Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[N:32]([CH:33]5[CH2:35][CH2:34]5)[CH:31]=[N:30][N:29]=4)[CH:23]=3)=[O:20])[CH:14]=2)=[CH:9][N:8]=1>CN1C=CC=CC1.O1CCCC1>[CH:33]1([N:32]2[CH:31]=[N:30][N:29]=[C:28]2[C:24]2[CH:23]=[C:22]([NH:21][C:19](=[O:20])[C:15]3[CH:14]=[C:13]([C:10]4[CH:9]=[N:8][C:7]([CH:1]5[CH2:3][CH2:2]5)=[N:12][CH:11]=4)[CH:18]=[CH:17][N:16]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:35][CH2:34]1
Reactant: Br[Mg]C1CC1
Reactant: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2cnc(Cl)nc2)ccn1
Agent: CN1C=CC=CC1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2cnc(C3CC3)nc2)ccn1
Reaction time: 0.08 h
Yield: 45 %

Procedure:
Cyclopropyl magnesium bromide (0.5 M solution in tetrahydrofuran, 6.3 mL, 3 equiv) was added to a solution of 4-(2-chloropyrimidin-5-yl)-N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)picolinamide (440 mg, 1.06 mmol) and Fe(acac)3 (37 mg, 10 mol %) in N-methylpyridine (20 mL) and tetrahydrofuran (5 mL). After stirring for 5 minutes, the brown solution was quenched with 1 M hydrochloric acid (6 mL) and concentrated under reduced pressure at 70° C. The residue was purified by reverse-phase HPLC to give N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)-4-(2-cyclopropylpyrimidin-5-yl)picolinamide as a pale-yellow powder (200 mg, 45% yield).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1)#[N:2].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([OH:22])=[CH:20][C:19]=1[OH:25].B(F)(F)F.CCOCC>>[Cl:17][C:18]1[C:19]([OH:25])=[CH:20][C:21]([OH:22])=[C:23]([C:14](=[O:16])[CH2:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])=[CH:12][CH:11]=2)[CH:24]=1
Reactant: N#CCCCOc1ccc(CC(=O)O)cc1
Reactant: Oc1ccc(Cl)c(O)c1
Agent: FB(F)F
Solvent: CCOCC
Product: N#CCCCOc1ccc(CC(=O)c2cc(Cl)c(O)cc2O)cc1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
This compounds was synthesised in the same manner as described above. [4-(3-Cyano-propoxy)-phenyl]-acetic acid (0.5 g, 2.28 mmol), 4-chlororesorcinol (0.33 g, 2.28 mmol), boron trifloride etherate (5 ml). After standing for two hours a precipitate formed which was filtered, washed (water), and dried to give 4-{4-[2-(5-Chloro-2,4-dihydroxy-phenyl)-2-oxo-ethyl]-phenoxy}butyronitrile as a white solid (0.62 g, 78.7%); Rf 0.6 hexane/ethyl acetate (20/80).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13]([OH:21])=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])[S:5][C:6]=1[Cl:7].[O:22]1[C:26]2[CH:27]=[CH:28][C:29](B(O)O)=[CH:30][C:25]=2[CH2:24][CH2:23]1>>[Cl:7][C:6]1[S:5][C:4]([S:8]([NH:11][C:12]2[C:13]([OH:21])=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])=[CH:3][C:2]=1[C:29]1[CH:28]=[CH:27][C:26]2[O:22][CH2:23][CH2:24][C:25]=2[CH:30]=1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2cc(Br)c(Cl)s2)c1O
Product: O=C(O)c1cccc(NS(=O)(=O)c2cc(-c3ccc4c(c3)CCO4)c(Cl)s2)c1O
Yield: 46 %

Procedure:
The product was prepared from 3-{[(4-bromo-5-chlorothiophen-2-yl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 22) (20.6 mg, 0.050 mmol) and 2,3-dihydrobenzofuran-5-boronic acid (9 mg, 0.055 mmol) according to the General Procedure 12, described in Example 135. The title compound was obtained in 46% yield (10.6 mg). 1H NMR (500 MHz, MeOH-d4) δ ppm 3.23 (t, J=8.70 Hz, 2 H) 4.58 (t, J=8.70 Hz, 2 H) 6.76 (d, J=8.24 Hz, 1 H) 6.90 (t, J=7.95 Hz, 1 H) 7.14-7.17 (ddt, J=8.24, 1.97, 0.71 Hz, 1 H) 7.25 (dt, J=1.97, 1.30 Hz, 1 H) 7.31 (s, 1 H) 7.66 (dd, J=7.95, 1.65 Hz, 1 H) 7.74 (dd, J=7.95, 1.65 Hz, 1 H). MS (ESI+) m/z 452 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1.[OH-].[Na+].C1COCC1.CO>O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1
Reactant: CCOC(=O)CCCOc1cccc(CNC(=O)c2nc3ccccc3c(=O)[nH]2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCOc1cccc(CNC(=O)c2nc3ccccc3c(=O)[nH]2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A mixture of ethyl 4-{[3-({[(4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl]amino}methyl)phenyl]oxy}butanoate obtained in Reference Example 43 (525 mg, 1.28 mmol), 4N aqueous sodium hydroxide solution (1.6 mL), THF (10 mL), methanol (10 mL) and water (10 mL) was stirred at 100° C. for 2 hr. The mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. Water and 1N hydrochloric acid (6.41 mL) were added to the residue, and the resulting precipitate was collected by filtration, washed with water, and dried. The obtained crude crystals were recrystallized from ethanol to give the title compound as a white powder (339 mg, 69%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[F:13][C:14]1[C:15](/[CH:20]=[N:21]/[S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])=[N:16][CH:17]=[CH:18][CH:19]=1.CCOC(C)=O>C1COCC1>[F:13][C:14]1[C:15]([C@H:20]([C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)[NH:21][S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ncccc1F
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Reaction time: 4 h

Procedure:
To a stirred suspension of magnesium (170 g, 2365 mmol) in THF (1.35 L), was added 4-bromobenzotrifluoride (532 g, 2365 mmol). Stirring was continued for 4 h (caution: slightly exothermic, cooled with a water bath if needed). The solution was cannulated to a stirred solution of (S,E)-N-((3-fluoro-pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (270 g, 1182 mmol) in THF (1.3 L) at −78° C. dropwise. Stirring was continued for 1 h. The progress of the reaction was monitored by TLC (50% EtOAc in petroleum ether). After completion of the reaction, the reaction mixture was quenched with saturated aqueous NH4Cl (2.5 L), and the solution was extracted with Et2O (5×500 mL). The organic layers were combined, dried over Na2SO4, concentrated, and purified by column chromatography using silica (100-200 mesh) with 25-30% EtOAc in petroleum ether as eluent to give the title compound as a brown oil. 1H-NMR (400 MHz, CDCl3): δ ppm 8.45 (d, J=3.6 Hz, 1H), 7.73-7.78 (m, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.63 (m, 2H), 7.43-7.48 (m, 1H), 6.23 (d, J=6.8 Hz, 1H), 5.99 (d, J=6.8 Hz, 1H), 1.36 (s, 9H). MS (ESI pos. ion) m/z: 375.1 (M-O and t-Bu).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[OH:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1.O>CN(C=O)C>[OH:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: OCCC1CCCCN1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCCC4CCO)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4—(chloromethyl)phenyl]-3—(4-methylphenyl)cinnamamide (200 mg), and to the mixture was added 2—(2-hydroxyethyl)piperidine (214 mg). The mixture was stirred at room temperature for 18 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[2—(2-hydroxyethyl)piperidinomethyl]phenyl]-3—(4-methylphenyl)cinnamamide (Compound 69) (202 mg) as colorless crystals.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[O:9]C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(CCNC(=O)C(C)(C)C)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)NCCc1ccc(O)c(O)c1
Temperature: 25 °C

Procedure:
Dissolve 0.53 g. of N-[β-(3,4-dimethoxyphenyl)-ethyl]-2,2-dimethylpropionamide in 10 ml. of benzene and 15 g. of aluminum chloride. Reflux the mixture overnight (17 hours) with vigorous stirring. Cool the mixture to room temperature and, cautiously, pour the reaction mixture into dilute hydrochloric acid and ice with vigorous stirring. Separate the liquid phases and discard the benzene layer. Extract the aqueous layer with ethyl-acetate, then wash the extract with saturated sodium bicarbonate and water. Dry the extract over anhydrous sodium sulfate, filter and vaporate to a residue. Crystallize the residue from a 9:1 mixture of toluene:ethanol to obtain the title product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([O:17]C)=O)=[CH:4][CH:3]=1.[CH2:20]([NH2:23])[CH2:21][NH2:22]>O1CCOCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[NH:23][CH2:20][CH2:21][N:22]2[C:15](=[O:17])[C:11]2[N:10]([CH:14]=[CH:13][CH:12]=2)[CH2:9]3)=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(O)cc1
Solvent: C1COCCO1
Product: O=C1c2cccn2CC2(c3ccc(O)cc3)NCCN12
Yield: 86.8 %

Procedure:
To a solution of methyl 1-[2-(4-hydroxyphenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (200 mg, 0.77 mmol) in 1,4-dioxane (40 mL) was added ethane-1,2-diamine (1 mL, 15 mmol), after 48 h extra ethane-1,2-diamine (1 mL, 15 mmol) was added and the mixture heated for 48 additional hours. After that time 90% of the starting material was converted into the above product. The resulting mixture was then concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4, 12 g cartridge, gradient 0-10% MeOH in CH2Cl2) to give 10a-(4-hydroxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (180 mg, yield: 86%). ESI-MI m/z [M+H]+ 270.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:24]1[C:25]2[S:32][CH:31]=[C:30]([CH3:33])[C:26]=2[N:27]=[CH:28][N:29]=1.N12CCN(CC1)CC2>CC#N>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[O:8][C:24]1[CH:25]2[S:32][CH:31]=[C:30]([CH3:33])[CH:26]2[N:27]=[CH:28][N:29]=1
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Reactant: Cc1csc2c(Cl)ncnc12
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CC1=CSC2C(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)=NC=NC12
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
To a mixture of 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (24 mg, 0.075 mmol, Compound A of Example 3), 4-chloro-7-methylthieno[3,2-d]pyrimidine (13.8 mg, 0.075 mmol, commercially available) and 1,4-diazabicyclo[2.2.2]octane (DABCO, 8.4 mg, 0.075 mmol) was added MeCN (2 mL). The reaction was stirred at RT for 4 h and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give the title compound (11.2 mg, 31%) as a white solid. 1H NMR (CDCl3) δ 12.45 (s, 1H), 8.79 (s, 1H), 8.61 (s, 1H), 7.93 (dd, 1H, J=13.8, 2.2 Hz), 7.46 (s, 1H), 7.43 (m, 1H), 7,28 (m, 3H), 7.12 (m, 2H), 3.72 (s, 2H), 2.51 (s, 3H); MS(ESI+) m/z 471 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:34])[CH2:15][N:16]([CH2:30][C:31]([OH:33])=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[C:41](O)=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46].C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:34])[CH2:15][N:16]([CH2:30][C:31]([O:33][C:41]2[C:40]([F:43])=[C:39]([F:44])[C:38]([F:45])=[C:37]([F:46])[C:36]=2[F:35])=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:18]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)O)c2cccc(Oc3ccccc3)c2)C1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)c2cccc(Oc3ccccc3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [[2-((S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-oxo-ethyl]-(3-phenoxyphenyl)amino]acetic acid 27 (4.36 g, 9.39 mmol) in DMF (30 mL) were added pentafluorophenol (1.88 g, 10.21 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (1.96 g, 10.22 mmol). The reaction mixture was stirred overnight at room temperature. It was then diluted with ethyl acetate, washed with 10% hydrochloric acid (×2), brine (×2), dried (Na2SO4) and concentrated in vacuo. The resultant solid was evaporated twice from diethyl ether to give the title compound as a colourless, glassy solid (3.4 g, 57%) which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([O:16][CH3:17])[C:13]([OH:15])=O)[CH:8]=2)[O:3]1.[NH2:19][CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[C:20]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:13](=[O:15])[CH:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[O:3][C:2]([CH3:1])([CH3:18])[CH2:11][CH2:10]3)[O:16][CH3:17])=[CH:23][CH:22]=1)#[N:19]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccc2c(c1)CCC(C)(C)O2
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc2c(c1)CCC(C)(C)O2

Procedure:
(RS)-(2,2-Dimethyl-chroman-6-yl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2,2-dimethyl-chroman-6-yl)-2-methoxy-acetamide. Off-white semi-solid. MS 365.2 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16])([O-:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Product: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1
Yield: 78.2 %

Procedure:
Using aniline (1.50 ml, 16.5 mmol) and 3-nitrobenzoic acid (2.64 g, 15.0 mmol), the procedure of Reference Example 16 was repeated to obtain 2.84 g (78.2%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12]C(O)=O.C[Mg]Br.C(N(CC)CC)C>S(Cl)(Cl)=O.O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8](=[O:10])[CH2:12][C:11]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)O
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: C[Mg]Br
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1cnc(Cl)cn1
Temperature: 0 °C
Yield: 53 %

Procedure:
5-Chloropyrazine-2-carboxylic acid (Intermediate 44, 21 g, 0.132 mol) was taken in thionyl chloride (100 mL) which was heated to reflux for 2 h and excess thionyl chloride was distilled off under reduced pressure to obtain a residue, which was dissolved in dry tetrahydrofuran (100 mL). In another round bottom flask ethyl hydrogen malonoate (15.8 g, 0.132 mol) was dissolved in tetrahydrofuran (500 mL) which was cooled to 0° C. To the resulting solution was added methyl magnesium bromide (88 mL, 0.265 M) and stirred the reaction mixture was stirred for 30 min before triethylamine (39.9 g, 0.396 M) was added. To this reaction mixture the above prepared acid chloride mixture was added, stirred for 2 h at room temperature and tetrahydrofuran was evaporated from the reaction mixture and the water (500 mL) was added and extracted with ethyl acetate (2×200 mL). The organic layers were combined and dried over anhydrous sodium sulphate, concentrated under reduced pressure to get obtain crude product which was purified by flash column chromatography (10% ethyl acetate/pet ether) to afford 16.0 g (53.16%) of ethyl 3-(5-chloropyrazin-2-yl)-3-oxopropanoate white solid.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][CH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[N:13]2.[N+:22]([O-])([O:24]C(C)C)=[O:23]>>[Br:6][CH2:7][C:8]1[CH:17]=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[N:13]2
Reactant: COc1nc2cccc(CBr)c2nc1OC
Reactant: CC(C)O[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
25 ml of sulfuric acid are cooled to 0° C. and then 9.5 g (33.55 mmol) of 5-bromomethyl-2,3-dimethoxy-quinoxaline are added. After a further 10 minutes, 3.39 ml (1 equiv.) of isopropyl nitrate are added and the mixture is stirred at 0° C. for 1 hour. The mixture is poured onto ice, and the solid is filtered off and washed with water. The title compound is obtained in the form of a beige solid.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[F:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[C:14]([O:26][CH3:27])[C:15](=[O:25])[N:16]([CH3:24])[C:17]=3C(Cl)=O)[C:12]2=[O:28])=[CH:8][CH:7]=1>O.CC(C)=O>[NH2:1][C:17]1[N:16]([CH3:24])[C:15](=[O:25])[C:14]([O:26][CH3:27])=[C:13]2[C:18]=1[CH2:19][CH2:20][N:11]([CH2:10][C:9]1[CH:29]=[CH:30][C:6]([F:5])=[CH:7][CH:8]=1)[C:12]2=[O:28]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1c2c(c(C(=O)Cl)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1c2c(c(N)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Reaction time: 0.5 h

Procedure:
To a solution of sodium azide (0.091 g, 1.4 mmol) in 2 mL water cooled to 0° C. was add 6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carbonyl chloride (0.48 g, 1.28 mmol) in acetone (8 mL). The solution was stirred for 30 minutes, then evaporated. The residue was partitioned between CHCl3 and saturated Na bicarbonate, dried with Na2SO4, filtered and evaporated to give the crude product, which was chromatographed on silica eluting with 5% MeOH/CHCl3 saturated with NH3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)=[CH:3][CH:2]=1.[OH-].[K+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CC(C)=O.C(OCC)(=O)C>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(CCl)cc1
Reactant: c1ccc(-c2nc(Nc3ccncc3)c3ccccc3n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ccncc2)c2nc(-c3ccccc3)nc3ccccc23)cc1
Temperature: 25 °C

Procedure:
4-(4-pyridylamino)-2-phenyl quinazoline, 1 equivalent, was dissolved in reagent grade acetone, to this was added 5 equivalents of potassium hydroxide and 1.5 equivalents of 4-methoxybenzyl chloride. The mixture was refluxed under nitrogen for 4 hours. After cooling to room temperature the reaction mixture was concentrated and the residue taken up in ethyl acetate and washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate and concentrated to give an oil. This crude material was dissolved in ethyl acetate and chromatographed as in Example 1. EIMS confirmed the product.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:4]([CH:26]=[O:27])[CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:28])=[O:15])=[C:4]([CH:26]=[O:27])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CN(CCCCC(=O)O)c2cc(C)c(Br)cc2C=O)cc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCCCN(Cc1ccc(OC)cc1)c1cc(C)c(Br)cc1C=O
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of 5-((4-bromo-2-formyl-5-methylphenyl)(4-methoxybenzyl)amino)pentanoic acid (3.5 g) and potassium carbonate (1.34 g) DMF in (30 ml) was added dropwise a solution of iodomethane (1.6 g) in DMF (10 ml) under nitrogen atmosphere at 0° C. After returning to room temperature, the reaction mixture was stirred for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water five times and with saturated brine once, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give methyl 5-((4-bromo-2-formyl-5-methylphenyl)(4-methoxybenzyl)amino)pentanoate (3.5 g) as a brown oily material.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18]Cl>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:7]=[O:8])[CH3:2]
Reactant: COCCOCCl
Reactant: CCOc1cc(C=O)ccc1O
Product: CCOc1cc(C=O)ccc1OCOCCOC
Yield: 91.5 %

Procedure:
The hydroxyl group of 3-ethoxy-4-hydroxybenzaldehyde (2.0 g) was protected by use of 2-methoxyethoxymethyl chloride (1.5 g) in accordance with (production process 1), to thereby produce 3-ethoxy-4-methoxyethoxymethoxybenzaldehyde (2.8 g, yield: 91%). The thus-produced 3-ethoxy-4-methoxyethoxymethoxybenzaldehyde (2.8 g) and 3,4-dimethoxybenzyl cyanide (2.0 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.35 g, yield: 37%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([C:15]([OH:17])=[O:16])=[C:8]2[CH2:7]1)=[O:5].[OH-].[Ca+2:33].[OH-]>CO>[NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]2[C:12]([C:18]([F:21])([F:19])[F:20])=[N:13][C:14]([C:15]([O-:17])=[O:16])=[C:8]2[CH2:7]1)=[O:5].[Ca+2:33].[NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]2[C:12]([C:18]([F:21])([F:19])[F:20])=[N:13][C:14]([C:15]([O-:17])=[O:16])=[C:8]2[CH2:7]1)=[O:5]
Reactant: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: [Ca+2]
Agent: [OH-]
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)[O-])c2C1)Cc1cc(F)c(F)cc1F
Reaction time: 20 h
Yield: 99.7 %

Procedure:
(R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 3 (100 mg, 0.22 mmol) was dissolved in 10 mL of methanol followed by addition of aqueous calcium hydroxide solution (8.1 mg, 0.11 mmol). The mixture was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound calcium (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate 7 (103 mg, 100%) as a white solid. HPLC: 99.60%. MS m/z (ESI): 451.2 [M+1]. 1H NMR (400 MHz, CD3OD, ppm): δ 7.28-7.34 (m, 1H), 7.11-7.21 (m, 1H), 5.10-5.21 (m, 2H), 4.22-4.36 (m, 2H), 4.03-4.09 (m, 2H), 3.55-3.59 (m, 1H), 2.76-2.85 (m, 2H), 2.60-2.71 (m, 2H).