Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[C:9]([C:17]([OH:19])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.[CH3:22][O:23]C1C=CC(OC)=CC=1C1C(C(OC)=O)=CC([N+]([O-])=O)=CC=1>>[CH3:21][O:20][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[C:8]1[C:9]([C:17]([OH:19])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[C:12]([O:23][CH3:22])[CH:13]=1
Reactant: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(OC)ccc1OC
Product: COc1ccccc1-c1cc(OC)c([N+](=O)[O-])cc1C(=O)O
Yield: 99 %

Procedure:
This compound was prepared in a manner similar to that of 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl 2',5'-dimethoxy-4-nitro-2-biphenylcarboxylate (2.07 g) to afford 1.93 g (99%) of 2',5-dimethoxy-4-nitro-2-biphenylcarboxylic acid as a white solid. Data for 2',5'-dimethoxy-4-nitro-2-biphenylcarboxylic acid: 1H NMR (400 MHz, acetone-d6) 8.64 (d, J=2.5, 1H), 8.43 (dd, J=8.4, 2.6, 1H), 7.67 (d, J=8.5, 1H), 6.94 (m, 2H), 3.80 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:22][C:12]2=[C:13]3[N:18]([N:19]=[C:11]2[CH2:10]1)[C:17]([CH3:20])=[C:16]([Cl:21])[CH:15]=[N:14]3)=O)(C)(C)C>CC(O)=O.C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[N:14][C:13]2[N:18]([N:19]=[C:11]3[CH2:10][NH:9][CH2:22][C:12]3=2)[C:17]=1[CH3:20]
Reactant: Cc1c(Cl)cnc2c3c(nn12)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1c(Cl)cnc2c3c(nn12)CNC3
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A 32% solution of HCl (0.14 mL) was added to a solution of 6-chloro-7-methyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (140 mg; 0.44 mmol; 1 eq.) in AcOH (0.5 mL) and the reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with DCM, washed with 1M NaOH (2×), dried over sodium sulfate and concentrated in vacuo to afford the title compound (80 mg, 86%) as a yellow solid. 1H NMR (DMSO-d6) δ 8.48 (s, 1H), 4.12-4.03 (m, 4H), 3.73-3.57 (m, 1H), 2.80 (s, 3H). HPLC (max plot) 99.6%, Rt 1.33 min. UPLC/MS: (MS+) 209.1 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=O)=[CH:11][C:10]=1[OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:54][C:55]([CH3:61])([CH3:60])[C:56]([O:58][CH3:59])=[O:57].C(N(CC)C(C)C)(C)C>CC(N(C)C)=O.O.C(OCC)(=O)C>[CH3:59][O:58][C:56](=[O:57])[C:55]([NH:54][C:17](=[O:19])[C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([OH:28])[CH:11]=1)([CH3:61])[CH3:60]
Reactant: COC(=O)C(C)(C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(O)c1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)C(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(S)-3-(4-benzyloxy-3-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid (465 mg) was dissolved in anhydrous DMA (5 ml) and HBTU (910 mg) added in portions followed by methyl 2-aminoisobutyrate hydrochloride (366 mg). N,N-Diisopropylethylamine (0.4 ml) was added and the solution stirred at room temperature for 3 days. The mixture was diluted with water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with dil HCl, with aq sodium bicarbonate with water and with brine. Drying (MgSO4) and evaporation of solvent gave the crude 2-[(S)-3-(4-benzyloxy-3-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionylamino]-2-methyl-propionic acid methyl ester as a gum, 690 mg; HPLC/MS retention time 5.77 min, m/z 487.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:9]([O:22][CH3:23])[C:8]([Cl:24])=[C:7]([CH3:25])[C:6]=1[C:26](=[O:28])[CH3:27].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:24][C:8]1[C:7]([CH3:25])=[C:6]([C:26](=[O:28])[CH3:27])[C:5]([O:4][CH2:3][CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:9]=1[O:22][CH3:23]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccc(F)cc1
Reactant: C1COCCN1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCOCC2)c1OCCCc1ccc(F)cc1
Yield: 26 %

Procedure:
Example 1e (83 mg, 0.18 mmol) was reacted with morpholine (3 mL) as described under General Procedure G and the crude mixture was purified by flash chromatography (silica-gel, DCM/EtOAc/MeOH 1:0:0, 9:8:2) to afford the title compound (23 mg, 26%) as light creamy oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.13 (m, 2H), 6.99-6.93 (m, 2H), 4.10-4.03 (m, 4H), 3.86 (s, 3H), 3.68 (t, J=4.4 Hz, 4H), 2.78 (t, J=7.6 Hz, 2H), 2.62 (t, J=5.5 Hz, 2H), 2.51 (s, 3H), 2.46 (t, J=4.45 Hz, 4H), 2.18 (s, 3H), 2.07-1.98 (m, 2H). MS (ES+) m/z 479.9 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1(O)[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:1](=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2)[CH3:2]
Reactant: CCC1(O)CC2CCC1C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC=C1CC2CCC1C2
Yield: 78.9 %

Procedure:
In 600 ml of benzene was dissolved 125.0 g of 2-ethylbicyclo[2.2.1]heptan-2ol in endo-form. To the solution was added 8.5 g of p-toluenesulfonic acid monohydrate. This reaction mixture was heated, agitated under reflux for 6 hours while removing,water, and subjected to conventional post-treatment. The resulting oily substance was purified by silica gel column chromatography, obtaining 85.9 g of 2-ethylidenebicyclo[2.2.1]heptane. The yield was 78.8%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][O:11][C:12](=[O:19])[C:13]([CH3:18])([CH3:17])[CH2:14][CH:15]=O>C(Cl)Cl>[CH3:10][O:11][C:12](=[O:19])[C:13]([CH3:18])([CH3:17])[CH2:14]/[CH:15]=[N:8]/[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COC(=O)C(C)(C)CC=O
Solvent: ClCCl
Product: COC(=O)C(C)(C)C/C=N/CC(=O)OC(C)(C)C
Yield: 98.1 %

Procedure:
Step D In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.09 g, 8.32 mmol) was reacted with 2,2-dimethyl-4-oxo-butyric acid methyl ester (1.2 g, 8.32 mmol) in CH2Cl2 at room temperature for 18 h to give 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid methyl ester as a colorless oil (2.1 g, 100%).
Reaction SMILES: [OH-].[K+].[C:3]([NH:11][C:12]1([CH2:16][C:17]([O:19]CC)=[O:18])[CH2:15][CH2:14][CH2:13]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCO>[C:3]([NH:11][C:12]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][CH2:14][CH2:13]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC1(NC(=O)c2ccccc2)CCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1(NC(=O)c2ccccc2)CCC1
Reaction time: 1 h
Yield: 91.2 %

Procedure:
3N KOH (10 mL, 30 mmol) was added to a solution of ethyl 1-(benzoylamino)-cyclobutylacetate (3.87 g, 14.8 mmol) in EtOH (30 mL) at room temperature and the mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo and 6N HCl (5.0 mL) was added. The resulting precipitate was collected by filtration, washed successively with water and diisopropylether and dried to give the title compound (3.15 g, 91%) as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.76-1.89 (2H, m), 2.16-2.26 (2H, m), 2.28-2.40 (2H, m), 2.90 (2H, s), 7.43 (2H, t, J=6.7 Hz), 7.50 (1H, t, J=6.7 Hz), 7.83 (2H, d, J=6.7 Hz), 8.45 (1H, s), 12.00 (1H, brs).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Br)=[O:8])=[CH:5][CH:4]=1.[C:12]([O:16][C:17](=[O:31])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[CH:21][C:20]=1[NH2:30])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl.Cl>[C:12]([O:16][C:17](=[O:31])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[CH:21][C:20]=1[NH:30][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: O=C(Br)c1ccc(CBr)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CBr)cc1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
4-Bromomethyl-benzoyl bromide (0.70 g, 2.52 mmol) was made 0.21 M in anhydrous DCM and cooled to −78° C. To this stirring solution was added (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (0.73 g, 2.52 mmol) followed by DIPEA (0.98 g, 7.56 mmol). The resulting solution was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was then diluted with 0.1 N HCl and extracted with EtOAc. The organic layer was then washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO4), and concentrated in vacuo to afford the title compound: 1H NMR (DMSO-d6, 600 MHz) 9.90 (s, 1H), 8.72 (s, 1H), 7.94 (d, J=7.8. Hz, 2H), 7.78-7.80 (m, 1H), 7.57-7.62 (m, 3H), 7.47-7.51 (m, 2H), 7.42-7.44 (m, 1H), 7.09-7.12 (m, 1H), 4.77 (s, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:45][C:46](=[O:49])[CH2:47][NH2:48]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:48][CH2:47][C:46]([OH:45])=[O:49])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)NCC(=O)O)cc2)cc1

Procedure:
The product from Example 234B and glycine methyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.13-12.77 (br.s, 1 H), 8.94 (s, 1 H), 8.12 (t, 1 H), 7.24 (m, 7 H), 7.03 (t, 1 H), 6.94 (m, 6 H), 6.82 (d, 2 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.93 (t, 2 H), 3.73 (d, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.19 (t, 2 H), 1.55-1.79 (m, 4 H); MS (ESI+) m/z 646 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB(/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])O1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>O.C(O)CC>[CH3:28][O:27][CH2:26]/[CH:25]=[CH:24]/[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1cc(Br)cc2ccccc12
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCO
Product: COC/C=C/c1cc(C(=O)OC)c2ccccc2c1
Temperature: 90 °C

Procedure:
Methyl 3-bromo-1-naphthalenecarboxylate (1 eq.) and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.5 eq.) were combined in a 5:1 (v/v) mixture of DMF:n-PrOH (0.2 M). To this solution was then added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.) and the vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 N aq. Na2CO3 (2 eq.) was added and the resulting biphasic suspension was heated at 90° C. for 8 h. The now black suspension was cooled to RT, diluted with water and extracted with 1:1 (v/v) hexanes:ether. The combined organic extracts were then washed further with 1 N aq. NaOH, 1 N aq. HCl, water and brine. This was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound as a red oil.
Reaction SMILES: [F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3]([O-:5])=[O:4].O(C)[Na:11]>CO>[F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3]([O-:5])=[O:4].[Na+:11]
Reactant: CO[Na]
Agent: C=CCC(F)(F)C(=O)[O-]
Solvent: CO
Product: [Na+]

Procedure:
4,01 g (29.9 mmol) of 2,2-difluoro-4-pentenoate acid are dissolved in 20 ml of methanol, and 1 equivalent of NaOCH3 in methanol is added at room temperature (RT). After evaporation in the RE, 4.65 g (100%) of colourless crystals of melting point 168°-170° C. (decomposition) remain.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20](O)=O.C=O.[OH-].[Na+]>O>[CH3:20][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:18][CH:19]=2)[CH2:6][CH2:5]1
Reactant: CCCCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCOC(=O)c1ccc(N2CCN(C)CC2)cc1

Procedure:
19.6 g. (75 mmole) n-Butyl 4-(piperazin-1-yl)-benzoate are heated to reflux temperature for 12 hours in a mixture of 112 ml. 80% formic acid and 37.5 ml. 40% formaldehyde solution. After cooling, the reaction mixture is poured into 2.5 liters of water, rendered alkaline with 10N aqueous sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extracts are dried and evaporated to give 17.8 g. (86% of theory) of the desired product; m.p. 118°-120° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[I-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[C:27]([N+:33]([O-:35])=[O:34])[CH:26]=1>CN(C)C=O>[OH:1][CH2:2][CH:3]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:29][C:28]1[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][C:27]=1[N+:33]([O-:35])=[O:34])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CO)N(Cc1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a solution of 0.289 g (1 mmol) of methyl 3-hydroxy-2-(4-methoxybenzenesulfonylamino)propionate in 4 ml of N,N-dimethylformamide cooled in an ice bath was added 40 mg of NaH (60% in oil) (1 mmol). After the gas evolution ceased, 0.165 g (1.1 mmol) of sodium iodide was added, followed by the addition of 0.226 g (1.1 mmol) of 4-chloro-2-nitrobenzyl chloride in 1 ml of dimethylformamide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:42])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([CH3:41])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:26]3[CH2:25][C:24](=[O:42])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:21])([F:22])[F:20])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:39]=[C:38]([CH3:40])[N:37]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C)c3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M308) (0.41 g, 0.68 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (267 mg, 81%).
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:3])[CH3:2].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>CN(C=O)C.CC(OC)(C)C>[CH2:16]([O:15][C:6]1[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([C:1](=[O:3])[CH2:2][CH3:28])[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]=12)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(C)C2=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(=O)CC)CCN(C)C2=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (0.60 g, 1.62 mmol; Example 7, step 7) in anhydrous DMF (17 mL), a solution of lithium bis(trimethylsilyl)amide (1.94 mL, 1.94 mmol) in MTBE was added. The mixture was stirred at −78° C. for 15 minutes, treated with iodomethane (0.12 mL, 1.94 mmol), allowed to slowly warm up to room temperature, and stirred at the temperature overnight. The product mixture was concentrated under vacuum. The residue was partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to preparation HPLC on C-18 stationary phase eluting with a gradient of methanol in water in the presence of ammonium acetate (1 g/L). Collection and concentration of appropriate fractions provided the title compound. The corresponding bis-methylated ketone was also isolated and was used for the preparation of Examples 60 & 61.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:15]=[N:16][C:17]([C:18]([O:20]CC)=[O:19])=[C:4]2[CH2:3]1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:15]=[N:16][C:17]([C:18]([OH:20])=[O:19])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(C)cccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc2c1C(=O)N(C)Cc1c(C(=O)O)ncn1-2

Procedure:
25 g (85 mmol) of ethyl 5,6-dihydro-5,7-dimethyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate were heated to boiling under reflux for 1 hour with 3.40 g (85 mmol) of sodium hydroxide in 200 ml of ethanol and 15 ml of water. After evaporation of the ethanol the mixture was diluted with water and acidified with 21 ml of 4 normal hydrochloric acid. The suspension obtained was suction filtered and washed with water. After drying the suction filter cake there was obtained 5,6-dihydro-5,7-dimethyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of decomposition point 274-275°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:18]=[C:19]1[NH:23][CH2:22][CH2:21][O:20]1.[C@@H]1(N)CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:18]=[C:19]1[N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][O:20]1
Reactant: O=C1NCCO1
Reactant: CC(C)(C)OC(=O)C1(c2ccc(Br)cc2)CC1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1(c2ccc(N3CCOC3=O)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (297.2 mg, 1.0 mmol), 2-oxo-1,3-oxazolidine (1.2 mmol), copper(I) iodide (20.0 mg, 0.1 mmol), (trans)-cyclohexane-1,2-diamine (22.8 mg, 0.2 mmol) and potassium carbonate (300.0 mg, 2.17 mmol) was deaerated under vacuum and then charged with nitrogen. To the mixture was added toluene (2.0 mL). The resulting mixture was heated at 100° C. for overnight. Then ethyl acetate (10 mL) was added to the mixture. The resulting mixture was filtered through a pad of celite, and the solid was washed with additional ethyl acetate. The filtrate was concentrated. The residue was purified by flash chromatography with ethyl acetate/hexane to afford tert-butyl 1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]cyclopropanecarboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([C:17]4([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=5)[CH2:19][CH2:18]4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33].CN[C@H]1CCCC[C@@H]1NC.C(=O)([O-])[O-].[K+].[K+].C(=O)=O.CC(C)=O>O1CCOCC1.[Cu]I>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2([C:14]3[N:12]4[N:13]=[C:8]([C:5]5[CH:6]=[CH:7][C:2]([N:28]6[CH2:32][CH2:31][CH2:30][C:29]6=[O:33])=[CH:3][CH:4]=5)[CH:9]=[N:10][C:11]4=[N:16][N:15]=3)[CH2:19][CH2:18]2)=[CH:21][CH:22]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc(C2(c3nnc4ncc(-c5ccc(Br)cc5)nn34)CC2)cc1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C2(c3nnc4ncc(-c5ccc(N6CCCC6=O)cc5)nn34)CC2)cc1
Temperature: 150 °C

Procedure:
A mixture of 6-(4-bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]-triazolo[4,3-b][1,2,4]triazine (Example 17, isomer-I, 25.3 mg, 0.0600 mmol), 2-Pyrrolidinone (5.47 μL, 0.0720 mmol), (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (1.9 μL, 0.012 mmol), copper(I) iodide (1.14 mg, 0.00600 mmol), and potassium carbonate (17.4 mg, 0.126 mmol) in 1,4-dioxane (0.75 mL) was cooled (dry-ice acetone bath), purged in vacuo, and charged with nitrogen. Then the mixture was heated at 150° C. for 4 h. After cooling, the mixture was diluted with methanol. The resulting solution was purified by RP-HPLC (pH=10) to give the desired product. Analytical LCMS: (M+H)+=427.1.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)O1.Br[C:23]1[C:24]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[N:25][N:26]2[CH2:30][CH2:29][O:28][C:27]=12.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2]>[F:37][C:34]1[CH:33]=[CH:32][C:31]([C:24]2[C:23]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]4[CH2:19][CH2:20]4)=[O:17])[CH:10]=3)=[C:27]3[O:28][CH2:29][CH2:30][N:26]3[N:25]=2)=[CH:36][CH:35]=1
Reactant: CC1(C)OB(c2ccnc(NC(=O)C3CC3)c2)OC1(C)C
Reactant: Fc1ccc(-c2nn3c(c2Br)OCC3)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2OCC3)ccn1)C1CC1
Temperature: 120 °C
Yield: 61.7 %

Procedure:
115 mg (0.40 mmol) of N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]cyclopropanecarboxamide and 124 mg (1.1 eq 0.44 mmol) of 7-bromo-6-(4-fluorophenyl)-2,3-dihydropyrazolo[5,1-b][1,3]oxazole are dissolved in 2 mL 1,4-dioxan. To this are added 30 mg of bis(tricyclohexylphosphine)-palladium(II)dichloride (0.04 mmol, 0.1 eq) and 2 mL sodium carbonate solution (2M in H2O). The reaction mixture is flushed for 5 mins with argon and then sealed. Next the mixture is heated for 12 mins at 120° C. in the microwave (CEM Explorer). After cooling, insoluble components are filtered off and the salt residue washed with 1,4-dioxan. The organic phase is evaporated and the crude product purified by silica gel chromatography (eluent cyclohexane/ethyl acetate). 90 mg (61%) of N-{4-[6-(4-fluorophenyl)-2,3-dihydropyrazolo[5,1-b][1,3]oxazol-7-yl]pyridin-2-yl}cyclopropanecarboxamide are obtained as a colourless solid.