Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: Oc1ccc(I)cc1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(O)cc2)c1)c1ccccc1
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a degassed solution of 1.3 mL DMF at room temperature containing (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (63 mg, 0.22 mmol), 4-iodophenol (121 mg, 0.55 mmol), and triethylamine (0.09 mL, 0.66 mmol) was added dichlorobis(triphenylphosphine)palladium(II) (15 mg, 0.022 mmol) and copper(I)iodide (4 mg, 0.022 mmol). After proceeding for 1 hour the reaction was partitioned between EtOAc and H2O. The mixture was filtered to remove an insoluble brown precipitate and the EtOAc layer was washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown film was chromatographed eluting with CHCl3/EtOAc to give a yellow solid which was recrystallized from CHCl3/hexane to give the title compound as an off-white solid (38 mg, 45%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:7]([Si:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:12][CH2:13][CH:14]=[CH:15][CH2:16][OH:17])([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.CO>CN(C)C1C=CN=CC=1.ClCCl>[C:7]([Si:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:12][CH2:13][CH:14]=[CH:15][CH2:16][O:17][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)[Si](OCC=CCO)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(C)C(=O)OCC=CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
Isobutyryl chloride (10.4 mL, 98.04 mmol) was added drop wise to a stirred and a cooled (0° C.) solution of the product of Example 5E (61.28 mmol), diisopropylethyl amine (21.3 mL, 122.56 mmol), and 4-dimethylaminopyridine (0.30 g, 3.0 mmol) in dry dichloromethane (150 mL). The resulting solution was allowed to stir at 0° C. for five hours. After the completion of reaction (monitored by TLC), methanol (5 mL) was added to quench excess acid chloride. The solvent was removed under reduced pressure and the resulting slurry was partitioned using diethyl ether (200 mL) and saturated NH4Cl (100 mL). The organic layer was washed successively with 20% NaHSO4, NaHCO3, brine, and it was dried over MgSO4. After removal of solvent, the crude oil was purified over silica gel column using 10% diethyl ether in hexanes to give the title compound as a colorless oil: (20.5 g, 84% over 2 steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1CC=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([CH:29]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:26][CH2:27][CH3:28])=[O:25].[CH2:49]1COC[CH2:50]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][C@@H:9]1[CH2:49][CH:50]=[CH:29][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC=O)C1
Reactant: C1CCOC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C=CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C

Procedure:
Heat a mixture of (S)-2-(2-oxoethyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (1.38 g, 4.21 mmol) and (carbethoxymethylene)triphenylphosphorane (1.87 g, 5.38 mmol) in THF (17 mL) at reflux for 4 h. Concentrate the mixture under reduced pressure and purify by silica gel chromatography eluting with 20% to 50% EtOAc in hexanes. Combine the purified fractions, concentrate under reduced pressure, azeotrope with CH2Cl2/hexanes (1:2) and place under vacuum to give the title compound: yellow tar (0.961 g), mass spectrum (m/e): 416.09(M+NH4).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C@@H:17]([CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:18][N:19]2C(=O)C4C(=CC=CC=4)C2=O)[CH2:10]3)=[CH:5][CH:4]=[N:3]1.NN>CO.O1CCCC1>[NH2:19][CH2:18][C@@H:17]([N:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)[C:12]1=[O:16])[CH2:30][C:31]1[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cc(F)cc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1ccc2c(c1)CN([C@H](CN)Cc1cc(F)cc(F)c1)C2=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
The product of Step D (0.72 g, 1.41 mmol) was dissolved in methanol (4 mL) and tetrahydrofuran (4 mL). To the resulting solution was added hydrazine (2 mL, 60 mmol). The solution was stirred at 50° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by combi-flash chromatography eluting with MeOH/EtOAc (20-60%). The product was further purified by prep.-LC/MS (pH=10). The purification afforded 210 mg (39.0% yield) of the final product as a white solid. LC/MS found: 383.1 (M+1)+; 1H NMR (300 MHz, DMSO-d6) δ: 7.9 (d, J=13.8 Hz, 2H), 7.58 (dd, J1=7.9 Hz, J2=1.1 Hz, 1H), 7.48 (d, J=1.9 Hz, 1H), 6.96 (m, 3H), 6.45 (d, J=1.9 Hz, 1H), 4.47 (s, 2H), 4.41 (m, 1H), 3.86 (s, 3H), 3.04 (dd, J1=14.3 Hz, J2=4.8 Hz, 1H), 2.89 (dd, J1=14.0 Hz, J2=3.9 Hz, 1H), 2.85 (d, J=6.80 Hz, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]([OH:25])=O)=[CH:22][C:16]=3[N:15]=2)=[O:12])[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.S(O)(O)(=O)=O.[NH2:55][C:56]1[NH:57][CH:58]=[CH:59][N:60]=1>CN(C=O)C.CCN(C(C)C)C(C)C.O>[NH:57]1[CH:58]=[CH:59][N:60]=[C:56]1[NH:55][C:23]([C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:14]([NH:13][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:12])=[N:15][C:16]=2[CH:22]=1)=[O:25]
Reactant: O=C(O)c1ccc2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1
Reactant: Nc1ncc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ncc[nH]1)c1ccc2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1
Temperature: 25 °C
Yield: 5.6 %

Procedure:
0.15 g (0.45 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-5-carboxylic acid was reacted with 0.26 g (0.68 mmol) of HBTU and 0.06 g (0.45 mmol) of 2-aminoimidazole sulfate in 3.0 mL of DMF and 1.0 mL of DIEA as described in general procedure A. After cooling to room temperature, the reaction mixture was diluted with water, the solid was collected by filtration, dissolved with MeOH and evaporated onto silica gel, and isolated by flash column chromatography (500 mL DCM/20 mL NH3/MeOH) to yield ˜10 mg of the desired isoquinoline-3-carboxylic acid [5-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 398.0 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[CH:23]([CH3:25])[CH3:24].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:29][CH3:30])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([CH:23]([CH3:24])[CH3:25])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:27]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(C(C)C)cc3c(=O)[nH]2)c1
Reactant: CCNCC
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(C(C)C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C19H22FN5O2, 371.2
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8].[K].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(Cl)(Cl)Cl.O>CN(C=O)C>[C:14]1(=[O:24])[N:18]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12
Reactant: C#CCOC(=O)CCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C#CCOC(=O)CCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
Prop-2-ynyl 6-bromohexanoate (0.606 g, 2 mmol, 1 eq.) was added to a solution of phthalimide potassium salt (0.441 g, 2.4 mmol, 1.2 eq.) in 50 mL of DMF and stirred overnight under argon. CHCl3 was added to the solution flask and was transferred to a separatory funnel containing water. The aqueous layer was separated and twice extracted with CHCl3. The combined organic layers were twice extracted with water then the solvent was removed on a rotary evaporator. Remaining solvent was removed under high vacuum overnight to yield a brown oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]1([CH2:31][C:32]([NH:34][CH:35]2[C:60](=[O:61])[N:37]3[CH:38]([C:44]([O:46][CH:47]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:45])[C:39]([CH:42]=O)=[CH:40][S:41][C@H:36]23)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.[Zn].C(OCC)(=O)C>[C:25]1([CH2:31][C:32]([NH:34][CH:35]2[C:60](=[O:61])[N:37]3[CH:38]([C:44]([O:46][CH:47]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)=[O:45])[C:39]([CH:42]=[C:20]([Br:24])[Br:21])=[CH:40][S:41][C@H:36]23)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C=C(Br)Br)=CS[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
To a stirred mixture of triphenylphosphine (40.7 g) and zinc powder (18.5 g) in methylene chloride (250 ml) was added carbontetrabromide (45 g) at 20°-30° C. Benzhydryl 7-phenylacetamido-3-formyl-2-cephem-4-carboxylate (10 g) was added portionwise to the above reaction mixture, and the mixture was stirred for 30 minutes at room temperature. Triphenylphosphine oxide was solidified by addition of ethyl acetate to the reaction mixture and removed by filtration. The residue left by removal of the solvents was chromatographed on silica gel. The elution with chloroform containing ethyl acetate (10%) gave benzhydryl 7-phenylacetamido-3-(2,2-dibromovinyl)-2-cephem-4-carboxylate (4.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[N:5][C:4](=C(Cl)Cl)[N:3]=1.[CH:11]([NH:14][CH:15]=[O:16])([CH3:13])[CH3:12].O>>[CH:11]([NH:14][C:15]([C:4]1[NH:3][C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=1)=[O:16])([CH3:13])[CH3:12]
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Reactant: CC(C)NC=O
Solvent: O
Product: CC(C)NC(=O)c1nc(Cl)c(Cl)[nH]1
Yield: 85 %

Procedure:
From 4,5-dichloro-2-dichloromethylene-imidazole ("one-pot process"). 654 g (3 mol) of 4,5-dichloro-2-dichloromethyleneimidazole in a finely powdered form were added incrementally in the course of about one hour, to a mixture, which had been initially introduced, of 783 g (9 mol) of isopropylformamide and 162 g (9 mol) of water, while stirring and cooling slightly, whereupon the internal temperature rose to about 75° C. The reaction mixture was then heated to about 90°-110° C. for a further half hour. After cooling, the product was precipitated in water, filtered off, washed with water and dried. In this way, 566 g (85% of theory) of 4,5-dichloro-imidazole-2-carboxylic acid isopropylamide with a melting point of 150° C. were obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][Cl:10].[OH-].[K+].[CH2:13]([OH:16])[CH2:14][OH:15]>>[Cl:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:15][CH2:14][CH2:13][OH:16]
Reactant: ClCCOCCOCCCl
Reactant: OCCO
Agent: [K+]
Agent: [OH-]
Product: OCCOCCOCCOCCCl
Yield: 30 %

Procedure:
A solution of 1,8-dichloro-3, 6-dioxaoctane (40 g) and potassium hydroxide (11.8 g) in ethylene glycol (100 ml) was stirred at 100° C. for 18 h. The mixture was then cooled, filtered and the residue washed with acetone (2×35 ml). The combined filtrate was then distilled to yield the product as a clear oil (13.5 g, 30%), b.p. 120°-122° C./0.2 mm Hg; I.r. (liquid film) 3430 cm-1.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[C:24]([C:28]2[C:36]3[C:35](=[O:37])[NH:34][C:33]([C:38](OCC)=[O:39])=[N:32][C:31]=3[S:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1)=[O:21])[CH3:18].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:86]2[CH:90]=[N:89][C:88]([O:91][CH2:92][CH2:93][O:94][C:95]3[CH:96]=[C:97]([CH2:101][NH2:102])[CH:98]=[CH:99][CH:100]=3)=[N:87]2)C=CC=CC=1>>[O:37]=[C:35]1[NH:34][C:33]([C:38](=[O:39])[NH:102][CH2:101][C:97]2[CH:98]=[CH:99][CH:100]=[C:95]([O:94][CH2:93][CH2:92][O:91][C:88]3[N:89]=[CH:90][NH:86][N:87]=3)[CH:96]=2)=[N:32][C:31]2[S:30][CH:29]=[C:28]([C:24]3[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=3)[C:20]([O:19][CH2:17][CH3:18])=[O:21])[C:36]1=2
Reactant: CCOC(=O)c1cccc(-c2csc3nc(C(=O)OCC)[nH]c(=O)c23)c1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: CCOC(=O)c1cccc(-c2csc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c23)c1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-[3-(ethoxycarbonyl)phenyl]-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 82 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (132.7 mg, 58%).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:24])[CH:20]([CH3:23])[CH2:21][CH3:22])=[N:18][C:12]=2[O:11][C@@H:10]([CH2:25][O:26][CH3:27])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:34]>CO.[OH-].[OH-].[Pd+2]>[ClH:34].[CH3:27][O:26][CH2:25][C@H:10]1[CH2:9][NH:8][CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:24])[CH:20]([CH3:23])[CH2:21][CH3:22])=[N:18][C:12]=2[O:11]1
Reactant: CCC(C)N(C)c1cnc2c(n1)O[C@@H](COC)CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(C)N(C)c1cnc2c(n1)O[C@@H](COC)CNC2
Temperature: 50 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of (6R)-8-benzyl-6-(methoxymethyl)-N-methyl-N-(1-methylpropyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (297 mg) in methanol (10 mL) was added 20% Pd(OH)2/C (40 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 4 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the obtained crude product in ethyl acetate (10 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (220 μL), and the mixture was stirred for 1 hr. The reaction mixture was filtered, and the obtained crystals were washed with ethyl acetate to give the title compound (141 mg, 55%).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:4][N:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:23][S:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2nc(S)ncc2-c2ccc(Cl)cc2)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(-c2nc(SC)ncc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-mercapto-4-(4-methoxyphenyl)-5-(4-chlorophenyl)pyrimidine* (7 g) and potassium carbonate (8 g) in 200 ml acetone was treated with methyl iodide (4.8 ml) and stirred 5 hours at room temperature. The reaction mixture was filtered and concentrated on the rotary evaporator. Chromatography on silica gel and crystallization from ethanol gave the title compound (3.4 g), m.p. 127°-130°. Infrared and H-NMR spectra were consistent with the assigned structure. MS 342 (M+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[C:33]2[S:37][CH2:38][O:39][CH3:40])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[C:33]4[S:37][CH2:38][O:39][CH3:40])[CH:27]=3)[CH2:23][C:22](=[O:41])[NH:21][C:9]=2[CH:10]=1
Reactant: COCSc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccccc3F)ccc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCSc1nccn1-c1cccc(C2=Nc3ccc(-c4ccccc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from (2′-fluoro-3-{3-[3-(2-methoxymethylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K71) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (100 mg).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][C:9]1[CH:17]=[CH:16][C:12]([NH:13][CH:14]=[O:15])=[CH:11][CH:10]=1.Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH2:23]([O:22][C:20](=[O:21])[C@H:19]([CH3:25])[N:13]([CH:14]=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:4]2[NH:3][CH:7]=[CH:6][N:5]=2)=[CH:17][CH:16]=1)[CH3:24]
Reactant: CCOC(=O)C(C)Br
Reactant: O=CNc1ccc(Cc2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)N(C=O)c1ccc(Cc2ncc[nH]2)cc1
Temperature: 100 °C
Yield: 52.5 %

Procedure:
In a 200 ml round-bottom flask is placed a solution of 8.0 g of p-(1-imidazolylmethyl)aniline prepared as described in Reference Example 3, and 30 ml of formic acid in 80 ml of toluene. The flask was fitted with a water separator, and the solution was refluxed for 4 hours. After concentration under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give 6.4 g of p-(1-imidazolylmethyl)-N-formylaniline as colorless prisms. M.P.: 121°-123° C. To a suspension of 0.48 g of 50% sodium hydride in 50 ml of dry dimethylformamide was added 2.01 g of the formylaniline and mixture was heated to 100° C. A solution of 1.81 g of ethyl α-bromopropionate in 30 ml of dry dimethylformamide was added to the mixture and the reaction mixture was heated at 100° C. for 16 hours. After removal of the solvent under reduced pressure, 50 ml of dichloromethane was added to the residue, and the solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel using dichloromethane-ethanol (20:1 by volume) to give 1.58 g of N-formyl-N-[p-(1-imidazolylmethyl)phenyl]alanine ethyl ester as a pale brown oil. Then, a solution of 1.58 g of the resulting ester and 5 ml of concentrated hydrochloric acid in 50 ml of ethanol was stirred for 40 hours at room temperature. After concentration under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give 1.18 g of N-[p-(1-imidazolylmethyl)phenyl]alanine ethyl ester dihydrochloride as pale yellow crystals. M.P.: 154°-159° C.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]([C:11]([O:13]CC)=[O:12])=[O:10])=[N:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].O.C(O)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]([C:11]([OH:13])=[O:12])=[O:10])=[N:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1ncc(CC)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CCc1cnc(NC(=O)C(=O)O)s1
Reaction time: 0.17 h

Procedure:
Ethyl 5-ethylthiazol-2-ylcarbamoylcarboxylate (685 mg., 3 mmoles), 1 N potassium carbonate (3 ml., 3 equivalents), water (22 ml.) and ethanol (2--3 ml.) were heated on a steam bath. After 10 minutes, dissolution was nearly complete. After an additional 15 minutes, tlc (chloroform-5% acetic acid) indicated reaction was complete. The cooled reaction mixture was filtered, and crude product (380 mg.) precipitated from the filtrate by acidification with acetic acid. Recrystallization of the crude from isopropyl alcohol gave purified 5-ethylthiazol-2-ylcarbamoylcarboxylic acid [280 mg., m.p. 206.5° C. (dec)].
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:12]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])[C:11]([Si](C(C)(C)C)(C)C)=[N:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(OCC)(=O)C.CCCCCC>C1COCC1>[CH:1]1([CH2:7][C:8]2[N:12]([S:13](=[O:18])(=[O:17])[N:14]([CH3:15])[CH3:16])[CH:11]=[N:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)S(=O)(=O)n1c(CC2CCCCC2)cnc1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cncc1CC1CCCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
2-Tert-butyldimethylsilyl-1-dimethylsulfamoyl imidazole (1) (4.1 g, 14.2 mmol) is taken up in 47 mL of anhydrous THF and cooled to −200° C. n-BuLi (8.9 mL, 14.2 mmol) is added dropwise to the solution of (1). The resultant solution is stirred at −20° C. for 45 min. Cyclohexylmethyl iodide (2) (3.14 g, 14 mmol) is then added dropwise to the reaction mixture. Then reaction is warmed to rt and stirred overnight. The next day the reaction is quenched with saturated ammonium chloride and diluted with water. The mixture is extracted with ethyl acetate (3×100 mL). The organic layers are combined and washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (4:1 ethyl acetate/hexane) affords 2.26 g (5.6 mmol) of 5-cyclohexylmethyl-2-tert-butyldimethylsilyl-1-dimethylsulfamoyl imidazole (3). (3) (2.26 g, 5.6 mmol) is taken up in 56 mL of THF and cooled to 0° C. A 1M solution of TBAF in THF (5.6 mL, 5.6 mmol) is added dropwise to the solution of (3). The reaction is warmed to rt and stirred overnight. The next day the reaction is quenched with water and then extracted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (1:1 ethyl acetate/hexane) affords 1.2 g (4.42 mmol) of 5-cyclohexylmethyl-1-dimethylsulfamoyl imidazole (4). (4) (1.2 g, 4.42 mmol) is taken up in 25 mL of a 1.5N HCl solution and heated at reflux for 2 h. The reaction is cool to rt and diluted with ethyl acetate. The mixture is brought to pH 13 with 2N NaOH and then extracted with chloroform (4×100 mL). The organic layers are combined and washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (9:1 chloroform/methanol) affords 700 mg (4.27 mmol) of 4(5)-cyclohexylmethyl-1H-imidazole (5) (J-1).