Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C@H:2]([C:27](O)=[O:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:21])[CH3:20])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:80]([O:84][C:85]([N:87]1[CH2:92][CH2:91][NH:90][CH2:89][CH2:88]1)=[O:86])([CH3:83])([CH3:82])[CH3:81]>CN(C=O)C>[C:80]([O:84][C:85]([N:87]1[CH2:92][CH2:91][N:90]([C:27](=[O:28])[C@@H:2]([NH:1][C:30]([O:32][CH2:33][CH:34]2[C:46]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:40]3[C:35]2=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:3][CH2:4][CH2:5][NH:6]/[C:7](/[NH2:26])=[N:8]/[S:9]([C:12]2[C:13]([CH3:14])=[C:15]([CH3:16])[C:17]3[O:18][C:19]([CH3:21])([CH3:20])[CH2:22][C:23]=3[C:24]=2[CH3:25])(=[O:10])=[O:11])[CH2:89][CH2:88]1)=[O:86])([CH3:83])([CH3:81])[CH3:82]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a solution of Fmoc-Arg(Pbf)-OH 1 (25.0 g, 38.5 mmol) in DMF (200 mL) at room temperature was added DIEA (13.41 mL, 77.1 mmol). After stiffing at room temperature for 10 min, the reaction mixture was cooled to ˜5° C. To the reaction mixture was added HATU (16.11 g, 42.4 mmol) in portions and stirred for 20 min and a solution of tert-butyl-1-piperazine carboxylate (7.18 g, 38.5 mmol) in DMF (50 mL) was added dropwise. The reaction mixture was stirred at ˜5° C. for 5 min. The mixture reaction was then allowed to warm to room temperature and stirred for 2 h. Solvent was removed in vacuo and the residue was dissolved in EtOAc (500 mL), washed with water (2×750 mL), 1% H2SO4 (300 mL) and brine (750 mL). The organic layer was separated, dried over Na2SO4 and solvent removed in vacuo to a total volume of 100 mL. Compound A was taken to the next step as EtOAc solution (100 mL). LC-MS [M+H] 817.5 (C43H56N6O8S+H, calc: 817.4).
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH2:13]([OH:15])[CH3:14]>>[C:7]1([C:5]2[N:6]=[C:2]3[N:3]([CH:4]=2)[C:5]2[CH2:7][CH2:8][CH2:14][C:13](=[O:15])[C:4]=2[S:1]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCO
Reactant: Sc1nc(-c2ccccc2)c[nH]1
Product: O=C1CCCc2c1sc1nc(-c3ccccc3)cn21

Procedure:
2-Mercapto-4-phenylimidazole (10.6 g) and 2-bromo-1,3-cyclohexadione (12.6 g) were placed into absolute ethanol (200 ml) and the reaction mixture was heated to reflux for 16 hours and then cooled to give hydrobromide salt of the desired compound (16.3 g). The hydrobromide salt was neutralized with 10% sodium carbonate solution in an aqueous system to give the titled compound (12.3 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([O:18]C)=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=[O:17])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1=C(C(=O)O)C(c2ccc(F)cc2)CC(=O)N1
Temperature: 60 °C
Reaction time: 16 h
Yield: 67.6 %

Procedure:
The product from Step 1 (0.200 g, 0.76 mmol, 1.00 equiv) was dissolved in MeOH (3 mL). Following addition of 2.5N NaOH (1 mL), the reaction mixture was heated to 60° C. for 6 hours, then stirred at room temperature for an additional 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed again with 1N NaOH. The aqueous phases were combined and acidified to pH˜1 with 5N HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with satd NaCl, dried over Na2SO4, and filtered. The filtrate was concentrated en vacuo and azeotroped several times with hexanes to afford 128 mg (67%) of the acid as an off-white solid. MS (ES+) m/e 250 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=[O:11])[CH3:8])[CH3:3].C1(C)C=CC=CC=1.[CH3:19][C:20](=[CH:22][CH2:23][CH2:24][CH:25]([CH2:27][CH:28]=[O:29])[CH3:26])[CH3:21].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>CC(OC)(C)C>[CH3:3][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:1].[CH3:19][C:20](=[CH:22][CH2:23][CH2:24][CH:25]([CH2:27][CH2:28][OH:29])[CH3:26])[CH3:21]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: CC(C)=CCCC(C)=CC=O
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(C)=CCC/C(C)=C/CO
Product: CC(C)=CCCC(C)CCO

Procedure:
FIG. 4 illustrates the profiles of citral biotransformation by Zymomonas mobilis in the aqueous/toluene and in the aqueous/MTBE two-phase system. For the former the increase of citronellal concentration continued rather linearly over the three hour period. When the concentration of the NADPH regenerating system was doubled, the same final citronellal concentration was achieved. This indicates that the reaction was not limited by the NADPH regenerating system. Concentrations of both citral isomers, geranial and neral, decreased over time. The alcohols nerol, geraniol and citronellol were not detected. For the aqueous/MTBE two-phase system, citronellal formation was observed to slow over time, though both of the citral isomers, geranial and neral, were consumed linearly over time. Of the alcohol by-products, 0.34 mM of geraniol and less than 0.1 mM of citronellol were formed. The molar balance after 3 h indicated a loss of 16% of the initial substrate in the toluene system and 10% in the MTBE system. In comparison, controls without biomass showed no loss of citral or citronellal over 3 hours. However, controls with boiled biomass lost citral and citronellal to a similar extent as observed in the biotransformations.
Reaction SMILES: [CH2:1]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:21]1([CH2:25][N:26]2[CH2:44][CH2:43][C@@:33]34[C:34]5[CH:35]=[C:36]([O:41][CH3:42])[CH:37]=[CH:38][C:39]=5[CH2:40][C@@H:27]2[C@@H:28]3[C@@H:29]([CH3:46])[CH2:30][C:31](=O)[CH2:32]4)[CH2:24][CH2:23][CH2:22]1.[ClH:47]>CS(C)=O>[ClH:47].[CH:21]1([CH2:25][N:26]2[CH2:44][CH2:43][C@@:33]34[C:34]5[CH:35]=[C:36]([O:41][CH3:42])[CH:37]=[CH:38][C:39]=5[CH2:40][C@@H:27]2[C@@H:28]3[C@@H:29]([CH3:46])[CH2:30][C:31](=[CH2:1])[CH2:32]4)[CH2:22][CH2:23][CH2:24]1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)[C@]13CCN(CC4CCC4)[C@H](C2)[C@@H]1[C@@H](C)CC(=O)C3
Agent: Cl
Solvent: CS(C)=O
Product: C=C1C[C@H](C)[C@H]2[C@H]3Cc4ccc(OC)cc4[C@@]2(CCN3CC2CCC2)C1
Yield: 37 %

Procedure:
To a solution of methylenetriphenylphosphorane (14.4 mmole) in dimethyl sulfoxide (30 ml) prepared in the usual fashion was added a solution of 17-cyclobutylmethyl-3-methoxy-8β-methyl-morphinan-6-one. The reaction was heated at 75° for 2 hours under an atmosphere of nitrogen. Workup followed by chromatography gave the free base of TR-5377 as a foam. This was converted to the HCl salt which was crystallized from toluene to give 860 mg (37%) of TR-5377, mp. 221°-224°.
Reaction SMILES: OS(O)(=O)=O.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][N:7]=1.C1C(=O)N([Cl:27])C(=O)C1>>[Cl:27][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[C:9]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][N:7]=[CH:6]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cncc2ccccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1cncc2cccc(Cl)c12
Temperature: 60 °C
Yield: 77.7 %

Procedure:
To a well stirred solution of conc. H2SO4 (28.5 mL) and methyl isoquinoline-4-carboxylate (5.0 g, 26.7 mmol) at 0° C. was added, NCS (35.7 g, 267 mmol) slowly and the reaction mixture was allowed to come to RT and then heated to 60° C. overnight. After completion (TLC), it was quenched with ice, neutralized (NaHCO3) and extracted with EtOAc (100 mL×3). The organic phase was separated, dried (Na2SO4) and concentrated to give dark brown oil (4.6 g) as crude product that was purified by flash column chromatography (15% EtOAc in Hexanes) to furnish the desired compound (3.8 g, 64%) as pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12]>C1(C)C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:1][C:2]2[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=2)=[O:19])=[CH:21][CH:22]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A solution of 10.9 g (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 10.2 g (0.055 mole) 4-nitrobenzoyl chloride in 200 ml toluene was heated at reflux for 20 hours. Upon cooling to room temperature, the crude product precipitated from the reaction mixture and was isolated by filtration. After washing with hexane, 13.5 g (73% yield) of pure product was obtained; m.p. 214° C.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](Cl)=[O:8])(=[O:3])[CH3:2].Cl.[NH2:18][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20]>C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:18][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
3-Acetylthio-2-benzylpropanoyl chloride and (L)-alanine, methyl ester, hydrochloride are reacted in the presence of triethylamine according to the procedure of Example 25 to give (±)-N-[2-(acetyl-thiomethyl) -1-oxo-3-phenylpropyl]-L-alanine, methyl ester.
Reaction SMILES: [F:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5]([CH:7]=O)[N:6]=1.[Br-].[CH2:29]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:30]=[CH2:31].[OH-].[Na+]>C(Cl)Cl>[CH:7]([C:5]1[N:6]=[C:2]([F:1])[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1)=[CH:31][CH:30]=[CH2:29]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: C=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
2-Fluoro-4-formyl-1-triphenylmethylimidazole was reacted with allyl triphenyl phosphonium bromide in CH2Cl2 in the presence of aqueous NaOH to give 4-(buta-1,3-dienyl)-2-fluoro-1-triphenylmethylimidazole having the following n.m.r. spectrum in CDCl3 : 5.06-5.39 (m, 2H); 5.87 (d, 1H); 6.06 (dd, 1H); 6.49 (s, 1H); 7.51 and 7.7 (d of t, 3H); 7.08-7.44 (br, 15H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH2:20]O)=[CH:4][C:3]=1[F:22].S(Cl)([Cl:25])=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH2:20][Cl:25])=[CH:4][C:3]=1[F:22]
Reactant: OCc1nc(-c2ccc(F)cc2)oc1-c1ccc(Cl)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Fc1ccc(-c2nc(CCl)c(-c3ccc(Cl)c(F)c3)o2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(4-chloro-3-fluorophenyl)-2-(4-fluoro-phenyl)-4-hydroxymethyloxazole (965 mg) and thionyl chloride (1.1 ml) in tetrahydrofuran (30 ml) was stirred at 0° C. for 30 minutes, followed by stirring at room temperature for 2 hours. Additional thionyl chloride (1.1 ml) was added to the mixture and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure. The remaining volatiles were removed by evaporation with toluene, and further dried under reduced pressure to obtain a crude product of 5-(4-chloro-3-fluorophenyl)-4-chloromethyl-2-(4-fluoro-phenyl)oxazole (925 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[NH4+].[H][H]>CO.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][NH2:15])=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1cncnc1-c1ccc(F)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCc1cncnc1-c1ccc(F)cc1
Yield: 32 %

Procedure:
A mixture of 4-(4-fluorophenyl)pyrimidine-5-carbonitrile (1.0 equiv.) and Raney-nickel (20 mol %) in MeOH (0.1 M) was degassed under vacuum and followed by the addition of 30% ammonium hydroxide (10 equiv.). The resulting mixture was hydrogenated with hydrogen gas at room temperature overnight. The mixture was filtered through a pad of celite and the cake was rinsed with MeOH. The filtrate was concentrated and further dried to give a brown oil, which was purified by silica gel column chromatography (0-10% MeOH in DCM, 25 g column) to give the title compound (32% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ (ppm) 9.19 (s, 1H), 8.88 (s, 1H), 7.71-7.78 (m, 2H), 7.17-7.24 (m, 2H), 3.99 (s, 2H), 1.41 (br. s., 2H). MS (ESI) m/z 204.1 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][C:16]([F:19])([F:18])[CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:19][C:16]1([F:18])[CH2:17][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(F)(F)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(F)CN(C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 4-(3,3-difluoroazetidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (0.265 g, 0.96 mmol) in DCM/TFA (3 mL/3 mL). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 4-(3,3-Difluoroazetidin-1-yl)piperidine as a white solid (0.154 g, 91%). 1H NMR (300 MHz, CDCl3): δ 3.54 (t, J=11.9 Hz, 4 H), 3.10 (dt, J=12.7, 3.9 Hz, 2 H), 2.59 (td, J=11.9, 2.6 Hz, 2 H), 2.24-2.13 (m, 1 H), 1.76-1.65 (m, 2 H), 1.30-1.15 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[F:15][C:16]([F:32])([F:31])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][C:2]([N:8]1[CH2:13][CH2:12][CH:11]([NH:30][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:31])[F:32])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)N1CCC(=O)CC1
Reactant: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 67.1 %

Procedure:
A mixture of methyl 2-methyl-2-(4-oxo-1-piperidinyl)propanoate (Int. A3) (14.28 g, 1 equiv), {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amine (Int. A1) (19.6 g, 0.85 equiv), DCE (300 ml), acetic acid (3.8 ml, 0.90 equiv) and sodium triacetoxyborohydride (20.7 g, 1.25 equiv) was stirred at room temperature under nitrogen for 17.5 h. Aqueous sodium carbonate (2M solution, excess) was added and stirred for 4 h, then the mixture was extracted with a mixture of diethyl ether and THF. The organic extracts were backwashed with water and brine, dried over sodium sulfate and filterered through a pad of silica gel which was rinsed with 2.5% methanol in DCM. After evaporation in vacuo, the crude product was crystallised from ether/hexane, finally at ice bath temperature, which after drying yielded a white solid (20.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH:10]=[C:11]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18][CH2:17]2)=[O:14])[N:12]=1.[Si](I)(C)(C)C.CO.C[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[CH:10]=[C:11]([C:13]([NH:15][CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)=[O:14])[N:12]=1
Reactant: CCOC(=O)N1CCC(NC(=O)c2cn(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)n2)CC1
Agent: C[O-]
Agent: C[Si](C)(C)I
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1CCNCC1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Yield: 35.5 %

Procedure:
To a solution of ethyl 4-({[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}amino)-1-piperidinecarboxylate (Table entry 221) (0.595 g, 1.221 mmol) in CH2Cl2 (10 mL) was added TMSI (0.176 mL, 2.7 mmol). The mixture was heated at reflux for 3 h, diluted by methanol, and concentrated. The residue was dissolved in methanol and NaOMe (0.62 mmol) was added. The mixture was concentrated and purified by flash chromatography (2M NH3 in methanol:EtOAc=15:85) to afford the product 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(4-piperidinyl)-1H-imidazole-4-carboxamide (180 mg, 36% yield): LC-MS m/z 415.3 (MH+), retention time 2.22 min (method 1); Rf=0.25 (1:1 EtOAc/2M NH3 in MeOH). 1H NMR (300 MHz, CDCl3) δ 1.35-1.51 (2H, m), 1.91-2.15 (3H, br), 2.63-2.78 (2H, m), 3.03-3.09 (2H, m), 3.97-4.15 (1H, m), 6.96-7.52 (8H, m), 7.81 (1H, s).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([O:17][C:18]([C:20]1([NH:25][C:26]([CH:28]2[CH2:32][CH:31]([OH:33])[CH2:30][CH:29]2[C:34](=[O:43])[N:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[CH3:36])=[O:27])[CH2:22][CH:21]1[CH:23]=[CH2:24])=[O:19])[CH3:16].O[C:45]1[C:54]2[C:49](=[C:50]([CH3:57])[C:51]([O:55][CH3:56])=[CH:52][CH:53]=2)[N:48]=[C:47]([N:58]2[CH:62]=[CH:61][C:60]([CH:63]([CH3:65])[CH3:64])=[N:59]2)[N:46]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:25][C:26]([CH:28]2[CH2:32][CH:31]([O:33][C:45]3[C:54]4[C:49](=[C:50]([CH3:57])[C:51]([O:55][CH3:56])=[CH:52][CH:53]=4)[N:48]=[C:47]([N:58]4[CH:62]=[CH:61][C:60]([CH:63]([CH3:65])[CH3:64])=[N:59]4)[N:46]=3)[CH2:30][CH:29]2[C:34](=[O:43])[N:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[CH3:36])=[O:27])[CH2:22][CH:21]1[CH:23]=[CH2:24])=[O:19])[CH3:16]
Reactant: COc1ccc2c(O)nc(-n3ccc(C(C)C)n3)nc2c1C
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-n3ccc(C(C)C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
DIAD (280 μL, 1.42 mmol) was added at −20° C. under nitrogen atmosphere to a solution of the alcohol (143) (367 mg, 0.90 mmol), 4-hydroxy-2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinazoline (141) (270 mg, 0.90 mmol) and triphenyl-phosphine (288 mg, 1.42 mmol) in dry DMF (35 mL). After 2 h, the solution was warmed up to room temperature. After 12 h, the reaction mixture was partitioned between ice-cold water and ether, organic layer was dried (Na2SO4) and evaporated. The residue was purified by column chromatography (gradient AcOEt/CH2Cl2, 1:9 to 10:0) to give the title compound (230 mg, 34%), m/z=687 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])=O>C(C(C)=O)C>[CH2:10]([O:9][C:7]([C:5]1[N:6]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])[N:1]=[C:2]2[S:3][CH:4]=1)=[O:8])[CH3:11]
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)c1csc(N)n1
Solvent: CCC(C)=O
Product: CCOC(=O)c1csc2nc(-c3ccccc3[N+](=O)[O-])cn12
Temperature: 25 °C
Yield: 79.4 %

Procedure:
In a typical run, 2.1 g of ethyl 2-aminothiazole-4-carboxylate (Combi-Blocks, 0.0123 mol) was mixed with 25 mL of methyl ethyl ketone along with 2-bromo-2′-nitroacetophenone (3.0 g, 0.0123 mol). The reaction mixture was stirred under reflux for 18 hours. It was then cooled to room temperature and filtered to remove some of the solids. The filtrate was concentrated to afford 3.10 g of 6-(2-nitro-phenyl)-imidazo[2,1-b]thiazole-3-carboxylic acid ethyl ester (MS, M++H=318).
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:29][C:30]([Cl:37])([Cl:36])[CH2:31][O:32][C:33](Cl)=[O:34].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:29][C:30]([Cl:37])([Cl:36])[CH2:31][O:32][C:33]([N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:4][CH2:3]1)=[O:34]
Reactant: CN1CCC(=C2c3ccccc3Oc3ccccc32)CC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC(=C2c3ccccc3Oc3ccccc32)CC1
Temperature: 25 °C

Procedure:
To a mixture of 430 mg (1.55 mmol) of 1-methyl-4-(9H-xanthene-9-ylidene)piperidine [Tetrahedron Letters, 29, 5701 (1988)] and 649 μL (4.65 mmol) of triethylamine in 20 mL of dry toluene at 85° C. under an atmosphere of argon was added over 10 min 1.06 mL (7.7 mmol) of 2,2,2-trichloroethyloxycarbonyl chloride. After 30 min the mixture was cooled to room temperature, poured into a solution of 25% aqueous sodium hydroxide, and was extracted with ethyl acetate (3×). The combined organic portions were dried over sodium sulfate, filtered, and concentrated with vacuo to afford the title compound as a crude oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].[Cl:17][C:18]1[CH:19]=[C:20]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:21][N:22]1[CH2:27][CH2:26][O:25][C@@H:24]([CH2:28][NH2:29])[CH2:23]1>>[CH:14]([OH:16])=[O:15].[Cl:17][C:18]1[CH:19]=[C:20]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:21][N:22]1[CH2:27][CH2:26][O:25][C@@H:24]([CH2:28][NH:29][C:14](=[O:16])[CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])[CH2:23]1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: Cc1oc(-c2cccnc2)nc1CC(=O)O
Product: Cc1oc(-c2cccnc2)nc1CC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=CO
Temperature: 22 °C
Reaction time: 1 h
Yield: 209.3 %

Procedure:
N,N′-carbonyldiimidazole (15 mg) was added to a stirred solution of Intermediate 34 (20 mg) at 22° C. under nitrogen, and the mixture was stirred at 22° C. for 1 h. Intermediate 9 (26 mg) was added and the mixture stirred at 22° C. for 24 h. The mixture was applied directly to a sulphonic acid ion exchange cartridge (Isolute SCX, 2 g) and eluted with methanol followed by 10% 0.880 ammonia in methanol. Evaporation of the methanolic ammonia fraction gave a gum (50 mg) which was further purified by solid phase extraction on silica gel (1 g Varian Bondelut cartridge), eluting with chloroform, ether, ethyl acetate, acetone and methanol to give a gum (38 mg). The gum was partitioned between dichloromethane and water, and the organic layer treated with polystyrene methylisocyanate resin (Argonaut, 95 mg, 1.6 mmol/g). After shaking for 4 h the resin was filtered off and the filtrate evaporated to give a gum (29 mg), which was further purified by chromatography on silica gel, eluting with dichloromethane:ethanol:0.880 ammonia 100:0:0-95:5:0.5, followed by mass directed preparative HPLC to give the title compound (7.6 mg).