Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[CH:12]([Cl:15])([Cl:14])[Cl:13].[OH-].[K+]>CN(C=O)C.CO>[Cl:13][C:12]([CH:7]([OH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([Cl:15])[Cl:14]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: ClC(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=[N+]([O-])c1cccc(C(O)C(Cl)(Cl)Cl)c1
Temperature: -5 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 3-nitrobenzaldehyde (200 g, 1.32 mol) and chloroform (238 ml, 2.97 mol) in 800 ml of DMF cooled to -9° C. under nitrogen was added dropwise a solution of potassium hydroxide (59.8 g, 0.92 mol) in 180 ml of methanol over a 2.7 hour period. The deep purple reaction mixture was aged for 2 hours at -8° C. before quenching over 40 minutes into 1.8 liter of lN HCl and 1.8 liter of toluene cooled to -5° C. The quench mixture was stirred and cooled for an additional 0.5 hour and then brought to ambient temperature. The toluene layer was separated and washed twice with 1.8 liter of water. After treatment with 35 g of Darco G-60 charcoal for 1 hour and filtration through Super-Cel, the organic layer was washed with 1.8 liter of aqueous 5% sodium bicarbonate solution and then 1.8 liter of water. After evaporation to 550 ml the desired product was crystallized by the addition of 450 ml of hexanes. The resulting slurry was cooled at 0° C. for 2 hours and the solid was collected by filtration and rinsed with hexanes. After drying, 320 g (90% yield) of TMBA was obtained; m.p. 91- 95° C; 1H NMR 3.75 (1H, d, J=1 Hz), 5.25 (1H, d, J=1 Hz), 7.20-8.45 (5H, m).
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](#[N:12])[CH:10]=[CH2:11].C[O-].[Na+]>>[CH2:7]([S:8][CH2:11][CH2:10][C:9]#[N:12])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC#N
Reactant: SCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: N#CCCSCc1ccccc1

Procedure:
β-Benzylmercaptopropionitrile was prepared according to the procedure of Example 1 using α-toluenethiol (25.0 g; 0.20 moles), acrylonitrile (10.6 g; 0.20 moles) and sodium methoxide (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.O.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: NCC/C=C\c1cccc(Cl)c1
Agent: O=[Pt]=O
Solvent: O
Solvent: CO
Product: NCCCCc1cccc(Cl)c1
Yield: 74.2 %

Procedure:
A solution of cis-4-(3-chlorophenyl)-but-3-enylamine (1.2 g) in 20 mL methanol was added to platinum(IV) oxide monohydrate (0.12 g). The mixture was stirred under 1 atm of hydrogen for 16 h. The mixture was filtered through celite, and the methanol was removed in vacuo to yield 0.9 g of 4-(3-chlorophenyl)-butylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C(Br)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
3-Chlorophenylacetic acid (20.90 g, 122.51 mmol) and N-Bromosuccinimide NBS (23.50 g, 132.03 mmol) were dissolved in carbon tetrachloride (300 mL). Benzoyl peroxide BPO (300 mg) was added and the resulting reaction mixture was heated to reflux under a sunlamp for 5 hours, then cooled to room temperature, filtered and concentrated to give the desired α-bromo-3-chlorophenylacetic acid, component “A”. 10.00 g of this acid were dissolved in MeOH (100 mL) and 2 mL of sulfuric acid were added. The resulting reaction mixture was refluxed for 3 hours, and then concentrated. The residue was diluted with ether (150 mL) and washed with water, dried over sodium sulfate, and then concentrated to give the methyl ester. The methyl ester was reacted with the component “B”, 3,4-dimethylaniline (CAS 95-64-7) (6.89 g, 1.5 eq), and potassium carbonate (13.00 g, 2.5 eq) in methylethyl ketone and the mixture heated with stirring at 80° C. for 14 hours. After concentration, MeOH (50 mL) was added, followed by KOH (5.00 g). The reaction mixture was refluxed for 6 hours, acidified with concentrated HCl, and then concentrated. The resulting residue was diluted with ether and washed with water, then dried over sodium sulfate and concentrated to the 2-(3-chlorophenyl)-2-((3,4-dimethylphenyl)amino)acetic acid, which was used in the next step without further purification. Crude 2-(3-chlorophenyl)-2-(3,4-dimethylphenyl)amino)acetic acid reacted with 1,1′-carbonyldiimidazole (2.40 g, 14.81 mmol) and (Z)-N′-hydroxy-2-(methylamino) nicotinimidamide (1.80, 10.83 mmol) according to the protocols as outlined in general procedure described above to afford Compound 1.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:17]=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CO.O>[CH3:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:2])[C:7]=2[N:17]=1
Reactant: Cc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)C
Reactant: [NH4+]
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2c(N)nc3cccnc3c2n1CC(C)C
Temperature: 10 °C

Procedure:
Under a nitrogen atmosphere, aqueous ammonium hydroxide (four equivalents) was quickly added with continuous stirring to a suspension of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-5-oxide in methanol (6 mL/g) while maintaining the reaction temperature at 20° C. to 24° C. Methanol was used to rinse the addition vessel and added to the reaction. The reaction was stirred until all material was dissolved. With continuous stirring, benzenesulfonyl chloride (2 equivalents) was added over a period of 15 to 45 minutes while maintaining the reaction temperature at 20° C. to 30° C. Methanol was used to rinse the addition vessel and added to the reaction. The reaction was stirred for 45 to 75 minutes at 20° C. to 24° C. Aqueous sodium hydroxide (3 equivalents of 10% w/w) was added to the reaction mixture over a period of 15 to 45 minutes while maintaining the reaction temperature between 20° C. and 25° C. Water (10 L), used to rinse the addition vessel, was added to the reaction mixture. The resulting mixture was cooled to 10° C. and stirred for 2 to 24 hours. A precipitate was present and was isolated by filtration and washed with deionized water until the filtrate was pH 7. The solid was dried at 50° C. under vacuum to provide 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[NH2:9][NH2:10].O>C(O)C>[CH:2]([C:3]1[CH:4]=[C:5]([NH2:6])[NH:10][N:9]=1)([CH3:8])[CH3:1]
Reactant: CC(C)C(=O)CC#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)c1cc(N)[nH]n1

Procedure:
A solution of 4-methyl-3-oxopentanenitrile (Compound [CCLX]) (8.8 g, 79.2 mmol, 1.00 equiv) and NH2NH2.H2O (80%, 7.5 g, 120 mmol, 1.50 equiv) in ethanol (300 mL) was heated to reflux for 1 h under nitrogen. After removed the solvent under vacuum, the residue was loaded onto a silica gel column with dichloromethane/methanol as an eluent to give Compound [CCLXI] as a yellowish oil: LC-MS m/e 126 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 5.17 (s, 1H), 2.75 (septet, J=6.9 Hz, 1H), 1.14 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[Cl:21][C:22]1[S:26][C:25]([CH2:27]O)=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:21][C:22]1[S:26][C:25]([CH2:27][O:19][C:16]2[CH:17]=[CH:18][N:13]([C:10]3[CH:11]=[CH:12][C:5]4[N:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[C:6]=4[CH:9]=3)[C:14](=[O:20])[CH:15]=2)=[CH:24][CH:23]=1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1ccc(Cl)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
To a mixture of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (500 mg), (5-chloro-2-thienyl)methanol (552 mg) and tributylphosphine (1.38 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.41 g), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc to MeOH/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (143 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.CN(C=O)C.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([Cl:20])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2,6-dichlorophenylacetic acid (4.16 g, 20.3 mmol, 1.1 eq), DMF (0.4 mL), and CH2Cl2 (40 mL) under a nitrogen atmosphere was treated with thionyl chloride (1.88 mL, 25.8 mmol, 1.4 equiv.). The resulting mixture was stirred at rt for 20 h. The mixture was concentrated afford (2,6-dichloro-phenyl)-acetyl chloride as a yellow syrup. A solution of the acid chloride in DMA (10 mL) was added to a solution of 6-chloro-N4-(4-trifluoromethyl-phenyl)-pyrimidine-4,5-diamine hydrochloride (6.0 g, 18.5 mmol, 1.0 eq) in DMA (20 mL) under a nitrogen atmosphere. After 2 h, isopropanol (50 mL) was added. The resulting solid precipitate was collected by filtration, rinsed with EtOH, and dried under vacuum at 50° C. for 18 h to give the title compound as a white solid (5.6 g, 64%). 1H NMR (d6-DMSO): 9.93 (s, 1H), 9.35 (s, 1H), 8.44 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.7 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.33 (t, J=7.7 Hz, 1H), 4.24 (s, 2H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[C:13]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=4)[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.575 g, 0.76 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.227 g, 0.85 mmol), tetrakis(triphenyl-phosphine)palladium (0.051 g, 0.038 mmol) in toluene (5 mL) was heated under reflux conditions for 4 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), placed in freezer for 30 min, added heptane (total volume: 25 mL), filtered the precipitate off, washed with toluene/heptane (ca. 1:1, 3×10 mL), dried in HV to give the title compound as an off-white solid (305 mg, 70%). MS (ISP) 576.3 [(M+H)+]; mp 236° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.OS(O)(=O)=O.[OH-].[Na+].[CH3:23]O>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:23])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(-c2ccncc2)cc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-[pyridin-4-yl]-benzoic acid (2.0 g, 10 mmol) (reference example 11a) in methanol (30 mL) is added conc. H2SO4 (4 mL). The resulting solution is warmed to 60° C. and stirred at this temperature for 2.5 hours. The reaction mixture is then allowed to cool to room temperature then poured into ice. The pH of the resulting solution is adjusted to 7 using a 10 M solution of NaOH. The product is then extracted into ethyl acetate. This solution is washed with brine, dried over MgSO4 and concentrated to give 2.1 g of the title compound as a white solid. 1H NMR (CDCl3) d 3.94 (s, 3H), 7.50 (d, J=5 Hz, 2H), 7.69 (d, J=8 Hz, 2H), 8.13 (d, J=5 Hz, 2H) 8.68 (d, J=5 Hz, 2H). MS (EI) m/z 213 (M)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH:21]([CH3:23])[CH3:22]>CN(C)C=O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:21]([CH3:23])[CH3:22])[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C=O)c1
Temperature: 60 °C
Yield: 98 %

Procedure:
To methyl 3-formyl-4-hydroxy-benzoate (10.0 g, 55.5 mmol), potassium carbonate (30.7 g, 222 mmol) and N,N-dimethylformamide (63 mL) was added 2-iodopropane (11.1 mL, 111 mmol). The mixture was heated at 60° C. for 18 hours. The mixture was filtered using ethyl acetate (200 mL) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and was washed with water (3×75 mL) and a saturated aqueous solution of sodium chloride (1×75 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield methyl 3-formyl-4-isopropoxy-benzoate (98%) as a yellow viscous liquid. ESI-MS m/z calc. 222.2. found 223.3 (M+1)+; Retention time: 1.51 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.23 (d, J=2.3 Hz, 1H), 8.17 (dd, J=8.8, 2.3 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 4.98-4.83 (m, 1H), 3.85 (s, 3H), 1.38 (d, J=6.0 Hz, 6H).
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][NH2:7].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:7][CH3:6])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a mixture of sat aq. NaHCO3 (42 g, 0.5 mol), CH2Cl2 (400 mL) and methylamine (51.7 g, 0.5 mol, 30% in methanol) was added a solution of 4-bromo-benzenesulfonyl chloride (127 g, 0.5 mol) in CH2Cl2 (100 mL). The reaction was stirred at 20° C. overnight. The organic phase was separated and dried over Na2SO4. Evaporation of the solvent under reduced pressure provided the 4-bromo-N-methyl-benzenesulfonamide (121 g, crude), which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 7.64-7.74 (m, 4H), 4.62-4.78 (m, 1H), 2.65 (d, J=5.4 Hz, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].C(=O)([O-])[O-:9].[K+].[K+].[CH3:14][C@@:15]12[C@H:25]3[C@@H:26]([OH:39])[CH2:27][C@:28]4([CH3:38])[C@@:32]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:31][CH2:30][C@H:29]4[C@@H:24]3[CH2:23][CH2:22][C:21]1=[CH:20][C:18](=[O:19])[CH2:17][CH2:16]2>C(Cl)(Cl)Cl>[CH3:14][C@@:15]12[C@H:25]3[C@@H:26]([OH:39])[CH2:27][C@:28]4([CH3:38])[C@@:32]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:31][CH2:30][C@H:29]4[C@@H:24]3[CH2:23][CH2:22][C:21]1=[CH:20][C:18](=[O:19])[CH2:17][CH2:16]2.[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O-:6])=[O:9]
Reactant: O=C(Cl)CCCBr
Reactant: O=C([O-])[O-]
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C([O-])CCCBr
Reaction time: 120 h

Procedure:
Five portions of 4-bromobutanoylchloride (0.35 ml×5) and potassium carbonate (0. 4 g×5) were added in 24 hours to a solution of hydrocortisone (1 g) in CHCl3 dried over P2O5 and stirred for 5 days. The solution was treated with water, the organic phase was separated, dried (Na2SO4) and deprived of the solvent at reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)=[CH:4][C:3]=1[C:18]#[N:19].C1C(=O)N([Br:27])C(=O)C1.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][Br:27])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[N:9]2)=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: Cc1cc(C(F)(F)F)nn1-c1ccc(F)c(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2CBr)ccc1F
Yield: 50.1 %

Procedure:
To a solution of 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-methylpyrazole (4.0 g, 14.9 mmol) in CCl4 (75 mL) was added NBS (5.3 g, 29.7 mmol) and benzylperoxide (0.2 g, 1.49 mmol). The reaction was brought to reflux overnight. The next day the CCl4 was evaporated and the residue was partitioned between ethyl acetate and sodium bicarbonate (sat.). The organic phase was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography gave 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-bromomethylpyrazole (2.6 g, 50% yield) as pure compound: MS (CI): 348 (M+H)+ (100%).
Reaction SMILES: [H][H].[CH2:3]([OH:11])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1>CCCCCC.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:3]([OH:11])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCCCC#CCCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCCC/C=C\CCO

Procedure:
Hydrogen gas was blown into a solution prepared by dissolving 126 g of 3-octyn-1-ol in 100 ml of n-hexane with admixture of 10 g of a Lindlar catalyst and 10 g of pyridine and the introduction of hydrogen was continued for about 4 hours when absorption of hydrogen had ceased. Removal of solid matter from the reaction mixture by filtration and stripping of n-hexane gave cis-3-octen-1-ol, which was dissolved in a mixture of 250 g of methylene chloride and 111 g of triethylamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(Cl)Cl>[Si:16]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: OCc1ccncc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
At room temperature, 10.9 g of 4-pyridylcarbinol (100 mmol) was treated with 60 mL of DCM followed by 21 mL (150 mmol) of triethylamine. After being cooled to 10° C., 18 g (120 mmol) of t-butyldimethylsilyl chloride (dissolved in 20 mL DCM) was added dropwise. The resulting reaction mixture was warmed to room temperature slowly and stirred overnight. Subsequently, it was filtered over a pad of celite, rinsed with ether. Volatiles were removed and the residue was taken up in hexane and filtered over celite again, washed with hexane/ether, and the solvents removed by rotoevaporation. This was repeated twice. Pumping under high vac of the residue thus obtained provided 22 g (99%) of the desired product as a light brown oil, mass spectrum (CI) m/e=224 (M+1)+.
Reaction SMILES: [C:1]1(O)C2C(=CC=CC=2)C=CC=1.[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[OH:23].BrNC(C)(C)C.C(=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[O:23][CH3:1]
Reactant: Oc1cccc2ccccc12
Reactant: Oc1c(Br)ccc2ccccc12
Agent: CC(C)(C)NBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1c(Br)ccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-naphthol was converted into 2-bromo-1-naphthol by reaction with a slurry of N-bromo-t-butylamine at -78° C. according to the procedure described in Pearson, Wysong, Breder, J. Org. Chem., 32, 2358 (1967). To a solution of 1 mole (crude) of the bromonaphthol in 750 mL of acetone was added 175 g of potassium carbonate. Over a 2-hour period, 95 mL of dimethylsulfate was added dropwise to the mechanically stirred reaction mixture. The resulting slurry was stirred at 25° C. overnight. The solids were filtered and the solution was stripped to yield a dark brown oil. Initial purification was accomplished by vacuum distillation (80-120° C., 0.2 Torr) followed by further purification by HPLC with hexane to yield 145 g of 2-bromo-1-methoxynaphthalene as a pale yellow oil. NMR confirmed the structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15]CC)=[O:14])=[CH:7]2)([O-:3])=[O:2].[OH-].[Li+]>CO.C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 90 °C

Procedure:
16.5 g (66.93 mmol) of ethyl 5-nitroindole-2-carboxylate are dissolved in 200 ml each of methanol and THF, and 67 ml (133.85 mmol) of lithium hydroxide solution are added. The mixture is heated at 90° C. for half an hour. After cooling, the mixture is, for work-up, diluted and extracted with aqueous hydrochloric acid and ethyl acetate. The organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[CH3:11]O>>[ClH:1].[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1
Reactant: CO
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 22 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a freshly prepared sat. solution of hydrogen chloride in methanol (100 ml) was added trans-4-hydroxy-L-proline (10.0 g, 76.26 mmol). The resulting mixture was stirred at 22° C. for 24 h, concentrated in vacuo and triturated with acetone at 0° C. Filtration afforded the title compound (12.8 g, 92%) as a white solid.
Reaction SMILES: CS([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[Cl-].[C-:31]#[N:32].[K+]>C(Cl)(Cl)(Cl)Cl.O>[C:31]([CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:32]
Reactant: [C-]#N
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 72.2 %

Procedure:
In 120 ml of carbon tetrachloride are dissolved 12.2 g of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone and 2.44 g of tri-n-octlymethylammonium chloride and, under stirring, a solution of 2.15 g of potassium cyanide in 30 ml of water is added. The mixture is stirred vigorously at the same temperature for 15 minutes and the organic layer is separated, while the aqueous layer is extracted with chloroform. The organic layers are combined, washed with water and treated in the same manner as (1) of Example 13 to give 7.66 g of (3S,4RS)-4-cyano-3-tritylamino-2-azetidinone.