Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO>ClCCl>[C:26]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]([C:10]([OH:12])=[O:11])[NH2:3])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: N[C@@H](CCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 43 %

Procedure:
Lysine 2HCL (1.012 g, 4.34 mmol) was suspended in 300 ml dichloromethane, and sonicated until suspension was homogeneous. Triethylamine (7.5 ml, 54.1 mmol, 2.5 eq.) was added and the mixture was left to stir for 20 minutes in Brine/Ice bath (−15° C). Triphenylmethylchloride (Trityl chloride) (6.00 g, 21.5 mmol, 1 eq.) was dissolved in 200 ml dichloromethane and then slowly added over a period of 1 hour via a dropping funnel to the reaction flask. The reaction was followed by TLC (Silica, 5% methanol/95% CH2Cl2) and was stopped 1 hour after disappearance of Trityl chloride. Volume was reduced by reduced pressure distillation. The reaction product was washed first with 5% sodium bicarbonate (2×, 20 ml each), brine (1×, 20 ml), dried over sodium sulfate, filtered, and the solvent removed at reduced pressure distillation. The product was purified by flash column chromatography (Silica Gel, 3% methanol/97% CH2Cl2) and isolated as a clear golden oil (0.753 g. Yield: 43%). 1H NMR (CDCl3, 300 MHz δ1.40 (m, 2H), 1.52 (m, 2H), 1.67 (m, 2H), 2.11 (t,2H), 3.41 (t, 1H), 3.69 (s,3H), 7.14-7.51 (m, 15H); 13C NMR (CDCl3, 75 MHz) δ23.6, 30.7, 35.0, 43.5, 51.9, 54.5, 71.0, 126.2, 127.8, 128.7, 146.4, 176.6; ESI-MS calculated for C27H30N2O2 402.53; found 403.6 [M++1].
Reaction SMILES: CS[CH:3]([S:8][CH3:9])[CH2:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[O:19][C:18]([CH2:20][N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>O1CCOCC1>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH3:22][N:21]([CH3:23])[CH2:20][C:18]1[O:19][C:15]([CH2:14][S:13][CH2:12][CH2:11][NH:10][C:3]([S:8][CH3:9])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:16][CH:17]=1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC(C[N+](=O)[O-])SC
Agent: O=C(O)C(=O)O
Solvent: C1COCCO1
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 99.4 %

Procedure:
A solution of 1,1-bis(methylthio)-2-nitroethane (19.8 g) and 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (6.42 g) in dry dioxan (120 ml) was heated at 80° C. for 6 hours. Oxalic acid (3.8 g) in dry dioxan (40 ml) was added and the crystalline solid which separated was filtered, washed with dioxan and dried to give the title compound (12.55 g) m.p. 140°-143° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:13][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: N#Cc1ccccn1
Reactant: Cc1ccc(S)c(C(=O)O)c1
Solvent: c1ccncc1
Product: Cc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Yield: 43 %

Procedure:
A mixture of 5-methyl-2-mercaptobenzoic acid (1.60 g, 9.5 mmol), 2-cyanopyridine (1.10 g, 10.1 mmol) and pyridine (20.0 ml) was refluxed for 8 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-ethanol to give the titled compound (1.04 g, 43%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:39]([C:41]1[CH:42]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1)#[N:40]>C(Cl)Cl>[C:39]([C:41]1[CH:42]=[C:43]([S:47]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[C:17]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=5)=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1)#[N:40]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(S(=O)(=O)N2CCN(c3ccc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
To a stirred solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (0.318 g) in CH2Cl2 (20 mL) containing. Et3N (90 mg) was added dropwise 3-cyano-benzenesulfonyl chloride (0.179 g) and the mixture was stirred at room temperature for 48 hours. The solution was then washed with water, with brine, dried over Na2SO4, filtered and evaporated. The residue was then purified by flash chromatography eluting with CH2Cl2 to give the title compound (0.39 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[Cl:16])=[CH:4][CH:3]=1.[N+:17]([C:20]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23])([O-:19])=[O:18].O>O1CCOCC1>[N+:17]([C:20]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:21]=1[C:22]([NH:24][C:25]([NH:13][C:12]1[CH:14]=[CH:15][C:9]([O:8][C:5]2[N:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[C:10]([Cl:16])[CH:11]=1)=[O:26])=[O:23])([O-:19])=[O:18]
Reactant: O=C=NC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Nc1ccc(Oc2ccc(Br)nn2)c(Cl)c1
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])Nc1ccc(Oc2ccc(Br)nn2)c(Cl)c1
Yield: 40.7 %

Procedure:
1.10 g of 4-(6-bromo-3-pyridazinyloxy)-3-chloroaniline obtained in the same manner as in the above Synthetic Example 1 (1), was dissolved in 7 ml of dioxane. To this solution, 8 ml of a dioxane solution containing 0.87 g of 2,4-dinitrobenzoyl isocyanate was dropwise added, and the mixture was reacted at room temperature for 4 hours. After the completion of the reaction, the reaction product was poured into warm water, and the precipitates were separated by filtration. The precipitates were stirred in ethyl acetate, and again filtered to obtain 0.80 g of the desired product having a melting point of from 217° to 219° C.
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+].Cl>CO.O>[C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][CH2:11][CH:10]([NH2:26])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)(N2CCCCC2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: NC1CCC(c2ccccc2)(N2CCCCC2)CC1

Procedure:
4-Phenyl-4-(1-piperidino)cyclohexanone of Example 3 (0.95 g, 3.7 mmol) and ammonium acetate (4.3 g, 55 mmole) were dissolved in 30 ml of anhydrous methanol. Sodium cyanoborohydride (0.5 g, 8 mmole) was added to the mixture while stirring. The mixture was stirred at room temperature overnight and concentrated HCl was then added until a white precipitate was obtained. The precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to give a solid residue. The residue was taken up in 100 ml of water and to the aqueous extract was added concentrated HCl to pH 2. The solution was extracted with ethyl ether to remove the unreacted starting material. The mixture was then stirred in an ice bath and sodium hydroxide was added until the solution pH reached 11. The mixture was then extracted with chloroform. The chloroform extract was washed once with water and dried over anhydrous sodium sulfate. Removal of chloroform under reduced pressure gave the desired cyclohexylamine in quantitative yield as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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(#N)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[C:2]1[C:3]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: Cc1cc(NC(=O)c2cnn3cccnc23)c(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2Cl)cn1
Yield: 46.1 %

Procedure:
N-(5-bromo-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (82.2 mg, 0.247 mmol, 1 eq), 2,5-dichlorophenylboronic acid (122.1 mg, 0.6399 mmol, 2.59 eq), and bis(triphenylphosphine)palladium(II) chloride (15.4 mg, 0.0219 mmol, 0.09 eq) were combined in a microwave vial. To these solids were added sodium carbonate (1.0 mL of a 1.0 M aqueous solution, 1.0 mmol, 4.0 eq) and 3.0 mL acetonitrile. The vial was sealed and subjected to microwave irradiation (120° C., 30 W) for 30 minutes. The reaction was partitioned between ethyl acetate and water, and the organic layer dried over magnesium sulfate and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 45.3 mg (46%) of N-(5-(2,5-dichlorophenyl)-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=398.0; 1H NMR (400 MHz, DMSO-d6) δ: 9.75 (s, 1H), 9.32 (d, 1H), 8.71 (s, 1H), 8.48 (s, 1H), 8.26 (s, 1H), 8.21 (d, 1H), 7.78 (d, 1H), 7.75 (d, 1H), 7.69 (s, 1H), 7.26 (d of d, 1H), 2.55 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[CH:23][C:24]([F:27])=[C:25]([CH3:26])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.Cl>C(O)(=O)C>[F:27][C:24]1[CH:23]=[CH:22][C:14]2[NH:15][C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[N:12][C:13]=2[C:25]=1[CH3:26]
Reactant: CCOC(=O)c1cnn(-c2nc3c(C)c(F)ccc3n2COCCOC)c1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(F)ccc2[nH]c(-n3cc(C(=O)O)cn3)nc12
Temperature: 100 °C
Yield: 59.9 %

Procedure:
A mixture of 1-[5-fluoro-1-(2-methoxy-ethoxymethyl)-4-methyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.131 g, 0.481 mmol), glacial acetic acid (4.8 mL), and 6M aqueous HCl (4.8 mL) was heated at 100° C. for 4 h in a sealed tube. The reaction mixture was cooled to 23° C. and then 0° C. The resulting precipitate was filtered and washed with cold water to yield the titled compound (75.0 mg, 60%). MS (ESI/CI): mass calcd. for C12H9FN4O2, 260.1; m/z found, 261.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.88 (s, 1H), 8.29 (s, 1H), 7.35 (dd, J=8.7, 4.5 Hz, 1H), 7.06 (dd, J=10.4, 8.8 Hz, 1H), 2.46 (d, J=1.3 Hz, 3H).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[F:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](CC)([O-])=O>[F:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:10]=1[CH2:11][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[S:2](=[O:4])(=[O:3])[NH:5][C:6]1=[O:7]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Fc1cccc(F)c1CNc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: O=C1NS(=O)(=O)c2ccccc2N1Cc1c(F)cccc1F
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 366 %

Procedure:
A solution of chlorosulfonylisocyanate (0.29 mL, 3.33 mmol) in nitroethane (5 mL) was cooled to approximately −40° C. and a solution of N-(2,6-difluorobenzyl)aniline (562 mg, 2.56 mmol) in nitroethane (3 mL) was added dropwise over approximately 10 min. The mixture was stirred at −40° C. for approximately 10 min, then at 0° for 15 min. Aluminium chloride (479 mg, 3.59 mmol) was then added and the mixture heated at reflux for 30 min before cooling to rt. Separately, the process was repeated using chlorosulfonylisocyanate (1.20 mL, 13.8 mmol) in nitroethane (20 mL), N-(2,6-difluorobenzyl)aniline (2.32 g, 10.6 mmol) in nitroethane (15 mL), followed by aluminium chloride (1.97 g, 14.8 mmol). The two reaction mixtures were combined and cautiously added to stirred ice-H2O (approximately 100 mL) and the title compound (3.04 g, 9.37 mmol) was isolated by filtration.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28](O)(=[O:32])[CH:29]([CH3:31])[CH3:30]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CC(C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CC(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (38 mg, 59%), MS (ISP) m/z=401.5 [(M+H)+], mp 203.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) isobutyric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=[O:5].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:1][C:2]1[C:9]([Br:11])=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cl)cc1C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1c(Br)cc(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Amino-5-chlorobenzaldehyde (2.1 g, 13.5 mmol) was dissolved in chloroform (20 mL) and treated with N-bromosuccinimide (2.6 g, 14.9 mmol). The reaction was stirred for 30 min at ambient temperature. The reaction was diluted with methylene chloride and washed with sodium thiosulfate (2×), 5% sodium bicarbonate (2×), water (2×), brine, dried over sodium sulfate, and concentrated to afford 3.0 g (95%) as a pale yellow powder. 1H-NMR (CDCl3, 500 MHz) δ 9.75 (s, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H). Mass spec.: 236.01 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[F:15][C:16]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]([Cl:22])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:22].[F:15][C:16]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1ccc(F)cc1F
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Fc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)c(F)c1

Procedure:
To a solution of (E)-2,4-difluorocinnamic acid (331 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-2,4-difluorocinnamoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-2,4-difluorocinnamoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 369.80; mp: 194.8-196.8° C.; 1H-NMR (DMSO) δ: 8.84-8.79 (1H, m), 8.30-8.08 (2H, m), 7.96-7.82 (3H, m), 7.78-7.69 (1H, m), 7.61-7.13 (6H, m).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19])C.[OH-].[Na+]>CO>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:20])=[O:3])=[C:8]([CH2:17][CH2:18][CH3:19])[C:9]=1[OH:16])(=[O:15])[CH3:14]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCC(=O)O)ccc(C(C)=O)c1O
Yield: 82.9 %

Procedure:
To 5.6 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester in 50 ml of methanol was added 50 ml of 1.0N sodium hydroxide and the solution was stirred at reflux for 2 hours. The methanol was removed in vacuo, the residue was acidified and the product was extracted with ether. The dried (over magnesium sulfate) extract was concentrated in vacuo to a solid which was recrystallized from ether-hexane to give 4.18 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid, the titled compound, mp 128°-130°, (83% yield).
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14](O)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:24]1([N:30]=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.Cl.CN.C(N(C(C)C)CC)(C)C>O1CCCC1>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([NH:30][CH3:24])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 10 h
Yield: 58.6 %

Procedure:
Boc-Asp(OBzl) (6.4 g) was dissolved in tetrahydrofuran (30 ml), added with dicyclohexylcarbodiimide (4.1 g), hydroxybenzotriazole (3.0 g), methylamine hydrochloride (2.0 g) and diisopropylethylamine (3.9 g) under ice cooling and stirred for 10 hours. Insolubles were removed from the mixture by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was washed with 10% aqueous solution of citric acid and saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. Then the ethyl acetate was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give Boc-Asp(OBzl)-NHMe (3.9 g).
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.P(Cl)(Cl)([Cl:18])=O.N>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]3[O:13][CH2:14][CH2:1][O:2][C:3]=3[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=c1[nH]cnc2cc3c(cc12)OCCO3
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: Clc1ncnc2cc3c(cc12)OCCO3
Temperature: 0 °C

Procedure:
A mixture of 25.3 g. of 6,7-ethylenedioxyquinazolin-4(3H)-one and 50 ml. of phosphorus oxychloride is refluxed for 10 minutes, cooled, and added with stirring to one liter of ice. After addition of concentrated ammonia the resulting mixture is extracted with chloroform and the chloroform solution chromatographed through 300 mls. of silica gel while eluting with chloroform. Evaporation of the eluent yields 4-chloro-6,7-ethylenedioxyquinazoline, m.p. 169°-174° C.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CS(C)=O.O>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]3[C:3]=2[CH2:4][N:5]([CH3:15])[C:6]3=[O:14])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN1Cc2c(F)ccc([N+](=O)[O-])c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CN1Cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ccc([N+](=O)[O-])c2C1=O
Temperature: 60 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
To a suspension of 4-fluoro-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one (2.0 g, 8.52 mmol) and potassium carbonate (657.9 mg, 4.76 mmol), triethylamine (2.0 mL, 14.3 mmol) in dimethylsulfoxide (20 mL), piperazine-1-carboxylic acid tert-butyl ester (1.77 g, 9.52 mmol) is added and the mixture is stirred at 60° C. for 6 hours. The mixture is poured into iced water and the resulting brown solids are collected by filtration. The obtained solid is dried in vacuo at 50° C. to afford 4-(2-methyl-7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as brown solid in 75% yield. Rf=0.25 (Hexane/AcOEt=1/1). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.50 (s, 9H), 3.13 (t, 4H), 3.20 (s, 3H), 3.61 (t, 4H), 4.37 (s, 2H), 7.04 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)(C)C)(C)(C)C.[Li]C(CC)C.CN([CH:25]=[O:26])C.Cl>C1COCC1.C1CCCCC1>[Cl:16][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([Cl:15])[C:12]=1[CH:25]=[O:26]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cc(O)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl-(3,5-dichlorophenoxy)-dimethylsilane (2.7 g, 9.8 mmol) in THF (20 mL) at −78° C., under a N2 atmosphere, was added dropwise sec-BuLi (7.2 mL of a 1.4 M solution in cyclohexane, 10.1 mmol). After 30 min, anhydrous DMF (1.2 mL, 15.2 mmol) was added slowly to the solution. After the addition, the solution was stirred at −78° C. for 1.5 h then 20 mL of 1N HCl was added and the suspension was warmed to ambient temperature. The aqueous layer was extracted with EtOAc and the organic layer was washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure to give 2,6-dichloro-4-hydroxybenzaldehyde as a pale yellow solid.
Reaction SMILES: I[C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)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.C1COCC1>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#C[Si](C)(C)C
Temperature: 50 °C
Reaction time: 17 h
Yield: 91.8 %

Procedure:
5-(5-Iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (2.0 g, 5 mmol), bis(triphenylphosphine)-Palladium dichloride (700 mg, 1 mmol) and CuI (100 mg, 0.5 mmol) were added to 14 mL dry THF under nitrogen. Trimethylsilyl acetylene (1.4 mL, 10 mmol) was added, followed by 7 mL diisopropylethylamine. The reaction mixture was stirred at 50° C. under nitrogen for 17 hours, then was allowed to cool for two hours with stirring. The reaction mixture was poured into 15% aqueous NHCl and extracted into EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on 150 g of flash silica (2%-4% MeOH/CH2Cl2) to give 1.70 g of 5-(2-Isopropyl-4-methoxy-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine, MS (M+H)=371.