Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Li].[CH3:3][C:4]1([CH3:13])[O:8][C@@H:7]2[CH:9]=[CH:10][C:11](=[O:12])[C@@H:6]2[O:5]1.[CH2:14]1COCC1.CCOCC>CCOCC.[Cu]I>[CH3:3][C:4]1([CH3:13])[O:8][C@@H:7]2[C@@H:9]([CH3:14])[CH2:10][C:11](=[O:12])[C@@H:6]2[O:5]1
Reactant: CC1(C)O[C@@H]2C=CC(=O)[C@@H]2O1
Reactant: C1CCOC1
Agent: [Cu]I
Agent: [Li]C
Solvent: CCOCC
Product: C[C@H]1CC(=O)[C@@H]2OC(C)(C)O[C@H]12
Temperature: -40 °C

Procedure:
Copper(I) iodide (3.7 g, 19.5 mmol, 5 equiv) was suspended in Et2O (35 mL) and cooled to −40° C. Methyllithium (20.2 mL, 32.3 mmol, 8.3 equiv, 1.6M in THF) was added dropwise over 45 minutes. The mixture was warmed to 0° C. and (3aR,6aR)-2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (5-1) (600 mg, 3.9 mmol, 1 equiv) in 1:1 THF/Et2O (20 mL) was added dropwise over 10 minutes. The resulting mixture was stirred warming to ambient temperature over 1 hour. The mixture was then cooled to 0° C., quenched carefully with 25 mL of 15% acetic acid and extracted with EtOAc (3×40 mL). The combined organics were washed with NH4Cl (50 mL), dilute NH4OH (2×50 mL) and water (50 mL), dried over MgSO4, filtered and concentrated to afford (3aR,6S,6aR)-2,2,6-trimethyldihydro-3aH-cyclopenta[d][1,3]dioxol-4(5H)-one (6-1) as a light yellow oil. 1H NMR (500 MHz, CDCl3): δ 4.50 (d, J=5.5 Hz, 1H); 4.23 (d, J=5.0 Hz, 1H); 2.80 (dd, J=18.5, 8.0 Hz, 1H); 2.53 (quin, J=8.0 Hz, 1H); 1.96 (d, J=18.5 Hz, 1H); 1.43 (s, 3H); 1.35 (s, 3H); 1.05 (d, J=7.5 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH:15]=[CH2:16])=[CH:8][CH:7]=1.[OH-].[Na+].CO>C1COCC1.O>[CH2:13]([O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:3]([OH:25])=[O:2])=[CH:11][CH:10]=1)[CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl ester 18 (3.20 g, 9.16 mmol) was dissolved in THF (30 mL) and NaOH (0.552 g, 13.8 mmol) dissolved in water (10 mL) was added. Methanol (10 mL) was added to obtain a homogenous solution and this was stirred at rt for 18 h. The reaction mixture was then concentrated in vacuo and the residue was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted twice more with EtOAc and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield a white solid, 2.60 g, 85%. m.p. 148-150° C.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[CH2:5]([O:12][C:13]([NH:15][CH:16]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=O)[CH2:17]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:27]([OH:29])[CH3:28]>>[CH2:5]([O:12][C:13]([NH:15][CH:16]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[CH:3][C:2]([O:29][CH2:27][CH3:28])=[O:1])[CH2:17]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(NC1CC(=O)c2ccccc2C1)OCc1ccccc1
Reactant: CCO
Reactant: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C=C1CC(NC(=O)OCc2ccccc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of triethyl phosphonoacetate (0.202 mL) in ethanol (2 mL) stirring at 0° C. under nitrogen was added a solution of sodium ethoxide in ethanol (21% by weight, 0.379 mL). After 1 h, a solution of 3-benzyloxycarbonylamino-1-oxo-1,2,3,4-tetrahydronaphthalene (100 mg) in ethanol (1 mL) was added. Upon completion of addition, the reaction mixture was stirred for 12 h and allowed to warm to room temperature. The reaction mixture was then quenched with 1.0 M aqueous hydrochloric acid solution and the ethanol was removed under reduced pressure. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated under vacuum to yield a residue. The residue was purified by reverse phase preparative HPLC (trifluoroacetic acid containing solvents were used) to obtain the title compound (55 mg) as a 2.7:1 mixture of the olefin isomers, which were separable but were combined for use in the next step.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[CH2:11]([Sn](CCCC)(CCCC)CCCC)[CH:12]=[CH2:13].[Li+].[Cl-]>C1(C)C=CC=CC=1>[CH2:13]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1)[CH:12]=[CH2:11]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C#N)c(F)c1

Procedure:
A mixture of 4-bromo-2-fluorobenzonitrile (250 mg, 1.3 mmol), allyl-tributyl-stannane (500 mg, 1.5 mmol), LiCl (160 mg, 3.8 mmol) and Pd(PPh)4 (15 mg) in 5 mL of anhydrous toluene was refluxed under N2 overnight. Checked the reaction with TLC and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product 4-allyl-2-fluorobenzonitrile. MS m/z: 162 (M+1)+.
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:9]\[O:10][CH3:11])/[C:6]([OH:8])=O)(=[O:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl.O1CCCC1>[C:1]([NH:4]/[C:5](=[CH:9]\[O:10][CH3:11])/[C:6]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CO/C=C(\NC(C)=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CO/C=C(\NC(C)=O)C(=O)NCc1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of (D1) (20 g, 0.125 mol) in CH2Cl2 (300 ml, 15 vol) and tetrahydrofuran (THF) (100 ml, 5 vol), N-methylmorpholine (NMM) (16.6 ml, 0.15 mol) was added slowly at −40° C. After 20 min, isobutylchloroformate (IBCF) (19.67 ml, 0.15 mol) was added at same temperature and stirred for 20 min. Benzylamine (16.5 ml, 0.15 mol) in tetrahydrofuran (40 ml) was added at −40° C., then the reaction mixture was stirred for 1 h and allowed to room temperature. Solvent was evaporated under reduced pressure. The obtained crude was purified by column chromatography in 5% methanol in chloroform to afford (A1) as a white colored powder. Yield: 17 g; 55%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C@@H:21]2[CH2:23][C@H:22]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:15][CH2:14]1)[C:6]([O-:8])=[O:7])#[N:2].[K+].[C:31]([O-:34])([O-])=[O:32].[Na+].[Na+].C(O)(=O)[CH2:38][C:39]([CH2:44]C(O)=O)([C:41](O)=O)O>C1COCC1.O>[C:39]([O:34][C:31]([N:20]([CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:11]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[C:1]#[N:2])[CH2:14][CH2:15]1)[C@@H:21]1[CH2:23][C@H:22]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32])([CH3:44])([CH3:41])[CH3:38]
Reactant: N#Cc1cc(C(=O)[O-])ccc1CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1CCN(Cc2ccc(C(=O)O)cc2C#N)CC1)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
To a stirred solution of potassium 3-cyano-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate (1 g, 2.57 mmol) in a mixture of THF (20 mL) and water (4 mL) was added Na2CO3 (0.680 g, 6.42 mmol), Boc-anhydride (0.715 mL, 3.08 mmol) at RT. Then the reaction mixture was stirred at RT for 16 h. Reaction mixture was diluted with water and pH (˜6) was adjusted with citric acid solution (aq) and then extracted with EtOAc (3×70 mL). The combined organic layer was washed with brine (80 mL), dried over Na2SO4 and concentrated to afford the crude residue (1.2 g). Crude was further purified by Prep HPLC and isolated 4-((4-(((tert-butoxycarbonyl)((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)-3-cyanobenzoic acid (400 mg, 0.812 mmol, 31.6% yield). LCMS (ES) m/e 490.11 (M+H)+.
Reaction SMILES: [CH2:1]([CH2:7][CH:8]([NH2:12])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[O:13]1CCC[CH2:14]1.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[O:13]=[C:14]1[NH:12][CH:8]([CH2:7][CH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:9](=[O:11])[O:10]1
Reactant: C1CCOC1
Reactant: NC(CCCCC(=O)O)C(=O)O
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(O)CCCCC1NC(=O)OC1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 1.752 g of DL-2-aminopimelic acid, 55 ml of tetrahydrofuran and 16 ml of 1.93M phosgene in toluene is heated, in an oil bath, at 50° C. for 1 hour. Argon is bubbled through the reaction to remove the excess phosgene and the solvents are removed under house vacuum. The resulting oil is dissolved in 14 ml of ethyl alcohol, diluted with 14 ml of petroleum ether and the solution stored overnight at room temperature. The formed crystals are collected and dried to give 1.6 g of the desired product.
Reaction SMILES: Br[C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Br:10][C:11]1[N:16]=[C:15]([CH:17]=O)[CH:14]=[CH:13][CH:12]=1.[NH2:19][NH2:20]>>[Br:10][C:11]1[N:16]=[C:15]([C:17]2[C:2]3[C:3](=[N:4][C:5]([Cl:8])=[N:6][CH:7]=3)[NH:20][N:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: NN
Reactant: Clc1ncc(Br)c(Cl)n1
Product: Clc1ncc2c(-c3cccc(Br)n3)n[nH]c2n1

Procedure:
Alternatively, for compounds of formula Ia where X is N and Y is CH, in accordance to Scheme 2 below, 5-bromo-2,4-dichloro-pyrimidine (1) is reacted with 6-bromo-pyridine-2-carbaldehyde (3) by a Grignard reaction and the corresponding coupled alcohol is oxidized to the ketone. The ketone is reacted with hydrazine to give 3-(6-bromo-pyridin-2-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine. The remaining chloro group can then be replaced by reacting with the appropriate amine and the bromide can be displacement with the required amine under Buckwald conditions to give compounds Ia of this invention.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:22])[CH2:3][CH2:2]1.O[CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:26][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:22])[CH2:2][CH2:3]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-1,3-benzoxazol-6-ol (1.00 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (0.878 g) and triphenylphosphine (1.32 g) in THF (10 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 2.64 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (0.744 g). 1H NMR (300 MHz, CDCl3) δ 0.35-0.45 (2H, m), 0.63-0.76 (2H, m), 1.29-1.39 (4H, m), 1.46 (9H, s), 3.91-4.02 (4H, m), 4.04-4.18 (1H, m), 4.70-4.85 (1H, m), 6.95 (1H, dd, J=8.7, 2.3 Hz), 7.04 (1H, t, J=8.3 Hz), 7.10 (1H, d, J=2.3 Hz), 7.60 (1H, d, J=8.7 Hz), 7.84-8.01 (2H, m).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=O.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:20][O:19][C:13](=[O:18])[CH2:14][C:15]1([CH3:17])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1
Reactant: OCCC1=CCc2ccccc21
Reactant: COC(=O)CC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)CC1(C)OCCC2=C1Cc1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of indene-3-ethanol (8 g) and methyl acetoacetate (6 g) in 250 ml of dry benzene containing hydrated alkali-aluminum silicate (Molecular Sieves No. 4, about 2 g) is added 1 ml of boron trifluoride-etherate and the mixture stirred at room temperature for 4 hr. An additional 1 ml of boron trifluoride-etherate is added, the reaction mixture is stirred at ambient temperature overnight and then heated at reflux for 1 hr. The hydrated alkali-aluminum silicate is collected and the filtrate washed with 10% solution of sodium bicarbonate and water. After drying over magnesium sulfate the benzene is removed under reduced pressure affording 1-methyl-1,3,4,9-tetrahydroindeno[2,1-c]pyran-1-acetic acid methyl ester, νmaxfilm 1724 cm-1.
Reaction SMILES: [Cl: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][CH:15]=3)[C:6]=2[CH:20]=1.C(Cl)(Cl)Cl.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH:13][C:32](=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCCCCC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
To a mixture of 2.85 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 50 parts by volume of chloroform and 2 parts by volume of triethylamine, a solution of 1.6 parts of enanthylchloride in 20 parts by volume of diethyl ether is gradually added with ice-cooling. The mixture is stirred for a while to complete the reaction. After evaporation of the solvent under reduced pressure, the residue is treated with methanol to yield 7-chloro-2-(2-enanthylhydrazino)-5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from a mixture of dimethylformamide and water yields colorless needles melting at 205° C to 206° C (effervescence).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23](Cl)=[O:24]>>[O:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:12]([F:15])([F:13])[F:14])=[N:11][N:2]1[NH:1][C:23](=[O:24])[CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: O=C(Cc1cccs1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 11B and 2-(thiophen-2-yl)acetyl chloride were treated using a method similar to that described in Example 53 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.88-11.97 (m, 1H), 8.41-8.48 (m, 1H), 8.13 (td, J=7.7, 1.6 Hz, 1H), 8.00-8.09 (m, 2H), 7.43 (dd, J=5.1, 1.3 Hz, 1H), 7.04-7.08 (m, 1H), 7.01 (dd, J=5.1, 3.5 Hz, 1H), 3.96 (d, J=0.9 Hz, 2H); MS (ESI−) M/Z 352 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[CH:18])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1>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.[Cu]I>[CH3:26][C:22]1[N:21]=[C:20]([C:18]#[C:17][CH:16]=[C:13]2[CH2:14][CH2:15][N:10]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:11][CH2:12]2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cccc(Br)n1
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1cccc(C#CC=C2CCN(c3ncccc3[N+](=O)[O-])CC2)n1
Temperature: 80 °C
Yield: 69.6 %

Procedure:
A mixture of Compound 1c (0.21 g, 0.86 mmol), 2-bromo-6-methylpyridine (0.11 mL, 0.95 mmol), tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol), CuI (16 mg, 0.09 mmol) in anhydrous and degassed triethylamine (10 mL) was heated at 80° C. under a nitrogen atmosphere for 2 h in sealed vessel. The reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 3.5:6.5) affording the title product (0.20 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:27]=[N+:28]=[N-:29].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][N:27]=[N+:28]=[N-:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CN=[N+]=[N-]
Temperature: 25 °C

Procedure:
In a flask protected by a safety screen, a solution of N-t-butoxycarbonyl-4(S)-t-butyldimethylsilyloxy-2(S)-methanesulfonyloxy methyl pyrrolidine(10.40 g, 25.39 mmol) and tetrabutylammonium azide (8.18 g, 28.7 mmol) in toluene (250 ml) was stirred at 80° C. for 5 hr. The reaction was cooled to room temperature and diluted with EtOAc (250 ml), washed with water and brine and dried (Na2SO4). The solvent was evaporated in vacuo to afford the title compound as a yellow oil which was used in the next step without furthur purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].CCCC(O[C@@]1(C(COC(C)=O)=O)[C@@]2(C)C[C@H](O)[C@]3(F)[C@]4(C)C(=CC(C=C4)=O)[C@@H](F)C[C@H]3[C@@H]2CC1)=O.[N+:48]([O-])([OH:50])=[O:49]>S(=O)(=O)(O)O>[N+:48]([C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6])([O-:50])=[O:49]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: O=[N+]([O-])O
Agent: CCCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 77.4 %

Procedure:
Into 100 mL of 96% sulfuric acid was placed 3,4-difluorobenzoic acid(11.95 g, 0.0756 mol). The solution was stirred at room temperature until the DFBA was dissolved, and then cooled to 0° C. Nitric acid (7.9 g of 90% fuming) was added dropwise to the cooled mixture. After addition, the solution was warmed to room temperature and stirred until completion of the reaction. After drying, 11.88 g of 2-nitro-4,5-difluorobenzoic acid was isolated. The material was identified by GCMS and 19F NMR analysis. An additional 2.41 g of product was obtained by extraction of the acid washes and removal of the solvent.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([Sn](CCCC)(CCCC)COCC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)CCC.C(OCC)C.[F-].[K+]>C(Cl)(Cl)Cl>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:9])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC[Sn](CCCC)(CCCC)COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(=O)C(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
Diphenylacetyl chloride (4.6 g), tri-n-butyl-((3,5-bis(trifluoromethyl)phenyl)methyloxymethyl)tin (12.6 g; Example 1a, (Method Ai)and benzylchlorobis(triphenylphosphine) palladium (II)(80 mg)were dissolved in chloroform (10 ml) and the solution heated at 80° C. for 6h. On cooling diethyl ether and saturated aqueous potassium fluoride were added and after 30 minutes the solution was filtered through Hiflo™. The organic layer was washed with water, saturated brine and dried (MgSO4). After evaporation in vacuo the residual oil was purified by chromatography on silica gel (eluting with 0 to 10% ethyl acetate in petroleum ether bp=60°-80° C.) to give 1-(3,5-bis(trifluoromethyl)phenyl)methyloxy)-3,3-diphenyl acetone as an oil. 1H NMR (CDCl3, 360MHz) δ7.80 (1H; s; 4-aryl CH) 7.71 (2H; s; 2,6-aryl CH), 7.43-7.24 (10H; m; phenyl), 5.30 (1H; s; Ph2CH), 4.56 (2H; s), 4.31 (2H; s). m/e Found 452.1191, C24H13F6O2 requires 452.12110.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[CH:8]2.[C-:14]#[N:15].[Na+].O.CCOCC>CS(C)=O>[CH3:13][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:3]([CH2:2][C:14]#[N:15])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: [C-]#N
Reactant: Cc1ccc2cccc(CBr)c2n1
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2cccc(CC#N)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a solution of 8-(bromomethyl)-2-methylquinoline (1.50 g, 6.35 mmol) in DMSO (20 mL) was added NaCN (0.62 g, 12.7 mmol). The mixture was stirred at ambient temperature for 10 minutes. Water (100 mL) and ether (100 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:1 hexane/ethyl acetate) to give 2-(2-methylquinolin-8-yl)acetonitrile (0.75 g, 58.3%) as a solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:19][CH3:20])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)#[N:2].[OH-:21].[Na+]>Cl>[C:1]([N:3]=[C:4]([NH:19][CH3:20])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)(=[O:21])[NH2:2]
Reactant: CNC(=NC#N)NCCSCc1nsc(NC(=N)N)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CNC(=NC(N)=O)NCCSCc1nsc(NC(=N)N)n1

Procedure:
A mixture of 3-[-2-(2-cyano-3-methylguanidino)ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole (0.2 g.) and 1 N hydrochloric acid (50 ml.) was heated under reflux for 30 minutes, cooled, neutralised with 1 N sodium hydroxide and extracted with ethyl acetate (6×25 ml.). The combined extracts were dried (MgSO4) and evaporated in vacuo to a white solid which was dissolved in ethanol (3 ml.) and added to a solution of oxalic acid (0.071 g.) in ethanol (2 ml.). The precipitated solid was filtered off, washed with ethanol and dried at 50°/0.1 m.m. to give 3-[2-(2-carbamoyl-3-methylguanidino)ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole. 1.75 oxalate. Found: C, 31.0; H, 4.3; N, 25.7; S, 13.5; C9H17N9OS2.1.75 C2H2O4 requires C, 30.7; H, 4.2; N, 25.8; S, 13.1%.