Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[NH2:4].[OH-].[Na+].[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].Cl>O.C(OC)(C)(C)C>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[NH:4][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1cc(N)c(Br)cc1OC
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: COc1cc(Br)c(NC(=O)C(C)(C)C)cc1OC
Reaction time: 1 h

Procedure:
A dry 500 mL three-necked flask was charged with 2-bromo-4,5-dimethoxyaniline (23.4 g, 0.10 mol) and t-BuOMe (200 mL), NaOH (25.3 g, 25%, 0.158 mol) was added in portions at 0° C. Then pivaloyl chloride (12.9 g, 0.106 mol) was added dropwise slowly under N2 at 0° C. After addition, the mixture was stirred for an additional 1 hour and diluted with water (100 mL), acidified by 5% HCl to pH=7 and extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (100 mL×3), dried over anhydrous MgSO4, filtrated and concentrated in vacuum to afford the compound N-(2-bromo-4,5-dimethoxyphenyl)-2,2-dimethylpropanamide. MS (M+H)=316 and 318.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[NH:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=1)[CH3:2].[OH-].[Na+].O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[NH:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(Nc2ccc(OCC)c(OCC)c2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ccc(Nc2ncc(C(=O)O)c(=O)[nH]2)cc1OCC
Reaction time: 1 h
Yield: 65.3 %

Procedure:
Ethyl 1,6-dihydro-2-(3,4-diethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (5 g) and sodium hydroxide (2 g) are added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (40 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(3,4-diethoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (3 g). M.p. 243°-245° C.
Reaction SMILES: [C:1]1([C:7]([CH:9]=[N+]=[N-])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C@:13]12[C@@H:33]([OH:34])[CH2:32][C@@:31]3([CH3:35])[C@@H:23]([CH2:24][C@@H:25]([OH:37])[C@:26]3([OH:36])[C:27](=[O:30])[CH2:28][OH:29])[C@@H:22]1[CH2:21][CH2:20][C:19]1[C@:14]2([CH3:39])[CH2:15][CH2:16][C:17](=[O:38])[CH:18]=1>CO>[F:12][C@:13]12[C@@H:33]([OH:34])[CH2:32][C@@:31]3([CH3:35])[C@@H:23]([CH2:24][C@@H:25]([O:37][CH2:9][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH2:8])[C@:26]3([OH:36])[C:27](=[O:30])[CH2:28][OH:29])[C@@H:22]1[CH2:21][CH2:20][C:19]1[C@:14]2([CH3:39])[CH2:15][CH2:16][C:17](=[O:38])[CH:18]=1
Reactant: C=C(C=[N+]=[N-])c1ccccc1
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Solvent: CO
Product: C=C(CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of 2-phenyl-3-diazo-1-propene prepared as described above is diluted with 150 ml of cold methanol and stirred well at 0°C as 13 g of 9-fluoro-11β,16α,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added in portions. The slurry is stirred for 1 hour at 0°C and filtered to give 9.6 g of the title compound. The filtrate is stirred at room temperature for 1 hour with 4 g of the cycloborate and the resulting solution is cooled to 0°C and filtered to give 4.2 g of the title compound. The filtrate is evaporated in vacuo and the residue is dissolved in 400 ml of 3:1 ether-methanol and cooled to -10°C to give a further 3.0 g of material. A small sample recrystallized from acetone-hexane has a melting point of 161°-163.5°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][CH2:22][OH:23])=[O:9])([CH3:6])[CH3:5].[F:25][C:26]1[CH:27]=[C:28](O)[CH:29]=[C:30]([F:32])[CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][CH2:22][O:23][C:28]1[CH:27]=[C:26]([F:25])[CH:31]=[C:30]([F:32])[CH:29]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: Oc1cc(F)cc(F)c1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCCOc1cc(F)cc(F)c1

Procedure:
To a solution of 67 mg 2-{[1-(2-hydroxy-ethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester and 29 mg 3,5-difluorophenol in 1 ml THF at 0° C. 58 mg triphenyl phosphine and 46 μl diisopropylazodicarboxylate were added. After 16 h at room temperature the reaction was concentrated in vacuo and after chromatography on silica (ethyl acetate/heptane) 80 mg 2-({1-[2-(3,5-difluoro-phenoxy)-ethoxy]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester were obtained.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:5][CH:4]=1.Br.[OH-].[Na+]>>[N:13]1([CH2:12][CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: COc1ccc(CCCCn2ccnc2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc(CCCCn2ccnc2)cc1
Temperature: 0 °C

Procedure:
1.90 g (8.25 mmol) 1-[4-(4-methoxy-phenyl)-butyl]-1H-imidazole and 28 ml (247 mmol) 48% aqueous hydrobromic acid were stirred at 80° C. for 10 h. The mixture was cooled to 0° C., 23 ml of 4 N NaOH added, extracted with toluene and the aqueous phase adjusted to pH=6.3 by addition of 6 N HCl. The resulting precipitate was isolated, washed with ethyl acetate/n-heptane 2:1 and dried. 1.2 g (67%) slightly yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](=[O:11])[NH:9][N:8]([C:12]2[CH:17]=[CH:16][C:15](N)=[CH:14][CH:13]=2)[CH:7]=1)=[O:5])[CH3:2].N([O-])=[O:20].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]([O:3][C:4]([C:6]1[C:10](=[O:11])[NH:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:20])=[CH:14][CH:13]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccc(N)cc2)[nH]c1=O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(O)cc2)[nH]c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
4-Ethoxycarbonyl-2-(4-amino phenyl)-3-pyrazolin-5-one (610 mg, 2.46 mmol) in 5N Sulphuric acid (90 ml) was stirred on a boiling water bath to give a solution. This was cooled to 0° C. and the colloidal precipitate formed treated with sodium nitrite (190 mg, 2.71 mmol) in water (2 ml). The whole was then allowed to stir for 2 hours at 0° C. under nitrogen and then added dropwise to boiling 5N sulphuric acid (30 ml) so as not to interrupt boiling. The solution was then allowed to cool and was extracted with ethyl acetate which, after drying (MgSO4) and evaporation, gave the crude product (190 mg). This was purified by chromatography on silica (hexane; ethyl acetate) to give the desired product (101 mg) νmax (KBr Disc) 1660, 1595, 1520, 1433, 1277, 1140 cm-1, δ(D6 -Acetone) 1.33(3H, t, J7 Hz,--OCH2CH3), 3.30(1H, br), 4.33(2H,q,J7 Hz--OCH2CH3), 6.94 (2H, d, J9 Hz, protons o--OH), 7.65 (2H,d, J9 Hz, protons m--OH), 8.44 (1H, s, C3 pyrazole proton), 8.75 (1H, brs); Found: M+, 248.0773; C12H12N2O4 requires M, 248.0797. Calculated: C,58.1; H,4.8; N,11.3, Found: C, 58.3; H,5.1; N, 11.0
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[Cl:7].[Cl:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[C:12]=1[C@H:20]([C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[NH:24][CH:23]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:7][C:6]1[N:5]([CH3:8])[N:4]=[C:3]([CH3:9])[C:2]=1[C:28]1[CH:29]=[C:30]2[C:22]([C@@H:20]([C:12]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([F:17])[C:11]=3[Cl:10])[CH3:21])=[CH:23][NH:24][C:25]2=[N:26][CH:27]=1
Reactant: Cc1nn(C)c(Cl)c1Br
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3c(C)nn(C)c3Cl)cc12
Temperature: 100 °C

Procedure:
A solution of 4-bromo-5-chloro-1,3-dimethyl-1H-pyrazole (0.0219 g, 0.104 mmol), 3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.030 g, 0.070 mmol), potassium carbonate (0.0289 g, 0.209 mmol) and Pd(PPh3)4 (8.04 mg, 0.00697 mmol) in previously degassed 4:1 dioxane:water (1.50 mL) was evacuated and charged with N2 (2×) and heated under microwave conditions [Biotage, 100° C., 30 min, high absorption]. This was further purified by Gilson HPLC resulting in the title compound as white solid. 1H NMR (400 MHz, CD3OD): δ=1.82 (d, J=7.3 Hz, 3H), 2.13 (s, 3H), 3.66 (br. s., 3H), 3.84 (s, 3H), 5.12 (q, J=7.2 Hz, 1H), 6.91 (dd, J=4.2, 9.0 Hz, 1H), 7.09 (dd, J=8.8, 8.8 Hz, 1H), 7.39 (d, J=1.3 Hz, 1H), 7.45 (s, 2H). MS (ES+): m/z 433.03, 435.01 (76/24) [MH+]. HPLC: tR=4.25 min (polar—5 min, ZQ3).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH:5]([C:16]([OH:18])=[O:17])[S:6][CH2:7][C:8](O)([CH3:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:9]([C:8]1([CH3:14])[O:17][C:16](=[O:18])[CH:5]([CH2:4][C:3]([OH:2])=[O:19])[S:6][CH2:7]1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(C)(O)CSC(CC(=O)OC)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCCCCC1(C)CSC(CC(=O)O)C(=O)O1

Procedure:
2.7 g of 6-hydroxy-3-hydroxycarbonyl-6-methyl-4-thiaundecanoic acid methyl ester is boiled with 3.3 g of α,α-dipyridyl disulphide and 5.4 g of triphenyl phosphine for 5 hours in 105 ml of xylene. After the usual working up, 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid is obtained
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl.[CH:8]([O:10][CH2:11][CH3:12])=[CH2:9]>C(Cl)Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][CH2:8][O:10][CH2:11][CH3:12])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: C=COCC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOCCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.4 %

Procedure:
To a solution of 4-bromopyrazole (70.0 g, 0.476 mol) in CH2Cl2 (600 mL) was added a solution of 3.1 M HCl in dioxane (4 mL) and ethyl vinyl ether (41 g, 0.569 mol, 1.2 equiv) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 3 h. The reaction was quenched with aqueous NaHCO3 and the two layers were separated. The organic layer was washed with water, dried over Na2SO4, and concentrated under reduced pressure to dryness to afford 4-bromo-1-(ethoxyethyl)-1H-pyrazole (113 g, 104.3 g theoretical, 97% yield) as an oil (GC purity: 89%), which was directly used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[NH:5][C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][N:9]1[C:10]2[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[NH:5][C:6]=2[N:7]=[CH:8]1)[CH3:25]
Reactant: CCOC(=O)CCl
Reactant: Cn1c(=O)[nH]c2nc[nH]c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2[nH]c(=O)n(C)c(=O)c21
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of 1-methyl xanthine (120, 1 g, 6.01 mmol) in DMF, potassium carbonate (0.91 g, 6.6 mmol) was added and the reaction mixture was heated to 90° C. and stirred for 1 h. A solution of ClCH2COOEt (0.36 g, 3.0 mmol) in DMF was then added dropwise to the reaction over 45 min. After stirring an additional 15 min, the reaction was cooled to room temperature and poured into ice cold 1N HCl (50 ml). The reaction was then extracted with chloroform (50×2 ml). The combined organic layers were washed with water (100 mL), dried over Na2SO4 and concentrated in vacuo. To the resulting solid was added 30% dichloromethane in hexanes (400 mL) and the resulting mixture was stirred for 15 min and filtered to yield compound 121 as a yellow solid (0.6 g, 40%). MS (APCI): m/z 253.32 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:9]=1[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23].[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:9]=1[CH:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[OH:23]
Reactant: O=C(c1cccnc1)c1c(Cc2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1c(Cc2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 50 mg (0.11 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorobenzyl)-4-[(3-pyridyl)carbonyl]isoxazole in 15 mL of THF was added 21 mg (0.56 mmol) of sodium borohydride at room temperature. After 2 hrs, the solution was diluted with ethyl acetate, washed with saturated sodium chloride, and dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation. The crude product was purified by prep TLC to give 39 mg (0.088 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorobenzyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole. 1H NMR (CDCl3): δ 3.91 (d, 1), 4.00 (d, 1), 6.97 (br s, 1), 7.64 (d, 1), 8.42 ppm (br m, 2). MS m/z: 445.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24](O)=[O:25].Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH2:36][NH:35][CH2:34][CH2:33]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)[N:6]=[C:5]2[C:24]([N:35]1[CH2:34][CH2:33][C:32]2[C:37](=[CH:38][CH:39]=[C:30]([O:29][CH3:28])[CH:31]=2)[CH2:36]1)=[O:25]
Reactant: COc1cc(-c2nc(C(=O)O)c3cc(F)ccc3n2)cc(OC)c1OC
Reactant: COc1ccc2c(c1)CCNC2
Agent: Cl
Product: COc1ccc2c(c1)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccc(F)cc13)C2
Yield: 53.8 %

Procedure:
Reaction of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 105 (53.8% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.84 and 2.90 (2t, 2H), 3.60 and 4.06 (2t, 2H), 3.76-3.3.81 (m, 6H), 3.85 and 3.92 (2s, 6H), 4.55 and 4.98 (2s, 2H), 6.50-7.27 (m, 3H), 7.62-7.86 (m, 3H), 7.98-8.07 (m, 1H), 8.23-8.28 (m, 1H); MS (ESI) m/z 504 ([M+H]+).
Reaction SMILES: C(N(CC)CC)C.[N+](C1C=C[C:14]([O:17]C=O)=CC=1)([O-])=O.Cl.[NH2:21][C@H:22]([C@@H:46]([OH:57])[CH2:47][C@H:48]([C:50](=[O:56])[NH:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH3:49])[CH2:23][C@@H:24]([CH:43]([CH3:45])[CH3:44])[CH2:25][NH:26][C:27](=[O:42])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1[O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41]>ClCCl>[CH2:52]([NH:51][C:50]([C@H:48]([CH3:49])[CH2:47][C@H:46]([OH:57])[C@@H:22]([NH:21][CH:14]=[O:17])[CH2:23][C@@H:24]([CH:43]([CH3:45])[CH3:44])[CH2:25][NH:26][C:27](=[O:42])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1[O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[O:56])[CH2:53][CH2:54][CH3:55]
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)C[C@H](CNC(=O)c1cccc(OC)c1OCCCOC)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](CNC(=O)c1cccc(OC)c1OCCCOC)C(C)C)NC=O
Reaction time: 0.5 h

Procedure:
Triethylamine (0.034 ml) and formic acid 4-nitrophenyl ester (28 mg) are added at room temperature, with stirring, to a solution of (2S,4S,5S,7R)-N-(4-amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-octyl)-3-methoxy-2-(3-methoxypropoxy)-benzamide hydrochloride (Example 6a) (67 mg) in dichloromethane (4 ml). The resulting reaction solution is stirred for a further 30 minutes and is then concentrated by evaporation. The residue is purified by FC (18 g of silica gel; eluant E, then ethyl acetate-hexane-methanol 5:5:1). (2S,4S,5S,7R)-N-(7-Butylcarbamoyl-4-formylamino-5-hydroxy-2-isopropyl-octyl)-3-methoxy-2-(3-methoxypropoxy)-benzamide is obtained in the form of a white foam: Rf (L)=0.58. HPLC Rt =13.2 min. MS(FAB) m/e 552 (M+ +1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:22][CH2:23][CH3:24])[N:3]=1.[S-2:25].[Na+].[Na+]>CN(C=O)C>[CH2:23]([O:22][C:4]1[C:5]([C:20]#[N:21])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:7]([C:8]#[N:9])=[C:2]([SH:25])[N:3]=1)[CH3:24]
Reactant: CCOc1nc(Cl)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g (2.909 mmol) of 2-chloro-6-ethoxy-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile is initially charged in 7.5 ml of DMF, 454 mg (5.818 mmol) of sodium sulphide are added and the mixture is stirred at room temperature overnight. The mixture is concentrated, the residue is triturated with acetonitrile and the solid is filtered off and dried under high vacuum. This gives 230 mg (24% of theory) of the target compound.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:37]3[CH2:42][CH2:41][N:40]([CH:43]4[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]4)[CH2:39][CH2:38]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[C:23]([O:35][CH3:36])[CH:22]=3)[C:13]=12>ClCCl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([CH:37]3[CH2:42][CH2:41][N:40]([CH:43]4[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]4)[CH2:39][CH2:38]3)[N:19]=2)=[CH:22][C:23]=1[O:35][CH3:36]
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 28 mL) was added to a solution of tert-butyl N-{4-[4-amino-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}carbamate (0.914 g, 1.70 mmol) in dichloromethane (5 mL) at 0° C. After 15 minutes, the ice-bath was removed and the reaction mixture was stirred at room temperature for 5 hours. Solvents were then evaporated and the residue was dissolved in dichloromethane. Saturated sodium bicarbonate was added to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated give 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.726 g, 97%). 1H NMR (CDCl3) δ 1.67 (m, 2H) 1.83 (m, 4H), 2.00 (m, 2H), 2.27 (s, 3H), 2.39 (m, 5H), 2.91 (m, 2H), 3.08 (m, 2H), 3.92 (s, 3H), 3.99 (m, 2h), 4.73 (m, 1H), 5.56 (bs, 2H), 6.82 (d, J=7.87, 1H), 7.08 (d, J=7.84, 1H), 7.13 (s, 1H), 8.34 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][CH:18]=[C:19]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30](=O)[CH3:31])=[CH:26][CH:25]=3)[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].[CH3:37][NH:38][CH3:39].[ClH:40]>C(Cl)Cl>[ClH:40].[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[O:17][CH:18]=[C:19]([CH2:21][CH2:22][O:23][C:24]3[CH:25]=[CH:26][C:27]([CH:30]([N:38]([CH3:39])[CH3:37])[CH3:31])=[CH:28][CH:29]=3)[N:20]=2)[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:15])[CH3:14]
Reactant: CNC
Reactant: CC(=O)c1ccc(OCCc2coc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC(c1ccc(OCCc2coc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n2)cc1)N(C)C
Temperature: 60 °C
Yield: 80 %

Procedure:
Title compound was prepared substantially in accordance with the procedure in Example 1E above using the compound of Step A, 1.23 g (19.5 mmole) of sodium cyanoborohydride and dimethylamine (19.4 ml, 293 mmole), heating to 60° C. for 24 hours. The organic layer was chromatographed on silica gel using a methylene chloride/methanol gradient to give the free base which was dissolved in methylene chloride, treated with hydrogen chloride gas, and evaporated to give 8.31 g (80%) of the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[N:9]1([C:7]([C:6]2[CH:5]=[C:4]([CH:16]=[CH:15][CH:14]=2)[NH2:1])=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(c1cccc([N+](=O)[O-])c1)N1CCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cccc(C(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a solution of 1.91 g of 1-(3-nitrobenzoyl)pyrrolidine obtained in stage a) below in 50 mL of methanol are added, under argon, 4.38 g of ammonium formate and 9 mg of 10% palladium-on-charcoal. The reaction mixture is stirred at room temperature for 1 hour and then filtered through Celite and concentrated under reduced pressure. The residue is taken up in water and extracted with ethyl acetate. The organic phase is then washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 1.12 g of 3-(pyrrolidin-1-ylcarbonyl)aniline, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[BrH:20]>CS(C)=O.O>[NH2:1][C:2]1[C:7]([Br:20])=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: Br
Reactant: COc1cc(N)c(C(=O)c2ccccc2)cc1OC
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(C(=O)c2ccccc2)c(N)c(Br)c1OC
Temperature: 60 °C
Yield: 65 %

Procedure:
To a solution of 900 mg (3.5 mmol) of (2-amino-4,5-dimethoxyphenyl)(phenyl)methanone (XXIaa) in 60 ml of DMSO, add dropwise at 0° C. 15 g of HBr 40% by weight in water. Heat at 60° C. for 24 hours. Add 400 ml of H2O and extract four times with 200 ml of AcOEt; dry on MgSO4, evaporate the AcOEt and purify by silica chromatography (AcOEt 1/hexane 4). Yield: 65%. 1H-NMR (CDCl3, 300 MHz): d 3.67 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 6.59 (s, 2H, NH2), 7.06 (s, 1H Ar), 7.47–7.65 (m, 5H Ar). Mass: (M+H)+=335.98+337.98.