Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)([CH3:7])[C:3]([O:5]C)=[O:4].C[Si](C)(C)[O-].[K+].Cl>C1COCC1.CCOC(C)=O>[CH3:7][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)c1cccc(Oc2ccccc2)c1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)O)c1cccc(Oc2ccccc2)c1
Temperature: 45 °C

Procedure:
To a solution of methyl 2-methyl-2-(3-phenoxy-phenyl)-propionate (712 mg, 2.63 mmol) in THF (8 mL) was added potassium trimethylsilanolate (90% technical grade; 563 mg; 1.5 eq) and the solution heated to 45° C. for 5 hrs. The solution was allowed to cool, diluted with EtOAc (15 mL) and acidified with 2M HCl to ˜pH 3. The organic layer was separated and the aqueous phase extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered and evaporated to dryness to afford the desired acid, 2-methyl-2-(3-phenoxy-phenyl)-propionic acid, as a colorless powder. 1H NMR (500 MHz, CDCl3) δ 7.25-7.35 (3H, m), 7.08-7.16 (3H, m), 7.01 (2H, dd, J=7.7, 0.6 Hz), 6.86 (1H, dd, J=8.1, 2.3 Hz), 1.58 (6H, s).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][OH:13])[CH3:9]>C1(C)C=CC=CC=1>[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][O:13][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH3:9]
Reactant: C=C1CC(=O)O1
Reactant: CN(C)CCCO
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCCN(C)C
Temperature: 25 °C
Reaction time: 70 h
Yield: 100.1 %

Procedure:
Diketene (2.54 mL, 33.0 mmol, 1.30 equiv) was added to a solution of 3-(N,N-dimethyl)aminopropan-1-ol (3.00 mL, 25.4 mmol, 1.00 equiv, Aldrich) in toluene (30 mL) and the mixture was stirred at room temperature for 70 hours. The solvent was removed to afford 4.76 g of brown oil, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]1([C:8](Cl)=[O:9])[CH2:7][CH2:6]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=1.Cl>C(=S)=S>[CH:5]1([C:8]([C:20]2[O:19][C:18]([C:15]3[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=3)=[CH:22][CH:21]=2)=[O:9])[CH2:7][CH2:6]1
Reactant: Clc1ccc(-c2ccco2)cc1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(c1ccc(-c2ccc(Cl)cc2)o1)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
To a stirring mixture of 128 g (0.96 mole) of AlCl3 and 720 ml of CS2 was added portionwise 100 g (0.96 mole) of cyclopropanecarboxylic acid chloride while keeping the temperature below 30° by means of an ice bath. A solution of 172 g (0.96 mole) of 2-(4-chlorophenyl)furan in 480 ml of CS2 was added dropwise while maintaining the temperature between 10°-15° with large volume of HCl gas being given off. The reaction mixture was stirred in an ice bath for 15 minutes, allowed to warm to room temperature over a one hour period, and then added to 2000 ml of ice/water. The aqueous layer was separated from the CS2 layer and extracted with 2 × 500 ml portions of CH2Cl2. The CS2 and CH2Cl2 layers were combined, were washed with 1000 ml of 6% Na2CO3 solution and with 1000 ml of water, and then dried over magnesium sulfate. The solvent was removed on a rotary evaporator leaving red-brown residue which was extracted several times with boiling hexane. The combined hexane extracts were cooled and the resulting solid filtered and air dried to yield 41 g (17%) of product. An analytical sample was prepared by recrystallizing a sample from hexane/Darco, m.p. 88°-89°.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][SiH:10]([CH2:12][SiH:13]([Cl:15])[Cl:14])[Cl:11]>C1C=CC=CC=1>[Cl:9][Si:10]([Cl:11])([CH2:12][SiH:13]([Cl:15])[Cl:14])[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Reactant: C#Cc1ccccc1
Solvent: c1ccccc1
Product: Cl[SiH](Cl)C[Si](Cl)(Cl)C=Cc1ccccc1
Reaction time: 2 h
Yield: 5.5 %

Procedure:
Hydrosilation of phenylacetylene with bis(dichlorosilyl)methane in the presence of RhCl(PPh3)3. Into the same apparatus as described in Example 1 were added 0.99 g of bis(dichlorosilyl)methane, 0.102 g of RhCl(PPh3)3, and 20 ml of dried benzene. The flask content was heated to reflux and 0.52 ml of phenylacetylene was added over a 10 minute period. The flask content was refluxed, with stirring, for another 2 hours and then the solvent removed at atmospheric pressure. The products were vacuum distilled at 67 Pa to give a mixture comprising 0.9 g of 3,3,5,5-tetrachloro-1-phenyl-3,5-disilapent-1-ene (TCD-GC area 5.5%) and 3,3,5,5-tetrachloro-1,7-diphenyl-3,5-disilahepta-1,6-diene (TCD-GC area 66.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2([CH3:8])[CH2:7][O:19]2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CC1(c2ccc(Cl)cc2)CO1
Yield: 52.4 %

Procedure:
To a stirred and cooled solution (0°-5° C.) of 4-chloro-α-methylstyrene (15.2g) in chloroform (350 mL), add m-chloroperbenzoic acid (21.6 g). Stir the reaction mixture for 1 hr by which time all starting material will haye reacted to give virtually a single product. Remove the m-chlorobenzoic acid formed by washing chloroform solution with aqueous NaHCO3 followed by water (150 mL). Dry the chloroform solution (Na2SO4) and evaporate to dryness to provide a colorless oil. Distill the oil in vacuo (1 mm) and collect fractions distilling between 65°-72° to give the title compound (8.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[CH3:13][NH2:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:14][CH3:13])=[O:11])=[CH:5][CH:4]=1
Reactant: CN
Reactant: COc1ccc(CC(=O)Cl)cc1
Product: CNC(=O)Cc1ccc(OC)cc1

Procedure:
was prepared from 4-methoxyphenylacetic acid chloride and methylamine following Method B. 1H NMR (300 MHz, CDCl3) δ 7.14 (d, 2H, J=8.67 Hz), 6.86 (d, 2H, J=8.67 Hz), 3.78 (s, 3H), 3.49 (s, 2H), 2.72 (d, 3H, J=4.71 Hz). LCMS (ESI+) [M+H]/z Calc'd 180, found 180.
Reaction SMILES: C[C@@H](PC)[C]1[C](P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[CH][CH][CH]1.[F:31][C:32]1[CH:33]=[C:34]([CH:53]=[CH:54][CH:55]=1)[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=2)[CH2:39][CH2:38][C:37]=1[NH:48][C:49](=[O:52])[CH2:50][CH3:51].[H][H]>[Rh+].ClC1CCCCC=CC=1.CO>[F:31][C:32]1[CH:33]=[C:34]([CH:53]=[CH:54][CH:55]=1)[CH2:35][C@@H:36]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=2)[CH2:39][CH2:38][C@@H:37]1[NH:48][C:49](=[O:52])[CH2:50][CH3:51]
Reactant: [H][H]
Reactant: CCC(=O)NC1=C(Cc2cccc(F)c2)c2cc(OC)ccc2CC1
Agent: [Rh+]
Agent: CP[C@H](C)[C]1[CH][CH][CH][C]1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: ClC1=CC=CCCCC1
Solvent: CO
Product: CCC(=O)N[C@H]1CCc2ccc(OC)cc2[C@H]1Cc1cccc(F)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 86.6 %

Procedure:
Chlorocyclooctadiene rhodium(I) dimer (0.165 g, 0.669 mmol of Rh), Josiphos SL-J216-2 (0.451 g, 0.702 mmol), and N-(1-(3-fluorobenzyl)-7-methoxy-3,4-dihydronaphthalen-2-yl)propionamide (45.4 g, 134 mmol) were combined in a metal reactor, and the vessel was inerted with argon. Degassed methanol (223 ml) was added, and the reactor was agitated under argon for 20 min at 50° C. The reactor was pressurized with 60 psig of hydrogen and stirred at 60° C. for 30 hrs. HPLC analysis indicated complete conversion and 95.2% ee. The mixture was concentrated, filtered in EtOAc through silica gel, concentrated, slurried in hot heptane, filtered, and dried to yield 39.6 g (yield: 87%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.Cl.[F:14][C:15]1([F:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:18]2[CH2:19][CH2:20][C:15]([F:21])([F:14])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc(Br)cc1
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC1(F)CCN(CCCOc2ccc(Br)cc2)CC1
Temperature: 60 °C
Yield: 50.9 %

Procedure:
A suspension of 1-bromo-4-(3-bromopropoxy)benzene (1.85 g, 6.29 mmol), 4,4-difluoropiperidine hydrochloride (1.0 g, 6.34 mmol) and potassium carbonate (2.17 g, 15.7 mmol) in acetonitrile (100 mL) was heated to 60° C. overnight, then concentrated in vacuo. The residue was partitioned between ether and saturated aqueous sodium bicarbonate. The layers were separated; the organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography on an analogix SF40-80g column (hexanes/ethyl acetate=7:3) afforded the title compound as a clear oil (1.07 g, 50%). LCMS m/z 334.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.90-2.08 (m, 6H) 2.47-2.64 (m, 6H) 3.99 (t, J=6.34 Hz, 2H) 6.75-6.81 (m, 2H) 7.34-7.40 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCC(C(O)=O)CC1.C([O:38][C:39](=[O:50])[C@@H:40]([NH:46]C(O)=O)[CH2:41][CH2:42][C:43](O)=[O:44])(C)(C)C>>[NH2:46][C@@H:40]([CH2:41][CH2:42][C:43](=[O:44])[NH:24][C:21]1[CH:22]=[N:23][C:18]([O:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15]3)=[CH:19][CH:20]=1)[C:39]([OH:50])=[O:38]
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)O
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: O=C(O)C1CCNCC1
Product: N[C@@H](CCC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1)C(=O)O

Procedure:
(S)-2-Amino-4-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]butyric acid was prepared as described for piperidine-4-carboxylic acid [6-(2-phenyl-chroman-6-yloxy)pyridine-3-yl]amine in Example 19 a) and b) but replacing N-(tert-butoxycarbonyl)isonipecotic acid with (S)-2-carboxyaminopentanedioic acid 1-tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[N:3]=1.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([N:23]3[C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[CH2:26][N:20]4[CH:19]=[CH:18][CH:17]=[C:21]4[CH2:22]3)=[O:13])=[CH:10][CH:9]=2)[N:3]=1
Reactant: Cc1cc(C)n(-c2ccc(C(=O)Cl)cc2)n1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)n(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
The 4-(3,5-dimethylpyrazol-1-yl)benzoyl chloride (0.75 g) was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.55 g) and diisopropylethylamine (0.42 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the title compound (0.79 g) was obtained as an amorphous solid, MS m/z: 383 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][Cl:20])=[O:17]>C(OCC)C>[C:16](=[O:17])([O:3][C@H:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH3:4])[O:18][CH2:19][Cl:20]
Reactant: CCOC(=O)[C@H](C)O
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)[C@H](C)OC(=O)OCCl
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.1 %

Procedure:
To the mixture of ethyl (S)-lactate (23.6 g), pyridine (15.8 g) and diethyl ether (400 ml) was added dropwise a solution of chloromethyl chloroformate (25.6 g) in diethyl ether (100 ml) under ice cooling over the period of 40 minutes. After stirring at room temperature for 14 hours, the resulting solid was removed off by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (250 ml). The solution was washed with water (150 ml×2) and a saturated sodium chloride aqueous solution (150 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain chloromethyl [(1S)-1-(ethoxycarbonyl)ethyl] carbonate (38.5 g) as a colorless liquid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)=[CH:5][C:4]([C:20]([OH:22])=O)=[N:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][C:25]=1[O:32][CH3:33].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:20]([C:4]2[CH:5]=[C:6]([C:9]3[CH2:13][CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:11][N:10]=3)[C:7](=[O:8])[N:2]([CH3:1])[N:3]=2)=[O:22])=[CH:26][C:25]=1[O:32][CH3:33]
Reactant: Cn1nc(C(=O)O)cc(C2=NOC(c3ccccc3)C2)c1=O
Reactant: COc1cc(CN)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccccc4)C3)c(=O)n(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.2 %

Procedure:
To a solution of 1-methyl-6-oxo-5-(5-phenyl-4,5-dihydroisoxazol-3-yl)-1,6-dihydropyridazine-3-carboxylic acid (150 mg, 0.501 mmol, Preparation #34) in DMF (4 mL) was added (4-fluoro-3-methoxyphenyl)methanamine (93 mg, 0.601 mmol, WO 2008/083056), N-ethyl-N-isopropylpropan-2-amine (194 mg, 1.504 mmol, Spectrochem) and followed by HATU (286 mg, 0.752 mmol, Molekule). The reaction mixture was stirred at RT for 16 h. and was quenched with ice cold water (10 mL). The product was extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulphate and evaporated to dryness under vacuum. The residue obtained was purified by silica gel column chromatography by eluenting with 40-60% EtOAc in hexane. The relevant fractions containing the product were combined and evaporated under reduced pressure to afford N-(4-fluoro-3-methoxybenzyl)-1-methyl-6-oxo-5-(5-phenyl-4,5-dihydroisoxazol-3-yl)-1,6-dihydropyridazine-3-carboxamide 90 mg, (41.1%) as pale yellow solids. 1H NMR (400 MHz, DMSO) δ 9.159-9.127 (m, 1H), 8.143 (s, 1H), 7.422-7.331 (m, 5H), 7.167-7.117 (m, 2H), 6.886-6.849 (m, 1H), 5.812-5.763 (m, 1H), 4.436-4.420 (d, J=6.4 Hz, 2H), 3.964-3.892 (m, 1H) 3.819 (s, 3H), 3.781 (s, 3H), 3.508-3.443 (m, 1H). MS m/z 437.3 (M+H)+;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[C:33](OC(=N)C(Cl)(Cl)Cl)([CH3:36])([CH3:35])[CH3:34].B(F)(F)F.CCOCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 6-bromo-2-(4-carboxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg) and 2,2,2-trichloroacetoimidate tert-butyl ester (400 mg) in methylene chloride (6 ml) was added dropwise a catalytic amount of boron trifluoride diethyl etherate at room temperature and the mixture was stirred for 1 hr. To the reaction mixture was added 10% aqueous potassium carbonate solution, and the mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) and the obtained crystals were washed with methanol to give the title compound (260 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](C(F)(F)F)=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].BrC1C=CC([C:38](C2C=C([N+]([O-])=O)C=CC=2C)=[O:39])=C(Cl)C=1.COC1C=CC(N)=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:39][CH3:38])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Solvent: COc1ccc(N)cc1
Product: COc1ccc(Nc2ccc(C(=O)c3cc([N+](=O)[O-])ccc3C)c(Cl)c2)cc1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (0.56 mmol) and 4-methoxy-phenylamine (0.56 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 35:65 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: C([O:5][C@H:6]([CH3:43])[C@@H:7]([C:16]1[O:20][N:19]=[C:18]([C@@H:21]2[CH2:25][C:24](=[N:26][O:27][CH3:28])[CH2:23][N:22]2[C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[O:30])[N:17]=1)[NH:8]C(OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:28][O:27][N:26]=[C:24]1[CH2:25][C@@H:21]([C:18]2[N:17]=[C:16]([C@@H:7]([NH2:8])[C@H:6]([OH:5])[CH3:43])[O:20][N:19]=2)[N:22]([C:29]([C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)=[O:30])[CH2:23]1
Reactant: CON=C1C[C@@H](c2noc([C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON=C1C[C@@H](c2noc([C@@H](N)[C@@H](C)O)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 30 %

Procedure:
4-{[(2S,4EZ)-2-(5-{(1S,2R)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]propyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl (100 mg, 1.80 mmol) was treated with a 25% TFA/DCM solution at 0° C. for 1 hour. The reaction was then made basic with a sodium carbonate solution (10%) and extracted with DCM. The organic phases were combined and dried over magnesium sulfate and solvent removal afforded a residue, which was purified by flash-chromatography using dichloromethane/methanol as eluent to give the desired product, (3EZ,5S)-5-{5-[(1S,2R)-1-amino-2-hydroxypropyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime, as a mixture of E-/Z-isomers in 30% yield (90.3% purity by HPLC).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7][CH:6]=1)[CH3:2].C([N:21]=[C:22]=[S:23])(=O)C1C=CC=CC=1.[O-]CC.[Na+]>C1COCC1.C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:22]([NH2:21])=[S:23])=[N:7][CH:6]=1)[CH3:2]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)c1ccc(N)nc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(N)=S)nc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
A mixture of ethyl-6-amino-nicotinate (2.5 g, 15 mmol) and benzoyl isothiocyanate (2.45 g, 15 mmol) in THF (20 mL) was heated at 40° C. for 4 h. To this mixture at RT, was added sodium ethoxide (2.04 g, 30 mmol) in ethanol (10 mL). After stirring the resulting mixture at RT for 16 h, the volatiles were removed in vacuo. The residue was suspended in aqueous NH4Cl and the solid formed was collected by filtration, rinsed with water and dried to afford 6-thioureido-nicotinic acid ethyl ester as a white solid (2.6 g, 77% yield). LC/MS; (M+H)+=226.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:12][CH:11]([CH2:13][C:14](O)=[O:15])[CH2:10][C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:24])=O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:12][CH:11]([CH2:13][C:14]([Cl:24])=[O:15])[CH2:10][C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CC(=O)O)O2
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CC(=O)Cl)O2

Procedure:
To a suspension of (RS)-2-(2,3-dihydro-5-acetyloxy-4,6,7-trimethylbenzofuranyl) acetic acid (see example 2) (4.4 g) in benzene (36 ml) is added dropwise oxalyl chloride (7 ml) over 30'.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[NH:6][CH:7]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH-].[Na+]>O.C1COCC1>[OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[N:6]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:7]=1
Reactant: Cc1nc(CO)c[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(CO)nc2C)cc1
Yield: 30 %

Procedure:
4-Hydroxymethyl-2-methylimidazole (0.7 g, 6.25 mmol), prepared as in Example 180A, and p-toluenesulfonylchloride (1.2 g, 6.25 mmol) were suspended in 5 mL of distilled water and 3 mL of THF. Sodium hydroxide (1N) was added to maintain a pH of 9 over a period of 3 hours. The reaction mixture was extracted with ethyl acetate (3×50 mL). The extracts were combined, dried over magnesium sulfate, concentrated and crystallized from ethyl acetate, collected by vacuum filtration and dried to give 4-hydroxymethyl-2-methyl-1-p-toluenesulfonylimidazole (0.5 g, 35%) as a white solid; m.p. 140-143°; 1H NMR (300 MHz, CDCl3) δ 7.78 (d, 8.25 2H), 7.36 (d, J=8.25 Hz, 2H), 7.33 (s, 1H), 4.49 (s, 2H), 2.50 (s, 3H), 2.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 146.38, 140.96, 134.85, 130.51, 127.57, 116.05, 57.37, 21.84, 15.02; MS m/e calc'd: 266.0725, found: 266.0714.
Reaction SMILES: C[O-].[Na+].Cl.Cl.[CH2:6]([NH:13][NH2:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15]([CH2:17][C:18]([C:20]1[O:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=1)=O)#[N:16].O>C(O)C>[NH2:16][C:15]1[N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:14]=[C:18]([C:20]2[O:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=2)[CH:17]=1
Reactant: NNCc1ccccc1
Reactant: N#CCC(=O)c1ccc(CO)o1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccc(CO)o2)nn1Cc1ccccc1

Procedure:
44.1 g (817 mmol) of sodium methoxide is added with stirring to a solution of 79.5 g (408 mmol) of benzylhydrazine dihydrochloride in 1.3 l of ethanol. After 15 min 67.4 g (408 mmol) of 2-cyanomethylcarbonyl-5-hydroxymethylfuran are added and the mixture is stirred under reflux for 3 hours. After cooling, 1 l of water is added, the ethanol part is evaporated in vacuo and the precipitated crystals are filtered off with suction. After washing, with water and then with ether, the precipitate is dried over P2O5, 91 g(83% of theory) of product having an m.p. of 163° C. are obtained.