Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].O.O.O.C([O-])(=O)C.[Na+]>>[CH3:14][O:13][C:11](=[O:12])[CH2:10][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)CCl
Reactant: Nc1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CNc1cccc(F)c1

Procedure:
3-Fluoroaniline (55.5 g), methyl chloroacetate (44 ml), and sodium acetate trihydrate (114 g) were treated according to the method of Intermediate 1 to give a solid (50 g), a small sample of which (ca. 1 g) was purified by FCC eluting with System B (1:3) to give a solid which was recrystallised from petroleum ether (60°-80°) to give the title compound, m.p. 68°-69°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:34]=CC)=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:37]1CCCC1>O.O=[Os](=O)(=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:34]=[O:37])=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC=Cc1c(NC(=O)OCc2ccccc2)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(NC(=O)OCc4ccccc4)c(C=O)c3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution {(2R)-7-{[(benzyloxy)carbonyl]amino}-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (4.5 g, 8.84 mmole) in tetrahydrofuran (225 mL) was added OsO4 (1.65 mL, 0.270 mmole). Then a solution of NaIO4 (9.45 g, 44.2 mmole) in water (100 mL) was added dropwise. The reaction was stirred at room temperature under nitrogen overnight. Water (250 mL) was added to the mixture and it was then extracted with ethyl acetate. The organic phase was then washed with brine, dried over magnesium sulfate, filtered and evaporated to 4.45 g (>95%) of the (R)-enantiomer of the title compound as a yellow solid. 1H (CDCl3) broad singlet 10.8 δ (1 H); singlet 10.1 δ (1 H); doublet 7.9 δ (1 H); doublet 7.8 δ (2 H); multiplet 7.4 δ (7 H); doublet 7.0 δ (1 H); singlet 5.2 δ (2 H); multiplet 4.5 δ (1 H); multiplet 4.2 δ (3 H); multiplet 4.1 δ (1 H); singlet 2.4 δ (3 H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][CH2:7][OH:8])[CH2:4][OH:5].[CH3:9][C:10]1C=CC(S(O)(=O)=O)=C[CH:15]=1.C(N(CC)CC)C>CC(C)=O>[CH3:9][C:10]1([CH3:15])[O:5][CH2:4][CH:3]([CH2:6][CH2:7][OH:8])[CH2:2][O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCC(CO)CO
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CCO)CO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 989.3 %

Procedure:
A solution of compound 31 (160 g, 1.30 mol) and 2,2′-dimethoxypropane (207 g, 1.90 mol) in dry acetone (800 mL) was added p-TsOH (9.2 g, 0.053 mol) under N2 and stirred at RT for 12 h. To this was added triethylamine drop-wise to neutral pH and then concentrated under vacuum below 35° C. The crude residue was purified by column chromatography over neutral alumina (12% ethyl acetate in pet. ether) to give the title compound (84 g, 39%). TLC: Pet. ether/EtOAc, 1:1, Rf=0.2
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:14])=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.[CH3:31]C1C=CC(C=O)=CN=1>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:31])=[CH:14][CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Product: Cc1ccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 6-methylnicotinaldehyde provided the title compound. 400 MHz 1H NMR (CD3OD) δ 8.38 (d, J=2.1 Hz, 1H), 7.99 (s, 1H), 7.77 (d, J=2.07 Hz, 1H), 7.75 (d, J=2.07 Hz, 1H), 4.94-4.83 (m, 1H), 4.09-4.05 (m, 2H), 3.78-3.57 (m, 4H), 3.31-3.28 (m, 1H), 3.11-3.06 (m, 1H), 3.01-2.91 (m, 2H), 2.72-2.65 (m, 1H), 2.50 (s, 3H), 2.33-2.23 (m, 3H), 1.90-1.86 (m, 2H), 1.14 (d, J=7.1 Hz, 3H). MS: (M+H m/z 409.2).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=[O:2].[BH4-].[Na+]>CO.C(OCC)(=O)C>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:14]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: COC(=O)c1ccc(-c2ccc(C=O)cc2OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(CO)cc2OC)cc1

Procedure:
A solution of Example 122I (270 mg, 0.5 mmol), and sodium borohydride (80 mg) in methanol (5 mL) at room temperature was stirred for 30 minutes, diluted with ethyl acetate (70 mL), washed with water (20 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccncc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(Cc1ccncc1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
200 mg (0.366 mmol) of (2R*,4S*)-2-benzyl-1-(4-pyridylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 55 mg (1.46 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR45## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.31, FD-MS: M+ =450.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:46]=[CH:45][C:25]([O:26][CH2:27][CH:28]([OH:44])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:32]=2)=[CH:24][CH:23]=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.[C:47](OC(=O)C)(=[O:49])[CH3:48]>N1C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH:28]([O:44][C:47](=[O:49])[CH3:48])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:32]=2)=[CH:45][CH:46]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(OCC(O)COc2ccc(CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(COc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1)COc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of (2R and 2S)-3-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanol (6.08 g, 9.5 mmol) in a mixture of pyridine (15 ml) and acetic anhydride (15 ml) was stirred at 22° C. for 1 hour. The excess reagents were then evaporated in vacuo and the residue was filtered through a silica gel pad (elution toluene-ethyl acetate, 95:5) to give 6.48 g (100%) of the title material as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][CH2:26][C:27]([OH:29])=O)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[NH:30]([C:27](=[O:29])[CH2:26][CH2:25][C:11]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:13][N:12]1[C:14]([N:16]([CH3:17])[CH3:18])=[O:15])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CCC(=O)O)c1ccccc1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CCC(=O)Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 40 mg (0.10 mmol) of acid 24-1 in DMF was added 11 μL (0.12 mmol) of aniline, 29 mg (0.15 mmol) of EDCI, 17 mg (0.13 mmol) HOAT, and 28 μL (0.20 mmol) of triethylamine. After stirring overnight at room temperature, the reaction was partitioned between EtOAc and 10% KHSO4, the organic phase was washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 24-2 as a white solid. Data for 24-2: 1HNMR (500 MHz, d6-DMSO) δ 9.8 (s, 1H), 7.5-7.0 (m, 13H), 6.2 (s, 1H), 5.0 (m, 1H), 4.8 (m, 1H), 3.0 (m, 1H), 2.75 (s, 6H), [(˜2.5, under solvent peak (m, 1H)], 2.2 (m, 2H) ppm. HRMS (ES) calc'd M+H for C28H27F2N3O2: 476.2144. Found: 476.2162
Reaction SMILES: C(OC([NH:8][C@H:9]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:10][N:11]1[C:16](=O)[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[C:12]1=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C@H:9]([CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1)[CH2:10][N:11]1[CH2:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[CH2:12]1
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C2=C(C)N(Cc3c(F)cccc3F)CN(C[C@H](N)C3CCCCC3)C2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To compound 11c (300 mg, 0.5 mmol) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at ambient temperature for 1 hour. Volatiles were evaporated and the residue was partitioned between saturated NaHCO3/water and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by reverse phase HPLC (C-18 column, 15–75% ACN/water) to give compound 11d. MS (CI) m/z 502.2 (MH+).
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=O)[C:3](=[C:4]23)[CH:2]=1)=[O:22].[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1.N1C=CN=C1>>[CH:26]1([N:31]2[C:21](=[O:22])[C:5]3[C:4]4[C:19]5[C:8](=[CH:7][CH:6]=3)[C:9]3[C:20]6[C:13]([CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=[CH:16][C:17]=6[C:18]=5[CH:1]=[CH:2][C:3]=4[C:24]2=[O:23])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Reactant: NC1CCCC1
Agent: c1c[nH]cn1
Product: O=C1c2ccc3c4cccc5cccc(c6ccc(c2c36)C(=O)N1C1CCCC1)c54
Temperature: 145 °C

Procedure:
0.30 g (0.93 mmol) of perylene-3,4-dicarboxylic anhydride is mixed with 0.24 g (2.80 mmol) of cyclopentylamine and 3 g of imidazole, and the mixture is heated under nitrogen at 145° C. for 4 h. The reaction product is removed from the flask by washing with ethanol, and the mixture is then treated with 10% hydrochloric acid and boiled until no more ethanol is present. The precipitated product is filtered off with suction, boiled in potassium carbonate solution and the solid residue is filtered off with suction and washed with hot dist. water. 60 mg (20%) of perylene-3,4-dicarboxylic anhydride can be recovered by acidifying the filtrate with conc. hydrochloric acid. The red residue is recrystallized 3 times by extraction with methanol and then dried in a drying cabinet at 120° C. Yield 0.22 g (61%) of dark-red small needles showing a strong red solid fluorescence, m.p. >315° C. Rf (CHCl3 /silica gel)=0.18. UV (CHCl3): λmax (ε)=506 (31013), 485 (31425) 355 (3050), 336 (3000), 319 (2680), 264 (34268), 256 (sh., 18100). Fluorescence (CHCl3): λmax (Irel)=541 (1), 572 (sh., 0.49).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:12])[N:10]=[CH:11][C:6]2=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:4]=1.[CH3:22][S:23]([O-:25])=[O:24].[Na+]>CCO.CN(C=O)C>[CH3:22][S:23]([CH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:12])[N:10]=[CH:11][C:6]2=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:4]=1)(=[O:25])=[O:24]
Reactant: CS(=O)[O-]
Reactant: Cn1ncc2c(-c3ccc([N+](=O)[O-])cc3)cc(CBr)nc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cn1ncc2c(-c3ccc([N+](=O)[O-])cc3)cc(CS(C)(=O)=O)nc21
Temperature: 25 °C
Yield: 100.1 %

Procedure:
1.04 g 6-bromomethyl-1-methyl-4-(4-nitro-phenyl)-1H-pyrazolo[3,4-b]pyridine (Intermediate 13.1; 3 mmol, 1 eq.) were dissolved in 55 mL 10:1 EtOH/DMF, treated with 459 mg sodium methanesulfinate (4.5 mmol, 1.5 eq.) and refluxed for 150 min. The mixture was cooled to rt and concentrated in vacuo. Addition of water was followed by precipitation to yield 1040 mg of the crude product (quantitative yield).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[SH:8][CH2:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@H:14]([CH2:18][S:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:15]([OH:17])=[O:16])=[O:12].O.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[SH:8][CH2:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@H:14]([CH2:18][S:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:15]([O:17][CH3:30])=[O:16])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(CSC[C@H](NC(=O)[C@H](C)CS)C(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](CSCc1ccc(C)cc1)NC(=O)[C@H](C)CS

Procedure:
Anhydrous sodium sulfate (3 g) is added to a solution of (2R)-2-[(2S)-3-mercapto-2-methylpropionylamino]-3-(4-methylbenzylthio)propionic acid (compound No. 1-1, 300 mg) and p-toluenesulfonic acid monohydrate (240 mg) in methanol (10 ml), and the mixture is refluxed for three hours and 30 minutes. Sodium sulfate is filtered out, and the filtrate is concentrated under reduced pressure. A 5% aqueous sodium hydrogencarbonate solution is added to the obtained residue, and the whole is extracted with ethyl acetate. The organic layer is washed with a 5% aqueous sodium hydrogencarbonate solution, a 5% aqueous citric acid solution and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the titled compound. The following compound is obtained by a method similar to Example 5.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[C:34]([F:43])=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[C:34]([F:43])=[C:35]([S:39]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc(Cl)c1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3-chloro-2-fluorobenzene-1-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[CH2:22][C@H:23]4[C@@H:28]([C:29]=3[CH:30]=2)[CH2:27][CH2:26][CH2:25][NH:24]4)=[CH:14]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[CH2:25][CH2:26][CH2:27][C@@H:28]4[C:29]5[CH:30]=[C:18]([C:15]6[CH:16]=[CH:17][O:13][CH:14]=6)[CH:19]=[CH:20][C:21]=5[CH2:22][C@H:23]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: c1cc(-c2ccc3c(c2)[C@H]2CCCN[C@H]2C3)co1
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3cc(-c4ccoc4)ccc3C[C@@H]21
Yield: 14 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6-furan-3-yl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 14% of theory; LC (method 1): tR=2.89 min; Mass spectrum (ESI+): m/z=384 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[C:47]([CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)=[O:48])[CH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH:49]([C:47]([C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)=[O:48])[CH2:50][CH2:51]2)([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(F)cc3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccc(F)cc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-(4-fluoro-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-[l-(2-ethoxy-ethyl)-1H-benzoimidazole-2-carbonyl]-piperidine to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33])[CH:26]=[CH:25]2>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:38]2[CH2:37][CH2:36][N:35]([S:32]([C:27]3[CH:26]=[CH:25][C:24]4[C:29](=[CH:30][CH:31]=[C:22]([Cl:21])[CH:23]=4)[CH:28]=3)(=[O:34])=[O:33])[CH2:40][CH2:39]2)=[O:16])=[CH:18][CH:19]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1

Procedure:
In the same manner as in Referential Example 48, a reaction was conducted using methyl 4-(N-tert-butoxycarbonylaminomethyl)benzoate and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride, whereby the title compound was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:33]([CH:30]3[CH2:31][CH2:32][N:27]([C:25]([O:24][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:26])[CH2:28][CH2:29]3)=[O:34])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCC(NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 58A, 300 mg (1.35 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 355 mg (1.35 mmol) 1-[(benzyloxy)carbonyl]-4-piperidinecarboxylic acid and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CCNC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]pyrrolidine-1-carboxylate (3.485 g, 7.39 mmol) in DCM (30 ml) was added TFA (30 ml). The reaction was allowed to stir at ambient temperature for 1 hour. The solvents were then removed in vacuo, residue partitioned between DCM and 2M NaOH, extracted twice and the combined organics dried (Na2SO4), filtered and evaporated to dryness to give the product, N-(3,4-dichlorophenyl)-4-(pyrrolidin-3-ylcarbonyl)piperazine-1-carboxamide, as a pale yellow foam (2.745 g, 7.39 mmol, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:22][N:21]=[C:20](Cl)[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:22][N:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nc(Cl)ns3)cc(C)c21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ncns3)cc(C)c21
Yield: 33.3 %

Procedure:
To a solution of [6-(3-chloro-[1,2,4]thiadiazol-5-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (400 mg, 1.08 mmol) in MeOH (10 mL) was added Pd/C (300 mg, 75%). The resulting solution was degassed, and reacted under H2 (60 psi) for 2 days. The mixture was filtrated. The filtration was removed in vacuo and purified by column chromatography (silica, DCM/MeOH 4:1) affording the title compound (120 mg, 35%) as a white solid. MS found: (M+H)+: 335.