Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(O)C.CC(=O)C>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[N:18]1([CH2:17][CH2:16][CH2:15][NH:14][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCCCn1ccnc1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCCn1ccnc1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
A solution of 11.5 g (0.0519 mol) of o-nitrobenzenesulfonyl chloride in approximately 30 ml of dichloromethane was added slowly over several minutes to a cold (0° C.) solution of 5.4 g (0.043 mol) of N-(3-aminopropyl)imidazole in 100 ml pyridine, under nitrogen. The resulting reaction mixture was gradually warmed to room temperature and allowed to react overnight. When the reaction was complete, as determined by thin layer chromatography, the reaction solution was reduced to dryness under reduced pressure. The resultant oil was redissolved in an ethyl acetate/aqueous sodium bicarbonate mixture containing trace amounts of ethanol and propanone. The resulting layers were separated, the organic layer was washed with water and then reduced to dryness under reduced pressure to provide a gum. This gum was then purified using column chromatography (8000 ml of a gradient eluent of 0-10% methanol in dichloromethane). The fractions containing the desired product were combined, reduced to dryness under reduced pressure and then recrystallized from methanol to provide 3.4 g of the desired subtitled intermediate (m.p. 166°-170° C).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:9]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(#N)C.[CH:53]([C@H:55]1[CH2:60][CH2:59][C@H:58]([C:61]([O:63][CH3:64])=[O:62])[CH2:57][CH2:56]1)=O>C1COCC1>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:53][C@H:55]2[CH2:56][CH2:57][C@H:58]([C:61]([O:63][CH3:64])=[O:62])[CH2:59][CH2:60]2)[C:10]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:9]1=2
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Reactant: Cc1cc(C)c2c(c1)[C@@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)cc(C)c32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Charge a flask equipped with an overhead stirrer, temperature probe, nitrogen inlet with (S)—N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-amine (5 g, 10.03 mmoles) and sodium triacetoxyborohydride (3.19 g, 15.05 mmoles) and acetonitrile (40 mL). Immerse the flask in an ice bath to cool the slurry to below about 5° C., then add (trans)-methyl 4-formylcyclohexanecarboxylate (2.99 g, 17.57 mmoles, prepared essentially according to the procedures in Houpis, I. N. et al, Tetrahedron Let. 1993, 34(16), 2593-2596 and JP49048639) dissolved in THF (10 mL) via a syringe while maintaining the reaction mixture at or below about 5° C. Allow the reaction to warm to RT and stir overnight. Add NH4Cl (25 mL, 50% saturated aqueous solution) and separate the aqueous layer from the organic layer. The pH of the organic layer should be about 5.5. Warm the organic layer to about 45° C. and add water (16 mL). Add a seed crystal of the titled compound and cool to about 35° C. Collect the resulting solid by filtration and rinse with ACN. Dry to provide 5.80 g of the title compound.
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])[CH3:8])[CH:4](C)C.[OH:10][CH2:11][C@H:12]([CH3:40])[O:13][C:14]1[CH:15]=[C:16]([CH:27]=[C:28]([C:30]([NH:32][C:33]2[CH:38]=[N:37][C:36]([CH3:39])=[CH:35][N:34]=2)=[O:31])[CH:29]=1)[O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC1CCN1>CN(C=O)C.C(OCC)(=O)C>[OH:10][CH2:11][C@H:12]([CH3:40])[O:13][C:14]1[CH:29]=[C:28]([CH:27]=[C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:3]3[CH2:4][CH2:9][CH:7]3[CH3:8])=[O:24])=[CH:20][CH:19]=2)[CH:15]=1)[C:30]([NH:32][C:33]1[CH:38]=[N:37][C:36]([CH3:39])=[CH:35][N:34]=1)=[O:31]
Reactant: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)O)cc3)cc(O[C@@H](C)CO)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: CC1CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4C)cc3)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.6 %

Procedure:
DIPEA (0.20 mL, 1.04 mmol) was added to a suspension of 4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(5-methylpyrazin-2-yl)amino]carbonyl}phenoxy)benzoic acid (0.11 g, 0.26 mmol), HATU (210 mg, 0.55 mmol) and 2-methylazetidine (37 mg, 0.52 mmol) in DMF (3 mL) and the mixture stirred at ambient temperature for 24 hours. Ethyl acetate (30 mL) was added and washed with water (3×20 mL), brine (20 mL), dried (MgSO4), filtered and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-20% methanol in ethyl acetate, to give the desired compound (54 mg).
Reaction SMILES: [N-:1]=[C:2]=[O:3].[K+].FC(F)(F)C(O)=O.[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH:19]2[CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:15][CH:14]=1.[NH4+].[OH-]>ClCCl>[NH2:1][C:2]([NH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH:19]2[CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:15][CH:14]=1)=[O:3]
Reactant: [N-]=C=O
Reactant: Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Temperature: 5 °C
Reaction time: 3 h

Procedure:
A solution of potassium isocyanate (1.5 g) dissolved in dichloromethane (20 ml) was cooled to 5° C. and a solution of trifluoroacetic acid (1.9 g) in dichloromethane (20 ml) was added dropwise. To the resulting mixture was added dropwise a solution of 1-(6-aminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine, 2a (3 g) in dichloromethane (10 ml). The temperature was allowed to raise to room temperature. After stirring for another 3 hours the mixture was poured on ice (500 g) and diluted aqueous NH4OH was added until pH>9. The organic phase was separated and worked-up as above. The crude title product was purified by column chromatography on silica gel (eluted with 4% triethylamine in ethanol/ethyl acetate 1:3). The purified product (2 g) was dissolved in acetone (20 ml) and added to a solution of fumaric acid (0.6 g) in ethanol (20 ml). The precipitated hemifumarate salt was filtered off and dried. Yield: 1.6 g, mp: 172-174° C. 1H NMR (DMSO-d6): δ 1.65-1.90 (m, 5 H); 2.10-2.35 (m, 3 H); 2.45-2.90 (m, 5 H); 3.10-3.25 (m,2 H); 3.45 (qui, 1 H); 6.85 (s, 2 H); 6.60 (s, 1 H); 7.00-7.15 (m, 4 H); 7.30 (dd, 2 H); 7.45 (s, 1 H); 8.45 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:21][C:22](=[O:24])[CH3:23])([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:21][C:22](=[O:24])[CH3:23])([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1ccccc1[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1N)(NC(C)=O)C(=O)OCC

Procedure:
A mixture of 1.0 eq. of 79 and 0.1 wt/wt eq. of 10% Pd on carbon in EtOH was hydrogenated at 10-60 psi of hydrogen for a time sufficient for reaction completion. The reaction mixture was filtered through Celite. The filtrate was concentrated by rotary evaporation. The crude material was dried under vacuum to give product 80.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19](Cl)=[O:20]>>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[CH:9]=2)[NH:1][CH:2]=1)=[O:20]
Reactant: O=C(Nc1cc2cc[nH]c2cn1)C1CC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Product: O=C(c1c(Cl)cccc1Cl)c1c[nH]c2cnc(NC(=O)C3CC3)cc12

Procedure:
1H NMR (400 MHz, DMSO-d6): δ 12.00 (br. s., 1H), 10.75 (br. s., 1H), 8.84-8.93 (m, 1H), 8.13 (d, J=5.27 Hz, 1H), 8.06 (s, 2H), 7.94 (br. s., 1H), 3.45-3.51 (m, 4H), 3.29 (s, 3H), 2.19 (s, 3H). MS: 449.81 (M+), 451.78 (M+2). N-[3-(2,6-Dichlorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide was prepared using N-(1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane carboxamide and 2,6-dichloro benzoyl chloride (Compound No. 18).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([OH:28])=O)[C:18]([C:32]([F:35])([F:34])[F:33])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[OH-]>CN(C=O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([NH2:37])=[O:28])[C:18]([C:32]([F:35])([F:34])[F:33])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(=O)O)c4)n3)c2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(N)=O)c4)n3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
To a solution of 3-(2-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzoic acid (I30) (0.048 g, 0.10 mmol) and HATU (0.051 g, 0.13 mmol) in DMF (2 mL) was added DIPEA (0.068 mL, 0.39 mmol), the resulting solution was then stirred for 10 minutes before addition of NH4OH (0.2 mL). The resulting mixture was then stirred overnight (16 hours) at room temperature. The mixture was diluted with water and extracted with EtOAc (2×20 mL). The combined organic extracts were dried using a phase separation cartridge before concentrating under reduced pressure. The organic residues were then purified using silica gel column chromatography (0-30% MeOH/EtOAc with 1% NH4OH in the MeOH) to give the title compound (6)(0.028 mg, 58%) as a white solid; NMR (400 MHz, d6-DMSO) δ 10.07 (s, 1H), 8.67 (s, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.72 (m, 1H), 7.54 (s, 1H), 7.38 (m, 2H), 7.34 (m, 1H), 7.14 (d, J=5.2 Hz, 2H), 6.64 (m, 1H), 3.10 (m, 8H), 2.42 (m, 4H), 2.19 (s, 3H). LCMS Method C: rt 4.80 min; m/z 485.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:4]=2[N:3]=1.CN(C)C=O.N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:9][CH2:8]2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:4]=2[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1ccc2c(c1)nc(N)n2[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)nc(N)n2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 2-amino-1-(trans-4-hydroxycyclohexyl)-1H-benzimidazole-5-carboxylate (0.97 g, 0.0032 mol) was dissolved in N,N-dimethylformamide (10 mL, 0.2 mol) at room temperature. 1H-Imidazole (0.50 g, 0.0074 mol) and tert-butyldimethylsilyl chloride (0.53 g, 0.0035 mol) were added and the mixture stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated bicarbonate then brine. The organics were collected and dried over sodium sulfate and concentrated. The crude solid was purified by combiflash chromatography using methylene chloride and methanol as eluent. Product fractions were concentrated to give an off white solid (1.099 g). MS (ESI (+)m/z) 418.04 (M+H+)
Reaction SMILES: FC(F)(F)S([O:6][C:7]1N=[C:9]([CH3:21])[C:10]2C([CH:16]=1)=C[C:13](OC)=[C:12](OC)[CH:11]=2)(=O)=O.[OH:24][C:25]1[CH:26]=C(B(O)O)C=CC=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O.C(#N)C>[CH3:16][CH2:7][O:6][C:25]([CH3:26])=[O:24].[CH3:21][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: COc1cc2cc(OS(=O)(=O)C(F)(F)F)nc(C)c2cc1OC
Reactant: OB(O)c1cccc(O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCCC
Temperature: 100 °C

Procedure:
6,7-Dimethoxy-1-methylisoquinolin-3-yl trifluoromethanesulfonate (200 mg), 3-hydroxyphenylboronic acid (157 mg, 2 eq.), Pd(OAc)2 (13 mg, 0.1 eq.), XPhos (54 mg, 0.2 eq.), and Cs2CO3 (650 mg, 3.5 eq.) were combined in a flask with 9 mL ACN and 3 mL H2O and degassed. Reaction mixture was then refluxed at 100° C. for 5 hours. Solution was cooled to room temperature then diluted with EtOAc and washed with saturated NaHCO3. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 50% EtOAc/hexane yielding product as white solid (78 mg, 46% yield). 1H NMR (400 MHz) (CDCl3) δ 7.66-7.63 (m, 2H), 7.38 (d, J=4 Hz, 1H), 7.20 (t, J=8 Hz, 1H), 7.17 (s, 1H), 7.00 (s, 1H), 6.73-6.71 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.87 (s, 3H). 13C NMR (100 MHz) (CDCl3) δ 156.74, 156.12, 152.88, 149.93, 149.19, 141.46, 133.56, 129.85, 122.35, 118.72, 115.49, 115.25, 114.59, 105.66, 103.87, 56.05, 56.01, 22.20. IR (thin film NaCl) 3002, 2255, 1621, 1576, 1501, 1468, 1425, 1409, 1372, 1324, 1292, 1245, 1222, 1205, 1178, 1159, 1062, 1027, 995, 973, 924, 913, 896, 878, 846, 837, 781, 762, 745, 738, 726, 691, 645.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[I:13][CH2:14][C:15](O)=[O:16].C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[I:13][CH2:14][C:15]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])=[O:16]
Reactant: O=C(O)CI
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(CI)ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.6 %

Procedure:
N-Hydroxyphthalimide (1.4 g, 8.7 mmol), iodoacetic acid (1.6 g, 8.7 mmol) and DCC (1.7 g, 8.7 mmol) were added to dry EtOAc (250 mL), and the mixture was stirred for 5 hours at room temperature. The reaction mixture was then filtered, the filtrate was dried, and the residue was crystallized from ethanol to give a white solid (2.15 g, 75%), m.p. 120° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][C:18]3=[O:24])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[CH:34][C:33]([F:50])=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1)(=[O:27])[CH3:26].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.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]>[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[CH:34][C:33]([F:50])=[CH:32][C:31]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][C:18]3=[O:24])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: CN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C(=O)C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4=O)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 78.8 %

Procedure:
A reaction vessel was charged with the mixture of 1-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)-4-methylpiperazin-2-one (332f) (0.3 g, 0.76 mmol),4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (0.37 g, 0.76 mmol), PdCl2(dppf) (65 mg, 0.076 mmol), K3PO4 (325 mg, 1.53 mmol), and NaOAc (125 mg, 1.53 mmol) in MeCN (15 mL) and water (1 mL). It was then bubbled with argon for 15 min and heated at 110° C. for 3 h. After evaporation of solvent in vacuo, the residue was purified on silica-gel column eluting with 50:1 methylene chloride/methanol to afford 332g (0.4 g, 63%). MS: [M+H]+ 668.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.O1CCOCC1.[CH:32]1([N:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][O:44][C:45]3[CH:53]=[CH:52][C:48]([C:49]([OH:51])=O)=[CH:47][C:46]=3[F:54])[CH2:37][CH2:36]2)[CH2:34][CH2:33]1.[CH3:55][N:56]1[C:65]2[NH:64][C:63]3[CH:66]=[CH:67][CH:68]=[CH:69][C:62]=3[NH:61][CH2:60][C:59]=2[CH:58]=[N:57]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:32]1([N:35]2[CH2:36][CH2:37][N:38]([CH2:41][CH2:42][CH2:43][O:44][C:45]3[CH:53]=[CH:52][C:48]([C:49]([N:61]4[CH2:60][C:59]5[CH:58]=[N:57][N:56]([CH3:55])[C:65]=5[NH:64][C:63]5[CH:66]=[CH:67][CH:68]=[CH:69][C:62]4=5)=[O:51])=[CH:47][C:46]=3[F:54])[CH2:39][CH2:40]2)[CH2:33][CH2:34]1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: O=C(O)c1ccc(OCCCN2CCN(C3CC3)CC2)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCCCN3CCN(C4CC4)CC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
HBTU (325 mg, 0.9 mmol) and 4M HCl in dioxan (0.45 ml, 1.8 mmol) were added to a solution of 4-[3-(4-cyclopropyl-piperazin-1-yl)-propoxy]-3-fluoro-benzoic acid from Example E48.3 (230 mg, 0.7 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 30 min. 3-Methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E65 (186 mg, 0.9 mmol) and DIEA (pH=9) were added and the mixture was stirred at room temperature for 18 h. The mixture was heated at 60° C. for 3 h then HBTU (300 mg, 0.8 mmol) was added. The mixture was heated at 60° C. for 2 days then solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in EtOAc, washed with saturated Na—HCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a brown solid identified as the title compound (55 mg, 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=O)[C:11]3[CH2:14][CH2:15][CH2:16][C:10]=3[NH:9]2)=[C:4]([F:17])[CH:3]=1.P(Br)(Br)([Br:20])=O.C(N(CC)C1C=CC=CC=1)C.[OH-].[Na+]>O.CN(C)C=O>[Br:20][C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:17])[N:9]=[C:10]2[CH2:16][CH2:15][CH2:14][C:11]=12
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCC2
Reactant: O=P(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(Cl)ccc1-n1nc2c(c1Br)CCC2

Procedure:
A mixture of 6.3 parts of 2-(4-chloro-2-fluorophenyl)-1,4,5,6-tetrahydrocyclopentapyrazol-3(2H)-one, 7.9 parts of phosphorous oxybromide, 3.7 parts of N,N-diethylaniline and 10 parts of N,N-dimethylformamide was refluxed 24 hours and poured into 100 parts of water. After neutralizing with 50% aqueous sodium hydroxide solution, the mixture was extracted twice with 100 parts of diethyl ether. The ether extract was dried over anhydrous magnesium sulfate and the solvent was removed under a reduced pressure of 100 mm. Hg at ambient temperature. The crude product was recrystallized from ethanol-water to yield 2.1 parts of 3-bromo-2-(4-chloro-2-fluorophenyl)-2,4,5,6-tetrahydrocyclopentapyrazole melting at 106°-110°.
Reaction SMILES: [CH:1]1([NH:6][C@H:7]([CH2:12][CH3:13])[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1>C1CCCCC1>[Cl:19][C:20]1[N:25]=[C:24]([N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C@H:7]([CH2:12][CH3:13])[C:8]([O:10][CH3:11])=[O:9])[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1
Reactant: CC[C@@H](NC1CCCC1)C(=O)OC
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Product: CC[C@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
Methyl (2R)-2-(cyclopentylamino)butanoate 1k (2.50 g, 13.50 mmol) and sodium bicarbonate (4.54 g, 54 mmol) were dissolved in 100 mL of cyclohexane, stirred for 30 minutes followed by the addition of 2,4-dichloro-5-nitro-pyrimidine (2.88 g, 14.84 mmol), heated to 60° C. and stirred for another 12 hours. The reaction mixture was filtered, washed with dichloromethane (50 mL), and the filtrate was concentrated under reduced pressure, the resulting residue was recrystallized by 150 mL of the mixture solvent of ethyl acetate and n-hexane (V/V=1:4) to obtain the title compound methyl (2R)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-(1-cyclopentyl)amino]butanoate 1m (3.36 g, yield: 72.6%) as a light yellow solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]4[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)=[N:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[CH2:40]([O:42][C:43](=[O:47])[C:44](Cl)=[O:45])[CH3:41]>C(Cl)Cl>[CH2:40]([O:42][C:43](=[O:47])[C:44](=[O:45])[N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[N:18][C:17]([NH:20][C:21]4[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1)[CH3:41]
Reactant: CCOC(=O)C(=O)Cl
Reactant: FC(F)(F)c1ccc(Nc2ccc(-c3ccc(C4CCNCC4)cc3)cn2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
[5-(4-Piperidin-4-yl-phenyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine hydrochloride (200 mg, 0.46 mmol) was slurried in DCM (2 mL) and to it was added N,N-diisopropylethylamine (1.320 mL, 7.6 mmol). Chloro-oxo-acetic acid ethyl ester (0.076 mL, 0.69 mmol) was added dropwise, and the reaction was stirred for 18 hours. The reaction mixture was partitioned between EtOAc and water, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to obtain 229 mg of the title compound as a crude oil, which was taken to the next step without purification: MS (M+H)+ 499.2.