Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45](=[O:57])[N:46]([C:48]1C=C(N)C=[CH:50][C:49]=1OC)C)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:57])[N:46]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:33])[CH3:34])[C:14]2=[O:37])[CH:5]=1)[CH2:48][CH2:49][CH3:50])([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: COc1ccc(N)cc1N(C)C(=O)OC(C)(C)C
Product: CCCN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained as the hydrochloride salt by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (5-amino-2-methoxy-phenyl)-methyl-carbamic acid tert-butyl ester (prepared in two steps from 2-methoxy-5-nitrophenylisocyanate) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-propyl-carbamic acid tert-butyl ester (Example 41, step a) according to the method of Example 41, step b. 1H NMR (CDCl3) 11.00-10.00 (1H, br s), 8.16-8.12 (1H, m), 7.61-7.27 (5H, m), 7.02-6.89 (2H, m), 4.74-4.68 (2H, m), 4.37 (1H, d, 16.8), 4.18 (1H, d), 3.90 (3H, s), 2.99 (3H, s), 2.84 (1H, m), 2.05-1.70 (6H, m), 1.36-1.12 (13H, m). Found: C, 61.98; H, 7.12; N, 11.65%; C30H39N5O4.1.4HCl requires: C, 61.66; H, 6.97; N, 11.99%.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][C:13]1[CH2:14][C:15]2[C:20]([CH:21]=1)=[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:18]=[CH:17][CH:16]=2.[Cl:28][Si:29](Cl)([CH3:31])[CH3:30]>CCOCC>[Cl:28][Si:29]([CH:14]1[C:15]2[C:20](=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:13]1[CH3:12])([CH3:31])[CH3:30]
Reactant: CC1=Cc2c(cccc2-c2ccccc2)C1
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A 2.5 M solution of n-BuLi in hexane (4.85 mL, 12.12 mmol) was added at 0° C. to a solution of 2.50 g of 2-methyl-4-phenyl-indene (Boulder Scientific Company, Mw=206.29, 12.12 mmol, n-BuLi:2-Me-4-Ph-Ind=1:1) in 30 mL of ether. The resulting mixture was stirred for additional 2 h at room temperature with final formation of an orange solution. This solution was cooled again to 0° C. and added slowly of a solution of 1.58 mL of dichlorodimethylsilane (Aldrich, Mw=129.06, d=1.064, 13.03 mmol, Me2SiCl2:2-Me-4-Ph-Ind=1.08:1) in 20 mL of ether. The reaction mixture was then allowed to warm up to room temperature and stirred for 1 h. The final straw yellow suspension was concentrated under vacuum and the residue was extracted with 50 mL of toluene. The extract was dried under vacuum to give 3.36 g of a straw yellow solid, which was characterized by GC-MS analysis and 1H-NMR spectroscopy. Yield=92.8%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1ccccc1F
Yield: 24.7 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 2-fluoro-phenylboronic acid (27 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (13 mg, 25%). LC-MS m/e 405.28 (M+H+)
Reaction SMILES: [Cl].[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCOCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([Br:2])=[CH:4][CH:5]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Oc1ccc(F)cc1
Agent: [Cl]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Oc1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ten ml of dioxane, 5 mmol (1.1 g) of 4-bromo-benzoic acid chlorine, and 5 mmol (0.56 g) of 4-fluoro-phenol were added to 50 ml four-mouth-flask sequentially and dissolved at room temperature. Triethylamine dissolved in dioxane was slowly dripped into this solution and the solution was stirred for three hours at room temperature. The precipitated crystals were filtered and extracted with benzene. The extracted solution was washed with sodium hydrocarbonate several times, magnesium anhydrate was added, and the resulting solution was dried and filtered. The solution was distilled under low pressure and crystallized. The row crystals were yellowish-white, weighing 1.37 g. A portion of this crystal (0.5 g) was dissolved in benzene and purified with 100 g of silica gel (Wako gel C-300, Japan). The purified product was white, and the purity was confirmed to 99.93% by liquid chromatography (LC). The structure was confirmed by NMR as follows. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (2H, d, J=8.8 Hz), 7.83 (2H, d, J=8.8 Hz), 7.38˜7.29 (4H, m) 13C NMR (100 MHz, DMSO-d6) δ 159.72 (C—F, d, J=240 Hz) 163.95 (C═O)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8]S(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O[C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:41])[CH2:38][O:39][CH3:40])=[CH:33][CH:32]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:41])[CH2:38][O:39][CH3:40])=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: COCC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
1.8 g of methanesulfonic acid 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl ester, 1.8 g of potassium carbonate and 1.97 g of 1-(4-hydroxy-phenyl)-2-methoxyethanone are stirred in 30 ml of dimethylformamide at 50° C. for 17 hours. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phases and purification over silica gel, 1-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-2-methoxy-ethanone is obtained.
Reaction SMILES: N1C[C@H](O)C[C@H]1C(O)=O.[CH3:10][O:11][C:12]([C@@H:14]1[C@H:18]([OH:19])[CH2:17][CH2:16][NH:15]1)=[O:13].[Cl:20][C:21]1[C:28]([CH3:29])=[C:27]([N:30]=[C:31]=[O:32])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>C(Cl)Cl>[CH3:10][O:11][C:12]([C@@H:14]1[C@H:18]([OH:19])[CH2:17][CH2:16][N:15]1[C:31](=[O:32])[NH:30][C:27]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:20])[C:28]=1[CH3:29])=[O:13]
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Reactant: COC(=O)[C@H]1NCC[C@H]1O
Agent: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of hydroxyproline compound 1F (493 mg, 3.40 mmol) in CH2Cl2 (15 mL) was added 4 Å molecular sieves (˜3.0 g), followed by isocyanate 23E (725 mg, 3.22 mmol), and the resulting mixture was stirred at rt overnight, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0.5% MeOH in EtOAc/hexane, 1:1) to afford the title compound (736 mg) as an off-white solid. HPLC column: YMC S-5 C18 (4.6×50 mm), 0% to 100% B, 4 min gradient, 1 min hold (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA), flow rate at 4 mL/min, UV detection at 220 nm, 1.57 min retention time (100%); MS (ES) m/z 338 [M+H]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1>ClCCl>[C:1]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)cc1
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Acetic anhydride (16.0 mL, 169 mmol) was added dropwise over 1 h to a mixture of p-anisidine (20.0 g, 162 mmol) and dichloromethane (60 mL), with moderation by cooling in a water bath. The mixture was stirred at room temperature for 1 h, during which time a solid formed. Petroleum spirit (190 mL) was added, and the mixture was stirred for a further 1 h. The mixture was filtered and washed with petroleum spirit to afford 4-acetamidoanisole as a pale grey solid (25.8 g, 96%), m.p. 127-128° C. 1H NMR (399.7 MHz, CDCl3) δ 2.13, 3.78 (2 s, 2×3H, 2×CH3); 6.83 (app. d, 2H, J=8.8 Hz, BB′); 7.38 (app. d, 2H, J=8.8 Hz, AA′); 7.59 (br s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C@@H:20]5[CH2:27][C@:24]6([CH2:26][O:25]6)[CH2:23][CH2:22][C@:21]5([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C@@H:20]5[CH2:27][C@@:24]([CH3:26])([OH:25])[CH2:23][CH2:22][C@:21]5([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1.[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C@H:20]5[CH2:27][C@:24]([CH3:26])([OH:25])[CH2:23][CH2:22][C@@:21]5([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2ncc3cc4c(cc32)CCC[C@@H]2C[C@@]3(CC[C@]42Cc2ccccn2)CO3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@]1(O)CC[C@@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@H]2C1
Product: C[C@]1(O)CC[C@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@@H]2C1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of (2′R,4aS,12bS)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[6,7]cyclohepta[1,2-f]indazole-3,2′-oxirane]compound with (2′S,4aR,12bR)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[6,7]cyclohepta[1,2-f]indazole-3,2′-oxirane] (12, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (500 mg, 1.10 mmol) in EtOH (10 mL) was treated with NaBH4 (104 mg, 2.76 mmol). The reaction was warmed to 60° C. for about 20 min and then allowed to stir at rt for about 18 h. The reaction was concentrated under reduced pressure, then sat. aq. NH4Cl (25 mL) was added and the product was extracted with EtOAc (2×25 mL). The organic solution was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (25 g) using EtOAc as eluent. Product fractions were combined and concentrated to yield (3R,4aS,12bS)-9-(4-fluorophenyl)-3-methyl-12b-(pyridin-2-ylmethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol; compound with (3S,4aR,12bR)-9-(4-fluorophenyl)-3-methyl-12b-(pyridin-2-ylmethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (13, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl, R3=Methyl) (503 mg, 100%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[NH:50])[NH2:49])=[CH:44][C:43]=1[O:51][CH3:52])(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:42]2[CH:47]=[CH:46][C:45]([C:48](=[NH:49])[NH2:50])=[CH:44][C:43]=2[O:51][CH3:52])=[O:18])=[CH:20][CH:21]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=N)N)ccc1OS(C)(=O)=O
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: COc1cc(C(=N)N)ccc1OC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of 3.7 g of 4-benzyloxycarbonylaminomethylbenzoic acid in 40 ml of dried pyridine, was added 3.1 g of DCC with cooling in ice. The mixture was stirred for 30 minutes. After addition of 3.1 g of 4-amidino-2-methoxyphenol methanesulfonate, the mixture was further stirred overnight at room temperature. The reaction mixture was removed of the insolubles and mixed with ethyl ether to precipitate a colorless solid substance which on recrystallization from a methanolethyl ether mixture gave 3.2 g of colorless crystals of 4-amidino-2-methoxyphenyl 4-benzyloxycarbonylaminomethylbenzoate methanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13](S(C)(=O)=O)=[N:12][CH:11]=1)[CH3:9])=[O:6].[CH2:23]([S:25]([C:28]1[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([CH:34]=1)[NH2:33])(=[O:27])=[O:26])[CH3:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:33][C:32]2[CH:34]=[C:28]([S:25]([CH2:23][CH3:24])(=[O:26])=[O:27])[CH:29]=[CH:30][C:31]=2[O:35][CH3:36])=[N:12][CH:11]=1)[CH3:9])=[O:6]
Reactant: CCS(=O)(=O)c1ccc(OC)c(N)c1
Reactant: CC(NC(=O)c1cccc(Br)c1)c1cnc(S(C)(=O)=O)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)c1
Reaction time: 24 h
Yield: 34.1 %

Procedure:
To a stirred solution of 3-bromo-N-{1-[3-(methylsulfonyl)-1,2,4-triazin-6-yl]ethyl}benzamide (Intermediate 6) (240 mg, 0.62 mmol) in tetrahydrofuran (10 mL) was added 5-(ethylsulfonyl)-2-methoxyaniline (270 mg, 1.2 mmol) and 4-toluenesulfonic acid monohydrate (20 mg). After stirring for 24 hours, silica gel (2.5 g) was added to the solution, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (20:80) to ethyl acetate:hexanes (80:20) using a RediSep silica gel cartridge (12 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 3-bromo-N-[1-(3-{[5-(ethylsulfonyl)-2-methoxyphenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (110 mg) as a white solid. 1H NMR (CDCl3): δ9.00 (d, J=2.2 Hz, 1H), 8.44 (s, 1H), 8.03 (s, 1H), 7.95 (dd, J=1.9, 1.4 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.62 (d, J=7.4 Hz, 1H), 7.57-7.52 (m, 1H), 7.22 (dd, J=8.1, 7.7 Hz, 1H) 7.00 (d, J=8.8 Hz, 1H) 5.44 (dq, J=7.2, 7.0 Hz, 1H), 3.98 (s, 3H), 3.10 (q, J=7.3 Hz, 2H), 1.68 (d, J=7.0 Hz, 3H), 1.24 (t, J=7.3 Hz, 3H). MS m/z 520, 522 (M+1, M+3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH3:38][C:39]1[NH:40][CH:41]=[C:42]([CH:44]=O)[N:43]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:44][C:42]4[N:43]=[C:39]([CH3:38])[NH:40][CH:41]=4)[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCNCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Cc1nc(C=O)c[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(-c2nn(C3CCN(Cc4c[nH]c(C)n4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
N2-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (250 mg, 0.503 mmol), 2-methyl-1H-4-imidazolecarbaldehyde (83 mg, 0.755 mmol), sodium triacetoxyborohydride (159 mg, 0.755 mmol) and glacial acetic acid (30 mg, 0.554 mmol) were mixed in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution 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. The residue was purified by flash column chromatography using dichloromethane/methanol/ammonium hydroxide (95:5:0.5 to 80:20:05) as mobile phase to give N2-[4-(4-amino-1-{1-[(2-methyl-1H-4-imidazolyl)methyl]-4-piperidyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (215 mg, 72%). 1H NMR (DMSO-d6) δ 1.91 (m, 2H), 2.23 (m, 7H), 3.00 (m, 2H), 3.41 (s, 2H), 3.96 (s, 3H), 4.04 (s, 3H), 4.78 (m, 1H), 6.72 (s, 1H), 7.15 (m, 1H), 7.32 (m, 4H), 7.78 (d, J=8.43 Hz, 1H), 7.70 (d, J=7.92 Hz, 1H), 8.11 (d, J=7.92 Hz, 1H), 8.24 (s, 1H), 9.44 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 0.8 mL/min.): RT=2.00 min. MH+=591.3.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:32]([C:35]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:36]=1[S:44](Cl)(=[O:46])=[O:45])([O-:34])=[O:33].C([O-])(O)=O.[Na+]>C(Cl)Cl>[N+:32]([C:35]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:36]=1[S:44]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=2)[CH2:18][CH2:19]1)(=[O:46])=[O:45])([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
To a 20 mL resealable vial was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.27 g, 0.67 mmol, Example 91, Step 1), DCM (6 mL), triethylamine (0.47 mL, 3.4 mmol) and finally 2,4-dinitrobenzenesulfonyl chloride (0.22 g, 0.81 mmol). The mixture was stirred at room temperature for 15 min. To the reaction mixture was added saturated aqueous NaHCO3. This was stirred for 5 min and then the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was concentrated and purified by silica gel chromatography (0 to 70% EtOAc/hexane) afforded 2-(4-(4-((2,4-dinitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.31 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]([CH3:7])[C:4]([OH:6])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:30][C:31]1[N:36]=[C:35]([C:37]#[C:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:34]([N:45]([CH3:55])[S:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)(=[O:48])=[O:47])=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:11]([O:10][C:8](=[O:9])[N:2]([CH:3]([CH3:7])[C:4]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([N:45]([S:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH3:55])=[C:35]([C:37]#[C:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:36]=1)=[O:6])[CH3:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CN(c1ccc(N)nc1C#Cc1ccccc1)S(=O)(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C(=O)Nc1ccc(N(C)S(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (54 mg, 0.26 mmol) and N,N′-dicyclohexylcarbodiimide (27 mg, 0.13 mmol) in DCM (1.5 ml) is stirred at RT for 20 minutes. This mixture is added to N-[6-amino-2-(2-phenylethynyl)pyridin-3-yl]-N-methylbenzenesulfonamide E5a (16 mg, 0.04 mmol) and DIPEA (9 μl; 0.05 mmol) in DCM (0.5 ml). After stirring for 4 days at 40° C. the reaction mixture is diluted with DCM and extracted with water. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The crude product (22 mg) is used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][N:14]=1>CO>[N:16]1[CH:17]=[CH:18][C:13]([CH:12]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[N:14][CH:15]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccncn1
Solvent: CO
Product: O=C1c2ccccc2C(=O)C1c1ccncn1

Procedure:
7.87 g (53.1 mmol) phthalic acid anhydride and 22 ml (0.24 mol) 4-methylpyrimidine are stirred for 1 h at 140° C. and for 4 h at 210° C. The reaction mixture is then stirred with 15 ml methanol, filtered, and the residue washed with methanol. Further product is obtainable by evaporating the filtrate and stirring the residue with water: m.p.: 168-169° C.); Anal. calc. (C13H8N2O2) C 69.64%, H 3.60%, N 12.49%; found C 69.8%, H 3.7%, N 12.4%; FAB MS (M+H)+=225.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]([CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=O)=[CH:4][CH:3]=1.[CH:30]([NH:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50]CC)=[O:49])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-:53].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:9][CH2:10][CH2:11][C:12]([N:43]([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])=[O:13])=[O:53])=[CH:28][CH:29]=1
Reactant: [OH-]
Reactant: O=C(O)CCCN(C(=O)c1ccc(Cl)cc1)C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCCNC(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CCO
Product: O=C(O)CCCCN(C(=O)CCCN(C(=O)c1ccc(Cl)cc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-benzhydrylaminobutyric acid and ethyl 5-benzhydrylaminovalerate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-4-benzhydrylaminobutyryl]-5-benzhydrylaminovaleric acid.