Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:19]([CH2:20]I)[CH2:18][C:17]3[C:22]4[C:9]2=[N:10][CH:11]=[N:12][C:13]=4[CH:14]=[C:15]([O:25][CH3:26])[C:16]=3[O:23][CH3:24])=[C:4]([F:27])[CH:3]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]([CH3:20])=[CH:18][C:17]3[C:22]4[C:9]2=[N:10][CH:11]=[N:12][C:13]=4[CH:14]=[C:15]([O:25][CH3:26])[C:16]=3[O:23][CH3:24])=[C:4]([F:27])[CH:3]=1
Reactant: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccc(Br)cc1F
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COc1cc2ncnc3c2c(c1OC)C=C(C)N3c1ccc(Br)cc1F
Temperature: 120 °C

Procedure:
To a solution of 4-(4-bromo-2-fluoro-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene (33 mg, 0.06 mmol) (from Example 19, Step F, supra) in toluene (7 mL) was added DBU (0.09 mL, 0.6 mmol) (Fluka). The reaction mixture was heated at 120° C. for 1 hour. The mixture was then diluted with chloroform (100 mL), and washed with H2O. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2 /Et3N (1:1:0.05) as eluent to give the desired 4-(4-bromo-2-fluoro-phenyl)-7,8-dimethoxy-5-methyl-4H-1,3,4-triaza-phenalene as a white solid. (Yield 0.027 g 100%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[N:7]2[CH2:13][CH:14]=O.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[N:7]2[CH2:13][CH2:14][N:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2c(F)cc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
(5,7-Difluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (2.1 g; 9.4 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (2.82 g; 14.1 mmol) were dissolved in a 1:1 mixture of chloroform and MeOH (60 ml:60 ml) and stirred at rt for 1 h. This was then treated with NaBH(OAc)3 (8.92 g; 42.3 mmol) and stirred for a further 1 h. More 1,1-dimethylethyl 4-piperidinylcarbamate (470 mg; 2.35 mmol) was added and the reaction stirred under the same conditions for 20 mins, this was then treated with NaBH(OAc)3 (1.98 g; 9.4 mmol) and stirred for 25 mins. More 1,1-dimethylethyl 4-piperidinylcarbamate (470 mg; 2.35 mmol) was then added and the reaction stirred for 20 mins. More NaBH(OAc)3 (500 mg; 2.38 mmol) was then added to the reaction and it was stirred overnight at rt. The solvents were then removed and the crude residue purified by column chromatography on silica gel using a 0-15% MeOH/DCM gradient to give the desired product (2 g; 52%).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:31]=[CH:32][CH:33]=2)O1>>[Si:13]([O:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:32]3[CH:31]=[C:30]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:29]=[CH:28][CH:33]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Product: CC(C)(C)[Si](C)(C)OCc1ccn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-(tert-butyldimethylsilanyloxymethyl)imidazo[1,2-a]pyrimidine (1.37 g, 4.00 mmol) was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-[7-(tert-butyldimethylsilanyloxymethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile as a yellow solid. This solid was suspended in methanol (25 ml) and treated with conc. hydrochloric acid (1 ml) and left to stir at ambient temperature for 5 min. The solution was loaded onto a cartridge of strong cation-exchange resin, eluting with methanol then with 10% conc. ammonia in methanol. The basic fractions were concentrated in vacuo and the residue purified further by chromatography on silica gel. Elution with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (2-5%) afforded 3′-(7-hydroxymethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (587 mg, 45%) as a yellow powder: δH (400 MHz, CDCl3) 1.90 (1H, s), 4.88 (2H, s), 6.91 (1H, d, J 7), 7.51 (1H, td, J 8 and 1), 7.57-7.73 (5H, m), 7.77 (1H, dd, J 1 and 1), 7.82 (1H, dd, J 8 and 1), 7.89 (1H, s), 8.94 (1H, d, J 7); m/z (ES+) 327 (M++H).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])(O)[C:5]1=[CH2:11])([CH3:3])=[CH2:2].[CH:12]([O:14]CC)=[CH2:13]>>[CH:12]([CH2:13][CH2:11][C:5]1[CH:4]([C:1]([CH3:3])=[CH2:2])[CH2:8][CH2:7][C:6]=1[CH3:10])=[O:14]
Reactant: C=COCC
Reactant: C=C(C)C1CCC(C)(O)C1=C
Product: C=C(C)C1CCC(C)=C1CCC=O
Yield: 68.5 %

Procedure:
12 drops of 85% phsophoric acid were added to a mixture, cooled to -15° C in a laboratory autoclave, of 76 g of 3-isopropenyl-1-methyl-2-methylene-cyclopentan-1-ol and 72 g of ethyl vinyl ether. After gassing with argon, the autoclave was brought, in an oil bath of 180° C, to an internal temperature of 150° C (this took about 15 minutes) and held at this temperature until a distinct drop in pressure occurred (about 100 minutes). The reaction mixture was then quenched, taken up in ether, washed with aqueous bicarbonate solution and water, the solution dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The crude product (110 g), obtained as a yellow oil, was fractionated and yielded 61 g (68%) of pure 2-(2-formylethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene having a woody, earthy fragrance; boiling point 0.2 = 64°-65° C; nD20 = 1.4888; IRfilm : νmax = 3080, 2725, 1725, 1642, 1440, 1370, 1060 and 895 cm-1.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22](O)=[O:23])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].Cl.[NH:30]([CH2:32][C:33]([OH:35])=[O:34])[CH3:31].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:15][CH2:16][C:17]([C:22]([N:30]([CH2:32][C:33]([OH:35])=[O:34])[CH3:31])=[O:23])([CH2:18][CH2:19]3)[CH2:20][CH2:21]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CNCC(=O)O
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)N(C)CC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a stirred mixture of 0.100 g (0.257 mmol) of 4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid (Example 13), 0.039 g (0.257 mmol) of sarcosine hydrochloride, 0.143 ml (1.03 mmol) of NEt3, and 2 ml anhydrous acetonitrile was added 0.103 g (0.270 mmol) of HATU. The reaction solution was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo and combined with 10 ml EtOAc and 10 ml of 10% citric acid. The aqueous layer was separated and washed twice with 10-ml portions of EtOAc. The combined organic fractions were washed with 10-ml portions of sat'd NaHCO3 and brine and conc'd in vacuo. The resultant solid was dissolved in a mixture of 5 ml of MeOH and 5 ml of 1 N NaOH and stirred for 16 h. The reaction solution was conc'd in vacuo, taken up in 10 ml of water, and washed twice with 10-ml portions of CH2Cl2. The aqueous layer was acidified with conc'd HCl and the resultant precipitate collected by suction filtration to give 0.094 g (77% yield) of an off-white solid. (MH+=460.18)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:14]([O:18][C:19]([CH:21]([O:23][NH2:24])[CH3:22])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([CH:21]([O:23][N:24]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:12])=[O:11])[CH3:22])=[O:20])([CH3:16])([CH3:15])[CH3:17]
Reactant: O=C(O)C(=O)c1ccc(O)c(Cl)c1
Reactant: CC(ON)C(=O)OC(C)(C)C
Product: CC(ON=C(C(=O)O)c1ccc(O)c(Cl)c1)C(=O)OC(C)(C)C
Yield: 96.3 %

Procedure:
2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2.0 g.) and O-(1-t-butoxycarbonylethyl)hydroxylamine (3.2 g.) were reacted according to a similar manner to that of Preparation (5-7) to give 2-(1-t-butoxycarbonylethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (3.3 g.), mp 148° to 151° C.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[NH:23]1[CH2:26][CH:25]([C:27]2[O:28][C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:24]1>>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[CH:25]1[CH2:24][N:23]([C:13]2[N:14]3[C:18]([N:19]=[C:11]4[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=24)=[CH:17][CH:16]=[N:15]3)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: c1ccc2oc(C3CNC3)nc2c1
Product: c1ccc2oc(C3CN(c4c5c(nc6ccnn46)CCNCC5)C3)nc2c1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 2-azetidin-3-yl-benzooxazole was used as the amine.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][C:12]=1[C:13]([NH2:15])=O)[CH3:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH2:8]([O:10][C:11]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)(=[O:22])=[O:21])=[CH:16][C:12]=1[C:13]#[N:15])[CH3:9]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C#N
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Triethylamine (49.1 g, 0.485 Mol) was added to a slurry of 2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)benzamide (40.9 g, 0.125 Mol) in dichloromethane (200 mL) and this mixture was cooled to 0° C. Trifluoroacetic anhydride (58.9 g, 0.28 Mol) was added dropwise over 45 min and was washed in with DCM (25 mL) before the reaction was stirred at ambient temperature for 18 h. Water (125 mL) was added to the reaction with cooling. The layers were separated and the organic phase was washed with water before evaporation. The residue was stirred with ethyl acetate (150 mL) giving a crystalline solid which was filtered off and dried under vacuum; 27.4 g, 71%. m.p.=130–131° C. M/Z=310 (M+H); 1H NMR (300 MHz, CDCl3): 1.55 (t, 3H), 2.30 (s, 3H), 2,50 (m, 4H), 3.06 (m, 4H), 4.26 (quart. 2H), 7.08 (d, 1H), 7.90 (dd, 1H), 7.97 (d, 1H)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][C:22]1([CH3:25])[CH2:24][O:23]1>>[CH3:21][C:22]([OH:23])([CH3:25])[CH2:24][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)CO1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 120 °C
Yield: 90 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.58 mmol) in 2,2-dimethyl-oxirane (3 mL) was added cesium carbonate (130 mg, 0.40 mmol). The reaction was heated at 120° C. for 30 minutes using microwave irradiation. The reaction was cooled then filtered through a plug of cotton wool, flushing with DCM. The filtrate was concentrated in vacuo giving 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol as a beige solid (620 mg, 90%). 1H NMR δ (ppm) (CDCl3): 7.82 (1 H, d, J=0.65 Hz), 7.69 (1 H, s), 4.07 (2 H, s), 1.32 (12H, s), 1.15 (6 H, s). 1 Exchangeable proton not observed
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C:19]3[CH:30]=[CH:29][C:22]4[O:23][CH:24]([CH2:27][OH:28])[CH2:25][O:26][C:21]=4[CH:20]=3)=[N:14][CH:15]=2)[N:10]([CH3:31])[C:9]1=[O:32].[S:33](Cl)([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34].N1C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C:19]3[CH:30]=[CH:29][C:22]4[O:23][CH:24]([CH2:27][O:28][S:33]([C:36]5[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=5)(=[O:35])=[O:34])[CH2:25][O:26][C:21]=4[CH:20]=3)=[N:14][CH:15]=2)[N:10]([CH3:31])[C:9]1=[O:32]
Reactant: CN1C(=O)N(c2ccccc2Br)Cc2cnc(Nc3ccc4c(c3)OCC(CO)O4)nc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3cc(Nc4ncc5c(n4)N(C)C(=O)N(c4ccccc4Br)C5)ccc3O2)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
520 mg of the product from example 1 were dissolved in 20 ml CHCl3. 213 mg tosyl chloride and 13 mg 4-dimethylaminopyridine were added and the mixture was cooled to 5° C. 166 mg pyridine were added dropwise and stirring was continued at room temperature for 3 hrs. The mixture was stirred 1 hr at 60° C., then another 105 mg tosyl chloride were added and stirring was continued at room temperature for 16 hrs. The mixture was diluted with 50 ml CHCl3 and washed with 0.5 M HCl, dried and evaporated. Chromatography on silica yielded 180 mg of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCC[P:19]([Cl:21])[Cl:20])C=CC=CC=1>>[C:1]1([CH2:7][CH2:8][P:19]([Cl:21])[Cl:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)CCCc1ccccc1
Reactant: BrCCc1ccccc1
Product: ClP(Cl)CCc1ccccc1

Procedure:
This compound was prepared from 2-phenylethylbromide (230g, 1.24 mole) by the method described above for the preparation of 3-phenylpropylphosphonous dichloride. 2-Phenylethylphosphonous dichloride was obtained as a pungent colourless liquid (115g, 45%), b.p. 64-66 at 0.001 mm.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:36]([O:38][CH3:39])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH:40]1[CH:45]=[CH:44][C:43]([CH2:46][O:47][C:48]([NH:50][C@H:51]([C:56](OC2C=CC([N+]([O-])=O)=CC=2)=[O:57])[CH2:52][C:53]([NH2:55])=[O:54])=[O:49])=[CH:42][CH:41]=1>CN(C)C=O>[NH:50]([C:48]([O:47][CH2:46][C:43]1[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=1)=[O:49])[C@H:51]([C:56]([NH:1][C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:36]([O:38][CH3:39])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[O:57])[CH2:52][C:53](=[O:54])[NH2:55]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
5.4 g of H-Lys(BOC)-Phe-His-OMe (compare Example 1) and 4.5 g of Z-Asn-ONP in 20 ml of dimethylformamide are stirred for 20 hours at room temperature. The peptide derivative is precipitated by adding ethyl acetate, filtered off and washed with ether. After recrystallisation from methanol the product melts at 182°-183°C. In a thin layer chromatogram RF100 = 0.57 (on silica gel). [α]D20 = -28° (c = 1 in dimethylformamide).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:20])[C@H:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:21]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:22]([C:30](O)=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[CH2:36]([O:35][C:33]([NH:21][C@@H:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]([NH:12][C@@H:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:20])=[O:31])=[O:34])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
A solution of L-PHENYLALANINE BENZYL ESTER HYDROCHLORIDE (2 g, 6.85 mmol), Z-Phe-OH (2.257 g, 7.54 mmol), DIPEA (2.99 mL, 17.14 mmol) and DCM (100 mL) was treated with 1-HYDROXY-7-AZABENZOTRIAZOLE (1.120 g, 8.23 mmol) and EDC (1.577 g, 8.23 mmol) and stirred at rt for 15 h. The mixture was washed with saturated NaHCO3 (2×100 mL), 1 M HCl (2×50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-benzyl 2-((S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanamido)-3-phenylpropanoate (3.2 g, 5.96 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.42-7.11 (m, 21H), 4.96 (d, J=2.0 Hz, 4H), 4.63-4.45 (m, 1H), 4.06-3.91 (m, 2H), 3.34-2.96 (m, 3H), 2.85 (br. s., 4H)
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].C[C:8]([NH:10]C(C([O-])=O)C([O-])=O)=[O:9].[F:18][C:19]1[CH:31]=[CH:30][C:22]([CH:23]=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1>O1CCCC1.[Cl-].[Na+].O>[CH2:28]([O:27][C:25]([C@H:24]1[C@H:23]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:31][CH:30]=2)[CH2:1][C:2](=[O:4])[NH:10][C:8]1=[O:9])=[O:26])[CH3:29]
Reactant: CCOC(=O)C=Cc1ccc(F)cc1
Reactant: CC(=O)NC(C(=O)[O-])C(=O)[O-]
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C(=O)NC(=O)C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
Potassium t-butoxide (1.01 g) was added to a solution of ethyl amidomalonate (1.38 g) in tetrahydrofuran (38 ml) maintained at 33°. After cooling to 25°, ethyl 4-fluorocinnamate (1.50 g) was added and the mixture stirred overnight at room temperature. Brine was added, the mixture extracted with ethyl acetate (3×60 ml) and the organic solution dried and evaporated to give the crude product. This was chromatographed on silica gel, using dry ether as eluent, to give the title compound (0.92 g, 43%), m.p. 97°-99°.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH3:40])[C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>>[C:37]([N:36]([CH3:40])[C:33]1[CH:34]=[CH:35][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)N(C)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(N(C)C(C)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (650 mg, 1.04 mmol) is coupled to aryl bromide 62 (238 mg, 1.04 mmol) using Method A to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[C:15]1([C:21]2[CH:31]=[CH:30][C:24]([CH:25]=[CH:26][C:27](O)=O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:27](/[CH:26]=[CH:25]/[C:24]3[CH:30]=[CH:31][C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:22][CH:23]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2)cc1
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(-c4ccccc4)cc3)nc2n(CC)c1=O
Yield: 39 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.12 g (13.9 mmol) of 4-phenylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.90 g (yield 39%) of Compound 163 as yellow flocculent precipitates.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.O[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][O:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:30][CH:31]4[CH2:35][CH2:34][CH2:33][O:32]4)=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: OCC1CCCO1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCC3CCCO3)cc2)cc1
Yield: 62.6 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl](4-hydroxyphenyl)methanone (390 mg, 1 mmol) and 2-hydroxymethyl tetrahydrofuran (153 mg, 1.50 mmol) were converted to 297 mg of the title compound by the procedure of Example 9 using 393 mg (31.5 mmol) of triphenylphosphine and 0.24 mL (1.5 mmol) of diethyl azodicarboxylate the only differences being that the chromatography eluent was 3:7 ethyl acetate:hexanes.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@H:10]2[CH2:15][N:14]3[CH2:16][CH2:17][NH:18][CH2:19][C@H:13]3[CH2:12][N:11]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(N1[C@H](C2C=CC(F)=C(C#N)C=2C)CN2CCN(C(OCC3C=CC=CC=3)=O)C[C@@H]2C1)C=C>>[C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@@H:10]2[CH2:15][N:14]3[CH2:16][CH2:17][NH:18][CH2:19][C@@H:13]3[CH2:12][N:11]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@H:10]2[CH2:15][N:14]3[CH2:16][CH2:17][NH:18][CH2:19][C@@H:13]3[CH2:12][N:11]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Cc1c([C@H]2CN3CCNC[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Agent: C=CCN1C[C@H]2CN(C(=O)OCc3ccccc3)CCN2C[C@H]1c1ccc(F)c(C#N)c1C
Product: Cc1c([C@@H]2CN3CCNC[C@@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Product: Cc1c([C@H]2CN3CCNC[C@@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N

Procedure:
The title compound was prepared in an analogous fashion to that described for the synthesis of (3S,9aS)-tert-butyl 3-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate starting from (7R,9aS)-benzyl 8-allyl-7-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (obtained from the synthesis of (3S,9aR)-tert-butyl 3-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate). LC/MS: 375.14 (M+1)+.