Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>ClCCl.N1C=CC=CC=1>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=2)=[O:13])=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: CS(=O)(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc1
Yield: 56 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-aminophenyl methyl sulfone (2.00 g, 11.7 mmol) in 16 mL of pyridine. The crude product was recrystallized from acetonitrile-DMF to yield 2.0 g of the title compound, mp 236°-238° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 54 h
Yield: 82.1 %

Procedure:
N-t-Butyloxycarbonyl-β-alanine (2.0 g, 10.6 mmol) in methylene chloride (50 mL) was treated with benzyl alcohol (1.66 mL, 26.0 mmol), N,N-dicyclohexylcarbodiimide (2.39 g, 11.6 mmol) and N,N-dimethylaminopyridine (1.42 g, 11.6 mmol) and the subsequent reaction mixture was stirred at room temperature for 54 h. The reaction mixture was filtered and evaporated at reduced pressure. The residue was purified using flash chromatography (silica gel, 50% ethyl acetate/hexane) to yield the title compound (25) (2.43 g, 82%). 1H NMR (CDCl3) ε 1.47 (s, 9H), 2.61 (t, 2H, J=6 Hz), 3.45 (q, 2H, J=7.5 Hz), 5.15 (br s, 1H), 5.27 (s, 2H), 7.43 (s, 5H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])=[O:24])[C:5]1=[O:34].[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])=[O:24])[C:5](=[O:34])[N:4]3[CH2:3][CH2:2][NH:1][C:41]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:42])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCCn1c(=O)c(C(=O)NCCN2CCNC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Product: O=C(NCCN1CCNC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-[2-(2-oxo-1-imidazolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as an orange solid: ES+ MS: 582 (M+H+).
Reaction SMILES: [OH:1][CH:2]([CH2:10][CH3:11])[CH2:3][CH2:4][CH2:5][C:6](=[O:9])[CH:7]=[CH2:8].[C:12]1([CH:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC>[C:12]1([CH:18]([NH:20][CH2:11][CH2:10][C:2]2([OH:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH2:7][CH3:8])[O:9]2)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(N)c1ccccc1
Reactant: C=CC(=O)CCCC(O)CC
Solvent: CCCCCC
Product: CCC1CCCC(O)(CCNC(C)c2ccccc2)O1

Procedure:
A solution of racemic 7-hydroxy-1-nonen-3-one [21.3 g.; crude obtained as in Example 1(d)] in hexane (200 ml.) was treated for 15 hours at 25°C. with a solution of (-)-α-phenylethylamine (11.5 g.) in hexane (115 ml.). The reaction mixture was then purified by chromatography on alumina (660 g.). Elution with hexane first gave unpolar by-products. Hexane-ether-(4:1)-, (1:1), and straight ether then eluted 2-[2-(1-phenylethylamino)-ethyl]-6-ethyl-2-tetrahydropyranol obtained in solid form after evaporation of the solvents.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[C:7](I)[CH:6]=1.C(N(CC)CC)C.[Cl:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30]>C(#N)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:17])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[C:7]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][Cl:25])[CH:6]=1
Reactant: COC(=O)Nc1ccc(OC(=O)OC)cc1I
Reactant: C#CCCCCl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)Nc1ccc(OC(=O)OC)cc1C#CCCCCl
Temperature: 70 °C

Procedure:
Carbonic acid 3-iodo-4-methoxycarbonylamino-phenyl ester methyl ester (28.0 g, 79.75 mmol) was dissolved in acetonitrile (350 mL). Triethylamine (22.2mL, 160 mmol), Copper (I) iodide (300 mg, 1.58 mmol), bis(triphenylphosphine)palladium (II) chloride (1.12 g, 1.6 mmol) and 5-chloro-1-pentyne (10.0 mL, 95.54 mmol) were added and the mixture heated 3 h at 70° C. The reaction was cooled and partitioned between ethyl acetate (100 mL) and IM pH4 phosphate buffer (100 mL). The phases were separated, the aqueous phase extracted with ethyl acetate and the combined organic phases washed with 10% sodium thiosulfate solution, brine, dried over sodium sulfate and evaporated. The orange/brown residue (23.5 g, 90%) was used without further purification. (A small sample was purified by column chromatography on silica gel (5:1 hexane/ethyl acetate) for analytical purposes). ISP-MS: m/e=326.3 ([M−H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([F:14])[F:13])[C:5](Cl)=[O:6].O[NH:16][C:17](=[NH:37])[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[C:23]2[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:16]=[C:17]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[C:23]4[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:37]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([F:14])[F:13]
Reactant: O=C(Cl)c1ccc(OC(F)F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OC(F)F)c(Cl)c4)n3)cccc12
Reaction time: 0.83 h
Yield: 28.7 %

Procedure:
A solution of 3-chloro-4-[(difluoromethyl)oxy]benzoyl chloride (D18; 69.5 mg, 0.289 mmol) in dry DMF (1 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 70 mg, 0.222 mmol) and triethylamine (0.046 ml, 0.333 mmol) in dry DMF (2 ml) at 0° under nitrogen and stirring was continued at room temperature for 50 min, then heated at 100° for 5 h. The cooled mixture was partitioned between saturated aqueous sodium bicarbonate (30 ml) and ethyl acetate (3×20 ml), and the organic layer was washed with 50:50 brine:water and brine, dried (MgSO4) and evaporated in vacuo to give a brown gum. The crude product was purified by flash chromatography on silica gel, eluting with 0-30% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white solid (32 mg).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:16][C:11]=2[S:10][C:9]1=[N:22]C(=O)C(F)(F)F)(=O)=O.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.CO.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH:22]=[C:9]1[N:8]([CH2:7][CH2:6][N:39]2[CH2:40][CH2:41][N:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH3:29])[CH2:37][CH2:38]2)[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:16][C:11]=2[S:10]1
Reactant: CS(=O)(=O)OCCn1c(=NC(=O)C(F)(F)F)sc2cc(OC(F)(F)F)ccc21
Reactant: Cc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccccc1N1CCN(CCn2c(=N)sc3cc(OC(F)(F)F)ccc32)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
Using the procedure described in Example 1, starting with 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)ethyl methanesulphonate (5.88 g) in toluene (200 cc) and 4-(2-methylphenyl)piperazine (6.87 g) and after 2 hours under reflux, the toluene filtrate is evaporated under reduced pressure. To the residue thereby obtained, methanol (100 cc) and a 7% strength aqueous-alcoholic solution (20 cc) of potassium carbonate are added and the mixture is stirred for 2 hours at approximately 20° C. The alcohol is evaporated off under reduced pressure and the residue is purified by chromatography on a silica column with a dichloromethane/ethyl acetate mixture (70:30 by volume) as eluent, and then an ethyl acetate/cyclohexane mixture (50:50 by volume) as eluent. 2-Imino-3-{2-[4-(2-methylphenyl)-1-piperazinyl]ethyl}-6-trifluoromethoxybenzothiazoline (1.8 g), m.p. 135° C., is thereby obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].OS(O)(=O)=O.O>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:17])[C:12](=[CH:15][CH:16]=1)[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the benzaldehyde G3a (127.5 g, 0.52 mol) in MeOH (1 L) at 0 ° C., NaBH4 (16 g, 0.42 mol) was added. The reaction mixture was stirred for 18 h at rt. Reaction progress was monitored by TLC. Upon completion, the reaction mixture was reduced to one-fourth volume and was treated with 0.5 N aq H2SO4 to adjust pH to about 6-7 followed by addition of H2O (1 L). Upon vigorous stirring white precipitate formed. After filtration, the precipitate was lyophilized, washed using chilled toluene (ca. −50° C.) and dried under vacuum to obtain G3 (89 g, 0.38 mol, 73%) as an off-white solid: mp 86-88° C. (Lit.8 88-90° C.); 1H NMR (DMSO, 400 MHz) δ 9.33 (1H, s), 7.35 (5H, m,) 7.08 (1H, d, J=8.4 Hz), 6.42 (2H, m), 5.01 (2H, s), 4.80 (1H, m), 4.39 (2H, s).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:1]1([NH:5][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Cyclobutylamine (370 mg) was added to an ice-cold suspension of tert-butyl bromoacetate (1.0 g) and potassium carbonate (700 mg) in acetonitrile (20 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, which was then extracted with chloroform. The organic phase was separated out and the solvent was distilled off under reduced pressure to afford tert-butyl N-cyclobutylglycinate (949 mg) as the residue.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-(3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 10% of the corresponding Z isomer as a colorless foam, MS (ESI+): m/z=461.05 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[NH:12]1[CH2:17][CH2:16][C:15](O)([OH:18])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)=[O:5]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: OC1(O)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1C(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a solution of 2-methylbenzoyl chloride (800 mg, 5.2 mmol) in 5 mL of DICHLOROMETHANE was added a mixture of piperidine-4,4-diol hydrochloride salt 800 mg, 5.2 mmol) and potassium carbonate (716 mg, 5.2 mmol) in 5 mL H2O and stirred at room temperature for 2 hours. Layers were separated and aqueous layer was extracted with dichloromethane (3×10 mL). Organic layers were combined, dried, filtered and the filtrate was concentrated in vacuo to give the tile compound (1.2 g) as light yellow oil. MS (M+1): 218.0
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([Cl:12])=[N:7]2.[Li+].[CH3:14]C([N-]C(C)C)C.IC.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6]([Cl:12])=[N:7]2
Reactant: CC(C)[N-]C(C)C
Reactant: Clc1ccc2c(Br)cccc2n1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(Br)cccc2nc1Cl
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-chloroquinoline (1.0 g, 4.1 mmol) in anhydrous THF (20 mL) at −78° C. was added LDA (2.0 M in heptane/THF/ethylbenzene, 3.1 mL, 6.2 mmol) dropwise. After stirring for one hour, iodomethane (1.28 mL, 20.6 mmol) was added, and the mixture was stirred at −78° C. for another hour. The mixture was poured into saturated NH4Cl (aq) then extracted twice with EtOAc. The organic extracts were concentrated and the residue was purified by reverse-phase HPLC to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 8.34 (s, 1H); 7.96 (d, J=8.3 Hz, 1H); 7.80 (d, J=7.5 Hz, 1H); 7.53 (d, J=7.8 Hz, 1H); 2.60 (s, 3H) LC3: 1.41 min. (M+H) 258.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]#[C:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16].O.[NH3:18]>O1CCOCC1>[NH2:18][C:2]1[N:10]=[C:9]([C:11]#[C:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16]
Reactant: CC(O)C#Cc1nc(Cl)c2ncn(C)c2n1
Reactant: N
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C#Cc1nc(N)c2ncn(C)c2n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(6-chloro-9-methyl-9H-purin-2-yl)but-3-yn-2-ol (4.8 g, 20.34 mmol) in dioxane (30 ml) was added 30% w/w water solution of ammonia (60 ml). The reaction mixture was stirred overnight in an autoclave at 70° C. The solution was evaporated at atmospheric pressure at 50° C. and then under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH: 97/3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:12][O:13][CH:14](OC)[C:15](=[CH2:18])[C:16]#[N:17]>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[C:6]([CH2:18][C:15]([C:16]#[N:17])=[CH:14][O:13][CH3:12])[C:5]([CH3:11])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: C=C(C#N)C(OC)OC
Reactant: COc1ccc(C)cc1OC
Solvent: ClCCl
Product: COC=C(C#N)Cc1cc(OC)c(OC)cc1C
Reaction time: 6 h

Procedure:
To a solution of 10 g. of 3,4-dimethoxytoluene and 9.6 g. of 2-dimethoxymethylacrylonitrile in 200 ml. of dry methylene chloride was added dropwise at 0°, 2.3 ml. (0.0197 mole) of stannic chloride. The reaction mixture was stirred for 6 hours at 20°-25°, diluted with 500 ml. of ether, and the resulting solution washed with a 5% sodium bicarbonate solution until the aqueous layer remained basic. The combined aqueous washings were backwashed with ether and the organic layers were then combined and dried (MgSO4). The solvent was then removed under reduced pressure leaving an off-white residue of crude 1,2-dimethoxy-4-methyl-5-(2-cyano-3-methoxy-2-propenyl)benzene.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(OC)c1Br
Yield: 40 %

Procedure:
2-(4-Bromo-3,5-dimethoxyphenyl)furan was coupled with N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the method used for the synthesis of Example 12. Purification by chromatography (50-80% EtOAc-hexanes) provided 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone as a yellow foam (0.356 g, 40% yield). MS: m/z 513.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([S:25](F)(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[CH2:37]([NH:44][S:25]([C:2]([F:1])([F:29])[C:3]([F:23])([F:24])[C:4]([F:22])([F:21])[C:5]([F:19])([F:20])[C:6]([F:18])([F:17])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:10])([F:12])[F:11])(=[O:26])=[O:27])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(NCc1ccccc1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
50.21 g (100.0 mmol) of perfluorooctanesulfonyl fluoride is added in drops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 10.72 g (100.0 mmol) of benzylamine at 80° C. while being stirred vigorously. It is stirred for 2 days at 80° C., the reaction mixture is mixed with 300 ml of water and extracted 3 times with ethyl acetate. The combined organic extracts are dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol=4/1).
Reaction SMILES: [CH3:1][NH2:2].C(O)C.[Br:6][C:7]1[C:8]([CH2:17]Br)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10](OC)=[O:11]>C1COCC1>[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:9]2[C:8]=1[CH2:17][N:2]([CH3:1])[C:10]2=[O:11]
Reactant: COC(=O)c1cccc(Br)c1CBr
Reactant: CN
Solvent: CCO
Solvent: C1CCOC1
Product: CN1Cc2c(Br)cccc2C1=O
Reaction time: 2 h

Procedure:
An 8M solution of methylamine in ethanol (10 mL, 80 mmol) was added to a solution of methyl 3-Bromo-2-(bromomethyl)benzoate in THF (30 mL) and allowed to stir for 2 h. The reaction mixture was concentrated to dryness and the residue was triturated with water. The solids produced were collected by filtration and dried to afford 4-bromo-2-methyl-2,3-dihydroisoindol-1-one which used immediately in the next step. To a cold suspension of 4-bromo-2-methyl-2,3-dihydroisoindol-1-one (60 g, 265 mmol) in concentrated sulfuric acid (60 mL) was added pre-cooled mixture of conc. nitric acid (12.5 mL, 265 mmol) and conc. sulfuric acid (60 mL) over 20 min. The reaction mixture was stirred for 30 min at 0° C. and 2 h at room temperature. The reaction mixture was poured into an ice-water mixture (300 mL) and the precipitate that formed was collected by filtration and washed with water (3×100 mL). The solids were suspended in isopropanol (200 mL) and heated on a steam bath for 10 minutes. The mixture was cooled and the solid was collected by filtration and air dried to afford 53 g of the title compound (74%). 1H NMR (CDCl3, 300 MHz) δ 3.22 (s, 3H), 4.36 (s, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][NH:9][C:10]1[N:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([B:25]3[O:29]C(C)(C)[C:27](C)(C)[O:26]3)=[C:21](C=O)[CH:20]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13])(C)(C)C.[BH4-].[Na+].Cl>CO>[OH:29][B:25]1[C:22]2[CH:21]=[CH:20][C:19]([O:18][C:16]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([NH:9][CH2:8][CH2:7][OH:6])[N:17]=3)=[CH:24][C:23]=2[CH2:27][O:26]1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)c(NCCO[Si](C)(C)C(C)(C)C)n3)cc2C=O)OC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1NCCO
Reaction time: 8 h
Yield: 13.1 %

Procedure:
To a solution of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (7, 1.11 g, 2.12 mmol) in MeOH (anhydrous, 60 mL) was added NaBH4 (0.48 g, 12.7 mmol). The reaction was stirred at r.t for 4 h, before the addition of HCl (1 M, 20 mL). After overnight stirring, all volatile components were removed. Purification was accomplished by preparative HPLC, eluting with 5%-90% ACN/water gradient, to afford 86.3 mg (13% yield) of the title compound as a white solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].O>CO>[CH:10](=[C:2]1[C:3](=[O:9])[CH:4]2[CH2:7][CH2:8][N:1]1[CH2:6][CH2:5]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CN2CCC1CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2ccccc2)N2CCC1CC2
Yield: 61.9 %

Procedure:
A mixture of 3-quinuclidinone (6.25 g, 50 mmol), benzaldehyde (5.83 g, 55 mmol) and KOH (0.84 g, 15 mmol) in 30 mL MeOH is heated under reflux for 16 h. The reaction is cooled and water is added. The mixture is extracted with CHCl3, dried (MgSO4), filtered and concentrated. The yellow solid is triturated with warm heptane, filtered and dried to provide 6.6 g (62%) of 2-benzylidene-1-azabicyclo[2.2.2]octan-3-one. A suspension of 2-benzylidene-1-azabicyclo[2.2.2]octan-3-one (6.6 g, 31 mmol) in MeOH is treated with a THF slurry of 10% Pd/C (0.38 g) in a Parr hydrogenation bottle. The bottle is charged with 40 psi of hydrogen gas and allowed to shake for 1 h. The mixture is filtered through Celite, and the solvent is removed in vacuo. The residue is purified by chromatography (Biotage 40M, 30% EtOAc/hexanes—100% EtOAc) to afford 0.48 g (7%) of 2-benzylidene-1-azabicyclo[2.2.2]octan-3-ol and 4.8 g (72%) of 2-benzylquinuclidin-3-one. MS (ESI+) for C14H17NO m/z 216.1 (M+H)+.