Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH2:12])=[O:11])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Cl:17][CH:18](Cl)[C:19](=O)[CH3:20]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:12]=[C:10]([CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:13]([F:14])([F:15])[F:16])[O:11][CH:20]=1
Reactant: NC(=O)C=Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(=O)C(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1ccc(C=Cc2nc(CCl)co2)c(C(F)(F)F)c1
Yield: 70.9 %

Procedure:
3-(4-Fluoro-2-trifluoromethyl-phenyl)-acrylamide (1.0 g, 4.29 mmol), dichloro acetone (2.18 g, 17.15 mmol) and toluene (10 ml) were kept at reflux temperature for 16 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 2:1) yielding 0.93 g (71%) 4-chloromethyl-2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-vinyl]-oxazole as tan solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[Cu].C(OCC)C.CCCCCC>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: Oc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Brc1cncc(Oc2ccccc2)c1

Procedure:
3,5-Dibromopyridine (4.74 g), phenol (1.88 g), anhydrous potassium carbonate (3.04 g), copper bronze (0.1 g) in dry N,N-dimethylformamide (20 ml) were stirred under an atmosphere of nitrogen at 145–150° C. for 4.25 hours then cooled and poured into water. The mixture was extracted with diethyl ether (three times), the extracts were combined, washed with water (three times) then dried over magnesium sulphate and evaporated under reduced pressure to give an oil. The oil was fractionated by chromatography (silica; hexane: diethyl ether; 2:1 by volume) to give the required product, 1.70 g, as a colourless oil.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6]1)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH:5]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[CH:6]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(CN2CCOCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: c1cc(CN2CCOCC2)c[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in Step A (75 mmoles) in THF (100 ml) there is added, dropwise, at 0° C., Bu4NF 1.0M in THF (75.0 mmoles). After stirring at 0° C. for one hour, the solution is poured onto ice and is then extracted with DCM. The organic phases are combined and then washed with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness to yield the title product, which is used directly in the next Step.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: CN(C)CCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
1.52 g (10 mmol) of methyl 4-hydroxybenzoate was dissolved in 40 ml of N,N-dimethylformamide and 2.16 g (15 mmol) of 2-dimethylaminoethyl chloride hydrochloride and 4.15 g (30 mmol) of potassium carbonate were further added. The mixture was heated at 80° C. and stirred overnight. After cooling, water was added to the reaction mixture, the obtained mixture was extracted twice with ethyl acetate, and the extract was washed with brine. The organic phase was dried (Na2SO4) and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=70:1 to 15:1 (v/v)) to obtain 0.69 g (3.09 mmol) of methyl 4-(2-dimethylaminoethoxy)benzoate as a pale brown oily substance. Its spectroscopic data are as follows:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6](Cl)[C:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1.[CH:22]([OH:25])([CH3:24])[CH3:23]>>[Cl:3][C:4]1[N:5]=[C:6]([O:25][CH:22]([CH3:24])[CH3:23])[C:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
Sodium hydride (12 mg of a 60% of a dispersion in mineral oil, 0.3 mmol) was added to isopropanol (5 ml). The mixture was stirred at room temperature for 10 minutes. Then, 2,4-dichloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (60 mg, 0.2 mmol) was added to this solution. The resulting mixture was stirred at room temperature for another 40 minutes. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of isopropanol and dichloromethane in a volume ratio of 1:200, yielding the pure title compound (21 mg, yield 30%) as a white solid which was characterised as follows: MS (m/z): 318 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].FC(F)(F)C1C=CC(C=O)=CC=1.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: O=Cc1ccc(C(F)(F)F)cc1
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 34 b]) was reacted with 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (prepared from 4-trifluoromethyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 2 a] and b]) in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:12]3[C:13](=[O:16])[NH:14][CH2:15][C:11]=3[CH:10]=[C:9]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[N:8]=2)[CH:4]=[N:3]1.[Cl:32]N1C(=O)CCC1=O.O.C(Cl)(Cl)Cl>C(Cl)Cl>[Cl:32][C:10]1[C:11]2[CH2:15][NH:14][C:13](=[O:16])[C:12]=2[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:8][C:9]=1[NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29]
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Cl)c3c2C(=O)NC3)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (30 mg, 0.070 mmol) and N-chlorosuccinimide (9.86 mg, 0.074 mmol) in DCM (1 mL) was stirred at RT overnight. Additional N-chlorosuccinimide (1 eq) was added and the mixture was stirred at RT for 3 h. Water and CHCl3 were added to the mixture and the organic phase was washed with brine, dried over MgSO4, and evaporated. The residue was purified by preparative HPLC to give the title compound (20 mg, 61.7%). 1H NMR (500 MHz, CDCl3) δ ppm 1.18-2.09 (m, 17 H), 4.02 (s, 3 H), 4.28-4.45 (m, 2 H), 5.80 (br s, 1 H), 8.39 (br s, 1 H), 9.03 (br s, 1 H). [M+H] calc'd for C22H29ClN6O3, 461; found, 461.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([CH:71](OC)[O:72]C)[CH2:67]/[CH:68]=[CH:69]\[CH3:70])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C>ClCCl.FC(F)(F)C(O)=O.O>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@@H:66]([CH2:67]/[CH:68]=[CH:69]\[CH3:70])[CH:71]=[O:72])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:52])([CH3:53])[CH3:54])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: C/C=C\C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C)C(OC)OC
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C/C=C\C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
0.05 g (0.04 mmol) of (Z)-N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N 1-[1(S)-(dimethoxymethyl)-3-pentenyl]-L-leucinamide was dissolved in 4 ml of a 1:1 solution of dichloromethane and trifluoroaceticacid and containing 3 drops of water. The solution was stirred at room temperature for 1 hour. After removal of the solvent by evaporation the crude product was triturated using diethyl ether to afford 0.03 g of (Z)-2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-alpha-aspartyl]-L-alpha-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-hexenal as a white solid; MS: m/e 845.7 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OC)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.2 %

Procedure:
To a solution of methyl 3-hydroxy-5-methoxybenzoate (6.00 g) in DMF (50 mL) were added benzyl bromide (6.20 g) and potassium carbonate (5.50 g), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.90 g) as a white solid.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[CH:21]1([Mg]Cl)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>O1CCCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:21]1([C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Reactant: Cl[Mg]C1CCCCC1
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2CCCCC2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
34 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of tetrahydrofuran, followed by adding 1 mg of [1,3-bis(diphenylphosphino)propane] nickel (II) chloride. Under stirring in nitrogen atmosphere, 0.1 ml of cyclohexyl magnesium chloride (2.0M ether solution) was added dropwise thereinto. The mixutre was stirred at room temperature in nitrogen atmosphere for 1 hour, followed by heating under reflux for 72 hours. After cooling to room temperature, water was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (chloroform/methanol system), to give 5 mg of the title compound.
Reaction SMILES: FC(F)(F)C1C=CC(NS(C(C)=COCC)(=O)=O)=CC=1.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.Cl[S:33]([C:36]1[CH:37]=[N:38][O:39][C:40]=1[CH3:41])(=[O:35])=[O:34]>>[F:21][C:22]([F:30])([F:31])[C:23]1[CH:29]=[CH:28][C:26]([NH:27][S:33]([C:36]2[CH:37]=[N:38][O:39][C:40]=2[CH3:41])(=[O:35])=[O:34])=[CH:25][CH:24]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1oncc1S(=O)(=O)Cl
Agent: CCOC=C(C)S(=O)(=O)Nc1ccc(C(F)(F)F)cc1
Product: Cc1oncc1S(=O)(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
AA16 was prepared starting from 2-(4-trifluoromethylphenylaminosulfonyl)1-ethoxypropene under the same conditions as described for AA11. Alternatively, AA16 was prepared from 4-trifluoromethylaniline and 4-chlorosulfonyl-5-methylisoxazole.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]([CH:13]=[CH:14][N:15]=2)[N:9]=[C:10]([Cl:12])[CH:11]=1)=O)C.O.[NH2:17][NH2:18]>C(O)C>[Cl:12][C:10]1[CH:11]=[C:6]([C:4]([NH:17][NH2:18])=[O:3])[C:7]2[N:8]([CH:13]=[CH:14][N:15]=2)[N:9]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(Cl)nn2ccnc12
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(Cl)nn2ccnc12
Reaction time: 0.25 h
Yield: 57 %

Procedure:
To a solution of crude 6-chloro-imidazo[1,2-b]pyridazine-8-carboxylic acid ethyl ester (5.00 g, “22 mmol”) in 40 mL of ethanol at 0-5° C. was added 10 mL of hydrazine hydrate. Yellow solid immediately precipitated. After 15 min. at 0-5° C., the solid was isolated by Buchner filtration, rinsing well with ice-cold ethanol (250 mL total) and dried by sucking air through then in vacuo. A small amount of additional solid precipated from the filtrate and was isolated and dried similarly to the first crop. A total of 2.38 g (57% over three steps) of 6-chloro-imidazo[1,2-b]pyridazine-8-carboxylic acid hydrazide was isolated as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:57]1([NH2:62])[CH2:61][CH2:60][CH2:59][CH2:58]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:30])[NH:62][CH:57]3[CH2:61][CH2:60][CH2:59][CH2:58]3)=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCC1
Reactant: O=C(O)c1ccc(-c2cnc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)s2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NC1CCCC1)c1ccc(-c2cnc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)s2)cc1

Procedure:
From (S)-2-[5-(4-Carboxy-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5353, example 353, 0.03 g, 0.07 mmol), HATU (0.033 g, 0.086 mmol), and (0.03 mL, 0.26 mmol) of cyclopentylamine using General Procedure 3F. 1HNMR (DMSO-d6) δ(ppm)12.42 (m, 0.7H), 8.30-8.27 (d, 1H), 7.80-7.11 (m, 10H), 5.06-4.89 (m, 2 H), 4.50 (m, 1H), 3.51-3.48 (m, 1H), 2.26 (m, 1H), 1.89-1.52 (m, 9H), 1.14 (s, 1H); MS: 519.2 (M+H+).
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.[NH:11]1[CH:15]=[C:14]([S:16](Cl)(=[O:18])=[O:17])[N:13]=[CH:12]1>C1(C)C=CC=CC=1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[S:16]([C:14]1[N:13]=[CH:12][NH:11][CH:15]=1)(=[O:18])=[O:17]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1c[nH]cn1)N1CCc2ccccc2C1
Reaction time: 8 h

Procedure:
A solution of 1,2,3,4-tetrahydroisoquinoline (13.22 g) and imidazole-4-sulphonyl chloride (7.57 g) in toluene (70 ml) was stirred for 1 hour and then allowed to stand overnight. It was evaporated and the residue partitioned between diethyl ether and aqueous sodium hydroxide. The aqueous layer was clarified by ether extraction and then acidified with concentrated hydrochloric acid. The precipitate was collected, washed with water and dried to give crude 4-(1,2,3,4-tetrahydroisoquinolin-2-ylsulphonyl)-1H-imidazole. A solution of this product (9 g) in dimethylformamide was treated with sodium hydride (1.13 g of 80% in oil), followed by dimethylsulphamoyl chloride (5.4 g). The mixture was stirred for 1 hour and poured into water. The precipitate was collected and worked up to give the starting material.
Reaction SMILES: CC(C)([O-])C.[Na+].[H-].[Na+].[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]=1[OH:23])([CH3:12])([CH3:11])[CH3:10].[CH2:24]([N:28]1[C:32](=[O:33])[CH:31]=[CH:30][C:29]1=[O:34])[CH2:25][CH2:26][CH3:27]>C(O)(C)(C)C.O.C(O)(=O)C>[C:19]([C:15]1[CH:16]=[C:17]([CH:31]2[CH2:30][C:29](=[O:34])[N:28]([CH2:24][CH2:25][CH2:26][CH3:27])[C:32]2=[O:33])[CH:18]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:14]=1[OH:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCCCN1C(=O)C=CC1=O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: CC(C)(C)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: CCCCN1C(=O)CC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 11.8 %

Procedure:
To a solution of sodium tert-butoxide prepared from 2.40 g (0.1 mol) of sodium hydride and 135 ml of tert-butyl alcohol is added dropwise a solution of 20.63 g (0.1 mol) of 2,6-di-tert-butylphenol in 100 ml of tert-butyl alcohol. The reaction mixture is stirred at room temperature for 150 minutes and then to the resultant green solution is added dropwise over 120 minutes a solution of 15.31 g (0.1 mol.) of N-n-butylmaleimide in 50 ml of tert-butyl alcohol. The reaction mixture is stirred at room temperature overnight and is then mixed with 10 ml of glacial acetic acid. The reaction mixture is poured into 1.5 1 of water and the resultant mixture is extracted twice with chloroform. The organic extracts are combined and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue is purified by flash chromatography (3:1 heptane:toluene eluent) to give 4.25 g (12%) of a white solid: mp 109°-112° C.;
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:54]1[CH:55]=[C:56]([C:64]([O:66][CH3:67])=[O:65])[C:57]2[C:62]([CH:63]=1)=[CH:61][CH:60]=[CH:59][CH:58]=2.[CH3:68][O:69][CH2:70][CH2:71][NH2:72]>C1(C)C=CC=CC=1.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:68][O:69][CH2:70][CH2:71][NH:72][C:54]1[CH:55]=[C:56]([C:64]([O:66][CH3:67])=[O:65])[C:57]2[C:62]([CH:63]=1)=[CH:61][CH:60]=[CH:59][CH:58]=2
Reactant: COCCN
Reactant: COC(=O)c1cc(Br)cc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COCCNc1cc(C(=O)OC)c2ccccc2c1
Temperature: 100 °C

Procedure:
Freshly purified cesium carbonate (1.4 eq.), palladium(II) acetate (0.02 eq.) and rac-BINAP (0.03 eq.) were combined in anhydrous toluene (0.25 M). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, methyl 3-bromo-1-naphthalenecarboxylate (1 eq.) and 2-methoxyethylamine (1.2 eq.) were added and the resulting mixture was heated at 100° C. for 20 h. The now black suspension was cooled to RT, diluted with ether and filtered through a pad of celite. Concentration of the filtrate in vacuo afforded a brown oil that can be purified further by way of column chromatography (SiO2, 19:1 (v/v) Hex:EtOAc→1:1 (v/v) Hex:EtOAc) to afford the title compound as a yellow oil.
Reaction SMILES: O[C:2]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.CC1C=CC=C(C)N=1.[F:28][C:29]([F:42])([F:41])[S:30]([O:33]S(C(F)(F)F)(=O)=O)(=[O:32])=[O:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:28][C:29]([F:42])([F:41])[S:30]([O:33][C:3]1[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][CH:2]=1)(=[O:32])=[O:31]
Reactant: Oc1ccc2c3ccccc3c3ccccc3c2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=S(=O)(Oc1cccc2c3ccccc3c3ccccc3c12)C(F)(F)F
Temperature: -78 °C
Reaction time: 5 h
Yield: 89.8 %

Procedure:
Under an argon atmosphere, 12.5 g of 2-hydroxytriphenylene and 0.93 g of 4-dimethylaminopiridine were placed in a flask, 200 mL of methylene chloride was added thereto and the reaction solution was cooled to −78° C. 8.22 g of 2,6-dimethylpiridine was added to the reaction solution and then, 17.3 g of trifluoromethanesulfonic acid anhydride was dropwise added thereto. The reaction solution was stirred for 5 hours while increasing temperature of the reaction solution to room temperature. The deposited solid was collected by filtration, washed with water and methanol and then dried to obtain 17.3 g (yield: 90%) of triphenylenyl trifluoromethanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]3[CH2:15][CH2:16]NC[C:19]=3[CH:20]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Br[C:22]1[C:23](=O)[N:24](C)[CH:25]=C(Br)C=1.CN1CCCC1C1C=CC(N)=NC=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([CH:15]3[CH2:16][CH2:22][CH2:23][N:24]3[CH3:25])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2cc3c(cn2)CCNC3)c1=O
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: CN1CCCC1c1ccc(N)nc1
Product: CN1CCCC1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Yield: 81 %

Procedure:
Using the same general procedure as described for the preparation of 226b, reaction of 3,5-dibromo-1-methylpyridin-2(1H)-one (1.51 g, 5.65 mmol) with 5-(1-methylpyrrolidin-2-yl)-2-amino pyridine (1.00 g, 5.65 mmol) gave an 81% yield (1.65 g) of 229a as a yellow solid: mp 143-145° C.; 1H NMR (300 MHz, DMSO-d6) d 8.73 (s, 1H), 8.68 (d, 1H, J=2.4 Hz), 8.15 (d, 1H, J=2.1 Hz), 7.55 (dd, 1H, J=8.9, 2.1 Hz), 7.52 (s, 1H), 7.30 (d, 1H, J=8.9 Hz), 3.52 (s, 3H), 3.13 (t, 1H, J=7.5 Hz), 2.99 (t, 1H, J=7.5 Hz), 2.19 (m, 1H), 2.10 (m, 1H), 2.05 (s, 3H), 1.79 (m, 2H), 1.71 (m, 1H); MS (ESI+) m/z 363.3 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])#[CH:15]>>[NH2:19][C:18]1[CH:17]=[C:16]([C:14]#[C:15][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: C#Cc1cccc(N)c1
Reactant: COC(=O)CCc1ccc(I)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccc(N)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-iodophenyl)propanoate (100 mg, 0.34 mmol) and 3-ethynylaniline (0.04 mL, 0.38 mmol) according to the general procedure IC to give 89 mg (93%) of an orange solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:3). Rf: 0.35 (EtOAc:hexanes, 1:1); 1HNMR (CDCl3) δ 7.44-7.42 (m, 2H), 7.18-7.09 (m, 3H), 6.93-6.91 (m, 1H), 6.83 (s, 1H), 6.66-6.63 (m, 1H), 3.66 (s, 3H), 2.98-2.93 (t, 2H, J=7.8 Hz), 2.65-2.60 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 173.1, 146.3, 140.7, 131.7, 129.2, 128.3, 124.0, 122.0, 121.3, 117.7, 115.2, 89.3, 88.6, 51.6, 35.4, 30.8; EI-MS m/z 279 (M+).