Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([N:23]([CH3:37])[C@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1)[C:25]([OH:27])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:38][C:39]1(C)[O:44]C(=O)C[C:41](=O)[O:40]1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.COC(C)(C)C>[CH3:41][O:40][C:39](=[O:44])[CH2:38][C:25](=[O:27])[C@H:24]([N:23]([C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])[CH3:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: COC(=O)CC(=O)[C@@H](Cc1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (2.9011 g, 13.9 mmol) in toluene (3 ml) is added to a stirred mixture of (R)-2-(tert-butoxycarbonyl-methyl-amino)-3-(3,4-dichloro-phenyl)-propionic acid (1, 4.179 g, 12 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (2, 1.7815 g, 12.36 mmol) and dimethyl-pyridin-4-yl-amine (2.0943 g, 16.8 mmol) in toluene (32 ml) at 29-31° C. over a period of approx. 1 hour. Toluene (1 ml) is used for rinsing. Stirring at 29-31° C. is continued for approx. 3 hours. After cooling to ca. 0° C., a 25% w/w solution of potassium hydrogen sulfate (approx. 9 ml) is added to the suspension at −2° C./2° C., until pH 2-3 is reached. Stirring is stopped and the layers are allowed to separate. The mixture is slowly stirred and filtrated cold (0-5° C.) and the filter cake is rinsed with toluene (12 ml, 0-5° C.). The layers of the filtrate are allowed to separate at approx. 0-5° C. The lower, aqueous layer is separated. The upper, organic layer, containing the intermediate [(R)-1-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-yl)-2-oxo-ethyl]-methyl-carbamic acid tert-butyl ester (3) is passed through a filter charged with anhydrous sodium sulfate (5 g) at 0-5° C. and the filtrate is added to a reactor, containing methanol (18 ml, 20-25° C.). The filter cake is rinsed with toluene (5 ml) and the filtrate is also added to the reactor. The resulting solution is heated (mantle temperature ca. 68° C.) and stirred at approx. 63° C. for approx. 4 hours, then concentrated at a mantle temperature of approx. 50° C. under reduced pressure to obtain an oily residue, which is dissolved in tert-butyl methyl ether (24 ml) at normal pressure and a mantle temperature of ca. 50° C., then concentrated again under reduced pressure to obtain (R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-dichloro-phenyl)-1-oxo-pentanoic acid methyl ester (4) as an oily residue. The residue is dissolved again in tert butyl methyl ether (24 ml) at normal pressure and a mantle temperature of 50° C., then cooled to 18-22° C. and used as such in the next step.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N:22]([C:24](=[O:34])[CH2:25][NH:26][C:27](=[O:33])[C@@H:28]4[CH2:32][CH2:31][CH2:30][NH:29]4)[CH3:23])[C:16]=3[Cl:35])[C:7]2=[N:6][C:5]=1[CH3:36].[C:37](OC(=O)C)(=[O:39])[CH3:38].N1C=CC=CC=1>C(Cl)Cl>[C:37]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:27]([NH:26][CH2:25][C:24]([N:22]([C:17]1[C:16]([Cl:35])=[C:15]([C:20]([Cl:21])=[CH:19][CH:18]=1)[CH2:14][O:13][C:12]1[C:7]2[N:8]([C:4]([Br:3])=[C:5]([CH3:36])[N:6]=2)[CH:9]=[CH:10][CH:11]=1)[CH3:23])=[O:34])=[O:33])(=[O:39])[CH3:38]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)[C@@H]4CCCN4)c3Cl)cccn2c1Br
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC[C@H]1C(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-[N-(L-prolylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine dihydrochloride (40 mg), acetic anhydride (0.01 ml), pyridine (0.03 ml) and methylene chloride (2 ml) was stirred for 2 hours at ambient temperature. The mixture was washed with water twice, dried over magnesium sulfate, and concentrated in vacuo to give 8-[3-[N-(acetyl-L-prolylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (31 mg).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH2:21][NH2:22])[CH2:13][CH2:12]1)[CH3:3].[CH2:26]1[CH2:30][C:29]2([CH2:37][C:35](=O)[O:34][C:32](=[O:33])[CH2:31]2)[CH2:28][CH2:27]1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:3][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:21][N:22]3[C:35](=[O:34])[CH2:37][C:29]4([CH2:30][CH2:26][CH2:27][CH2:28]4)[CH2:31][C:32]3=[O:33])[CH:23]=[CH:24][CH:25]=2)[CH2:13][CH2:12]1)[CH3:1]
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Reactant: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CN)c2)CC1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CN3C(=O)CC4(CCCC4)CC3=O)c2)CC1

Procedure:
A solution of 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]-benzyl amine (2.50 g, 7.37 mmol), prepared as described above, 3,3-tetramethyleneglutaric anhydride (1.12 g, 6.66 mmol), and toluene (30 mL) was heated to reflux, cooled slightly, and treated with thionyl chloride (9.72 mL, 13.32 mmol). The resulting slurry was refluxed for 30 min, cooled and the solid collected by filtration. This material was partitioned between CH2Cl2 /3N NAOH and the organic layer was separated, dried, filtered and evaporated giving 8-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-8-azaspiro[4.5]decane-7,9-dione as a crude oil. The oil was converted to the maleate salt in i-PrOH. The isolated residue was converted back to the free base which was obtained as an oil (2.10 g). Chromatography of this material on flash silica using EtOAc/hexane of varying proportions gave an oil which was dissolved in ether and added to ethereal HCl causing formation of a solid. Filtration afforded 8-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride (0.94 g, 25%), m.p. 212°-216° C. (dec). 1H NMR and mass spectral analysis supported the assigned structure.
Reaction SMILES: C([O:4][CH2:5][C:6]1[S:7][CH2:8][C:9]([CH2:12][Cl:13])(O)[N:10]=1)(=O)C.C(OCC)C>Cl.C(O)(C)C>[ClH:13].[Cl:13][CH2:12][C:9]1[N:10]=[C:6]([CH2:5][OH:4])[S:7][CH:8]=1
Reactant: CC(=O)OCC1=NC(O)(CCl)CS1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: OCc1nc(CCl)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
7.48 g of 2-acetoxymethyl-4-chloromethyl-4-hydroxy-thiazoline, prepared according to either Example 3 or 4, was suspended in 20 ml of 5N hydrogen chloride in isopropanol and heated to reflux for 45 minutes. The suspension was cooled in an ice bath and 30 ml of diethyl ether added dropwise over 30 minutes. The slurry was stirred a further 30 minutes at 0° C. and the precipitate filtered, washed with ether and dried under vacuum. 4-chloromethyl-2-hydroxymethylthiazole hydrochloride, 6.22 g (93% yield) was obtained.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH:21]([CH2:23][CH2:24][CH2:25][CH3:26])[OH:22])[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.[CH3:27]I>>[CH3:27][O:22][CH:21]([C:15]1[N:16]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[C:4]([NH2:3])[C:13]=2[N:14]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(O)c1nc2c(N)nc3ccccc3c2n1CC(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCCCC(OC)c1nc2c(N)nc3ccccc3c2n1CC(C)C
Reaction time: 2 h
Yield: 16 %

Procedure:
Sodium hydride (0.32 g; 10.1 mmol) was added to a suspension of 4-amino-α-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol (3 g; 9.2 mmol, Example 60) and the resulting mixture was stirred for about 2 hours. Methyl iodide (0.82 mL; 13.8 mmol) was added to the mixture and stirring was continued overnight. Thin layer chromatography indicated that the reaction was incomplete so sodium hydride (0.25 g) was added followed two hours later by methyl iodide (1 mL). The reaction was stirred for several additional hours then quenched with water and diluted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated under vacuum to provide an oil. The oil was purified by silica gel chromatography (1-3% methanol in methylene chloride as eluent) to provide 0.5 g of a solid, m.p. 125-128° C. Analysis: Calculated: C, 70.55; H, 8.3; %N, 16.5; Found: C, 70.2; H, 8.3; N, 16.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:11]3([C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH3:19])[C:13](SCCC)=[N:12]3)[CH2:10][C@H:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:30].[I-]>N.CCO>[NH2:30][C:13]1[N:14]([CH2:17][CH2:18][CH3:19])[C:15](=[O:16])[C@:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C@@H:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10]2)[N:12]=1
Reactant: CCCSC1=N[C@]2(C[C@H](c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CCC
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: CCCN1C(=O)[C@@]2(C[C@H](c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Yield: 22.6 %

Procedure:
A solution of (2R,4S)-6-bromo-2-phenyl-1′-propyl-2′-(propylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (75 mg, 0.16 mmol), and NH4I (46 mg, 0.32 mmol) in NH3/EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford (2R,4S)-2′-amino-6-bromo-2-phenyl-1′-propylspiro-[chroman-4,4′-imidazol]-5′(1′H)-one (15 mg, 23%). 1H-NMR (MeOD): 1.00 (m, 3H), 1.45 (m, 2H), 2.23 (m, 1H), 2.48 (m, 1H), 3.75 (m, 2H), 5.85 (m, 1H), 6.90 (m, 1H), 7.14 (m, 1H), 7.40 (m, 6H).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[N:10]#[C:11]Cl.[OH-].[Na+]>>[CH3:4][CH2:3][CH2:2][CH2:1][N:5]([C:11]#[N:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCNCCCC
Reactant: N#CCl
Agent: [Na+]
Agent: [OH-]
Product: CCCCN(C#N)CCCC

Procedure:
In the manner given in Example 1, dibutylamine is treated with cyanogen chloride and aqueous sodium hydroxide to give dibutylamine-N-carbonitrile.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=O)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:57]=[N+:58]=[N-:59])(C)C>C1COCC1>[CH:1]1([N:4]2[C:5]([CH:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)=[N:59][N:58]=[N:57]2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NC2CC2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nnnn2C2CC2)CC1
Reaction time: 0.08 h
Yield: 24 %

Procedure:
The title compound from Step A above (200 mg, 0.745 mmol) and triphenylphosphine (391 mg, 1.49 mmol) were placed in a 50 ml round bottom flask and then THF (20 ml) was added followed by DIAD (0.29 mL, 1.49 mol) at RT. After 5 min of stirring, trimethylsilylazide (0.2 mL, 1.50 mmol) was added and the resulting mixture was stirred overnight at RT. The volatiles were removed under reduced pressure and the resulting residue was partitioned between ethyl acetate and brine, combined, dried over sodium sulfate, filtered and concentrated. The material was purified by Mass Directed HPLC to give the title compound (52 mg, 24%) as a clear oil/film. ESI-MS calculated for C14H23N5O2: Exact Mass: 293.38. Found 194.35 (M-Boc)+ and 316.36 (MNa)+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1([CH3:12])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13](Br)[CH:14]=C>>[C:1]([NH:5][S:6]([C:9]1([CH2:12][CH:13]=[CH2:14])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)NS(=O)(=O)C1(C)CC1
Product: C=CCC1(S(=O)(=O)NC(C)(C)C)CC1
Yield: 97 %

Procedure:
This compound was obtained in 97% yield according to the procedure described in the synthesis of N-tert-butyl-(1-methyl)cyclopropylsulfonamide using 1.25 equivalents of allyl bromide as the electrophile. The compound was used in the next reaction without further purification: 1H NMR (CDCl3) δ 0.83 (m, 2H), 1.34 (s, 9H), 1.37 (m, 2H), 2.64 (d, J=7.3 Hz, 2H), 4.25 (br s, 1H), 5.07-5.10 (m, 2H), 6.70-6.85 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=O)[N:4]([CH3:6])[CH3:5].C(Cl)(=O)C(Cl)=O.[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>ClC(Cl)C>[CH3:1][N:2]([CH3:8])[C:3]([N:4]([CH3:6])[CH3:5])=[N:19][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCN
Reactant: CN(C)C(=O)N(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Product: CCCCN=C(N(C)C)N(C)C
Temperature: 70 °C

Procedure:
N,N,N′,N′-tetramethyl-N″-butylguanidine was prepared as follows: 9.3 g tetramethyl urea was added to 80 mL dry dichloroethane in a two-neck 250 mL round-bottom-flask. 11.3 mL oxalyl chloride was added and the solution was heated at 70° C. for two hours. The solvent was evaporated in vacuo after the solution cooled to room temperature. Residual solid was then dissolved in dry acetonitrile and cooled to 0° C. 15 mL butyl amine (1.02 eq) was slowly added. The solution was slowly warmed and allowed to reflux for one hour. Finally, the mixture was cooled to room temperature and the solvent was removed in vacuo to yield 9 g of a clear oil. 1H (CDCl3): δ (ppm): 2.99 (t, 2H); 2.62 (s, 3H); 2.53 (s, 3H); 1.39 (quintet, 2H); 1.24 (quintet, 2H); 0.78 (t, 3H). The synthesis was performed several times and the yield ranged from 37%-70%.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3](=[O:27])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7]Br.[CH3:29][C:30]1([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CC#N.CCOC(C)=O>[CH3:1][N:2]([CH3:28])[C:3](=[O:27])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][N:33]1[CH2:34][CH2:35][C:30]([OH:36])([CH3:29])[CH2:31][CH2:32]1
Reactant: CC1(O)CCNCC1
Reactant: CN(C)C(=O)C(CCCBr)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(C)C(=O)C(CCCN1CCC(C)(O)CC1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reaction time: 16 h
Yield: 34.9 %

Procedure:
A solution of 107 mg (0.23 mmol) of (rac)-5-bromo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-pentanoic acid dimethylamide in 4 ml of CH3CN was treated with 115 mg (0.28 mmol) of 4-methyl-piperidin-4-ol (intermediate 8) and 63 mg (0.46 mmol) of potassium carbonate. After 16 h at RT, the reaction mixture was diluted with AcOEt and a white solid was filtered off. The filtrate was evaporated and chromatographed by amine-silica gel column (AcOEt:MeOH 19:1) to yield 40 mg (35%) of the title compound as yellow oil. MS: 499.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.[SH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>O1CCOCC1.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].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>[CH:15]1([CH2:14][N:6]2[C:5]3[CH:18]=[CH:19][C:2]([S:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:3][C:4]=3[N:8]=[C:7]2[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:17][CH2:16]1
Reactant: COC(=O)CS
Reactant: CC(C)(C)Cc1nc2cc(Br)ccc2n1CC1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CSc1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Yield: 129.1 %

Procedure:
To a solution of 5-bromo-1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazole (Step D, 1.40 g, 4.36 mmol) in 1,4-dioxane (9 mL) were added N,N-diisopropylethylamine (1.52 mL, 8.72 mmol), methyl mercaptoacetate (0.39 ml, 4.36 mmol), tris(dibenzylideneacetone)dipalladium(0) (200 mg, 0.218 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (252 mg, 0.436 mmol). The mixture was heated to reflux for 21 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a dark brown syrup. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1 as eluent) to afford the title compound (1.95 g, quant.) as an orange syrup.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH2:19][C:20]1[N:25]=[CH:24][C:23]([O:26][C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:18][CH2:19][C:20]2[N:25]=[CH:24][C:23]([O:26][C:27](=[O:31])[N:28]([CH3:29])[CH3:30])=[CH:22][CH:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CN(C)C(=O)Oc1ccc(CO)nc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CN(C)C(=O)Oc1ccc(COc2nc(N)nc(-c3ccco3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, dimethyl-carbamic acid 6-hydroxymethyl-pyridin-3-yl ester and DBU in DME. ES-MS m/e (%): 403 (M+Na+, 45), 381 (M+H+, 100).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[N:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][N:25]=2)=[O:34])=[O:10])[N:12]=1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2n[nH]c3ccccc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 1H-Indazole-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([N:18]2[C:22]([CH2:23]O)=[N:21][N:20]=[C:19]2[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[C:7]([CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])=[O:9].[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>COCCOC>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([N:18]2[C:22]([CH2:23][N:36]3[C:32](=[O:42])[C:33]4=[CH:41][CH:40]=[CH:39][CH:38]=[C:34]4[C:35]3=[O:37])=[N:21][N:20]=[C:19]2[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[C:7]([CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])=[O:9]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)CCc1nnc(CO)n1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1B, 5-(trifluoromethyl)-2'-chloro-2-[3-[2-(dimethylamino)ethyl]-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone in 1,2-dimethoxyethane is treated with phthalimide, triphenylphosphine and diethyl azodicarboxylate to give 5-(trifluoromethyl)-2'-chloro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH3:10])[CH:8]=1)([O-])=O.[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:32][CH:33]([CH2:37][CH2:38][CH3:39])[C:34](O)=[O:35])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([CH:9]([N:7]2[CH:8]=[C:4]([NH:1][C:34](=[O:35])[C@@H:33]([NH:32][C:30](=[O:31])[CH2:29][C:24]3[CH:25]=[C:26]([F:28])[CH:27]=[C:22]([F:21])[CH:23]=3)[CH2:37][CH2:38][CH3:39])[N:5]=[CH:6]2)[CH3:10])=[CH:12][CH:13]=1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC(c1ccc(C(F)(F)F)cc1)n1cnc([N+](=O)[O-])c1
Product: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)c2ccc(C(F)(F)F)cc2)cn1

Procedure:
4-Nitro-1-[1-(4-trifluoromethyl-phenyl)-ethyl]-1H-imidazole was reduced and then coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 509.5 m/z (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:11]1[C:16]([Br:17])=[N:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[Br:17][C:16]1[CH:11]=[N:12][C:13]([N:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]2)=[CH:14][N:15]=1
Reactant: Brc1nccnc1Br
Reactant: CN1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2cnc(Br)cn2)CC1

Procedure:
To sodium hydride (0.20 g) taken in dry THF (15 ml), N-methyl piperazine (0.93 ml) was added under nitrogen at 0° C. 2,3-Dibromopyrazine (2 g) taken in 15 ml dry THF was added to the above mixture at 0° C. The reaction mixture was allowed to reflux for overnight and quenched with water (5 ml). The organic layer was removed under vacuum. The resulting crude mass was purified by column chromatography to afford 2-bromo-5-(4-methylpiperazin-1-yl)pyrazine as pure product.
Reaction SMILES: [Na].[SH:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[CH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO>[C:5]([CH2:4][CH2:3][S:2][CH:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([OH:7])=[O:6]
Reactant: CCCCCCCCCCCCc1ccccc1C=CC(=O)OC(C)(C)C
Reactant: O=C(O)CCS
Agent: [Na]
Solvent: CO
Product: CCCCCCCCCCCCc1ccccc1C(CC(=O)OC(C)(C)C)SCCC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium (155.5 mmoles) was added slowly to methanol (200 ml ) under an atmosphere of argon. The mixture was cooled to 0° C. in an ice bath and 3-mercaptopropionic acid (78 mmoles) was added dropwise. This mixture was stirred for 30 minutes and the compound of Example 9 (a) (7.8 mmoles) was added dropwise. The reaction mixture was stirred for 24 hours. The solvent was evaporated. The residue was taken up in ice water and acidifed with 10% phosphoric acid to a pH of 6.5. The product was extracted into ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The resulting residue was flash chromatographed with 1.0% methanol and 1.0% formic acid in methylene chloride. This provided the product as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1.[Li+].[OH-].Cl>C1COCC1.O>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1csc(-c2ccccc2CO)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1csc(-c2ccccc2CO)n1
Yield: 79.7 %

Procedure:
To a solution of 2-(2-hydroxymethyl-phenyl)-thiazole-4-carboxylic acid, ethyl ester (1.3 g) in THF (5 mL) was added an aqueous solution of LiOH:H2O (472 mg in 5 mL water) and the resulting biphasic mixture was stirred vigorously at room temperature for 3 h. The reaction mixture was then acidified with 1N HCl, diluted with water and extracted three times with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated. The crude product was dissolved in a small amount of ethyl acetate and precipitated by addition of hexanes to give 2-(2-hydroxymethyl-phenyl)-thiazole-4-carboxylic acid (926 mg) as a light yellow solid. HRMS calcd for Cl1H9NO3S (M+) 235.0303, observed 235.0302.