Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][C@H:4]([NH:6][C:7]2[C:8]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[N:12]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>C(Cl)Cl>[CH3:19][N:17]1[CH:18]=[C:14]([NH:13][C:11]2[N:12]=[C:7]([NH:6][C@H:4]3[CH2:3][C@H:2]([NH:1][C:40](=[O:43])[CH:41]=[CH2:42])[CH2:5]3)[C:8]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:9]=3[N:10]=2)[CH:15]=[N:16]1
Reactant: Cn1cc(Nc2nc(N[C@H]3C[C@H](N)C3)c3ccn(COCC[Si](C)(C)C)c3n2)cn1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1C[C@H](Nc2nc(Nc3cnn(C)c3)nc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N4-((trans)-3-aminocyclobutyl)-N2-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (87 mg, 0.2 mmol) was dissolved in DCM (5 mL). DIPEA (53 μL, 0.3 mmol) was added and the reaction was cooled to 0° C. Acryloyl chloride (16 μL, 0.2 mmol) was added via a 10 μL syringe and the reaction was allowed to stir at 0° C. for 1 hr. The reaction was concentrated and purified via flash chromatography eluting with a gradient of 1%-20% EtOH in DCM. The fractions containing the product were pooled and dried down to afford the title compound as a tan solid (confirmed to be product by LCMS). This tan solid was taken directly to the final step.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl:15][C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)(=O)C.O.O1CCCC1>[Cl:15][C:16]1[O:20][C:19]([CH:21]([OH:22])[C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(O)c2ccc(Cl)o2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.4 %

Procedure:
To a mixture of 4-iodobenzonitrile (3.0 g, 13 mmol) and tetrahydrofuran (40 mL) was added dropwise isopropyl magnesium chloride (1-2 M diethyl ether solution, 11 mL, 11-22 mmol) at −78° C., which was stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., 5-chloro-2-furaldehyde (2.2 g, 17 mmol) was added at that temperature, and the temperature was gradually raised to 0° C. Following 30 minutes of stirring at 0° C., saturated aqueous ammonium chloride solution, water and ethyl acetate were added to extract the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. Ethyl acetate was added to the residue, which was then filtered with NH silica gel. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.2 g) as a crude product. This compound was used in the subsequent reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([CH2:16]C(O)=O)#[N:15].C(=O)=O>C(O)(=O)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:16][C:14]#[N:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C=NCC2
Reactant: N#CCC(=O)O
Agent: O=C=O
Solvent: CC(=O)O
Product: N#CCC1NCCc2ccc([N+](=O)[O-])cc21
Yield: 76.2 %

Procedure:
A suspension of 7-nitro-3,4-dihydroisoquinoline (13.4 g, 76.1 mmol) and cyanoacetic acid (12.5 g, 150 mmol) in acetic acid (55 ml) was heated at reflux for 0.5 h. After evolution of carbon dioxide had ceased and the reaction mixture had cooled, the solvent was removed on the rotoevaporator. The residue was triturated with isopropanol (100 ml) and the solid was collected. The crude product was partitioned between ethyl acetate and dilute potassium carbonate solution. The dried (MgSO4) organic phase was concentrated to give the title compound as an orange solid (12.6 g, 76%), MS 218 (M+H)+. 1H NMR (CDCl3) 8.03 (dd, 1H), 7.99 (d, 1H), 7.31 (d, 1H), 4.45 (t, 1H, 3.1-3.4 (m, 3H), 2.9-3.0 (m, 3H), 2.07 (broad s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:18]([CH3:20])[CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:47](=O)([O-])[O-:48].[Cs+].[Cs+]>CO.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:18]([CH3:20])[CH3:19])=[N:15][C:16]([O:48][CH3:47])=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1nc(C(C)C)n2c1C(CCc1ccc(C(F)(F)F)cc1)N(C(=O)OC(C)(C)C)CC2

Procedure:
A solution of 1-iodo-3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (150 mg; 0.266 mmol) in anhydrous MeOH (3 ml) was treated successively with copper(I) iodide (5 mg; 0.026 mmol), 1,10-phenanthroline (10.5 mg; 0.053 mmol), and cesium carbonate (138.8 mg; 0.426 mmol). The resulting brown suspension was sealed and put in the microwave oven (35 W; 100° C.; 6 bars; 1 h). This microwave-assisted methoxylation was repeated two additional times with the same amount of starting material. The resulting mixed brown suspension was concentrated to dryness under reduced pressure and the crude was purified by preparative HPLC. The expected product 3-isopropyl-1-methoxy-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester was obtained as a yellow oil (107.5 mg; 29%). LC-MS: tR=0.94 min.; [M+H]+=468.55 g/mol.
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:20])[NH:15]3)=[CH:7][CH:6]=1.Cl>CO.O.C(O)(=O)C.[Pt](=O)=O>[NH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:20])[NH:15]3)[CH2:9][CH2:10]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2C2CCNCC2)N1
Reaction time: 72 h
Yield: 95.2 %

Procedure:
To a suspension of 4-pyridin-4-yl-1,3-dihydroindol-2-one acetic acid salt (5.50 g, 20.4 mmol) in methanol (160 mL), water (70 mL) and acetic acid (30 mL) was added concentrated hydrochloric acid (2 mL) followed by platinum(IV) oxide (360 mg). The mixture was hydrogenated for three days. It was then filtered through celite, which was washed with methanol. The filtrate was evaporated and dried under high vacuum. The residue was dissolved in methanol (500 mL) and treated with a basic resin (hydroxide form) at pH=9–10. The resin was removed by filtration and washed with methanol. The filtrate was evaporated and dried under high vacuum to give 4.2 g (96%) of 4-piperidin-4-yl-1,3-dihydroindol-2-one.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:16](=[C:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[N:18]3)[NH:15][S:14](=[O:24])(=[O:23])[C:13]1[C:8]2=[CH:9][C:10]([C:25](O)=[O:26])=[CH:11][CH:12]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(Cl)Cl>[CH3:1][N:2]([CH3:3])[C:25]([C:10]1[CH:9]=[C:8]2[C:13]([S:14](=[O:24])(=[O:23])[NH:15][C:16]3[C:7]2=[CH:6][C:5]([Cl:4])=[C:22]2[C:17]=3[N:18]=[CH:19][CH:20]=[CH:21]2)=[CH:12][CH:11]=1)=[O:26]
Reactant: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
Dimethyl amine (0.2M in THF, 2.77 ml, 0.69 mmol) was added to a solution of 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 524 (100 mg, 0.27 mmol), EDC.HCl (80 mg, 0.41 mmol), HOBt (56 mg, 0.41 mmol) and TEA (0.12 ml, 0.83 mmol) in DMF (1 ml) and the mixture was stirred at room temperature for 12 h. The mixture was diluted with water and DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with chloroform/MeOH (95:5) as the eluent to give the title compound (45 mg, 42%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[C:27]([CH3:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C1COCC1.CN(C=O)C>[F:32][C:31]1[C:26]([NH:25][C:13](=[O:15])[C:12]2[CH:16]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=[C:10]([CH3:18])[C:11]=2[CH3:17])=[C:27]([CH3:34])[C:28]([OH:33])=[CH:29][CH:30]=1
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)O)c1C
Reactant: Cc1c(O)ccc(F)c1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2C)c1C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 5-(3-fluorophenyl)-2,3-dimethyl-benzoic acid (intermediate III(m)) (500 mg, 2.0 mmol, 1.0 eq) in CH2Cl2 (10 mL) at 0° C. was added oxalyl chloride (770 mg, 6.1 mmol, 3.0 eq) and DMF (0.1 mL) and the reaction was stirred for 1 h. The solvent and excess reagent were removed under reduced pressure and the residue obtained was dissolved in THF (10 mL) and added to a mixture of 3-amino-4-fluoro-2-methyl-phenol (intermediate X(e)) (280 mg, 2.0 mmol, 1.0 eq) and Na2CO3 (860 mg, 8.1 mmol, 4.0 eq) in THF (10 mL) at 0° C. The reaction was stirred for 3 h, then filtered and concentrated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 400:1 to 4:3) to give the title compound as a brown solid (300 mg, 40%).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:22].CCCCCC.C(OCC)(=O)C>ClCCl>[CH:5]12[O:22][CH:4]1[CH2:3][CH2:2][N:1]([C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[CH2:6]2
Reactant: O=C(OCc1ccccc1)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(OCc1ccccc1)N1CCC2OC2C1
Temperature: 25 °C

Procedure:
A stirred solution of benzyl 3,6-dihydropyridine-1(2H)-carboxylate (20.0 g, 92.0 mmol) in dichloromethane (280 ml) was cooled to 0° C. A solution of m-chloroperoxybenzoic acid (22.5 g, approx. 130 mmol) in dichloromethane (560 ml) was added drop-wise and the resulting colourless reaction mixture warmed to room temperature. After an additional 4 h at room temperature (reaction complete by tlc using 50:50 hexane:ethyl acetate as eluent.) the reaction mixture was washed with aqueous potassium carbonate solution (5 wt %, 3×200 ml) and brine (200 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to furnish benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate as a yellow oil (22.0 g; 100%).
Reaction SMILES: CN(C)CCCN=C=NCC.[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16].[CH2:21]([O:23][CH:24]([O:28][CH2:29][CH3:30])[C:25]([O-])=[O:26])[CH3:22].[Na+].O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][C:25](=[O:26])[CH:24]([O:28][CH2:29][CH3:30])[O:23][CH2:21][CH3:22]
Reactant: CCOC(OCC)C(=O)[O-]
Reactant: NCc1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)C(=O)NCc1ccccc1Br
Reaction time: 18 h

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (1.15 g, 6.00 mmol) was added to a mixture of 2-bromobenzylamine (0.744 g, 4.00 mmol), sodium 2,2-diethoxyacetate (0.816 g, 4.80 mmol), 1-hydroxybenzotriazole hydrate (0.919 g, 6.00 mmol) and Hunig's base (1.53 mL, 8.80 mmol) in DMF (10 mL) with stirring. After 18 hours at room temperature, the mixture was partitioned between water and ethyl acetate. The organic layer was washed successively with 2 M HCl, saturated sodium bicarbonate solution and brine, then dried (Na2SO4) and concentrated to a viscous colourless oil (1.02 g, 81%). LC-MS (1) Rt==2.23 min; m/z (ESI+) 316 & 318 (M+H+).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26]([NH:28][C@@H:29]([CH2:33][CH2:34][NH2:35])[C:30]([OH:32])=[O:31])=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH:20]1[C:21]2[CH:22]([CH2:24][O:25][C:26]([NH:28][C@@H:29]([CH2:33][CH2:34][NH:35][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[C:30]([OH:32])=[O:31])=[O:27])[C:23]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(Cl)C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CCNC(=O)C1CCCC1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopentanecarbonyl chloride (78 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and of NaOH (1N, 0.7 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude materials were purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (84.1 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:27]=[C:28]=[O:29])(C)[CH2:22][CH:21]=1.F[C:31]1C=CC(C)=CC=1N=C=O>>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28]([NH:27][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[C:25]([CH3:31])[CH:24]=3)=[O:29])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Reactant: CC1(N=C=O)C=CC(F)=CC1
Product: Cc1cc(NC(=O)Nc2ccc(-c3cncc4c3c(N)nn4C)cc2)ccc1F

Procedure:
The title compound was prepared using the procedure described in Example 1E using the product from Example 6A and 1-fluoro-4-isocyanato-4-methyl-benzene instead of the product from Example 1D and 1-fluoro-2-isocyanato-4-methyl-benzene. MS (ESI(+)) m/e 391 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.22 (d, J=1.70 Hz, 3H) 4.02 (s, 3H) 7.06 (t, J=9.15 Hz, 1H) 7.24-7.33 (m, 1H) 7.35-7.43 (m, 1H) 7.52 (d, J=8.81 Hz, 2H) 7.67 (d, J=8.81 Hz, 2H) 8.10 (s, 1H) 8.77 (s, 1H) 8.99 (s, 1H) 9.21 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3]1.S(Cl)([Cl:10])=O.[CH3:12]O>>[ClH:10].[CH3:12][O:6][C:5]([C:2]1([NH2:1])[CH2:4][CH2:3]1)=[O:7]
Reactant: NC1(C(=O)O)CC1
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)C1(N)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
1-aminocyclopropanecarboxylic acid (1.46 g, 14.45 mmol) and methanol (50 ml) were charged. An ice bath was set and thionyl chloride (2.6 ml, 36.12 mmol) was slowly added thereto. Then, the ice bath was removed, and the mixture was stirred at room temperature for 4 hours. The resultant product was vacuum-distilled to remove a solvent, and dried in a 60° C. oven so as to obtain methyl-1-aminocyclopropanecarboxylate hydrochloride (2.08 g, 13.72 mmol, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]3[C:18]=2[CH2:19][C:20]([OH:22])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH:30][CH2:31][CH2:32][O:33][CH3:34]>>[ClH:1].[CH3:34][O:33][CH2:32][CH2:31][N:30]([CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)[C:20](=[O:22])[CH2:19][C:18]1[N:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]2=[N:10][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: COCCNCc1ccccn1
Reactant: Cc1ccn2c(CC(=O)O)c(-c3ccc(Cl)c(Cl)c3)nc2c1
Product: COCCN(Cc1ccccn1)C(=O)Cc1c(-c2ccc(Cl)c(Cl)c2)nc2cc(C)ccn12
Product: Cl
Yield: 68.6 %

Procedure:
According to the method of Example 14, 2-(3,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-(2-pyridinylmethyl)-2-methoxyethylamine were used as raw materials for synthesis, to obtain light yellow solid powder, yield 68.6%. m.p. 236-238° C., ESI-MS m/z: 484[M+H]+, 1H NMR(DMSO-d6, 400 MHz)δ: 2.57(s, 2H), 2.60(s, 1H), 3.16(s, 1H), 3.27(s, 2H), 3.40(t, 0.7H, J=4.76 Hz), 3.47(t, 0.7H, J=4.76 Hz), 3.60(t, 1.3H, J=4.76 Hz), 3.84(t, 1.3H, J=4.76 Hz), 4.56(s, 0.7H), 4.66(s, 1.3H), 4.84(s, 1.3H), 4.93(s, 0.7H), 7.43-7.50(m, 1H), 7.62-7.65(dd, 1H, J=8.40 Hz, 2.24 Hz), 7.69-7.81(m, 2H), 7.88-7.90(d, 1H, J=8.40 Hz), 7.92-7.93(d, 1H, J=2.24 Hz), 7.95(s, 1H), 8.62-8.78(m, 2H), 8.76-8.84(m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH3:23])=[O:21]>ClCCl>[CH3:23][O:22][C:20](=[O:21])[NH:12][C:10]1[O:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1
Reactant: COC(=O)Cl
Reactant: COc1cccc2oc(N)nc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1nc2c(OC)cccc2o1
Reaction time: 3.5 h
Yield: 52.9 %

Procedure:
To a stirred solution of 65 g (40 mmol) 4-methoxy-benzooxazol-2-yl-amine and 4.5 ml (56 mmol) pyridine in 250 ml dichoromethane at 0° C. was added dropwise a solution of 4.1 ml (49 mmol) methyl chloroformate in 50 ml dichoromethane and stirring continued for 3.5 hours. The mixture was then poured onto water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (dichloromethane) afforded 4.7 g (54%) (4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester as an off-white crystalline solid. EI-MS m/e (%): 222 (M+, 100), 190 (27), 163 (23).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[CH3:32].C(O)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[CH3:32])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Yield: 41.6 %

Procedure:
A mixture of 0.0398 g (0.00013 mole) of 2-chloro-9-cyclopentyl-5,7,7-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-38), 0.022 g (0.000143 mole) of 4-amino-3-methylbenzoic acid, 0.7 mL of ethanol, 2.8 mL of water and 3 drops of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the white precipitate that formed was collected by filtration to give 0.0229 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-56a) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][NH:14][CH2:15][C@@H:16]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:27]([CH2:39][OH:40])[CH:26]=2)[O:17][Si](C(C)(C)C)(C)C)[CH:7]=1)[CH3:2].[F-].[NH4+]>CO.O>[NH3:14].[CH2:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([C@@H:16]([OH:17])[CH2:15][NH:14][CH2:13][CH2:12][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:41])[CH:11]=[CH:10][CH:9]=2)=[CH:26][C:27]=1[CH2:39][OH:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)Cc1cccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCOC(=O)Cc1cccc(CCNC[C@H](O)c2ccc(OCc3ccccc3)c(CO)c2)c1
Product: N
Temperature: 40 °C
Yield: 198 %

Procedure:
A solution of ethyl(3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]ethyl}phenyl)acetate (Preparation 54) (2.39 g, 4.14 mmol) in methanol (15 ml) and water (10 ml) was treated with ammonium fluoride (1.53 g, 41.4 mmol) and the reaction heated to 40° C. for 16 hours. The methanol was removed in vacuo and the aqueous residue extracted with dichloromethane (3×50 ml). The combined organics were dried (sodium sulfate) and the sovent removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (97:3:0.3 changing to 95:5:0.5, by volume) to give the title compound as an orange gum (1.90 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.P(Br)(Br)[Br:11]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Br:11]
Reactant: BrP(Br)Br
Reactant: OCc1cccc(Cl)c1
Solvent: C1CCOC1
Product: Clc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 260 ul of 3-chlorobenzyl alcohol dissolved in 2.5 ml of dry tetrahydrofuran is cooled to 0° C. and 120 ul of PBr3 added. The reaction is stirred for 3 hours and extracted with ether. The organic layer is washed with saturated sodium bicarbonate and evaporated to give the desired product.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14].C(N(CC)CC)C>ClCCl>[CH3:15][C:13](=[CH2:14])[C:12]([O:8][C@@H:6]1[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[CH:9]([CH3:11])[CH3:10])=[O:16]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
In a 100 ml flask, equipped with a magnetic stirrer, 5.0 g of L-(−)-menthol and 3.51 g of methacryloyl chloride were added to a solution of 6.67 ml of triethylamine in 30 ml of dichloromethane at room temperature. The clear solution turned turbid after a few minutes (exothermic reaction). After 4 hours, the suspension was extracted with 25 ml of 0.5 N HCl, 25 ml of water, 25 ml of saturated aqueous NaHCO3 and 25 ml of brine to give a clear orange solution (after drying over Na2SO4). Concentrating at reduced pressure gave a light brown/orange oil, which was stored overnight at 4° C. Purification by column chromatography (eluens:ethyl acetate/heptane=1/4) gave 5.30 g (73.8%) of a colourless oil. 1H-NMR confirmed the expected structure.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl.C(OCC)(=O)C>[C:31]([NH:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Of the compound from Example 22A, 75 mg (0.25 mmol) were introduced in 2.5 ml of dichloromethane together with 60 μl (0.35 mmol) of N,N-diisopropylethylamine and admixed at RT with 21 μl (0.30 mmol) of acetyl chloride. The mixture was stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate and washed in succession twice each with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and then with saturated aqueous sodium chloride solution, dried over sodium sulphate and freed from the solvent on a rotary evaporator. Further drying in an HV gave 88 mg of the title compound (100% of theory).