Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([N:14]([CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)C(=O)CC(C)(C)C)[C:11](=[O:29])[N:10]2[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([NH:14][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[C:11](=[O:29])[N:10]2[CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1ccc(CCN2C(=O)N(N(Cc3ccncc3)C(=O)CC(C)(C)C)CC2c2ccc(C)c(C)c2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCN2C(=O)N(NCc3ccncc3)CC2c2ccc(C)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 104.7 %

Procedure:
A solution of N-{4-(3,4-dimethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-2-oxo-imidazolidin-1-yl}-3,3-dimethyl-N-pyridin-4-ylmethyl-butyramide (205 mg, 0.386 mmol) in CH2Cl2 (1.5 mL) is cooled in an ice bath and triethylsilane (0.129 mL, 0.81 mmol) is added, followed by trifluoroacetic acid (1.5 mL). The ice bath is removed and the reaction is stirred at ambient temperature for 2.5 hours. The reaction is concentrated to an oil, dissolved in ethyl acetate, and washed with 10% aqueous NaHCO3, and brine. The organic phase is dried (Na2SO4), treated with 2N HCl/ether (0.7 mL), and concentrated under reduced pressure. The solid which results is re-crystallized from dichloromethane/ether to afford 174 mg (76% yield) of the desired compound. 1H NMR (DMSO-d6) δ 8.92 (d, J=6.0 Hz, 2H), 8.21 (d, J=6.0 Hz, 2H), 7.14 (d, J=7.5 Hz, 1H), 7.00 (m, 4H), 6.82 (d, J=8.1 Hz, 2H), 4.38 (m, 3H), 3.74 (s, 3H), 3.72 (m, 1H), 3.44 (m, 1H), 3.14 (t, J=7.8 Hz, 1H), 2.68 (m, 1H), 2.52 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H). MS 431 (MH+). Anal. calcd. for C26H30N4O2 2HCl: C, 62.03; H, 6.41; N, 11.13. Found: C, 61.99; H, 6.41; N, 11.13.
Reaction SMILES: COC(=O)[C@H:4]([NH:16][CH2:17][CH2:18][NH:19][C:20]([O:22]C(C)(C)C)=O)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[CH2:5][C@H:4]1[NH:16][CH2:17][CH2:18][NH:19][C:20]1=[O:22]
Reactant: COC(=O)[C@@H](Cc1ccc2ccccc2c1)NCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCN[C@@H]1Cc1ccc2ccccc2c1
Reaction time: 8 h
Yield: 89.6 %

Procedure:
##STR197## (2R)-2-((2-(tert-butoxycarbonylamino)ethyl)amino)-3-(2-naphthyl)propionic acid methylester (3.4 g, 9.1 mmol) was stirred for 1 h in a mixture of TFA (5 ml) and methylene chloride(5 ml). The volatiles were removed in vacuo and the residue was dissolved in a mixture of water (40 ml) and methanol (100 ml). Sodium hydrogencarbonate (2.3 g) was added and the mixture was stirred overnight. The solvent was removed in vacuo and the residue was dissolved in water (40 ml) and extracted with ethyl acetate (10×50 ml). The combined organic phases were dried (magnesium sulphate) and the solvent was removed in vacuo to afford 1.96 g of (3R)-3-((2-naphthyl)methyl)piperazin-2-one.
Reaction SMILES: C[Si](C)(C)[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[NH2:10][C:11](N)=[O:12].[Cl-].[NH4+].N>C1(C)C=CC=CC=1>[CH3:5][Si:4]([NH:10][C:11](=[O:12])[NH:3][Si:4]([CH3:5])([CH3:6])[CH3:7])([CH3:7])[CH3:6]
Reactant: NC(N)=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Temperature: 110 °C
Yield: 98.4 %

Procedure:
A mixture containing 750 parts by volume of hexamethyldisilazane, 750 parts by volume of toluene, 180 parts urea and 0.5 part of ammonium chloride is heated to reflux temperature (approx. 110° C.). After refluxing for 1.25 hours the evolution of ammonia has stopped and the reaction is considered to be complete. The product is cooled, filtered andthe filtered residue dried at 12 mm Hg (abs.). Approximately 603 parts (98.4 percent of theoretical) of bis-(trimethylsilyl-)urea having a purityin excess of 99 percent by weight are obtained.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][C:21](=[O:26])[C:22](Br)([CH3:24])[CH3:23])[CH3:19].O>CN(C=O)C>[CH2:18]([O:20][C:21](=[O:26])[C:22]([NH:11][CH:8]1[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]1)([CH3:24])[CH3:23])[CH3:19]
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)NC1CCN(S(C)(=O)=O)CC1
Reaction time: 16 h
Yield: 14.2 %

Procedure:
2.40 g (13.5 mmol) of 1-methanesulfonyl-piperidin-4-ylamine are dissolved in DMF (32.8 mL). 5.58 g (40.4 mmol) of K2CO3, 3.06 mL (20.2 mmol) ethyl-2-bromoisobutyrate and 1.12 g (6.73 mmol) of KI are added at RT. The reaction is stirred 16 h. Additional ethyl-2-bromoisobutyrate (3.06 mL) and KI (1.12 g) are added and the reaction mixture is stirred for further 16 h. Water and sat. aq. K2CO3 solution is added, the aqueous layer extracted with EE. The combined organic layers are dried over MgSO4 and filtered. The solvent is removed under reduced pressure to afford the crude product, which is purified by silica gel chromatography (eluent: EE/MeOH 95/5) to afford 0.56 g of 2-(1-methanesulfonyl-piperidin-4-ylamino)-2-methyl-propionic acid ethyl ester. Yield: 14%; ESI-MS: 293 [M+H]+; HPLC (Rt): 0.97 min (method E)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCOC.CC1OC(C=CC2C=C3CCCN4CCCC(=C34)C=2)=CC(=C(C#N)C#N)C=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:59])=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:59])[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: CC1=CC(=C(C#N)C#N)C=C(C=Cc2cc3c4c(c2)CCCN4CCC3)O1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 186.7 %

Procedure:
To a solution of tert-butyl-4-carbamoylpiperidine-1-carboxylate (2.65 g, 11.62 mmol) in a DME/DCM 2:1 mixture (78 mL), Lawesson reagent (2.35 g, 5.81 mmol, 0.5 eq) was added and the mixture was stirred at r.t. overnight. The solvent was removed and the residue was taken up with ethyl acetate and washed with saturated aqueous K2CO3. The organic layer was separated, dried over Na2SO4 and concentrated to dryness. The residue was triturated with diethyl ether and dried to give 2.65 g (92%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:38]([O:37][C:35](=[O:36])[CH2:34][N:13]1[C:14](=[O:16])[C:15]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][CH:31]=3)[C:8]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=3)=[N:9][C:10]=2[N:11]([CH3:18])[C:12]1=[O:17])([CH3:41])([CH3:40])[CH3:39]
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(CC(=O)OC(C)(C)C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 50 °C
Yield: 99.7 %

Procedure:
Step 1 7-(4-Chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (1.0 g, 2.14 mmol, intermediate 9), tert-butyl 2-bromoacetate (0.34 mL, 2.36 mmol), and potassium carbonate (0.45 g, 3.21 mmol) were combined in DMF (20 mL) and heated at 50° C. for 2 h. The reaction was cooled to room temperature diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with 1N lithium chloride (2×100 mL), dried with magnesium sulfate, filtered and evaporated under reduced pressure to give tert-butyl-2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate (1.24 g, 100% yield) as a clear oil. LCMS retention time=4.817 minutes and 97% purity, LCMS MH+ 581.
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH2:3][OH:4].[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11](Cl)[CH:12]=1.[OH-].[Na+]>CS(C)=O>[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:4][CH2:3][CH2:2][OH:5])[CH:12]=1
Reactant: OCCO
Reactant: Clc1cncc(Cl)c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CS(C)=O
Product: OCCOc1cncc(Cl)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium (2.0 g, 89.5 mmol) and ethylene glycol (50 ml) was stirred at 70° C. for 30 min. 3,5-Dichloropyridine (11.0 g, 74.5 mmol) and dimethyl sulfoxide (50 ml) were added to the crude mixture. The crude mixture was stirred for 10 h at 110° C. Aqueous sodium hydroxide (100 ml) was added and the crystals were filtered. Yield 8.0 g, 51%.
Reaction SMILES: [NH2:1][C:2]1[CH:49]=[C:48]([N:50]([CH2:52][CH2:53][N:54]([CH3:56])[CH3:55])[CH3:51])[CH:47]=[CH:46][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:16]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:8]=1)=[O:5].[O:57]1[CH2:62][CH2:61][C:60](=O)[CH2:59][CH2:58]1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCl>[F:25][C:23]1[CH:24]=[C:19]([S:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[NH:9][N:8]=[C:7]3[NH:6][C:4](=[O:5])[C:3]2[CH:46]=[CH:47][C:48]([N:50]([CH2:52][CH2:53][N:54]([CH3:55])[CH3:56])[CH3:51])=[CH:49][C:2]=2[NH:1][CH:60]2[CH2:61][CH2:62][O:57][CH2:58][CH2:59]2)(=[O:18])=[O:17])[CH:20]=[C:21]([F:26])[CH:22]=1
Reactant: O=C1CCOCC1
Reactant: CN(C)CCN(C)c1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCN(C)c1ccc(C(=O)Nc2n[nH]c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a solution of 2-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-benzamide (400 mg, 0.52 mmol) in dichloromethane (5 mL) were added tetrahydro-pyran-4-one (0.071 mL, 0.78 mmol), trifluoroacetic acid (0.108 mL, 1.4 mmol) and tetramethylammonium triacetoxyborohydride (205 mg, 0.78 mmol). The mixture was stirred at room temperature overnight, then additional trifluoroacetic acid (0.8 mL) and tetramethylammonium triacetoxyborohydride (410 mg) were added. After stirring for additional 3 hours at room temperature the mixture was diluted with dichloromethane, washed with saturated solution of sodium hydrogenocarbonate, brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol/NH4OH 96:4:0.5 as the eluant, affording 175 mg of the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([NH:8][CH3:9])[CH:7]=1.[Sn](Cl)Cl.[CH:16](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[CH:9][N:8]([CH3:16])[C:6]=2[CH:7]=1
Reactant: COC(OC)OC
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1cnc2ccc(Br)cc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
To a suspension of (5-bromo-2-nitro-phenyl)-methyl-amine (1.2 g, 5.19 mmol) in ethanol (25 mL) was added tin(II) chloride (1.97 g, 10.39 mmol). The reaction mixture was stirred at 80° C. for 4 h, then it was concentrated in vacuo. To the residue was added toluene (12 mL), trimethyl orthoformate (0.625 mL, 5.71 mmol), and para-toluenesulfonic acid (49 mg, 0.26 mmol). The reaction mixture was stirred at 110° C. for 15 h, then it was concentrated in vacuo and the residue was adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-8% methanol/dichloromethane afforded 482 mg of 6-bromo-1-methyl-1H-benzoimidazole as a dark orange solid (44% yield): 1H NMR (DMSO-d6) δ 3.83 (s, 3H), 7.33 (dd, 1H), 7.59 (d, 1H), 7.86 (d, 1H), 8.21 (s, 1H); MS (m/z) 211, 213 [M+H+]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[F:18])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[F:18])[CH2:9][O:10][S:27]([CH3:30])(=[O:29])=[O:28])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1cccc(Cl)c1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of [(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (550 mg, 1.9 mmol) and triethylamine (0.29 mL, 2.09 mmol) in CH2Cl2 (5.5 mL) cooled at −10° C. was added under nitrogen atmosphere mesylchloride (0.16 mL, 2.09 mmol) and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was quenched with ice and water then extracted twice with EtOAc. The combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated. The crude material was used without purification in the next step. MS (UPLC/MS): 412.3/414.3 [M+HCOO]−; tR (HPLC conditions a): 3.66 min.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([C:16]([OH:18])=O)[CH:2]=1.C[Li].[CH3:21]COCC.[Cl-].[NH4+]>C1COCC1>[C:16]([C:3]1[CH:2]=[CH:1][C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=1)(=[O:18])[CH3:21]
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1C=C2
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)Sc1ccccc1C=C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of dibenzo[b,f]thiepin-3-carboxylic acid (U.S. Pat. No. 4,536,507 (1985)) (415 mg, 1.63 mmole) in THF (20 mL) at 0° C. there was added methyl lithium in ether 1.4M (2.56 mL, 3.59 mmol); the mixture was stirred at 0° C. for 1 hour, then poured onto a well-stirred saturated aqueous ammonium chloride solution (100 mL). The organic phase was collected, washed twice with brine, dried and evaporated. Column chromatography on silica gel, eluting with a 1:2 mixture of ethyl acetate-hexane, afforded the title compound as a yellow solid (320 mg), m.p.: 82°-84° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(#N)C.CN(C)C=O.[I:20]N1C(=O)CCC1=O>>[OH:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][C:5]([I:20])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ncccc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: Oc1ncc(I)cc1C(F)(F)F
Temperature: 80 °C
Yield: 80 %

Procedure:
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80° C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80% yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130° C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55%). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II) acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40%). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1′-bis(diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92%). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95%). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25° C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74% to 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH2:14][CH2:13][N:12]=[C:11]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].[CH2:24]=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH2:14][CH2:13][N:12]=[C:11]1[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:24]
Reactant: Clc1ccc(CN2CCN=C2Cc2ccccc2)c(Cl)c1
Reactant: C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C1=NCCN1Cc1ccc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
1-(2,4-Dichlorophenyl)methyl-4,5-dihydro-2-phenylmethylimidazole (3.19 g, 0.01 mol) was added to a slurry of sodium hydride (80% dispersion in mineral oil, 0.3 g, 0.01 mol) in dry dimethylformamide (15 ml) and the mixture was stirred at room temperature for 30 minutes. Paraformaldehyde (3 g, 0.01 mol) was added to the reaction mixture and the resulting mixture was heated at 70° C. for 6 hours. The reaction mixture was cooled, water was added and the resulting mixture was extracted with ether. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel in ammonia/methanol/ethyl acetate (1:4:45) to yield 1-(2,4-dichlorophenylmethyl)-4,5-dihydro-2-(1-phenylethenyl)imidazole (2.6 g), (δ(CDCl3) 3.3 (2H, t, J=6 Hz), 3.95 (2H, t, J=6 Hz), 4.1 (2H, s), 5.65 (1H, s), 5.8 (1H, s), and 7.0-7.5 (8H, m) p.p.m. having the formula ##STR24##
Reaction SMILES: [NH2:1][C@@H:2]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:3]([OH:31])[CH2:4][C@@H:5]([NH:18][C:19](=[O:30])[C@H:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[NH:21][C:22]([O:24][CH3:25])=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=1.[CH3:39][O:40][C:41]([NH:43][C@@H:44]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45](O)=[O:46])=[O:42].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:39][O:40][C:41](=[O:42])[NH:43][C@@H:44]([C:48]([CH3:50])([CH3:49])[CH3:51])[C:45](=[O:46])[NH:1][C@@H:2]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:3]([OH:31])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[NH:18][C:19](=[O:30])[C@H:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[NH:21][C:22](=[O:23])[O:24][CH3:25]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a solution containing the product from Example 146C (0.035 g, 0.065 mmol) in tetrahydrofuran (0.70 mL) were added the product from Example 1F (0.012 g, 0.063 mmol), DEPBT (0.029 g, 0.097 mmol), and N,N-diisopropylethylamine (0.056 mL, 0.321 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic was washed with additional 10% Na2CO3 solution and then brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on reverse phase HPLC on a C18 column, eluting with a gradient starting with water (containing 0.1% trifluoroacetic acid) and ending with acetonitrile to give the product (0.021 g, 46% yield). 1H NMR (300 MHz, MeOH-d6), δ ppm 0.86 (s, 9 H), 0.88 (s, 9 H), 1.61-1.71 (m, 2 H), 2.58-2.65 (m, 1 H), 2.76-2.96 (m, 4 H), 3.57 (s, 3H), 3.65 (s, 3 H), 3.74-3.79 (m, 1 H), 3.81 (s, 1 H), 3.1 (s, 1 H), 4.19-4.28 (m, 1 H), 4.30-4.40 (m, 1 H), 7.10-7.28 (m, 7 H), 7.56 (d, J=3.3 Hz, 1 H), 7.78 (d, J=8.1 Hz, 2 H), 7.83 (d, J=3.3 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([N:15]1[C:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=2[NH:17][C:16]1=[O:25])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[CH3:27][C:28]1[C:36]2[C:35]([CH2:37]O)=[CH:34][S:33][C:32]=2[CH:31]=[CH:30][CH:29]=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(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([N:15]1[C:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=2[N:17]([CH2:37][C:35]2[C:36]3[C:28]([CH3:27])=[CH:29][CH:30]=[CH:31][C:32]=3[S:33][CH:34]=2)[C:16]1=[O:25])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H](CCc1ccccc1)n1c(=O)[nH]c2ccc(C)cc21
Reactant: Cc1cccc2scc(CO)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](CCc1ccccc1)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
To a solution of (S)-3-(6-Methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-5-phenyl-pentanoic acid ethyl ester (0.2 g, 0.57 mmol), (4-Methyl-benzo[b]thiophen-3-yl)-methanol (0.10 g, 0.57 mmol), and triphenylphosphine (0.18 g, 0.68 mmol) was added dropwise DIAD (0.14 g, 0.68 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and concentrated. The resulting oily residue was purified by prep TLC using 4:1 Hexane:EtOAc as an eluent to afford 0.12 g of the desired product as a brown oil.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].C.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S([O-])(O)(=O)=O.[Na+]>O.C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O:5][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])=[O:4]
Reactant: CCCCCCCCCCCCO
Reactant: CSCCC(O)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCOC(=O)C(O)CCSC
Temperature: 25 °C

Procedure:
To a 4 neck 1 L round bottom flask fitted with a reflux condenser, dean stark trap, thermocouple, and mechanical overhead stirrer was added 2-hydroxy-4-(methylthio)butanoic acid (150 g, 999 mmol, obtained for example by stirring Alimet over activated charcoal, filtering and concentrating in a rotovap), 1-dodecanol (335 mL, 1498 mmol), sodium hydrogen sulfate (2.40 g, 19.97 mmol) and toluene (625 mL). The reaction was heated to reflux with removal of water (19 mL) during the course of about 5.5 hours and the reaction was monitored by GC analysis. The reaction was cooled to room temperature overnight and then the organic layer was washed with saturated NaHCO3 (1×300 mL) and a white solid formed which was filtered. The organic layer was washed with water (1×300 mL) and brine (2×300 mL), dried over sodium sulfate, filtered and evaporated to give an amber oil (487 g). The oil was purified by kugelrohr distillation at 135° C. and 0.1 Torr vacuum to give an oil (133.18 g, 42%). m/z 341 (MNa+).