Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]1[C:19]([OH:21])=[O:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:22](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[CH3:22][O:20][C:19]([C@@H:9]1[CH2:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)C[C@H]1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4.48 g of commercially available (2S,4S)-Boc-4-phenyl-pyrrolidine-2-carboxylic acid (15.37 mmol) were dissolved in 50 ml dimethylformamide. 2.59 g of potassium carbonate (18.76 mmol) and 2.66 g of methyl iodide (18.76 mmol) were added and the reaction was stirred for 48 h at room temperature. Standard work-up with ethyl acetate yielded 5.3 of the product.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31]([OH:34])(=O)[CH3:32].CCN(C(C)C)C(C)C.[CH3:44][N:45]([C:47](ON1N=NC2C=CC=CC1=2)=[N+:48]([CH3:50])C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:31](=[O:34])[CH2:32][N:48]4[CH:50]=[CH:44][N:45]=[CH:47]4)[CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNCc1cc(F)ccc1-3
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(=O)O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)Cn1ccnc1)Cc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1 eq of methyl-14-cyclohexyl-3-fluoro-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocin-11-carboxylate (prepared as described in Example 18, Step 5) in DCM (0.06 M), 1.1 eq of imidazo-1-yl acetic acid in DCM (0.05 M), 3 eq of DIPEA and 1.5 eq of TBTU were added and the mixture stirred at RT overnight. Volatiles were removed in vacuo and the crude material was used in the next step without further purification; MS (ES+) m/z 515 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[S:11][C:12]([CH:15]=[O:16])=[CH:13][N:14]=1)=[O:4].[CH3:18][C@H:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20](O)=[O:21].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[CH:15]([C:12]1[S:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][N:23]([C@@H:19]([CH3:18])[CH:20]=[O:21])[C:24](=[O:25])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH3:17])=[N:14][CH:13]=1)=[O:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H](N)C(=O)NCCCNc1ncc(C=O)s1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H](NN(C(=O)OC(C)(C)C)[C@@H](C)C=O)C(=O)NCCCNc1ncc(C=O)s1
Yield: 66.2 %

Procedure:
Following the procedure as described in Example 24, except using the material from Example 70 (260 mg, 0.790 mmol), N-alpha-t-BOC-L-Alanine (161 mg, 0.853 mmol), 1-hydroxy-7-azabenzotriazole (53.7 mg, 0.395 mmol), CH2Cl2 (15 mL), N-methylmorpholine (178 μlit, 1.62 mmol), and EDC (182 mg, 0.948 mmol), 223.5 mg (66.2%) of the title compound is obtained as an off white solid. Purification is done by BIOTAGE® Silica gel chromatography on a 25 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 100% ACN over 10 column volumes, with a hold at 100% ACN for 15 column volumes. LC/MS (Condition A): ret. T=2.59 min, (M+H)+ 428.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:12][NH:13][O:14][CH3:15].CCN(CC)CC.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:7]
Reactant: CNOC
Reactant: COc1ncccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncccc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a cooled mixture of 2-methoxy-nicotinic acid (2 g, 13.05 mmol), N,O-dimethylhydroxylamine (1.91 g, 19.59 mmol) in CH2Cl2 (20 mL) and Et3N (7.26 mL, 15.66 mmol) was added 1-propane phosphonic acid cyclic anhydride (9.96 mL, 15.66 mmol; 50 wt % solution in EtOAc) dropwise and stirred at room temperature for 2 h. The reaction mixture was filtered, washed with CH2Cl2 (10 mL), evaporated to dryness and subjected to column chromatography (SiO2, 50% EtOAc-hexanes) to obtain 2,N-dimethoxy-N-methyl-nicotinamide (2.33 g) in 91% yield.
Reaction SMILES: COC1C=CC(C[N:8]2[C:13]3[NH:14][N:15]=[C:16]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]=3[C:11](=[O:24])[N:10]([CH3:25])[C:9]2=[O:26])=CC=1.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH3:25][N:10]1[C:11](=[O:24])[C:12]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][NH:14][C:13]=2[NH:8][C:9]1=[O:26]
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3c(Nc4ccccc4)n[nH]c32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)[nH]c2[nH]nc(Nc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 7-(4-Methoxybenzyl)-5-methyl-3-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (6.6 g, 17.5 mmol) in CH2Cl2 (200 mL) is added TFA (30 mL) slowly at room temperature, followed by adding trifluoromethanesulfonic acid (10 mL) dropwise. After the reaction mixture is stirred at r.t. for 2 hours, solvent is removed under reduced pressure, and then 200 mL of 1N NaOH is added with cooling. The mixture is extracted with ethyl acetate five times, dried over Na2SO4, and then filtered. The filtrate is evaporated to dryness to give 4.3 g of crude product as white solids (Yield: 96%). MS (ESI) m/z 258.1 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1([N:10]2[C:14]3=[N:15][C:16]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:17][C:18](=[O:19])[C:13]3=[C:12]([CH2:27][CH3:28])[NH:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([N:10]2[C:14]3=[N:15][C:16]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([N+:1]([O-:4])=[O:2])=[CH:25][CH:26]=4)=[N:17][C:18](=[O:19])[C:13]3=[C:12]([CH2:27][CH3:28])[NH:11]2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccccc3)nc(=O)c1-2
Reactant: O=[N+]([O-])O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc([N+](=O)[O-])cc3)nc(=O)c1-2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
and (b) To 90% HNO3 (95 mL) at -10° to -15° C. was added 1-cyclopentyl-3-ethyl-6-(phenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one (9.62 g, 30 mmol). The reaction mixture was stirred as such for 1.5 hours, and then was poured into ice water. A precipitate formed which was collected by filtration, recrystallized from ethyl acetate and dried at 100° C. and 0.2 mm Hg to afford 2.31 g of 1-cyclopentyl-3-ethyl-6-(4-nitrophenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 221°-223° C. [labelled as Example 25 (a)]. The mother liquors were combined and concentrated in vacuo to afford a mixture of 1-cyclopentyl-3-ethyl-6-(2-nitrophenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one and 1-cyclopentyl-3-ethyl-6-(3-nitrophenylmethyl]pyrazolo[3,4-d]pyrimidin-4-one [labelled as Example 25 (b)].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>C(Cl)Cl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:5](=[O:7])[CH3:6])=[CH:12][CH:11]=1
Reactant: CC(=O)Cl
Reactant: Oc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Oc1ccc(Br)cc1
Temperature: 0 °C
Yield: 84.8 %

Procedure:
Anhydrous aluminum chloride (84 g, 0.486 mol) is suspended in methylene chloride (1200 mL), and then acetyl chloride (49.2 g, 0.629 mol) is added while stirring and cooling on ice. The mixture is stirred for 20 minutes while cooling on ice and 4-bromophenol (98 g, 0.57 mol) is added. The reaction mixture is stirred at room temperature for 1 h, and then ice water is added and extraction is performed with ethyl acetate. The organic layer is washed with brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue is purified by silica gel column chromatography to yield acetic acid 4-bromo-phenyl ester (104 g, 85%). 1H-NMR (CDCl3): 2.28 (s, 3H), 6.98 (d, 2H), 7.48 (d, 2H).
Reaction SMILES: Cl[C:2]1[C:7](C(F)(F)F)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:26])[C@@H:15]1[CH2:19][CH2:18][C:17](=[O:20])N1CC(C)(C)C.C(=[O:34])C1C=CC=CC=1>>[O:26]=[C:14]1[N:13]([CH2:12][C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C@H:18]([C:17]([OH:20])=[O:34])[CH2:19][CH2:15]1
Reactant: CC(C)(C)CN1C(=O)CC[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Reactant: O=Cc1ccccc1
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1

Procedure:
5-oxo-1-(phenylmethyl)proline was prepared in an analogous manner to that described above for the synthesis of 1-(2,2-dimethylpropyl)-5-oxoproline (example 100) but using benzaldehyde in the place of trimethylacetaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=CC=C[C:33]=2N=N1.C(N(CC)C(C)C)(C)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][CH:34]([CH3:35])[CH3:33])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NC(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (98.5 mg, 0.3 mmol) in DMF (1.5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (106 mg, 0.33 mmol), N,N-diisopropyl ethyl amine (257 μL, 1.5 mmol) and isopropylamine (28.3 μL, 0.33 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0:100) afforded the title compound 57 mg, 51%) as an off white solid. MS: m/e=370.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH:12]2[CH:10]([CH:11]2[N+:15]([O-:17])=[O:16])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].B(F)(F)F.C1COCC1.O>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:12]([CH:11]2[N+:15]([O-:17])=[O:16])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2C(C(=O)N1Cc1ccccc1)C2[N+](=O)[O-]
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])C1C2CN(Cc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
To a solution of 3-benzyl-6-nitro-3-azabicyclo[3.1.0]hexane-2,4-dione (3.0 g, 12.2 mmol) in dry THF (30 ml) was added NaBH4 (1.15 g, 30.48 mmol). The reaction was stirred for 15 min at r.t. under N2. BF3.THF complex (3.15 ml, 13.4 mmol) was added dropwise and the reaction heated at 40° C. for 4 h. Further NaBH4 (0.15 g) was added followed by BF3.THF complex (0.32 ml). Heating was continued at 45° C. for 30 min. A mixture of THF/H2O (1/1, 60 ml) was added dropwise with stirring. The resulting mixture was heated at 50° C. for 1 h before standing at r.t. for 16 h. The THF was removed to leave mainly water. This was extracted with EtOAc, dried (MgSO4) and evaporated to dryness to give the title compound as a yellow oil (2.47 g, 93%). m/z 219 [M+H]+, 1H NMR (300 MHz, CDCl3) δ: 2.50 (4H, s), 3.15 (2H, d), 3.65 (1H, s), 4.55 (1H, s), 7.2-7.4 (5H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[CH2:7][CH:6]([NH2:18])[CH2:5]2.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:35]1([S:41]([Cl:44])(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[ClH:44].[ClH:44].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[CH2:7][CH:6]([NH:18][S:41]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:43])=[O:42])[CH2:5]2
Reactant: NC1Cc2cc(Br)ccc2N(Cc2c[nH]cn2)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cl
Product: O=S(=O)(NC1Cc2cc(Br)ccc2N(Cc2c[nH]cn2)C1)c1ccccc1

Procedure:
The title compound was prepared in a manner similar to step F of Example 1. Thus, 6-Bromo-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-quinolinamine (42 mg, 0.1 mmol) in dimethylformamide (0.2 mL) was treated with triethylamine (0.3 mL, 2.1 mmol), dimethylaminopyridine (10 mg) and benzenesulfonyl chloride (0.014 mL, 0.11 mmol) to afford a solid (17 mg, 32%). MS; (M+H)+=447, 1 Br pattern.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:4]2[O:23][CH:24]=[CH:25][C:3]=12.[Si:26]([O:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([N:40]2[CH:44]=[C:43](B(O)O)[CH:42]=[N:41]2)[CH2:36][CH2:35]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Si:26]([O:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([N:40]2[CH:44]=[C:43]([C:2]3[CH:7]=[N:6][C:5]([N:8]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[C:4]4[O:23][CH:24]=[CH:25][C:3]=34)[CH:42]=[N:41]2)[CH2:36][CH2:35]1)([C:29]([CH3:32])([CH3:30])[CH3:31])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(I)c2ccoc12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(B(O)O)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2ccoc12
Temperature: 70 °C

Procedure:
A mixture of di-tert-butyl (4-iodofuro[2,3-c]pyridin-7-yl)imidodicarbonate (1.2 g, 2.6 mmol), [1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]boronic acid (1.06 g, 3.26 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane complex (213 mg, 0.261 mmol) and potassium carbonate (0.901 g, 6.52 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was degassed with nitrogen for 10 min. The mixture was then heated to 70° C. for 20 min. Ethyl acetate was added, and the layers separated. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification of the residue by ISCO chromatography (0% to 35% EtOAc:heptane) afforded 1.15 g (72%) of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.38 (s, 1 H), 7.89 (s, 1 H), 7.82-7.77 (m, 2 H), 7.02 (d, J=2.0 Hz, 1 H), 4.21 (tdd, J=3.9, 7.7, 11.5 Hz, 1 H), 3.82-3.66 (m, 1 H), 2.33-2.17 (m, 2 H), 2.09-2.01 (m, 2 H), 2.00-1.87 (m, 2 H), 1.59-1.49 (m, 2 H), 1.40 (s, 18 H), 0.91 (s, 9 H), 0.09 (s, 6 H); MS (ESI): 613.46 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17]>COCCO>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:17][CH:16]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: N=CN
Solvent: COCCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(F)ccc12
Reaction time: 1 h
Yield: 65.7 %

Procedure:
2-Amino-4-fluorobenzoic acid (15 g, 96 mmol) was dissolved in 2-methoxyethanol (97 ml). Formamidine acetate (20.13 g, 193.4 mmol) was added and the mixture heated to reflux for 18 hours. The reaction was cooled, concentrated and the residue stirred in aqueous ammonium hydroxide (0.01 N, 250 ml) for 1 hour. The suspension was filtered, washed with water and dried over phosphorus pentoxide to yield 7-fluoroquinazolin-4(3H)-one as an off-white solid (10.35 g, 65% yield):
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][NH2:21])(=[O:19])=[O:18])=[CH:13][CH:12]=1>CO.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[CH:8]=[N:21]/[NH:20][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:19])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=Cc1cc(Br)ccn1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N/N=C/c2cc(Br)ccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromopicolinaldehyde (2.0 g, 10.8 mmol) and 4-methylbenzenesulfonohydrazide (2.0 g, 10.8 mmol) were mixed in MeOH (20 mL) and dichloromethane (20 mL). The mixture was stirred at room temperature for 1 hour. The solvents were removed under reduced pressure to give 3.80 g (theoretical) of the title compound as a yellow solid m/z ES+ 354, 356 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O.[C:31]([O:34][CH2:35]C)(=[O:33])C>CO.[Cl-].[Na+].O>[CH3:35][O:34][C:31]([C:15]1[N:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@H:10]1[N:18]2[C@H:19]([CH3:21])[CH2:20][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:33]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.4 %

Procedure:
To a solution of 6.0 g (16.3 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) in 60 ml methanol were added 0.57 g (0.8 mmol) and 3.4 ml (2.5 g, 24.4 mmol) triethylamine and the reaction mixture was stirred at 80 deg C. for 24 h under a carbon monoxide atmosphere of 40 bar. The suspension was cooled to room temperature, poured into a mixture of water, ethyl acetate and brine and was extracted with further portions of ethyl acetate. The combined organic layers were separated, dried over magnesium sulfate and filtered. The residue was purified by chromatography on silica gel (0.032–0.063 mm) to afford the product as a light yellow foam (74.4%).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:24](ON3C(=O)CCC3=O)=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>O1CCOCC1.O>[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:24]([NH:7][C:6]3[CH:5]=[CH:4][C:3]([NH2:8])=[CH:2][CH:1]=3)=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1

Procedure:
4-((9-Fluorenylmethyloxycarbonyl)amino)aniline is prepared from p-phenylenediamine (2.16 g, 0.02 mole) and N-(9-fluorenylmethoxycarbonyloxy)succinimide (6.75 g, 0.02 mole) in dioxane-water (1:1). Purification is achieved by crystallization. This product is coupled to BOC-L-Glu-α-O-Benzyl using HOBT/DCC. After the usual work-up, the fully-protected amino acid derivative is dissolved in MeOH and treated with hydrogen gas at 1 atmosphere pressure in the presence of palladium-on-carbon catalyst until hydrogen consumption is complete (about 2 hours). Following the usual workup, the starting material:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(Cl)c(C(F)(F)F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light grey solid (89 mg, 88%), MS (ISP) m/z=404.3 [(M+H)+], mp 224.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-chloro-3-trifluoromethyl-phenylboronic acid (72.9 mg, 0.325 mmol).
Reaction SMILES: C(O)([C:3]([F:6])([F:5])[F:4])=O.Br[C:9]1[CH:26]=[C:25](/[CH:27]=[CH:28]/[CH:29]([C:34]2[CH:39]=[C:38]([Cl:40])[C:37]([Cl:41])=[C:36]([Cl:42])[CH:35]=2)[C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:23][C:10]=1[C:11]([NH:13][CH:14]([CH3:22])[C:15]([O:17]C(C)(C)C)=[O:16])=[O:12]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[CH:29]([C:34]1[CH:39]=[C:38]([Cl:40])[C:37]([Cl:41])=[C:36]([Cl:42])[CH:35]=1)/[CH:28]=[CH:27]/[C:25]1[CH:24]=[CH:23][C:10]([C:11]([NH:13][C@H:14]([CH3:22])[C:15]([OH:17])=[O:16])=[O:12])=[C:9]([C:3]([F:6])([F:5])[F:4])[CH:26]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
TFA (1 mL) was added to a stirred solution of tert-butyl 2-(2-bromo-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)propanoate (1.0 g, 1.63 mmol) in CH2Cl2 (20 mL) at 0° C. and the reaction mixture was stirred at ambient temperature for 18 h. The volatiles were evaporated under vacuum and the residue was triturated with pentane to afford the title compound as brown solid (0.65 g, 67%): 1HNMR (400 MHz, DMSO-d6) δ 12.60 (bs, 1H), 8.82 (d, J=8.0 Hz, 1H), 7.99 (s, 1H), 7.92-7.89 (m, 3H), 7.51 (d, J=8.0 Hz, 1H), 7.08 (dd, J=15.6, 8.8 Hz, 1H), 6.88 (d, J=15.6 Hz, 1H), 4.88-4.83 (m, 1H), 4.41-4.34 (m, 1H), 1.34 (d, J=7.2 Hz, 3H); ESIMS: m/z 545.7 ([M−H]+); IR (KBr) 3410, 3281, 2928, 1728, 1172, 744 cm−1.
Reaction SMILES: C[O:2][C@@H:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:27]=[C:15]3[C:16]4[C:21]([CH2:22][CH2:23][N:14]3[C:13](=[O:28])[CH2:12][N:11]=2)=[C:20]([C:24]([CH3:26])=[CH2:25])[CH:19]=[CH:18][CH:17]=4)[CH:9]=1)[CH3:4].[BH4-].[Na+]>CO.C(Cl)Cl.O>[CH:24]1([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[CH2:22][CH2:23][N:14]2[C:13](=[O:28])[CH2:12][N:11]=[C:10]([N:8]4[CH:9]=[C:5]([CH:3]([OH:2])[CH3:4])[N:6]=[CH:7]4)[CH:27]=[C:15]23)[CH2:26][CH2:25]1
Reactant: C=C(C)c1cccc2c1CCN1C(=O)CN=C(n3cnc([C@@H](C)OC)c3)C=C21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(O)c1cn(C2=NCC(=O)N3CCc4c(cccc4C4CC4)C3=C2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.3 %

Procedure:
A solution of 2-(4-acetyl-1H-imidazol-1-yl)-9-cyclopropyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (202 mg, 0.35 mmol, it can be obtained by analogy to example 118) in MeOH (8 mL) was treated with NaBH4 (27 mg, 0.71 mmol) and the mixture was stirred at RT for 10 min. The mixture was then diluted with DCM and H2O, and the aqueous phase was extracte with DCM. The combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by SFC (column: PPU 5 m, 250×30 mm, 60A, Princeton; eluent: 12-17% MeOH/CO2 over 14 min; flow 100 mL/min; UV detection at 220 nm) and crystallization in Et2O gave the title compound as a solid (41 mg). UPLC-MS: MS 363.2 (M+H+); UPLC rt 0.86 min. 1H NMR (600 MHz, DMSO-d6): δ ppm 0.55-0.71 (m, 2H); 0.88-1.02 (m, 2H); 1.35 (d, J=6.40 Hz, 3H); 1.87-2.05 (m, 1H); 2.99-3.17 (m, 2H); 3.79-3.97 (m, 2H); 4.17-4.31 (m, 2H); 4.55-4.71 (m, 1H); 5.01 (d, J=4.89 Hz, 1H); 7.09-7.25 (m, 2H); 7.25-7.39 (m, 1H); 7.46 (s, 1H); 7.84-7.98 (m, 1H); 8.16 (br s, 1H).