Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C(O)C>[F:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:38][CH:39]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]([NH:42][C:40](=[O:41])[C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)=[S:44])=[CH:28][CH:27]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1
Agent: O=C(N=C=S)c1ccc(F)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 80%).
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH:44]1([O:48][C:49]2[CH:50]=[C:51]([CH:55]=[C:56]([N:58]3[CH2:62][CH2:61][CH2:60][C:59]3=[O:63])[CH:57]=2)[C:52]([OH:54])=O)[CH2:47][CH2:46][CH2:45]1.[CH:64]12[CH2:70][CH:67]([CH2:68][CH2:69]1)[CH2:66][CH:65]2[NH:71][C:72](=[O:87])[C@H:73]([CH3:86])[CH2:74][C@H:75]([OH:85])[C@@H:76]([NH2:84])[CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[CH2:77]([C@H:76]([NH:84][C:52](=[O:54])[C:51]1[CH:55]=[C:56]([N:58]2[CH2:62][CH2:61][CH2:60][C:59]2=[O:63])[CH:57]=[C:49]([O:48][CH:44]2[CH2:45][CH2:46][CH2:47]2)[CH:50]=1)[C@@H:75]([OH:85])[CH2:74][C@H:73]([C:72](=[O:87])[NH:71][CH:65]1[CH2:66][CH:67]2[CH2:70][CH:64]1[CH2:69][CH2:68]2)[CH3:86])[C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: O=C(O)c1cc(OC2CCC2)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(OC2CCC2)cc(N2CCCC2=O)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6 from 3-cyclobutyloxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D46) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:10]=[CH:11][CH:12]=1)=[O:6].[CH3:21]I>>[CH3:20][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH3:21])[C:14]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CN(C)C=CC(=O)c1cccc(NC(=O)C2CCC2)c1
Reactant: CI
Product: CN(C)C=CC(=O)c1cccc(N(C)C(=O)C2CCC2)c1

Procedure:
This compound was then converted to N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]cyclobutanecarboxamide, mp 155°-157° C., by the procedure of Example 1 and further alkylated by the procedure of Example 6, using methyl iodide to give 8.32 g of N-[3-[3-(dimethylamino)1-oxo-2-propenyl]phenyl]-N-methylcyclobutanecarboxamide, mp 117°-119° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:39]1([CH2:45][CH2:46][CH2:47][C:48]#[N:49])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:42]3[CH2:43][CH2:44][N:39]([CH2:45][CH2:46][CH2:47][C:48]#[N:49])[CH2:40][CH2:41]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:37])[CH3:38])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: N#CCCCN1CCNCC1
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCC#N)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-piperazin-1-yl-butyronitrile (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H48N5O2Cl2 [(M+H)+] 688.3180, observed 688.3186.
Reaction SMILES: [CH2:1]([CH:3]([CH2:21][CH3:22])[CH:4]([NH2:20])[C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:8]=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[Cl:30][C:31]1[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:30][C:31]1[S:35][C:34]([S:36]([NH:20][CH:4]([C:5]2[N:9]([S:10]([C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)(=[O:12])=[O:11])[N:8]=[CH:7][CH:6]=2)[CH:3]([CH2:1][CH3:2])[CH2:21][CH3:22])(=[O:38])=[O:37])=[CH:33][CH:32]=1
Reactant: CCC(CC)C(N)c1ccnn1S(=O)(=O)c1ccc(C)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1S(=O)(=O)c1ccc(C)cc1
Yield: 32.9 %

Procedure:
To (2-ethyl-1-{1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl}butyl)amine (0.200 g, 0.630 mmol) in CH2Cl2 (10 mL) was added triethylamine (0.18 mL, 1.3 mmol) and 5-chlorothiophene-2-sulfonyl chloride (0.14, 0.76 mmol). After 1 day the reaction mixture was diluted with chloroform (30 mL), washed with H2O (2×30 mL), dried (Na2SO4) and concentrated. Column chromatography (EtOAc/hexane, 3:7) provided 5-chloro-N-(2-ethyl-1-{1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl}butyl)thiophene-2-sulfonamide (0.104 g, 33%) as a white solid (mp=146-148° C.).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].CS[C:15]1[S:19][CH:18]=[CH:17][S+:16]=1>CC(C)=O.C(OCC)C>[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].[S:16]1[CH:17]=[CH:18][S:19][C:15]1=[N+:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCNCC1
Reactant: CSc1scc[s+]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CC(C)=O
Product: c1csc(=[N+]2CCCCCC2)s1

Procedure:
0.25 g of hexahydroazepine and 0.5 g of 2-methylthio-1,3-dithiolium perchlorate were teated in the same manner as in Example 26, and the product was recrystallized from acetone-ethyl ether, whereby 0.31 g (yield: 52.0%) of 1-(1,3-dithiol-2-ylidene)hexahydroazepinium perchlorate (Compound No. 37) was obtained as crystals having a melting point of from 86° to 88° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27].[N:37]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][CH:42]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:43][CH2:44]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C1c2c(-c3ccc(F)cc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C1c2c(-c3ccc(F)cc3)cc(N3CCC(N4CCCC4)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 44.8 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (68.5 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (54.7 mg, 45%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH3:11].[CH3:12]OC(OC)N(C)C.N1CCCC1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:11]=[CH:12][NH:8]2
Reactant: COC(OC)N(C)C
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: Brc1cccc2[nH]ccc12
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 68 %

Procedure:
2-Bromo-6-nitrotoluene (3.2 g, 15 mmol), N,N-dimethylformamide dimethyl acetal (5.4 g, 45 mmol) and pyrrolidine (1.1 g, 15 mmol) were combined in 30 mL of DMF and heated at 110° C. The reaction mixture was stirred at 110° C. for 2.5 hours and then water was added. The aqueous layer was extracted with Et2O and the combined organic layers were washed with water and brine, dried over MgSO4 and concentrated. The brown syrup was dissolved in 80% aqueous AcOH (80 mL) and heated to 75° C. Zn powder (8.5 g), 130 mmol) was then added portionwise over 1 hour and the temperature was raised to 85° C. for 2 hours. The reaction mixture was filtered and water was added. The aqueous layer was extracted with Et2O and the combined organic layers were washed with saturated aqueous sodium bicarbonate and water, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 20% EtOAc in Hexanes to provide 2 g of the title compound as a greenish oil used as such.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[C:16]([F:35])[CH:15]=3)[CH:9]=[C:10]([CH2:11][CH2:12]Br)[N:6]2[N:5]=[CH:4][N:3]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[C:16]([F:35])[CH:15]=3)[CH:9]=[C:10]([CH2:11][CH2:12][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: Nc1ncnn2c(CCBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ncnn2c(CCN3CCOCC3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Temperature: 55 °C
Yield: 34.4 %

Procedure:
A mixture of the crude 1-{4-[4-amino-7-(2-bromoethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (500 mg, crude, 0.331 mmol), morpholine (0.10 ml, 1.12 mmol), triethylamine (0.08 ml, 0.60 mmol) and sodium iodide (7 mg, 0.05 mmol) in 4 ml DMF was heated at 55° C. in a closed vial for 16 h. Cooled to rt, the crude was diluted with 20 ml EtOAc and was washed with aq saturated NaHCO3, brine and dried over Na2SO4. The crude was concentrated and purified via column chromatography (95:5 v/v CH2Cl2—CH3OH) to afford 64 mg of the title compound (yield 47%). 1H-NMR (DMSO-d6 and 1 drop TFA-d) δ 9.44 (d, J=3 Hz, 1H), 9.33(d, J=3 Hz, 1H), 8.65(dd, J=7, 2 Hz, 1H, 8.32(t, J=8 Hz, 1H), 8.15(s, 1H), 7.55-7.51(m, 1H), 7.48-7.24(m, 4H), 6.83(s, 1H), 4.03-4.01 (m, 2H), 3.69-3.49(m, 8H), 3.38-3.33(m, 2H); MS [M+H]+=562.3; LCMS RT=2.84 min.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:5]([N:21]=1)=[CH:6][C:7]1[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:11]=1[CH:12]=2.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC>C1COCC1.C(Cl)Cl>[CH:15]1([CH2:14][CH2:13][N:10]2[C:11]3[CH:12]=[C:4]4[NH:3][C:2]([NH:1][C:22](=[O:29])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[N:21][C:5]4=[CH:6][C:7]=3[C:8]([CH3:19])([CH3:20])[C:9]2=[O:18])[CH2:17][CH2:16]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)C(=O)N(CCC2CC2)c2cc3[nH]c(N)nc3cc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)N(CCC2CC2)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21

Procedure:
A solution of D8 (120 mg), benzoic acid chloride (87 μl), NEt3 (150 μl) in THF (1 ml) and CH2Cl2 (3 ml) is stirred at RT for 3 h. After evaporation EtOAc is added and the organic phase is washed with saturated NaHCO3 solution and brine, dried over MgSO4 and evaporated again. The residue is purified by preparative RP-HPLC to give the desired compound (13.4 mg).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:18]([O:26][O:27][CH:28]([CH2:33][CH2:34][CH2:35][CH3:36])[CH:29](Br)[CH2:30][CH3:31])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:37][N:38](C)C=O.C(N)CN>O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:18]([O:26][O:27][CH:28]([CH2:33][CH2:34][CH2:35][CH3:36])[CH:29]([C:37]#[N:38])[CH2:30][CH3:31])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCC(OOC(=O)c1ccccc1)C(Br)CC
Reactant: CN(C)C=O
Agent: CCCCCc1ccc(-c2ccccc2)cc1
Solvent: NCCN
Solvent: O
Product: CCCCC(OOC(=O)c1ccccc1)C(C#N)CC

Procedure:
2.75 g (5.10-3 moles) of p-pentyl biphenyl-3-bromo-4-octyloxy benzoate and 0.6 g (6.7.10-3 moles) of cuprous cyanide are introduced into 10 ml of dimethyl formamide. After system had been heated under reflux for 6 hours, it is cooled and poured into a mixture of 60 ml of deionized water and 5.5 ml of ethylene diamine. The solution is stirred and then extracted with ether. 2.3 g of crude product are obtained and then purified chromatographically on a column of silica, followed by recrystallization in ethanol. 1.8 g of pure product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:31]2[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][C:21]=3[OH:30])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:47]([CH3:49])[CH3:48]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:31]2[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][C:21]=3[O:30][CH:47]([CH3:49])[CH3:48])[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(C)N1CCN(C(CN2CCN(CCCCc3c(O)ccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc2ccccc2c1CCCCN1CCN(CC(c2ccc(F)cc2)N2CCN(C(C)C)CC2)CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
0.05 g of 1-[2-(4-Fluorophenyl)-2-(4-isopropylpiperazino)ethyl]-4-[4-(2-hydroxynaphthalen-1-yl)butyl]piperazine obtained in Example 7 was dissolved in 5 ml of dimethylformamide, and 0.19 g of potassium carbonate and 0.068 ml of 2-iodopropane were added, followed by stirring at 70° C. for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=1:1) to give 0.03 g of 1-[2-(4-fluorophenyl)-2-(4-isopropylpiperazino)ethyl]-4-[4-(2-isopropoxynaphthalen-1-yl)butyl]piperazine as an oil.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=[O:13])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:23]O>>[N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([O:14][CH3:23])=[O:13])(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CO
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCC2)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1
Yield: 68.3 %

Procedure:
3-(pyrrolidin-1-ylsulfonyl)benzoic acid (200 mg, 0.783 mmol) was refluxed in the presence of con. Sulfuric acid (5.06 mg, 0.039 mmol) in methanol at 70° C. for overnight. Reaction was monitored by TLC. After completion of the reaction, solvent was removed by vacuum and then compound was purified by flash chromatography afforded the methyl 3-(pyrrolidin-1-ylsulfonyl)benzoate (150 mg, 0.535 mmol, 68.3% yield). 1H NMR (CDCl3, 400 MHz): δ 8.47 (m, 1H), 8.25 (d, 1H, J=7.6 Hz), 8.02 (dt, 1H, J=1.2 & 8.0 Hz), 7.63 (t, 1H, J=7.6 Hz), 3.96 (s, 3H), 3.27 (m, 4H), 1.77 (m, 4H). Mass [M+H]+: 270.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20]([OH:22])=O.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[F:33])[NH:29][N:28]=[CH:27]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[F:33][C:32]1[CH:31]=[C:30]2[C:26]([CH:27]=[N:28][NH:29]2)=[CH:25][C:24]=1[NH:23][C:20]([C:13]1[CH:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[F:1])[CH2:17][C:16](=[O:18])[NH:15][C:14]=1[CH3:19])=[O:22]
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Reactant: Nc1cc2cn[nH]c2cc1F
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
The product of Example 21, Step 2 (245 mg, 0.772 mmol, 1.00 equiv), 5-amino-6-fluoroindazole (117 mg, 0.772 mmol, 1.0 equiv), and EDC (177 mg, 0.927 mmol, 1.20 equiv) were suspended in 2.0 mL DMF. Et3N (0.129 mL, 0.927 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 141 mg (41%) of the title compound as an off white solid. MS (ES+) m/e 451 [M+H]+
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:12]([C:17]([CH:19]=[CH2:20])=[CH2:18])[CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:12]([C:17]1[CH2:19][CH2:20][CH:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:3][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CC(=O)OCC
Reactant: C=CC(=C)CCCCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCCCC1=CCC(C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Ethyl acrylate (1.92 ml) is added to toluene (15 ml) and aluminum chloride (215 mg). The resulting solution is cooled to 0° C., after which 2-pentyl-1,3-butadiene (2.0 g) is added dropwise over a period of 30 minutes. The reaction mixture is then stirred for 5 hr at 0° C., and stored in a 4° C. refrigerator overnight. The resulting mixture is placed in an extraction funnel, and washed with two 200 ml aliquots of 1% HCl. The reaction mixture is further washed with 100 ml water, then with 100 ml saturated sodium chloride, and dried over a combination of sodium sulfate and potassium carbonate. The mixture is filtered through celite, and the solvent removed in vacuo. The resulting liquid is distilled at 107°-109° C. at 1 mm Hg to produce ethyl 4-pentyl-3-cyclohexen-1-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:23]([F:40])=[C:24](/[CH:28]=[C:29](/[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])\[C:30]#[N:31])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[C:23]=2[F:40])[C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])([C:30]#[N:31])[CH:9]([CH2:10][C:11]([CH3:12])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:19])[NH:8]1)=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)C/N=C/CC(C)(C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1NC(CC(C)(C)c2ccccc2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 22.2 %

Procedure:
In a manner similar to the method described in Example 1c, [[3-methyl-3-phenyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 82a (2.3 g, 8.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.4 g, 7.7 mmol) prepared in Example 52a, AgF (0.7 g, 5.5 mmol), and triethylamine (2.1 g, 21 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1 g, 22%).
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].S(=O)(=O)(O)O.[CH2:24]=[C:25]([CH3:27])[CH3:26].N#N>ClCCl.C(Cl)(Cl)Cl.CCCCCC>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([O:8][C:13]([CH3:18])([CH3:14])[CH3:12])=[O:7])[C@@H:3]([CH3:5])[O:4][C:25]([CH3:27])([CH3:26])[CH3:24]
Reactant: C=C(C)C
Reactant: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: N#N
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 48 h

Procedure:
Z-Thr-OH (25.3 g, 0. 1 mol, Peptide Research Laboratories, Japan) was suspended in dichloromethane (250 ml), to which was added conc. sulfuric acid (1 ml). The mixture was cooled on a dry ice-acetone bath, to which was blown isobutene (the volume increased by 200 ml). The vessel was closed tightly, and the mixture was stirred for 2 days at 20° C. The vessel was opened, into which was blown N2 at 20° C. to purge isobutene, followed by addition of water. The mixture was neutralized with a 10% (W/V) aqueous solution of sodium hydrogencarbonate, which was subjected to extraction twice with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, then the solvent was distilled off. The residue was purified by means of a silica gel column chromatography (n-hexane:chloroform =1:2) to give an oily product. The yield was 26.6 g (72.7%). Rf: 0.21 (n-hexane:chloroform =1:2) FAB-MS (M+H+)=366 (Theoretical value =366)