Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[C:31]2[CH:37]=O.N1CCCCC1>CO>[Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9]/[C:8](=[CH:37]\[C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([Cl:27])[CH:29]=4)[NH:33][N:32]=3)/[C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: O=Cc1n[nH]c2ccc(Cl)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2O/C(=C\c2n[nH]c4ccc(Cl)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.261 mmol) synthesized in Example B13, Step 2 in methanol (1 mL) was added with 5-chloro-1H-indazole-3-carbaldehyde (0.0471 g, 0.261 mmol) synthesized in Example B9, Step 3, and piperidine (0.00222 g, 0.0261 mmol) at room temperature, and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, then added with methanol (4 mL), and suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({5-chloro-2-[(5-chloro-1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.050 g, 35%).
Reaction SMILES: N[C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:18]>O.[Cu]Br>[Br:18][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Br
Reactant: Nc1ccc(C(=O)O)c2c1OCO2
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(Br)c2c1OCO2
Reaction time: 0.25 h

Procedure:
1.95 g of 7-amino-benzo[1,3]dioxole-4-carboxylic acid in 25 ml of hydrobromic acid (48%) and 20 ml of water are mixed at 0° C. with a solution of 760 mg of sodium nitrite in 4.2 ml of water. It is stirred for 15 minutes and then added to a solution of 2.07 g of copper(I) bromide in 5.5 ml of hydrobromic acid (48%). It is heated for 30 minutes to 100° C., added to water and extracted with ethyl acetate. It is washed with brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. 2.88 g of 7-bromo-benzo[1,3]dioxole-4-carboxylic acid is obtained as a brown solid. The latter is reacted in 50 ml of DMF at 0° C. with 4.08 g of cesium carbonate and 0.8 ml of methyl iodide. It is stirred for 4 hours at room temperature, added to water, and extracted with ethyl acetate. It is washed several times with water and brine, dried and concentrated by evaporation in a vacuum. 1.81 g of 7-bromo-benzo[1,3]dioxole-4-carboxylic acid methyl ester is obtained as a red solid. The latter is dissolved in 5 ml of ether, and 10 ml of THF is added to a solution of 5.06 ml of methylmagnesium chloride (3 M in THF) and 6 ml of ether at room temperature. After 3.5 hours, the batch is added to 1N hydrochloric acid, extracted with ethyl acetate, washed with brine, dried and concentrated by evaporation in a vacuum. 1.79 g of 2-(7-bromo-1,3-benzodioxol-4-yl)-propan-2-ol is obtained as an orange-colored oil.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:18][C:19]([F:43])([F:42])[C:20](=O)[CH2:21][C:22]([C:24]1[CH:40]=[CH:39][C:27]([O:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)=[CH:26][CH:25]=1)=O>>[ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:22]([C:24]3[CH:40]=[CH:39][C:27]([O:28][CH2:29][CH2:30][NH2:31])=[CH:26][CH:25]=3)=[CH:21][C:20]([C:19]([F:18])([F:42])[F:43])=[N:17]2)=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Product: NCCOc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 87.5 %

Procedure:
The title compound (12.9 g, 87.5%) was prepared from 1-[4-(benzyloxy)phenyl]hydrazine hydrochloride obtained by Example 79-1 and tert-butyl 2-[4-(4,4,4-trifluoro-3-oxobutanoyl)phenoxy]ethylcarbamate obtained by Example 78-2 in a similar manner to that of Example 78-3.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[SH:18][C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1>C(O)C.[OH-].[Na+]>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][S:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][S:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)[C:9]=1[CH3:10]
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(SCc2ccco2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
One equivalent (2.92 g) of 2-chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride (dissolved in 10 ml of water) is added dropwise at 40° C. in the course of 20 minutes to a solution of 2-mercapto-1H-benzimidazole (1.5 g/10 mmol) in 40 ml of ethanol and 21 ml of 1N sodium hydroxide solution. The mixture is subsequently stirred at 50°-60° C. for 2-3 h and at RT for a further 3-4 h, ethanol is distilled off on a rotary evaporator (1 kPa/40° C.), the residue is extracted 3 times using in each case 20 ml of dichloromethane, and the dichloromethane phase is washed with 0.1N sodium hydroxide solution, dried over potassium carbonate and evaporated fully in vacuo. For purification, the crude product is chromatographed on silica gel (dichloromethane/methanol 20:1 to 3:1); the collected pure fractions are together concentrated in vacuo and crystallized from dichloromethane/diisopropyl ether. The product is subsequently recrystallized from methanol/toluene. Yield: 2.61 g (71%) of the title compound as a colorless solid of m.p. 188°-189° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:37][CH2:38][C:39](Cl)=[O:40]>C1COCC1>[CH2:1]([N:8]([CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=1)[OH:12])[C:39](=[O:40])[CH2:38][Cl:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(F)c1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(CN(Cc1ccccc1)C(=O)CCl)C(O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (1RS,2SR)-3-(benzylamino)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(4-chloro-3-fluorophenyl)propan-1-ol (29.3 g) and triethylamine (11.2 ml) in THF (335 ml) was added chloroacetyl chloride (5.37 ml) under ice-cooling, and the mixture was stirred at 0° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (35.0 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:16](C)=[CH2:17])=[N:11]2)[CH2:2][CH2:3][CH3:4].C[N+]1([O-])CC[O:28]CC1>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:16](=[O:28])[CH3:17])=[N:11]2)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C)c1nc2ccnc(OCCCC)c2c2cc(F)ccc12
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1nccc2nc(C(C)=O)c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-butoxy-9-fluoro-6-isopropenylbenzo[c]-1,6-naphthyridine (100 mg, 0.320 mmol) in tetrahydrofuran (1.0 ml) and water (0.25 ml) was added 4-methylmorpholine 4-oxide (NMO) (39.6 mg, 0.338 mmol) followed by osmium tetroxide (525 uL of a 4 wt % aqueous solution. The reaction mixture was stirred at room temperature for 1 hr. Additional tetrahydrofuran (1.0 ml) and water (0.25 ml) were added, followed by an additional portion of NMO (39.6 mg, 0.338 mmol). The reaction mixture was partitioned between EtOAc and water. The organic layer was dried over sodium sulfate, filtered, and concentrated to a crude residue that was adsorbed on to silica gel and purified by silica gel chromatography eluting with an EtOAc/hexanes gradient to afford 1-(1-butoxy-9-fluorobenzo[c]-1,6-naphthyridin-6-yl)ethanone. LRMS (ESI) calc'd for (C18H17FN2O2) [M+H]+, 313.1; found 313.1.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=[O:12])C.O.[NH2:15][NH2:16]>C(O)C>[O:12]=[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]1[CH2:5][C:4]([NH:15][NH2:16])=[O:3]
Reactant: CCOC(=O)Cn1ccccc1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)Cn1ccccc1=O
Temperature: 25 °C
Yield: 78 %

Procedure:
As described for example 112a, (2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester (Begley, William J. et. al. Journal of the Chemical Society, Perkin Transactions 1 (1981), (9), 2620-4) in ethanol was reacted with hydrazine hydrate (1.1 equivalents) at 60° C. for 36 h. The mixture was cooled to rt and the precipitated product was filtered off and dried to afford the title compound as a white solid (yield: 78%). MS: m/e=168.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][C:45]=1[Cl:46])[NH:42][N:41]=[C:40]2[C:47]([OH:49])=[O:48].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CCO>[C:12]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][C:45]=3[Cl:46])[NH:42][N:41]=[C:40]4[C:47]([OH:49])=[O:48])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9]1)(=[O:13])[NH2:14]
Reactant: NC(=O)C1(c2ccc(Br)cc2)CCC1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: NC(=O)C1(c2ccc(-c3cc4c(C(=O)O)n[nH]c4cc3Cl)cc2)CCC1
Temperature: 130 °C
Yield: 3.2 %

Procedure:
A suspension of 1-(4-bromophenyl)cyclobutanecarboxylic acid amide (101 mg, 0.37 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (136 mg, 0.37 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.0 mg, 0.018 mmol) and potassium acetate (107 mg, 1.09 mmol) in 1,4-dioxane (1 mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. To the mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg, 0.018 mmol), 2 N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol) and EtOH (2 mL). The mixture was sealed and heated to 130° C. for 1 hour. Water (3 mL) was added to the reaction mixture, followed by 1 N HCl solution to adjust the pH to 2. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 0% H2O/100% MeCN in 10.5 min, HOLD at 0% H2O/100% MeCN to 12.0 min. Flow: 25 mL/min) to afford the title compound (4.3 mg, 3% yield). MS (ES+) 343.1 (M+H)+. Retention time=2.45 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[C:4]([C:22]([OH:24])=[O:23])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(C(C)=O)C>[CH2:31]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[CH:17][CH:16]=2)[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[C:22]([O:24][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:23])=[CH:13][CH:12]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(OCc1ccccc1)c1ccccc1C(c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1

Procedure:
In 500 ml of methyl ethyl ketone were dissolved 50 g of phenolphthalin and 75 g of anhydrous potassium carbonate, and the solution was ice cooled. Subsequently, 58 ml of benzyl bromide was added dropwise to the solution, and the mixture was heated under reflux for 24 hours. The temperature of the mixture was brought back to room temperature, and concentrated. Thereafter, water was added to the residue, and the aqueous mixture was extracted with ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. ]he organic layers were combined, washed with an aqueous 10% citric acid and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give 114.61 g of the desired product.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10][C:11]1[NH:12][C:13]2[C:18]([N:19]=1)=[C:17]([NH2:20])[N:16]=[CH:15][N:14]=2.Br[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:20][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[C:18]=1[N:19]=[C:11]([S:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[I:1])[N:12]2[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1ccc(I)c(Sc2nc3c(N)ncnc3[nH]2)c1
Reactant: CC(C)(C)C(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(I)c(Sc2nc3c(N)ncnc3n2CCCNC(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
To a solution of 8-((2-iodo-5-methoxyphenyl)thio)-9H-purin-6-amine (200 mg, 0.5 mmol) in DMF (3 mL) was added N-(3-bromopropyl)pivalamide (445 mg, 2 mmol) and Cs2CO3 (326 mg, 1 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2Cl2:NH3-MeOH (7N), 20:1) to yield WS64 as a white solid (53 mg, 20%). 1H NMR (500 MHz, CDCl3): δ 8.26 (s, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.43 (br s, 1H), 6.66 (s, 1H), 6.50 (d, J=8.7 Hz, 1H), 5.86 (br s, 2H), 4.20 (t, J=6.1 Hz, 2H), 3.61 (s, 3H), 2.78 (m, 2H), 1.82 (m, 2H), 1.21 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 178.8, 160.5, 155.0, 153.2, 152.0, 145.0, 140.6, 137.7, 120.1, 117.2, 115.4, 88.4, 55.5, 40.7, 38.8, 34.8, 29.1, 27.7; HRMS (ESI) m/z [M+H]+ calcd. for C20H26IN6O2S, 541.0883. found 541.0898.
Reaction SMILES: [OH2:1].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([CH2:27][CH2:28][C@H:29]([OH:35])[C:30]([CH3:34])([CH3:33])[C:31]#[N:32])(C(C)(C)C)(C)C>>[OH:1][CH2:27][CH2:28][C@H:29]([OH:35])[C:30]([CH3:34])([CH3:33])[C:31]#[N:32]
Reactant: CC(C)(C#N)[C@@H](O)CC[Si](C)(C)C(C)(C)C
Reactant: O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(C#N)[C@@H](O)CCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12.18 g (46.61 mmol) of tetrabutylammonium fluoride hydrate is added to a solution that consists of 3 g (11.65 mmol) of 5-tert-butyldimethylsilyl-2,2-dimethyl-3(S)hydroxy-pentane-nitrile of the title compound of Example 8b, dissolved in 40 ml of tetrahydrofaran, and it is stirred for 16 hours at room temperature. Then, it is evaporated to the dry state in a vacuum. The residue is purified by RP-18 chromatography (mobile solvent: acetonitrile/water gradient).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CC(O)=O.C(OCC)C>[CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH2:13][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc2[nH]ccc2c1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc2c(c1)CCN2
Yield: 61.7 %

Procedure:
To a solution of the product of Step B (0.08 g; 0.35 mmol) in AcOH (1.5 ml) NaBH3CN was added at 0° C., with stirring. The resulting mixture was stirred for 2 h at room temperature, then diluted to 20 ml with diethyl ether and washed with 10% NaOH (2×5 ml), H2), brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; hexane/EtOAc; 9:1) to give the title compound (0.05 g; 62%) as a colourless syrup. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=7 Hz); 1.26 (m, 10H); 1.54 (m, 2H); 2.48 (tr, 2H, J=7.9 Hz); 2.98 (tr, 2H, 9.2 Hz) 3.52 (tr, 2H, J=9.2 Hz); 6.56 (d, 1H, 7.8 Hz); 6.83 (d, 1H, J=7.8 Hz); 6.93 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[O:28][CH3:29].Cl.CN(C)CCCN=C=NCC.C(Cl)Cl.CO>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)=[CH:23][C:22]=1[O:28][CH3:29]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: COc1cc(N)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)n2C)ccc1F
Yield: 15.4 %

Procedure:
The product is prepared according to the procedure described in example 5, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 205 mg of 4-fluoro-3-methoxyaniline, and 185 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 3 ml of N,N-dimethylformamide. After extractions with ethyl acetate and silica column purification of the residue obtained, eluent: 95/05 then 90/10 CH2Cl2/MeOH, 42 mg of N-(4-fluoro-3-methoxyphenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:28])[CH2:13][CH2:12][CH2:11][CH:10]1[NH:14][C:15](=[O:27])[O:16][C@@H:17]1[CH2:22][C@H:21]([CH3:23])[CH2:20][CH2:19][C@H:18]1[CH:24]([CH3:26])[CH3:25])=O)(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[NH2:8][C:9]1([CH3:28])[CH2:13][CH2:12][CH2:11][CH:10]1[NH:14][C:15](=[O:27])[O:16][C@@H:17]1[CH2:22][C@H:21]([CH3:23])[CH2:20][CH2:19][C@H:18]1[CH:24]([CH3:25])[CH3:26]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-{[(tert-butoxy)carbonyl]amino}-2-methylcyclopentyl)carbamate (6.12 g, 15.43 mmol) in 1,4-dioxane (35 ml) was added HCl in 1,4-dioxane (4 M, 38.6 ml, 154 mmol). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo and azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH:19]([C:23](O)=[O:24])[CH2:20]4)=[CH:15][CH:14]=3)[C:5]=2[CH:4]=[CH:3]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][C:60]1[CH:61]=[C:62]([CH:72]=[C:73]([C:75]([F:78])([F:77])[F:76])[CH:74]=1)[CH2:63][NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68]>CN(C=O)C.O>[O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH:19]([C:23]([NH:59][C:60]5[CH:61]=[C:62]([CH:72]=[C:73]([C:75]([F:76])([F:77])[F:78])[CH:74]=5)[CH2:63][NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:24])[CH2:20]4)=[CH:15][CH:14]=3)[C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)C1CCc2ccc(Oc3ccnc4[nH]c(=O)ccc34)cc2C1
Reactant: CC(C)(C)OC(=O)NCc1cc(N)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc5[nH]c(=O)ccc45)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a solution of 7-[(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (0.18 g, 0.00053 mol) in DMF (5.3 mL) was added diisopropylethylamine (0.11 mL, 0.00063 mol) and HATU (0.24 g, 0.00063 mol). The reaction mixture was allowed to stir at rt for 1 hr. tert-Butyl [3-amino-5-(trifluoromethyl)benzyl]-carbamate (0.15 g, 0.00053 mol) was added and the reaction mixture was allowed to stir for an additional 15 hr. Water was added to the reaction mixture and a solid precipitated. This solid was collected by filtration and purified by column chromatography to give tert-butyl [3-[({7-[(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)amino]-5-(trifluoromethyl)benzyl]carbamate as a white solid (0.24 g, 75%). LCMS: (FA) ES+ 609.4.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:15][C:16](=[O:33])[NH:17][C:18]4[CH:24]=[C:23]([C:25]#[N:26])[C:22]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:21][C:19]=4[N:20]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>ClCCl.CN(C=O)C>[CH2:29]([N:27]([CH3:28])[C:22]1[C:23]([C:25]#[N:26])=[CH:24][C:18]2[NH:17][C:16](=[O:33])[CH2:15][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:2][N:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)=[CH:4][N:5]=[N:6]4)[CH:9]=3)=[N:20][C:19]=2[CH:21]=1)[CH:30]([CH3:31])[CH3:32]
Reactant: C1CCNC1
Reactant: CC(C)CN(C)c1cc2c(cc1C#N)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)CN(C)c1cc2c(cc1C#N)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 2-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]8-(isobutyl-methyl-amino)-4-oxo-4,5-dihydro-3H -benzo[b][1,4]diazepine-7-carbonitrile (Example 111) (200 mg, 0.45 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light yellow solid (140 mg, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:17])=[O:5]
Reactant: Nc1ccccc1C=O
Reactant: O=C1CCCC(=O)O1
Solvent: c1ccccc1
Product: O=Cc1ccccc1NC(=O)CCCC(=O)O
Yield: 91.9 %

Procedure:
2-aminobenzaldehyde (2.87 g) and glutaric anhydride (3.26 g) were dissolved in benzene (60 ml) and the mixture was heated to reflux for 10.5 hours. Benzene was removed and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1- ethyl acetate) to obtain 5.12 g of 4-(N-(2-formylphenyl)carbamoyl)butanoic acid. Yield: 93%.