Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][OH:10].N1C=CC=CC=1.[Cl:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21].NO>C(Cl)Cl.CCCCCC>[Cl:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20]([N:9]([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[OH:10])=[O:21]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: ONCc1ccccc1Cl
Agent: NO
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(CCl)C(=O)N(O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
Under an argon atmosphere a stirred solution of 10.2 grams (0.065 mole) of N-(2-chlorophenylmethyl)hydroxylamine and 6.1 grams (0.077 mole) of pyridine in 80 ml of methylene chloride was cooled to -10°. A solution of 10.0 grams (0.065 mole) of 3-chloro-2,2-dimethylpropionyl chloride in 20 ml of methylene chloride was added dropwise to the hydroxylamine solution during a 20 minute period. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred for 16 hours. The reaction mixture was diluted with 100 ml of methylene chloride and washed with 100 ml of water, 100 ml of aqueous 10% hydrochloric acid, and finally 100 ml of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residual oil. The oil was taken up in 25 ml of hexane and cooled in an icewater bath. The resultant solid precipitate was collected by filtration and recrystallized from hexaneethyl acetate to give 3.7 grams of 3-chloro-N-(2-chlorophenyl)methyl-N-hydroxy-2,2-dimethylpropanamide; mp 108°-110°.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].C(=O)([O-])O.[Na+].[Cl:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(OCC)(=O)C>[Cl:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:18]2[CH2:19][CH2:20][N:15]([S:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)(=[O:14])=[O:13])[CH2:16][CH2:17]2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(c1ccc(CCl)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a mixture of 1-(2-naphthalenesulfonyl)piperazine hydrochloride (5.0 g) in ethyl acetate (60 ml) and an aqueous solution of 10% sodium hydrogen carbonate (40 ml) was added 4-chloromethylbenzoylchloride (3.02 g), and the solution was stirred at room temperature for 30 minutes. The organic layer was separated, washed with water and saturated sodium chloride, dried and concentrated. The residue was washed with diisopropylether and dried under reduced pressure to give the title compound (4.945 g, 78%).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][CH:7]=1)[CH:2]=[CH2:3].Br[CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([N:4]([CH2:5][C:6]1[CH:10]=[CH:9][O:8][CH:7]=1)[CH2:12][CH2:13][OH:14])[CH:2]=[CH2:3]
Reactant: C=CCNCc1ccoc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(CCO)Cc1ccoc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 6.597 g (48.09 mmol) of N-allyl-3-furylmethylamine and 18.0 g (144 mmol) of 2-bromoethanol in 100 ml of N,N-dimethylformamide, 33.2 g of potassium carbonate was added, followed by overnight stirring at 90° C. The reaction mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to yield 2-[allyl-(3-furylmethyl)amino]ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>CC(O)=O>[Br:1][C:2]1[C:3]([C:9]([F:10])([F:11])[F:12])=[CH:4][C:5]([OH:8])=[C:6]([N+:18]([O-:20])=[O:19])[CH:7]=1
Reactant: Oc1ccc(Br)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)c(C(F)(F)F)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
To a 0° C. mixture of 4-bromo-3-(trifluoromethyl)phenol (Apollo, 10.8 g, 44.8 mmol) in AcOH (40 mL) was added concentrated sulfuric acid (1.5 mL) followed by fuming nitric acid (5.2 g) and the mixture was stirred for 30 min. Additional concentrated sulfuric acid (9 mL) was added and the temperature was allowed to rise to ambient temperature and stirred for 3 h at rt. The mixture was poured into ice water (500 mL) and the aqueous solution was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10-20% EtOAc in petroleum ether) to give 4-bromo-2-nitro-5-(trifluoromethyl)phenol (4.7 g, 36%) as yellow oil. 1H NMR (DMSO-d6, 400 MHz): δ 12.0 (brs, 1H), 8.31 (s, 1H), 7.54 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.Cl.[NH:25]1[CH2:28][CH:27]([OH:29])[CH2:26]1.C(N(C(C)C)CC)(C)C>>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:22][N:25]5[CH2:28][CH:27]([OH:29])[CH2:26]5)=[CH:20][CH:21]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: OC1CNC1
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(CO)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(CN2CC(O)C2)cc1
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedures of Example 45, using the alcohol of Example 49 as starting material and using azetidin-3-ol hydrochloride (21 mg, 0.20 mmol, Oakwood) and diisopropylethylamine (34 μL, 0.20 mmol) in the displacement, which was performed overnight (10.3 mg, 58%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[N:20]=[CH:21][C:22]([C:33](OC)=[O:34])=[N:23][C:24]=1[O:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)(=[O:17])=[O:16].C(O)(=O)C>O1CCCC1>[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[C:24]([O:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[N:23][C:22]([CH2:33][OH:34])=[CH:21][N:20]=1)(=[O:17])=[O:16]
Reactant: COC(=O)c1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cccnc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S(=O)(Nc1ncc(CO)nc1OCc1cccnc1)c1cccc(Cl)c1Cl
Temperature: -65 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
Lithium aluminium hydride (0.85 mL of a 1M solution in tetrahydrofuran) was added dropwise to 5-(2,3-dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazine-2-carboxylic acid, methyl ester (Example 134) (0.2 g) in tetrahydrofuran (10 mL) cooled to −65° C. The reaction mixture was allowed to warm to room temperature and stirred for 1h. Aqueous acetic acid was added and the mixture extracted with ethyl acetate. The organic solution was dried (MgSO4) and evaporated. Chromatography on silica gel eluting with ethyl acetate/methanol mixtures gave the title compound (0.08 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[CH:4]=[CH:5][N+:6]([O-:8])=[O:7].[CH3:16][N:17]([CH3:21])[C:18](=[S:20])[S-:19].C[NH2+]C>C(=S)=S>[CH3:16][N:17]([CH3:21])[C:18](=[S:19])[S:20][CH:4]([CH2:5][N+:6]([O-:8])=[O:7])[C:3]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: CN(C)C(=S)[S-]
Reactant: O=[N+]([O-])C=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1cc([N+](=O)[O-])ccc1Cl

Procedure:
As in Example 17, reaction of 2-chloro-β,5-dinitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave 2-chloro-5-nitro-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 120° C.-121° C. after recrystallization without heating from acetone-methanol solution.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2cccc([N+](=O)[O-])c2)cn1
Temperature: 140 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
A mixture of 6-methylpyridin-3-ol (17.6 g, 161 mmol), 1-fluoro-3-nitrobenzene (25.0 g, 177 mmol), potassium carbonate (66.8 g, 483 mmol) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 13 hr, 120° C. for 5 hr and 140° C. for 4 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (28.6 g, 77%) as a yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[C:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=2[C:11]([S:19][CH3:20])=[C:5]2[O:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41].CO>N1C=CC=CC=1>[Br:41][CH2:2][C:3]1[C:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=2[C:11]([S:19][CH3:20])=[C:5]2[O:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=12
Reactant: BrC(Br)(Br)Br
Reactant: CSc1c2c(c(CO)c3c1OC(C)(C)O3)OC(C)(C)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: CSc1c2c(c(CBr)c3c1OC(C)(C)O3)OC(C)(C)O2

Procedure:
4-Hydroxymethyl-8-methylthio-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole is dissolved in pyridine. The solution is chilled and triphenylphosphine followed by carbontetrabromide are added. the reaction is stirred for an appropriate time. Methanol is added and the product is isolated by a suitable method.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][C:22]([F:35])([F:34])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31](=[O:32])[C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:22]([F:35])([F:34])[F:21])=[CH:30][N:29]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(2,2,2-trifluoroethoxy)picolinic acid [D. Banner et al. WO2010128058 (2010)] following General Procedure G yielded the title compound as a colorless amorphous solid. MS: m/z=495.4 [M+H]+.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([C:31](=[O:33])[CH3:32])[CH:17]2[C:21]([O:23]CC1C=CC=CC=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([C:31](=[O:33])[CH3:32])[CH:17]2[C:21]([OH:23])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N1CSC2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CSC2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a cooled solution of benzyl 7-phenoxyacetamido-8-oxo-3-acetyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (300 mg.) in tetrahydrofuran (9 ml.) was added an aqueous solution (8 ml.) of sodium carbonate (107 mg.). The mixture was stirred at 0° C. for 75 minutes and at room temperature for additional 30 minutes. After removal of the tetrahydrofuran, the remaining aqueous layer was washed with ethyl acetate, acidified to pH 2 with 1 N hydrochloric acid and extracted three times with methylene chloride. Drying over magnesium sulfate and removal of the solvent gave an amorphous solid (235 mg) of 7-phenoxyacetamido-8-oxo-3-acetyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylic acid.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.[NH2:12][CH2:13][C@H:14]([OH:16])[CH3:15].Cl.NCC(N)=O>>[OH:16][C@H:14]([CH3:15])[CH2:13][NH:12][C:9]([C@@H:1]1[C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:2]1)=[O:11]
Reactant: O=C(O)C1CC12CCCCC2
Reactant: C[C@@H](O)CN
Agent: Cl
Agent: NCC(N)=O
Product: C[C@@H](O)CNC(=O)[C@H]1CC12CCCCC2

Procedure:
The title compound was prepared as described in Example 3 substituting the product from Example 6 for the product from Example 1B and substituting (R)-1-amino-2-propanol, purchased from Aldrich, for 2-aminoacetamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 3.80 (m, 1H), 3.16 (m, 2H), 1.20-1.70 (m, 11H), 1.13 (d, 3H), 1.02 (dd, 1H), 0.69 (dd, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 173.9, 67.5, 48.0, 38.7, 30.2, 30.0, 28.9, 27.5, 26.9, 26.8, 21.1, 19.4; MS (CI) m/z 212 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[I-].[CH2:11]([OH:16])[CH2:12][CH2:13][C:14]#[CH:15]>C(NCC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[C:14][CH2:13][CH2:12][CH2:11][OH:16])=[CH:3][CH:4]=1
Reactant: C#CCCCO
Reactant: COc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COc1ccc(C#CCCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
4-Iodoanisol (10 g, 42 mmol), palladium (II) chloride (0.2 g, 1.1 mmol) and triphenylphosphine (0.6 g, 2.2 mmol) were dissolved in diethylamine (100 mL) then cupper(I) iodide (0.5 g, 2.2 mmol) and 4-pentyn-1-ol (5 mL, 53 mmol) were added. The reaction mixture was stirred overnight at room temperature, then the solvent was removed under reduced pressure. Ethyl acetate (150 mL) was added to the residue and the mixture was washed with 2N HCl, brine and water. The organic fraction was isolated, dried with sodium sulfate and the solvent was removed under reduced pressure. The product 16 (7.1 g. 87%) was isolated by flash chromatography (silica gel, 1:2 ethyl acetate/hexanes) as an oily yellow solid. 1H NMR (300 MHz, CDCl3) δ1.88 (m, 2H), 2.53 (m, 2H), 3.72 (s, 3H), 3.74 (m, 2H), 6.83 (d, 2H), 7.45 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[Br:22][CH:23]([Br:27])[C:24](Cl)=O.C([O-])(=O)C.[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:24]([CH:23]([Br:27])[Br:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: O=C(Cl)C(Br)Br
Reactant: NNC1=Nc2ccc(F)cc2C(c2ccccc2Cl)=NC1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(C(Br)Br)n1-2

Procedure:
In the manner given in Example 2, 7-fluoro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with dibromoacetyl chloride and after 1.5 hours with sodium acetate, then the mixture was refluxed to give 8-fluoro-1-(dibromomethyl)-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Si:1]([CH2:8][CH2:9][C@H:10]([O:16]C(=O)C)[C:11]([CH3:15])([CH3:14])[C:12]#[N:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].O>C(O)C>[Si:1]([CH2:8][CH2:9][C@H:10]([OH:16])[C:11]([CH3:15])([CH3:14])[C:12]#[N:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)O[C@@H](CC[Si](C)(C)C(C)(C)C)C(C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C#N)[C@@H](O)CC[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.8 g (16 mmol) of 5-tert-butyldimethylsilyl-2,2-dimethyl-3(S)-acetoxy-pentane-nitrile is dissolved in 50 ml of ethanol and mixed with 1.28 g of NaOH (32 mmol). It is stirred for 3 hours at 25° C., added to 200 ml of water, extracted with 2×200 ml of MTB ether, dried on sodium sulfate and concentrated by evaporation.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl.Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C(C(C)=O)C>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4]1
Reactant: OCC1CCCNC1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: OCC1CCCN(Cc2ccncc2)C1
Yield: 93.5 %

Procedure:
To a solution of 3-hydroxymethylpiperidine (5.0 g, 43 mmol) in methyl ethyl ketone (50 ml) were added successively potassium carbonate (60 g, 0.43 mol), sodium iodide (1.30 g, 8.68 mmol), 4-chloromethylpyridine hydrochloride (8.54 g, 52.1 mmol) and the mixture was heated under reflux for 8 hours. The reaction mixture was filtered with Celite and the solvent was distilled off from the filtrate under reduced pressure. The residue was chromatographed using silica gel column and the fraction from methanol-chloroform (1/20) gave 3-hydroxymethyl-1-(4-pyridylmethyl)piperidine (8.29 g). Yield=93%.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[O:15])[CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:38]1[CH:43]=[CH:42][C:41]([C:44](=[O:49])NCCC)=[CH:40][CH:39]=1)=O)C2>>[C:44]([N:5]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[O:15])[CH2:6]1)(=[O:49])[C:41]1[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(NCCCCC1CNC1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: O=C(NCCCCC1CN(C(=O)c2ccccc2)C1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(4-(azetidin-3-yl)butyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 7.67-7.57 (m, 2H), 7.57-7.39 (m, 3H), 7.39-7.23 (m, 4H), 6.28 (s, 1H), 4.56 (s, 4H), 4.34 (t, J=8.3 Hz, 1H), 4.11 (t, J=9.0 Hz, 1H), 4.01-3.82 (m, 1H), 3.65 (dd, J=9.8, 5.8 Hz, 1H), 3.07 (dd, J=12.7, 6.8 Hz, 2H), 2.66-2.53 (m, 1H), 1.59 (dd, J=15.3, 7.7 Hz, 2H), 1.51-1.36 (m, 2H), 1.25 (dd, J=13.5, 6.4 Hz, 2H); MS (ESI(+)) m/e 378 (M+H)+.
Reaction SMILES: O[C:2]1([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O-:22])=[O:21].C([SiH](CC)CC)C.[B]>C(Cl)Cl>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)[CH:3]2[C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1
Reactant: COc1ccc(C2(O)C(C(=O)[O-])=C(c3ccc4c(c3)OCO4)c3ccccc32)cc1
Agent: CC[SiH](CC)CC
Agent: [B]
Solvent: ClCCl
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl (1R)2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.80 g, 1.9 mmol) in CH2Cl2 (10 ml) at 0° C. under an argon atmosphere was added triethylsilane (0.28 a, 2.4 mmol), followed by boron tritluoride etherate (1 ml, 8.1 mmol). The resulting solution was stirred at 0° C. for 10 min, and was then partitioned between EtOAc and 3M HCl. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacun, and the residue was filtered through a pad of silica gel, eluting with CH2Cl2. The title compound (mixture of Δ1 and Δ2 double bond isomers) was obtained as a glassy, yellow solid (0.72 g, 94%).
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[C:5]([C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@@H:15]2[CH2:17][O:16]2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@H:15]2[O:16][C:2]([NH2:3])=[N:1][CH2:17]2)=[CH:11][CH:10]=1)([CH3:6])([CH3:7])[CH3:8]
Reactant: N#CN
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Agent: [Na]
Solvent: CO
Product: CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a vigorously stirred solution of sodium hydrogen cyanamide (2.92 g, 44.5 mmol) in methanol (40 mL) was added dropwise (S)-2-(4-tert-butylphenoxymethyl)-oxirane (9.18 g, 44.5 mmol). The reaction mixture was stirred at room temperature overnight after which the reaction mixture was concentrated to remove methanol. Anhydrous diethyl ether (150 mL) was added. The resulting white precipitate was filtered through celite and the filtrate was concentrated. The residue was purified by flash chromatography (silica, 7N NH3 in methanol/methylene chloride) to give 4.53 g (41%) of (S)-5-(4-tert-butyl-phenoxymethyl)-(4,5-dihydro-oxazol-2-yl)amine.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([O:13][Si](C)(C)C)[C:4]1=[O:18].C(N(CC)CC)C.C(OCC)(=O)C>CO.C[Si](C)(C)Cl>[OH:13][C@H:5]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:3][C:4]1=[O:18]
Reactant: C[Si](C)(C)OC1C(=O)N([Si](C)(C)C)C1c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2ccccc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
To a heterogeneous solution of N-trimethylsilyl-3-trimethylsiloxy-4-phenyl-azetidin-2-one (150 g, 0.49 mol) in methanol (500 mL) was added a catalytic amount of trimethylchlorosilane (1.08 g, 1 mmol) and the mixture was stirred at ambient temperature to give a clear solution. Thin layer chromatography (TLC) monitoring of the reaction eluting with ethyl acetate and hexanes (3:1) indicated that complete conversion was achieved after 15 minutes. The reaction mixture was quenched with triethylamine (10.1 g, 0.1 mol) and the methanol was removed under rotary evaporation at 40° C. until crystals formed. Ethyl acetate (300 mL) was added and the evaporation was continued to remove the remaining methanol to give a thick slurry before cooling to 0 to 5° C. for 20 minutes. The white crystals were collected via vacuum filtration following by washing with cold 0° C. ethyl acetate (75 mL) and dried to constant weight of 75 g (94% yield) of the desire product described previously.