Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]4[NH:22][CH:23]=[C:24]([C:26]([O:28]C)=O)[N:25]=4)=[CH:16][CH:15]=3)[C:10]([CH2:30][CH3:31])=[C:9]([CH3:32])[N:8]=2)=[CH:4][CH:3]=1.[NH3:33]>C(O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]4[NH:22][CH:23]=[C:24]([C:26]([NH2:33])=[O:28])[N:25]=4)=[CH:16][CH:15]=3)[C:10]([CH2:30][CH3:31])=[C:9]([CH3:32])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Cc2nc(C(=O)OC)c[nH]2)cc1
Reactant: N
Solvent: CCO
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Cc2nc(C(N)=O)c[nH]2)cc1
Temperature: 25 °C
Yield: 32 %

Procedure:
A 25-mL round bottomed flask was charged with methyl 2-[[4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methyl]-1H-imidazole-4-carboxylate (18 mg, 0.038 mmol) and 2N NH3 in ethanol (10 ml). The mixture was stirred under reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure and the residue was purified by chromatography on silica gel using 10% acetone in dichloromethane as eluent to afford the title compound (5.5 mg, 32% yield). MW=452.96. 1H NMR (400 MHz, CDCl3) δ 7.68˜7.65 (m, 4H), 7.30 (d, J=8.0 Hz, 2H), 6.93 (d, J=4.0 Hz, 1H), 6.54 (brs, 1H), 4.45 (brs, 2H), 4.19 (s, 2H), 2.65 (q, J=7.6 Hz, 2H), 2.49 (s, 3H), 1.26 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:12][CH2:13][CH2:14]Br)[C:8](=[O:9])[NH:7][C:6](=[O:10])[NH:5][C:4]1=[O:11])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+].O>CC(C)=O>[CH2:1]([C:3]1([CH2:12][CH2:13][CH2:14][N:16]=[N+:17]=[N-:18])[C:8](=[O:9])[NH:7][C:6](=[O:10])[NH:5][C:4]1=[O:11])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC1(CCCBr)C(=O)NC(=O)NC1=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCC1(CCCN=[N+]=[N-])C(=O)NC(=O)NC1=O

Procedure:
A solution of 30 g of 5-ethyl-5-(3-bromopropyl) barbituric acid and 13 g of sodium azide in 350 ml of acetone was added to 240 ml of water and refluxed for approximately 18 hours. Thereafter, the solution was cooled on ice, filtered, air dried, and dissolved in a minimal amount of hot 95% ethanol. Crystals appeared after cooling and were filtered and air-dried. The melting point was 182°-184° C.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.Cl.C(O)C.O>O1CCCC1>[C:3]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)#[CH:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=C(Br)Br)cs2)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C#Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of tert-butyl 4-[4-(2,2-dibromovinyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (1.26 g, 2.79 mmol) in anhydrous tetrahydrofuran (25 ml) was added dropwise at −78° C. a mixture of 1.6M-n-butyllithium-hexane solution (5.2 ml, 8.4 mmol) and anhydrous tetrahydrofuran (10 ml). After stirring at −78° C. for 2 hrs, 1.25M hydrogen chloride-ethanol solution (6.7 ml, 8.4 mmol) was added dropwise to the reaction mixture. The mixture was warmed to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was concentrated, and the concentrated residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9→1:4) to give tert-butyl 4-(4-ethynyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (553 mg, yield 68%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3]1.[Br:19]N1C(=O)CCC1=O>C(#N)C>[Br:19][C:7]1[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][CH:2]([CH3:1])[CH2:11][CH2:10]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1CCc2c(cccc2Oc2ccccc2)N1
Solvent: CC#N
Product: CC1CCc2c(ccc(Br)c2Oc2ccccc2)N1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
A 50-mL round bottomed flask equipped with a magnetic stir bar and thermocouple was charged with rac-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (0.574 g, 2.399 mmol) and acetonitrile (11.5 mL). The solution was cooled to 0° C., and N-bromosuccinimide (0.427 g, 2.399 mmol) was added in one portion. The solution turned yellow, and the internal temperature rose to 5° C. before falling back to 0° C. After 10 min, additional N-bromosuccinimide (0.021 g, 0.120 mmol) was added. After an additional 10 min, the reaction mixture was removed from the ice bath and concentrated under reduced pressure. The residue was then partitioned between ethyl acetate and 10% aqueous sodium carbonate solution. The layers were separated, and the ethyl acetate layer was washed with 5% aqueous sodium chloride solution (10 mL) and concentrated to a yellow oil (0.81 g). The crude product was purified by column chromatography on silica gel (eluting with 12:1 hexanes-ethyl acetate followed by 10:1 hexanes-ethyl acetate) to afford rac-6-bromo-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (0.60, 79%) as a colorless syrup. MS (ESI, pos. ion) m/z 318, 320 [M+1].
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH:14]([C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21](B(O)O)[CH:22]=1)([CH3:16])[CH3:15].C([O-])([O-])=O.[Na+].[Na+].C(O)C>CC(O)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.O>[CH:14]([C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([C:2]2[C:3]([C:4]#[N:5])=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=2)[CH:22]=1)([CH3:16])[CH3:15]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: N#Cc1cc(C(F)(F)F)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(O)C(C)O
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C#N
Temperature: 25 °C

Procedure:
To a solution of 2-iodo-5-(trifluoromethyl)benzonitrile (2.0 g, 6.7 mmol) and (5-isopropyl-2-methoxyphenyl)boronic acid (1.6 g, 8.4 mmol) in dimethyl ethylene glycol (30.4 mL) was added 2M Na2CO3 (6.8 mL), ethanol (9.6 mL), and water (10 mL). The solution was degassed with nitrogen for 2 minutes. Pd(PPh3)4 (774 mg, 0.67 mmol) was added and the solution was degassed with nitrogen again for 2 minutes. The solution was divided equally into two 40 mL microwave tubes. Each tube was degassed with nitrogen for 1 minute, sealed, and placed in a microwave reactor. The wattage was set for 200 W until the temperature reached 150° C. and then the temperature was held at 150° C. for ten minutes. The tubes were then cooled to room temperature, combined, poured into H2O (50 mL), and extracted with EtOAc (100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 15% CH2Cl2/hexanes afforded 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile as a light yellow oil. Rf=0.65 (25% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 7.97 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 3.82 (s, 3H), 2.93 (m, 1H), 1.27 (d, J=7.0 Hz, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]2[CH:25]=[CH:24][C:12]([C:13]([NH:15][C@H:16]([C:21]([OH:23])=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])=[C:11]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:10]=2)[CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:44](O)[CH2:45][CH:46]([CH3:48])[CH3:47].[O-]CC.[Na+]>C1COCC1>[CH2:44]([O:22][C:21](=[O:23])[C@H:16]([CH2:17][CH2:18][S:19][CH3:20])[NH:15][C:13](=[O:14])[C:12]1[CH:24]=[CH:25][C:9]([NH:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:10][C:11]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:45][CH:46]([CH3:48])[CH3:47]
Reactant: CSCC[C@H](NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1)C(=O)O
Reactant: CC(C)CCO
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1)C(=O)OCCC(C)C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
[4-(3-pyridylmethylamino)-2-phenylbenzoyl]methionine (200 mg, 0.46 mmol), prepared as in Example 192, carbonyldiimidazole (74 mg, 0.46 mmol), and isoamyl alcohol (40 mg, 0.46 mmol) were combined in 10 mL THF. After 2 hours at room temperature, sodium ethoxide (2.68 M in ethanol, 0.02 mmol) was added. After an additional 18 hours, the mixture was evaporated to dryness, partitioned between ethyl acetate and water, washed with water and brine, dried over Na2SO4, and chromatographed (Ethyl acetate) to give [4-(3-pyridylmethylamino)-2-phenylbenzoyl-L-methionine isoamyl ester (90 mg). MS m/e 506 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 0.90 (d, J=7 Hz, 6H), 1.48 (m, 2H), 1.64 (m, 4H), 1.88 (m, 1H), 2.01 (s, 3H), 2.11 (t, J=7 Hz, 2H), 4.08 (m, 2H), 4.42 (s, 2H), 4.60 (m, 1H), 5.87 (d, J=8 Hz, 1H), 6.51 (d, J=3 Hz, 1H), 6.63 (m, 1H), 7.28-7.44 (m, 5H), 7.68 (m, 2H), 8.55 (m, 1H), 8.63 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][CH2:8][CH3:9])[CH2:6][O:5][CH2:4]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>>[CH3:10][S:11]([O:1][CH2:2][C:3]1([CH2:7][CH2:8][CH3:9])[CH2:6][O:5][CH2:4]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC1(CO)COC1
Product: CCCC1(COS(C)(=O)=O)COC1

Procedure:
3-n-Propyloxetan-3-ylmethyl methanesulphonate was prepared from 3-hydroxymethyl-3-n-propyloxetane and methanesulphonyl chloride using methodology outlined in stage i) of Example II.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:29])[N:22]([CH3:28])[C:23](=[O:27])[N:24]([CH3:26])[CH:25]=2)=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[ClH:31]>O1CCOCC1>[ClH:31].[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:29])[N:22]([CH3:28])[C:23](=[O:27])[N:24]([CH3:26])[CH:25]=2)=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)cc1
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
A solution of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester (1.94 mmol, 0.811 g) in dioxane (5 mL) was treated with 4.0 N (5 mL, 20 mmol) hydrochloric acid in dioxane at room temperature and the solution was stirred for 0.5 h. By this time, a light yellow precipitate slowly formed. The solids were collected by filtration and were washed with hexane to afford 412 mg (60% yield), mp 187-193° C. The mother liquour was concentrated under vacuum and the residue was triturated with dichloromethane. The combined solids, which contained some starting material, were combined and dissolved in methanol. The major portion of the methanol was evaporated and dichloromethane was added to form a precipitate. The solids were collected and dried to obtain 330 mg (48%) of 4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (mp 187-193° C.). EI-HRMS m/e calcd for C16H19N3O4 (M+H) 318.1454, found 318.1447.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:28])[C:7]=2[CH:29]=1.Cl.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:37][CH2:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:38])=[O:24])=[CH:26][CH:27]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:28])[C:7]=2[CH:29]=1
Reactant: CCOC(=O)CCN
Reactant: CCCCCCC(Nc1ccc(C(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)OCC)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a mixture of 4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptyl]amino}benzoic acid (300 mg) synthesized above, β-alanine ethyl ester hydrochloride (175 mg), 1-hydroxybenzotriazole monohydrate (175 mg), triethylamine (318 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (219 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-100% ethyl acetate/hexane) to give the title object compound (320 mg, 85%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]([OH:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC(O)C(NCC2C=CC=CC=2)C1)=O)(C)(C)C.C(N(CC)CC)C.[Cl:52][CH2:53][C:54](Cl)=[O:55]>C(Cl)Cl>[CH2:15]([N:14]([C:54](=[O:55])[CH2:53][Cl:52])[CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]1[OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(O)C1
Reactant: O=C(Cl)CCl
Agent: CC(C)(C)OC(=O)N1CCC(O)C(NCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)C(=O)CCl)C(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl-4-(benzylamino)-3-hydroxypiperidine-1-carboxylate and tert-butyl-3-(benzylamino)-4-hydroxypiperidine-1-carboxylate (153 g, 0.42 mol, crude) and triethylamine (126 g, 1.25 mol) in DCM (800 mL) was added drop wise chloroacetyl chloride (33 g, 0.45 mol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with water (300 mL) at 0° C., and extracted with DCM (500 mL×3). The organic layer was washed with brine (1 L), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford tert-butyl 4-[benzyl(chloroacetyl)amino]-3-hydroxypiperidine-1-carboxylate as a mixture of trans diastereomers which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:14][C:15]1([C:21](O)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])O.[Na+].Cl.C(N=C=NCCCN(C)C)C>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]1[O:9][C:21](=[O:22])[C:15]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:14]=1
Reactant: NC1(C(=O)O)CCCCC1
Reactant: Cc1oncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cc1oncc1C1=NC2(CCCCC2)C(=O)O1
Reaction time: 8 h
Yield: 16 %

Procedure:
1 g (7.87 mmol) of 5-methylisoxazole-4-carboxylic acid was added to 3 ml of thionyl chloride, and the mixture was stirred overnight. Under reduced pressure, the reaction solution was concentrated, and the obtained residue was added to a solution of 1.13 g (7.87 mmol) of 1-aminocyclohexanecarboxylic acid and 6.6 g (79 mmol) of sodium hydrogencarbonate in 30 ml of toluene-30 ml of water. After the mixture was stirred at room temperature overnight, the toluene layer was separated. The aqueous layer was neutralized by potassium hydrogensulfate, and it was extracted with ethyl acetate. After the obtained organic layer was washed with saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, methylene chloride was added thereto, and under ice-cooling, 332 mg (1.73 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added. After the mixture was stirred at room temperature overnight, under reduced pressure, the reaction solution was concentrated, ethyl acetate was added thereto, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 295 mg (16%) of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C>[C:24]([O:23][C:21]([NH:20][CH2:19][C@H:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:15]([O:17][CH3:18])=[O:16])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCNCC1

Procedure:
(21 mmol) of methyl(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate (prepared as described in example 17.4) in 120 ml of ethanol, degassed beforehand under a nitrogen stream. The reaction medium is then placed under a hydrogen atmospheric pressure for 24 h and then filtered through celite and thoroughly rinsed with dichloromethane. After concentration under vacuum, 6.1 g (100%) of methyl (S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate are obtained.
Reaction SMILES: C(O)(=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+].Br[C:15]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][CH2:25][C:26]2=[O:29])=[CH:21][CH:20]=1>CC(N(C)C)=O.C([O-])(=O)C(C)(C)C.[Pd+2].C([O-])(=O)C(C)(C)C.FC1C=CC(P(C2C=CC(F)=CC=2)C2C=CC(F)=CC=2)=CC=1>[Cl:34][C:31]1[CH:32]=[CH:33][C:15]2[C:20]3[CH:21]=[C:22]4[CH2:23][CH2:24][CH2:25][C:26](=[O:29])[C:27]4=[CH:28][C:19]=3[O:18][CH2:17][C:16]=2[CH:30]=1
Reactant: O=C1CCCc2ccc(OCc3cc(Cl)ccc3Br)cc21
Agent: [Pd+2]
Agent: CC(C)(C)C(=O)O
Agent: CC(C)(C)C(=O)[O-]
Solvent: CC(=O)N(C)C
Product: O=C1CCCc2cc3c(cc21)OCc1cc(Cl)ccc1-3
Temperature: 60 °C
Reaction time: 24 h
Yield: 66.4 %

Procedure:
To a 1 L flask containing palladium(II) pivalate (1.18 g, 3.8 mmol), tri(4-fluorophenyl)phosphine (1.20 g, 3.8 mmol), pivalic acid (2.33 g, 22.8 mmol) and potassium carbonate (31.8 g, 228 mmol) was added a solution of 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (27.8 g, 76.2 mmol) in dimethylacetamide (380 mL). The flask was evacuated and backfilled with argon 5 times and then stirred under argon at 60° C. for 24 hours. The reaction was cooled to room temperature and diluted with MTBE and water. The resulting biphasic mixture was stirred for 3 hours and filtered through Celite, rinsing with MTBE. The organic layer of the filtrate was separated and then washed twice with water and once with brine. The organics were then dried with magnesium sulfate, filtered, concentrated and purified by flash column chromatography (Hexanes/DCM) to yield 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (14.4 g, 67% yield) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:4]=1[CH2:5][C:6]1[NH:7][C:8]2[C:13]([N:14]=1)=[C:12]([NH2:15])[N:11]=[C:10]([NH2:16])[N:9]=2.N1C=C2C(N=CN2)=NC=1.Cl[CH2:33][CH2:34][CH2:35][C:36]#[CH:37].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:4]=1[CH2:5][C:6]1[N:7]([CH2:37][CH2:36][CH2:35][C:34]#[CH:33])[C:8]2[C:13]([N:14]=1)=[C:12]([NH2:15])[N:11]=[C:10]([NH2:16])[N:9]=2
Reactant: COc1ccc(OC)c(Cc2nc3c(N)nc(N)nc3[nH]2)c1
Reactant: C#CCCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ncc2[nH]cnc2n1
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc(OC)ccc2OC)nc2c(N)nc(N)nc21
Temperature: 50 °C
Yield: 25.1 %

Procedure:
A mixture of the purine 8-(2,5-Dimethoxy-benzyl)-9H-purine-2,6-diamine (19.0 g, 63 mmol), 5-chloro-pent-1-yne (12.3 ml, 116 mmol), and Cs2CO3 (37.8 g, 116 mmol) in DMF (180 g) was heated to 50° C. for 16 h. Filtration and washing (2×200 ml H2O) afforded some desired product (5.8 g, 25%). The mother liquor was concentrated, diluted with EtOAc, and heated to reflux for 1 h to yield additional product (6.0 g, 26%). After cooling to room temperature, addition of 1 volume hexane to the EtOAc mother liquor gave additional product (2.6 g, 11%). Final work-up (CH2Cl2:MeOH 4:1—water) yielded additional product (5.3 g, containing 1 equivalent penty-4-yn-1-ol, 18%). Rf=0.65 in 1:10 MeOH:EtOAc. 1H NMR (DMSO-d6) δ 6.92 (d, J=8.9 Hz, 1H), 6.98 (dd, J=8.9 & 3.0 Hz, 1H), 6.59 (s, J=2.9 Hz, 1H), 6.58-6.53 (br. s, 2H), 5.72-5.68 (br. s, 2H), 4.02 (s, 2H), 3.92 (t, J=7.4 Hz, 2H), 3.73 (s, 3H), 3.62 (s, 3H), 2.84 (t, J=2.5 Hz, 1H), 2.13 (td, J=7.0 & 1.7 Hz, 2H), 1.74 (quint., J=7.3 Hz, 2H); MS 367 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[N:15]([CH2:18][CH3:19])[CH2:16][CH3:17]>[Pd]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[N:15]([CH2:16][CH3:17])[CH2:18][CH3:19]
Reactant: CCN(CC)c1cc(NC)c([N+](=O)[O-])cc1C(=O)OC
Agent: [Pd]
Product: CCN(CC)c1cc(NC)c(N)cc1C(=O)OC
Yield: 94.7 %

Procedure:
5-Amino-2-diethylamino-4-methylamino-benzoic acid methyl ester (1.015 g) was prepared by following General Procedure B starting from 2-diethylamino-4-methylamino-5-nitro-benzoic acid methyl ester (1.2 g) and Pd/C (10% by weight, 120 mg). The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(CC)CC)C>CN(C=O)C>[CH2:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[N:13]=[CH:14][N:15]=2)[CH2:23][CH2:24]1)=[O:30])[CH3:33]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 82.6 %

Procedure:
Compound A2 (0.13 mmol, 50 mg), and ethyl chloroformate (0.13 mmol, 13 μL) were dissolved in DMF (1 mL) and triethylamine (0.36 mmol, 50 μL). The reaction was heated in a microwave at 80° C. for 4 minutes. The mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo provided Compound A10 as a yellow solid (50 mg, 89%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.97 (s, 1H), 8.20 (s, 1H), 7.77 (d, 2H), 7.66 (d, 2H), 5.41 (heptet, 1H), 3.96 (q, 2H), 3.47 (m, 4H), 2.88 (s, 3H), 1.72 (m, 4H), 1.08 (t, 3H). LCMS (ESI), m/z 466.3 (M+H+, 100%).