Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][N:3]=1.Cl>CO.[C].[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[CH:9]=[N:8][N:7]3[C:2]([OH:1])=[N:3][CH:4]=[N:5][C:6]=23)=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(-c2cnn3c(O)ncnc23)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(-c2cnn3c(O)ncnc23)cc1
Temperature: 25 °C
Reaction time: 46 h
Yield: 77.2 %

Procedure:
4-Hydroxy-8-(4-nitrophenyl)pyrazolo[1,5-a]-1,3,5-triazine (660 mg) and 5% palladium-carbon (500 mg) are suspended in 80% aqueous methanol (100 ml), and the mixture is stirred under hydrogen atmosphere at room temperature. After reacting for 46 hours, to the reaction mixture is added conc. hydrochloric acid (5 ml), and the insoluble material is removed off by filtration. The filtrate is concentrated to driness under reduced pressure to give the title compound (450 mg).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40][NH2:41]>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])=[O:3])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Reactant: CN(C)CCCN
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCCN(C)C)n3)cc2CC1

Procedure:
The title compound was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and N(1),N(1)-dimethyl-propane-1,3-diamine in an analogous manner to Example 1396. Product isolated as a yellow foam (27 mg, 45%). LCMS (m/e) 552 (M+H): 1H-NMR (CDCl3, 400 MHz) δ 11.62 (s, 1H), 8.91 (s, 1H), 8.72 (d, 1H, J=8.5 Hz), 8.10 (s, 1H), 7.47 (d, 1H, J=7.9 Hz), 7.46-7.40 (m, 1H), 7.36 (s, 1H), 7.30-7.23 (m, 1H), 7.10-7.00 (m, 2H), 6.96 (s, 1H), 3.64-3.53 (m, 4H), 3.39 (s, 3H), 2.97-2.88 (m, 4H), 2.82-2.70 (m, 6H), 2.55 (t, 2H, J=5.4 Hz), 2.33 (s, 6H), 1.84-1.75 (m, 2H).
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:11][CH:10](C(O)=O)[C:9]1=[O:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]([F:20])([F:21])[C:15]1[CH:14]=[C:13]([C@@H:12]2[NH:8][C:9](=[O:26])[CH2:10][CH2:11]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C(=O)O)C[C@@H]1c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC[C@H](c2cccc(C(F)(F)F)c2)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The mixture of (5R)-1-(tert-butoxycarbonyl)-5-[3-(trifluoromethyl)phenyl]-2-oxopyrrolidine-3-carboxylic acid obtained in Step E (ca. 1.21 mmol) and 30% TFA in DCM (6 mL) is stirred at rt for 30 min. The reaction mixture is then dissolved in DCM (120 mL), washed with saturated aq. NaHCO3 (40 mL) and brine (40 mL) and dried over Na2SO4. Concentration to give (R)-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one as a slight brown solid (278 mg, 100% overall yield for two steps). This product is used for the next step without further purification. HPLC-MS calculated for C11H10F3NO (M+H+) 230.07, found 230.00.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][C:29]1([CH3:41])[CH2:33][C:32]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=2[O:30]1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:35]2[CH:36]=[CH:37][C:31]3[O:30][C:29]([CH3:28])([CH3:41])[CH2:33][C:32]=3[CH:34]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.43 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (2.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.68 g, 60%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([CH2:20][OH:21])=[CH:18][N:17]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[N:16]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][CH:28]=2)[N:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1nn(Cc2ccc(Oc3ccccc3)cc2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1nn(Cc2ccc(Oc3ccccc3)cc2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of [3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazol-4-yl]methanol (2.85 g), active manganese dioxide (8.42 g) and tetrahydrofuran (50 ml) was stirred at room temperature overnight. After the manganese dioxide was separated by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carbaldehyde (2.61 g, yield 92%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 129–130° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8](Cl)=[O:9])[C:4]([CH3:11])=[N:3]1.[CH2:12]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH:23]([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])[NH2:19])[CH:13]([CH3:15])[CH3:14].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH2:12]([C:16]1[CH:17]=[C:18]([NH:19][C:8]([C:5]2[C:4]([CH3:11])=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])=[O:9])[CH:20]=[CH:21][C:22]=1[CH:23]([C:28]([F:29])([F:30])[F:31])[C:24]([F:25])([F:26])[F:27])[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1nn(C)c(C)c1C(=O)Cl
Reactant: CC(C)Cc1cc(N)ccc1C(C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1C(=O)Nc1ccc(C(C(F)(F)F)C(F)(F)F)c(CC(C)C)c1
Yield: 82.7 %

Procedure:
1,3,5-Trimethylpyrazole-4-carbonyl chloride (2.09 g, 10.0 mmol), 3-isobutyl-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline (2.0 g, 6.69 mmol), and triethylamine (1.35 g, 13.4 mmol) were dissolved in tetrahydrofuran (60 ml), and the mixture was heated under reflux for 5 hr. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to give the desired compound (2.41 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([C:15]([N:17]2[CH2:21][CH2:20][C@H:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18]2)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C.[C:36]1([S:42](Cl)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50]>ClCCl.ClCCl.CO>[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50].[C:36]1([S:42]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[CH2:10][C:11]2[CH:28]=[CH:27][C:14]([C:15]([N:17]3[CH2:21][CH2:20][C@H:19]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:18]3)=[O:16])=[CH:13][CH:12]=2)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(c1ccc(Cc2nc3ccccc3[nH]2)cc1)N1CC[C@H](N2CCCC2)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc(Cc2nc3ccccc3n2S(=O)(=O)c2ccccc2)cc1)N1CC[C@H](N2CCCC2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (3′S)-1′-[4-(1H-benzimidazol-2-ylmethyl)benzoyl]-1,3′-bipyrrolidine (100 mg, 0.267 mmol) in anhydrous dichloromethane was cooled to 0° C. under an inert atmosphere, treated with triethylamine (TEA) (32 mg, 0.32 mmol) followed by dropwise addition of a solution of benzenesulfonyl chloride (51.7 mg, 0.293 mmol) in anhydrous dichloromethane, stirred at 0° C. for 1 h, warmed to room temperature for 1 h and concentrated under reduced pressure. The resultant residue was partitioned between dichloromethane and 5% aqueous NaHCO3. The organic phase was separated, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give a residue. This residue was treated with fumaric acid in dichloromethane/methanol to afford the title compound, 1H NMR (300 MHz, DMSO-d6, +TFA): 7.96 (d, 1 H), 7.90 (d, 2 H), 7.78-7.66 (m, 2 H), 7.59 (m, 2 H), 7.49 (d, 2 H), 7.45-7.29 (m, 4 H), 6.63 (s, 2 H), 4.67 (s, 2 H), 3.58-3.41 (m, 4 H), 3.10-2.76 (m, 5 H), 2.19 (m, 1 H), 2.00 (m, 1 H), 1.91-1.73 (m, 4 H). [M+H] 515.1
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc2[nH]ccc2c1
Product: Cc1ccc(S(=O)(=O)n2ccc3ccccc32)cc1
Yield: 91 %

Procedure:
The title compound was prepared from toluene-4-sulfonyl chloride and 1H-indole, according to Method A, described above. Yield 91%; mp 60-62° C.; 1H NMR (CDCl3) δ 8.0-8.03 (dd, J=8 Hz, 1H), 7.78 (d, J=7 Hz, 2H), 7.57 (d, J=4 Hz, 1H), 7.52-7.56 (m, 1H), 7.26-7.36 (m, 2H), 7.20-7.23 (d, J=8 Hz, 2H), 6.66-6.68 (dd, J=4 Hz, 1H), 2.30 (s, 3H); 13C NMR (CDCl3) δ 145.4, 135.7, 135.3, 131.2, 130.3, 127.2, 126.8, 124.9, 123.7, 121.8, 113.9, 109.5, 21.9; MS (ES+) m/z 271.93 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
4-Hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) was dissolved in DMF (50 mL). K2CO3 (6.48 g, 46.9 mmol) and benzyl bromide (2.80 mL, 23.6 mmol) were added. The reaction mixture was stirred at room temperature overnight, quenched with H2O (150 mL), and extracted with EtOAc (2×150 mL). The organic layers were dried over MgSO4 and concentrated to give a white solid (7.18 g, 98% yield) which was used as it is for the next step. 1H NMR (400 MHz, CDCl3) δ 7.34-7.46 (m, 5 H) 7.21 (s, 1 H) 7.08 (s, 1 H) 5.13 (s, 2 H) 3.90 (s, 3 H) 3.02 (s, 2 H) 1.49 (s, 6 H); LCMS for C19H20O4 m/z 313.20 (M+H)+.
Reaction SMILES: [Na].[C:2]1([S:8]([C:11]2[C:12]([S:28][CH3:29])=[N:13][N:14]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:18][C:17](Cl)=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([OH:33])[CH2:31][OH:32]>>[C:2]1([S:8]([C:11]2[C:12]([S:28][CH3:29])=[N:13][N:14]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:18][C:17]([O:32][CH2:31][CH2:30][OH:33])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nn2c(N3CCN(C)CC3)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Reactant: OCCO
Agent: [Na]
Product: CSc1nn2c(N3CCN(C)CC3)cc(OCCO)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
0.115 g (5 mmol) of sodium was added to 20 ml of ethylene glycol and this solution was treated with 0.22 g (0.5 mmol) of 3-benzenesulphonyl-5-chloro-7-(4-methyl-piperazin-1-yl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and subsequently stirred at 80° for 1 hr. After cooling to RT the reaction solution was poured on to 70 ml of ice-water and extracted three times with 50 ml of AcOEt. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) of the residue and crystallization from EtOH yielded 0.16 g (69%) of 2-[3-benzenesulphonyl-7-(4-methylpiperazin-1-yl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-5-yloxy]-ethanol as colorless crystals, m.p. 187-189°.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].O.O.[C:14]1([S:20]([O-:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+]>CS(C)=O>[C:14]1([S:20]([CH2:2][C:3]([O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:4])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CBr)OC1CCCCC1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(CS(=O)(=O)c1ccccc1)OC1CCCCC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
To a solution of cyclohexyl 2-bromoacetate (15.6 g, 0.07 mole) in dimethylsulfoxide (120 ml), sodium benzenesulfinate dihydrate (15 g, 0.075 mole) was added in a small portion at 30°-40° C., and stirring was continued at 60° C. for 6 hours. The resultant mixture was poured into ice-cold H2O (1.5 l). The precipitate was filtered, washed with H2O and dried to afford 15.3 g of cyclohexyl 2-phenylsulfonylacetate as white crystals.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[CH:29]=[N:28][NH:27][C:14]3=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:30][O-:31].[Na+]>CO>[CH3:30][O:31][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[CH:29]=[N:28][NH:27][C:14]3=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
To a solution of 5-[2-(methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine (90 mg, 0.2 mmol, obtained in example 127) in MeOH (5 mL) in a closed vessel, sodium methoxide (11 mg, 0.2 mmol) was added and heated to 60° C. for 24 h. Then, sodium methoxide (11 mg, 0.2 mmol) was added and it was stirred at 60° C. for 2 h more. It was allowed to cool and was concentrated. EtOAc and buffer (pH=5.3) were added. The phases were separated and the organic phase was washed with water, dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures at 50%, to afford 38 mg of the title compound (yield: 47%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1([CH2:18][O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:21])[CH2:17][CH2:16][CH2:15][O:14]1)=[O:10].C(N(CC)CC)C.[C:48](OC(=O)C)(=[O:50])[CH3:49]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:48]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9]([O:11][CH2:12][C:13]1([CH2:18][O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:21])[CH2:17][CH2:16][CH2:15][O:14]1)=[O:10])(=[O:50])[CH3:49]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(COC(=O)NCc2ccccn2)CCCO1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(COC(=O)N(Cc2ccccn2)C(C)=O)CCCO1

Procedure:
To 3.2 g (5.7 mmol) of the compound prepared in (b) above dissolved in 25 ml of chloroform was added, with stirring and under a nitrogen atmosphere, 18.15 g (180 mmol) of triethylamine, 11.63 g (114 mmol) of acetic anhydride and 0.035 g (0.29 mmol) of 4-dimethylaminopyridine. The resultant mixture was then heated to reflux and maintained at the reflux temperature for 72 hours. The volatiles were then removed under high vacuum and the resultant residue was dissolved in methylene chloride and washed rapidly with a saturated aqueous sodium bicarbonate solution. The organic layer was then dried over sodium sulfate, filtered and concentrated. The resultant residue was then chromatographed on silica gel employing a mixture of petroleum ether and ethyl acetate in a ratio of 1:1 by volume initially, with the product being eluted when the eluent was pure ethyl acetate. The resultant solution was then concentrated to obtain a semi-solid.
Reaction SMILES: B(F)(F)F.CO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:20]1([CH2:26][CH:27]([OH:31])[C:28]([OH:30])=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH:23]1[CH:22]=[CH:21][C:20]([CH2:26][C@H:27]([OH:31])[C:28]([OH:30])=[O:29])=[CH:25][CH:24]=1
Reactant: O=C(O)C(O)Cc1ccccc1
Agent: FB(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(O)[C@@H](O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
The derivatization was carried out with BF3-methanol (see above) or with trifluoroacetic anhydride. For the derivatization with trifluoroacetic anhydride, 5 mg of 3-phenyllactic acid were dissolved in 500 μl of CH2Cl2, treated with 5 drops of trifluoroacetic anhydride, shaken for 1 minute at room temperature and subsequently treated with approximately 500 μl of H2O. The organic phase is dried over Na2SO4, and the samples were then measured by GC on a chiral column.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]=2[S:28][CH2:27]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])=[O:5])[CH3:2].C(OCC)(=O)C.[ClH:52]>>[ClH:52].[CH2:1]([O:3][C:4]([C@@H:6]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH2:34][C:35]([OH:37])=[O:36])[C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]=2[S:28][CH2:27]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3 h

Procedure:
In 5 ml of 5 N hydrogen chloride-ethyl acetate solution is dissolved 0.12 g of tert-butyl 3(R)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and the solution is left standing at room temperature for 3 hours. Petroleum ether (70 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.10 g of 3(R)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride as a colorless powder.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH2:6]1>O1CCCC1>[N:4]([CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH2:6]1)=[C:1]=[S:3]
Reactant: S=C=S
Reactant: CCOC(=O)N1CCCC(N)CC1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCCC(N=C=S)CC1
Yield: 100 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 63 parts of carbon disulfide, 52.1 parts of N,N'-methanetetraylbis[cyclohexanamine] and 360 parts of tetrahydrofuran were added dropwise 46.9 parts of ethyl 4-aminohexahydro-1H-azepine-1-carboxylate. Upon complete addition, the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was evaporated and the residue was stirred in 2,2'-oxybispropane. The precipitate was filtered off and the filtrate was evaporated, yielding 70.75 parts (100%) of ethyl hexahydro-4-isothiocyanato-1H-azepine-1-carboxylate as a residue (interm. 29).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:59]=[C:60]([CH:63]=[CH:64][CH:65]=1)[C:61]#[N:62])=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:65]=[CH:64][CH:63]=[C:60]([C:61]#[N:62])[CH:59]=2)=[O:57])[CH2:49][CH2:48]1
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(NC(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 8 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3-isocyanatobenzonitrile as starting materials in 8% yield. LCMS for C32H31ClN9O2 (M+H)+: m/z=608.2.
Reaction SMILES: C([Cl:4])(=O)C.[CH2:5]([C:9]1[S:18][C:17]2[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]=[C:12]([N:23]3[CH2:28][CH2:27][NH:26][C@@H:25]([CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:24]3)[C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8].CO>C(O)C>[ClH:4].[ClH:4].[CH2:5]([C:9]1[S:18][C:17]2[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]=[C:12]([N:23]3[CH2:28][CH2:27][NH:26][C@@H:25]([CH2:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:24]3)[C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)Cl
Agent: CCCCc1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Solvent: CCO
Solvent: CO
Product: Cl

Procedure:
Add a solution of acetyl chloride (0.0601 mL, 0.842 mmol) in absolute ethanol at ambient temperature to (S)-2-Butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.075 g, 0.17 mmol) in absolute ethanol, with added drops of methanol to solubilize the freebase, stir and concentrate under reduced pressure to give the title compound (0.078 g): Mass spectrum (ES+, m/e): 446 (M+1−2HCl); exact mass spectrum (ES+, m/e, C26H31N5S.2HCl): calc. 446.2378 (M+1–2HCl), found 446.2397.