Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[C:9]1[CH3:29])(C)(C)C.Cl[CH2:32][C:33]1[C:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:35][O:36][C:37]=1[CH3:38]>>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]([CH3:29])=[C:10]2[CH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20](=[O:27])(=[O:28])[N:19]1[CH2:32][C:33]1[C:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:35][O:36][C:37]=1[CH3:38]
Reactant: Cc1onc(-c2ccccc2)c1CCl
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Product: Cc1onc(-c2ccccc2)c1CN1C(c2c(C)n(CC(=O)O)c3ccc(Cl)cc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 6, step c) and 4-chloromethyl-5-methyl-3-phenyl-isoxazole. 1H NMR (DMSO-d6) 7.99-7.91 (m, 1H), 7.69-7.60 (m, 2H)), 7.43 (d, J=8.7 Hz, 1H), 7.36 (d, J=7.2 Hz, 2H), 7.23-6.75 (m, 6H), 5.94 (s, 1H), 4.96 (s, 2H), 4.33 (d, J=14.1 Hz, 1H), 4.07 (d, J=14.1 Hz, 1H), 3.30 (s, 3H), 2.41 (s, 3H); MS: ESI (negative): 560, 562 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH:12]([CH3:17])[CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:15][CH2:14][CH2:13][CH:12]2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(CCCO)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC1CCCC1(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 51 %

Procedure:
The resulting 5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-4-methyl-1-pentanol (isomer mixture) was dissolved in toluene (10 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (1.00 g, 4.14 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=20:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (423 mg, 1.14 mmol, 51%) was obtained as a white powder.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: COc1ccc(Cl)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(Cl)c(-c2n[nH]c3ncnc(N)c23)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 7.9 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0770 g, 4.12 mmoles) in DMF (10 ml), ethanol (5 ml) and water (5 ml), 2-chloro-5-methoxyphenyl boronic acid (1.00 g, 5.364 mmoles) and sodium carbonate (2.186 g, 20.63 mmoles) were added and the system is degassed for 30 min. Tetrakis triphenylphosphine Palladium (0.905 g, 0.783 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as green solid (0.090 g, 16% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.61 (s, 1H), 8.19 (s, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.09 (d, J=8.9 Hz 1H), 7.06 (d, J=2.6 Hz 1H), 3.78 (s, 3H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=1>>[CH3:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: Cc1cccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)c1

Procedure:
The product of Example 1B and 2-(3-methylphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.31 (d, J=7.9, 1H), 8.04-8.01 (m, 1H), 8.01-7.96 (m, 1H), 7.94-7.88 (m, 1H), 7.26-7.22 (m, 1H), 7.19-7.16 (s, 2H), 7.11-7.08 (t, J=9.0, 1H), 3.86-3.78 (m, 4H), 3.62 (s, 2H), 3.13-3.06 (m, 4H), 2.31 (s, 3H); MS (ESI+) M/Z 379 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:17](Br)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>>[CH3:1][C:2]1[C:10]2[C:5]([N:6]([CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH:7]=[CH:8][CH:9]=2)=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(-c2ccccc2)[nH]c2ncccc12
Reactant: O=C(CBr)c1ccccc1
Product: Cc1c2cccn(CC(=O)c3ccccc3)c-2nc1-c1ccccc1

Procedure:
The title compound was prepared from 3-methyl-2-phenylpyrrolo[2,3-b]pyridine and phenacylbromide on a 4 mmol scale according to the procedure described in example 8 yielding 1.58 g (97%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1)[CH2:9][N:10]([C:18]1[S:19][C:20]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[N:30][CH:29]=[CH:28]3)=[C:21](C=O)[N:22]=1)C(OC(C)(C)C)=O)(C)(C)C.S1C=[C:50]([CH:52]=[O:53])[N:49]=[CH:48]1.CO.C[O-].[Na+].C1(C)C=CC(S(C[N+]#[C-])(=O)=O)=CC=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>C([SiH](CC)CC)C.C1(C)C=CC=CC=1>[NH2:7][C@@H:8]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:38][CH:37]=1)[CH2:9][NH:10][C:18]1[S:19][C:20]([C:25]2[CH:34]=[C:33]3[C:32](=[CH:27][CH:26]=2)[CH:31]=[N:30][CH:29]=[CH:28]3)=[C:21]([C:52]2[O:53][CH:48]=[N:49][CH:50]=2)[N:22]=1
Reactant: O=Cc1cscn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nc(C=O)c(-c2ccc3cnccc3c2)s1
Agent: CC[SiH](CC)CC
Agent: C[O-]
Agent: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N[C@H](CNc1nc(-c2cnco2)c(-c2ccc3cnccc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Yield: 96.9 %

Procedure:
To a 100 mL round-bottomed flask was added thiazole 4-carboxaldehyde tert-butyl (S)-1-(4-formyl-5-(isoquinolin-6-yl)thiazol-2-yl-(Boc)amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.098 g, 0.15 mmol), MeOH (0.0060 mL, 0.15 mmol), sodium methoxide (0.027 g, 0.51 mmol) and p-toluenesulfonylmethylisonitrile (0.035 g, 0.18 mmol). The resulting solution was stirred at reflux for about 1 hour until LCMS indicated that the reaction was complete. LCMS indicated complete conversion with removal of one of the Boc groups. The crude reaction was quenched with water and extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed. The crude product was used immediately in the next step. To a 100 mL round-bottomed flask was added the crude material from the previous step (0.100 g, 0.14 mmol), DCM (0.0092 mL, 0.14 mmol), TFA (0.011 mL, 0.14 mmol), and a few drops of triethylsilane. The reaction was stirred at room temperature and followed by LCMS. Toluene was added, and the solvent was removed. The residue was dissolved in 2 N ammonia in MeOH, and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with a gradient of 1% to 10% MeOH in DCM, to provide N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(isoquinolin-6-yl)-4-(oxazol-5-yl)thiazol-2-amine (0.072 g, 101% yield).
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16]([OH:18])=O)[CH2:6]1)(=[O:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=1)[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16](=[O:18])[NH:19][C:20]2[CH:31]=[CH:30][CH:29]=[C:22]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH:21]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)c1cccc(N)c1
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1cccc(NC(=O)[C@@H]2C[C@H](SC(C)=O)CN2C(=O)OCC=C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.1 %

Procedure:
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-carboxypyrrolidine (2.54 g, 9.3 mM), allyl 3-aminobenzoate (1.5 g, 8.5 mNM), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.72 g, 11 mM) were dissolved in toluene (50 ml) and stirred for 18 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with 2M HCl (3 by 30 ml), water, saturated NaHCO3, and brine. Drying over MgSO4 and evaporation gave (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(3-allyloxycarbonylphenylcarbamoyl)pyrrolidine as a gum (3.7 g, 100%) in a state sufficiently pure for further work. Nmr (CDCl3): δ 2.32 (s, 3H); 2.60 (br, 2H); 3.40 (dd, 1H); 4.03 (quintet, 1H); 4.13 (dd, 1H); 4.57 (t, 1H); 4.66 (dm, 2H); 4.82 (dt, 2H); 5.23-5.46 (m, 4H); 5.86-6.12 (m, 2H); 7.41 (t, 1H); 7.82 (d, 1H); 7.91 (d, 1H); 8.07 (t, 1H); 9.18 (br, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)=[O:15]>>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[O:15][C:5]3[C:6](=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=3)[CH:13]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COc1cc(O)cc(OC)c1
Product: Oc1ccc(-c2cc3c(O)cc(O)cc3o2)cc1
Yield: 93 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(4-methoxyphenyl)ethanone: Yield 93% following procedures A.2 and A.5; m.p. 216-217° C.; IR 3309, 1613, 1510, 1439, 1241, 1134, 1064 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.76 (5, 1H), 9.67 (s, 1H), 9.28 (s, 1H), 7.59 (d, J=8.7 Hz, 2H), 6.97 (s, 1H), 6.83 (d, J=8.7 Hz, 2H), 6.39 (d, J=0.8 Hz, 1H), 6.16 (d, J=1.8 Hz, 1H); 13C-NMR (126 MHz, δ ppm, CD3OD) 158.7, 158.4, 157.3, 154.8, 152.1, 126.8, 124.3, 116.7, 113.1, 98.8, 97.4, 90.9.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:30]([O-])=O)[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CCOC(C)=O>[NH2:30][C:17]1[C:18]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][C:28]#[N:29])[CH2:24][CH2:25]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: N#CCCN1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#CCCN1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 753.8 %

Procedure:
A suspension of 3-[4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (19.3 g, 4.25 mmol) and palladium on carbon (3.7 g, 10%, wet, Degussa, E101 NE/W) in EtOAc (150 ml) was stirred under a hydrogen atmosphere (2-3 balloons) at 50° C. for 24 h. The reaction mixture was cooled to 25° C. then was filtered through Celite and the Celite washed with EtOAc (2×20 ml). The filtrate and washings were concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 6% CH3OH in CH2Cl2) afforded 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (13.6 g, 75%) as a grey foam. 1H NMR (400 MHz, CDCl3) δ 8.17-8.09 (m, 2H), 7.83 (s, 1H), 7.54 (t, J=7.4 Hz, 1H), 7.49-7.41 (m, 3H), 6.52 (d, J=4.2 Hz, 1H), 4.76 (d, J=8.4 Hz, 1H), 3.79-3.66 (m, 1H), 2.94-2.82 (m, 3H), 2.72 (t, J=6.9 Hz, 2H), 2.51 (t, J=6.9 Hz, 2H), 2.29 (td, J=11.5, 2.1 Hz, 2H), 2.12-2.00 (m, 2H), 1.58 (qd, J=10.9, 3.6 Hz, 2H). This material was used in the next step below without additional characterization.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[CH2:14][CH2:13][C@H:12]([O:15]C(=O)CCC)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[CH2:3]([N:10]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCC(=O)O[C@H]1CCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Product: O[C@H]1CCN(Cc2ccccc2)C1

Procedure:
Next, 50 ml of 1 N-NaOH was added to the (S)-N-benzyl-3-butyryloxypyrrolidine obtained above, and hydrolysis was performed while the mixture was heated. The reaction mixture was then extracted three times with 50 ml portions of methylene chloride, and the solvent was removed under reduced pressure to yield 3.31 g of (S)-N-benzyl-3-hydroxypyrrolidine. This crude product was vacuum-distilled at 111° C./2 mm Hg to yield 3.00 g of a colorless oily product. The NMR and IR spectra of this product coincided with those of the reference sample, and the results obtained by elemental analysis agreed well with the calculated values. The specific rotation of this product was [a]D20 -3.79 (c=5, MeOH), and the measurement by HPLC showed that the optical purity was 100% e.e. The specific rotation of the distilled (R)-N-benzyl-3-hydroxypyrrolidine was [a]D20 +3.73° (c=5, MeOH), and the optical purity was 99% e.e.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[N+:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1B(O)O)([O-:41])=[O:40].C(=O)([O-])O.[Na+].CN(C)C=O>ClCCl.C(OCC)(=O)C>[N+:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:20])=[O:21])[CH:9]=2)[NH:4][N:3]=1)([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccccc3[N+](=O)[O-])c2c1
Yield: 16.2 %

Procedure:
N-[3-(2-Nitrophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 47 from 620 mg of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 202 mg 2-nitrophenylboronic acid, 2 ml of a saturated aqueous sodium hydrogencarbonate solution, 31.7 mg of tetrakis(triphenylphosphine)palladium[0] and of 20 ml of dimethylformamide. 70 mg of N-[3-(2-nitrophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a yellow solid (Rf=0.53 silica gel thin layer chromatography, eluent: dichloromethane/ethyl acetate (80-20 by volume)).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C:11]1[O:15][C:14](=O)[NH:13][N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:30]=[N:31][N:32]4[C:37]([N:38]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])=[CH:36][C:35]([CH:55]5[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]5)=[N:34][C:33]=34)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH2:1]([O:8][C@@H:9]([C:11]1[O:15][C:14]([N:58]2[CH2:57][CH2:56][CH:55]([C:35]3[CH:36]=[C:37]([N:38]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[N:32]4[N:31]=[CH:30][C:29]([C:26]5[CH:27]=[N:28][C:23]([C:17]6[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=6)=[CH:24][CH:25]=5)=[C:33]4[N:34]=3)[CH2:60][CH2:59]2)=[N:13][N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1ccccc1)c1n[nH]c(=O)o1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](OCc1ccccc1)c1nnc(N2CCC(c3cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n4ncc(-c5ccc(-c6ccccc6)nc5)c4n3)CC2)o1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a stirred solution of (R)-5-(1-(benzyloxy)ethyl)-1,3,4-oxadiazol-2(3H)-one (44 mg, 0.2 mmol), 3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (150 mg, 0.24 mmol) and DIEA (70 ul, 0.4 mmol) in DMF (1.4 mL) was added BOP (97 mg, 0.22 mmol) and the resulting solution was allowed to stir overnight. Water was added and was extracted with EtOAc (3×) and combined organic layers were washed with water (3×), brine once and dried (MgSO4). After concentration in vacuo the residue was purified on silica gel. Elution with EtOAc/Hexanes (0-10%) gave the title compound (142 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][SH:17])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH3:19][C:20]1[CH2:25][CH2:24][CH:23]([C:26]([CH3:28])=[CH2:27])[CH2:22][CH:21]=1>CCOCC>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][S:17][C:26]([CH:23]1[CH2:24][CH2:25][C:20]([CH3:19])=[CH:21][CH2:22]1)([CH3:28])[CH3:27])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)[C@H](CS)NC(=O)OCc1ccccc1
Reactant: C=C(C)C1CC=C(C)CC1
Solvent: CCOCC
Product: COC(=O)[C@H](CSC(C)(C)C1CC=C(C)CC1)NC(=O)OCc1ccccc1

Procedure:
The ether is prepared from N-CBZ-L-cysteine methyl ester and α-limonene in a manner similar to that described in Example 1B. The product can be characterized by NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:6]=2[CH:16]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][CH:23]([CH:28]=O)[CH2:22]2.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[F:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:28][CH:23]4[CH2:22][C:21]5[C:25](=[CH:26][CH:27]=[C:19]([F:18])[CH:20]=5)[CH2:24]4)[CH2:14][CH2:15]3)[C:6]=2[CH:16]=1
Reactant: O=CC1Cc2ccc(F)cc2C1
Reactant: Cc1cc2ncn(C3CCNCC3)c2cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc2ncn(C3CCN(CC4Cc5ccc(F)cc5C4)CC3)c2cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
A mixture of 6-fluoro-5-methyl-1-piperidin-4-yl-1H-benzoimidazole (70 mg, 0.300 mmol) and 5-fluoroindane-2-carbaldehyde (49 mg, 0.300 mmol) in CH3OH (4 mL) and acetic acid (0.2 mL) was stirred at rt for 15 minutes. NaCNBH3 (40 mg, 0.635 mmol) was added and then the reaction mixture was stirred for 1 hour. The solvent was removed and the residue was diluted with CH2Cl2. The organic layers were washed with saturated NaHCO3, brine, and dried over Na2SO4. The organic extracts were removed under the reduced pressure and the residue was purified by flash chromatography (5% CH3OH in CH2Cl2) to afford 6-fluoro-1-[1-(5-fluoro-indan-2-ylmethyl)-piperidin-4-yl]-5-methyl-1H-benzoimidazole (28 mg, 24%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C[O:14][CH:15](OC)[CH2:16][CH2:17][CH2:18][CH:19]=O>CCOC(C)=O.CCCCCC>[N+:10](/[C:9](/[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[CH:19]/[CH2:18][CH2:17][CH2:16][CH:15]=[O:14])([O-:12])=[O:11]
Reactant: COC(CCCC=O)OC
Reactant: Cc1ccc(CC[N+](=O)[O-])cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C/C(=C\CCCC=O)[N+](=O)[O-])cc1
Yield: 34.9 %

Procedure:
Prepared according to the general procedure B from 1-methyl-4-(2-nitroethyl)benzene 112f (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.38 g, 35% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: C([O:8][C:9](=[O:41])[CH2:10][C:11]1([NH:16][C:17](=[O:40])[CH:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:31]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([CH2:27][CH:18]([C:17]([NH:16][C:11]2([CH2:10][C:9]([OH:41])=[O:8])[CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:40])[CH2:19][C:20]([OH:22])=[O:21])=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)NC1(CC(=O)OCc2ccccc2)CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)NC1(CC(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 4-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentylamino)-3-(biphenyl-4-ylmethyl)-4-oxobutanoate was dissolved in EtOAc (6 mL) and hydrogenated with 10% Pd/C at room temperature under hydrogen. After 2 hr, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in DCM, and to the mixture was added TFA. After stirred at room temperature for 1.5 hr, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by reverse phase HPLC [40 to 75% ACN-water (0.1% TFA) over 10 min by Sunfire C18 column] to give the title compound (23 mg). LCMS (condition B): 410.1 (M+1); retention time=0.99 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.61 (m, 6H), 1.95-2.05 (m, 2H), 2.10 (dd, J=16.4, 5.8 Hz, 1H), 2.41-2.49 (m, 1H), 2.57 (dd, J=12.9, 7.1 Hz, 1H), 2.73 (dd, J=35.4, 14.7 Hz, 2H), 2.82-2.99 (m, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.34 (t, J=7.3 Hz, 1H), 7.45 (t, J=7.7 Hz, 2H), 7.56 (d, J=8.3 Hz, 2H), 7.63 (d, J=7.1 Hz, 3H), 11.97 (br. s., 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[N:10]([O-:12])=[O:11].[Na+].[N+]([O-])(O)=O.O>C(O)(=O)CC>[N+:10]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[OH:9])([O-:12])=[O:11]
Reactant: COc1cccc(O)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)O
Solvent: O=[N+]([O-])O
Product: COc1ccc([N+](=O)[O-])c(O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38102.4 %

Procedure:
To a solution of 3-methoxyphenol (11.1 g, 0.09 mmol) in propionic acid (90 mL) at 0° C., was added NaNO2 (6.3 g, 0.09 mmol, in 5 mL water) dropwise. The mixture was stirred at 0° C. for 1 hour. Concentrated nitric acid (12 mL) was then added dropwise and the mixture was stirred for 1 hour at 0° C. and 2 hour at r.t. Water (30 mL) was subsequently added and the resulting precipitate was collected and washed with 50% propionic acid, giving 2-nitro-5-methoxyphenol as yellow solid (5.8 g, 40% yield).