Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C@@H:2]1[CH2:6][N:5]([C:7](OC(C)(C)C)=O)[C@H:4]([C:14](=[O:24])[NH:15][C@@H:16]2[C@@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[CH2:18][CH2:17]2)[CH2:3]1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.Br[C:37]1C=C(C(F)(F)F)C=CN=1>>[CH3:7][NH:5][C@H:4]([C:14]([NH:15][C@H:16]1[C@H:23]2[C@H:19]([CH2:20][N:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=3)[CH2:22]2)[CH2:18][CH2:17]1)=[O:24])[CH2:3][CH:2]([CH3:6])[CH3:37]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Reactant: FC(F)(F)c1ccnc(Br)c1
Product: CN[C@@H](CC(C)C)C(=O)N[C@@H]1CC[C@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@H]21

Procedure:
The title compound was prepared by substituting tert-butyl methyl((S)-4-methyl-1-((3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-ylamino)-1-oxopentan-2-yl)carbamate from Example 349 for (2S,4S)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate and 2-bromo-5-(trifluoromethyl)pyridine for 2-bromo-4-(trifluoromethyl)pyridine in the procedure described in Example 637: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.62 (dd, J=1.6, 0.7, 1H), 8.37 (d, J=7.5, 1H), 7.67 (dd, J=8.9, 2.5, 1H), 6.39 (d, J=8.9, 1H), 4.51-4.38 (m, 1H), 3.83 (d, J=9.7, 1H), 3.74-3.64 (m, 1H), 3.63-3.53 (m, 1H), 3.37-3.29 (m, 1H), 3.24 (dd, J=8.3, 5.8, 1H), 2.82-2.68 (m, 2H), 2.45 (s, 3H), 2.23-2.13 (m, 1H), 2.12-1.99 (bs, 1H), 2.00-1.87 (m, 2H), 1.79-1.67 (m, 2H), 1.67-1.57 (m, 1H), 1.42 (dtd, J=13.2, 8.0, 5.1, 1H), 0.93 (d, J=6.6, 3H), 0.87 (d, J=6.6, 3H); MS (ESI+) m/z 399 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(C=O)[O:3]1.[CH:15]1([Mg]Br)CCC1.[O:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.Cl.O>O1CCCC1>[CH3:22][CH:23]([CH3:15])[CH2:24][CH:25]([C:6]1[CH:5]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:3][C:2]=1[CH3:1])[OH:21]
Reactant: Br[Mg]C1CCC1
Reactant: C1CCOC1
Reactant: CC1C=CC(C=O)(c2ccccc2)O1
Agent: Cl
Solvent: O
Product: Cc1oc(-c2ccccc2)cc1C(O)CC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 2-methyl-5-phenylfuran-5-carbaldehyde (1.3 g) in tetrahydrofuran (30 mL) was added dropwise 1N cyclobutylmagnesium bromide-tetrahydrofuran solution (10.5 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (1.5 g, 87%) as a yellow crystal.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH:26]([NH:30][C:31]([O:33]C(C)(C)C)=O)[C:27]([OH:29])=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(=O)O[C:41](=[O:42])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12>ClCCl.Cl.C1(C)C=CC=CC=1>[CH2:14]([O:21][C:22]([NH:24][CH2:25][C@H:26]([N:30]1[C:31](=[O:33])[C:39]2=[CH:47][CH:46]=[CH:45][CH:44]=[C:40]2[C:41]1=[O:42])[C:27]([OH:29])=[O:28])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(NC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of (2S) 3-benzyloxycarbonylamino-2-tert-butoxycarbonylaminopropionic acid dicyclohexylamine salt (3 g, 5.8 mmol) in dichloromethane (200 ml) was washed four times with 1M HCl solution, dried (MgSO4) and concentrated. The resulting oil was dissolved in dry dichloromethane (35 ml), cooled to 0° C. and treated with trifluoroacetic acid (35 ml). This solution was stirred at 0° C. for 1.5 h then evaporated to dryness. Dichloromethane (50 ml) was added to the residue then removed under vacuum. This process repeated six times to afford a white solid. The white solid was suspended in toluene (50 ml), treated with powdered phthalic anhydride (940 mg, 6.35 mmol) and refluxed for 18 h. The resulting solution was concentrated to afford an oil which was purified by flash chromatography (2-10% methanol/dichloromethane) to afford 266, 2.01 g (94%) as a white powder: IR (KBr) 3600-2500br, 1776, 1714, 1530, 1469, 1455, 1392, 1263, 1131, 722; 1H NMR (CDCl3) δ 7.83 (2H, m), 7.72 (2H, m), 7.29 (5H, m), 5.41 (1H, m), 5.03 (2H, s), 3.90 (2H, m); MS (ES-), 367 (M-1).
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.Cl.Cl.N1([S:41]([CH2:44][CH2:45][CH2:46][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)(=[O:43])=[O:42])CCNCC1.CCN(C(C)C)C(C)C>C1COCC1>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:41]([CH2:44][CH2:45][CH2:46][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)(=[O:43])=[O:42])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: O=S(=O)(CCCN1CCOCC1)N1CCNCC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCCN3CCOCC3)CC2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) (150 mg, 0.378 mmol), 4-[3-(1-piperazinylsulfonyl)propyl]morpholine dihydrochloride (WO 2006/046040) (172 mg, 0.491 mmol) and DIPEA (0.40 mL, 2.27 mmol) in THF was stirred at room temperature for 17 hrs. The solvent was removed under vacuum, and the residue was diluted with water and extracted with CH2Cl2. The CH2Cl2 was dried (Na2SO4) and removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (98:2) followed by recrystallization from CH2Cl2/hexanes gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[3-(4-morpholinyl)propyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (188 mg, 78%). Treatment with methanesulfonic acid in CH2Cl2/MeOH and recrystallization from MeOH/EtOAc gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[3-(4-morpholinyl)propyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole methanesulfonate: mp 216-218° C.; 1H NMR (DMSO-d6) δ 9.50 (br s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 4.01-3.93 (m, 6H), 3.98 (s, 3H), 3.82 (m, 4H), 3.70 (br s, 4H), 3.63 (t, J=12.1 Hz, 2H), 3.45 (d, J=12.6 Hz, 2H), 3.32 (m, 4H), 3.21 (t, J=7.1 Hz, 4H), 3.09 (dd, J=21.2, 11.8 Hz, 2H), 2.30 (s, 3H), 2.09 (m, 2H); Anal. Calcd for C28H41F2N9O8S2: C, 45.8; H, 5.6; N, 17.2. Found: C, 45.7; H, 5.6; N, 17.2%.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13])#[N:2].[F:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20][Cl:21])=[CH:17][CH:16]=1>C(#N)C>[ClH:21].[C:1]([CH2:3][C:4]1[C:12]2[C:7]([N:8]([CH2:20][C:19]([C:18]3[CH:23]=[CH:24][C:15]([F:14])=[CH:16][CH:17]=3)=[O:22])[CH:9]=[CH:10][CH:11]=2)=[N:6][C:5]=1[CH3:13])#[N:2]
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: Cc1[nH]c2ncccc2c1CC#N
Solvent: CC#N
Product: Cc1nc2n(CC(=O)c3ccc(F)cc3)cccc-2c1CC#N
Product: Cl
Yield: 55 %

Procedure:
A solution of 7 5 mg (0.44 mmol) of 3-cyanomethyl-2-methyl-pyrrolo [2,3 -b]pyridine and 99 mg(0.57 mmol) of 4-fluorophenacyl chloride in 1 ml acetonitrile was refluxed for 48 h. The solvent was evaporated and the residue was treated with 0.4 ml acetonitrile. After filtration the solid was treated with 0,3 ml methanol and 0,4 ml acetonitrile to give 75 mg (55% ) of the title compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:33])[C@@H:17]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][CH2:19]SC)[C@H:11]([CH:34]([CH3:36])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+]>IC.CS(C)=O>[OH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@H:17]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]2=[O:33])[C@H:11]([CH:34]([CH3:35])[CH3:36])[CH2:10]1.[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@H:17]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]2=[O:33])[C@H:11]([CH:34]([CH3:36])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CS(C)=O
Product: CC(C)[C@@H]1C[C@H](O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Product: CC(C)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzyl (S)-1-((1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-isopropylcyclohexylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate (5.3 g) was dissolved in iodomethane (90 mL), and the resulting solution was stirred at rt for 72 h before being concentrated in vacuo. The residue was dissolved in methylene chloride, and the resulting solution was concentrated; this was repeated to afford the salt. MS found: (M+H)+=586.5. This material was dissolved in DMSO (30 mL) and the solution was charged with Cs2CO3 (12.7 g). After 6 h, the reaction was partitioned between EtOAc and brine. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (S)-1-((1S,2S,4R)-4-hydroxy-2-isopropylcyclohexyl)-2-oxopyrrolidin-3-ylcarbamate [580 mg; MS found: (M+H)+=375.3] and benzyl (S)-1-((1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-isopropylcyclohexyl)-2-oxopyrrolidin-3-ylcarbamate [1.0 g; MS found: (M+H)+=489.4].
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:3]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](Cl)=[O:29])[CH:23]=[CH:24][C:25]=1[Cl:26].C(=O)([O-])[O-].[K+].[K+]>>[ClH:19].[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C@@:9]2([C:28](=[O:29])[CH2:27][C:22]3[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:3]1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: OC1CCCN(CC2NCCc3ccccc32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)[C@@]1(CN2CCC[C@H](O)C2)NCCc2ccccc21

Procedure:
Prepared as Example n° 1 from 4.83 g (19.6 mmoles) of 1-(3-hydroxypiperidin-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline--diast. mix.--, 5.15 g (23.1 mmoles) of 3,4-dichlorophenylacetyl chloride and 3.2 g (23.1 mmoles) of anhydrous potassium carbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:33]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:34][C:33]3[CH:35]=[CH:36][C:37]([CH3:39])=[CH:38][C:32]=3[F:31])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1ccc(N)c(F)c1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cc3nc(Nc4c(F)cccc4Cl)[nH]c3c3c2OC(C)(C)C3)c(F)c1
Yield: 51.8 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.150 g, 0.400 mmol), thionyl chloride (2.0 mL), 2-fluoro-4-methylaniline (0.075 g, 0.600 mmol), THF (5.0 mL) and DIPEA (3 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.100 g of the desired product. 1HNMR (DMSO-d6): δ 1.54 (s, 6H), 2.29 (s, 3H), 3.17 (s, 2H), 7.00 (d, J=8.4 Hz, 1H), 7.16 (d, J=12.3 Hz, 1H), 7.30 (s, 2H), 7.40 (m, 1H), 7.51 (s, 1H), 8.33 (t, J=8.4 Hz, 1H), 10.02 (s, 1H), 11.12 (s, 2H); MS [M+H]+: 483.17.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH:24]1([C:27]([C:29]2[CH:53]=[CH:52][C:32]([O:33][C@@H:34]([C:37]3[O:41][N:40]=[C:39]([C:42]4[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[C:44]([F:51])[CH:43]=4)[N:38]=3)[CH2:35][CH3:36])=[CH:31][CH:30]=2)=[O:28])[CH2:26][CH2:25]1.[NH2:54][C@H:55]1[C@@H:59]([OH:60])[CH2:58][O:57][C:56]1=[O:61]>C(OCC)(=O)C.O.CN(C)C=O>[CH:24]1([C:27]([C:29]2[CH:30]=[CH:31][C:32]([O:33][C@@H:34]([C:37]3[O:41][N:40]=[C:39]([C:42]4[CH:50]=[CH:49][C:45]([C:46]([NH:54][C@H:55]5[C@@H:59]([OH:60])[CH2:58][O:57][C:56]5=[O:61])=[O:47])=[C:44]([F:51])[CH:43]=4)[N:38]=3)[CH2:35][CH3:36])=[CH:52][CH:53]=2)=[O:28])[CH2:25][CH2:26]1
Reactant: N[C@@H]1C(=O)OC[C@@H]1O
Reactant: CC[C@@H](Oc1ccc(C(=O)C2CC2)cc1)c1nc(-c2ccc(C(=O)O)c(F)c2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@H](Oc1ccc(C(=O)C2CC2)cc1)c1nc(-c2ccc(C(=O)N[C@@H]3C(=O)OC[C@@H]3O)c(F)c2)no1
Reaction time: 0.5 h
Yield: 18 %

Procedure:
1-Hydroxybenzotriazole monohydrate (44.6 mg, 0.291 mmol) and N-(3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (55.8 mg, 0.291 mmol) were added to an N,N-dimethylformamide (0.5 mL) solution of the 4-(5-{(1R)-1-[4 -(cyclopropylcarbonyl) phenoxy]propyl}-1,2,4-oxadiazol-3-yl)-2-fluorobenzoic acid synthesized in Reference Example 8 (99.6 mg, 0.243 mmol) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Subsequently, an N,N-dimethylformamide (1.0 mL) solution of the crude (3S,4R)-3-amino-4-hydroxydihydrofuran-2-(3H)-one synthesized in Reference Example 14 (85.4 mg) was added, and the mixture was further stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was subjected to extraction twice with ethyl acetate. The organic layer thus obtained was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30→30:70, v/v) to give the title compound (22.5 mg, yield: 18%).
Reaction SMILES: N[C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:18])[CH:3]=1.C(OC1C=CC([NH:33]C2N=CN=C(OC3C=CC(NC(=O)CC(NC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1)C1C=CC=CC=1.[F:62][C:63]1[CH:78]=[CH:77][C:66]([CH2:67][NH:68][C:69]([C:71]2([C:74]([OH:76])=O)[CH2:73][CH2:72]2)=[O:70])=[CH:65][CH:64]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:62][C:63]1[CH:64]=[CH:65][C:66]([CH2:67][N:68]([C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([C:13](=[O:14])[NH2:15])[CH:8]=3)=[C:4]([F:18])[CH:3]=2)[C:69]([C:71]2([C:74]([NH2:33])=[O:76])[CH2:72][CH2:73]2)=[O:70])=[CH:77][CH:78]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Reactant: O=C(O)C1(C(=O)NCc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(Oc2ccc(N(Cc3ccc(F)cc3)C(=O)C3(C(N)=O)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)picolinamide (Compound B′ of Example 24, 49 mg, 0.2 mmol) in DMF (2 mL) at room temperature was added 1-((4-fluorobenzyl)carbamoyl)cyclopropanecarboxylic acid (47 mg, 0.2 mmol), HATU (Perseptive Biosystem, 114 mg, 0.3 mmol), and DIEA (0.2 mL, 1.1 mmol). The reaction mixture was stirred at rt for 2 h, and then quenched by adding 4 mL of methanol. The reaction mixture was purified by prep. HPLC. The desired fractions were combined, neutralized with aq. K2HPO4, and concentrated in vacuo. The solid which formed was collected by filtration (29 mg, 31%). 1H NMR (DMSO-d6) δ 10.78 (br s, 1H), 8.53 (d, 1H, J=5.5 Hz), 8.47 (t, 1H, J=5.5 Hz), 8.11 (s, 1H), 7.88 (dd, 1H, J=13.2, 2.3 Hz), 7.70 (s, 1H), 7.47 (d, 1H, J=9.2 Hz), 7.38 (t, 1H, J=9.2 Hz), 7.34-7.29 (m, 3H), 7.22 (dd, 1H, J=5.5, 2.8 Hz), 7.13 (t, 2H, J=8.8 Hz), 4.30 (d, 2H, J=5.5 Hz), 1.37 (d, 4H, J=10.6 Hz); MS(ESI+) m/z 467.12 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13]CC)=[O:12])[N:8]([CH2:16][C:17](=[O:26])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)[N:7]=1)=[O:5])[CH3:2].Cl>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[N:8]([CH2:16][C:17](=[O:26])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)Nc2ccc(Cl)cn2)n1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)O)n(CC(=O)Nc2ccc(Cl)cn2)n1
Reaction time: 16 h

Procedure:
To a solution of 8 g 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-pyrazole-3,5-dicarboxylic acid diethyl ester in 200 ml THF and 50 ml H2O 17.2 ml 1N NaOH is added. After standing for 16 h, the solution was acidified using 1 N HCl. THF was removed in vacuo and water was removed by lyophilization. The residue was purified by chromatography on silica gel using ethyl acetate followed by CH2Cl2/MeOH/HOAC/H2O=9/1/0.1/0.1. The fractions containing the product were evaporated and lyophilized to give a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:10])=[O:8].[CH:11](=O)[CH2:12][CH3:13].[H][H]>[Pd].CO>[CH2:11]([N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:10])=[O:8])[CH2:12][CH3:13]
Reactant: CCC=O
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCN1CCC[C@H]1C(=O)OC
Yield: 105.1 %

Procedure:
Methyl (S)-2-pyrrolidinecarboxylate hydrochloride (1.65 g, 0.01 mol) was added to a hydrogenation flask containing a mixture of propionaldehyde (2.4 g, 0.04 mol), 5% Pd/C (0.3 g) and 30 ml MeOH. The mixture was shaken an a Parr apparatus at 40 psi hydrogen pressure for 2 h at room temperature. After filtration and evaporation the residue was mixed with 10 ml 2M HCl and 40 ml ice-water and then extracted twice with Et2O. Solid NaCl was added to the aqueous phase which was made alkaline with 20 ml 2M NH3 during addition of ice. Extraction with Et2O twice, drying (MgSO4) and evaporation afforded 1.8 g of the title compound, which was used directly in Example 11A.
Reaction SMILES: C([CH:3]([C:7](Cl)=[O:8])[C:4](Cl)=[O:5])C.[NH2:10][C:11]1[CH:29]=[C:28]([Br:30])[C:14]([O:15][C:16]2[CH:17]=[C:18]([CH:25]([CH3:27])[CH3:26])[C:19]([OH:24])=[C:20]([CH:23]=2)[CH:21]=[O:22])=[C:13]([Br:31])[C:12]=1[CH3:32].CCN(CC)CC.C1C[O:43][CH2:42][CH2:41]1>>[CH2:42]([O:43][C:7](=[O:8])[CH2:3][C:4]([NH:10][C:11]1[CH:29]=[C:28]([Br:30])[C:14]([O:15][C:16]2[CH:17]=[C:18]([CH:25]([CH3:27])[CH3:26])[C:19]([OH:24])=[C:20]([CH:21]=[O:22])[CH:23]=2)=[C:13]([Br:31])[C:12]=1[CH3:32])=[O:5])[CH3:41]
Reactant: C1CCOC1
Reactant: Cc1c(N)cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c1Br
Reactant: CCC(C(=O)Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Nc1cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c(Br)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a stirred solution of ethyl malonylchloride (7.2 μl, 0.056 mmol) and compound 5-(4-amino-2,6-dibromo-3-methylphenoxy)-2-hydroxy-3-isopropylbenzaldehyde of Part 8E (25 mg, 0.056 mmol) in THF (0.5 mL) was added Et3N (15.7 μl, 0.112 mmol) at 4° C. After 30 minutes stirring at room temperature, the reaction mixture was washed with NH4Cl (saturated aqueous solution) and the organic phase removed in vacuo. The water phase was extracted with CHC13 and the two phases were separated with a phase separator (IST). The organic phase was concentrated and the resulting residue was purified on column (silica gel, gradient elution: n-heptane/EtOAc from 1:0 to 7:3) to give 15 mg (48%) of N-[3,5-dibromo-4-[3-formyl-4-hydroxy-5-isopropylphenoxy]-2-methylphenyl]-malonamic acid ethyl ester as a light yellow residue.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH2:4][CH2:3]1.I.CS[C:21]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)=[NH:22]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[NH:22])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH2:4][CH2:3]1
Reactant: CSC(=N)c1cccs1
Reactant: CN1CCC(n2ccc3cc(N)ccc32)CC1
Agent: I
Solvent: CCO
Product: CN1CCC(n2ccc3cc(NC(=N)c4cccs4)ccc32)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 56.2 %

Procedure:
Compound 81 (100 mg, 0.436 mmol) is charged to a small, argon purged flask fitted with a magnetic stir bar. Anhydrous ethanol (7 mL) and thiophene-2-carboximidothioic acid methyl ester hydroiodide (217.6 mg, 0.763 mmol) are added to the flask and the reaction was stirred under argon at ambient temperature for 23 hours, at which time the solvent was evaporated and the residue was partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95 to 7.5:92.5) to yield a yellow solid, 82 (83 mg, 56.2%). 1H NMR (DMSO-d6) δ 1.85-2.05 (m, 4H), 2.10-2.19 (m, 2H), 2.24 (s, 3H), 2.90 (d, 2H, J=11.4 Hz), 4.20-4.32 (m, 1H), 6.25 (br s, 2H), 6.35 (d, 1H, J=3.0 Hz), 6.69 (dd, 1H, J=9.8, 1.4 Hz), 6.98 (s, 1H), 7.07-7.10 (m, 1H), 7.41 (d, 1H, J=3.1 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.59 (d, 1H, J=5.1 Hz), 7.71 (d, 1H, J=3.1 Hz); ESI-MS (m/z, %): 339 (MH+, 100%); ESI-HRMS calculated for C19H23N4S (MH+): 339.1637, observed: 339.1647.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[C:12]([C:16]1[CH:25]=[CH:24][C:19]([CH:20]=[N+:21]([CH3:23])[CH3:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(C1C=CC(C=O)=CC=1)(C)(C)C.CNC>>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH:20]([N:21]([CH3:23])[CH3:22])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])=[CH:24][CH:25]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: C[N+](C)=Cc1ccc(C(C)(C)C)cc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC(C)(C)c1ccc(C=O)cc1
Agent: CNC
Agent: [Cl-]
Product: Cc1[nH]c2ccccc2c1C(c1ccc(C(C)(C)C)cc1)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methylindole and (4-tert-butyl-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 4-tert-butyl-benzaldehyde and dimethylamine.