Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C2C(=CC(S(N3CCC[C@H]3COC3C=CC=CC=3)(=O)=O)=CC=2)C(=O)C1=O.[O:29]([CH2:36][C@@H:37]1[CH2:40][CH2:39][N:38]1[S:41]([C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48](=[O:53])[C:47]2=[O:54])(=[O:43])=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Br[CH2:56][C:57]1[CH:62]=[CH:61][N:60]=[C:59]([F:63])[CH:58]=1>>[F:63][C:59]1[CH:58]=[C:57]([CH2:56][N:49]2[C:50]3[C:46](=[CH:45][C:44]([S:41]([N:38]4[CH2:39][CH2:40][C@H:37]4[CH2:36][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:43])=[O:42])=[CH:52][CH:51]=3)[C:47](=[O:54])[C:48]2=[O:53])[CH:62]=[CH:61][N:60]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Reactant: Fc1cc(CBr)ccn1
Agent: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Product: O=C1C(=O)N(Cc2ccnc(F)c2)c2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc21
Yield: 30 %

Procedure:
(S)-1-(2-Fluoropyridin-4-yl-methyl)-5-(2-phenoxymethylazetidine-1-sulfonyl)-1H-indole-2,3-dione (18h) was prepared according to the same procedure for compound 11a, except using compound 17 and 4-(bromomethyl)-2-fluoropyridine, and purified with ether to afford 36 mg (30%) of 18h as an orange solid, mp 159.0-159.9° C. 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=5.1 Hz, 1H), 8.08 (s, 1. H), 7.98 (dd, J=8.7 Hz, J=2.1 Hz, 1H), 7.22 (m, 2H), 7.10 (d, J=5.4 Hz, 1H), 6.93 (t, J=7.5 Hz, 1H), 6.84-6.72 (m, 4H), 4.93 (s, 2H), 4.49 (m, 1H), 4.07 (m, 2H), 3.91-3.81 (m, 2H), 2.35-2.22 (m, 2H). Anal. Calcd for C24.FN3O5S.0.5H2O: C, 58.77, H, 4.32; N, 8.57. Found: C, 58.69, H, 4.45; N, 8.26.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](Br)=[CH:18]4)=[CH:13][C:12]=3[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[BH:30]([OH:32])[OH:31]>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([B:30]([OH:32])[OH:31])=[CH:18]4)=[CH:13][C:12]=3[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OBO
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Product: CC(C)(C)[Si](C)(C)Oc1cc2ccc(B(O)O)cc2cc1C12CC3CC(CC(C3)C1)C2

Procedure:
Following the basic procedure of Example 7(e), beginning with 11.9 g (25.4 mmol) of 7-(1-adamantyl)-6-tert-butyldimethylsilyloxy-2-bromonaphthalene, 8.37 g (75%) of the expected boronic acid of melting point 221°-222° C. were obtained.
Reaction SMILES: [N:1]1([C:10](OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:7][NH:8][CH2:9][CH:2]12.CC1C=CC(S(OC2C3CCC[C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[C:30]=3[N:31]=[CH:32][N:33]=2)(=O)=O)=CC=1.CC1C=CC(S(OC2C3CCCC4C=CC=CC=4C=3N=C(N)N=2)(=O)=O)=CC=1>>[N:31]1[C:30]2[C:34]3[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=3[CH2:7][CH2:3][CH2:4][C:5]=2[C:6]([N:1]2[CH2:2][CH:9]([NH2:8])[CH2:10]2)=[N:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2CNCC21
Reactant: Cc1ccc(S(=O)(=O)Oc2ncnc3c2CCCc2ccccc2-3)cc1
Agent: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1
Product: NC1CN(c2ncnc3c2CCCc2ccccc2-3)C1

Procedure:
The title compound was prepared using the procedure outlined in Example 59D substituting Example 2B for t-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate, and substituting the product from Example 118C for the product from Example 59C, followed by the procedure outlined in Example 59E. 1H NMR (CD3OD) δ 2.20-2.36 (m, 4H), 2.36-2.40 (m, 3H), 2.60 (t, 2H), 3.65-3.74 (m, 1H), 4.06 (dd, 2H), 4.47-4.55 (m, 2H), 7.26-7.34 (m, 1H), 7.36-7.43 (m, 2H), 7.62-7.67 (m, 1H), 8.41-8.44 (m, 1H). MS (M+H)+ m/z 281.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[N:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH2:32]Cl)([CH3:23])[CH3:22])[C:15]1=[O:34].[CH3:35][NH2:36]>C(#N)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[N:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([CH3:22])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH2:32][NH:36][CH3:35])[CH3:23])[C:15]1=[O:34]
Reactant: CN
Reactant: CC(C)(Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2Cl)c1=O)c1ccccc1OCCCl
Solvent: CC#N
Product: CNCCOc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2Cl)c1=O
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 4-chloro-3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropylbenzamide (Example 330i, 0.22 g) dissolved in acetonitrile (3 mL) was treated with 40% aqueous methylamine (0.380 mL). The resulting mixture was stirred at 100° C. for 16 h in a sealed tube. The reaction mixture was filtered and purified by preparative HPLC (Phenominex Gemini column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent). The fractions containing the desired compound were evaporated to afford the title compound (0.087 g).
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:30][C:31]1([NH2:34])[CH2:33][CH2:32]1.FC(F)(F)C([O-])=O>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:30][C:31]1([NH:34][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:32][CH2:33]1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: COc1ccc(CC2(N)CC2)cc1OC
Agent: O=C([O-])C(F)(F)F
Product: COc1ccc(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)cc1OC

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 207 mg (1 mmol) 1-(3,4-dimethoxy-benzyl)-cyclopropylamine. Yield: 15 mg (3%, trifluoroacetate); mass spectroscopy: [M+H]+=415.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])O.C(O)C>O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C@@H:21]1[O:22][C@H:13]([CH2:12][OH:11])[C@@H:15]([OH:16])[C@H:17]([OH:18])[C@H:19]1[OH:20]
Reactant: Fc1cccc2c1CCN2
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: CCO
Product: OC[C@H]1O[C@@H](N2CCc3c(F)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
A mixture of 4-fluoroindoline (185 mg) and D-glucose (267 mg) in H2O (0.74 ml)-ethyl alcohol (9 ml) was refluxed under argon atmosphere for 24 hours. The solvent was evaporated under reduced pressure to give crude 4-fluoro-1-(β-D-glucopyranosyl)indoline, which was used in the subsequent step without further purification.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1>C(#N)C>[CH3:9][O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[I:1]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)Nc1ccc(Br)cc1
Solvent: CC#N
Product: COC(=O)Nc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
133 g (0.591 mol) N-iodosuccinimide and 5.0 mL (8.60 g, 0.0573 mol) trifuoromethanesulfonic acid were added to a solution of 130.0 g (0.5651 mol) of (4-bromo-phenyl)-carbamic acid methyl ester in 660 mL acetonitrile. The mixture was stirred at room temperature for 18 h. The precipitate was collected by filtration washed with 160 mL ice-cold acetonitrile and dried to constant weight to yield 187.0 g (92%) of the title compound as white crystals melting at 129.4-130.0° C.
Reaction SMILES: ClC1C=CC=C(F)C=1C(NCC1(CC2CC2)CCNCC1)=O.[F:23][C:24]([F:30])([F:29])[S:25]([O-:28])(=[O:27])=[O:26].[CH3:31][C:32]1[N:33](S(N2C=CN=C2C)(=O)=O)[CH:34]=[CH:35][N+:36]=1[CH3:37].O(C)S(C(F)(F)F)(=O)=O>C(#N)C.C(Cl)Cl>[F:23][C:24]([F:30])([F:29])[S:25]([O-:28])(=[O:27])=[O:26].[CH3:31][C:32]1[NH:33][CH:34]=[CH:35][N+:36]=1[CH3:37]
Reactant: Cc1nccn1S(=O)(=O)n1cc[n+](C)c1C
Agent: COS(=O)(=O)C(F)(F)F
Agent: O=C(NCC1(CC2CC2)CCNCC1)c1c(F)cccc1Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: Cc1[nH]cc[n+]1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2-chloro-6-fluoro-N-{[4-cyclopropylmethylpiperidin-4-yl]methyl}benzamide (I-4) in acetonitrile (2.5 mL) was added to a solution of 2,3-dimethyl-1-[(2-methyl-1H-imidazol-1-yl)sulfonyl]-1H-imidazol-3-ium trifluoromethanesulfonate (for synthesis see J. Org. Chem., 2003, 68, 115) (361 mg, 0.925 mmol) in acetonitrile (2 mL) The yellow solution was stirred at room temperature for 12 h then the solvent removed in vacuo. Biotage chromatography (2% methanol-DCM) afforded 2-chloro-N-{[4-cyclopropylmethyl)-1-[(2-methyl-1H-imidazol-1-ylsulfonyl)]-piperidin-4-yl]methyl}6-fluoro-benzamide (144 mg) that was directly methylated. A solution of methyl triflate (0.031 mL, 0.27 mmol) in DCM (1 mL) was added dropwise to a stirred solution of 2-chloro-N-{[4-cyclopropylmethyl)-1-[(2-methyl-1H-imidazol-1-ylsulfonyl)]-piperidin-4-yl]methyl}6-fluoro-benzamide (118 mg) in DCM (2 mL) cooled in an ice bath. The solution was stirred in an ice bath for 1.5 h then the volatile components removed in vacuo to leave 1-{[4-{[2-chloro-6-fluorobenzoyl)amino]methyl}-4-(cyclopropylmethyl)piperidin-1-yl]sulfonyl}-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (I-5) that was used in the next step without further purification. MS 483 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[C:7](=[CH2:13])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.[OH:14]I(C1C=CC=CC=1)OS(C1C=CC(C)=CC=1)(=O)=O>O.CO>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:13][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: C=C1CCCc2cc(OC)ncc21
Reactant: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: COc1cc2c(cn1)CC(=O)CCC2
Yield: 66.5 %

Procedure:
3-Methoxy-8-methylene-5,6,7,8-tetrahydroisoquinoline (125) (1.27 g, 7.25 mmol) in a mixture of water (5 mL) and MeOH (45 mL) was treated with [hydroxy(tosyloxy)iodo]benzene (2.84 g, 7.25 mmol) in MeOH (7 mL). After about 30 min water (15 mL) was added then the mixture was concentrated under reduced pressure to remove most of the MeOH. The mixture was basified to about pH 10 with sat. aq. NaHCO3 then EtOAc (˜30 mL) was added. Insoluble material was removed by filtration. The filtrate layers were separated then the aqueous layer was extracted with EtOAc (20 mL). The combined organic solutions were washed with brine (˜25 mL) then dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure then the material was purified on silica gel (40 g) using a gradient from 0-100% EtOAc in heptane. Pure product fractions were combined and concentrated under reduced pressure to yield 3-methoxy-6,7-dihydro-5H-cyclohepta[c]pyridin-8(9H)-one (126) (0.922 g, 67%); LC/MS, method 3, Rt=1.66 min, MS m/z 192 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 6.57 (s, 1H), 3.92 (s, 3H), 3.63 (s, 2H), 2.93-2.85 (m, 2H), 2.61-2.54 (m, 2H), 2.04-1.94 (m, 2H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:24]([O:25][CH3:26])=[CH:23][C:8]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[O:10])=[CH:7][C:6]=1[O:27][CH3:28])(=[O:3])[CH3:2].CC(C1C=C(C=C(C(C)(C)C)C=1O)C(NCC1C=CC([N+]([O-])=O)=CC=1)=O)(C)C>>[C:1]([O:4][C:5]1[C:24]([O:25][CH3:26])=[CH:23][C:8]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[O:10])=[CH:7][C:6]=1[O:27][CH3:28])(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)NCCc2ccc([N+](=O)[O-])cc2)cc(OC)c1OC(C)=O
Agent: CC(C)(C)c1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Product: COc1cc(C(=O)NCCc2ccc(N)cc2)cc(OC)c1OC(C)=O

Procedure:
The experimental protocol used is the same as that described for intermediate 2.2, with 4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide replacing the 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide. A colourless oil is obtained with a quantitative yield. The product is used directly in the following stage without additional purification.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.COP([CH2:19][C:20]1[N:21]([CH3:36])[C:22]2[C:27]([N:28]=1)=[C:26]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[N:25]=[C:24]([Cl:35])[N:23]=2)(=O)OC.[C:37]([O:41][C:42]([N:44]1[CH2:47][C:46](=O)[CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[C:37]([O:41][C:42]([N:44]1[CH2:47][C:46](=[CH:19][C:20]2[N:21]([CH3:36])[C:22]3[C:27]([N:28]=2)=[C:26]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[N:25]=[C:24]([Cl:35])[N:23]=3)[CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: COP(=O)(Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cn1c(C=C2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
To a solution of diisopropylamine (1.4 mL, 9.8 mmol) in THF (3 mL) at −78° C. was added n-BuLi (3.9 mL, 9.8 mmol, 2.5 M in hexanes) and the resulting mixture allowed to stir for 20 min. The resulting solution was added to a pale green solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)phosphonic acid dimethyl ester (3.36 g, 8.9 mmol) in THF (80 mL) at −78° C. The resulting mixture was warmed to r.t. before a solution of 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (1.76 g, 10.2 mmol) in THF (10 mL) was added. The resulting pink mixture was stirred for 16 h then quenched with H2O. The mixture was concentrated in vacuo and the residue was partitioned between DCM and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-70%) affording the title compound as a green powder (3.46 g, 92%). 1H NMR (CDCl3, 400 MHz): δ 6.33-6.32 (1 H, m), 4.91-4.90 (2 H, m), 4.71-4.70 (2 H, m), 4.28 (4 H, brd s), 3.81 (4 H, t, J=4.74 Hz), 3.71 (3 H, s), 1.48 (9 H, s).
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CCN([CH2:21][CH3:22])CC.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:23]1([S:29]([O:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][C:9]3[CH:14]=[CH:13][C:12]([O:15][S:29]([C:22]4[CH:21]=[CH:25][CH:24]=[CH:23][CH:28]=4)(=[O:31])=[O:30])=[CH:11][CH:10]=3)=[CH:3][CH:4]=2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Oc1ccc(Oc2ccc(O)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc(Oc2ccc(OS(=O)(=O)c3ccccc3)cc2)cc1)c1ccccc1
Yield: 62 %

Procedure:
An oven-dried 100 ml 3-necked flask is equipped with a magnetic stirring bar, a reflux condenser carrying a CaCl2 -Drierite drying tube, and a heating mantle, and is charged with 4,4'-oxydiphenol (Pfaltz & Bauer) (4.2 grams, 20.8 mmol), 4-dimethylaminopyridine (0.5 gram, 4.1 mmol), and anhydrous Et3N (40 ml), and the stirred solution is treated slowly with benzenesulfonyl chloride (6 ml, 47 mmol) via syringe. The resulting mixture is heated at reflux for 9 hours. Workup consists of partitioning the reaction mixture between CH2Cl2 (100 ml) and a mixture of water (150 ml) and concentrated HCl (40 ml), then washing the organic phase successively with 100 ml portions of water, 5 percent NaOH, water, and saturated brine. Drying (MgSO4), filtration and concentration gives a red oily residue. TLC analysis on silica gel shows one major 5 component (Rf =0.36; CH2Cl2), and some minor more polar components. Chromatography on a column packed with flash-grade silica gel (6"×1" i.d.), eluting with CH2Cl 2, gives 7.64 grams of a faintly yellowish oil, which solidifies on standing. Recrystallization from a mixture of EtOAc (20 ml) and water (10 ml) affords 6.23 grams (62 percent yield) of the title compound as a white crystalline solid, m.p. 129° C. to 130° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:33])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:16])[CH2:11][CH2:10]1)=[O:8].[H][H]>C1COCC1.CO.[Pd]>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:10][CH2:11][N:12]([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[O:33])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:16])[CH2:13][CH2:14]1)=[O:8]
Reactant: Cn1cccc1C(=O)N1CCN(C(=O)NC2CCN(c3ccc(C=CC(=O)N4CCOCC4)cc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cccc1C(=O)N1CCN(C(=O)NC2CCN(c3ccc(CCC(=O)N4CCOCC4)cc3)CC2)CC1

Procedure:
The 4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(3-morpholino-3-oxopropen-1-yl)-phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (100 mg, 0.19 mmol) obtained in Example 11 was dissolved in THF (20 ml) and methanol (5 ml), and 10% Pd—C (39 mg) was added thereto, followed by stirring in a hydrogen atmosphere for 12 hours. After the insoluble material was filtered with Celite, the filtrate was evaporated under reduced pressure, thereby obtaining 4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(3-morpholino-3-oxopropyl)-phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (84 mg, 84%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](OC)=[O:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37](=[O:49])[O:38][CH:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][NH:47][CH3:48])[CH2:41][CH2:40]1.[CH2:56](N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:30]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([O:38][CH:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][N:47]([CH3:48])[C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][N:8]([CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([O:27][CH3:56])=[O:26])=[CH:23][CH:22]=3)[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:11][CH:12]=2)=[O:17])[CH2:41][CH2:40]1)=[O:49]
Reactant: CCN(CC)CC
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: COC(=O)c1ccc(CN(Cc2ccc(C(=O)O)cc2)C(=O)OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN(Cc2ccc(C(=O)N(C)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
The compound (233 mg, 0.58 mmol) obtained in Example 100c was dissolved in 6.0 mL of dichloromethane, and 1-[2-(methylamino)ethyl]piperidin-4-yl biphenyl-2-ylcarbamate (227 mg, 0.64 mmol) and triethylamine (163 μL, 1.17 mmol) were added. The mixture was ice cooled, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (168 mg, 0.88 mmol) and 4-(dimethylamino)pyridine (10 mg, 0.082 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture to dilute the mixture, and the organic layer was washed with water and a saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried with anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure, and the resulting yellow oily substance was purified by NH silica gel chromatography (n-hexane:ethyl acetate, 50:50→20:80, v/v) to give the title compound (420 mg; yield, 98%) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[C:12]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[N:16]=[CH:15][CH:14]=2)=[C:11]([CH3:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:9]1=[O:37])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([N:17]2[C:13]([C:12]3[N:8]([CH2:7][C:6]([OH:38])=[O:5])[C:9](=[O:37])[N:10]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[C:11]=3[CH3:26])=[CH:14][CH:15]=[N:16]2)=[CH:19][CH:20]=1)#[N:25]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(CC(=O)OC(C)(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(CC(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
tert-Butyl-{5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-1-yl}acetate (Example 20) (75 mg, 0.143 mmol) was stirred in DCM (3 mL) and water (0.03 mL). To this mixture was added TFA (0.1 mL) and the mixture stirred overnight. Reaction was incomplete so further TFA (0.5 mL) was added and after 1 h 30 minutes, a further 1 ml was added. After 4 h reaction was complete, solvents were evaporated and the residue partitioned between EtOAc and water. The organic phase was separated, dried over Na2SO4 and evaporated to give the title compound as a gum.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[S:8]([CH3:11])(=O)=O)#[N:2].[Na].[Cl:18][C:19]1[CH:20]=[N+:21]([O-])[CH:22]=[C:23]([Cl:26])C=1S.C(N(C(C)C)C(C)C)C>C(O)(C)C.CO>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[S:8][C:11]1[C:19]([Cl:18])=[CH:20][N:21]=[CH:22][C:23]=1[Cl:26])#[N:2]
Reactant: [O-][n+]1cc(Cl)c(S)c(Cl)c1
Reactant: CCOC(=O)c1cc(C#N)c(S(C)(=O)=O)s1
Agent: [Na]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)c1cc(C#N)c(Sc2c(Cl)cncc2Cl)s1
Yield: 50.1 %

Procedure:
To a 5 mL Biotage microwave reaction vessel was charged with a solution of Ethyl 4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (0.26 g, 1 mmol) in isopropanol (1.5 mL), 3,5-dichloro-1-oxido-pyridin-1-ium-4-thiol sodium salt (0.2 g, 1 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.645 g, 5.0 mmol). The resulting reaction mixture was sealed and heated at 150° C. for 10 minutes under microwave irradiation (Biotage Initiator 8). After cooling down, a precipitation was formed and the solid was removed by filtration. The organic solution was concentrated under vacuo to give a brown oil residue. The residue was re-dissolved in methanol (3 mL) and extracted with hexane (15 mL×4). The organic layer was separated and concentrated under vacuum to afford a solid as the title product (180 mg, 50% yield). MS m/z: 358.94, 360.94 [M+H]+.
Reaction SMILES: [CH3:1]Br.[CH2:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[Na]>C(O)C>[CH:3]1([CH2:1][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C1CCCCCCC1
Reactant: CBr
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CCO
Product: c1cn(CC2CCCCCCC2)cn1

Procedure:
Cyclooctane methyl bromide (5.5 g, 0.027 mole) was added dropwise to a refluxing solution of imidazole (2.0 g, 0.03 mole) in a solution of sodium (0.7 g, 0.03 mole) in absolute ethanol (50 ml). After addition the mixture was refluxed for a further 15 hours.