Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:16][S:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]CS([O-])(=O)=O)=[CH:23][CH:22]=1)(=[O:19])=[O:18]>>[CH3:1][O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:28][CH2:27][C:24]2[CH:23]=[CH:22][C:21]([O:20][S:17]([CH3:16])(=[O:18])=[O:19])=[CH:26][CH:25]=2)=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Oc1ccc(CCCS(=O)(=O)[O-])cc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)OC
Product: COC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OC

Procedure:
3-(4-Hydroxyphenyl)-2-methoxypropanoic acid methyl ester was alkylated with 2-(4-methanesulfonyloxyphenyl)ethylmethanesulfonate (described in Example 1a) using the same method as in Example 1 (b) to give 3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]-phenyl}-2-methoxypropanoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](I)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:12]1([C@@:15]2([OH:22])[C@H:19]([CH3:20])[NH:18][C:17](=[O:21])[CH2:16]2)[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:18]2[C:17](=[O:21])[CH2:16][C@:15]([CH:12]3[CH2:14][CH2:13]3)([OH:22])[C@@H:19]2[CH3:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NC(=O)C[C@@]1(O)C1CC1
Reactant: Cc1c(I)ccc(C#N)c1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1c(N2C(=O)C[C@@](O)(C3CC3)[C@@H]2C)ccc(C#N)c1Cl

Procedure:
Using 2-chloro-4-iodo-3-methylbenzonitrile (522 mg), (4R,5S)-4-cyclopropyl-4-hydroxy-5-methylpyrrolidin-2-one (350 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (166 mg), tris(dibenzylideneacetone)dipalladium(0) (86 mg) and cesium carbonate (902 mg), and in the same manner as in Example 62, the title compound was obtained as a white powder (yield: 308 mg, 54%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][C:18]1([CH3:30])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[O:19]1>CN(C=O)C>[CH3:17][C:18]1([CH3:30])[C:22]([CH3:23])([CH3:24])[O:21][B:20]([C:25]2[CH:29]=[N:28][N:27]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[CH:26]=2)[O:19]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCCN3CCOCC3)c2)OC1(C)C
Temperature: 25 °C

Procedure:
A solution of 4-(3-Chloro-propyl)-morpholine (702 mg, 4.2 mmol), Cs2CO3 (753 mg, 2.31 mmol) and 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (832 mg, 4.2 mmol) in 5 ml dry DMF are heated at 80° C. under argon for 24 h and then allowed to cool to RT. DMF is removed under HV and the residue is re-taken in EtOAc and washed with de-ionized water. The aqueous phase is re-extracted with EtOAc and the combined organic extracts are washed with saturated brine, dried over Na2SO4, filtered and concentrated under vacuum to dryness. After drying under HV, the title compound is obtained as a pale orange oil, Rt=0.728 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 322 (M+1)+.
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[CH2:8])[CH:6]2[O:9][CH:3]1[C:4](=[CH2:11])[C:5]2=[CH2:10].[CH:12]([C:14]([CH3:16])=[O:15])=[CH2:13].C1(C=CC(O)=CC=1)O>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[CH2:11]=[C:4]1[C:5](=[CH2:10])[CH:6]2[O:9][CH:3]1[C:2]1[CH2:1][CH2:13][CH:12]([C:14]([CH3:16])=[O:15])[CH2:8][C:7]=12
Reactant: C=C1C(=C)C2OC1C(=C)C2=C
Reactant: C=CC(C)=O
Agent: Oc1ccc(O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: C=C1C(=C)C2OC1C1=C2CC(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
A mixture of 11.4 g of 2,3,5,6-tetramethylene-7-oxabicyclo[2.2.1]heptane, 2 g of anhydrous zinc chloride, 30 ml of methyl vinyl ketone and 75 ml of chloroform, containing 10 mg of hydroquinone, was stirred at room temperature for 20 hours under nitrogen. The mixture was concentrated under reduced pressure (ca 15 mmHg, room temperature) and rapidly eluted with methylene chloride/ethyl acetate (2:1) on a short column filled with 18 g of SiO2 (70-230 mesh). The first fractions contained methyl (1,2,3,4,5,6,7,8-octahydro-2,3-dimethylene-1,4-epoxynaphthalene-6-yl) ketone and unreacted methyl vinyl ketone. After the addition of 5 mg of hydroquinone, the mixture was concentrated to dryness at room temperature under reduced pressure (1 mmHg) until the methyl vinyl ketone had been completely removed. There were obtained 14.5 g (86%) of methyl (1,2,3,4,5,6,7,8-octahydro-2,3-dimethylene-1,4-epoxynaphthalen-6-yl) ketone in sufficient purity for the next step.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl.C(Cl)Cl>O1CCCC1>[O:6]1[CH2:7][CH2:8][N:3]([CH2:9][CH:11]2[O:13][CH2:12]2)[CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C1CN(CC2CO2)CCO1
Reaction time: 48 h
Yield: 18.5 %

Procedure:
0.87 g (20 mmole) of sodium hydride (as a 55% w/w suspension in mineral oil) were suspended in 20 ml of tetrahydrofuran. 1.74 g (20 mmole) of morpholine and subsequently 1.85 g (20 mmole) of epichlorohydrin were then added, whilst ice-cooling, to this suspension, and the reaction mixture was allowed to stand at room temperature for 48 hours. At the end of this time, methylene chloride was added to the reaction mixture, and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride), to give 530 mg of 1-morpholino-2,3-epoxypropane.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:67]=[CH:66][C:17](OCC3C=CC(C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=CC=3)=[CH:16][CH:15]=2)[C:3]=1[C:68]#[N:69].[OH:70][CH2:71][C:72]1[S:76][C:75]([N:77]2[CH2:86][CH2:85][C:84]3[C:79](=[C:80]([C:87](=[O:106])/[N:88]=[C:89]4/[S:90][C:91]5[CH:105]=[CH:104][CH:103]=[CH:102][C:92]=5[N:93]/4[CH2:94][O:95][CH2:96][CH2:97][Si:98]([CH3:101])([CH3:100])[CH3:99])[CH:81]=[CH:82][CH:83]=3)[CH2:78]2)=[N:74][C:73]=1[C:107]([O:109][CH3:110])=[O:108]>>[NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:67]=[CH:66][C:17]([O:70][CH2:71][C:72]3[S:76][C:75]([N:77]4[CH2:86][CH2:85][C:84]5[C:79](=[C:80]([C:87](=[O:106])/[N:88]=[C:89]6/[S:90][C:91]7[CH:105]=[CH:104][CH:103]=[CH:102][C:92]=7[N:93]/6[CH2:94][O:95][CH2:96][CH2:97][Si:98]([CH3:101])([CH3:100])[CH3:99])[CH:81]=[CH:82][CH:83]=5)[CH2:78]4)=[N:74][C:73]=3[C:107]([O:109][CH3:110])=[O:108])=[CH:16][CH:15]=2)[C:3]=1[C:68]#[N:69]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1CO
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1COc1ccc(-c2nn(C(=O)OC(C)(C)C)c(N)c2C#N)cc1

Procedure:
Compound 45E was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D with compound 45D in step 1 of Example 35: 1H NMR (DMSO-d6): δ 8.24 (dd, J=7.52, 1.38 Hz, 1H), 7.94 (d, J=7.67 Hz, 1H), 7.70 (d, J=7.98 Hz, 1H), 7.67 (s, 2H), 7.53-7.57 (m, 1H), 7.34-7.43 (m, 3H), 7.10-7.14 (m, 2H), 6.00 (s, 2H), 5.57 (s, 2H), 5.17 (s, 2H), 3.81 (s, 3H), 3.76 (t, J=5.98 Hz, 2H), 3.66-3.70 (m, 2H), 3.04 (t, J=6.14 Hz, 2H), 0.85-0.89 (m, 2H), −0.20 (s, 9H). MS (ESI(+)): m/z 892 (M+NH4—H2O).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:27][C:13]4=[N:14][C:15]([N:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=O)[CH2:19]5)=[CH:16][CH:17]=[C:12]4[N:11]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(N=C=N[CH2:33][CH2:34][CH2:35][N:36]([CH3:38])C)C.OC1C2N=NNC=2C=CC=1.N1CC=CC1>CN(C)C=O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:27][C:13]4=[N:14][C:15]([N:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([N:36]6[CH2:35][CH:34]=[CH:33][CH2:38]6)=[O:26])[CH2:19]5)=[CH:16][CH:17]=[C:12]4[N:11]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4cccc(C5CC5)n4)[nH]c3n2)C1
Reactant: CCN=C=NCCCN(C)C
Agent: C1=CCNC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cccc(C5CC5)n4)[nH]c3n2)C1)N1CC=CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.6 %

Procedure:
To a stirred solution of (R)-1-(2-(6-cyclopropylpyridin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (150 mg, 0.686 mmol) in N,N-dimethylformamide (15 mL) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (150 mg, 0.826 mmol), hydroxybenzotriazole (111 mg, 0.826 mmol), and 3-pyrroline (57 mg, 0.826 mmol) at room temperature. The reaction mixture was stirred for 24 h at room temperature then poured into ice water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude material was purified via preparative TLC (80% ethyl acetate in petroleum ether) to afford the title compound (30 mg, 17%). MS (ES+APCI) (M+H) 415.0; LCMS retention time 2.493 min (Method G). 1H NMR (300 MHz, CDCl3) δ 1.09 (m, 4H), 1.70 (m, 2H), 1.90 (m, 3H), 2.09 (m, 1H), 2.69 (m, 1H), 3.02 (m, 1H), 3.16 (m, 1H), 4.28 (m, 3H), 4.51 (m, 2H), 5.84 (m, 1H), 5.93 (m, 1H), 6.71 (d, 1H), 7.20 (d, 1H), 7.66 (m, 1H), 7.87 (d, 1H), 8.04 (m, 1H), 10.18 (br s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].C(OC(=O)[NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(C)(C)C.N12CCCN=C1CCCCC2>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:26]2[CH2:27][CH2:28][CH:23]([NH2:22])[CH2:24][CH2:25]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCNC(=O)c1ccc(N2CCC(N)CC2)nn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide (0.140 g, 0.610 mmol) in DMF (7 mL) was added piperidin-4-ylcarbamic acid tert-butyl ester (0.146 g, 0.730 mmol), followed by the addition of 1,8-diazabicyclo[5,4,0]undec-7-ene (0.280 mL, 1.84 mmol) and tetra-n-butylammonium iodide (6 mg). The reaction mixture was stirred at 80° C. for 16 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate, then washed with citric acid, sodium bicarbonate and brine solution. The organic layer was separated, and dried over anhydrous Na2SO4, and evaporated. The residue was purified by column chromatography and then treated with trifluoroacetic acid. The title compound was obtained as a white powder in 50% yield (0.090 g). 1H NMR (300 MHz, DMSO-d6) δ 8.75-8.77 (m, 1H), 7.79 (d, J=9.6 Hz, 1H), 7.34 (d, J=9.6 Hz, 1H), 4.29-4.35 (m, 2H), 3.29-3.22 (m, 1H), 3.06-3.12 (m, 1H), 2.85-2.87 (m, 1H), 2.50 (m, 1H), 1.77-1.80 (m, 2H), 1.56-1.64 (m, 4H), 1.40-1.44 (m, 2H), 1.17-1.25 (m, 1H), 0.90 (d, J=6.6 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][C:17]2[CH:18]=[N:19][C:20]([NH:23]C(OC(C)(C)C)=O)=[CH:21][CH:22]=2)[CH2:10][C@H:9]1[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)=[O:7].FC(F)(F)C(O)=O.[ClH:57]>ClCCl.C(OCC)(=O)C>[ClH:57].[ClH:57].[F:47][C:44]([F:45])([F:46])[C:42]1[CH:41]=[C:5]([CH:4]=[C:3]([C:2]([F:48])([F:1])[F:49])[CH:43]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][C:17]2[CH:18]=[N:19][C:20]([NH2:23])=[CH:21][CH:22]=2)[CH2:10][C@H:9]1[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C#CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)cn1

Procedure:
A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[3-[6-(tert-butoxycarbonylamino)pyridin-3-yl]-2-propynyl]piperazine (127 mg) prepared by a similar manner to that of Example 5-(1) and trifluoroacetic acid (5 ml) in dichloromethane (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The syrup obtained was dissolved into ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl) methyl]-4-[3-(6-aminopyridin-3-yl)-2-propynyl]piperazine dihydrochloride (80 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:9][C:10]([F:25])([F:24])[C:11]1[CH:12]=[C:13]([NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:20]2[CH2:21][CH2:22][CH2:23][CH:18]([NH:17][C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:9])([F:25])[F:24])[CH:12]=3)[CH2:19]2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cccc(NC2CCCNC2)c1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(NC2CCCN(c3ccc(Cl)nn3)C2)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 16.8 %

Procedure:
A mixture of 4.5 parts of 3,6-dichloropyridazine, 4.9 parts of N-[3-(trifluoromethyl)phenyl]-3-piperidinamine, 6.4 parts of sodium carbonate and 180 parts of N,N-dimethylformamide was stirred overnight at about 65° C. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off (the filtrate was set aside) and dried, yielding 1.2 parts (16.8%) of 1-(6-chloro-3-pyridazinyl)-N-[3-(trifluoromethyl)phenyl]-3-piperidinamine; mp. 92.6° C. (compound 146). The filtrate, which was set aside, was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, yielding 2.6 parts (32.9%) of 1-(6-chloro-3-pyridazinyl)-N-[3-(trifluoromethyl)phenyl[-3-piperidinamine monohydrochloride; mp. 173.5° C. (compound 147).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:12][S:11][C:10]1=[N:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:4].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([N:26]=[C:10]2[N:9]([CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:12][S:11]2)=[CH:28][CH:29]=1
Reactant: O=C(CBr)NCCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1CCCC1)NCCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound (200 mg) obtained in Example 356, pyrrolidine (0.32 ml) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 8 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol (97:3)] to give the title compound (123 mg) as oil.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:25][C:26](=[O:29])[NH:27][NH2:28])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:25][C:26](=[O:29])[NH:27][N:28]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(NC(=O)NN)cc1OC
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: COc1ccc(NC(=O)NN=c2c(=O)c3ccccc3c2=O)cc1OC

Procedure:
ninhydrin, 4-(3,4-dimethoxyphenyl)-semicarbazide hydrochloride
Reaction SMILES: [CH2:1]([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](=[O:29])(=[O:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:12][CH:11]=1)[C:6](Cl)=[O:7])[CH2:2][CH2:3][CH3:4].[F:30][C:31]([F:40])([F:39])[C:32]1[C:37]([OH:38])=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](=[O:28])(=[O:29])[NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:12][CH:11]=1)[C:6](=[O:7])[O:38][C:37]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:31]([F:39])([F:40])[F:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)Cl
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)Oc1ccccc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A mixture of 171 mg (0.391 mmole) of N-butyl-N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]carbamoyl chloride (from Step F), 63.9 mg (0.394 mmole) of α,α,α-trifluoro-o-cresol, 66 mg (0.48 mmole) of anhydrous potassium carbonate, and 3 mL of DMF was stirred under N2 at 90° C. overnight. The cooled mixture was partitioned between 20 mL of 2N HCl and 20 mL of EtOAc. The organic layer was washed with H2O (2×30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residual oil was flash chromatographed on silica gel (gradient elution with 20-35% EtOAc in hexane to yield 37.4 mg (17%) of the title compound as a yellow oil, homogeneous by TLC in 3:1 hexane-EtOAc; FAB-MS m/e 562 (M+1)+. The 1H NMR spectrum indicated the presence of two rotameric forms.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:41][C:24]4=[N:25][CH:26]=[C:27]([Br:40])[C:28]([NH:29][C@H:30]5[C@@H:35]([C:36](=[O:38])[NH2:37])[C@H:34]6[CH2:39][C@@H:31]5[CH:32]=[CH:33]6)=[C:23]4[N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:42](O)(C(F)(F)F)=O.C(OC(=O)C)(=O)C.C(N(CC)CC)C>C(Cl)Cl.C1COCC1.C(Cl)Cl>[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:41][C:24]4=[N:25][CH:26]=[C:27]([Br:40])[C:28]([NH:29][C@@H:30]5[C@@H:31]6[CH2:39][C@@H:34]([CH:33]=[CH:32]6)[C@@H:35]5[C:36]([NH2:37])=[O:38])=[C:23]4[N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(=[O:5])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Br)cnc4[nH]3)cc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(Cc2ccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Br)cnc4[nH]3)cc2)CC1
Temperature: 40 °C
Yield: 18 %

Procedure:
4-{4-[6-Bromo-7-((1R,2R,3S,4S)-3-carbamoyl-bicyclo[2.2.1]hept-5-en-2-ylamino)-3H-imidazo[4,5-b]pyridin-2-yl]-benzyl}-piperazine-1-carboxylic acid tert-butyl ester (172 mg, 0.276 mmol) was taken up into DCM and treated with TFA (3 ml) and stirred @ 40° C., O/N. the solution was then concentrated. The residue was taken up into methanol and treated with 900 mg mp carbonate for ½ hour. The resin was removed by filtration and filtrate concentrated. The residue was taken up into DCM/THF (˜30 mL) and acetic anhydride (0.56 ml, 5.9 mmol) was added followed by triethylamine (0.56 ml, 4.0 mmol). Solution was stirred at RT for 1 hr and then concentrated. The residue was purified via reverse phase chromotography using a gradient of MeCN with 0.1% TFA in Water with 0.1% TFA on a Phenomenex Gemini-NX C18 AXIA column. Fractions containing desired product were poured into sat'd sodium bicarbonate and extracted with 3 portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to yield an off white solid, 28 mg, 18% yield. (300 MHz, DMSO-d6) 13.28 (s, 1H), 8.10 (d, J=8 Hz, 2H), 8.02 (s, 1H), 7.75 (m, 1H), 7.48 (d, J=8 Hz, 2H), 7.19 (m, 2H), 6.44-6.33 (m, 2H), 5.23 (t, J=17 Hz, 9 Hz, 1H), 3.56 (s, 2H), 3.43 (s, 4H), 2.89 (s, 1H), 2.78 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.39 (s, 2H), 2.33 (s, 2H), 2.25 (d, J=8 Hz, 1H), 1.98 (s, 3H), 1.38 (d, J=8 Hz, 1H). MS=565 (M+H), HPLC: 1.5 min. (G Method)
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:8](=[CH:9][C:10]=1[O:11]C)[C:7](=[O:13])[O:6][C:5]2=[O:14].[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1>C(OCC)(=O)C>[OH:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:13])[O:6][C:5]2=[O:14]
Reactant: COc1cc2c(c([N+](=O)[O-])c1O)C(=O)OC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1OC(=O)c2c1cc(O)c(O)c2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Hydroxy-6-methoxy-4-nitro-isobenzofuran-1,3-dione (115 mg), aluminum chloride (80 mg) was mixed with ethyl acetate (3 ml). Pyridine (155 μl) in ethyl acetate (2 ml) was added dropwise. The resulting mixture was stirred at room temperature for 0.5 hours, heated to reflux for 3 hours, and then quenched with water (0.5 ml) and conc. HCl (0.5 ml) at 60° C. Ethyl acetate and water was removed in vacuo. The remainder was mixed with brine (2 ml) and extracted two times with ethyl acetate (15 ml). The combined organic layers were dried over anhydrous Na2SO4, filtrated, evaporated and triturated with diethyl ether.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:6][N:5]([C@H:13]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:14]([O:16]CC2C=CC(OC)=CC=2)=[O:15])[CH2:4]1)=O.[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:42][CH2:43][N:44]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:12]=[CH:11][S:10][CH:9]=4)[CH2:6][N:5]([C@H:13]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[C:14]([OH:16])=[O:15])[CH2:4]3)[CH2:45][CH2:46]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccsc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2ccsc2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-(3-thienyl)pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-methoxybenzyl ester (from EXAMPLE 90, Step A) and 4-(3-phenylpropyl)piperidine using procedures analogous to those described in EXAMPLE 1, Step J and EXAMPLE 10, Step F. For the title compound: 1H NMR (500 MHz) δ 0.85-4.20 (35H), 7.11-7.35 (81); ESI-MS 509 (M+H).