Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.Br[C:22]1[CH:23]=[C:24]([NH2:30])[C:25]([O:28][CH3:29])=[N:26][CH:27]=1.COCCOC>O>[CH3:29][O:28][C:25]1[C:24]([NH2:30])=[CH:23][C:22]([C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[CH:9][CH:10]=2)=[CH:27][N:26]=1
Reactant: COc1ncc(Br)cc1N
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Solvent: O
Solvent: COCCOC
Product: COc1ncc(-c2ccnn2C2CCCCO2)cc1N
Temperature: 92 °C

Procedure:
To a 100 ml flask was added 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 14.1.B (6.0 g, 22 mmol), 5-bromo-2-methoxypyridin-3-amine (4 g, 20 mmol), 100 ml of DME, and 30 ml of water. Argon was then bubbled through the solution for 8 minutes at which time Pd(Ph3)4 (460 mg, 0.39 mmole) was added and argon was then bubbled through the solution for an additional 2 minutes. The reaction was then heated to 92° C. for 12 hours at which time the crude was quenched with brine and extracted with EtAc. The solvent was removed and the crude purifed on silica gel (eluting with 0-70% EtAc in Hexanes) to 2-methoxy-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-amine 14.1.C (5.3 g, 97. % yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O/[CH:18]=[C:19](\[CH3:23])/[C:20](=O)[CH3:21]>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[C:20]([CH3:21])=[C:19]([CH3:23])[CH:18]=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)/C(C)=C/O
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Solvent: CC(=O)O
Product: Cc1cnc2c3c(nn2c1C)CN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.9 %

Procedure:
A mixture of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (1 g; 4.46 mmol; 1 eq.) and (3E)-4-hydroxy-3-methylbut-3-en-2-one (prepared according to J. Het. Chem. 1980, 17(1), 33-37) (0.6 g; 4.91 mmol; 1.1 eq.) in AcOH (5 mL) was stirred at room temperature for 18 hours then concentrated in vacuo. The residue was partitioned between 1M NaOH and DCM, the organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting oil was triturated in Et2O, the precipitate filtered off and the solution concentrated in vacuo. The residue was purified by SFC (column: Chiralpak IC, eluent 25% MeOH) to afford successively the title compound (140 mg, 11%) as a white solid and Intermediate C2. 1H NMR (CDCl3) δ 8.33 (s, 1H), 4.72-4.62 (m, 4H), 2.54 (d, J=3.1 Hz, 3H), 2.29 (d, J=0.7 Hz, 3H), 1.52 (d, J=3.3 Hz, 9H). HPLC (max plot) 87.3%; Rt 3.27 min. UPLC/MS: (MS+) 289.1 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1[CH2:31][CH2:30][O:29][CH:28]1[C:32]1[O:36][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][CH:33]=1>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:35]4[O:36][C:32]([CH:28]5[O:29][CH2:30][CH2:31][O:27]5)=[CH:33][CH:34]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5ccc(C6OCCO6)o5)cc34)cc2)cc1
Yield: 62.1 %

Procedure:
Prepared according to Procedure B from (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (1.5 g, 3.7 mmol) and 5-(1,3-dioxolan-2-yl)-2(tributylstannyl)-furan (1.9 g, 4.42 mmol) dissolved in dioxan (30 ml) and heated at reflux under nitrogen for 6 hr. The solvent was removed from the cooled reaction under vacuum, and the residual oil was triturated with iso-hexane/ethyl acetate to give the product (1.07 g, 62%) as a pale yellow solid; δH [2H6]-DMSO 9.96 (1H, b, NH), 8.80 (1H, s, 5-H), 8.51 (1H, s, 2-H), 8.18 (1H, d, 7-H), 7.80 (1H, d, 8-H), 7.70 (2H, d, 2′-H, 6′-H), 7.58-7.30 (5H, m, 5×Ph-H), 7.10 (3H, m, 3′-H, 5′-H, furan 3-H), 6.78 (1H, d, furan 4-H), 6.12 (1H, s, CHO2), 5.18 (2H, s, PhCH2), 4.22-3.94 (4H, m, 2×CH2); m/z 466 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH3:9])[C:7]=1[F:8].[N+:10]([O-])([OH:12])=[O:11]>>[CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([CH3:9])[C:7]=1[F:8]
Reactant: Cc1cccc(C)c1F
Reactant: O=[N+]([O-])O
Product: Cc1cc([N+](=O)[O-])cc(C)c1F
Reaction time: 1 h

Procedure:
In 120 ml of nitric acid was dissolved 120 g of 3,5-dimethyl-4-fluorobenzene (mfd. by Columbia Organic Chemical Co., Inc.) at -10° C. over a period of 1 hour, after which the temperature was adjusted to -15° C. and the reaction was carried out with stirring for another 1 hour. After completion of the reaction, the reaction solution was poured onto ice and the yellow crystals thus precipitated were collected by filtration and subjected to distillation at atmospheric pressure to obtain 40 9 of 3,5-dimethyl-4-fluoro-1-nitrobenzene as distillate having a boiling point of 111°-112° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][N:16]1[CH:24]=[C:23]2[C:18]([CH:19]=[C:20]([CH2:25][NH2:26])[CH:21]=[CH:22]2)=[N:17]1>>[CH3:15][N:16]1[CH:24]=[C:23]2[C:18]([CH:19]=[C:20]([CH2:25][NH:26][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[CH:21]=[CH:22]2)=[N:17]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1cc2ccc(CN)cc2n1
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3cn(C)nc3c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (2-methyl-2H-indazol-6-yl)methanamine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:4][N:3]=1.[H-].[Na+].[CH3:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1>CN(C)C=O>[CH3:30][C:31]1[CH:32]=[N:33][N:34]([C:2]2[N:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[C:5]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:4][N:3]=2)[CH:35]=1
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Reactant: Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnn(-c2ncc(C(=O)N3Cc4cccn4Cc4ccccc43)c(C(F)(F)F)n2)c1
Yield: 66.7 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-trifluoromethyl-pyrimidin-5-yl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.98 g), 60% sodium hydride in oil (0.15 g), 4-methylpyrazole (0.42 g) and dimethylformamide (25 ml), the title compound (0.73 g) was obtained as a crystalline solid, m.p. 214-217° C.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14])C1C=CC=CC=1>[Pd].C(O)C>[C:22]([O:21][C:19]([NH:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[CH2:12][CH2:11][NH2:10])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=O)CCN
Reaction time: 12 h

Procedure:
80 mg of palladium on activated carbon (10%) are added to a mixture of 0.30 g (0.82 mmol) of the compound from Example 254A in 10 ml of ethanol, and the mixture is then hydrogenated under atmospheric pressure for 12 h. The reaction mixture is filtered through kieselguhr, and the filtrate is concentrated in vacuo and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:28][C:29]([F:38])([F:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1>O1CCCC1>[F:28][C:29]([F:37])([F:38])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH3:16])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:31]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(OCC(C)Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2(α,α,α-trifluoro-p-tolyloxy)propoxy]phenyl}acetate (0.017 mole) is reacted with 2.75 g of α,α,α-trifluoro-m-cresol in 75 ml of tetrahydrofuran at 80° C. for 18 hrs to give the product as a viscous oil.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][C@H:6]1[CH2:18][CH2:17][N:9]2[C:10]3[C:15]([CH:16]=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)C.[OH-].[Na+].Cl>CO>[CH:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[C:8]1[CH2:7][C@@H:6]([CH2:5][C:4]([OH:19])=[O:3])[CH2:18][CH2:17][N:9]12
Reactant: CCOC(=O)C[C@H]1CCn2c(cc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C[C@H]1CCn2c(cc3ccccc32)C1

Procedure:
A solution of 17 g (63 mmol) of methyl alpha (R or S)-ethyl-6,7,8,9-tetrahydropyrido[1,2-a]indole-8(S)-acetate (diastereomers A+B) in 150 ml of methanol was treated with 130 ml of 2M sodium hydroxide and heated to reflux for 18 hours. The cooled solution was added to 150 ml of 4M hydrochloric acid and the resulting precipitate was filtered off and partitioned between 200 ml of dichloromethane and 100 ml of water. The organic phase was separated, dried over magnesium sulfate and evaporated to give 15 g of alpha (R or S)-6,7,8,9-tetrahydropyrido[1,2-a]indole-8(S)-acetic acid (diastereomers A+B) as a pale pink solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])=[CH:10][CH:9]=1.[CH2:22]([C:24]([C:43]1[CH:56]=[CH:55][C:46]([O:47][CH2:48][C@@H:49]2[O:53][C:52](=[O:54])[CH2:51][CH2:50]2)=[C:45]([CH3:57])[CH:44]=1)([C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([CH3:42])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(OCC)(=O)C>CN(C)C=O>[CH2:22]([C:24]([C:43]1[CH:56]=[CH:55][C:46]([O:47][CH2:48][C@@H:49]2[O:53][C:52](=[O:54])[CH2:51][CH2:50]2)=[C:45]([CH3:57])[CH:44]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])=[CH:10][CH:9]=2)=[C:29]([CH3:42])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CC(C)(O[Si](C)(C)C)c1ccc(Br)cc1
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2ccc(C(C)(C)O[Si](C)(C)C)cc2)c(C)c1
Temperature: 85 °C
Reaction time: 13.5 h
Yield: 47.8 %

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.49 mg, 0.002 mmol), a 2 M sodium carbonate solution (0.1 mL, 0.2 mmol) and [1-(4-bromo-phenyl)-1-methyl-ethoxy]-trimethylsilane (Example 15-(1); 26.25 mg, 0.091 mmol) were added to a solution of (R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(3); 30 mg, 0.061 mmol) in N,N-dimethylformamide (0.1 mL) at room temperature, and the mixture was stirred at 85° C. for 13.5 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1, developed three times) to give the title compound (16.7 mg, 47.9%).
Reaction SMILES: [CH3:1][C@H:2]([CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH2:19][C@H:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])[CH:13]=2)=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:25].ClC1C=C(C=CC=1)C(OO)=[O:34]>ClCCl>[CH3:1][C@H:2]([CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH2:19][C@H:20]([CH3:24])[CH:21]([CH3:22])[CH3:23])[CH:13]=2)(=[O:34])=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:25]
Reactant: Cc1ccc(S(=O)c2ccc(C)c(C[C@H](C)C(C)C)c2)cc1C[C@H](C)C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2ccc(C)c(C[C@H](C)C(C)C)c2)cc1C[C@H](C)C(C)C

Procedure:
(2S)-2,3-Dimethylbutyl-p-tolylsulfoxide (4) (52 mg, 0.2 mmol) was dissolved in 1.0 mL of anhydrous dichloromethane and 60 mg (0.3 mmol) of 3-chloroperoxybenzoic acid (80-85%, Sigma) added with stirring. The reaction mixture was stirred for 2 h and quenched with 10% sodium bicarbonate. More dichloromethane was added and the combined organic extracts were washed with aqueous sodium sulfite and brine and dried with MgSO4. The solvent was removed in vacuo and the crude sulfone was purified by silica gel flash chromatography using hexane ethyl acetate mixtures to afford sulfone (6) as a colorless oil. For analytical purposes this was also purified by HPLC (Zorbax Sil 9.4×25 cm column) using 10% ethyl acetate in hexane to give 42 mg of pure (2S)-sulfone (6): [α]D20 =+17 (c=3.5 in CHCl3); MS m/z (relative intensity) 240 (M+, 3), 197 (5), 157 (100), 92 (19), 91 (27), 85 (25), 84 (31), 43 (72); 1H NMR δ 0.77 (3H, d, J=7 Hz), 0.82 (3H, d, J=7.0 Hz), 1.00 (3H, d, J=7.0 Hz), 1.66-1.98 (2H, m), 2.45 (3H, s, CH3 -Aryl), 2.86 (1H, dd, J=8, 11 Hz), 3.06 (1H, dd, j=4, 12 Hz), 7.35 (2H, d, J=7.0 Hz, H-aryl ortho), 7.75 (2H, d, J=8, H-aryl ortho).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].NC1C=CC([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:28]([NH2:30])=[O:29])=CC=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[NH:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[CH:19]=[C:20]([C:28]([NH2:30])=[O:29])[NH:21]2
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: NC(=O)c1[nH]c2ccccc2c1-c1ccc(N)cc1
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccccc2-c2cccc3[nH]c(C(N)=O)cc23)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 226.9 %

Procedure:
0.115 cm3 (0.876 mmol) of 2-fluoro-5-methylphenyl isocyanate is added, at a temperature in the region of 20° C., under an argon atmosphere, to 0.2 g (0.796 mmol) of 3-(4-aminophenyl)-1H-indole-2-carboxamide in solution in 10 cm3 of tetrahydrofuran. After stirring for 18 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), to give 400 mg of a residue which is purified by flash chromatography [eluent: ethyl acetate/cyclohexane (7/3 by volume)]. After concentration under reduced pressure of the fractions containing the expected product, 250 mg of a yellow residue are obtained, which residue is stirred in 10 cm3 of dichloromethane and then filtered and dried under reduced pressure (2.7 kPa), to give 180 mg of 3-{4-[3-(2-fluoro-5-methylphenyl)ureido]phenyl}-1H-indole-2-carboxamide, in the form of a beige solid that melts at 220° C.;
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1)=O)(C)(C)C.NN>CCO>[C:35]([O:34][C:32](=[O:33])[NH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:18]([CH2:17][C:9]1[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=1)[CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2n1C(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2[nH]1
Yield: 63.2 %

Procedure:
To a solution of 2-{[(4-tert-Butoxycarbonylamino-butyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester (0.82 g, 1.57 mmol) in EtOH (8 mL) was added anhydrous hydrazine (0.50 mL, 15.9 mmol) and the resultant mixture was stirred at room temperature overnight. The mixture was filtered through filter paper and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 0.42 g (62%) of {4-[(1H-benzoimidazol-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][CH2:11][C:12]([O:14]CC)=[O:13].[OH-].[K+]>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CN=c1sc2ccccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN=c1sc2ccccc2s1
Yield: 58.5 %

Procedure:
A solution of [(1,3-benzodithiol-2-ylidene) amino]-acetic acid ethyl ester (2.5g, prepared as described in Example 1) and potassium hydroxide (550 mg) in 500 ml of anhydrous methyl alcohol is stirred at room temperature for 120 hours. The reaction mixture is then concentrated in vacuo. The resultant solid residue is triturated with diethyl either to remove unreacted starting material. The undissolved residue is then dissolved in 50 ml of water and filtered through Celite. The aqueous solution is treated with 10% hydrochloric acid until the pH is 5. The resultant precipitate is collected by filtration and dried in vacuo over phosphorous pentoxide at 60° C for about 16 hours. The dried solid is recrystallized twice from ethyl acetate to yield 1.3g of the title compound, melting point 195°-200° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23]CC5C=CC=CC=5)=[CH:19][CH:18]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:31])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1
Reactant: CC1(C)N=CC2=C3N=C(c4ccc(OCc5ccccc5)cc4)N=C3C(=O)CC2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)N=CC2=C3N=C(c4ccc(O)cc4)N=C3C(=O)CC2C1=O

Procedure:
A mixture consisting of 2.3 gm of 7,7-dimethyl-2-(4-benzyloxy-phenyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione, 200 ml of methanol and 0.5 gm of 10% palladium-on-charcoal was hydrogenated at 50° C. at a hydrogen pressure of 5 atmospheres for 4 hours. The catalyst was then filtered off, the filtrate was evaporated to 50 ml and the precipitated crystals were suction-filtered off.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O>C1(C)C=CC=CC=1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1Cc2ccccc2C1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(N2CCCC2)Cc2ccccc21

Procedure:
A mixture of 2-indanone (2.0 g, 15.1 mmol) and pyrrolidine (1.6 mL, 19.7 mmol) in anhydrous toluene (61 mL) was refluxed under nitrogen with azeotropic removal of water (Dean-Stark apparatus) for 2 h. The mixture was then cooled and concentrated to dryness in vacuo to give the title compound. MS:m/z=186.2 (M+1).
Reaction SMILES: [NH:1]([C:28]([CH3:30])=[O:29])[C@@H:2]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@@H:21]1[C:22]([OH:24])=O)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.[NH2:32][C@@H:33]([C:37]([NH2:39])=[O:38])[CH:34]([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[NH:1]([C:28]([CH3:30])=[O:29])[C@@H:2]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@@H:21]1[C:22]([NH:32][C@@H:33]([C:37]([NH2:39])=[O:38])[CH:34]([CH3:36])[CH3:35])=[O:24])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CC(C)[C@@H](N)C(N)=O
Reactant: CC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=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: CN(C)C=O
Product: CC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)N[C@@H](C(N)=O)C(C)C
Temperature: 5 °C
Reaction time: 1.65 h

Procedure:
In an inert thermostable reactor provided with a mechanical stirrer, 94.25 g of Ac-D-Lys(Z)-D-Pro-OH (XI) (224.7 mmol) are introduced followed by 470 ml of DMF. 32.58 g of HCl. H-D-Val-NH2 (V) (213.5 mmol, 0.95 eq) and 85.22 g of HBTU (1 eq) are then added. The medium is cooled down to 5° C., and 96.6 ml of ethyldiisopropylamine (2.5 eq) are added dropwise within 15 minutes. This is allowed to reach 0° C. again and after 1.30 to 2 hours, a strong crystallization could be observed. The reaction completion is CCM controlled. The reaction medium is then poured onto 2350 ml of AcOEt, stirred for 15 minutes, filtered and washed successively with 470 ml of AcOEt and 470 ml of diisopropyl ether. The derivate (XII) is vacuum dried at 25° C. This way, 107.2 g (92%) pf Ac-D-Lys(Z)-D-Pro-D-Val-NH2 are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[O:19][C:20]5[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[ClH:42]>CC(C)=O>[ClH:42].[ClH:42].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[O:19][C:20]5[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=5[N:22]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C(=O)OC(C)(C)C)CC5)c5ncnc(N)c45)cc3)nc2c1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCNCC5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 45 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 4-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (142 mg, 0.256 mmol) was dissolved in acetone (7 mL) and 6N aqueous hydrochloric acid (1.4 mL). The reaction was then heated at 45° C. which yielded a precipitate. After 2.5 hours, the precipitate was collected by vacuum filtration, washed with a minimal amount of acetone and dried on the lyophilizer to N2-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}-5,7-dimethyl-1,3-benzoxazol-2-amine dihydrochloride as an orange solid (130 mg, 96%); -HPLC 10.436 min, 96% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z (MH+)=455.3.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]([O:14]CC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])[C:19]=1[O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(NCc2ccccc2)c(Oc2ccccc2)c(S(=O)(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccccc1

Procedure:
Ethyl 3-benzylamino-5-dimethylsulphamyl-4-phenoxy-benzoate (1 g) was heated on a steam bath with 1N sodium hydroxide (15 ml) for 6 hours. From the resulting solution, the 3-benzylamino-5-dimethylsulphamyl-4-phenoxy-benzoic acid was precipitated by addition of 4N hydrochloric acid until a pH of 2.5. After isolating and recrystallizing from aqueous ethanol, the compound was obtained with a melting point of 205-206°C.