Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].CO[C:17](=O)[C:18]1C=C(N2CCCCC2)C=C[C:19]=1N.N1CCCCC1.S(=O)(=O)(O)O.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH:10][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1cc(N)ccc1[N+](=O)[O-]
Reactant: COC(=O)c1cc(N2CCCCC2)ccc1N
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CCCNc1ccc([N+](=O)[O-])c(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
5-Amino-2-nitro-benzoic acid methyl ester (compound A′) (800 mg) was dissolved in dry THF (15 ml). Propionaldehyde (compound D) (870 μl) dissolved in a mixed liquid composed of 3 M sulfuric acid (4 ml) and THF (1 ml) was added to the solution at room temperature. Subsequently, sodium borohydride (231 mg) was added thereto at 0° C., and the mixture was stirred at room temperature for 3 hr. Thereafter, distilled water was added thereto, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate and was then concentrated. The residue was purified by column chromatography using a hexane-acetone system to give 2-nitro-5-propylamino-benzoic acid methyl ester as a useful intermediate (608 mg, yield 63%).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][C:15]#[N:16])=O.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[C:15]([CH2:14][O:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:1][N:31]1[CH2:32][CH2:33][CH:28]([C:24]2[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=2)[CH2:29][CH2:30]1)#[N:16]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: N#CCOc1ccc2ccccc2c1C=O
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c(OCC#N)ccc4ccccc34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using [(1-formyl-2-naphthyl)oxy]acetonitrile and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 442.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:28](=[O:29])[CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)Cc4ccccc4)c3C2=O)C(=O)N1
Yield: 92 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added 2-phenylacetyl chloride (0.62 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.72 g (92%) of product as an off-white solid: mp 217–218°°C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 9.79 (s, 1H), 8.49 (d, J=8.4 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.60 (t, J=7.3 Hz, 1H), 7.41–7.27 (m, 5H), 5.13 (dd, J=5.1 and 12.7 Hz, 1H), 3.85 (s, 2H), 2.98–2.83 (m, 1H), 2.64–2.44(m, 2H), 2.08–2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.71, 170.07, 169.74, 167.60, 166.61, 136.38, 136.10, 134.70, 131.41, 129.41, 128.58, 126.97, 125.96, 118.39, 116.90, 48.89, 43.47, 30.90, 21.91; Anal. Calcd. For C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.23; H, 4.34; N, 10.53.
Reaction SMILES: [CH3:1][NH2:2].CO.C(OC([NH:12][C:13]1[C:21]2[CH:20]=[CH:19][S:18][C:17]=2[CH:16]=[C:15]([C:22]([O:24]CC)=O)[CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:12][C:13]1[C:21]2[CH:20]=[CH:19][S:18][C:17]=2[CH:16]=[C:15]([C:22]([NH:2][CH3:1])=[O:24])[CH:14]=1
Reactant: CN
Reactant: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)c2ccsc2c1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(N)c2ccsc2c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A 40% methylamine-methanol solution (3 ml) was added to ethyl 4-(tert-butoxycarbonylamino)benzo[b]thiophene-6-carboxylate obtained in Example 22 (Step 3) (110 mg), and the reaction solution was stirred at 90° C. overnight. Trifluoroacetic acid (0.5 ml) was added to the resultant residue, and the reaction solution was stirred at room temperature for 15 minutes. Thereafter, the solvent was evaporated under vacuum, and the residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain 4-amino-N-methylbenzo[b]thiophene-6-carboxamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1.[NH4+].[Cl-]>CCOCC.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: OC1(c2ccc(Br)cc2)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of 1,4-dibromobenzene (1.00 g, 4.24 mmol) at −78° C. in ether (20 ml) was added n-BuLi (2.65 ml, 1.6 M solution in hexane, 4.24 mmol) and the reaction mixture was stirred at −78° C. for 30 min. Cyclobutanone (348 μl, 4.66 mmol) was then added and the reaction mixture was stirred at −78° C. for 15 min. The reaction mixture was then slowly (over 2 h) warmed to 0° C. and stirred for a further 1 h. Water was added followed by sat. NH4Cl and the reaction mixture was extracted with ether. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:4 ether/pentane) to give 1-(4-bromophenyl)-cyclobutanol (330 mg, 34%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.50 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 2.57-2.48 (m, 2H), 2.41-2.31 (m, 2H), 2.02 (m, 1H), 1.69 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:24])[N:6]2[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 15 %

Procedure:
6-Amino-9-benzyl-2-pentylthiopurine (260 mg, 0.79 mmol) and bromine (0.5 ml) were dissolved in 100 ml of methylene chloride and the solution was stirred at room temperature for 7 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent of the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (49 mg, yield 15%).
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][C@@H:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:16][CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@@H](O)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCC[C@@H](O)c1ccc(C(=O)NC=CC(=O)OCC)cc1
Reaction time: 1 h
Yield: 100.9 %

Procedure:
N,N-dimethylformamide (16.9 mL) was added to a vial containing (R)-4-(1-hydroxybutyl)benzoic acid (2.6 g, 13.5 mmol), ethyl 3-aminopropanoate hydrochloride (4.16 g, 27.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (10.3 g, 27.1 mmol). Diisopropylethylamine (11.8 mL, 67.7 mmol) was then added. The reaction was stirred for 1 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded (R)-ethyl 3-(4-(1-hydroxybutyl)benzamido)propenoate (3.97 g, 100% yield) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.75 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.83 (br. s., 1H), 4.74 (t, J=8.2 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.73 (q, J=5.9 Hz, 2H), 2.64 (t, J=6.4 Hz, 2H), 1.87 (br. s., 1H), 1.84-1.62 (m, 2H), 1.49-1.30 (m, 2H), 1.28 (t, J=107.1 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (M+1): 294.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][CH:21]([C:23](N(OC)C)=[O:24])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][Mg]I.N#N>CCOCC>[Si:1]([O:18][CH:19]1[CH2:20][CH:21]([C:23](=[O:24])[CH3:29])[CH2:22]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)C1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Reactant: C[Mg]I
Agent: N#N
Solvent: CCOCC
Product: CC(=O)C1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1

Procedure:
A solution of 3-[tert-butyl(diphenyl)silyl]oxy-N-methoxy-N-methylcyclobutanecarboxamide (0.7 g, 0.002 mol) in ether (10 mL) was added into 3.0 M of methylmagnesium iodide in ether (3 mL) slowly under N2. The reaction was stirred and heated to reflux for 2 h. The mixture was quenched with ice and the ether layer separated. The aq. layer was acidified with 1N HCl and extracted several times with ether. The organic layers were combined, dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-30% EtOAc/Hex) to give the desired product (0.6 g) as colorless oil. LCMS calculated for C22H29O2Si(M+H)+: 353.2; Found: 353.3.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[Cl:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=2)[N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Cl)nc(Br)c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(Cl)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 55 °C
Yield: 67.4 %

Procedure:
To a degassed solution of 2-bromo-6-chloro-4-methyl-pyridine (900 mg, 4.37 mmol), 4-trifluoromethylbenzeneboronic acid (830 mg, 4.37 mmol), 2N Na2CO3 (4 mL) in DME (40 mL) was added tetrakis(triphenylphosphine)palladium (320 mg, 0.3 mmol) under argon. The mixture was heated to 55° C. for 5 h, cooled to room temperature, diluted with water, and extracted with methylene chloride (3×). The organic solution was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (10-25% methylene chloride in heptane) to give the product as an off white solid (800 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=7.91 Hz, 2H), 7.71 (d, J=8.29 Hz, 2H), 7.49 (s, 1H), 7.16 (s, 1H), 2.43 (s, 3H). MS m/e 272.1 (M+H).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:26]([OH:28])=[O:27])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:25])[NH:21][N+]([O-])=O)=[O:13])[CH3:11])=[O:8].CO.Cl>[Pd].O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:26]([OH:28])=[O:27])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:21])[NH2:25])=[O:13])[CH3:11])=[O:8]
Reactant: C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 6 h
Yield: 50.8 %

Procedure:
After 1.75 g (2.6 mmols) of Z-PyroGlu-Ala-Arg(NO2)-CHA was suspended in a solvent mixture of 112.5 ml of MeOH, 27.7 ml of H2O and 9.8 ml of 1N-HCl, 1 g of palladium black was added to the suspension followed by catalytic reduction at 30° C. for 6 hours. After the reaction, the catalyst was filtered off and the solvent was removed by distillation under reduced pressure. The residue was purified through TOYOPEARL HW40F column using MeOH as a developing solvent to give 0.471 g (34.4%) of H-PyroGlu-Ala-Arg-CHA.HCl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18](OCC)=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[CH2:18][OH:19])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)/C=C/c1ccc(Oc2cccnc2)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(/C=C/CO)ccc1Oc1cccnc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
2.99 g of ethyl (E)-3-[3-methoxy-4-(3-pyridyloxy)phenyl]acrylate was dissolved in 30 ml of anhydrous toluene. To the solution was dropwise added 22.0 ml of a 1M toluene solution of diisobutylaluminum hydride at -50° C. in a nitrogen atmosphere. The mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was dropwise added 1.6 ml of water. The mixture was stirred for 1 hour at room temperature. The resulting insolubles were removed by filtration. The filtrate was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 2.57 g of colorless oily (E)-3-[3-methoxy-4-(3-pyridyloxy)phenyl]allyl alcohol.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:31])[NH:10][C:11]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[O:16])=[N:12]2)=[CH:7][CH:6]=1)=[O:4].Cl.O1CCOCC1>C(Cl)Cl>[OH:1][NH:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:31])[NH:10][C:11]([C:15]([NH:17][CH:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[O:16])=[N:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3cc(C(=O)NO)ccc3c(=O)[nH]2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(NO)c1ccc2c(=O)[nH]c(C(=O)NC3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[({7-[(hydroxyamino)carbonyl]-4-oxo-3,4-dihydroquinazolin-2-yl}carbonyl)amino]piperidine-1-carboxylate (45 mg, 0.1 mmol) in methylene chloride (1.5 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (1.50 mL, 6.0 mmol). The reaction mixture was stirred at rt for 2 h. The solid was filtered and washed with DCM to afford N7-hydroxy-4-oxo-N2-piperidin-4-yl-3,4-dihydroquinazoline-2,7-dicarboxamide.HCl (34 mg, 89%). LC-MS: (FA) ES+ 332; 1H NMR (300 MHz, DMSO) δ 12.42 (s, 1H), 11.55 (s, 1H), 9.28 (s, 1H), 9.11 (d, J=7.7 Hz, 1H), 8.82 (s, 1H), 8.21 (d, J=8.2 Hz, 1H), 8.17 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 4.13-3.97 (m, 1H), 3.38-3.27 (m, 2H), 3.09-2.95 (m, 2H), 2.02-1.81 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[N:19](S(C5C=CC=CC=5)(=O)=O)[C:20]([C:22]5[CH:23]=[N:24][C:25]([N:28]6[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]6)=[N:26][CH:27]=5)=[CH:21][C:14]=34)=[CH:11][N:10]([CH3:50])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20]([C:22]5[CH:27]=[N:26][C:25]([N:28]6[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:32][CH2:33]6)=[N:24][CH:23]=5)=[CH:21][C:14]=34)=[CH:11][N:10]([CH3:50])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2ccnc3c2cc(-c2cnc(N4CCN(C(=O)OC(C)(C)C)CC4)nc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(N)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(-c2ccnc3[nH]c(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cc23)c(-c2ccc(N)cc2)n1
Temperature: 70 °C
Yield: 99 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{5-[4-[3-(4-aminophenyl)-1-methyl-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-pyrimidinyl}-1-piperazinecarboxylate (0.333 mmol) in methanol (20 ml) was added 6M NaOH(aq) (1.5 ml). The resulting solution was heated at 70° C. for 4 hours, concentrated in vacuo and the yellow residue taken up in chloroform. After washing with saturated NH4Cl(aq), the organic layer was dried (MgSO4), filtered and concentrated to yield the title product (99%) as a yellow solid which was used crude in the next step. ESMS [M+H]+: 552.2.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[OH:17]O.N>C(O)C.ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([NH2:16])=[O:17]
Reactant: OO
Reactant: Cc1cccc(C)c1-n1ncc(C#N)c1N
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: Cc1cccc(C)c1-n1ncc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g (9.4 mmol) of 5-amino-1-(2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (Example 1A) are dissolved in 25 ml of ethanol, and a mixture of 20 ml of 30% strength hydrogen peroxide and 40 ml of 25% strength ammonia is added. The solution is stirred at room temperature overnight and then concentrated to about 15 ml in a rotary evaporator. The oily emulsion resulting thereby is taken up in dichloromethane. It is washed several times with water and saturated sodium thiosulphate solution. Drying over magnesium sulphate is followed by removal of the solvent in vacuo. The residue is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 0.88 g (40% of theory) of the product is obtained as colourless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](=[S:33])[NH2:32]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:33][C:31]([C:30]([CH3:35])([CH3:34])[CH3:29])=[N:32][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)C(N)=S
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Yield: 53.3 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6, using N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (1.00 g, 2.36 mmol) and 2,2-dimethylpropanethioamide (0.277 g, 2.36 mmol) the title compound was obtained (690 mg, 53.3% yield). MS (ESI): 521.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2O.[Cl:28]CCl.C(Cl)(C(Cl)=O)=O>CN(C=O)C>[Cl:28][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[C:8]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:7]=1
Reactant: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(O)c2cc1OC
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(Cl)c2cc1OC
Temperature: 5 °C

Procedure:
Into a 1-L 3-necked round-bottom flask, was placed 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol (12 g, 32.23 mmol, 1.00 equiv), dichloromethane (400 mL) and DMF (cat.) (0.1 g). This was followed by the addition of (COCl)2 (40 g, 315.21 mmol, 9.78 equiv) dropwise with stirring at 0-10° C. The resulting solution was heated to reflux for 5 h. The mixture was cooled to room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was dissolved in 400 mL of dichloromethane. The resulting mixture was washed with 2×200 mL of NaHCO3 (sat.) and 1×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/ethyl acetate (2:1). This resulted in 5 g (40%) of 4-chloro-6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline as a yellow solid. MS (ESI) m/z 391 [M+H]+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:33]2([CH3:34])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:35])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:28])[CH:21]([OH:27])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[CH2:9]1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>N1C=CC=CC=1.O>[CH3:43][S:44]([O:27][CH:21]([C@H:20]([C@@H:19]1[C@:29]2([CH3:35])[C@H:16]([C:15]3[C@H:32]([CH2:31][CH2:30]2)[C@:33]2([CH3:34])[C:12]([CH2:11][C@@H:10]([O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)[CH2:9][C@@H:8]2[O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:13][CH:14]=3)[CH2:17][CH2:18]1)[CH3:28])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:46])=[O:45]
Reactant: CC(C)CCC(O)[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)CCC(OS(C)(=O)=O)[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
In 20 ml of pyridine was dissolved 0.58 g of the 1α,3β-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-ol obtained as above. To this solution was added 0.12 g of methanesulfonyl chloride and the mixture was stirred at 0° C. for 2 hours. Then, at room temperature, the reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. The low-boiling fraction was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The procedure yielded 0.57 g of 1α,3β-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-yl methanesulfonate (yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([OH:9])=[O:8].C(N(CC)CC)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:8]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1[nH]ccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)c1[nH]ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 3-chloro-1H-pyrrole-2-carboxylic acid (15 g, 0.1 mol) in N,N-dimethylformamide (300 mL) and triethylamine (72 mL, 0.52 mmol) under argon atmosphere was added benzyl bromide (61 mL, 0.52 mmol) at 0-5° C. and the reaction was stirred mechanically overnight at room temperature. Next day, the reaction mixture was concentrated in vacuum and the residue was suspended in 4% aqueous solution of sodium bicarbonate (300 mL) and extracted with ethyl acetate (2×250 mL). The organic layers were mixed and washed with more 4% aqueous solution of sodium bicarbonate, water and brine, and were dried (magnesium sulphate, MgSO4) and concentrated under reduced pressure to give 21.4 g of a residue corresponding to the title compound (88% yield).