Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]1[CH2:21][CH:20]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:19][CH2:18][O:17][C:15]1=[O:16].CI>O1CCCC1.CCCCCC>[CH3:13][C:14]1([CH3:1])[CH2:21][CH:20]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:29])[CH3:28])[CH2:19][CH2:18][O:17][C:15]1=[O:16]
Reactant: CC1CC(CCCCO[Si](C)(C)C(C)(C)C)CCOC1=O
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: CC1(C)CC(CCCCO[Si](C)(C)C(C)(C)C)CCOC1=O
Reaction time: 0.25 h

Procedure:
To a solution of 10 ml (65 mmol) diisopropylamine in 120 ml dry tetrahydrofuran is added dropwise 26 ml of a 2.5M solution of n-butyllithium in hexane and the mixture is stirred for 15 min. To this solution is added slowly a solution of 10.11 g (32 mmol) of 2-methyl-4-(4-t-butyldimethylsilyloxybutyl)-epsilon-caprolactone in 48 ml dry tetrahydrofuran. The mixture is stirred at room temperature for 35 min and 14.0 ml (0.22 mole) of methyl iodide is added rapidly while the flask is cooled in a water bath. After stirring for 3.5 h, the reaction is quenched using saturated ammonium chloride solution and is extracted with ether. The organic phase is washed with water and brine, dried, filtered and concentrated to give an amber oil which is purified by silica gel chromatography using 3:2 hexane/ether to give impure product. Further purification by a second silica gel chromatography using 4:1 hexane/ether as eluent yields 2,2-dimethyl-4-(4-t-butyldimethylsilyloxybutyl)-epsilon-caprolactone; NMR (CDCl3): delta 4.32 (t,2H), 3.6 (t,2H), 1.3 (d,6H), 0.88 (s,9H).
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[N:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[N:10]=1.[CH3:17][OH:18]>>[F:16][C:11]1[CH:12]=[C:13]([F:15])[N:14]=[C:9]([O:18][CH3:17])[N:10]=1
Reactant: Fc1cc(F)nc(F)n1
Reactant: CO
Solvent: CCN(CC)CC
Product: COc1nc(F)cc(F)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 48 %

Procedure:
3.8 g (0.0373 mol) of triethylamine were added at -20° C. to a mixture of 5 g (0.0373 mol) of 2,4,6-trifluoropyrimidine in 50 ml of methanol within 5 minutes, and the mixture was stirred at this temperature for a further 40 minutes. After the reaction was complete, the mixture was warmed to 25° C. and the excess methanol was removed by distillation under reduced pressure. The residue obtained in this way was partitioned between methylene chloride and water, and the organic phase was dried over magnesium sulfate and concentrated. 4.6 g (85% of theory) of an isomer mixture which, according to investigation by gas chromatography, contained 46% of the title compound and 48% of 4,6-difluoro-2-methoxypyrimidine were obtained in this way.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23](F)=[C:22]([Cl:27])[CH:21]=1)(=[O:19])=[O:18]>>[Cl:27][C:22]1[CH:21]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:25]=[CH:24][C:23]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc(C(F)(F)F)c2)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (iv) and 3-chloro-4-fluorophenyl methyl sulfone.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.Cl.C[CH:20]([NH2:35])[C:21]1C=[CH:25][C:24](CCC2C=CC=CC=2)=[CH:23][CH:22]=1>>[ClH:1].[CH3:2][CH:3]([N:17]=[C:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:35]1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CC(N)c1ccc(Oc2ccccc2)cc1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(Oc2ccccc2)cc1

Procedure:
Following essentially the same procedure described in Example IV above and substituting α-methyl-ρ-phenoxybenzylamine hydrochloride for the α-methyl-ρ-phenethylbenzylamine hydrochloride above, results in the formation of 2-(α-methyl-ρ-phenoxybenzylimino)hexahydroazepine hydrochloride having a M.P. of 210°-2° C., (dec.)
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1I.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:27]1[CH:28]=[N:23][CH:24]=[N:25][CH:26]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(Br)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(Br)c(-c2cncnc2)c1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
4-Bromo-3-iodo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 117.2, 3 g, 6.17 mmol), pyrimidin-5-ylboronic acid (841 mg, 6.79 mmol), Pd(PPh3)2Cl2 (217 mg, 0.309 mmol) and Na2CO3 (1.963 g, 18.52 mmol) in a mixture of DME (17.28 mL), water (4.94 mL), EtOH (2.469 mL) was degassed and stirred at 80° C. for 23 h under argon. Additional pyrimidin-5-ylboronic acid (76 mg, 0.613 mmol) was added to the RM and stirring was continued for 5 h. The RM was treated with Si-Thiol (Silicycle, 1.27 mmol/g, 1.215 g, 1.543 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 80 g, cyclohexane/EtOAc, from 10% to 45% EtOAc) to yield the title compound as a white crystalline solid. UPLC-MS (condition 1) tR=2.80 min, m/z=437.9-439.9 [M+H]+, m/z=436.0-438.0 [M−H]−.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]([CH3:12])[CH2:5][CH2:6][C:7]([O:9][CH2:10]C)=[O:8]>CO>[Br:1][CH2:12][C:4](=[O:3])[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: BrBr
Reactant: CCOC(=O)CCC(C)=O
Solvent: CO
Product: COC(=O)CCC(=O)CBr
Reaction time: 8 h
Yield: 29.4 %

Procedure:
A solution of bromine (27.71 g, 173.4 mmol) in methanol (40 mL) was added dropwise to a solution of ethyl 4-oxopentanoate (25.0 g, 173.4 mmol) in methanol (200 mL) at room temperature over a period of 30 minute, and the reaction mixture was stirred overnight. The reaction mixture was concentrated, and the residue was partitioned between 3:1 ether:ethyl acetate and water, washed with saturated sodium bicarbonate, water, brine, dried, and concentrated to afford 17 g of a crude clear oil. The oil was purified by MPLC (Biotage) eluting with 8:1 hexane ethyl acetate to afford methyl 5-bromo-4-oxopentanoate (10.65 g, 29.38% yield) as a clear oil. 1H NMR (CDCl3) δ 3.96 (s, 2H), 3.69 (s, 3H), 2.96 (t, 2H), 2.66 (t, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]([OH:17])=[O:16])=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[Br:20]Br>C(O)(=O)C>[Br:20][C:12]1[C:11](=[O:14])[C:10]([C:15]([OH:17])=[O:16])=[CH:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:19][CH:18]=2)[CH:13]=1
Reactant: N#Cc1ccc(Cn2ccc(=O)c(C(=O)O)c2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: N#Cc1ccc(Cn2cc(Br)c(=O)c(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 1-(4-cyano-benzyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 12a, 2.57 g, 10.1 mmol) in glacial acetic acid (10 ml) is added bromine (2 mL). The reaction mixture is stirred for 6 days at room temperature and additional bromine (1 mL) is added on the first 2 days, respectively. The reaction mixture is evaporated under reduced pressure and co-evaporated with toluene twice. The remaining residue is purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 566 mg (17% of theory); ESI mass spectrum: [M+H]+=333 (bromine isotope pattern); Retention time HPLC: 0.84 min (Z002—002).
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Si:8]([O:15][CH2:16][CH:17]=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>>[Si:8]([O:15][CH2:16][CH:17]=[N:7][S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Product: CC(C)(C)[S@](=O)N=CCO[Si](C)(C)C(C)(C)C

Procedure:
(S)-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethylidene)-2-methylpropane-2-sulfinamide was prepared from (S)-(−)-2-methyl-2-propanesulfinamide and (tert-butyldimethylsilyloxy)acetaldehyde essentially according to the procedure of Barrow, J. C.; Ngo, P. L. Tetrahedron Lett. 2000, PAGES.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[CH:11][CH:10]=1.[OH-].[Na+].O>C(OCC)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:19])([CH3:18])[CH2:16][NH2:17])=[CH:11][CH:10]=1
Reactant: COc1ccc(C(C)(C)C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C(C)(C)CN)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A reaction vessel was charged with lithiumaluminium hydride (0.433 g, 11.41 mmol) and dry diethyl ether (20 mL). After cooling to 5° C. a solution of 2-(4-methoxyphenyl)-2-methylpropanenitrile (2.00 g, 11.41 mmol) in dry diethylether (10 mL) was added dropwise. The reaction mixture was stirred at 5° C. for 2 h. The reaction mixture was then cooled in an ice bath and 2N aqueous sodium hydroxide solution (0.8 mL) and water (1.5 mL) were added. After stirring for 20 min additional water (40 mL) was added and the reaction mixture was extracted with ethyl acetate (2×30 mL). The combined extracts were dried (MgSO4) and the solvent was evaporated in vacuo. The crude product (1.94 g, 10.82 mmol) was used without further purification for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH:21]1[C:22]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:20]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc2cc(-c3ccc4ccccc4c3)ccc2c1
Yield: 48.2 %

Procedure:
In a three-necked flask were placed 26.8 g of 6-bromo-2-naphthol, 4.6 g of tetrakistriphenylphosphinepalladium and 100 ml of toluene and the mixture was stirred at 50° C. When the solids nearly dissolved, a solution of 20.6 g of 2-naphthaleneboronic acid in 100 ml of ethanol was added and stirred. When the solutions mixed with each other, a solution of 30 g of sodium carbonate in 100 ml of water was added, the mixture was heated to the reflux temperature and stirred for 1 hour. Upon completion of the reaction, dilute hydrochloric acid was added until the aqueous layer became weakly acidic, the organic layer was recovered and the solvent was distilled off under reduced pressure. The crude product was recrystallized from a mixture of toluene and ethyl acetate, the crystals were collected by filtration, washed with toluene and dried at 80° C. under reduced pressure to give 15.6 g of 6-(2-naphthyl)-2-naphthol. The unreacted 6-bromo-2-naphthol was not detected.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:13](Cl)(Cl)=[S:14]>O>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1)=[C:13]=[S:14]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1ccc(N=C=S)cc1

Procedure:
4-amino-benzenesulfonamide Compound 2a (40 g, 240 mmol) in water (400 mL) in the presence of concentrated hydrochloric acid (100 mL) was reacted with thiophosgene (26.8 g, 240 mmol) at r.t. for 30 mins to provide 4-isothiocyanato-benzenesulfonamide Compound 2b (85% yield) (procedure described in McKee R L and Bost R W, J. Am. Chem. Soc., 1946, 68, 2506-7).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)(O)=[O:2].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O.CN(C)C=O>CCCCCCC>[Cl:23][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:2]
Reactant: O=C(O)c1ccc2c(c1)COC2=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: O=C(Cl)c1ccc2c(c1)COC2=O
Temperature: 25 °C

Procedure:
5-Carboxyphthalid (53 g, 0.3 mole) was suspended toluene (200 mL) and thionylchloride (44 g, 0.6 mole). N,N-dimethylformamide (DMF) (1 mL) was added and the mixture was heated at reflux temperature for 3 hours. The mixture was cooled to room temperature and n-heptane was added (200 ml). The crystals formed were collected and washed with heptane (100 mL). Yield 52 g, 88%. DSC onset: 131° C. 1H NMR (CDCl3, 500 MHz): 5.47 (2H, s), 8.06 (1H, d , J=7.5 Hz), 8.28(1H, d, J=7.5 Hz), 8.3(1H, s). 13C NMR (CDCl3, 125 MHz): 69.4, 125.1, 126.1, 131.1, 131.6, 137.8, 146.6, 167.4, 169.0.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1>C1C=CC=CC=1>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH:2][CH3:1])=[CH:6][CH:7]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Solvent: c1ccccc1
Product: CNCc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 12.0 g. (0.379 mole) anhydrous methyl amine in 150 ml. benzene is treated dropwise with 34.8 g. (0.127 mole) α-bromo-p-benzoyl toluene in 300 ml. benzene for about 30 minutes. The resulting mixture is stirred for 4 hours at room temperature and the solvent removed in vacuo. The resulting residue is dissolved in ether and washed with water. The ether layer is then extracted three times with 2N hydrochloric acid and the acidic solution made basic by the addition of potassium hydroxide and extracted with ether. The ether layer is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue is then chromatographed on silica gel to yield 4-benzoyl N-methyl benzyl amine (identified by spectral analysis).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Li]C(C)(C)C.B(CC)(CC)CC.Br[C:24]1[C:25]([O:34][CH3:35])=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=1)[CH:29]=[O:30].[OH-].[Na+].OO>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:33][O:32][C:27]1[CH:26]=[C:25]([O:34][CH3:35])[C:24]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:31][C:28]=1[CH:29]=[O:30]
Reactant: Cn1ccc2ccccc21
Reactant: COc1cc(OC)c(C=O)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCB(CC)CC
Agent: OO
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
Ex-116A: To a solution of N-methyl indole (1.3 g, 10 mmol) in 50 ml THF, t-BuLi (1.7 m in THF, 7.1 ml, 12 mmol) was slowly added at 0° C. under nitrogen. The mixture was stirred at room temperature for 1 hr, BEt3 (1.0 M in THF, 12 ml, 12 mmol) was added, and the mixture stirred for another 1 hr at room temperature. Then, PdCl2(PPh3)2 (0.35 g, 0.5 mmol) and 5-bromo-2,4-dimethoxybenzaldehyde (3.7 g, 15 mmol) were added, and the mixture was heated to about 60° C. for 30 minutes. The reaction mixture was poured into 50 ml 10% NaOH and treated with 30% H2O2 and then stirred for 10 minutes. The mixture was extracted with EtOAc and combined organic phase was washed with H2O and brine, dried over MgSO4, and absorbed to small amount of silica gel. Column chromatography (EtOAc:Hexane, 1:2) gave 0.72 g (25%) 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)-benzaldehyde. 1H-NMR (CDCl3) δ 10.33 (s, 1H), 7.84 (s, 1H), 7.60 (d, J=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H), 7.18–7.24 (m, 1H), 7.07–7.12 (m, 1H), 6.53 (s, 1H), 6.46 (s, 1H), 4.00 (s, 3H), 3.89 (s, 3H), 3.53 (s, 3H). HRMS (EI) Calcd. for C18H17NO3: 295.1208. Found: 295.1202.
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.Br[CH:21]([CH3:40])[C:22]([N:24]1[C:29]2([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[O:28][C:27]2[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=2[C:25]1=[O:39])=[O:23].P([O-])([O-])([O-])=O>[Zn].O1CCCC1>[Si:13]([O:12][C@@H:10]([C@@H:6]1[C@@H:5]([C@@H:21]([CH3:40])[C:22]([N:24]2[C:29]3([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[O:28][C:27]3[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=3[C:25]2=[O:39])=[O:23])[NH:8][C:7]1=[O:9])[CH3:11])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CC(Br)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Yield: 74.6 %

Procedure:
1.0 g of (3R, 4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2azetidinone, 1.8 g of 3-(2-bromopropionyl)-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one and 0.68 g of zinc powders are added to 15 ml of tetrahydrofuran and the mixture is refluxed for 30 minutes. After cooling, the reaction mixture is poured into 0.2M phosphate buffer (pH 7.0) and the mixture is extracted with methylene chloride. The extract is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate =3:1)to obtain 1.3 g of 3-{(2R)-2-[(3S, 4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH2:9]1COCC1.[H-].[Na+].IC>CC(C)=O>[CH3:9][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[N:6]1
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1cn[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1cc([N+](=O)[O-])nn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a 100-mL single-neck round-bottomed containing 4-nitro-2H-1,2,3-triazole (2.0 g, 17.5 mmol) and THF (10 mL) at 0° C. was added NaH (1.7 g, 35.0 mmol, 2.0 eq.). The mixture was stirred at 0° C. for 15 min. A solution of iodomethane (3.68 g, 26.3 mmol, 1.5 eq.) in acetone (40 mL) was added and the resulting reaction mixture was stirred at room temperature for 2 h. After this time, the reaction was quenched by water (20 mL) at 0° C. and concentrated under reduced pressure. The residue was diluted with dichloromethane (100 mL). It was then washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 6:1 petroleum ether/ethyl acetate to afford 293a (800 mg, 35%) as a light yellow solid and the regioisomer 1-methyl-5-nitro-1H-1,2,3-triazole (1.34 g, 60%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 4.26 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[CH2:14]1[O:16][CH2:15]1>C(O)C>[OH:16][CH2:15][CH2:14][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1]
Reactant: CC1CC(C)(C)NC2CCCCC12
Reactant: C1CO1
Solvent: CCO
Product: CC1CC(C)(C)N(CCO)C2CCCCC12

Procedure:
1-(2'-hydroxyethyl)-2,2,4-trimethyl decahydroquinoline was prepared. 150 milliliters of ethanol and 84.0 grams (0.3 mole) of 2,2,4-trimethyl decahydroquinoline of about 96% cis structure were placed in a reactor vessel equipped for heating and agitation. 15.4 grams (0.35 mole) of ethylene oxide was added dropwise to the reactor vessel and the mix then heated to reflux for 21 hours. The ethanol was then evaporated off and the reaction mixture distilled to yield 10.2 grams of a liquid product boiling at 103° - 105° C. at 0.3 mm Hg. The NMR and mass spectrometer spectra were consistent with the desired product. Calculated contents for the formula C14H27NO are 74.61% carbon, 12.08% hydrogen, and 6.22% nitrogen and the measured contents were 74.62% carbon, 12.11% hydrogen, and 6.13% nitrogen.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:24](=[O:25])[C:11]3=[CH:12][NH:13][C:14]([CH3:23])=[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=4)[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:24](=[O:25])[C:11]3=[CH:12][NH:13][C:14]([CH3:23])=[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:26]5[CH:30]=[CH:29][N:28]=[CH:27]5)[CH:17]=4)[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(-n2ccnc2)c1
Temperature: 140 °C
Yield: 34.7 %

Procedure:
A mixture of 2-(4-chlorophenyl)-2,5-dihydro-7-(3-iodophenyl)-6-methylpyrazolo[4,3-c]pyridin-3-one (0.100 g, 0.217 mmol), imidazole (33.9 mg, 0.498 mmol), potassium carbonate (29.9 mg, 0.216 mmol), and copper bronze (1 mg) in 1-methyl-2-pyrrolidinone (0.6 ml) was heated at 140° C. under nitrogen for 90 h. Purification by flash chromatography (silica gel, 3-10% MeOH/CH2Cl2) gave 30.3 mg (35%) of the title compound. This was recrystallised from CH2Cl2-MeOH-EtOAc; 1H NMR (400 MHz, DMSO-d6) δ2.29 (3H, s), 7.16 (1H, br s), 7.42 (2H, d), 7.50 (1H, d, J 7.6 Hz), 7.65 (1H, t J 7.8 Hz), 7.73 (1H, d, J 8.1 Hz), 7.80 (1H, s), 7.85 (1H, br s), 8.11 (2H, d), 8.36 (1H, br s), 8.61 (1H, s), 12.53 (1H, br d, J 5.6 Hz); MS (ES+) m/z 402/404 [MH]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][OH:15])=[CH:11][CH:12]=2)[N:7]=[C:6]([CH3:16])[CH:5]=1.F[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>CN(C)C=O>[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][O:15][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[CH:11][CH:12]=2)[N:7]=[C:6]([CH3:16])[CH:5]=1
Reactant: Cc1cc(Cl)c2ccc(CO)cc2n1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c2ccc(COc3ccc(C#N)cc3)cc2n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
Sodium hydride (55–65% dispersion in mineral oil, 220 mg, 5.50 mmol) was added to a solution of (4-chloro-2-methyl-quinolin-7-yl)-methanol (example 2c, 1.10 g, 5.30 mmol) and 4-fluorobenzonitrile (642 mg, 5.30 mmol) in N,N-dimethylformamide (20 mL), and the resulting mixture was stirred at 50° C. for 3 h. After cooling the mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane, the organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 19:1) yielded the title compound (1.28 g, 78%). Yellow solid, ISP-MS: m/e=309.3 ([M+H]+).