Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[NH:8][C:9]([Cl:13])=[C:10]([Cl:12])[N:11]=1)=[O:6])([CH3:3])[CH3:2].C=O.[C:16]([O:19][C:20](=O)C)(=[O:18])[CH3:17]>C(#N)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:1]([O:4][C:5]([C:7]1[N:8]([CH2:20][O:19][C:16](=[O:18])[CH3:17])[C:9]([Cl:13])=[C:10]([Cl:12])[N:11]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OC(=O)c1nc(Cl)c(Cl)[nH]1
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CC(=O)OCn1c(C(=O)OC(C)C)nc(Cl)c1Cl
Yield: 64.4 %

Procedure:
44.6 g (0.2 mol) of 4,5-dichloro-imidazole-2-carboxylic acid isopropyl ester were stirred in 200 ml of acetonitrile together with 12 g (0.4 mol) of paraformaldehyde, 40.7 g (0.4 mol) of acetic anhydride and 0.5 g of p-toluenesulphonic acid for 20 hours at 85° C. After distilling off the solvent and stirring the residue in isopropanol, 38 g (64% of theory) of 1-acetoxymethyl-4,5-dichloro-imidazole-2-carboxylic acid isopropyl ester with a melting point of 81°-82° C. were obtained.
Reaction SMILES: [C:1]([CH:8]([NH2:28])[CH2:9][N:10]([C:17](=[O:27])[CH2:18][C:19]1[C:20](=[O:26])[NH:21][C:22](=[O:25])[NH:23][CH:24]=1)[CH2:11][C:12]([O:14]CC)=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl>[OH-].[Na+]>[C:1]([CH:8]([NH2:28])[CH2:9][N:10]([C:17](=[O:27])[CH2:18][C:19]1[C:20](=[O:26])[NH:21][C:22](=[O:25])[NH:23][CH:24]=1)[CH2:11][C:12]([OH:14])=[O:13])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCOC(=O)CN(CC(N)C(=O)OC(C)(C)C)C(=O)Cc1c[nH]c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)C(N)CN(CC(=O)O)C(=O)Cc1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
Ethyl N-(2-BOC-aminoethyl)-N-(uracil-5-ylacetyl)glycinate (35, 1.00 g, 2.5 mmol) was dissolved in 1 M aqueous sodium hydroxide (50 ml) and the mixture was stirred for 15 min at room temperature. The reaction mixture was cooled to 0° C. and the pH was adjusted to 1.5 by the addition of 2 M hydrochloric acid. After 30 min the aqueous solution was extracted with n-butanol (4×80 ml). The n-butanol of the combined organic phases was evaporated under reduced pressure. Residual n-butanol was removed azeotropically with water (5×50 ml). The resultant aqueous solution was freeze-dried to yield 0.93 g (100%) of the title compound as a white solid. Due to hindered rotation around the amide bond several of the NMR signals are comprised of a major (ma) and minor (mi) component. 1H-NMR (DMSO-d6/TMS): δ=1.44 (s, 9H, BOC); 3.07-3.48 (m, CH2CON, NCH2, CH2N and water); 4.00 (ma), 4.26 (mi) (s, 2H, CH2COO); 6.75 (mi), 6.94 (ma) (br, 1H, BOC-NH); 7.28 (mi), 7.32 (ma) (d, 1H, J=5.5 Hz, H-6); 10.87 (br, 1H, H-1); 11.12 (br, 1H, H-3). MS(FAB+) m/z (%): 371 (26, M+H). Calcd. for C15H22N4O7: C, 48.65; H, 5.99; N, 15.13; C/N, 3.22. Found: C, 35.13; H, 4.66; N, 10.48; C/N, 3.35.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[O:14])=[CH:9][CH:8]=1.[CH:22]1([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]=[CH:3][CH2:2][N:25]([CH:22]3[CH2:24][CH2:23]3)[C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])=[CH:8][CH:9]=2)=[O:14])=[CH:16][CH:17]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(OC/C=C/CBr)cc1
Reactant: O=C(NC1CC1)C(F)(F)F
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: O=C(c1ccc(Br)cc1)c1ccc(OCC=CCN(C(=O)C(F)(F)F)C2CC2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 97.8 %

Procedure:
A suspension of 10 g of (E)-[4-(4-bromo-but-2-enyloxy)-phenyl]-(4-bromo-phenyl)-methanone, 7.47 g of N-cyclopropyl-2,2,2-trifluoro-acetamide, 6.7 g of potassium carbonate and 0.55 g of benzyltriethylammonium bromide in 200 ml of acetonitrile is heated to boiling while stirring for 7 h. After cooling to room temperature the suspension is filtered. The filtrate is concentrated and the residue is dissolved in a mixture of 500 ml of melthylene chloride and 50 ml of methanol and stirred with 50 g of a strongly acidic and strongly basic ion exchanger, subsequently filtered and washed with methylene chloride to give two phases. The organic phase is dried and concentrated. 11.5 g of N-[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-N-cyclopropyl-2,2,2-trifluoroacetamide are obtained as a yellowish solid, MS: m/e 412 (M+-CF3, 1Br).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].CO.[CH3:8][C:9]([CH2:11][CH3:12])=O>[Pd].O>[CH:9]([NH:1][CH2:2][C:3]([OH:5])=[O:4])([CH2:11][CH3:12])[CH3:8]
Reactant: CCC(C)=O
Reactant: NCC(=O)O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCC(C)NCC(=O)O

Procedure:
338 g of glycine (4.5 mols), 1.5 liters of methanol, 15 g of 10% Pd on C, wet with water, and 500 g of methylethylketone (6.93 mols) are charged into the autoclave.
Reaction SMILES: [Li+].[OH-].[CH2:3]([C:10]1[CH:11]=[C:12]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:30][CH:29]([C:31]([O:33]C)=[O:32])[CH2:28]4)=[CH:22][C:21]=3[F:35])=[CH:17][C:13]2=[N:14][C:15]=1[Cl:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.P([O-])([O-])([O-])=O.Cl>O.C1COCC1>[CH2:3]([C:10]1[CH:11]=[C:12]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]4)=[CH:22][C:21]=3[F:35])=[CH:17][C:13]2=[N:14][C:15]=1[Cl:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C1CN(Cc2ccc(-c3cc4nc(Cl)c(Cc5ccccc5)cc4o3)c(F)c2)C1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CN(Cc2ccc(-c3cc4nc(Cl)c(Cc5ccccc5)cc4o3)c(F)c2)C1
Reaction time: 0.5 h

Procedure:
To a solution of LiOH (0.022 g, 0.90 mmol) in water (3.0 mL) was added methyl 1-((4-(6-benzyl-5-chlorofuro[3,2-b]pyridin-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylate (0.084 g, 0.18 mmol) in THF (2.0 mL). The solution was stirred for 30 min and then the solvent was removed under reduced pressure to afford a white suspension. To the mixture was added 0.5M phosphate buffer, pH 6.0 (3 mL), and then 1 N HCl was added until the pH was 6.0 as indicated by pH paper. The resulting suspension was filtered, and the off white solid was collected and dried under vacuum at 50° C. 1H NMR (400 MHz, DMSO-d6 with 1 drop of TFA-d) 8 ppm 8.04-8.21 (2H, m), 7.44-7.70 (3H, m), 7.18-7.40 (5H, m), 4.45-4.60 (2H, m), 4.13-4.40 (6H, m), 3.60-3.76 (1H, m); MS (ESI) m/z: Calculated: 450.1; Observed: 451.1 (M++1).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]([CH:15](O)[CH3:16])[C:13]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:12][N:11]=2)=[CH:6][C:5]=1[CH3:30].O.[OH-].[Li+].O1CCCC1>O>[Cl:29][C:24]1[CH:23]=[C:22]([C:13]2([C:18]([F:20])([F:19])[F:21])[O:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[C:5]([CH3:30])[CH:6]=3)[C:14]2=[CH:15][CH3:16])[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2C(C)O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC=C1C(c2ccc(C(=O)O)c(C)c2)=NOC1(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-[5-(3,5-dichloro-phenyl)-4-(1-hydroxy-ethyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (Example 7.1) (0.242 g, 0.51 mmol), lithium hydroxide monohydrate (0.06 g, 1.4 mmol), tetrahydrofuran (5 ml) and water (5 ml) was stirred at ambient temperature for 2 days. Then further portions of lithium hydroxide monohydrate were added to complete the reaction. In total, 545 mg of lithium hydroxide monohydrate were added over 5 days. The mixture was concentrated and the residue dissolved in water. The solution was acidified by addition of aqueous hydrochloric acid (1N) and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated to give a residue which was used without further purification in the following step. LC-MS showed the presence of 4-[5-(3,5-dichloro-phenyl)-4-ethylidene-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid: RT=2.20 min, m/z=442/444/446 (M−H+).
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[O:5][N:4]=1)[CH3:2].Cl.O.[OH-].[Na+]>C(Cl)Cl.O1CCOCC1>[CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (2.79 g; compound B7) in DCM (20 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (15 ml, 4.0 M) for 12 h at RT. Subsequently water is added (50 ml) and the pH is adjusted to about pH14 by addition of aqueous sodium hydroxide solution (5 M). The mixture is extracted with DCM (3×100 ml) and the combined organic layers are dried over sodium sulfate. After filtration and evaporation of the solvent a residue is obtained which is recrystallized from DCM to yield the title compound as a solid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH:26]1(B(O)O)[CH2:28][CH2:27]1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([CH:26]3[CH2:28][CH2:27]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(C2CC2)c1OC
Temperature: 140 °C
Yield: 59.6 %

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 0.347 g), cyclopropyl boronic acid monohydrate (0.087 g), palladium chloride dppf adduct with DCM (0.07 g) and cesium carbonate (0.8 g) in THF (9 ml) and water (1 ml) was sealed in a microwave vial and degassed. The mixture was then heated in the microwave at 140° C. for 15 minutes. After cooling, the mixture was dried (MgSO4) and filtered through Celite. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of t-butyl methyl ether and cyclohexane with a gradient from 0-60% to give ethyl 6-(benzenesulphonylmethyl)-3-cyclopropyl-2-methoxybenzoate (0.187 g) as a gum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15]OS(C)(=O)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.O.CCOCC>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:26]2[CH2:27][CH2:28][N:23]([CH2:21][CH3:22])[CH2:24][CH2:25]2)=[CH:13][N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(COS(C)(=O)=O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1CCN(Cc2ccc(NC(=O)OC(C)(C)C)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of methanesulfonic acid 6-tert-butoxycarbonylamino-pyridin-3-ylmethyl ester (Step 26.3) (0.8 g, 2.6 mmol), N-ethylpiperazine (0.37 mL, 2.9 mmol, 1.1 equiv), cesium carbonate (1 g, 3.2 mmol, 1.2 equiv), and DMF (10 ml) was stirred for 2 h at rt, diluted with EtOAc and H2O, and extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated to provide a yellow solid. Trituration in Et2O afforded 0.75 g of the title compound as a white solid: ES-MS: 321.2 [M+H]+.
Reaction SMILES: [ClH:1].[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][C:13](=[NH:17])OCC.[C:18]1(N)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].[OH-].[NH4+]>C(O)C>[ClH:1].[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][C:13]1[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]=1
Reactant: CCOC(=N)CC1COc2ccccc2O1
Reactant: Nc1ccccc1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2c(c1)OCC(Cc1nc3ccccc3[nH]1)O2
Yield: 40.9 %

Procedure:
Ethyl (1.4-benzodioxan-2-yl)acetimidate HCl, (5.0 g, 19.4 mmol) and o-phenylenediamine (2.16 g, 200 mmol) in ethanol (50 ml) were heated to reflux for 16 hours. The solution was cooled made basic with ammonium hydroxide, and extracted with ethyl acetate. The dried ethyl acetate extract was evaporated to a white solid which was triturated with ether and filtered to a white solid. This solid was dissolved in methanol and acidified with methanolic hydrogen chloride. The precipitated HCl salt was filtered and washed with ether to afford 2.4 g of 2-(1,4-benzodioxan-2-ylmethyl)benzimidazole hydrochloride, m.p. 230°-232°.
Reaction SMILES: [CH2:1]([O:3][CH:4]([S:30][CH2:31][CH3:32])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:29])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)=[CH:13][C:12]=1[N+:26]([O-:28])=[O:27])[CH3:2].[OH:33][C:34]1[C:48]([O:49][CH3:50])=[CH:47][C:37]2[C:38](=[O:46])[N:39]3[CH2:45][CH2:44][CH2:43][C@H:40]3[CH2:41][NH:42][C:36]=2[CH:35]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC(C)=O.O>[CH2:1]([O:3][CH:4]([S:30][CH2:31][CH3:32])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:29])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:33][C:34]2[C:48]([O:49][CH3:50])=[CH:47][C:37]3[C:38](=[O:46])[N:39]4[CH2:45][CH2:44][CH2:43][C@H:40]4[CH2:41][NH:42][C:36]=3[CH:35]=2)=[CH:13][C:12]=1[N+:26]([O-:28])=[O:27])[CH3:2]
Reactant: COc1cc2c(cc1O)NC[C@@H]1CCCN1C2=O
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCCBr)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1[N+](=O)[O-]

Procedure:
A solution of (2S)-N-[4-(5-bromopentyloxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula I. (549 mg, 1 mmol), 8-hydroxy-7-methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (248 mg, 1 mmol) II and K2CO3 (414 mg, 3 mmol) in dry acetone (20 mL) was refluxed for 48 h. After the completion of reaction as indicated by TLC, EtOAc, the reaction mixture was poured on to the water and then extracted with ethylacetate. Evaporation of the organic layer gave the crude product, which was further purified by column chromatography on silica gel eluting with EtOAc:hexane (8:2) gave the pure (2S)-N-{4-[5-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)pentyloxy]-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: [H][H]
Reactant: CCCCCCN(CCC#N)CCC#N
Solvent: C1COCCO1
Product: CCCCCCN(CCCN)CCCN
Yield: 100.6 %

Procedure:
31.0 g of N,N-bis(2-cyanoethyl)hexylamine, 4.65 g of RaneyCo, 150 ml of 1,4-dioxane was charged to an autoclave, and hydrogen addition reaction was carried out by supplying hydrogen at an initial pressure of 9.1 MPa at 110° C. for 2 hours. After removing a catalyst by filtration, the obtained filtrate was concentrated and dried to obtain 32.4 g of a target compound as a pale red oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11]O)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:37]I>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][I:37])[CH3:2]
Reactant: CCOc1ccccc1CCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1ccccc1CCI
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
Into a 50-mL round-bottom flask was placed dichloromethane (20 mL) and 2-(2-ethoxyphenyl)ethan-1-ol (1.33 g, 8.00 mmol, 1.00 equiv). The solution was cooled to 0° C. in a water/ice bath. Then PPh3 (2.72 g, 10.37 mmol, 1.30 equiv), imidazole (707 mg, 10.40 mmol, 1.30 equiv) and I2 (2.44 g, 9.61 mmol, 1.20 equiv) were added. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of 50 mL of NaHSO3 (aq.). The organic layer was separated and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:100). Purification afforded 1.34 g (61%) of 1-ethoxy-2-(2-iodoethyl)benzene as a colorless oil.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:24]([OH:26])=O)[CH2:20][CH:21]([CH3:23])[CH3:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:35]>C(#N)C>[C:1]([NH:18][C@H:19]([C:24]([F:35])=[O:26])[CH2:20][CH:21]([CH3:23])[CH3:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
FMOC-L-Leucine (5 g, 14.14 mmol) (Bachem) was dissolved in acetonitrile (70 mL). Pyridine (1.14 mL, 14.14 mmol) (Aldrich) and cyanuric fluoride (1.91 g, 14.14 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred overnight. Ice cold water (300 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford FMOC-L-leucyl fluoride as a white powder. (Yield 4.57 g, 91%).
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[C:7]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH:16]([CH2:20][C:21](OCC)=[O:22])[N:15]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:14]2=[O:30])([CH3:10])([CH3:9])[CH3:8]>C(O)C>[C:7]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH:16]([CH2:20][C:21]([NH:5][C:4]([NH2:6])=[NH:3])=[O:22])[N:15]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:14]2=[O:30])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)CC1c2ccc(C(C)(C)C)cc2C(=O)N1CC(C)C
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: CC(C)CN1C(=O)c2cc(C(C)(C)C)ccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
N-[(5-tert-Butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 9, starting with 10 cm3 of absolute ethanol, 0.19 g of sodium, 0.80 g of guanidinium chloride and 1.81 g of ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate in 10 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 18 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in a mixture of 10 cm3 of water and 30 cm3 of diethyl ether and then stirred at a temperature in the region of 0° C. for 1 hour. The precipitate obtained is filtered off, washed with twice 10 cm3 of ice-cold water and then dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 1.1 g of N-[(5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine are thus obtained in the form of a white powder melting at 262-263° C. Ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate is described in Example 10. (Analysis: C19 H28 N4 O2; % calculated C: 66.25, H: 8.19, N: 16.27, 0: 9.29% found C: 66.13, H: 8.50, N: 16.12).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[C:8]2[C:17]3[CH:16]=[CH:15][C:14]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:26])[C:9]=2[N:27]=1)(=O)C.[OH-].[Na+]>CO>[NH2:26][C:10]1[C:9]2[N:27]=[C:6]([CH2:5][OH:4])[N:7]([CH2:28][C:29]([CH3:31])([OH:32])[CH3:30])[C:8]=2[C:17]2[CH:16]=[CH:15][C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:13][C:12]=2[N:11]=1
Reactant: CC(=O)OCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(OCc4ccccc4)ccc3c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of [4-amino-7-benzyloxy-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate (34.0 g, 0.0782 mol) in methanol (150 mL) was heated at reflux, and a solution of aqueous sodium hydroxide (50 mL of 1.7 M) was added over a period of five minutes. A white precipitate formed, and the reaction was heated at reflux for one hour. The reaction mixture was allowed to cool to room temperature and stirred for about three hours. The precipitate was isolated by filtration, washed with deionized water and methanol, and then dried under vacuum at 50° C. to provide 24.9 g of the crude product. The crude product (6.0 g) was recrystallized from a mixture of 2-propanol:acetic acid 9:1 (470 mL); the hot solution was treated with activated charcoal and filtered through a layer of CELITE filter aid. The crystals were isolated by filtration, washed with a small volume of 2-propanol:acetic acid, and dried under vacuum at 50° C. The product was stirred with aqueous sodium hydroxide (200 mL of 0.15 M) for three hours, isolated by filtration, washed with deionized water, stirred with methanol (100 mL) for one hour, isolated by filtration, washed with methanol, and dried under vacuum at 60° C. Finally, the product (4.5 g) was recrystallized from DMF, isolated by filtration, and dried under vacuum to provide 1-[4-amino-7-benzyloxy-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 284.5-285.5° C.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:12]=2)=[C:7]([F:27])[CH:6]=1.[C:33]([C:35](=[CH:39][CH:40]([CH3:42])[CH3:41])[C:36](O)=[O:37])#[N:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:36]([C:35](=[CH:39][CH:40]([CH3:42])[CH3:41])[C:33]#[N:34])=[O:37])[CH2:22]3)[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])=[CH:6][C:7]=3[F:27])[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2[C@@H]1CCCNC1
Reactant: CC(C)C=C(C#N)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 19.4 %

Procedure:
To a mixture of (R)-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.23 mmol, 1.0 eq), 2-cyano-4-methyl-pent-2-enoic acid (38 mg, 0.27 mmol, 1.2 eq) and DIEA (88 mg, 0.68 mmol, 3.0 eq) in 10 ml DCM was added HATU (130 mg, 0.34 mmol, 1.5 eq). The reaction mixture was stirred for 4 h at RT under N2. The mixture was purified by Pre-HPLC to give the title compound (25 mg 40% yield). LCMS: m/Z+(562.2) (M+H)+ 1HNMR (400 MHz, CDCl3): δ 0.784˜1.186 (m, 7H), 1.765-2.254 (m, 5H), 2.861-4.937 (m, 4H), 6.218 (m, 0.4H), 6.857˜7.600 (m, 6H), 8.255 (s, 1H) and 9.888 (m, 1H).