N-dimethylformamide diethyl acetal at a bath temperature of 90° C. for 16 h. After cooling, the mixture is concentrated under reduced pressure, the residue is stirred with diisopropyl ether and the solid is filtered off and finally washed with diisopropyl ether. Yield: 49.0 g (95% of theory)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(=O)[CH3:11]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: NNc1ccc(I)cc1
Reactant: CC(=O)c1ccncc1
Product: CC(=NNc1ccc(I)cc1)c1ccncc1

Procedure:
Analogously to the process described in Example 1A, 5.0 g (21.36 mmol) of 4-iodophenylhydrazine and 4-acetylpyridine give 6.67 g (92% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[CH:4][N:3]=1.CN(C=O)C.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>>[Cl:13][C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:3]=[CH:4][N:5]=1
Reactant: COC(=O)Cc1c(Cl)ncnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1c(Cl)ncnc1NCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of methyl 2-(4,6-dichloropyrimidin-5-yl)acetate (1.00 equiv; 65.10 mmol; 14.39 g) in DMF (0.5 M; 1.68 mol; 130.20 mL), add 4-methoxybenzylamine (1.10 equiv; 71.61 mmol; 9.36 mL) and DIPEA (1.20 equiv; 78.12 mmol; 13.62 mL) and stir the mixture at 60° C. for 1 h. Quench with ice-water, extract with EA, and wash the organic layer with 1N HCl, water and brine, dry over MgSO4, filter and concentrate in vacuo to the title compound (54.98 mmol; 17.69 g; 84.45%) as a yellow solid and use without further purification. 1H NMR (300 MHz, DMSO): 8.20 (s, 1H), 7.21-7.18 (m, 2H), 6.89-6.85 (m, 2H), 4.53 (d, J=5.8 Hz, 2H), 3.76 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=2[C:21]2[CH:41]=[CH:42][CH:43]=[CH:44][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:23]3[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=3[C:21]3[CH:41]=[CH:42][CH:43]=[CH:44][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-K), the title compound was prepared. The reaction was monitored by tic (Rf=0.35, 3% MeOH/CHCl3) and product was purified by chromatography (silica, 3% MeOH/CHCl3).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:52][CH2:53][NH:54]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:52][CH2:53][NH2:54])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(O)ccc21
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To 1-(phenylsulfonyl)-1 H-indol-5-ol, (Intermediate 8, 8.0 g, 29 mmol) were 1,1′-azobis(N,N-dimethylformamide) (7.6 g, 44 mmol), triphenylphosphine (15.4 g, 580 mmol), tert-butyl N-(2-hydroxy-ethyl)carbamate (9.4 g, 58 mmol) and DCM (200 mL) added. The reaction mixture was heated at 50° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature and TFA (50 mL) was added. The reaction mixture was stirred for 3 hours and evaporated. The crude material was purified with flash chromatography on silica gel (DCM:MeOH, 95:5) to give the title compound (9.6 g). MS m/z 317 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C:10]([C:11](=[O:25])[N:12]([CH:22]2[CH2:24][CH2:23]2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:9]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][C:36]3[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:43])=[CH:28][CH:27]=2)[CH2:8][CH2:7][N:6]1[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C@@H:5]1[C:10]([C:11](=[O:25])[N:12]([CH:22]2[CH2:24][CH2:23]2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[C:9]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][C:36]3[C:37]([Cl:43])=[CH:38][CH:39]=[CH:40][C:41]=3[Cl:42])=[CH:28][CH:27]=2)[CH2:8][CH2:7][N:6]1[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)=C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)[C@H]1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)=C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)[C@H]1CN
Yield: 18 %

Procedure:
Into a 10 mL round bottom flask was added 19C (200 mg, 302 μmol) and THF (3 mL). Triphenylphosphine (166 mg, 634 μmol) and water (112 mg, 6.22 mmol) was added and the flask was fitted with a reflux condenser and nitrogen inlet. The mixture was refluxed for three hours. Solvent was removed under vacuum and the residue was purified by preparatory LCMS to give 19D (40 mg, 21%). ESI-MS:m/z 734.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([NH:23][NH2:24])=[O:22])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:24]/[NH:23][C:21](=[O:22])[C:20]2[CH:25]=[CH:26][CH:27]=[C:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[CH:19]=2)/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cccc(N2CCOCC2)c1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(N2CCOCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 68.6 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (40 mg, 0.234 mmol) and 3-morpholinobenzohydrazide (51.9 mg, 0.234 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (60 mg) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, 1H, J=2.4 Hz), 7.42-7.32 (m, 4H), 7.20 (m, 1H), 6.94 (d, 1H, J=8.8 Hz), 3.77 (m, 4H), 3.19 (m, 4H), 2.48 (s, 3H). ESI-MS: 374.1 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][N:17]=2)[CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc(CN2CCC(NC(=O)OC(C)(C)C)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCC(N)CC2)nc1

Procedure:
The product of example 30 is heated for 3 hours at 40° C. in a solution of CH2Cl2 containing 11 ml of CF3COOH. The solvent is evaporated off and the substance crystallised in acetone. The named product is obtained: M. P. 173-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[CH3:12][O:13][CH2:14]Cl>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][O:6][CH2:12][O:13][CH3:14])[CH:3]=1
Reactant: COCCl
Reactant: OCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOCc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
To a tetrahydrofuran (100 mL) solution of 3-bromobenzyl alcohol (10 g, 54 mmol) was added sodium hydride (2.3 g, 98 mmol, 60% in oil) at room temperature. Then, chloromethyl methyl ether (5.2 g, 64 mmol) was added to this suspension, which was stirred for 15 minutes at 60° C. This mixture was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=8:1) to obtain the title compound (10 g, 83%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[N:16]([O-])=[O:17].[Na+]>O>[C:1]([O:5][C:6](=[O:11])[C:7](=[N:16][OH:17])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a mixture of 158 g of acetoacetic acid-tert. butylester and 1000 ml of glacial acetic acid is added dropwise, while maintaining the temperature at 5°, a solution of 86.4 g of NaNO2 in 500 ml of water. After 4 hours stirring at 5°, the mixture is extracted 5 times with ether, the purified ether extracts are washed 5 times with water and twice with saturated sodium chloride and evaporated to dryness to obtain the heading compound, m.p. 55°-63°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:6]#[N:7].Cl.[C:13]([O:17][C:18](=[O:22])[CH2:19][NH:20][CH3:21])([CH3:16])([CH3:15])[CH3:14]>>[Cl:11][C:9]1[CH:10]=[C:3]([CH:4]=[C:5]([C:6]#[N:7])[CH:8]=1)[CH2:2][N:20]([CH3:21])[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22]
Reactant: N#Cc1cc(Cl)cc(CBr)c1
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Product: CN(CC(=O)OC(C)(C)C)Cc1cc(Cl)cc(C#N)c1

Procedure:
The title compound was prepared following general procedure 10, starting from 3-(bromomethyl)-5-chlorobenzonitrile and sarcosine tert-butyl ester hydrochloride. It was isolated as a yellow oil (570 mg, 78%). LC/MS (Method B): 295.1 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([OH:12])(=O)[CH:8]=[CH:9][CH3:10].[C:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:13]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[CH:17][C:16]([C:9]([CH3:10])=[CH:8][CH2:7][OH:12])=[CH:15][CH:14]=1
Reactant: CC=CC(=O)O
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=CCO)c1ccc(-c2ccccc2)cc1
Yield: 40.6 %

Procedure:
LiAlH4 reduction of ethyl 3-([1,1′-biphenyl]-but-2-enoate (3e) using THF as solvent under similar conditions furnished 40.6% yield of 3-([1,1′-biphenyl]-4yl)-2-butenol (4e).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CN1CCCC1)OC2

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), pyrrolidine (0.5 ml) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 315 (M+, 0.5), 95 (4), 85 (6), 84 (bp), 75 (4), 55 (7).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[CH:16][C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][N:13]=1)[CH3:2].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:14][N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(OS(=O)(=O)C(F)(F)F)cn1
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(-c2ccccc2)cn1
Yield: 86.2 %

Procedure:
Compound II (22 mg, 0.046 mmol), Pd(PPh3)4 (1.6 mg, 0.0014 mmol), phenylboronic acid (11.2 mg, 0.092 mmol) and potassium carbonate (9.5 mg, 0.07 mmol) were stirred in toluene (2 mL) at 90° C. in a sealed tube for 20 h. Then the reaction mixture was filtrated through celite and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 to 70:30) to furnish 16 mg of III in mixture with the starting material.
Reaction SMILES: Cl[C:2]1C(F)=C(NC2C3C(=CC(OC)=C(CN(C)[C@H](C(N)=O)CCOC)C=3)N=CN=2)C=CC=1.[C:33]([O:37][C:38]([NH:40][C@H:41]([C:46]([OH:48])=[O:47])[CH2:42][CH2:43][O:44][CH3:45])=[O:39])([CH3:36])([CH3:35])[CH3:34].C(OC(N[C@H](C(O)=O)COC)=O)(C)(C)C>>[C:33]([O:37][C:38]([N:40]([CH3:2])[C@H:41]([C:46]([OH:48])=[O:47])[CH2:42][CH2:43][O:44][CH3:45])=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: COCC[C@@H](C(N)=O)N(C)Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Reactant: COCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: COCC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C

Procedure:
The N2,O-dimethyl-L-homoserinamide used as starting material was prepared by methylating N-(tert-butoxycarbonyl)-O-methyl-L-homoserine using an analogous method to that described in Example 7 for the methylation of N-(tert-butoxycarbonyl)-O-methyl-L-serine, to give N-(tert-butoxycarbonyl)-N,O-dimethyl-L-homoserine; 1H NMR spectrum: (DMSO d6, 100° C.) 1.40 (s, 9H), 1.91 (m, 1H), 2.09 (m, 1H), 2.75 (s, 3H), 3.24 (s, 3H), 3.34 (m, 2H), 4.44 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([C:12]([CH2:14][CH3:15])=[O:13])=[CH2:11].C(N(CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[CH2:11][CH2:10][C:12](=[O:13])[CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: C=CC(=O)CC
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC(=O)CCC(=O)c1ccc(F)cc1
Temperature: 70 °C
Yield: 89.5 %

Procedure:
A mixture of 36.61 g (295 mmol) of 4-fluorobenzaldehyde, 25 g (297.2 mmol) of ethyl vinyl ketone, 29 mL (206.9 mmol) of triethylamine and 11.94 g (44.25 mmol) of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride is stirred and heated at 70° C. for six hours. The cooled solution is diluted with 2 liters of diethylether and washed with 2×300 mL of water, 2×100 mL of 2M hydrochloric acid, 100 mL of water, 200 mL of a saturated solution of sodium bicarbonate and brine. The organic layer is separated, dried (magnesium sulfate), filtered, and concentrated to provide 55 g of 1-(4-fluorophenyl)1,4-hexanedione after recrystallization from methanol; mp 56°-57° C.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:24])[C@H:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH3:16])C1C=CC=CC=1.[BH4-].[Na+]>C1COCC1.O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:15]([CH3:16])[CH2:14][OH:24])=[CH:22][CH:21]=1
Reactant: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
To a room-temperature solution of (S)-4-benzyl-3-((S)-2-(4-fluorophenyl) propanoyl)oxazolidin-2-one (1.8 g, 5.5 mmol, 1.0 equiv) in THF (18 mL) was added a solution of NaBH4 (1.0 g, 26.4 mmol, 4.8 equiv) in water (6 mL). The reaction mixture was stirred for 3 h at room temperature and then quenched by the careful addition of aq. 1 M HCl. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the organic layer was subsequently washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (10-75% EtOAc/Hexanes) provided the title compound (0.824 g, 97%) which was characterized by 1H NMR.