Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.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>[C:27]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:21]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1nccc(-c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)n1
Reactant: Brc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: c1ccc(Nc2nccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)cc3)n2)cc1
Reaction time: 14 h
Yield: 83.2 %

Procedure:
4-(4′-Diphenylaminobiphenyl-4-yl)pyrimidine-2-amine (100 mg, 0.24 mmol), bromobenzene (27.8 μL, 0.264 mmol), dichlorobis(triphenylphosphine)palladium(II) (17 mg, 0.024 mmol), Xantphos (14 mg, 0.024 mmol) and sodium t-butoxide (35 mg, 0.36 mmol) were added in toluene (3 mL), and fluxed under nitrogen atmosphere for 14 hours. This solution was cooled, and the precipitated solid was filtered and washed with cold toluene and water to obtain the title compound (98 mg).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])=[O:3].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]([NH:4][C:5]1[CH:10]=[C:9]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])=[O:3]
Reactant: CC(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 4, N-methylcarbonyl 2-nitro-5-fluoroaniline (1.0 g, 5.1 mmol), phenol (0.47 g, 5.1 mmol) and potassium carbonate (1.4 g, 10.2 mmol) are reacted together to give N-methylcarbonyl 2-nitro-5-phenoxyaniline, 1.2 g of which is then reacted with 20% hydrochloric acid (50 ml) to give 2-nitro-5-phenoxyaniline. The 2-nitro-5-phenoxyaniline (0.9 g, 3.9 mmol) is reacted with potassium hydroxide (0.2 g, 3.9 mmol) and sodium hypochlorite (11 ml of 5.2% solution, 0.6 g, 7.8 mmol) to yield 5-phenoxybenzo-2,1,3-oxadiazole N-oxide, m.p. 76°-77°.
Reaction SMILES: [C:1](B(O)O)([CH3:3])=[CH2:2].[Br:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10](I)[N:9]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Br:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([C:1]([CH3:3])=[CH2:2])[N:9]=1
Reactant: COc1ccc(I)nc1Br
Reactant: C=C(C)B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)c1ccc(OC)c(Br)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 23.7 %

Procedure:
To 0.5M-isopropenyl magnesium bromide/tetrahydrofuran is added trimethyl borate (3.3 ml) and the mixture is stirred under nitrogen atmosphere at room temperature for 30 minutes. To the reaction solution are added 6N-hydrochloric acid and diethylether, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give isopropenylboronic acid as a crude product (818 mg). The above crude isopropenyl boronic acid (287 mg) and 2-bromo-6-iodo-3-methoxy-pyridine (800 mg) are dissolved in a mixed solvent of 1,2-dimethoxy-ethane (8 ml) and ethanol (3.2 ml) and thereto are added a 1M-aqueous sodium carbonate solution (6.4 ml) and tetrakis(triphenylphosphine)palladium (240 mg) and the mixture is stirred under nitrogen atmosphere at 80° C. for 5 hours. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→9:1), followed by NH-silica gel column chromatography (hexane:ethyl acetate=49:1→9:1) to give 2-bromo-6-isopropenyl-3-methoxy-pyridine (138 mg). MS (m/z): 228/230 [M+H]+
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[CH3:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[CH3:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Pyridine (200 mg) and a 40% aqueous solution (250 mg) of methylamine were added to 1(5-amino-2,4-difluorophenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), arid the mixture was heated and stirred overnight at 70° C. After the solvent was distilled off under reduced pressure, and ethanol (2 ml) and acetic acid (1 drop) were added to the residue to stir the mixture, solids deposited were collected by filtration and washed successively with ethanol and diethyl ether to obtain the title compound (51 mg) as a pale brown powder.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:8]=3[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:10][CH:11]([CH3:12])[C:5]2=[N:4][N:3]=1.[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Br:23][C:20]1[CH:21]=[CH:22][C:7]2[N:6]3[C:2]([N:30]4[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][OH:24])[CH2:28][CH2:29]4)=[N:3][N:4]=[C:5]3[CH:11]([CH3:12])[N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]=2[CH:19]=1
Reactant: CC1N=C(c2ccccn2)c2cc(Br)ccc2-n2c(Br)nnc21
Reactant: OCCN1CCNCC1
Product: CC1N=C(c2ccccn2)c2cc(Br)ccc2-n2c1nnc2N1CCN(CCO)CC1

Procedure:
In the manner given in Example 1, 1,8-dibromo-4-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess of 1-(β-hydroxyethyl)piperazine to give 8-bromo-4-methyl-1-[4-(β-hydroxyethyl)piperazino]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH2:19]([NH2:21])[CH3:20].[OH-].[Na+]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:21][CH2:19][CH3:20])[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Product: CCNc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Temperature: 80 °C

Procedure:
(±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.544g, 2 mmol) was added to an ethyl amine-saturated methanol solution (14 mL). The solution was heated at 80° C. in a Parr bomb for 2.5 hours. 1 N NaOH (2 mL) was added, and solvent evaporated. The residual oil was chromatographed on silica gel. Title compound was eluted with 10% methanol-chloroform; white crystals after crystallization from acetonitrile-methanol (0.365 g, 67%); mp 171-173° C.;
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:8]([O-])([OH:10])=[O:9]>>[N+:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:7])([O-:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1
Product: Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Toluene (0.91 g, 10 mmol), 68% nitric acid (30% mmol, 2.8 g) and [C4min][OTf] (0.57 g, 2 mmol) and heated (oil bath at 110° C.) in a 25 ml round bottom flask equipped with a reflux condenser for 24 hours. The reaction mixture is cooled to room temperature and the nitrotoluene/residual nitric acid is distilled off at 140° C. at 1 mBar. Phase separation of the distillate yields pure nitrotoluene as a mixture of 2- and 4-isomers. The ionic liquid remains in the distillation flask and can be reused on further reactions.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36](=[O:52])[CH2:37][N:38]=[C:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:34])([CH3:33])[CH3:32].[OH-].[Na+].O>C(#N)C>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])[CH2:14][C:15]([CH:37]([N:38]=[C:39]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:52])([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C(=O)CC(c2cc(Cl)cc(Cl)c2)(C(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
To a solution of 4-[(E)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (1 g) and (benzhydrylidene-amino)-acetic acid tert-butyl ester (643 mg) in acetonitrile (5 mL) was added a solution of sodium hydroxide (0.6 mL, 32%) at room temperature. The reaction was stirred at ambient temperature for 18 hours, then water was added and the reaction mixture was extracted with dichloromethane and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 05% ethyl acetate in cyclohexane) to afford 4-[3-[(Benzhydrylidene-amino)-tert-butoxycarbonyl-methyl]-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester (1.12 g) as a yellow foam. 19F NMR (376 MHz, CDCl3) δ −60.99 and −61.88 ppm (mixture of 2 diastereoisomers).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:18][C:19](=O)[CH:20]([CH3:22])[CH3:21])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[NH2:24][N:25]1[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]1.CN(C)C=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[C:19]([CH:20]([CH3:22])[CH3:21])[N:24]([N:25]3[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]3)[C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC1CCN(N)CC1
Reactant: CC(C)C(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1CCN(n2c(C(C)C)cc(-c3ccc(F)cc3)c2-c2ccccc2)CC1

Procedure:
3.4 ml of conc. hydrochloric acid are added to 10.1 g (34 mmol) of the compound from Example 2 and 11.6 g (102 mmol) of N-amino-4-methyl-piperidine in 100 ml of toluene AR and 50 ml of dimethylformamide and the mixture is boiled for 24 hours in a water separator. The mixture is cooled, diluted using 200 ml of ethyl acetate and extracted three times using 1N hydrochloric acid and twice using saturated sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether 5:95).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12](I)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:20]([N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35])[CH2:21][CH2:22][C:23]#[CH:24].O.C(OCC)(=O)C>CN(C)C=O.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>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:24]#[C:23][CH2:22][CH2:21][CH2:20][N:25]3[C:26](=[O:35])[C:27]4[C:28](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]3=[O:30])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCCN1C(=O)c2ccccc2C1=O
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CCCCN1C(=O)c2ccccc2C1=O
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To a solution of N2-(3-fluorophenyl)-5-iodo-N4-propylpyrimidine-2,4-diamine (F2, 2.50 g), bis(triphenylphosphine)palladium(II) dichloride (472 mg) and copper(I) iodide (256 mg) in N,N-dimethylformamide (60 mL), triethylamine (4.7 mL) and N-(4-pentynyl)phthalimide (2.15 g) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water, saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue, hexane and ethyl acetate were added. The solid matter was taken by filtration, and dried under reduced pressure to obtain 2-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (F3, 1.44 g) as yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7].[C-:11]#[N:12].[K+]>CC#N>[C:11]([CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7])#[N:12]
Reactant: [C-]#N
Reactant: CNS(=O)(=O)CCCCCl
Agent: [K+]
Solvent: CC#N
Product: CNS(=O)(=O)CCCCC#N

Procedure:
4-Chloro-N-methylbutane-1-sulfonamide (54 mmol), KCN (108 mmol) and 18-crown ether-6 (11 mmol) were dissolved in CH3CN (100 ml). The mixture was stirred at reflux temperature overnight. The mixture was cooled and filtered. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2, then ethyl acetate). Yield: 3.2 g (70% purity).
Reaction SMILES: C[N:2]1CCOCC1.ClC(OCC)=O.[N:14]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:34])[C@H:15]([C:31](O)=[O:32])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>C1COCC1>[N:14]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:34])[C@H:15]([C:31]([NH2:2])=[O:32])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
Under cooling with ice, NMM (0.463 ml, 4.21 mmol) and ethyl chloroformate (0.403 ml, 4.21 mmol) were added to a solution of Boc-N-Me-Tyr(Bzl)-OH (1.35 g, 3.51 mmol) in THF (35 ml), followed by stirring for 15 min. The reaction mixture was stirred for further 30 min., while bubbling gaseous ammonia therein. The reaction mixture was then left standing at room temperature, diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1) to give Boc-N-Me-Tyr(Bzl)-NH2 (1.32 g, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Li]CCCC.CCCCCC.CON(C)[C:23]([C@@H:25]1[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:23]([C@@H:25]1[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]
Reactant: CON(C)C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Reactant: Clc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)c2cccc(Cl)c2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of 1-bromo-3-chlorobenzene (5 g, 18.2 mmol) in anhydrous THF (25 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (18.2 mmol). After stirring for 1 h at −78° C., a solution of (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (3.47 g, 18.2 mmol) in anhydrous THF (10 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 h. Tlc indicated the reaction was complete. The mixture was quenched with satd aq NH4Cl (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product (5.5 g, 93%), which was used immediately for next step without purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=O.[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([F:25])[CH:24]=1)[NH2:21].C(N(CC)CC)C>C(Cl)Cl.C(O)(=O)C.CN(C=O)C>[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([NH:21][C:20]1[CH:19]=[C:18]([F:17])[CH:24]=[C:23]([F:25])[CH:22]=1)=[O:15]
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=C(O)c1cncc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(F)cc(F)c1)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 90.3 %

Procedure:
Oxalyl chloride (1.2 mL) and DMF (25 μL) were added to 5-bromonicotinic acid (1.0 g, 4.95 mmol) suspended in CH2Cl2 (30 mL). The resulting mixture was stirred at room temperature for 12 min. It was then concentrated to dryness and azeotroped with toluene. The residual was then dissolved in toluene (30 mL). 3,5-Difluoroaniline (1.0 g, 7.8 mmol) was added followed by triethylamine (1.1 mL, 7.5 mmol). The resulting suspension was stirred at room temperature for 10 min. The reaction mixture was taken in 5% acetic acid(aq) (300 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extract was washed with 1.0 M Na2CO3(aq) (2×100 mL) and brine. The organic layers were combined, dried (Na2SO4) and concentrated to dryness to provide the title compound (1.4 g, 93%). MS (APCI) m/z 313, 315 (M+H)+.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[NH2:12][C@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:23]3[CH2:30][S:29][CH2:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:18][CH2:17]1)=[O:15]>C(Cl)Cl.CO>[NH2:12][C@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:23]3[CH2:30][S:29](=[O:9])[CH2:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:18][CH2:17]1)=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2CSC3)CC1
Solvent: CO
Solvent: ClCCl
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2CS(=O)C3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.7 %

Procedure:
m-CPBA (77%, 67 mg, 0.30 mmol) was added to a solution of (R)-2-amino-3-(4-chlorophenyl)-1-(4-(5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one (120 mg, 0.30 mmol) in DCM (10 mL) and MeOH (1 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was subject to column chromatography, eluted by DCM/MeOH (4:1-1:1) to afford (R)-2-amino-3-(4-chlorophenyl)-1-(4-(6-oxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one (21 mg, 17%) as the free amine. LCMS: 420.2 [M+H+] (APCI+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1.CC[O-].[Na+]>C(O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH:13]1[C:5]2[CH:6]=[C:7]3[O:11][CH2:10][O:9][C:8]3=[CH:12][C:4]=2[CH2:3][CH2:2][O:1]1)[CH3:19]
Reactant: CCOC(=O)C=Cc1cc2c(cc1CCO)OCO2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1OCCc2cc3c(cc21)OCO3
Yield: 60 %

Procedure:
1.3 g of ethyl 3-{6-(2-hydroxyethyl)-1,3-benzodioxol-5-yl}acrylate was dissolved in 30 ml of ethanol. A catalytic amount of sodium ethylate was added to the solution and the mixture was heated under reflux for 2 h. The solvent was distilled off and 1N hydrochloric acid and water were added to the residue. After extraction with ethyl acetate followed by washing with a saturated aqueous common salt solution and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified according to silica gel column chromatography (hexane/ethyl acetate=85:15) to obtain 0.78 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11](I)=[CH:10][N:9]=[C:8]([NH2:13])[N:7]=1.[C:14](#[N:17])[CH:15]=[CH2:16].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[NH2:13][C:8]1[N:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:11](/[CH:16]=[CH:15]/[C:14]#[N:17])=[CH:10][N:9]=1
Reactant: C=CC#N
Reactant: Nc1ncc(I)c(-c2ccco2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#C/C=C/c1cnc(N)nc1-c1ccco1

Procedure:
From 4-furan-2-yl-5-iodo-pyrimidin-2-ylamine, acrylonitrile, bis(triphenyl-phosphine)palladium(II) chloride and cesium carbonate in dioxane. EI-MS m/e (%): 212 (M+, 52), 195 ([M—NH3]+, 100), 184 (32), 158 (52).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:24])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O>[C:5]([Cl:3])(=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 4.81 ml (66 mmol) of thionyl chloride, and a water condenser, is placed 15.65 g (55 mmol) of stearic acid. Addition of the thionyl chloride is completed with heating to about 45° C. over the course of about 40 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 45 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, stearoyl chloride.