Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:16])[C:14]=1Cl.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C1(O)CCCCC1>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:16])[C:14]=1[N:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)C1CCNCC1
Reactant: Fc1cncc(Br)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OC1CCCCC1
Product: CC(C)(C)OC(=O)C1CCN(c2c(F)cncc2Br)CC1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
A 3 L flange flask equipped with a thermometer, condensor, nitrogen line and overhead stirrer was heated at 40° C. (external) then charged with cyclohexanol (750 mL), disodium carbonate (129.8 g, 1.225 mol), 3-bromo-4-chloro-5-fluoro-pyridine (Hydrochloric Acid 18) (137.5 g, 556.8 mmol) and tert-butyl piperidine-4-carboxylate (123.8 g, 668.2 mmol) rinsed in with cyclohexanol (350 mL). Mixture was heated to 120° C. internal temperature overnight (18 h). Reaction mixture was removed from hotplate and allowed to cool to room temperature. Water (687.5 mL) and EtOAc (687.5 mL) were added, stirred for 10 mins then transferred to separating funnel Additional EtOAc (1.238 L) was added, mixed and aqueous phase was removed. Organic phase was further washed with water (687 mL), aqueous phase removed, organic layer collected. Aqueous phases were combined and back extracted with EtOAc (687.5 mL), aqueous layer removed and organic phase combined with other organics. Organics concentrated in vacuo (water bath temp=60° C., vacuum down to 2 mBar) leaving a viscous brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[NH2:48][CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:48][CH2:49][CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)=[O:19])=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: O=C(NCC1CCCCC1)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 57.9 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol) obtained in Example 50 were added triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and aminomethylcyclohexane (30 μl, 0.23 mmol). The resulting mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with dichloromethane and washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (58 mg, 0.11 mmol, 59%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:11]12(O)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.CS(O)(=O)=O>>[C:11]12([C:6]3[C:5]4[O:8][CH2:9][O:10][C:4]=4[CH:3]=[C:2]([Br:1])[CH:7]=3)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Brc1ccc2c(c1)OCO2
Agent: CS(=O)(=O)O
Product: Brc1cc2c(c(C34CC5CC(CC(C5)C3)C4)c1)OCO2
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A mixture of 4-bromo-1,2-methylenedioxybenzene (2.00 g, 9.95 mmol), 1-adamantanol (1.52 g, 9.95 mmol), and MeSO3H (5 mL) was stirred for 1 h. The resulting solution was quenched with H2O (40 mL) and extracted with EtOAc (110 mL). The extract was washed with 0.5 N NaOH, sat. NaHCO3, and brine and dried. The residue obtained on concentration was purified on silica gel (hexane) to give 2.86 g (86%) of 4-(1-adamantyl)-6-bromobenzo[1,3]dioxole as a white solid, mp 135-136° C. IR 2901, 2843, 1435, 1189 cm−1; 1H NMR δ (CDCl3) 1.76 (bs, 6H, AdCH2), 1.98 (bs, 6H, AdCH2), 2.06 (bs, 3H, AdCH), 5.93 (s, 2H, CH2), 6.84 (s, 1H, 7-ArH), 6.86 ppm (s, 1H, 5-ArH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH:29]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=23)[CH:31]=[N:30]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Temperature: 120 °C
Yield: 67.8 %

Procedure:
4-Bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.20 g, 0.00061 mol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.15 g, 0.00079 mol) were combined in DMF (5.0 mL, 0.064 mol) and then potassium carbonate (0.25 g, 0.0018 mol) in 1 mL water was added. The reaction was degassed with nitrogen, then tetrakis(triphenylphosphine)-palladium(0) (0.08 g, 0.00007 mol) was added and in a sealed tube the reaction was heated to 120° C. oil bath. The reaction was heated for 30 minutes, allowed to cool and then taken up in ethyl acetate. The reaction mixture was washed with brine, dried over magnesium sulfate and concentrated to give an oil. The product was purified by FCC on silica gel eluting with a hexane:ethyl acetate gradient to give 4-(1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.13 gm, 70%) as a crystalline white powder, LC/MS (M+H)+: 315, 1H NMR (DMSO-d6) δ 13.35 (bs, 1H), 8.59 (bs, 1H), 8.32 (d, 1H, J=8.5), 8.26 (bs, 1H), 7.76 (d, 1H, J=6.0), 7.45 (d, 1H, J=8.5), 7.01 (d, 1H, J=6.0), 5.73 (s, 2H), 3.61 (t, 2H), 0.92 (t, 2H), 0.0 (s, 9H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH:38]=[CH:39][CH2:40][NH2:41])[CH2:33][CH2:32]1>N1C=CC=CC=1>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:37][CH:38]=[CH:39][CH2:40][NH:41][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([OH:13])=[CH:22][CH:21]=2)[CH2:35][CH2:36]1
Reactant: NCC=CCN1CCN(c2cccc(Cl)c2Cl)CC1
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Product: O=C(NCC=CCN1CCN(c2cccc(Cl)c2Cl)CC1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
1,1′-carbonyldiimidazole (0.18 g, 1.1 mmol) was added to a solution of the 4-hydroxy benzoic acid (0.15 g, 1.1 mmol) in absolute pyridine and the mixture was stirred at room temperature under Argon for 1 h. After that time a solution of 4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-but-2-enylamine (0.33 g, 1.1 mmol) in 3 ml amylene-stablized chloroform was added and the mixture was stirred overnight. All volatiles were removed in vacuo and the residue was purified by chromatography to give 0.23 g (51%) of the title compound.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.N1C=CC=CC=1.FC(F)(F)C(O)=O.C(O)(=O)C(O)=O>CS(C)=O.CO.O>[O:8]([CH:7]1[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:3][C:2]1=[O:1])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](Oc2ccccc2)[C@H](O)C1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: O=C1CN(C(=O)OCc2ccccc2)CCC1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
15.0 g (0.045 mol) of the trans-3-hydroxy-4-phenoxy-1-carbobenzyloxy-piperidine described in Example 14 are dissolved, together with 28.34 g (0.13 mol) of dicyclolohexylcarbodiimide and 3.7 ml (0.045 mol) of pyridine, in 80 ml of dry dimethylsulphoxide. The mixture is cooled to 0° with an ice-water bath and treated with 2.6 g (0.023 mol) of trifluoroacetic acid. The cooling bath is removed again and the reaction mixture is stirred for a further 4 hours at room temperature in a nitrogen atmosphere. The white suspension is diluted with 250 ml of ethyl acetate and treated dropwise with a solution of 12.3 g (0.13 mol) of oxalic acid in 200 ml of methanol. After the evolution of gas has ceased, the reaction mixture is cooled to 0° in an ice-water bath and diluted with 400 ml of water and the dicyclohexylurea which has precipitated is separated off. The aqueous phase of the filtrate is extracted with 250 ml of ethyl acetate and the combined organic phases are dried over sodium sulphate and evaporated to dryness under a water pump vacuum. The resulting crude product is dissolved in benzene and the solution is filtered through a layer of silica gel. 4-Phenoxy-1-carbobenzyloxy-3-piperidone is obtained in the form of a pale yellow oil by elution with a benzene/ethyl acetate mixture (95:5).
Reaction SMILES: [F:1][C:2]1[N:3]=[C:4]([NH2:29])[C:5]2[N:6]=[CH:7][N:8]([C:27]=2[N:28]=1)[C@@H:9]1[O:26][C@H:20]([CH2:21][O:22]C(=O)C)[C@@H:15]([O:16]C(=O)C)[C@H:10]1[O:11]C(=O)C.[OH-].[Na+].C(Cl)(Cl)Cl.CO>O1CCOCC1.O>[F:1][C:2]1[N:3]=[C:4]([NH2:29])[C:5]2[N:6]=[CH:7][N:8]([C:27]=2[N:28]=1)[C@@H:9]1[O:26][C@H:20]([CH2:21][OH:22])[C@@H:15]([OH:16])[C@H:10]1[OH:11]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)nc(F)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 0.03 h

Procedure:
2-Fluoro-2',3',5'-tri-O-acetyladenosine (0.41 g, 10 mmol) was dissolved in a mixture of 1,4-dioxane (7 mL) and water (2 mL) and the solution was cooled in an ice-water bath. 2.5 M NaOH (1.40 mL, 3.5 mmol) was added dropwise with vigorous stirring over a 2 min. period. The resulting bright yellow solution was stirred at 0° C. and monitored by TLC (9:1 Chloroform:methanol). After 2 hours, most of the yellow color had faded and TLC showed no acetylated intermediates remaining. The homogeneous reaction mixture was poured directly onto a column of AG 50-X4 (H+, 100-200 mesh, 10 mL bed volume) ion exchange resin and the column was eluted with several column volumes of 1:1 methanol:water. 2-Fluoroadenosine began to elute immediately, and all fractions which contained 2-fluoroadenosine were concentrated under vacuum to obtain a white partially crystalline solid which was dried overnight at 60° C. under vacuum: 0.20 g (70% yield), mp 220°-227° C. (d). This material was consistent by TLC, IR and UV with an authentic sample of 2-fluoroadenosine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:17])=[CH:4][C:3]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)c(F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: Fc1cc(CBr)ccc1Br
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-3-fluorotoluene (39.4 g, 0.21 mol), NBS (38.1 g, 0.22 mol) and AIBN (5 g, 0.03 mol) in 250 mL CH2Cl2 was heated at reflux for 6 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was washed with water, brine, and concentrated under vacuum to afford 1-bromo-4-(bromomethyl)-2-fluorobenzene, which was used without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO.O1CCCC1.O>[N:1]1([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(N2CCOCC2)c1
Yield: 85.3 %

Procedure:
A 500 mL roundbottom flask equipped with stir bar and 3-way stopcock charged with MeOH/tetrahydrofuran/water (200 mL of 2:1:1) was purged thoroughly with nitrogen. To this was added 1.0 g of 10% Pd/C followed by addition of 10 g (48.0 mmol) of 3-morpholinyl nitrobenzene. The mixture then was stirred under a hydrogen atmosphere for 4 days (1 atm). The reaction was filtered over GF/F filter paper and the filtrate concentrated in vacuo to remove MeOH and THF. The resulting solid was recovered by filtration, washed with water, air dried, then dried in vacuo to give 7.3 g (83% yield) of the desired aniline as beige crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[N:18]([CH2:29][CH3:30])[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:15])([F:16])[F:14])[CH:5]=[CH:4][C:3]=1[N:18]([CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCN(C(=O)CCc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Solvent: C1CCOC1
Product: CCN(CCCc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Yield: 90.9 %

Procedure:
A solution of 70 mg (0.15 mmol) of N-[2-chloro-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-3-phenyl-propionamide in 3 mL of THF was treated with 1 mL of 1M B3.THF-complex in THF and stirred for 10 hours at 80° C. in a sealed tube. Evaporation of the solvent and column chromatography on silica gel with CH2Cl2/n-heptane 1:1 yielded 60 mg (91%) of 2-{3-chloro-4-[ethyl-(3-phenyl-propyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, colorless oil, MS: 440 (MH+, 1Cl).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+].CN(C)[CH:29]=[O:30]>>[C:19]1([N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:13]2[CH:18]=[CH:17][C:16]([CH:29]=[O:30])=[CH:15][CH:14]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 72 %

Procedure:
4-(Diphenylamino)benzaldehyde can be obtained commercially from a supplier, such as Aldrich, Milwauke, Wis. or Fluka, Buchs SG, Switzerland. It could also be prepared by the following procedure. Dry dimethylformamide (DMF, 4.73 ml, 0.0612 mol) was added to a 25 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. After the flask was kept under nitrogen atmosphere and cooled to 0° C., phosphorus oxychloride (POCl3, 3.8 ml, 0.0408 mol) was added dropwise. The temperature inside the flask was kept below 5° C. during the addition of POCl3. After the addition of POCl3 was completed, the solution was allowed to warm up slowly to room temperature. Then a solution of triphenylamine (5 g, 0.0204 mol, from Aldrich, Milwauke, Wis.) in dry DMF (10 ml) was added dropwise. The reaction mixture was refluxed at 80° C. for 24 hours and then poured into ice water. This solution was neutralized with potassium hydroxide until the pH reached between 6 and 8. The product was extracted with chloroform. The chloroform extract was dried with anhydrous sodium sulfate, filtered, and evaporated off to form the crude product, which was recrystallized from methanol to yield 5.57 g (72%) of 4-(diphenylamino)benzaldehyde. The melting point was found to be 126.5° C. The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 6.57–7.56 (m, 12H, Ar), 7.60–7.98 (m, 2H, Ar), 10.21 (s, 1H, CHO). The IR spectrum of the product was characterized by the following absorption frequencies (KBr, cm−1): ν(C—H) 2743; 2830, ν(C—H in Ar) 3037, ν(C═O) 1689, ν(C═C in Ar) 1585; 1567; 1490, γ(Ar) 825. The mass spectrum of the product was characterized by the following mass peaks (m/z): 274 (100%, M+1).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)[CH:22]=[O:23]>>[C:14]1([N:7]([C:1]2[CH:2]=[CH:3][C:4]([CH:22]=[O:23])=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)C=O
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 90 °C

Procedure:
46 g of phosphoryl trichloride (POCl3) was added dropwise to 22 g of N,N-dimethylformamide while stirring on a ice bath, and the stirring was continued for about 1 hour to produce a sirupy Vilsmeier reagent. To this reagent, a solution containing 50 g of N,N,N-triphenylamine in 200 ml of N,N-dimethylformamide was added while maintaining on the ice bath. After continued the stirring for about 1 hour, the temperature of the bath was raised to about 90° C., and the mixture was stirred for 2 additional hours. After the reaction, the mixture was cooled to room temperature and poured into ice. The resulted aqueous solution was neutralized with alkali to form a yellow precipitate. After it was separated by filtration and dried, it was recrystallized with ethyl alcohol to obtain 43 g of p-(N,N-diphenylamino)benzaldehyde.
Reaction SMILES: [Al:1].[Cl-:2].[Al+3].[Cl-].[Cl-].[C:6]1([C:8](=[CH:10][C:11](=[C:13]([CH:15]=1)[CH3:14])[CH3:12])[CH3:9])[CH3:7].[Ti:16](Cl)(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1>[Cl-:17].[Cl-:2].[Ti+2:16].[Cl-:17].[Al+3:1].[Cl-:17].[Cl-:17].[C:6]1([C:8](=[CH:10][C:11](=[C:13]([CH:15]=1)[CH3:14])[CH3:12])[CH3:9])[CH3:7]
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: [Al]
Agent: Cc1cc(C)c(C)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: [Ti+2]
Temperature: 130 °C

Procedure:
20 g of aluminum power (BDH fine powder) and 27 g of aluminum chloride were introduced into a two liter flask. The mixture of solids was stirred and heated to a temperature of 130° C., which temperature was maintained for two hours. The mixture was then cooled, and a solution of 15.5 g of durene in one liter of toluene was added. The flask contents were stirred and heated to reflux temperature. 19.9 g of titanium tetrachloride in 100 ml of toluene were added dropwise over a period of 30 minutes. Heating was continued, at reflux temperature, for a further hour and the mixture was then allowed to cool. The mixture was then filtered and the filtrate was allowed to run directly into 2.5 liters of n-heptane. A dark-colored precipitate separated out and was filtered and then washed four times with 250 ml of n-heptane for each wash. The precipitate was then dried under vacuum (0.2 mm pressure) at ambient temperature (about 20° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].CNC1CCCCC1NC>[Cu]I.CN1CCCC1=O>[C:8]([C:5]1[N:6]=[CH:7][C:2]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[CH:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)nc2)CC1
Temperature: 120 °C

Procedure:
A mixture of the 5-bromopyridine-2-carbonitrile (0.957 g, 5.23 mmol), tert-butyl piperazine-1-carboxylate (1.36 g, 7.32 mmol), cesium carbonate (3.41 g, 10.5 mmol), racemic N,N′-dimethylcyclohexane-1,2-diamine (0.074 g, 0.52 mmol), and copper(I) iodide (0.010 mg, 0.052 mmol) was stirred with 13.1 mL of 1-methylpyrrolidin-2-one and purged with a stream of nitrogen. The reaction was heated to 120° C. for 8 hours. The mixture was diluted with dichloromethane (20 mL) and washed with water (3×20 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and subjected to purified by silica gel chromatography eluting with 0-50% EtOAc in hexanes. Collection of product containing fractions and removal of solvent yielded to yield tert-butyl 4-(6-cyanopyridin-3-yl)piperazine-1-carboxylate.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
To a solution of 1,2,3,4-tetra-hydroisoquinoline (2.664 g, 20 mmol) and ethyl bromoacetate (3.647 g, 22 mmol) in N,N-dimethylformamide (23 mL), was added Cs2CO3 (7.168 g, 22 mmol) under N2. The mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, and the remaining residue was subjected to silica gel chromatography, eluting with ethyl acetate/hexanes (33:66) to afford Intermediate 199(a) (3.39 g, 15.5 mmol) as yellow oil in 77% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([OH:11])[C:9]#[CH:10].C(N(C(C)C)CC)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1.[Cu](I)I>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:10]#[C:9][CH2:8][OH:11])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CCO
Agent: I[Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: OCC#Cc1cccnc1
Reaction time: 18 h
Yield: 79.3 %

Procedure:
A solution of 3-bromopyridine (2.0 g, 12.6 mmol), propargyl alcohol (1.1 mL, 19 mmol), diisopropylethylamine (3.2 mL, 23 mmol), copper iodide (133 mg, 0.7 mmol) and tri-(t-butyl)phosphine (286 mg, 1.4 mmol) in degassed THF (10 mL) was treated with Pd(CH3CN)2Cl2 (181 mg, 0.7 mmol) at 25° C. under N2. After 18 h, the reaction mixture was filtered through celite, washed with ethyl acetate (2×100 mL), and concentrated in vacuo. Purification by flash chromatography (EtOAc) afforded the title compound (1.33 g, 80%) as a yellow oil. MS 134 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([OH:11])[C:9]#[CH:10]>C(N(CC)CC)C.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.[Cu](I)I>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:10]#[C:9][CH2:8][OH:11])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: OCC#Cc1cccnc1
Temperature: 25 °C

Procedure:
A mixture of 3-bromopyridine (6.25 ml), propargyl alcohol (4.9 ml), bis(triphenylphosphine)palladium(II) chloride (0.45 g) and copper iodide (125 mg) in triethylamine (100 ml) was stirred under reflux for 1.5 hours. After being cooled at room temperature, the reaction mixture was filtered and the insoluble material on the filter was washed with ethyl acetate (about 200 ml). The filtrate and the washing were combined and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate as eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give 3-(3-pyridyl)-2-propyn-1-ol (7.9 g) as brownish crystals.