Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)C.[CH:5]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[C:20]([C@@H:23]3[CH:28]4[O:29][C@@H:25]([CH2:26][CH2:27]4)[C@@H:24]3[CH2:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH2:38][CH2:39][C:40]([OH:42])=O)[O:21][CH:22]=2)=[O:17])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:56]([CH2:58][NH2:59])[OH:57]>>[CH:5]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[C:20]([CH:23]3[CH:24]([CH2:30][C:31]4[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=4[CH2:38][CH2:39][C:40](=[O:42])[NH:59][CH2:58][CH2:56][OH:57])[CH:25]4[O:29][CH:28]3[CH2:27][CH2:26]4)[O:21][CH:22]=2)=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: NCCO
Reactant: O=C(O)CCc1ccc(F)cc1C[C@H]1[C@@H]2CCC(O2)[C@H]1c1nc(C(=O)NCCCCC2CCCCC2)co1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: O=C(CCc1ccc(F)cc1CC1C2CCC(O2)C1c1nc(C(=O)NCCCCC2CCCCC2)co1)NCCO
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
A dichloroethane (0.3 mL) solution of 3-(2-{(1S,2R,3S)-3-[4-(4-Cyclohexyl-butylcarbamoy)-oxazol-2-yl]-7-oxa-bicyclo[2.2.1]hept-2-ylmethyl}-4fluoro-phenyl)-propionic acid (1) (30 mg, 0.057 mmol) was treated with triethylamine (12 μL, 0.086 mmol) and ethyl chloroformate (7 μL, 0.073 mmol). After 30 min., ethanolamine (10 μL, 0.17 mmol) was added and the solution stirred for 18 h. The resulting mixture was partitioned between 10 mL 1 M NaOH and 15 mL dichloromethane. The dichloromethane solution was washed with 1 M NaOH (6×10 mL). A small amount of brine was added to avoid an emulsion. The dichloromethane solution was then washed with brine (15 mL) and then was dried (Na2SO4), filtered and evaporated. Purification by preparative thin layer chromatography (4% methanol/dichloromethane) gave 12 mg (0.021 mmol, 37%) of the title compound. 1H NMR (300 MHz, ppm) δ 8.11 (s, 1 H) 7.3–7.2 (m, 1 H) 7.11–7.06 (m, 1 H) 6.84–6.78 (m, 2 H) 6.2–6.1 (m, 1 H) 5.00 (d, J=4.0 Hz, 1 H) 4.81 (d, J=4.4 Hz, 1 H) 3.7–3.6 (br m, 2 H) 3.5–3.3 (m, 6 H) 2.84–2.79 (m, 2 H) 2.66–2.57 (m, 1 H) 2.4–2.0 (m, 4 H) 1.9–0.8 (overlapping m, 21 H).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1.Cl[C:12]1[N:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][N:13]=1.Cl>O1CCCC1.Cl[Ni]Cl>[F:2][C:3]1[CH:4]=[C:5]([C:12]2[N:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:16][N:17]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CCCCCc1cnc(Cl)nc1
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCc1cnc(-c2cc(F)cc(F)c2)nc1
Yield: 15.4 %

Procedure:
Grignard reagent was prepared from dried magnesium and 49.0 g (254 mmol) of 3,5-difluorobromobenzene in 200 ml of tetrahydrofuran (THF), 1 g of NiCl2 (dppp) was added thereto, 36.0 g (195 mmol) of the 2-chloro-5-pentylpyrimidine described above was added dropwise thereto, and the product was heated to reflux for 2 hours. The reaction solution was cooled down, and added into 200 ml of 1N-hydrochloric acid. The product was extracted with ether, and the extract was washed with saturated aqueous solution of sodium bicarbonate and water in turn, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (eluent: heptane/toluene=1/1) to obtain 8.0 g (30 mmol) of 2-(3,5-difluorophenyl)-5-pentylpyrimidine. Yield of this product was 15%.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][CH3:7])=[S:5])[NH2:3].[C:8]1([C:14](=O)[CH2:15][CH2:16][CH2:17]Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)(C)C>[CH3:7][N:6]1[C:4](=[S:5])[N:2]([CH3:1])[N:3]2[CH2:17][CH2:16][CH2:15][C:14]12[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: CNC(=S)N(C)N
Solvent: CC(C)O
Product: CN1C(=S)N(C)C2(c3ccccc3)CCCN12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 4.0 g of 2,4-dimethyl-thiosemicarbazide and 6.7 g of 1-phenyl-4-chlorobutan-1-one in 165 ml of isopropanol is refluxed for 48 hours. The mixture is then allowed to cool to room temperature and stirred for an additional 48 hours. The solvent is evaporated, the residue is dissolved in methylene chloride, and the methylene chloride solution is washed with saturated aqueous sodium bicarbonate and with saturated aqueous sodium chloride and dried over sodium sulfate. Evaporation of the solvent leaves a brownish oil which crystallizes and is treated with hexane. The resulting greyish powder is purified by flash chromatography using 4% ethyl acetate/methylene chloride as eluent, followed by crystallization from hexane to give 5,6,7,7a-tetrahydro-1,3-dimethyl-7a-phenyl-1H-pyrrolo[1,2-b][1,2,4]triazole-2(3H)-thione as tiny colorless needles melting at about 83°-85° C.
Reaction SMILES: Cl.Br[C:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:7])[CH2:4][CH2:5][NH2:6].CC(C)=[O:23]>O.S(=O)(=O)(O)O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:3]([OH:23])([CH3:7])[CH2:4][CH2:5][NH2:6])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)=O
Reactant: CC(Br)(CCN)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(O)(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
3.59 g of 3-bromo-3-(4'-fluoro-4-biphenylyl)butylamine hydrochloride [obtainable by reacting 3-hydroxy-3-(4'-fluoro-4-biphenylyl)-butyramide with PBr3 to give 3-bromo-3-(4'-fluoro-4-biphenylyl)-butyramide and reduction with LiAlH4 ] are dissolved in a mixture of 15 ml of acetone and 15 ml of water, 1 drop of sulfuric acid is added, and the mixture is warmed to 45° for 4 hours and worked up in the customary manner to give 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutylamine, m.p. 144°-146°. A little 3-(4'-fluoro-4-biphenylyl)-2-butenylamine, which can be removed by chromatography (over SiO2), is formed as a by-product.
Reaction SMILES: [ClH:1].[CH2:2]([OH:4])[CH3:3].O.[NH2:6][C@H:7]([C:19]([OH:21])=[O:20])[CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:16](O)=[O:17])[CH2:14][SH:15])=[O:11]>CCOCC>[ClH:1].[CH2:2]([O:4][C:16](=[O:17])[C@H:13]([CH2:14][SH:15])[NH:12][C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]([C:19]([OH:21])=[O:20])[NH2:6])[CH3:3]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)O)C(=O)O
Reactant: CCO
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)[C@H](CS)NC(=O)CC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
After 250 ml of hydrogen chloride-containing ethanol (7N HCl-EtOH) was added to a dehydrated ethanol suspension (750 ml) containing 50 g (about 185 mmol) of γ-L-glutamyl-L-cysteine monohydrate, the mixture was stirred at room temperature for 1 hour. Upon addition of hydrogen chloride, the suspension turned to a solution. The reaction solution was then poured into ether (7.5 l) which had been cooled to 0° C. beforehand and the mixture was kept stirring for 2 hours to make the crystals precipitate. Thus obtained product was separated by filtration to give 48.4 g (83%) of γ-L-glutamyl-L-cysteine ethyl ester hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1.B(O)O>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]2[C:10]=1[N:9]([C:23]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:21]([F:20])[CH:22]=1)[CH:8]=[CH:7]2
Reactant: Fc1cc(Br)c2[nH]ccc2c1OCc1ccccc1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Fc1cc(-n2ccc3c(OCc4ccccc4)c(F)cc(Br)c32)ccc1OCc1ccccc1
Reaction time: 20 h
Yield: 30 %

Procedure:
A mixture of 7-bromo-5-fluoro-4-[(phenylmethyl)oxy]-1H-indole (D5) (3 g, 9.37 mmol), {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (3.46 g, 14.06 mmol), copper (II) acetate (2.55 g, 14.06 mmol) and pyridine (0.834 mL, 0.815 g, 10.31 mmol) in dichloromethane (50 mL) were stirred together vigorously under an air atmosphere with powdered 4A molecular sieves (˜10 g). After stirring for 20 hours, another 0.5 g of boronic acid were added and the mixture was stirred for a further 24 hours. Then another 1.73 g boronic acid (0.75 eq), copper acetate (1.28 g, 0.75 eq) and pyridine (1.52 mL, 2 eq) were added and stirring was continued at room temperature. After a further 24 hours, the reaction was diluted with ethyl acetate and filtered through celite. The celite was washed with ethyl acetate and the combined filtrates were washed with water (2×), dried (Na2SO4) and concentrated. Chromatography SP4 (0-30% ethyl acetate in hexane) gave the title compound as a white solid (D6), (1.463 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:25][C:26](Br)=[O:27].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][N:9]2[CH2:25][C:26]([NH:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:22][CH:23]=1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1

Procedure:
prepared by reaction of 1-(4-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: Cl.[CH:2]([C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH:18]([NH2:23])[CH2:17]3)(=[O:13])=[O:12])=[N:7][N:6]=1)([CH3:4])[CH3:3].CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([O:55][C:56]1[CH:64]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:62]=[CH:61][C:57]=1[C:58](O)=[O:59])[CH3:54]>C(N(CC)CC)C>[CH2:53]([O:55][C:56]1[CH:64]=[C:63]([C:65]([F:66])([F:67])[F:68])[CH:62]=[CH:61][C:57]=1[C:58]([NH:23][CH:18]1[CH2:17][C:16]2[C:20](=[CH:21][CH:22]=[C:14]([S:11](=[O:13])(=[O:12])[NH:10][C:8]3[S:9][C:5]([CH:2]([CH3:4])[CH3:3])=[N:6][N:7]=3)[CH:15]=2)[CH2:19]1)=[O:59])[CH3:54]
Reactant: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CC(C)c1nnc(NS(=O)(=O)c2ccc3c(c2)CC(N)C3)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)NC1Cc2ccc(S(=O)(=O)Nc3nnc(C(C)C)s3)cc2C1
Temperature: 25 °C

Procedure:
The mixture of 2-amino-indan-5-sulfonic acid (5-isopropyl-[1,3,4]thiadiazol-2-yl)-amide hydrochloride (40 mg), 1.5 ml of dimethyl formamide, 0.037 ml of triethylamine, 41 mg of HATU and 25 mg of 2-ethoxi-4-trifluoromethyl-benzoic acid was stirred at room temperature over night. The solvents were evaporated in vacuo and the resulting crude material was purified by column chromatography (silica gel, eluent: dichloromethane:methanol=95:5).
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][CH:11]([OH:16])[CH2:12][CH2:13][CH2:14]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C)CCC(=O)CCC)C1C=CC=CC=1>>[CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][CH:11]([OH:16])[CH2:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(O)CCN(C)Cc1ccccc1
Agent: CCCC(=O)CCN(C)Cc1ccccc1
Product: CCCC(O)CCN(C)Cc1ccccc1

Procedure:
Using a method similar to that for 1-(Benzyl-methyl-amino)-heptan-3-ol, 1-(benzyl-methyl-amino)-hexan-3-one affords the title compound: mass spectrum (ion spray) m/z 222 (M+1); 1H NMR (CDCl3) δ 7.34-7.24 (m, 5H), 3.79-3.73 (m, 1H), 3.55 (dd, 2H), 2.81-2.74 (m, 1H), 2.59-2.55 (m, 1H), 2.22 (s, 3H), 1.72-1.62 (m, 1H), 1.56-1.31 (m, 5H), 0.93 (t, 3H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.F.[CH2:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1.[CH2:18]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[C:4]([CH:16]1[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH2:14][CH2:15]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6].[C:4]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: CCCCCCCCCCCCc1ccccc1
Reactant: C=C1CC(=O)O1
Reactant: c1ccc2c(c1)CCCC2
Agent: F
Product: CC(=O)CC(=O)C1CCCc2ccccc21
Product: CCCCCCCCCCCCc1ccccc1C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %
Yield: 40 %

Procedure:
100.8 g (1.2 mols) of diketene were added dropwise at -30°C to 0.5 1 of anhydrous hydrofluoric acid and a mixture of 0.6 mol of tetrahydronaphthalene and 0.6 mol of commercial grade dodecyl-benzene were dropped in. After stirring for 12 hours at room temperature, the reaction mixture was stirred into 3 1 of icewater. After extraction with methylene chloride, wahing with water to remove the acid from the organic phase and distillation of the methylene chloride, distillation of the reaction yielded 86 % of acetoacetyl-tetrahydronaphthalene boiling at 135°C under 0.5 torr and 77 g 40% of acetoacetyl-dodecyl-benzene boiling at 160°C under 0.5 torr as found by gas chromatographic determination of the fractions.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.[OH-].[K+].C1C2C(CCCC2)CCC1>[Cu].C(Cl)(Cl)Cl>[I:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([N:6]3[C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=4[CH:9]=[CH:10][C:11]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]3=4)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCC2CCCCC2C1
Product: Ic1ccc(-c2ccc(N3c4ccccc4C=Cc4ccccc43)cc2)cc1
Temperature: 200 °C
Reaction time: 36 h
Yield: 50 %

Procedure:
5H-Dibenz[b,f]azepine in an amount of 20.0 g (0.10 mol), 4,4'-diiodobiphenyl in an amount of 60.9 g (0.15 mol), potassium hydroxide in an amount of 6.7 g (0.12 mol) and a copper powder in an amount of 1.3 g (0.02 mol) were mixed with 20 ml of decalin, and heated with stirring in a stream of nitrogen for 36 hours at the external temperature of 200° C. After cooling to room temperature or its vicinity, the reaction solution was admixed with chloroform, and subjected to Celite filtration to remove the insoluble matter. The filtrate was concentrated, and the concentrated solution was purified by column chromatography on silica gel. Thus, 23.6 g of 5-(4'-iodobiphenyl-4-yl)dibenz[b,f]azepine was obtained (in a 50% yield).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].Br[C:6]1[C:7]([CH3:20])=[N:8][N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[CH:10]=1.CC[N+](CC)(CC)CC.CN(C=O)C>C(OCC)(=O)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>[CH3:20][C:7]1[C:6](/[CH:3]=[CH:2]/[C:1]#[N:4])=[CH:10][N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[N:8]=1
Reactant: C=CC#N
Reactant: Cc1nn(-c2ccnc3[nH]ccc23)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccnc3[nH]ccc23)cc1/C=C/C#N
Yield: 191.3 %

Procedure:
A solution of 2-propenenitrile (0.043 mL, 0.00065 mol), bis(triphenylphosphine)palladium(II) chloride (0.0091 g, 0.000013 mol), 4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.036 g, 0.00013 mol), and tetraethylamine (TEA) (0.15 mL, 0.0011 mol) in DMF (0.15 mL, 0.0019 mol) was microwaved at 120° C. for 2 h. The solution was then diluted with ethyl acetate and washed with water (×2) and brine successively. The organic phase was dried and concentrated in vacuo to give 62 mg of the product as an orange solid. The orange solid was purified by prep-LCMS to give 12 mg of an off-white solid as a trifluoroacetic acid (TFA) salt which was triturated with MTBE (1 mL) to provide the purified product as a pale green solid. (dried at 60° C. for 4 h, 9 mg, 28% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22]([O:24][CH2:25][CH2:26]Br)[CH3:23].O>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:23][CH2:22][O:24][CH2:25][CH3:26])[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1c(-c2ccco2)cc2ncnc(Cl)c21

Procedure:
To a solution of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (220 mg) in N,N-dimethylformamide (1.2 mL) was added cesium carbonate (489 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 15 min. 2-Bromoethyl ethyl ether (0.169 mL) was added and the mixture was stirred at room temperature for 2 days. Cesium carbonate (326 mg) and 2-bromoethyl ethyl ether (0.113 mL) were added and the mixture was stirred at room temperature for 1 day. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→1:4) to give the title compound (76 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].CN1CCOCC1.[C:22]([N:33]1[C@@H:37]([CH3:38])[C:36](=O)[O:35]C1=O)(=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:36](=[O:35])[C@H:37]([CH3:38])[NH:33][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCCCCCCCCC(=O)N1C(=O)OC(=O)[C@@H]1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Reaction time: 0.33 h
Yield: 71.4 %

Procedure:
L-Phenylalanine methyl ester hydrochloride (259 mg, 1.2 mmol) was suspended in tetrahydrofuran (6 mL), followed by the addition of N-methylmorpholine (121 mg, 1.2 mmol) at 0° C. The resulting mixture was stirred for 20 minutes. (S)-3-Decanoyl-4-methyl-2,5-oxazolidinedione (N-decanoyl-L-alanine-NCA) (270 mg, 1 mmol) was added as crystals at 0° C., followed by stirring for 5 minutes. The mixture was allowed to rise in temperature to room temperature, at which the mixture was stirred for 30 minutes. The reaction mixture was treated in a similar manner as in Example 19 to afford the title compound (289 mg, 71%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([NH2:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>CN1C(=O)CCC1.C([O-])(O)=O.[Na+]>[ClH:1].[Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([NH:11][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1csc2c(Cl)cccc12
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Clc1cccc2c(Nc3ccncc3)csc12
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
To a solution of 7-chloro-3-aminobenzo[b]thiophene (47.82 g, 325 mmole) in NMP (300 mL) was added 4-chloropyridine hydrochloride (50.78 g) and the reaction mixture was placed in a 130° C. oil bath. After stirring for 5 minutes, the reaction mixture was cooled, diluted with a saturated solution of NaHCO3, and extracted with ethyl acetate. The biphasic mixture was thick with precipitates which were removed by filtration over Celite. The organic layer was separated, washed with water, dried (MgSO4), and concentrated. Trituration of the resulting solid with diethyl ether/pentane yielded 28.95 g of product as a green solid. TLC revealed that the precipitates filtered in the initial extraction contained product. Flash chromatography (silica gel) and trituration of the resulting solid with diethyl ether/pentane yielded 11.32 g of an off-white solid. A 2.0 g portion of this material was dissolved in 40 mL of hot methanol allowed to stand for a half hour, filtered to remove orange precipitates. Ethereal hydrogen chloride was added to the filtrate. The hydrochloride salt was then filtered, washed with diethyl ether, and dried under high vacuum, P2O5, and refluxing xylenes to yield 1.89 g of a beige crystalline solid, mp 305° C. (dec.).
Reaction SMILES: C1CO[C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]2=3)[O:2]1.CC(C)=O>O>[CH:13]1[C:8]2[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=3[C:3](=[O:2])[C:9]=2[CH:10]=[CH:11][C:12]=1[CH:14]([CH3:18])[C:15]([OH:17])=[O:16]
Reactant: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: CC(C)=O
Solvent: O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 90 %

Procedure:
2.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is dissolved in 20 ml. of acetone and to the solution is added 20 ml. of N-hydrochloric acid. The mixture is refluxed for 1 hour, then cooled, diluted with water, and extracted with ethyl acetate. The extract is washed, dried and evaporated to give a 90% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5° C.
Reaction SMILES: Cl.[C:2]([NH2:7])(=[NH:6])[CH:3]([CH3:5])[CH3:4].CC[O-].[Na+].[C:12]([OH:20])(=[O:19])/[C:13](=[C:15](\[CH:17]=O)/[Br:16])/Br>CCO>[Br:16][C:15]1[C:13]([C:12]([OH:20])=[O:19])=[N:6][C:2]([CH:3]([CH3:5])[CH3:4])=[N:7][CH:17]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: CC(C)C(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1ncc(Br)c(C(=O)O)n1
Temperature: 50 °C
Yield: 38.6 %

Procedure:
To a stirred suspension of isobutyramidine hydrochloride (6.47 g, 47.5 mmol) at r.t. in EtOH (30 ml) under an argon atmosphere was added sodium ethylate solution (21 ml, 21% in EtOH) over 5 min. The suspension was heated to 50° C. and a solution of mucobromic acid (5.7 g, 22.1 mmol) in EtOH (24 ml) was added dropwise over 5 min at 50° C. An additional portion of sodium ethylate solution (12 ml, 21% in EtOH) was added dropwise over 5 min. The mixture was then cooled to r.t. The solids were filtered off, and the cake was washed with plenty of ethanol. The filtrate was concentrated to leave the crude product as a light brown solid. The crude material was triturated in 2 N HCl (100 ml). The product was collected by filtration, washed with plenty of H2O and plenty of n-heptane and dried to give the product (2.09 g, 73%) as beige solid. MS: M=244.9 (M−H)+
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][C@H:19]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Reaction time: 1 h

Procedure:
Fmoc-protected dipeptide 72 (500 mg, 1.00 mmol) was treated with a 5% v/v solution of piperidine in DMF (5 mL). After stirring for 1 h, the reaction mixture was concentrated to dryness. The crude material was used for the next step without purification.