Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11][C:12]1[C:17]([OH:18])=[CH:16][C:15]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=2)=[C:14]([F:33])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[C:17]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:16][C:15]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=2)=[C:14]([F:33])[CH:13]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(O)c(Cl)cc2F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cn3)c(Cl)cc2F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (952 mg, 6.01 mmol) and N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-(1-cyano-1-methylethyl)benzamide (2.00 g, 6.01 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.24 g, 9.01 mmol), and the mixture was stirred at 80° C. for 16 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate (200 mL and 100 mL). The combined organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL×2), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (2.28 g, 83%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C=C[O:42]C=3CCC2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[CH:14]=[CH:13][O:42][C:18]=3[CH2:17][CH2:16][CH2:15]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2CCCc3occc32)n1
Product: CCc1nc(NC2CCCc3occc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.29, 6.03, 5.18, 4.49, 2.81, 2.65, 2.55, 2.03, 1.89, 1.23; (FAB) calcd for C16H20BrN3O+H 351.0, found 351.0.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH3:4].[C:7]1([C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:14]2[CH:18]=[C:17]([CH:19]=[O:20])[N:16]=[CH:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+].O>O1CCCC1>[CH2:1]([CH:19]([C:17]1[N:16]=[CH:15][N:14]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=1)[OH:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Mg]Br
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 20 °C
Yield: 57.8 %

Procedure:
A solution of 0.22 mole of n-butyl magnesium bromide in 75 ml of tetrahydrofuran is slowly added, under an atmosphere of argon, to 67.6 g (0.2 mole) of 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde (obtained as described in 1.b. above) in 500 ml of tetrahydrofuran. The temperature of the mixture is maintained at about 20° C. by cooling on an ice-bath. When the addition is complete, stirring is maintained for 30 minutes at ambient temperature and then 11 g of ammonium chloride and 100 ml of water are successively added. The mixture is extracted with dichloromethane. The organic phases are dried over anhydrous sodium sulfate, then evaporated under reduced pressure. The residue is recrystallized from a 2:1 v/v ethyl acetate-diethyl ether mixture. 45.8 g of alpha-n-butyl-1-triphenylmethyl-1H-imidazole-4-methanol are obtained. Yield: 58% of theory; M.P.: 119°-120° C.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(CO[CH2:24][C:25]2([OH:39])[CH2:31][O:30][CH2:29][CH2:28][N:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26]2)CC1.S([O-])(O)(=O)=O.[Na+]>C1COCC1>[CH2:24]([C:25]1([OH:39])[CH2:31][O:30][CH2:29][CH2:28][N:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOCC(O)(COCC2CC2)C1
Agent: O=S(=O)([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC(O)(Cc2ccccc2)C1
Temperature: -80 °C
Yield: 54.5 %

Procedure:
1.6M solution of butyl lithium in hexane (150 mL, 0.24 mol, 1.1 eq) was added to a solution of bromobenzene (25.3 mL, 0.24 mol, 1.1 eq) in THF (200 mL) at −60° C. in a stream of argon. The reaction mixture was cooled to −80° C., and a solution of tert-butyl 6-[(cyclopropylmethoxy)methyl]-6-hydroxy-1,4-oxazepane-4-carboxylate (Preparation 80, 50 g, 0.22 mol, 1 eq) in THF was added. Then the mixture was cooled to −100° C., and a solution of etherate (30.4 g, 0.24 mol, 1.1 eq) was added at this temperature for 30 min. The reaction mixture was heated to 0° C. for 5 h, and 5M sodium hydrogen sulfate solution (50 mL) was added. The organic layer was separated, evaporated, and the residue was distributed between water and ether. The organic layer was separated, washed with water and brine, dried, evaporated, and the residue was dissolved in MeOH (200 mL). Ethylenediamine (30 mL) was added to the mixture, which was heated until boiled, cooled, evaporated, and coevaporated with dioxane. The residue was purified by chromatography on silica (1 L; carbon tetrachloride→chloroform, then MeOH 5%), evaporated and dried to give title compound (37.15 g, 0.12 mol, 55%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[N:6][CH:5]=1.C(N(C(C)C)CC)(C)C.[CH2:21]([O:28][C:29](=[O:38])[NH:30][CH:31]([C:35](F)=[O:36])[CH:32]([CH3:34])[CH3:33])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[C:9]([NH:10][C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:38])[CH:32]([CH3:34])[CH3:33])=[CH:8][CH:7]=[N:6][CH:5]=1
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(=O)F
Reactant: COC(=O)c1cnccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnccc1NC(=O)C(NC(=O)OCc1ccccc1)C(C)C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
Formula 506 where R1, R3 and R4 are H; R6 is Isopropyl; R6′ is H: W, Y and Z are —C═; and X is —N═: To a solution of dichloromethane (100 mL), 4-amino-nicotinic acid methyl ester (4.60 g, 30.2 mmol) and diisopropylethyl amine (8.25 mL, 46.7 mmol), was added (1-fluorocarbonyl-2-methyl-propyl)-carbamic acid benzyl ester (11.8 g, 46.7 mmol) at room temperature and the mixture stirred overnight. The solvent was removed under reduced pressure and the residue purified by flash silica gel chromatography using hexane-EtOAc (stepwise gradient from 3:1 to 1:1) as eluents to obtain the desired amide of Formula 506, 4-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-nicotinic acid methyl ester (10.5 g, 90.1%). MS (Cl) M/E: 386.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(F)c1
Yield: 47.9 %

Procedure:
To a mixture of methyl 3-fluoro-4-methylbenzoate (0.630 g; 3.75 mmol) in carbon tetrachloride (30 mL) was added N-bromosuccinimide (0.840 g, 4.67 mmol) and benzoyl peroxide (0.094 g; 0.375 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 1 to 12% ethyl acetate in heptane) to give 0.444 g (48%) of methyl 4-(bromomethyl)-3-fluorobenzoate as an oily residue which was directly used in the next step.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]1([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[N:16][CH:15]=[CH:14][CH:13]=2.[OH-].[Na+]>ClCCl>[CH2:1]([O:3][CH2:4][C:5]1[N:19]([CH2:20][C:21]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:18]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: Nc1cnc2cccnc2c1NCC1(O)CCCCC1
Reactant: CCOCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2cnc3cccnc3c2n1CC1(O)CCCCC1
Reaction time: 1.5 h
Yield: 75.7 %

Procedure:
Ethoxyacetyl chloride (1.78 g, 14.6 mmol) was added dropwise to a 0° C. solution of 1-{[(3-amino[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol (prepared as described in Part B of Example 57, 13.2 mmol) in dichloromethane (90 mL). After 1.5 h, more ethoxyacetyl chloride (0.3 mL) was added and stirring was continued for another 30 min. More ethoxyacetyl chloride (0.4 mL) was added and stirring was continued overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethanol (90 mL). Sodium hydroxide (1.06 g, 26.5 mmol) was added and the reaction was heated at reflux for about 1 d. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (200 mL) and water (100 mL). The aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to yield a brown foam. The foam was triturated with ethyl acetate and sonicated briefly. A white solid was isolated by filtration. The filtrate was concentrated and the trituration process was repeated two more times. The off white solids were combined and dried to yield 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}cyclohexanol (3.40 g, 76% over three steps).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[C:16]1([CH:23]=[CH:22][CH:21]=[C:19]([OH:20])[CH:18]=1)[OH:17].[N+](C1C=CC=CC=1)([O-])=O.Cl>>[OH:17][C:16]1[CH:18]=[C:19]([OH:20])[CH:21]=[CH:22][C:23]=1[C:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:14]
Reactant: Oc1cccc(O)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(O)cc2O)cc1
Temperature: 0 °C

Procedure:
Aluminum chloride (48 gm, 0.36 moles) was added gradually, with stirring to a mixture of 31 grams (0.18 moles) of anisoyl chloride, 19.82 grams (0.18 moles) of resorcinol and 300 ml. of dry nitrobenzene during 60 minutes. Sixty hours later the reaction mixture was poured on 200 grams of ice and 100 ml. of concentrated hydrochloric acid. After removal of the nitrobenzene with steam the residual crystalline solid product was washed with water and collected. The cake was then washed withd cold (-50 degrees C.) methanol to remove tarry impurities and dried.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10](=[O:19])[CH2:11][C:12]1[NH:13][C:14]([CH3:18])=[C:15]([CH3:17])[N:16]=1.C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]([C:11]1[CH:25]=[CH:24][C:23](=[O:26])[N:16]2[C:15]([CH3:17])=[C:14]([CH3:18])[NH:13][C:12]=12)=[O:19]
Reactant: Cc1nc(CC(=O)c2ccc(F)cc2F)[nH]c1C
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1[nH]c2c(C(=O)c3ccc(F)cc3F)ccc(=O)n2c1C

Procedure:
The compound is prepared as described in example 25 with 300 mg (1.05 mmol) of 2-(4,5-Dimethyl-1H-imidazol-2-yl)-1-(3-methylphenyl)ethanone hydrochloride (example XXIII), 65 mg (1.20 mmol) of sodium methylate and 88 mg (1.05 mmol) methyl propiolate.
Reaction SMILES: [CH3:1][N:2](/[CH:4]=C/C(C1C=NC=CN=1)=O)[CH3:3].N1C=CN=CC=1C(=O)C.[C:23]([N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:31]1[S:32][C:33]([C:37](=[O:39])[CH3:38])=[C:34]([CH3:36])[N:35]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[C:40]([N:30]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:31]1[S:32][C:33]([C:37](=[O:39])/[CH:38]=[CH:1]/[N:2]([CH3:4])[CH3:3])=[C:34]([CH3:36])[N:35]=1)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]
Reactant: CN(C)/C=C/C(=O)c1cnccn1
Reactant: CC(=O)c1sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1C
Agent: CC(=O)c1cnccn1
Product: Cc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1C(=O)/C=C/N(C)C
Yield: 16 %

Procedure:
Following the procedure described for the synthesis of enamino ketone 23a (scheme 6) but substituting 1-(pyrazin-2-yl)-ethanone for the ketone 336, title compound was obtained in 16% yield. 1H NMR (DMSO-d6) δ (ppm): 7.65 (d, J=12.1 Hz, 1H), 5.34 (d, J=12.1 Hz, 1H), 3.14 (s, 3H), 2.87 (s, 3H), 2.50 (s, 3H), 1.51 (s, 18H). MS (m/z): 411.52 (calc) 412.3 (MH+) (found).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:18]2[O:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[C:19]3[CH2:25][CH:24]4[N:26]([C:27](=[O:32])C(F)(F)F)[CH:21]([CH2:22][CH2:23]4)[CH2:20]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-:33].[Na+]>O1CCOCC1>[C:5]([O:32][C:27]([N:26]1[CH:21]2[CH2:22][CH2:23][CH:24]1[CH2:25][C:19](=[C:10]1[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:2])=[O:4])[C:18]=3[O:17][C:16]3[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:20]2)=[O:33])([CH3:18])([CH3:6])[CH3:3]
Reactant: [OH-]
Reactant: COC(=O)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(=C1c3ccccc3Oc3c(C(=O)O)cccc31)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of compound 7 (2.2 g, 4.96 mmol) in dioxane (25 mL) was added a 3N sodium hydroxide solution (3.5 mL) and the mixture was heated to reflux for 3 h. Additional 3N sodium hydroxide solution (3.5 mL) was added and the mixture was heated to reflux for 16 h. The mixture was allowed to cool to rt and Boc-anhydride (3.24 g, 14.9 mmol) was added. The mixture was stirred for 24 h at rt, the solvent was evaporated, and the residue was partitioned between water and ethyl acetate. The organic phase was separated, dried over sodium sulfate, filtered, and evaporated. The residue was used without further purification.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N+]=[N-].[H][H]>CCO.CC(O)=O.[Pd]>[NH2:1][CH2:4][C@H:5]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CN=[N+]=[N-])COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CN)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 1-azido-3-(benzyloxy)propan-2-yl(methyl)carbamate (4 g, 11.66 mmol) in EtOH (100 mL) and AcOH (10 mL) was added Pd/C (10%, 1.0 g). The resulting mixture was transferred to an autoclave and charged with hydrogen (45 psi). The reaction mixture was stirred at RT for 1 h and filtered. The filtrate was concentrated to give (S)-tert-butyl 1-amino-3-(benzyloxy)propan-2-yl(methyl)carbamate, which was used without further purification. LRMS (M+Na+) m/z 317.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.CC1N=C(N[CH2:45][CH2:46][OH:47])SC=1C1C=CN=C(NC2C=CC=C([N+]([O-])=O)C=2)N=1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:10]2[N:9]=[C:8]([C:4]3[S:3][C:2]([NH:1][CH2:45][CH2:46][OH:47])=[N:6][C:5]=3[CH3:7])[CH:13]=[CH:12][N:11]=2)=[CH:16][CH:17]=1
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2ccc(F)cc2)n1
Reactant: Cc1nc(NCCO)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Product: Cc1nc(NCCO)sc1-c1ccnc(Nc2ccc(F)cc2)n1

Procedure:
This compound was prepared from [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine in a manner analogous to that described for compound [58]. 1H-NMR (DMSO-d6) δ: 2.44 (s, 3H, CH3), 3.54 (m, 2H, CH2), 4.78 (m, 2H, CH2), 6.87 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 7.09 (m, 2H, Ph-H), 7.75 (m, 2H, Ph-H), 8.30 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 8.11 (m, 1H, NH), 9.43 (s, 1H, NH). DE MALDI-TOF MS: [M+H]+=345.79 (C16H16FN5OS requires 345.40).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH2:49]([N:48]([CH3:47])[C:41](=[O:43])[CH2:40][CH:37]1[CH2:38][CH2:39][N:34]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7]=2[O:44][CH2:45][CH3:46])=[O:33])[CH2:35][CH2:36]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CNCc1ccccc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)Cc2ccccc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with n-methylbenzylamine (MCB) to give the title product. LC-MS (ES+) 768 [(M+H)+].
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl[C:29]1[N:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:31][N:30]=1>CN(C)C=O>[C:24]([O:23][C:21]([NH:20][C@H:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:29]1[N:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:31][N:30]=1)[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:22])([CH3:26])([CH3:25])[CH3:27]
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CCOC(=O)CC[C@@H](CCCCN)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@@H](CCCCNc1ncc(-c2ccccc2)c(-c2ccccc2)n1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.7 %

Procedure:
481 mg (1.48 mmol) of cesium carbonate were added to a solution of 135 mg (0.49 mmol) of ethyl (R)-8-amino-4-tert-butoxycarbonylaminooctanoate in 3.5 ml of dimethylformamide, and the mixture was stirred at room temperature. After 60 minutes, a solution of 87 mg (0.33 mmol) of 2-chloro-4,5-diphenylpyrimidine in 2.5 ml of dimethylformamide was added, and the mixture was stirred at 90° C. for 6 hours. The solvent was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was dried and concentrated under high vacuum. The residue was purified by a preparative HPLC (Purosphere, gradient acetonitrile/(water+0.5% TFA), gradient 20% acetonitrile to 100% in 30 minutes). 10 mg of ethyl (R)-4-tert-butoxycarbonylamino-8-(4,5-diphenylpyrimidin-2-ylamino)octanoate were obtained. The product obtained in this way was stirred with 50% trifluoroacetic acid for 2 hours, mixed with water and freeze dried. 12 mg (4%) of the desired product were obtained.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:8][C:9]1[CH:10]=[C:11]([C:14]([OH:16])=O)[S:12][CH:13]=1)(=[O:7])[CH3:6].C(OC1C=C(C(Cl)=O)SC=1)(=O)C.[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([NH2:41])=[O:40])[C:34](=[O:42])[CH2:33]2>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([NH2:41])=[O:40])[C:34](=[O:42])[CH:33]2[C:14](=[O:16])[C:11]1[S:12][CH:13]=[C:9]([O:8][C:5](=[O:7])[CH3:6])[CH:10]=1
Reactant: CC(=O)Oc1csc(C(=O)O)c1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CC(=O)Oc1csc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)Oc1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1
Yield: 81.5 %

Procedure:
The title compound was prepared according to the procedure of Example 32. The reaction of 15 ml of thionyl chloride with 3.58 g (19.23 mmoles) of 4-acetoxy-2-thiophenecarboxylic acid (prepared according to Bohlmann, F., et al., Chem. Ber. 106:497 (1973)) gave a yellow oil. A 3.32 g (16.22 mmoles) sample of 4-acetoxy-2-thiophenecarbonyl chloride was coupled to 2.85 g (13.52 mmoles) of 5-chloro-2-oxindole-1-carboxamide in the presence of 4.16 g (34.07 mmoles) 4-(N,N-dimethylamino)pyridine to give 5.40 g of crude yellow product. Purification by recrystallization gave 4.18 g (11.02 mmoles, 82%) of pure title compound as a yellow solid, m.p. 222°-224° C. (acetic acid).
Reaction SMILES: I[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])=[CH:4][C:3]=1[F:20].[O:21]1[CH2:26][CH2:25][O:24][CH2:23]C1>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>[CH3:23][O:24][C:25]1[C:26](=[O:21])[CH:4]=[CH:3][C:2]([C:2]2[C:7]([F:8])=[CH:6][C:5]([N:9]3[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]3=[O:19])=[CH:4][C:3]=2[F:20])=[CH:7][CH:6]=1
Reactant: CC(=O)NCC1CN(c2cc(F)c(I)c(F)c2)C(=O)O1
Reactant: C1COCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1ccc(-c2c(F)cc(N3CC(CNC(C)=O)OC3=O)cc2F)ccc1=O
Temperature: 110 °C
Yield: 28 %

Procedure:
The (±)-N-[[3-(4-iodo-3,5-difluorophenyl)-2-oxo-5-oxazolidinyl]methyl ]acetamide (250 mg, 0.631 mmol) was dissolved in 1,4-dioxane (15 mL) and then treated with the stannyltropone (226 mg, 0.757 mmol). After degassing the solution 3 times with N2, the bis(triphenylphosphine)palladium(II) chloride (70 mg, 0.10 mmol) was added. The solution was degassed again (3×) and then it was heated to reflux (110° C.) for 7 h. At this point, the reaction was incomplete; fresh catalyst (70 mg, 0.10 mmol) was added, and after degassing again (3×), the solution was again heated to reflux for 7 h. At this time, the solvent was removed in vacuo and the residual oil was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with aqueous KF (40 mL) and brine (40 mL). After drying over anhydrous Na2SO4, the organic layer was filtered and concentrated under reduced pressure to yield a foamy, brown solid. This solid was chromatographed on silica gel (100 g), eluting with a gradient of 0-10% MeOH in 10% CH3CN/CHCl3 to give impure product. This product was repurified by preparative TLC (5% MeOH/CHCl3) to yield 72 mg (28%) of the title compound as an off-white solid with mp 218° C. (dec) and identical in all respects to material prepared as described above.