Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:30]=[CH:29][C:28]3[C:27]4[C:22](=[CH:23][C:24](Br)=[CH:25][CH:26]=4)[C:21]([F:33])([F:32])[C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39]([N:41]1[CH:46]([C:47]2[NH:51][C:50]3[CH:52]=[C:53](B4OC(C)(C)C(C)(C)O4)[CH:54]=[CH:55][C:49]=3[N:48]=2)[CH:45]2[CH2:65][CH:42]1[CH2:43][CH2:44]2)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:30]=[CH:29][C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:53]5[CH:54]=[CH:55][C:49]6[N:48]=[C:47]([CH:46]7[CH:45]8[CH2:65][CH:42]([CH2:43][CH2:44]8)[N:41]7[C:39]([O:38][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:40])[NH:51][C:50]=6[CH:52]=5)=[CH:25][CH:26]=4)[C:21]([F:33])([F:32])[C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(Br)ccc2-3)[nH]1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1
Temperature: 90 °C
Yield: 76.9 %

Procedure:
A mixture of 2-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (324 mg, 0.627 mmol), 3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.1 eq., 304 mg), [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3%, 15 mg), tetrakis(triphenylphosphine)palladium (3%, 22 mg) and potassium carbonate (3.3 eq., 285 mg) in 10 mL DME and 3 mL water was heated to 90° C. under Argon for 3 hours. The reaction mixture was cooled and diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(5-{9,9-Difluoro-7-[2-(2-Boc-2-aza-bicyclo[2.2.1]hept-3-yl)-3H-benzoimidazol-5-yl]-9H-fluoren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (361 mg, yield 77%). LCMS-ESI−: calc'd for C43H46F2N6O4: 748.86. Found: 749.2 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Br:15])[C:7]([NH2:14])=[C:8]([CH:13]=1)[CH2:9][N:10]([CH3:12])[CH3:11])(=[O:3])[CH3:2].[BH4-].[Na+]>>[NH2:14][C:7]1[C:6]([Br:15])=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:13][C:8]=1[CH2:9][N:10]([CH3:12])[CH3:11]
Reactant: CC(=O)c1cc(Br)c(N)c(CN(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cc(Br)c(N)c(CN(C)C)c1

Procedure:
2-Amino-3-bromo-N,N-dimethyl-5-(1-hydroxy-ethyl)-benzylamine, m.p. 69-72° C was prepared by reduction of 5-acetyl-2-amino-3-bromo-N,N-dimethyl-benzylamine with sodium borohydride analogous to Example 19.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14].Cl[C:22]1[CH:31]=[CH:30][N:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26]([CH3:32])=[N:27]2>>[CH3:16][N:15]([CH3:17])[C:13](=[O:14])[C:12]1[CH:18]=[CH:19][CH:20]=[C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[NH:1][C:22]2[C:23]3[C:28](=[N:27][C:26]([CH3:32])=[CH:25][CH:24]=3)[N:29]=[CH:30][CH:31]=2)[CH:11]=1
Reactant: Cc1ccc(Sc2cccc(C(=O)N(C)C)c2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Sc2cccc(C(=O)N(C)C)c2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 88b (0.175 g, 0.610 mmol) was reacted with the product from Example 1d (0.109 g, 0.61 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.1552 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.40 (s, 3H) 2.75 (s, 6H) 2.92 (s, 3H) 6.34 (d, J=6.99 Hz, 1H) 7.11-7.53 (m, 7H) 7.76 (d, J=8.82 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 8.94 (d, J=8.82 Hz, 1H); MS (ESI+) m/z 429.0 (M+H)+; (ESI−) m/z 427.0 (M−H)−
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH:15][CH:5]=[O:7]
Reactant: Nc1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
Acetic anhydride (189 ml, 2.0 mol) was mixed with formic acid (91 ml, 2.4 mol) at 0° C. and the mixture was stirred at 60° C. for 1 h and then cooled to 0° C. To the solution was added dropwise 3-chloroaniline (105.7 ml, 1.0 mol) and the mixture was stirred at room temperature for 18 h. After removal of solvent in vacuo, the residue was extracted with EtOAc-H2O. The organic layer was washed with 5% aqueous citric acid, saturated aqueous NaHCO3 and brine, dried over Na2SO4 and then concentrated. The residue was crystallized from iPr2O to give the title compound (115 g, 0.739 mol, 74%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20]([OH:22])=O)[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:33])[C@@H:29]([NH2:32])[CH2:30][CH3:31])([CH3:26])([CH3:25])[CH3:24].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20](=[O:22])[NH:32][C@H:29]([C:28]([O:27][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:33])[CH2:30][CH3:31])[C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](C(=O)O)c1ccc(O)cc1)OCc1ccccc1
Reactant: CC[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccc(O)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A solution of (R)-N-benzyloxycarbonyl-α-carboxy-4-hydroxybenzylamine (Method 17; 2.00 g, 6.64 mmol), (2S)-2-amino butanoic acid t-butyl ester (1.30 g, 6.64 mmol) and N-methylmorpholine (2.0 g, 19.8 mmol) in DCM (30 ml) was stirred at RT for 5 min, after which TBTU (2.60 g, 8.10 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel DCM:Acetone—60:40). The product was crystallized from toluene (20 ml) giving 1.85 g of the desired product as a white solid. NMR (400 MHz): 0.80 (3H, t), 1.45 (9H, s), 1.50–1.80 (2H, m), 4.10–4.20 (1H, m), 5.05 (1H, d(AB)), 5.15 (1H, d(AB)), 6.75 (2H, d), 7.20–7.40 (7H, m).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:3]([OH:26])[CH2:4][C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C@@H:17]([CH3:20])[CH2:18][CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[CH3:41][C@@H:42]([CH2:64][CH3:65])[C@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:56]=[CH:55][CH:54]=2)[C:48]1=[O:63])[C:44](O)=[O:45].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[CH:17]([CH3:20])[CH2:18][CH3:19])=[O:15])[CH2:4][C@H:3]([OH:26])[C@@H:2]([NH:1][C:44](=[O:45])[C@@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:56]=[CH:55][CH:54]=2)[C:48]1=[O:63])[CH:42]([CH3:41])[CH2:64][CH3:65])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2ccnc3ccccc23)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)CC)N1CCN(Cc2ccnc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.5 %

Procedure:
A solution containing the product from Example 5C (0.078 g, 0.171 mmol) in DMF (0.5 mL) was treated with the product from Example 4A (0.070 g, 0.205 mmol), EDAC (0.050 g, 0.261 mmol), HOBT (0.035 g, 0.259 mmol), and NMM (0.060 mL, 0.546 mmol) at 0° C., stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid, diluted sodium bicarbonate, and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.030 g, 23% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.76 (m, 12 H), 1.00 (m, 2 H), 1.29 (m, 2 H), 1.49 (m, 3 H), 1.81 (m, 1 H), 2.65 (m, 5 H), 3.01 (m, 3 H), 3.54 (s, 3 H), 3.61 (m, 1 H), 3.75 (t, J=8.82 Hz, 1 H), 3.99 (d, J=11.03 Hz, 1 H), 4.13 (m, 2 H), 4.62 (d, J=7.35 Hz, 1 H), 4.80 (m, 2 H), 6.89 (d, J=9.56 Hz, 1 H), 6.98 (m, 5 H), 7.15 (m, 5 H), 7.32 (d, J=9.93 Hz, 1 H), 7.41 (d, J=4.41 Hz, 1 H), 7.66 (m, 2 H), 7.77 (t, J=6.99 Hz, 1 H), 8.06 (d, J=7.72 Hz, 1 H), 8.30 (d, J=8.09 Hz, 1 H), 8.88 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4](Cl)[N:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][CH3:19])=[O:17].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([NH:18][CH3:19])=[O:17])[C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:7]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Yield: 8 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-trifluoromethylpyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (no microwave—20° C., 2 days) to afford 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-N-methyl-benzamide as a white solid in 8% yield. Mp: (209° C.); MS: 331.05 (M+H); 1H NMR (chloroform-d): δ 11.63 (br s, 1H), δ 8.59 (d, J=8 Hz, 1H), δ 8.47 (s, 1H), δ 7.59 (t, J=8 Hz, 1H), δ 7.52 (d, J=8 Hz, 1H), δ 7.19 (t, J=8 Hz, 1H), δ 6.20 (br s, 1H), δ 3.04 (d, J=5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=2)=[N:7]1)=[O:5])[CH3:2]>C(O)C.[C].[Pd]>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=2)[NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCC(c2cc(F)c(F)c(F)c2)=N1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
To a solution of (R)-5-(3,4,5-trifluorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylic acid ethyl ester (12.4 g) in ethanol (170 mL) was added 10% palladium-carbon (1.2 g, 50% water content). Under a hydrogen atmosphere, the reaction mixture was stirred for 16 hours at room temperature. The catalyst was filtered off over Celite. The obtained filtrate was concentrated, to thereby obtain the titled compound (11.98 g). The physical properties of the compound were as follows.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH2:10])=[N:2]1.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=2[F:30])[CH2:17][CH:16]1[CH3:31])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:1]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=3[F:30])[CH2:17][CH:16]2[CH3:31])=[O:14])[N:2]=1
Reactant: Nc1n[nH]c2ncccc12
Reactant: COc1cc(N2CCN(C(=O)CCl)C(C)C2)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(N)c4cccnc43)C(C)C2)c(F)cc1Cl
Temperature: 80 °C

Procedure:
1H-Pyrazolo[3,4-b]pyridin-3-ylamine (67 Mg), 2-Chloro-1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone (167 Mg) and K2CO3 (414 Mg) were combined in DMF (1 mL) and heated at 80° C. for 2 hr, then cooled to room temperature. The resultant mixture was purified by preparative HPLC to provide 2-(3-Aminopyrazolo[3,4-b]pyridin-1-yl)-1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)-2-methylpiperazin-1-yl]ethanone as a yellow powder. LCMS (ES) M+H 433.5, Rf 2.06 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 mL/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[O:18][C:19]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)[C:20]=4[C:21]=3[CH3:22])=[CH:11][C:9]=2[CH:10]=1)=O)C.[C-]#[N:40].[Na+].C(Cl)Cl.CO>N>[CH3:22][C:21]1[C:20]2[C:23]([O:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:24][CH:25]=[CH:26][C:19]=2[O:18][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][C:6]([C:4]([NH2:40])=[O:3])=[CH:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2cc(OCc3oc4cccc(OCCCNCc5cccnc5)c4c3C)ccc2o1
Reactant: [C-]#N
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(COc2ccc3oc(C(N)=O)cc3c2)oc2cccc(OCCCNCc3cccnc3)c12
Yield: 100.9 %

Procedure:
The compound in Example 36 (12 mg, 0.022 mmol) and NaCN (1 mg) in saturated NH3 anhydrous MeOH solution was heated at 70° C. in a sealed flask overnight. Silica gel column chromatography (CH2Cl2/MeOH=20/1 to 10/1) gave desired product (10 mg, 88%) as a colorless solid. FAB-MS: m/z 486 (MH+); 1H-NMR (CD3OD): δ 2.01 (2H, m); 2.26 (3H, s), 2.80 (1H, t, J=6.9 Hz), 3.78 (2H, s), 4.10 (1H, t, J=5.9 Hz), 5.04 (2H, s), 5.80 (1H, brs), 6.50 (1H, brs), 6.52 (1H, d, J=7.6 Hz), 7.04-7.20 (5H, m), 7.33 (1H, d, J=8.9 Hz), 7.39 (1H, s), 8.41 (1H, brd, J=4.5 Hz), 8.49 (1H, brs).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[F:28][C:29]([F:34])([F:33])[C:30](=[O:32])[CH3:31]>C1COCC1>[F:28][C:29]([F:34])([F:33])[C:30]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)([OH:32])[CH3:31]
Reactant: CC(=O)C(F)(F)F
Reactant: O=S(=O)(c1ccccc1)N1CCN(c2ccc(Br)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3ccccc3)CC2)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
A 250 ml, round-bottomed flask was charged with 1-(4-bromophenyl)-4-(phenylsulfonyl)piperazine (0.50 g, 1.31 mmol) and 20 mL of THF. After cooling to −78° C., n-BuLi (0.603 mL, 2.5 M in hexanes, 1.51 mmol) was slowly added. The mixture was stirred at −78° C. for 30 min, then 1,1,1-trifluoro-2-propanone (0.441 g, 3.93 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. The reaction was stirred at −78° C. for 1 h, and then quenched with saturated aqueous NH4Cl (15 mL). The organics were extracted with EtOAc (2×50 mL), dried (MgSO4), and concentrated to give an oil. Purification via column chromatography (40 g of silica, 0 to 40% EtOAc in hexanes) produced 1,1,1-trifluoro-2-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.215 g) as a mixture of two enantiomers.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:21]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:22]=[C:23]([CH3:25])[CH:24]=1)=[O:4].[OH-].[Li+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:20]2[N:21]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[N:22]=[C:23]([CH3:25])[CH:24]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:12])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1C1CCCCC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)O)n(C2CCCCC2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(2-cyclohexyl-5-methyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow oil which was used in the next step without further purification. MS (ESI): m/z=450.0 [M−H]−.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:24][CH:23]2[C:25](=[C:26]([C:28](O)=[O:29])[F:27])[CH:19]([CH2:20][CH2:21][CH2:22]2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl:31][C:32]1[S:33][C:34]([Cl:42])=[C:35]([Cl:41])[C:36]=1[S:37]([NH-:40])(=[O:39])=[O:38].CO>CN(C1C=CN=CC=1)C.CC(N(C)C)=O.O1CCOCC1>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH:19]2[C:25](=[C:26]([F:27])[C:28](=[O:29])[NH:40][S:37]([C:36]3[C:35]([Cl:41])=[C:34]([Cl:42])[S:33][C:32]=3[Cl:31])(=[O:38])=[O:39])[CH:23]([CH2:22][CH2:21][CH2:20]2)[CH2:24]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC2CCCC(C1)C2=C(F)C(=O)O
Reactant: [NH-]S(=O)(=O)c1c(Cl)sc(Cl)c1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CCCC(C1)C2=C(F)C(=O)NS(=O)(=O)c1c(Cl)sc(Cl)c1Cl
Reaction time: 8 h

Procedure:
69 μl of DIEA are added to a solution of 60 mg of 9-(carboxy-fluoro-methylene)-3-aza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester, 71 mg of 2,4,5-trichloro-thiophene-3-sulfonyl amide, 233 μl of PPA and 24 mg of DMAP in 2 ml of DMA, and the mixture obtained is stirred at 40° overnight. The mixture obtained is diluted with 10 ml of EtAc/c-HEX, and washed with 1M NaHSO4 solution. The organic layer obtained is dried and solvent is evaporated. The evaporation residue obtained is subjected to chromatography on silica gel and on Sephadex LH20 (MeOH) and relevant fractions obtained from chromatography are subjected to lyophilisation from dioxane. 9-[1-Fluoro-2-oxo-2-(2,4,5-trichloro-thiophene-3-sulfonylamino)-ethylidene]-3-aza-bicyclo[3.3.1]nonane-3-carboxylic acid tert.-butyl ester in the form of a powder is obtained.
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1CCCC1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([CH3:31])[S:19]([C:22]2[CH:26]=[C:25]([C:27](=[O:30])[CH2:28]Br)[S:24][CH:23]=2)(=[O:21])=[O:20])=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([CH3:31])[S:19]([C:22]2[CH:26]=[C:25]([C:27](=[O:30])[CH2:28][N:2]([CH3:3])[CH3:1])[S:24][CH:23]=2)(=[O:21])=[O:20])=[CH:12][CH:11]=1
Reactant: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc(C(=O)CBr)c1
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CC(=O)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1

Procedure:
To a solution (0.6 mL) of 2.0M dimethylamine-tetrahydrofuran diluted with tetrahydrofuran (2 mL), was added dropwise 5-(2-bromoacetyl)thiophene-3-sulfonic acid [2-(4-fluorophenyl)ethyl]-methyl-amide (46 mg) in tetrahydrofuran (1 mL) at room temperature. An aqueous solution of saturated sodium bicarbonate was added, and the solution was extracted with ethyl acetate. After the organic layer was washed with saturated sodium chloride water and dried with anhydrous sodium sulfate, the residuals that were obtained upon removing the solvent by evaporation were purified by silica gel column chromatography (dichloromethane/methanol), and the title compound (16 mg) was obtained as a yellow oily substance.
Reaction SMILES: Cl.Cl.C[O:4][C:5]([C:7]1[CH:8]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][CH2:25][NH:26][CH2:27][C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[OH:29])[CH:18]=2)[CH:10]=[CH:11][C:12]=1[C:13]([O:15]C)=[O:14])=[O:6].O.[OH-].[Li+]>>[Cl:36][C:32]1[CH:31]=[C:30]([C@@H:28]([OH:29])[CH2:27][NH:26][CH2:25][CH2:24][NH:23][C:19]2[CH:18]=[C:17]([C:9]3[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=3)[CH:22]=[CH:21][CH:20]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)cc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)cc1C(=O)O

Procedure:
n.m.r. (CD3OD) δ values include 2.97-3.00 (m,1 H), 3.43-3.45 (m, 2 H), 4.97 (dd, 1 H), 6.69 (d, 1 H), 6.97-6.99 (m, 2 H), 7.20-7.31 (m, 4 H), 7.42 (s, 1 H), 7.73 (d, 1 H), 8.19 (d, 1 H), 8.37 (s, 1 H); from (R)-3′-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-biphenyl]-3,4-dicarboxylic acid dimethyl ester dihydrochloride (500 mg), and lithium hydroxide monohydrate (303 mg).
Reaction SMILES: CC1(C)[O:6][C@H:5]2[C@@H:7]([C:25]3[O:29][N:28]=[C:27]([CH3:30])[N:26]=3)[O:8][C@@H:9]([N:10]3[CH:18]=[N:17][C:16]4[C:11]3=[N:12][CH:13]=[N:14][C:15]=4[NH:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C@@H:4]2[O:3]1.FC(F)(F)C(O)=O.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH:20]1([NH:19][C:15]2[N:14]=[CH:13][N:12]=[C:11]3[C:16]=2[N:17]=[CH:18][N:10]3[C@H:9]2[C@H:4]([OH:3])[C@H:5]([OH:6])[C@@H:7]([C:25]3[O:29][N:28]=[C:27]([CH3:30])[N:26]=3)[O:8]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: Cc1noc([C@H]2O[C@@H](n3cnc4c(NC5CCCC5)ncnc43)[C@@H]3OC(C)(C)O[C@H]32)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc([C@H]2O[C@@H](n3cnc4c(NC5CCCC5)ncnc43)[C@H](O)[C@@H]2O)n1
Reaction time: 6 h
Yield: 73.6 %

Procedure:
A mixture of N-{9-[(3aR,4R,6S,6aR)-2,2-dimethyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl}-N-cyclopentylamine (63 mg), trifluoroacetic acid (1 ml) and water (0.1 ml) was stirred at 0° for 6 h and then diluted with ethyl acetate (20 ml). The mixture was neutralised with sodium bicarbonate solution and the aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic extracts were washed with water (8 ml) and brine (10 ml) and dried (MgSO4). After concentration in vacuo the residue was purified by flahs column chromatography on silica gel, eluting with ethyl acetate:methanol (19:1) to give the title compound as a white foam (42 mg).
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([C:22]([NH:24][CH:25]1[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:35][CH2:36]O)[C:26]1=[O:38])=[O:23])=[CH:16]2>N1C=CC=CC=1.C1COCC1.CCOC(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([C:22]([NH:24][CH:25]1[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:35][CH2:36][Cl:10])[C:26]1=[O:38])=[O:23])=[CH:16]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(NC1Cc2ccccc2N(CCO)C1=O)c1cc2cc(Cl)ccc2[nH]1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(NC1Cc2ccccc2N(CCCl)C1=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.7 %

Procedure:
p-Toluenesulphonyl chloride (285 mg, 1.49 mmol) was added to a solution of 5-chloro-N-[1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-1H-indole-2-carboxamide (Example 36; 286 mg, 0.75 mmol) in pyridine (2 mL) under an inert atmosphere and stirred at ambient temperature for 18 hours. The mixture was diluted with THF (10 mL) and EtOAc (50 mL) and washed with 1M HCl aq. (20 mL), water (20 mL), brine (20 mL), dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:THF (9:1)) to afford the title compound (144 mg, 40%) as a yellow solid.