Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[N:27]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH:31]=[CH:30][N:29]=[CH:28]1>CN1C(=O)CCC1>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:35][CH2:34][CH2:33][CH2:32][N:27]5[CH:31]=[CH:30][N:29]=[CH:28]5)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: NCCCn1ccnc1
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(NCCCn4ccnc4)cc3)cc2s1)C1CC1

Procedure:
A solution of 4-fluorobenzenesulfonic 2-(cyclopropanecarbonylamino)benzo-thiazol-6-yl ester (example 7) (100 mg, 0.255 mmol) and 3-imidazol-1-yl-propylamine (123 μl, 1.019 mmol) in 2 ml of NMP is heated at 150° C. by microwave for 5 minutes. The crude reaction product is purified by preparative LC/MS (basic medium (pH 9)) to give after freeze-drying 63 mg of 4-(3-imidazol-1-ylpropylamino)benzenesulfonic 2-(cyclopropanecarbonylamino)benzothiazol-6-yl ester (white solid).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]([C:15]2[C:24]([OH:25])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:14])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([O-:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:32]2[CH:33]=[CH:34][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)=[CH:3][C:4]=1[CH2:10][CH2:11][NH:12][C:13]([C:15]1[C:24]([OH:25])=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:14]
Reactant: COc1ccc(Br)cc1CCNC(=O)c1cc2ccccc2cc1O
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1CCNC(=O)c1cc2ccccc2cc1O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To 0.05 g (0.1 mmol) of above resin-bound N-2-(3-bromo-6-methoxyphenyl)ethyl-3-hydroxyl-2-naphthamide in 2.0 mL of DME were added 36.6 mg (0.3 mmol) of 4-nitrophenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (100% methylene chloride) to give 22 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[N:6]([CH:12]([CH3:14])[CH3:13])[C:5]2=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([CH:12]([CH3:14])[CH3:13])[CH2:5]2
Reactant: CC(C)N1C(=O)c2ccc(Br)cc2C1=O
Solvent: C1CCOC1
Product: CC(C)N1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a solution of 5-bromo-2-(1-methylethyl)-1H-isoindole-1,3(2H)-dione (Intermediate 5, 4.27 g) in tetrahydrofuran (THF) (100 mL) under nitrogen at room temperature was added 1.0M borane-tetrahydrofuran complex in THF (80 mL). The reaction mixture was heated at reflux for 48 hours. More 1.0M borane-THF complex in THF (50 mL) was added and the reaction mixture was heated at reflux for a further 24 hours. The reaction mixture was allowed to cool to room temperature. The reaction was quenched by the dropwise addition of 2N hydrochloric acid (80 mL). The reaction mixture was then heated at reflux for 1 hour. The reaction mixture was separated between ethyl acetate (300 mL) and water (50 mL). The organic phase was washed with 2N hydrochloric acid (100 mL). The combined aqueous phases were basified using 2N sodium hydroxide solution and then extracted with ethyl acetate (300 mL). This organic phase was washed with brine (100 mL) and dried over magnesium sulphate. The solvent was evaporated in vacuo to give the title compound (3.0 g) as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: c1cn[nH]c1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
4-Fluorobenzonitrile (204.2 g), pyrazole (138.6 g, 1.22 eq) and potassium carbonate (281.5 g, 1.22 eq) in DMF (1110 ml) were heated at 120° C. for 7 hours. The suspension was cooled to 25° C. and water (2920 ml) added. The reaction was extracted with MTBE (3×1460 ml) and the combined extracts were washed with water (3×1460 ml) and saturated aqueous sodium chloride (1460 ml). The organic phase was concentrated at atmospheric pressure until the pot temperature rose to 65° C. Heptane (1700 ml) was added over 30 minutes at 60-65° C., and then a further 300 ml of distillate was collected. The solution was stirred at 60-65° C. for 15 minutes and then cooled to <5° C. The slurry was filtered and washed with heptane (2×200 ml), and dried under vacuum to constant weight to give the title compound as a solid (245.3 g, 87%).
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:16])=[C:12]([NH2:15])[CH:13]=2)[C:8]([CH3:18])([CH3:17])[CH2:7]1)(=[O:5])[CH3:4].[CH:19](N)=O>>[C:3]([N:6]1[C:14]2=[CH:13][C:12]3[NH:15][CH:19]=[N:16][C:11]=3[CH:10]=[C:9]2[C:8]([CH3:18])([CH3:17])[CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CC(C)(C)c2cc(N)c(N)cc21
Reactant: NC=O
Agent: Cl
Product: CC(=O)N1CC(C)(C)c2cc3nc[nH]c3cc21
Reaction time: 0.67 h

Procedure:
A mixture of 3.0 g. (0.01 mole) 1-acetyl-5,6-diamino-3,3-dimethylindoline dihydrochloride (Example 2b) and 35 ml. formamide is heated to reflx for 40 minutes and then evaporated. The residue is mixed with water, extracted with dichloromethane and the extract evaporated to give 2.6 g. (85% of theory) of the title compound; m.p. 214°-216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([OH:14])[C:10]=1[CH:15]([CH3:17])[CH3:16].[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][O:14][C:11]1[C:10]([CH:15]([CH3:17])[CH3:16])=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[O:13][N:12]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC(C)c1c(O)noc1-c1ccc(Cl)cc1Cl
Product: CC(C)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccc(Cl)cc1Cl
Yield: 85.2 %

Procedure:
5-(2,4-Dichlorophenyl)-3-hydroxy-4-isopropylisoxazole (0.06 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.04 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.078 g, 86%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.[CH3:11][NH:12][C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([O:16][CH3:17])=[O:15]>>[F:9][C:2]([F:1])([F:10])[CH2:3][CH2:4][CH2:5][C:6]([N:12]([C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([O:16][CH3:17])=[O:15])[CH3:11])=[O:8]
Reactant: O=C(O)CCCC(F)(F)F
Reactant: C=CC[C@H](NC)C(=O)OC
Product: C=CC[C@@H](C(=O)OC)N(C)C(=O)CCCC(F)(F)F
Yield: 48 %

Procedure:
Step H (1): 5,5,5-Trifluoropentanoic acid and (S)-methyl 2-(methylamino)pent-4-enoate from Step G (1) were coupled according to the conditions described in Step A (1). The crude reaction products were purified by silica-gel column chromatography to give 191 mg (48% yield) of (S)-methyl 2-(5,5,5-trifluoro-N-methylpentanamido)pent-4-enoate as a clear oil. LC-MS (M+H)+=282.1; 1H NMR (500 MHz, CDCl3) δ ppm 1.86-1.95 (m, 2H) 2.12-2.23 (m, 2H) 2.38-2.50 (m, 3H) 2.70-2.80 (m, 1H) 2.91 (s, 3H) 3.67-3.76 (m, 3H) 5.00-5.17 (m, 2H) 5.27 (dd, J=10.83, 5.04 Hz, 1H) 5.61-5.74 (m, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[O:47]1[CH2:52][CH2:51][CH:50]([CH2:53][CH:54]=[O:55])[CH2:49][CH2:48]1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:54]([OH:55])[CH2:53][CH:50]2[CH2:51][CH2:52][O:47][CH2:48][CH2:49]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: O=CCC1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cnc2c(c1)cc(C(O)CC1CCOCC1)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
To a suspension of 1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 10, 4 g, 13.9 mmol) in dry tetrahydrofuran (60 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (13 mL, 20.83 mmol) to a 0° C. solution of diisopropylamine (3.2 mL, 22.1 mmol) in dry tetrahydrofuran (20 mL)] dropwise. The mixture was stirred at −78° C. for 5 min and then treated with (tetrahydro-pyran-4-yl)-acetaldehyde (2.67 g, 20.8 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×300 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanol as a white solid (4.4 g, 77.2%): LC/MS m/e calcd for C21H24N2O5S [M+H]+ 417.50, observed 417.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:16](=[O:22])[C:17](=[O:21])[C:18]=2OC)[CH2:10]1.[NH2:29][C@@H:30]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]>CC#N>[CH:41]1([CH2:40][C@H:30]([NH:29][C:18]2[C:17](=[O:21])[C:16](=[O:22])[C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:10]2)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)CC1CCCCC1
Reactant: COCCCOC(c1ccccc1F)C1CCCN(c2c(OC)c(=O)c2=O)C1
Solvent: CC#N
Product: COCCCOC(c1ccccc1F)C1CCCN(c2c(N[C@H](CNC(=O)OC(C)(C)C)CC3CCCCC3)c(=O)c2=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To the crude 3-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)-4-methoxycyclobut-3-ene-1,2-dione in MeCN there was added tert-butyl (S)-2-amino-3-cyclohexylpropylcarbamate (27.0 mg, 0.11 mmol), the resulting solution was stirred at rt for 10 min, filtered through HPLC filter, purified by HPLC to give tert-butyl (2S)-3-cyclohexyl-2-(2-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino)propylcarbamate (17.4 mg, 40%) as on oil. MS ESI+ve m/z 616 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([OH:18])=O)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:48][C:47]=1[CH3:58].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([C:16](=[O:18])[CH2:15][N:8]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:14]4[C:6]([C:2]4[NH:1][CH:5]=[CH:4][N:3]=4)=[N:7]3)[CH2:54][CH2:53]2)=[CH:48][C:47]=1[CH3:58]
Reactant: Cc1cc(N2CCNCC2)ccc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)ccc1Cl
Temperature: 45 °C
Reaction time: 8 h

Procedure:
This compound was prepared by Protocol A. A vial was charged with 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (55 Mg, 0.226 Mmol), HBTU (125 mg, 0.33 Mmol), 1-(4-Chloro-3-methyl-phenyl)-piperazine dihydrochloride (142 Mg, 0.50 mmol), anhydrous DMF (2.0 mL), and DIPEA (0.5 mL). The vial was capped, heated to 45° C., and stirred overnight. The following day, the volatiles were removed in vacuo and separation by preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-methyl-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone: MS (ES) [M+H]+ found: 436.4
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:34][N:35]([CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][CH3:40]>CN(C=O)C>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:19])[CH3:20])[C:13]=2[N:14]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:39]([CH2:38][CH2:37][CH2:36][N:35]([CH3:41])[CH3:34])[CH3:40])[CH:4]=2)[CH:10]=1)=[O:22]
Reactant: CNCCCN(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CBr)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CN(C)CCCN(C)C)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
6-(3-(Bromomethyl)phenyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was suspended in DMF and N1,N1,N3-trimethylpropane-1,3-diamine (5 equiv.) was added to it. The reaction mixture was stirred at room temperature for overnight. On completion of reaction, solvent was removed under reduced pressure and the residue was purified by prep. HPLC chromatography to provide the desired compound (25% yield). LCMS: 544.30 (M+1)+; HPLC: 99.90% (@ 254 nm) (Rt;4.765); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H), 10.2-9.6 (m, 1H), 8.92 (bs, 1H), 8.38 (s, 2H), 8.14 (s, 1H), 7.70-7.66 (m, 2H), 5.91 (s, 1H), 5.36-5.35 (m, 1H), 4.41 (d, 2H), 3.39 (4H merged in DMSO peak), 3.08-2.98 (m, 2H+3H), 2.79 (s, 6H), 2.24 (s, 3H), 2.13 (s, 3H), 2.13 (m, 2H), 1.55 (d, 6H, J=4.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11]C)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(N)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A solution of 4-chloro-2-methoxybenzamide (0.74 g, 3.99 mmol) in dichloromethane (50 ml) was cooled to −78° C. followed by addition of BBr3 (1.15 ml, 11.96 mmol) under nitrogen atmosphere. The reaction mixture was allowed to stir at room temperature for 2 h. After the completion of reaction (TLC monitoring), the solution was cooled to 0° C. and quenched with water. The resulting solution was basified by aqueous NaHCO3 and extracted with EtOAc (3×100 ml). The combined organics was dried over anhydrous Na2SO4, filtered and concentrated to get the desired product (0.608 g, 89%). MS: 172.33 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:23][C@H:12]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:11]1([C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)=[O:8])[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:23][C@H:12]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(O)cc1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 25 %

Procedure:
The title compound is prepared from 4-hydroxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 25% of theory; LC (method 4): tR=1.91 min; Mass spectrum (ESI+): m/z=294 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:20][O:21][C:22](=[O:31])[C@@H:23]([NH2:30])[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C.ON1C(=O)C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.NC(N)=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:20][O:21][C:22](=[O:31])[C@@H:23]([NH:30][C:11](=[O:13])[CH:10]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)[C@@H](N)C1CCCCC1
Reactant: N#Cc1ccc(CC(C(=O)O)C2CCCCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(N)=O
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C#N)cc1)C1CCCCC1)C1CCCCC1
Reaction time: 36 h
Yield: 76.1 %

Procedure:
A solution of 3-(4-cyano-phenyl)-2-(R,S)-cyclohexyl-propionic acid (8.8 g, 34.2 mmol, prepared as described in example 1d), (S)-amino-cyclohexyl-acetic acid methyl ester (6.27 g, 36.6 mmol), diisopropylethylamine (6.8 ml, 40.0 mmol), 3-hydroxy-3H-benzo[d][1,2,3]triazin-4-one (1.40 g, 8.6 mmol), and dimethylformamide (200 ml) was cooled to 10° C. A solution of dicyclohexyl-carbodiimide (8.26 g, 40.0 mmol) in toluene (8 ml) was added dropwise over a period of 3 hours and the reaction mixture was stirred for 36 hours. The precipitated urea was sucked off and the filtrate was evaporated in vacuo. Crystallization from n-heptane/isopropanol gave 10.68 g of the desired product, which contained 1,3-dicyclohexyl-urea. The crude material was used without further purification. MS m/z: 411 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][CH2:15]3)[N:11]([CH2:26][C:27]3[CH:40]=[CH:39][C:30]([C:31](NC4NN=NN=4)=[O:32])=[CH:29][CH:28]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=[O:51].[OH-].[Na+]>C(Cl)Cl.C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([CH3:22])([CH3:24])[CH3:23])[CH2:18][CH2:19]3)[N:11]([CH2:26][C:27]3[CH:40]=[CH:39][C:30]([C:31]([OH:51])=[O:32])=[CH:29][CH:28]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)C(=O)N1CCC(c2cc(-c3cc(Cl)cc(Cl)c3)nn2Cc2ccc(C(=O)Nc3nnn[nH]3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)C(=O)N1CCC(c2cc(-c3cc(Cl)cc(Cl)c3)nn2Cc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the intermediate from step F (100 mg, 0.225 mmol) in DCM (3 mL) was added triethyl amine (94 μl, 0.675 mmol) followed by trimethyl acetyl chloride (33.25 μL, 0.27 mmol). After 2 hours the reaction was diluted with DCM (10 mL) and washed with 1N HCl, saturated Na2CO3, dried over brine and concentrated in vacuo to give a colorless oil. This material was dissolved in THF (2 mL) and MeOH (1 mL) and 2N NaOH (2 mL) were added and the reaction left stirring at room temperature for 16 hours. The reaction was concentrated in vacuo. The residue was suspended in 1N HCl (until the pH was less then 2). The resulting suspension was extracted with EtOAc (3×), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as a white solid. 1H NMR (DMSO, 500 MHz): δ 7.93 (d, J=8.2 Hz, 2H), 7.81 (d, J=1.8 Hz, 2H), 7.51 (t, J=2.1 Hz, 1H), 7.26 (d, J=8.3 Hz, 2H), 6.94 (s, 1H), 5.54 (s, 2H), 4.34 (d, J=13.3 Hz, 2H), 3.0 (m, 1H), 2.86 (t, J=12.9 Hz, 2H), 2.51 (t, J=1.6 Hz, 1H), 1.74 (d, J=11 Hz, 2H), 1.44 (dq, J=3.4, 12.8 Hz, 2H), 1.2 (s, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[O:20][CH:21]([CH3:23])[CH3:22])[CH2:10][CH2:9][S:8][CH2:7][CH2:6]1)=[O:4].[OH-].[K+].O>CCO>[CH:21]([O:20][C:14]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]([NH:11][C:5]1([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][S:8][CH2:9][CH2:10]1)=[O:24])([CH3:23])[CH3:22]
Reactant: COC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)CCSCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)CCSCC2)c1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
The mixture of 4-(2-isopropoxy-3-methyl-benzoylamino)-tetrahydro-thiopyran-4-carboxylic acid methyl ester (28) (75 mg, 0.21 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate came out of the water. The precipitate is filtered to give a pure product (29) as a pale yellow solid (68 mg, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:6]([C:24]([F:27])([F:26])[F:25])[CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[C:6]([C:24]([F:27])([F:25])[F:26])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2C(F)(F)F)CC1
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of tert-butyl 4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (0.75 g, 1.0 eq, 1.9 mmol) and Pd—C (10%, 0.3 g) in EtOH (50 mL) was hydrogenated at 30 psi for 2 hours. The mixture was filtered through celite and the filter cake washed with EtOH (2×10 mL). The filtrate was concentrated under vacuum to give the desired product in 90% yield. This product was taken to next step with out further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:9][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[CH2:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][NH2:26].[C:27](OC(=O)C)(=[O:29])[CH3:28]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:9][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:14])([F:15])[F:16])[CH2:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][NH:26][C:27](=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of 1-(2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]phenyl)methanamine (0.15 g) in THF (10 ml) was added acetic anhydride (0.04 g), and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure to give residual material which was purified by silica gel chromatography, to obtain N-{2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]benzyl}acetamide (0.1 g).