Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[CH:21]=2)[CH:10]=1)[CH2:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[C:51]([C:55]#[CH:56])([CH3:54])([CH3:53])[CH3:52]>[Cu]I.[Pd](Cl)Cl.O1CCCC1>[CH3:52][C:51]([CH3:54])([CH3:53])[C:55]#[C:56]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[CH:21]=2)[CH:10]=1)[CH2:6][CH3:7]
Reactant: C#CC(C)(C)C
Reactant: CCN(C/C=C/Cl)Cc1cccc(OCc2cc(-c3ccsc3)cs2)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCN
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(OCc2cc(-c3ccsc3)cs2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72 %

Procedure:
To 10 ml of tetrahydrofuran were added 1.01 g (2.5 mmol) of (E)-N-(3-chloro-2-propenyl)-N-ethyl-3-[4-(3-thienyl)-2-thienylmethyoxy]benzylamine, 23.8 mg (0.125 mmol) of copper (I) iodide, 8.9 mg (0.05 mmol) of palladium chloride and 26.2 mg (0.1 mmol) of triphenylphosphine, and further, 0.50 ml (5.0 mmol) of n-butylamine and 0.37 ml (3.0 mmol) of tert-butylacetylene under ice cooling. The mixture was stirred for 17 hours at room temperature, and extracted with a mixture of 70 ml of ethyl acetate and 30 ml of water. The organic layer was separated, washed with a mixture of 40 ml of water and 4 ml of 2N hydrochloric acid, a mixture of 40 ml of water and 6 ml of saturated sodium bicarbonate aqueous solution and 20 ml of saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After ethyl acetate was evaporated under reduced pressure, the residue was treated with 3 ml of methanol, and stirred for 17 hours under ice cooling. The resulting crystals were collected by filtration, washed with 2 ml of methanol and dried under reduced pressure to obtain 0.81 g (yield: 72%) of the above identified compound as slightly yellowish brown crystalline powder.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C([O-])([O-])=O.[K+].[K+].O>CCO>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nccs2)CC1
Yield: 69.2 %

Procedure:
A mixture of 5 g of tert-butyl 1-piperazinecarboxylate, 4.4 g of 2-bromo-1,3-thiazole and 7.4 g of K2CO3 in 50 ml of EtOH is refluxed for 4 days. Water is added to the reaction mixture, the EtOH is evaporated off under vacuum, the resulting aqueous phase is extracted with EtOAc, the organic phase is washed with saturated K2CO3 solution and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture (98/2; v/v). 5 g of the expected product are obtained after precipitation from a cold DCM/hexane mixture and filtration by suction, m.p.=114–116° C.
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11]([Mg]Cl)[CH2:12][CH3:13]>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:12][CH3:13]
Reactant: BrC1=Cc2ccccc2C1
Reactant: CCC[Mg]Cl
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Product: CCCC1=Cc2ccccc2C1
Yield: 99.8 %

Procedure:
To an oven-dried 250 mL round bottom flask containing a magnetic stir bar and equipped with a reflux condenser and vacuum adapter was added 2-bromoindene (15.0 g, 76.9 mmol) and Ni(dppp)Cl2 (0.42 g, 0.77 mmol) (dppp=1,3-bis(diphenyl-phosphino)propane). The flask was stoppered and evacuated. Deoxygenated anhydrous diethyl ether (150 mL) was added via cannula under argon at -78° C. The reaction was stirred under argon without exterior cooling as 42 mL of a 2.0 M propylmagnesium chloride in ether solution was added via syringe (84 mmol propylmagnesium chloride). The reaction was placed in a dry ice/acetone bath when a vigorous reflux was achieved. The dry ice/acetone bath was removed after 2 minutes, and the reaction was stirred at room temperature under argon for 90 minutes. The reaction was carefully poured into water and 10 weight percent aqueous HCl was added until the mixture was acidic. The mixture was extracted with ether (3×200 mL), and the combined organic layers were washed with water (1×250 mL), with aqueous sodium bicarbonate (1×250 mL), and with aqueous saturated sodium chloride solution (1×250 mL). Drying over anhydrous sodium sulfate followed by filtration and solvent removal yielded 12.14 g (99.7 percent) of the desired product.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.Cl.CNC>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 140 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Dimethylamine hydrochloride (7.3 g) is added to the bottle, and triethylamine (22 ml) is added thereto at the temperature within 30 min, the above mixture is further reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (8.9 g). The yield is about 59.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:32]1[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:34][CH2:33]1)=[O:20])=[N:5]2
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(Cl)c(Cl)cc4nc3OC)CC2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 65.6 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate (28 mg, 0.089 mmol) and 1-(3-methoxy phenyl)piperazine (35 mg, 0.18 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (27 mg, 0.18 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (1:1) mixture and concentration gave 27 mg of the titled compound (yield, 66%). 1H NMR (300 MHz, CDCl3) δ 3.28-3.30 (m, 4H), 3.74-3.76 (m, 4H), 3.81 (s, 3H), 4.19 (s, 3H), 6.47-6.49 (m, 3H), 6.53-6.57 (m, 1H), 7.30 (br s, 1H), 7.85 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:31]([O:34][CH2:35][CH2:36]Br)(=[O:33])[CH3:32]>CN(C)C=O>[C:31]([O:34][CH2:35][CH2:36][N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:7]2[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)=[N:17]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OCCBr
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21
Temperature: 60 °C
Reaction time: 11 h
Yield: 84.9 %

Procedure:
To a solution of 40 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine in 300 ml of dimethylformamide are added 34,2 g of potassium carbonate and 31 g of 2-acetoxyethyl bromide, and the mixture is stirred at 60° C. for 11 hours. The resulting mixture is poured into ice-cold water and the precipitate is extracted with ethyl acetate and then the extract is washed with water, dried and concentrated. The resulting residue is recrystallized from isopropyl alcohol to give 43 g of 1-(2-acetoxyethyl)-3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 115°-116° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)[CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2cccn3nc(N)nc23)c1
Reactant: Brc1cccc(N2CCOCC2)c1
Product: CS(=O)(=O)c1cccc(-c2cccn3nc(Nc4cccc(N5CCOCC5)c4)nc23)c1

Procedure:
[8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-morpholin-4-yl-phenyl)-amine was prepared from 8-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 4-(3-bromo-phenyl)-morpholine (126.0 mg, 0.5204 mmol) in a manner analogous to Step 2d and was isolated as a tan foam (0.018 g, 12%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.60-8.58 (m, 1H), 8.48 (dd, J=6.7, 1.1 Hz, 1H), 8.46-8.42 (m, 1H), 8.02-7.98 (m, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.68 (dd, J=7.5, 1.1 Hz, 1H), 7.33-7.30 (m, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.06 (dd, J=7.8, 1.5 Hz, 1H), 7.01 (dd, J=7.2, 7.2 Hz, 1H), 6.85 (s, 1H), 6.58 (dd, J=8.4, 2.1 Hz, 1H), 3.91-3.86 (m, 4H), 3.25-3.20 (m, 4H), 3.13 (s, 3H). MS=450 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[C:11]([CH2:16][CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:16](\[CH3:17])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C/c1ccc(F)c(Cl)c1
Yield: 101.5 %

Procedure:
3-Chloro-4-fluorobenzaldehyde (10 g, 63.1 mmol) was dissolved in 300 mL toluene. (Carboethoxyethylidene)triphenylphosphorane (25 g, 69.4 mmol) was added and the mixture was heated to reflux overnight. The solution was cooled, diluted with hexanes and the solid was filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in ether and filtered through a plug of silica using ether as eluent. The solvent was evaporated in vacuo to afford the title compound (15.55 g) as a semi solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.56 (s, 1H), 7.44 (m, 1H), 7.23-7.32 (m, 1H), 7.16 (m, 1H), 4.28 (q, J=7.12 Hz, 2H), 2.09 (d, J=1.36 Hz, 3H), 1.35 (t, J=7.36 Hz, 3H). MS (DCI+) 243 (M+H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[N:3]=1.[CH2:28]([OH:31])[C:29]#[CH:30].O>N(CC)CC.[Cu]I.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][C:13]3[N:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:16]4[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]=3)[N:3]=[C:2]([C:30]#[C:29][CH2:28][OH:31])[C:10]=12
Reactant: C#CCO
Reactant: Nc1ncnc2c1c(I)nn2Cc1nc2ccccc2n1-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCNCC
Product: Nc1ncnc2c1c(C#CCO)nn2Cc1nc2ccccc2n1-c1ccccc1
Reaction time: 2 h
Yield: 31.6 %

Procedure:
A mixture of 3-iodo-1-((1-phenyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 141 (1.5 g, 3.2 mmol), prop-2-yn-1-ol (0.4 g, 6.4 mmol), CuI (0.2 g, 0.64 mmol) and Pd(PPh3)2Cl2 (0.25 g, 0.32 mmol) in Et2NH (30 mL) was stirred at 25 for 2 hrs. Then the mixture was added H2O (50 mL) and extracted with CH2Cl2 (30 mL×3). The combined organic layers were concentrated in vacuo. The residue was treated with CH2Cl2 and filtered to give 152 (400 mg, yield 32%) as a yellow solid. LCMS (ESI), M+H+=394.15. 1HNMR (400 MHz, DMSO) δ 4.322-4.337 (d, J=6 Hz, 2H), 5.395-5.425 (t, J=6 Hz, 1H), 5.710 (s, 2H), 5.735 (s, 2H), 7.090-7.107 (d, J=6.8 Hz, 1H), 7.223-7.249 (m, 2H), 7.414-7.491 (s, 5H), 7.643-7.663 (d, J=8 Hz, 1H), 8.092 (s, 1H)
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])=[C:13]([CH3:16])[CH2:14]O)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.P(Br)(Br)[Br:25]>CCCCC>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])=[C:13]([CH3:16])[CH2:14][Br:25])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCC(C)(C)c1ccc(C(C)=C(C)CO)cc1
Solvent: c1ccncc1
Solvent: CCCCC
Product: CCC(C)(C)c1ccc(C(C)=C(C)CBr)cc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
A mixture of 72 g of 3-(p-tert.amyl-phenyl)-2,3-dimethyl-allyl alcohol and 7.2 ml of pyridine in 500 ml of n-pentane is cooled down to -5° C. At this temperature there are added dropwise while stirring over a period of 2 hours 40.2 g of phosphorus tribromide in 500 ml of n-pentane and the mixture is stirred at room temperature for 3 hours. The mixture is poured on to 500 g of ice and stirred up for 30 minutes. The pentane phase is separated and the aqueous phase is back-extracted with n-pentane. The combined n-pentane phases are washed neutral with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The crude 3-(p-tert.amyl-phenyl)-2,3-dimethyl-allyl bromide obtained [NMR: 60 Mc, CDCl3 →1-CH2 =3.9 and 4.1 ppm (2s)] was used in the process without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:18])=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCCc1cc(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)c(OC)nc1C
Yield: 67 %

Procedure:
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.[Mg].II.[C:10]([N:14]1[CH:18]=[C:17]([CH:19]=[O:20])/[C:16](=[N:21]/[C:22](=[O:32])[C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])/[S:15]1)([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([N:14]1[CH:18]=[C:17]([CH:19]([OH:20])[CH2:2][CH:3]2[CH2:6][CH2:5][CH2:4]2)/[C:16](=[N:21]/[C:22](=[O:32])[C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])/[S:15]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C=O
Reactant: BrCC1CCC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C(O)CC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
To (bromomethyl)cyclobutane (211 mg, 1.42 mmol) in THF (20 mL) was added magnesium (41.3 mg, 1.7 mmol), and initiator iodine (10 mg). The mixture was stirred at rt for 2 hrs, then cooled to −40° C. and added to a solution of Example 21A (100 mg, 0.28 mmol) in THF (20 mL). The mixture was allowed to warm to room temperature, quenched with saturated aqueous NH4Cl, and extracted with EtOAc (2×). The organics were combined, dried (MgSO4), filtered and solvent evaporated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 63 mg (53%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.62-1.78 (m, 2 H) 1.65 (s, 9 H) 1.76-1.94 (m, 2 H) 1.97-2.18 (m, 4 H) 2.47-2.59 (m, 1 H) 3.92 (s, 3 H) 4.88 (dd, J=8.29, 6.14 Hz, 1 H) 6.93 (d, J=8.90 Hz, 1 H) 7.37 (dd, J=8.90, 3.07 Hz, 1 H) 7.95 (s, 1 H) 8.05 (d, J=2.76 Hz, 1 H); MS (DCI/NH4+) m/z 423 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:34][CH2:35][CH2:36][CH2:37][C:38]#[CH:39]>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>[Cl:34][CH2:35][CH2:36][CH2:37][C:38]#[C:39][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccc(I)cc1)C(F)(F)F
Reactant: C#CCCCCl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C#CCCCCl)cc1)C(F)(F)F
Temperature: 55 °C

Procedure:
A mixture of 2,2,2-trifluoro-N-(4-iodophenyl)acetamide (3.2 g, 10 mmol, prepared according to Melissaris, A. P. and Litt, M. H. J Org Chem 1994, 59, 5818-5821), dichlorobis(triphenylphosphine)palladium(II) (0.14 g, 0.2 mmol), triphenylphosphine (19 mg, 0.07 mmol), and copper (I) iodide (0.019 g, 0.1 mmol) in triethylamine (50 mL) was degassed under Argon for 10 minutes while stirring in a 55° C. oil bath. The mixture was then treated with 5-chloropentyne (1.1 mL, 10 mmol). After four hours of heating, the mixture was allowed to cool to room temperature and was then filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the crude title compound, which was carried forward without further purification. ES/MS calcd. for C14H14ClF3NO+: 290.1, found m/z=290.1 (M+H)+
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:21]([NH2:24])[CH:22]=[CH2:23].CC(N(C)C)=O>C(OCC)(=O)C>[CH2:21]([NH:24][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])[CH:22]=[CH2:23]
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: C=CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C=CCNc1cc(C(F)(F)F)ccc1C(N)=O
Temperature: 140 °C
Yield: 98.4 %

Procedure:
A mixture of 2-fluoro-4-trifluoromethylbenzamide (5.60 g, 27.05 mmol.), K2CO3 (11.2 g, 81.16 mmol), allylamine (7.71 g, 135.26 mmol) and dimethylacetamide (50 mL) was heated at 140° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with a solution of aqueous saturated sodium bicarbonate (3×100 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to give the title compound (6.5 g, 98% yield) as a brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[CH3:15][NH:16][CH3:17]>O1CCCC1.C(OCC)(=O)C>[CH3:15][N:16]([CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: OCCCCCCCCCCCCBr
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 12-bromo-1-dodecanol (1 g, 3.8 mmoles) in anhydrous tetrahydrofuran (10 mL) was treated with a 2.0 M solution of dimethylamine in tetrahydrofuran (10 mL). The reaction was stirred at room temperature for 3 days. TLC analysis on silica using 25% ethyl acetate, 75% hexanes as eluent showed the formation of a polar product with little starting material. The reaction was diluted with ethyl acetate (75 mL) and washed twice with aqueous sodium bicarbonate and water. The ethyl acetate solution was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Yield=1.2 g (wax). TLC analysis on silica (25% methanol, 75% ethyl acetate) showed a streaking product with Rf ˜0.1. This product 4a, was used without purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]([N:10]1[CH2:14][CH2:13][C:12](=O)[CH2:11]1)=[O:9].C(=O)([O-])[O-].[K+].[K+]>CCOCC.C1(C)C=CC=CC=1>[N:1]1([C:12]2[CH2:11][N:10]([C:8]([O:7][CH3:6])=[O:9])[CH2:14][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)N1CCC(=O)C1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)N1CC=C(N2CCCC2)C1

Procedure:
Pyrrolidine (25 ml) is slowly added dropwise to a stirred suspension of 28.63 g of N-methoxycarbonyl-3-oxo-tetrahydropyrrole [prepared according to J Med Chem 5, 752 (1962)] and 29.5 g of anhydrous potassium carbonate in 200 ml ether and 100 ml toluene at 0°-5° under a nitrogen atmosphere. After 3 hours the suspension is filtered and the filtrate evaporated under reduced pressure to yield 3-pyrrolidino-N-methoxycarbonyl-2,5-dihydropyrrole as an oil. NMR (CDCl3): 4.12 (s), 4.01 (m), 3.63 (s), 3.00 (m), and 1.85 (m). Triethylamine (28 ml) and 2,4 g of 4-dimethylaminopyridine are added to a solution of 39.3 g (0.2 moles) of 3-pyrrolidino-N-methoxycarbonyl-2,5-dihydropyrrole in 850 ml of dry ether. The reaction mixture is cooled in an ice bath. A solution of 25.6 ml of ethyl malonyl chloride in 850 ml ether is added dropwise keeping the internal temperature below 5°. After 1 hour at 5° and 2 hours at room temperature, the suspension is filtered, the ether solution is washed with 10% ice cold citric acid and saturated NaHCO3 solution. The organic layer is dried over MgSO4, filtered and evaporated to yield 3-carboethoxyacetyl-4-pyrrolidino-N-methoxycarbonyl-2,5 dihydropyrrole as an oil; NMR (CDCl3) 4.44 (s), 4.37 (s), 4.17 (q) 3,73 (s), 3,42 (m), 3.32 (s), 1.90 (m) and 1.26 (t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[C:36]([C:37]#[N:38])=[CH:35][N:34]=[C:33](Cl)[CH:32]=1>C(O)C.CN(C1C=CN=CC=1)C>[Cl:30][C:31]1[C:36]([C:37]#[N:38])=[CH:35][N:34]=[C:33]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:32]=1
Reactant: N#Cc1cnc(Cl)cc1Cl
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Cl)c(C#N)cn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.00 g (10.9 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 7.59 mL (43.6 mmol) DIPEA were placed in 90 mL ethanol. 1.89 g (10.9 mmol) 4,6-dichloro-nicotinonitrile and 3 spatula tips of DMAP were added and the reaction mixture was stirred for 4 h at RT. The precipitated solid was suction filtered and dried.