Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([C:14]2[CH:24]=[CH:23][C:17]3[N:18]([CH3:22])[CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)=[O:13])[C@@H:4]([CH3:25])[CH2:3]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(N(CC)CC)C.[C:43](OCC)(=[O:45])[CH3:44]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:1]([C@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:12]([C:14]3[CH:24]=[CH:23][C:17]4[N:18]([CH3:22])[CH2:19][CH2:20][O:21][C:16]=4[CH:15]=3)=[O:13])[C@@H:4]([CH3:25])[CH2:3]2)[C:43](=[O:45])[CH3:44])=[CH:29][CH:28]=1
Reactant: CCOC(C)=O
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: C[C@H]1C[C@@H](N)c2ccccc2N1C(=O)c1ccc2c(c1)OCCN2C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc3c(c2)OCCN3C)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-(4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-methanone (662 mg, 1.87 mmol) in methylene chloride (8 mL) was added 4-chlorophenylboronic acid (583 mg, 3.74 mmol), triethylamine (1.81 ml, 13.09 mmol) and copper(II)acetate (681 mg, 3.74 mmol). The heterogeneous green mixture was stirred open to air for 1 hour and then warmed to 60° C. and stirred over night (14 h). The mixture was then cooled to room temperature, poured into rapidly stirred ethyl acetate (150 mL); solids were removed by filtration through Celite®. The extracts were washed several times with water and then once with brine. The extracts were then dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (95% methylene chloride/5% ethyl acetate) to afford the aniline product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][NH:24][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][CH:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:28][CH2:27]1
Reactant: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)O
Reactant: NCC1CC1
Product: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)NCC1CC1
Yield: 44 %

Procedure:
As described for example 90 g, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (99 mg, 0.3 mmol) was converted, using aminomethylcyclopropane instead of 4-aminotetrahydropyran, to the title compound (51 mg, 44%) which was obtained as an off white solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) and recrystallization from heptane/ethyl acetate. MS: m/e=385.1 [M+H]+.
Reaction SMILES: [F-].[K+].C[Si](C)(C)[C:5]([F:8])([F:7])[F:6].[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19](I)[CH:20]=2)[CH:15]=[CH:14][N:13]=1>CN1C(=O)CCC1.C(OCC)(=O)C.[Cu]I>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:5]([F:8])([F:7])[F:6])[CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Clc1nccc2ccc(I)cc12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc2ccnc(Cl)c2c1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
Into a 8 mL sealed tube, was placed potassium fluoride (300 mg, 5.17 mmol, 6.00 equiv, 100%), copper(I) iodide (900 mg, 4.66 mmol, 5.50 equiv, 100%), trimethyl(trifluoromethyl)silane (720 mg, 5.07 mmol, 5.00 equiv, 100%), NMP (3 mL, 100%) and a solution of 1-chloro-7-iodoisoquinoline (as prepared in the previous step, 250 mg, 0.86 mmol, 1.00 equiv, 100%) in NMP (1 mL). The reaction mixture was stirred for 12 h at 120° C. in an oil bath. The resulting mixture was diluted with 20 mL of ethyl acetate, washed with 3×10 mL of saturated solution of KI, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate:petroleum ether (1:50). The title compound was obtained as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:28]COC[CH2:24]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=[CH:47][C:46]([O:49][CH3:50])=CC=3)C=2N=1)(C)(C)C.C(O)(=O)C(O)=O.C1C2(CNC2)CO1>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:24][C:47]3([CH2:46][O:49][CH2:50]3)[CH2:28]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(Cn2nnc3c(N4CCOCC4)nc(C(C)(C)C)nc32)cc1
Reactant: COc1ccc(Cn2nnc3c(Cl)nc(C(C)(C)C)nc32)cc1
Agent: C1NCC12COC2
Agent: O=C(O)C(=O)O
Product: COc1ccc(Cn2nnc3c(N4CC5(COC5)C4)nc(C(C)(C)C)nc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of 4-(5-tert-butyl-3-(4-methoxy benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)morpholine (example 58, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-oxa-6-azaspiro[3.3]heptane oxalate and used without further purification in the consecutive step.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][N:26]=[N+]=[N-])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH2:26])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(CN=[N+]=[N-])cc3c21)NC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](Cn1ncc2ccc3oc(CN)cc3c21)NC(=O)OCc1ccccc1
Yield: 91.7 %

Procedure:
A solution of the product from Step A (1.28 g, 3.17 mmol) in THF (25 mL) was stirred with polymer supported triphenylphosphine (4 eq, 3 mmol/g, 12.7 mmol, 4.23 g) at 50° C. for 2 hours. Water (2.5 mL) was added and the mixture was stirred for another hour; more water (5 mL) was added and the reaction mixture was filtered. The solids were washed well with THF and the filtrate was evaporated to a residue which was dried under a vacuum to give a foam (1.10 g, 92%): LC/MS m/z 379 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[C:12]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24]Cl)[CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)=[O:6].[I-].[K+].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>O1CCCC1>[ClH:1].[ClH:1].[CH2:29]([N:31]([CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[C:12]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24][N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])[CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)=[O:6])[CH3:30]
Reactant: CCNCC
Reactant: O=C(CCCCl)c1ccc2c(c1)Cc1c(cccc1C(=O)CCCCl)S2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)CCCC(=O)c1ccc2c(c1)Cc1c(cccc1C(=O)CCCN(CC)CC)S2
Product: Cl
Temperature: 110 °C

Procedure:
A mixture of 32.6 g (0.08 mole) of 2,8-bis(4-chlorobutyryl)thioxanthene, 2 g of potassium iodide, 100 ml of diethylamine and 100 ml of tetrahydrofuran is heated for 24 hours with stirring in a Paar bomb at 110°C. Upon cooling, the mixture is evaporated to near dryness. The residue is dissolved in methylene chloride, washed with water then with saturated NaCl solution, dried over magnesium sulfate and filtered. The filtrate is evaporated to near dryness and recrystallized several times from methanol-diethyl ether and from acetone-methanol to give 2,8-bis(4-diethylaminobutyryl)thioxanthene dihydrochloride. M.P. 188°-191°C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]OC(=O)C=C)=[CH:11][CH:10]=1.[C:27]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]CCCCCCBr)(=[O:30])[CH:28]=[CH2:29].C(OCCCCCCBr)(=O)C=C>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:27](=[O:30])[CH:28]=[CH2:29])=[CH:13][CH:14]=1
Reactant: C=CC(=O)OCCCCCCCCCCCCBr
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Agent: C=CC(=O)OCCCCCCBr
Product: C=CC(=O)OCCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Yield: 24.1 %

Procedure:
The same procedure as in the synthesis (b) of Example 2 was repeated except that 6.7 g of 12-bromododecyl acrylate were used instead of 5.0 g of 6-bromohexyl acrylate to give 2.1 g (Y., 24.1%) of 2,3-difluoro-4'-[12-(acryloyloxy)dodecyloxy]biphenyl. m.p.; 59.7°-60.7° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([OH:17])=[O:16])=[N:9]1.C([O-])(=O)C.[Na+].[Br:23]Br>C(O)(=O)C>[Br:23][C:11]1[C:10]([C:15]([OH:17])=[O:16])=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:12]=1[O:13][CH3:14]
Reactant: BrBr
Reactant: COc1cc(C(=O)O)nn1-c1ccccc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(Br)c(C(=O)O)nn1-c1ccccc1F
Reaction time: 1 h
Yield: 90.7 %

Procedure:
50 mg (0.21 mmol) of 1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carboxylic acid were dissolved in 1.5 ml of acetic acid, sodium acetate (35 mg, 0.42 mmol) and bromine (50 mg, 0.21 mmol) were added and the mixture was stirred for 60 min. The solvent was removed in vacuo and the residue subjected to an aqueous work-up. The obtained crude title compound (60 mg) was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:19][CH3:20])[CH2:6][C:5](C(OC(C)C)=O)(C(OC(C)C)=O)[CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:27]([O:29]CC)C>>[OH:29][CH2:27][CH:6]1[CH2:5][CH2:4][C:3]1([O:2][CH3:1])[O:19][CH3:20]
Reactant: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COC1(OC)CCC1CO
Yield: 41 %

Procedure:
Diisopropyl 3,3-dimethoxy-cyclobutane-1,1-dicarboxylate (6.0 g, 20.8 mmol), prepared as described by P. E Pigou and C. H Schiesser, J Org Chem, 53, 3841-3 (1988), was dissolved in 200 mL of anhydrous diethyl ether and the ether solution was cooled to 0° C. with stirring under a nitrogen atmosphere. Lithium aluminum hydride (1.6 g, 42 mmol) was added to the ether solution in portions and the reaction mixture was stirred at 0° C. for 0.5 h. The reaction was then quenched by the addition of 1.6 mL of water, followed by 1.6 mL of 15% aqueous sodium hydroxide solution and 4.8 mL of water. The reaction mixture was filtered, the filter cake washed with diethyl ether and the combine ether filtrates were concentrated under reduced pressure. The residue (3.0 g) was dissolved in 2 mL of methylene chloride and purified on a 1.5×45 cm silica gel column eluted @2-3 psi with 200 mL of acetone:hexane (1:2 v/v), followed by 200 mL of acetone:hexane (1:1 v/v) to give 1.51 g (41% yield) of the title compound; MS DCI/NH3M-Z: 194 (M+NH4)+ ; 1H NMR (CDCl3) δ 1.99 (s, 4H), 2.35 (t, 2H-OH), 3.16 (s, 6H), 3.77 (d, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:21]1[N:22]([CH3:33])[C:23](=[O:32])[C:24]([CH3:31])=[CH:25][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:21]2[N:22]([CH3:33])[C:23](=[O:32])[C:24]([CH3:31])=[CH:25][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[C:4]([F:9])[CH:3]=1
Reactant: COC(=O)c1cc(C)c(=O)n(C)c1Cl
Reactant: Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of 4-bromo-2-fluorobenzenamine (0.058 g, 0.31 mmol) in THF (2mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (0.56 mL, 0.56 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at −78° C. Methyl 2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.060 g, 0.28 mmol) was then added dropwise as a solution in THF (1 mL) and the reaction mixture was stirred for 25 minutes at −78° C. The reaction mixture was quenched by the addition of H2O and the pH was adjusted with 0.1M HCl and then diluted with EtOAc and saturated NaCl and the layers separated. The aqueous layer was back extracted with EtOAc (1×). The combined EtOAc layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 20:1) gave 0.086 g (84%) pure desired product as a white crystalline solid. MS ESI (+) m/z 371, 373 (M+, Br pattern) detected; 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 7.79 (s, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 6.58 (t, 1H), 3.85 (s, 3H), 3.29 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:9][NH2:10].[C:11](Cl)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C1COCC1.CCOCC>[CH3:9][N:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: OCCCCCCBr
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(CCCCCCO)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
Unsymmetrical Primary/Secondary diamine: 6-(N-methyl-N-Carbobenzyloxyamino)-hexan-1-ol was synthesized as follows. To a solution of 6-bromo-hexan-1-ol (2.0 g, 17.4 mmol) was added 50 mL of a 2.0 M solution of methylamine (˜10 eq.) in THF and the reaction was allowed to stir overnight. The reaction mixture was diluted with 30 mL of ether, filtered, and concentrated. The crude material was then diluted in 30 mL of ether and 50 mL of saturated NaHCO3 solution. Carbobenzyloxychloride (2.5 g, 51 mmol) was then added and the reaction mixture was stirred vigorously for 2 hours. The reaction was then diluted with 100 mL of ether, washed with brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography (10-50% EtOAc:hexanes) afforded 3.1 g (76%) of product as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH:21]1([CH:24]=[O:25])[CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([CH:24]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[OH:25])[CH2:23][CH2:22]1
Reactant: COc1ccc(Br)cn1
Reactant: O=CC1CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)C2CC2)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a stirred −78° C. solution of 5-bromo-2-methoxypyridine (3.70 g, 19.79 mmol) in tetrahydrofuran (10 mL) was added 2.6 M n-butyllithium solution in hexane (8.4 mL, 21.84 mmol). The mixture was allowed to stir at −78° C. for 30 min, and then cyclopropanecarboxaldehye (1.70 g, 23.74 mmol) was added in one portion. The cooling bath was removed, and the mixture was allowed to warm to room temperature. After 2 h, the mixture was quenched by the addition of saturated aqueous ammonium chloride solution (100 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. Chromatographic purification of the residue (silica gel, 20% ethyl acetate in petroleum ether elute) afforded 2.90 g (80%) of cyclopropyl(6-methoxypyridin-3-yl)methanol as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11]([S:22][CH3:23])[N:10]=1)=[O:8].[CH3:28]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH2:5][N:6]([CH3:28])[C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11]([S:22][CH3:23])[N:10]=1)=[O:8]
Reactant: CSc1ncc(-c2ccccc2C)c(C(=O)NCc2cc(Cl)cc(Cl)c2)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: O
Product: CSc1ncc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(Cl)cc(Cl)c2)n1
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of 0.6 g (1.43 mmol) methylsulfanyl-5-o-tolyl-pyrimidine-4-carboxylic acid 3,5-dichloro-benzylamide in 10 ml N,N-dimethylformamide 0.073 g (1.85 mmol) sodiumhydride (60% dispersion in mineral oil) was added and the reaction stirred for 1 h. After the addition of 0.14 ml methyl iodide at 0°, the reaction mixture was stirred for 3 hrs at RT. The reaction mixture was distributed between 50 ml H2O, 50 ml brine and 50 ml CH2Cl2. The phases were separated and the aqueous layer washed twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 40:1) to give 0.57 g (92%) 2-methylsulfanyl-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-dichloro-benzyl)-methyl-amide as a colorless oil, MS (ISP): 432.2, 434.2 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:30][C:31]([NH:33][CH3:34])=[O:32].O.Cl>CN(C=O)C.C(OCC)(=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:30][C:31]([NH:33][CH3:34])=[O:32])[CH:20]=3)[CH2:13][CH2:14]2)=[O:8])=[CH:27][CH:28]=1
Reactant: O=C(NCCN1CCC(C(=O)c2ccc(Cl)cc2)CC1)c1cccc(O)c1
Reactant: CNC(=O)CCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)COc1cccc(C(=O)NCCN2CCC(C(=O)c3ccc(Cl)cc3)CC2)c1
Temperature: 80 °C

Procedure:
The product of step (iii) above (0.10 g) was dissolved in DMF (3 ml), Cs2CO2 (0.23 g) and 2-chloro-N-methylacetamide (0.26 g) were added and the mixture heated at 80° C. for 16 hours. The mixture was cooled to room temperature, water and ethyl acetate were added and the organic phase separated. Evaporation of the solvent gave a gum which was treated with 1.0M ethereal hydrogen chloride solution to give the titled product as a solid (0.05 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[N:9]([CH3:14])[N:10]=[CH:11][C:12]=1Br)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33](B4OC(C)(C)C(C)(C)O4)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:31]=[CH:32][C:33]([C:12]4[CH:11]=[N:10][N:9]([CH3:14])[C:8]=4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[CH:34][CH:35]=3)=[CH:28][CH:29]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: Cn1ncc(Br)c1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4NC(=O)OC(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: (4-bromo-2-methyl-2H-pyrazol-3-yl)-carbamic acid tert-butyl ester and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:36][CH3:37])[C@@H:33]([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:36][CH3:37])[C@@H:33]([OH:35])[CH3:34])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](N)[C@H](C)O
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Product: CC[C@@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)[C@H](C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.2 mL, 10.96 eq, 1.14 mmol) followed by (2S,3R)-3-amino-pentan-2-ol (60 mg, 5.5 eq, 0.58 mmol). The reaction mixture was placed in a preheated oil bath at 160° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and water (50 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 22 mg (57%). (80% de 3R,2S: 20% de 3R,2R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.90, 1.05 (2×t, 3H, J=6.95 & 7.42 Hz, —NHCH (CH2CH3)CH(CH3)OH), 1.17 & 1.25 (2×d, 3H, J=6.32 & 6.16 Hz, —NHCH (CH2CH3)CH(CH3)OH) 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.77-2.09 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 3.91-4.03 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 4.58-4.69 (m, 1H, —CH(CH3)2), 4.83-5.00 (m, 3H, —HNCH2-Pyr & OH), 6.16 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 7.24-7.33 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.55 (m, 1H, Pyr-H), 7.74 (d, 1H, J=7.42 Hz, Pyr-H), 8.67 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 370 ([M+H]+, 100), 324 (35), 289 (37), 243 (65), 199 (85). Accurate Mass (M+H): Actual: 370.2355, Measured: 370.2347.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:22][C:21]([CH3:23])=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[NH:24]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@@H:25]([C:34]([OH:36])=O)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CO.C(O)(C(F)(F)F)=O.[Pd]>[C:40]([O:39][C:37](=[O:38])[NH:24][CH:25]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:34]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:22][C:21]([CH3:23])=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:36])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1cc2ncnc(N3CCN(Cc4ccccc4)CC3)c2s1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2ncnc(N3CCN(C(=O)C(Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c2s1
Reaction time: 4 h
Yield: 58.1 %

Procedure:
To a solution of 4-(4-Benzyl-piperazin-1-yl)-6-methylthieno[3,2-d]pyrimidine (65 mg, 0.20 mmol) in MeOH (10 mL) was added Pd/C (10%, 20 mg) and two drop of TFA. The mixture was stirred under H2 balloon for 4 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in DCM (6 mL) and TEA (2 mL), then Boc-D-Phe(4-Cl)—OH (59 mg, 0.20 mmol) was added, followed by HOBT (50 mg, 0.37 mmol) and EDCI (74 mg, 0.39 mmol). The mixture was stirred at room temperature for 12 hours. The solvent was removed and the residue was subject to chromatography on silica gel to give the product {1-(4-chlorobenzyl)-2-[4-(6-methylthieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (60 mg, 59%). 1H NMR (CDCl3, 400 Hz) δ 8.54 (s, 1H), 7.28-7.26 (d, J=7.2 Hz, 2H), 7.17-7.15 (d, J=8.4 Hz, 2H), 7.08 (s, 1H), 5.37-5.35 9d, J=8.8 Hz, 1H), 4.86-4.84 (m, 1H), 3.87-3.57 (m, 7H), 3.24-3.22 (m, 1H), 3.00-2.98 (d, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.43 (s, 9H). MS (ESI+) [M+H]+ 516.