Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[OH:8])=[CH:5][N:4]=[CH:3]1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)=[O:8])=[CH:5][N:4]=[CH:3]1
Reactant: Cn1cncc1C(O)c1ccnc(C(F)(F)F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cn1cncc1C(=O)c1ccnc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A heterogeneous mixture of (1-methyl-1H-imidazol-5-yl)(2-(trifluoromethyl)pyridin-4-yl)methanol (0.300 g, 1.16 mmol, Intermediate 53: step a) and manganese dioxide (0.506 g, 5.83 mmol) in 1,4-dioxane (12 mL) was stirred at 100° C. for 1 h. The reaction mixture was then cooled to room temperature, filtered through Celite®, washed with EtOAc, and concentrated. The organic phase was dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-100% EtOAc-DCM) to provide the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: COc1ccc(C2CCN(C(=O)c3cnc4c(C(=O)O)cnn4c3Nc3cc(C)ccc3F)CC2)cc1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(OC)cc4)CC3)cnc12
Yield: 75.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-[4-(4-methoxyphenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.3 g, 0.60 mmol) obtained in step 2 and ethanesulfonamide (0.31 g, 2.98 mmol), the title compound (0.27 g, 75%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:20][C:21](Cl)=[O:22])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:12]=2)=[CH:4][CH:3]=1.[P:24]([O:31]CC)([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>O1CCCC1>[CH2:26]([O:25][P:24]([C:21]([OH:22])=[CH:20][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:10]=1)(=[O:31])[O:28][CH2:29][CH3:30])[CH3:27]
Reactant: O=C(Cl)Cc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1
Reactant: CCOP(OCC)OCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(O)=Cc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A solution of 17.5 g of 4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazoleacetic acid chloride in 100 ml of tetrahydrofuran is cooled to 10° C. and combined with 9.8 ml of triethyl phosphite. The mixture is stirred for 3 hours at 10°-15° C., the solution is concentrated under vacuum, and the oily residue is crystallized from diisopropyl ether, thus obtaining 18.8 g (83.4%) of 2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethenephosphonic acid diethyl ester, mp 96°-98° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](O)=[CH:14][CH:15]=1.CI.C[CH2:20][O:21]CC.C(=O)([O-])[O-].[K+].[K+]>O.CC(C)=O>[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[O:21][CH3:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCOCC
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: CCCCCCCCCc1ccccc1OC

Procedure:
Nonyl anisole was prepared from nonylphenol, available from Jefferson Chemicals, and methyl iodide under typical Williamson ether synthesis conditions. Nonylphenol (1.0 mole), methyl iodide (1.2 moles), potassium carbonate (1.25 moles) and acetone were placed in a round bottom flask and heated to reflux. After refluxing overnight, the reaction mixture was poured into water and extracted with ether. The ether extract was washed with saturated sodium chloride solution, dried and evaporated to an oil which was then purified by vacuum distillation. The product was analyzed as nonyl anisole by IR and NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2C(O)=O)[CH:5]=[CH:6][C:7]=1[F:8].C1(P([N:29]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[NH2:29])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A solution of (1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid (8.0 g, 40.40 mmol, 1.00 equiv.), diphenylphosphoryl azide (11.2 g, 40.73 mmol, 1.00 equiv.), triethylamine (6.2 g, 61.39 mmol, 1.50 equiv.) in toluene (60 mL) was heated at reflux for about 1 hour and then refluxing 6N hydrogen chloride was added. The mixture was kept at reflux for 16 hours, and then cooled to ambient temperature. The resulting mixture was concentrated in vacuo, and the resulting residue was dissolved in water/ether (1:1) 200 mL). Following standard extractive workup with ether (3×100 mL), the resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:4˜1:0)) to give the title product as a light-brown solid (6.2 g; yield=91%). 1H NMR (300 MHz, CDCl3) δ: 6.98-7.07 (m, 1H), 6.72-6.81 (m, 2H), 2.40 (m, 1H), 1.82-1.87 (m, 1H), 1.05-1.11 (m, 1H), 0.85-0.96 (m, 1H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]12[N:37]([CH2:38][CH2:39][OH:40])[CH:34]([CH2:35][CH2:36]1)[CH2:33][NH:32][CH2:31]2>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:32]5[CH2:31][CH:30]6[N:37]([CH2:38][CH2:39][OH:40])[CH:34]([CH2:35][CH2:36]6)[CH2:33]5)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25]([N:26]([CH3:28])[CH3:27])=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCN1C2CCC1CNC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5CCO)cn3)nc2n1C1CCCC1
Yield: 59 %

Procedure:
The 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethanol following amide formation method 3 which gave 7-cyclopentyl-2-(5-(8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (18 mg, 59% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.00-8.87 (m, 1H) 8.87-8.78 (m, 1H) 8.57 (d, J=8.08 Hz, 1H) 8.44 (s, 1H) 7.79 (dd, J=8.59, 2.53 Hz, 1H) 6.54-6.43 (m, 1H) 4.81 (dq, J=9.09, 8.93 Hz, 1H) 4.51 (br. s., 1H) 3.82-3.49 (m, 4H) 3.40-2.99 (m, 10H) 2.69-2.44 (m, 4H) 2.16-1.99 (m, 4H) 1.91 (d, J=5.56 Hz, 2H) 1.83-1.45 (m, 4H); HR-MS (m/z MH+) 533.30 RT 2.56 min
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>CS(C)=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][O:3][CH:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]([OH:11])=[O:10])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)c1ccccc1
Reaction time: 4 h
Yield: 48.9 %

Procedure:
(+)-Mandelic acid (3.04 g.) was added to a stirred suspension of sodium hydride (1.92 g., 50% w/w dispersion in mineral oil) in dimethyl sulphoxide (50 ml.) at 15°-20° C., and the mixture was then stirred at the same temperature for 4 hours. 4-(4-Chlorophenyl)benzyl chloride (4.74 g.) was then added to the mixture and stirring was continued at room temperature for 1 hour. The resultant mixture was adjusted to pH 1-3 by careful addition of N-hydrochloric acid, and then extracted thoroughly with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated. The solid residue obtained was recrystallised from a mixture of ethyl acetate and hexane to give (+)-2-[4-(4-chlorophenyl)benzyloxy]-2-phenylacetic acid (3.45 g.), m.p. 119°-121° C., [α]D25 +104° (C=1,CHCl3).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[C:13](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1)=[O:4].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[C:16]1(/[C:13](/[CH2:14][CH3:15])=[C:12](/[C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)\[C:9]2[CH:10]=[CH:11][C:6]([O:5][C:3](=[O:4])[CH2:2][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:7][CH:8]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1CCNCC1
Reactant: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OC(=O)CCl)cc1)c1ccccc1
Product: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OC(=O)CN2CCCCC2)cc1)c1ccccc1

Procedure:
Treatment of compound 32 with piperidine as described in Example 19 (Step 2) afforded the title compound, 33, as a light yellow solid (85 mg, 77%). 1HNMR (400 MHz, DMSO-d6): δ 0.85 (t, 3H), 1.35 (br, 2H), 1.74 (br, 4H), 2.40 (q, 2H), 3.00 (br, 2H), 3.44 (br, 2H), 4.36 (br, 2H), 6.51 (d, J=16.1 Hz, 1H), 6.87-6.90 (m, 4H), 7.09-7.19 (m, 5H), 7.25 (d, J=8.1 Hz, 2H), 7.58 (d, J=16.1 Hz, 1H), 7.70 (d, J=8.2 Hz, 2H), 10.17 (br, 1H), 12.39 (br, 1H); MS m/z 496 (M+H)+; Anal. calculated for C32H33N1O4.HCl.1.5H2O: C, 68.74; H, 6.67; N, 2.50; Found: C, 68.31; H, 6.34; N, 2.37.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-])=O)=[C:6]([CH3:14])[CH:5]=1.[H][H]>[Pd].CO>[NH2:11][C:7]1[C:6]([CH3:14])=[CH:5][C:4]([C:3]([NH:2][CH3:1])=[O:15])=[CH:9][C:8]=1[CH3:10]
Reactant: CNC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(C)c(N)c(C)c1

Procedure:
10% Palladium on carbon (100 mg) is added to a solution of N,3,5-trimethyl-4-nitrobenzamide (1 g) in methanol (10 mL) and the mixture is hydrogenated for 3 hours under 3 bar hydrogen pressure. Then the catalyst is filtered off and washed with methanol. The combined mother liquors are concentrated to give the title compound. Yield: 850 mg; LC (method 21): tR=6.02; Mass spectrum (ESI+): m/z=179 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])=[CH:5][CH:4]=1)[CH3:2].CO.[OH-].[Na+].Cl>O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)OC)cc3)nn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)O)cc3)nn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To methyl 4-[(2-{1-[5-(4-ethylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.172 mmol, 72.4 mg), methanol (4 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.861 mL) was added at room temperature. After 10 minutes of stirring at room temperature and 2 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.861 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was dried to give the desired product as a yellow solid (29.1 mg, yield 42%).
Reaction SMILES: [F:1][C:2]([F:35])([C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[C:28]([NH2:31])=[N:29][CH:30]=1)[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[F:36][C:37]([F:44])([CH:41]([F:43])[F:42])[C:38](Cl)=[O:39]>>[F:35][C:2]([F:1])([C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[C:28]([NH:31][C:38](=[O:39])[C:37]([F:44])([F:36])[CH:41]([F:43])[F:42])=[N:29][CH:30]=1)[C:3]([F:23])([F:24])[C:4]([F:21])([F:22])[C:5]([F:19])([F:20])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10]
Reactant: O=C(Cl)C(F)(F)C(F)F
Reactant: Nc1ncc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Product: O=C(Nc1ncc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1[N+](=O)[O-])C(F)(F)C(F)F

Procedure:
5-(Perfluorooctyl)-3-nitro-2-aminopyridine is reacted with 2,2,3,3-tetrafluoropropionyl chloride to obtain 5-(perfluorooctyl)-3-nitro-2-(2,2,3,3-tetrafluoropropionamido)pyridine, which when hydrogenated yields 6-(perfluorooctyl)-1-hydroxy-2-(1,1,2,2-tetrafluoroethyl)-1H-imidazo(4,5-b)pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Br[CH2:31][CH2:32][OH:33]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH2:32][OH:33])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: OCCBr
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCO)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 100 °C

Procedure:
5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) was dissolved in anhydrous DMF (1 mL). TEA (50 uL, 0.36 mmol, 3 equiv.) was added followed by 2-bromo-ethanol (0.018 mL, 0.24 mmol, 2 equiv.) dissolved in anhydrous DMF (0.7 mL). The reaction vessel was sealed and heated in a microwave at 100° C. for 20 min. After cooling to room temperature, the reaction was concentrated and the crude product was purified using preparative RP-HPLC to give 2-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)ethanol as a white solid: ESMS m/z 460.2 (M+H+).
Reaction SMILES: [Na:1].COC1O[CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[O:31]1[C:35]2(CCC(O)[CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1>>[Na:1].[O:31]1[C:35]2([CH2:36][CH2:37][CH:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]4[NH:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)=[O:20])[C:13]=3[CH3:30])[CH2:7][CH2:8]2)[O:34][CH2:33][CH2:32]1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Reactant: OC1CCC2(CC1)OCCO2
Agent: [Na]
Product: Cc1c(OC2CCC3(CC2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 7.3 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 1,4-dioxaspiro[4.5]decan-8-ol obtained in the step (27a) to obtain the title compound (230 mg, total yield: 7.3%) as a light yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:29]=[CH:28][N:27]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[C:25]=4[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:31]([CH:30]([N:27]1[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][CH:16]=3)[N:22]=[CH:23][C:24]=2[CH:29]=[CH:28]1)[CH2:33][CH3:34])[CH3:32]
Reactant: CCC(CC)n1ccc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)n1ccc2cnc(Nc3ccc(N4CCNCC4)cc3)nc21
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 4-{4-[7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (167 mg, 0.36 mmol) in dichloromethane (3 mL) is added trifluoroacetic acid (1 mL). The reaction mixture is stirred for 1 h and concentrated in vacuo. The residue is diluted with dichloromethane, washed with NaHCO3 solution, dried over Na2SO4, and concentrated in vacuo. Purification by preparative HPLC afforded 130 mg of [7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-(4-piperazin-1-yl-phenyl)-amine as a yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:29][OH:30]>C1(C)C=CC=CC=1>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:13](=[O:16])[CH2:14][C:29](=[O:30])[CH2:24][CH2:25][CH2:8][CH2:7][CH2:6][CH2:15][CH2:2][CH2:3][CH3:4])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(=O)CC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 20 °C
Yield: 63 %

Procedure:
To a solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) in 8 mL of toluene, magnetically stirred at 20° C., 103 mg of the compound of example 19 were added. The mixture was refluxed during 2.5 hours, and then allowed to cool to 20° C. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 79 mg (yield: 63%) of the desired product (formula below) as a red powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][CH2:17][CH2:16][C:15](=[O:22])[C:14]=3[C:13]=2[C:23]([OH:25])=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][CH2:17][CH2:16][CH:15]([OH:22])[C:14]=3[C:13]=2[C:23]([OH:25])=[O:24])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(C(=O)O)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2)ccc2c1C(O)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of Example 103B (25 mg, 0.068 mmol) in methanol (3 mL) was treated with NaBH4 (5.2 mg, 0.137 mmol), stirred at room temperature for 3 hours, and concentrated. The concentrate was purified by reverse phase HPLC to provide the desired product. MS (ESI) m/e 364 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.74 (m, 2H), 7.32 (m, 2H), 7.23 (d, 1H), 7.18 (br s, 1H), 6.9 (d, 1H), 4.59 (br s, 1H), 2.6 (m, 2H), 1.85 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: C([O-])(=O)C.[NH4+].C([BH3-])#N.[Na+].Cl.C(N1C2C=CC=C3CC(N)CC(C=23)C1)(=O)C1C=CC=CC=1.C(=O)CC.C([N:44]1[C:52]2[CH:51]=[CH:50][CH:49]=[C:48]3[CH2:53][CH:54]([N:56]([CH2:60][CH2:61][CH3:62])[CH2:57][CH2:58][CH3:59])[CH2:55][CH:46]([C:47]=23)[CH2:45]1)(=O)C1C=CC=CC=1>CO>[CH2:60]([N:56]([CH2:57][CH2:58][CH3:59])[CH:54]1[CH2:55][CH:46]2[CH2:45][NH:44][C:52]3[CH:51]=[CH:50][CH:49]=[C:48]([C:47]=32)[CH2:53]1)[CH2:61][CH3:62]
Reactant: CCCN(CCC)C1Cc2cccc3c2C(C1)CN3C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NC1Cc2cccc3c2C(C1)CN3C(=O)c1ccccc1
Solvent: CO
Solvent: CCC=O
Product: CCCN(CCC)C1Cc2cccc3c2C(CN3)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Four and six-tenths grams of 1-benzoyl-4-keto-1,2,2a,3,4,5-hexahydrobenz[d]indole and 12.4 g. of ammonium acetate were suspended in 400 ml. of methanol. 1.07 g. of sodium cyanoborohydride were added and the resulting mixture stirred at ambient temperature for 17 hours. The reaction mixture was then poured over a mixture of ice and 1N aqueous hydrochloric acid. This mixture was washed with ether and the resulting organic layer discarded. The aqueous layer was then made basic with 14N ammonium hydroxide and the alkaline layer extracted several times with a mixture of chloroform and isopropanol. The organic extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent yielded 3.9 g. of a foam consisting of 1-benzoyl-4-amino-1,2,2a,3,4,5-hexahydrobenz[cd]indole. The compound was dissolved in 150 ml. of methanol and 700 mg. of sodium cyanoborohydride were added followed by 6.6 ml. of propionaldehyde. The resulting reaction mixture was stirred at ambient temperature for 22 hours and then worked up by the same procedure as for the primary amine. A residue was obtained consisting of 5.1 g. of an oil comprising 1-benzoyl-4-(di-n-propyl)amino-1,2,2a,3,4,5-hexahydrobenz[cd]indole. This compound was in turn dissolved in 120 ml. of 6N aqueous hydrochloric acid and the acidic solution refluxed under a nitrogen atmosphere for 45 minutes. The reaction mixture was poured onto ice and the acidic aqueous layer made basic with 14N ammonium hydroxide. The alkaline layer was extracted several times with a chloroform-isopropanol solvent mixture. The organic extracts were combined, the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent in vacuo yielded 3.6 g. of 4-(di-n-propyl)amino-1,2,2a,3,4,5-hexahydrobenz[cd]indole formed in the above reaction.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:43])[C@@H:24]([NH:26][C:27](=[O:42])[C@@H:28]([NH:32][C:33](=[O:41])[C:34]([CH2:38][CH2:39]O)([CH3:37])[CH:35]=[CH2:36])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:43])[C@@H:24]([NH:26][C:27](=[O:42])[C@@H:28]([N:32]4[CH2:36][CH2:35][C:34]([CH3:37])([CH:38]=[CH2:39])[C:33]4=[O:41])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=CC(C)(CCO)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1)C(C)C
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: C=CC1(C)CCN([C@H](C(=O)N[C@@H](C)C(=O)N2CCC[C@@H](C(=O)N[C@H](C)c3ccc4ccc(Br)cc4n3)N2)C(C)C)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.6 %

Procedure:
A solution of (S)-1-((S)-2-{(S)-2-[2-(2-hydroxy-ethyl)-2-methyl-but-3-enoylamino]-3-methyl-butyrylamino}-propionyl)-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (186.4 mg, 0.282 mmol) and 4-dimethylaminopyridine (206.7 mg, 1.692 mmol) in dichloromethane (20 mL) was treated with para-toluenesulfonyl chloride (161.6 mg, 0.848 mmol). After stirring at room temperature for 2.5 h, more 4-dimethylaminopyridine (206.7 mg, 1.692 mmol) and para-toluenesulfonyl chloride (161.6 mg, 0.848 mmol) were added. After stirring at room temperature for 1.5 h, the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 20 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/acetone 1:0 to 3:2 to afford the title compound (77.0 mg, 42%) as a colourless gum and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 643.1 [M+H], Tr=1.90 min and LCMS (m/z) 643.1 [M+H], Tr=1.99 min.