Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Br.[C:11]([O:15][C:16]([NH:18][C@@:19]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:24]([OH:25])[C@H:23]([OH:26])[C@@H:22]2[C@H:20]1[C@H:21]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:17])([CH3:14])([CH3:13])[CH3:12]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(OCC)C.[Ag]=O>[C:11]([O:15][C:16]([NH:18][C@@:19]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:24]([O:25][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C@H:23]([OH:26])[C@@H:22]2[C@H:20]1[C@H:21]2[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1O
Agent: O=[Ag]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
Add 3,4-dichlorobenzyl bromide (1.02 mL, 1.02 g, 4.26 mmol) to di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3,4-dihydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (1.22 g, 2.84 mmol), tetra-n-butylammonium iodide (1.07 g, 2.84 mmol) and silver oxide (987.35 mg, 4.26 mmol) in dimethylformamide (17 mL) at room temperature. Stir overnight. Dilute with diethyl ether and hexanes (1:1), filter through celite, and then wash with ether and hexanes (1:1). The filtrate is washed with water, brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography, eluting with 0-30% ethyl acetate:hexanes to give the title compound (1.7 g, 2.84 mmol, 78%): MS (m/z): 610/612 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1.[Cl:20][C:21]1[C:22]([C:31](O)=[O:32])=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>>[F:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31]([C:22]2[C:21]([Cl:20])=[CH:26][C:25]([C:27]([F:29])([F:28])[F:30])=[CH:24][N:23]=2)=[O:32])=[CH:7][C:6]=1[C@:8]1([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]1
Reactant: CC1(C)C[C@@](C)(c2cc(N)ccc2F)NC(=S)CO1
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Product: CC1(C)C[C@@](C)(c2cc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)NC(=S)CO1
Yield: 61 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17A) (106 mg, 0.38 mmol) and commercially available 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid [CAS No. 80194-68-9] (100 mg, 0.44 mmol). The compound was obtained as light yellow foam (133 mg, 61%). MS (ISP): m/z=490.2 [(M+H)+] and 492.3 [(M+2+H)+].
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[C:8]([NH:13][C:14]([NH2:16])=[O:15])([CH2:11][CH3:12])([CH3:10])[CH3:9].O>C1C=CC=CC=1>[C:8]([NH:13][C:14]([NH:16][C:4]1[CH2:5][O:1][C:2](=[O:7])[CH:3]=1)=[O:15])([CH2:11][CH3:12])([CH3:10])[CH3:9]
Reactant: CCC(C)(C)NC(N)=O
Reactant: O=C1COC(=O)C1
Solvent: c1ccccc1
Solvent: O
Product: CCC(C)(C)NC(=O)NC1=CC(=O)OC1
Yield: 39.3 %

Procedure:
To a solution of 3 g of 2,4-furandione in 100 ml of benzene is added 4 g of tert-amylurea. The solution is heated under nitrogen at reflux for three hours with water removal. At the end of that period the solution is cooled and concentrated. The residual material is recrystallized from acetonitrile to give 2.5 g of 1-tert-amyl-3-(2,5-dihydro-5-oxo-3-furyl)urea, m.p. 169°-171° C. The infrared and n.m.r. spectra are consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[N:6]=1.[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:8]1([CH2:7][N:5]2[N:4]=[N:3][C:2]([NH:1][C:18](=[O:19])[CH:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:6]2)[CH2:10][CH2:9]1
Reactant: Nc1nnn(CC2CC2)n1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C(Nc1nnn(CC2CC2)n1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 147-148° and MS: m/e=334.3 (M++H) was prepared in accordance with the general method of example 1 from 5-amino-2-cyclopropylmethyl-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=[C:2]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:7]=1
Reactant: CC(C)(C)Nc1cc(Cl)nc(Cl)n1
Reactant: C1CCNC1
Product: CC(C)(C)Nc1cc(Cl)nc(N2CCCC2)n1
Yield: 73.8 %

Procedure:
By reacting 2,4-dichloro-6-(1,1-dimethylethylamino)pyrimidine with pyrrolidine as described in Example 12, the title product is obtained in a yield of 73.8%, m.p.: 148°-150° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:23])([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[F:23][C:11]1([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(=O)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(F)cc1)C1(F)CCNCC1

Procedure:
4-Fluoro-4-(4-fluoro-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.122 g, 0.375 mmol) was solved in dichloromethane (2 mL) and trifluoroacetic acid (0.258 mL, 3.37 mmol) was added at 0° C. Aqueous NaHCO3 is slowly added until pH 9 and the mixture extracted with 3 times with dichloromethane and ethyl acetate. The solvent was evaporated to yield g (0. mmol, 100%) of a white solid that was used without purification on the next steps. MS (m/e): 226.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.O.[NH2:19][NH2:20]>C(O)COCCO>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](=[N:19][NH2:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: NN
Solvent: O
Solvent: OCCOCCO
Product: NN=C(c1cc(Cl)ccc1N)c1ccccc1F

Procedure:
In the manner given in Preparation 1, 2-amino-5-chloro-2'-fluorobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-5-chloro-2'-fluorobenzophenone hydrazone.
Reaction SMILES: [NH2:1][C:2]1[N+:3]([O-:18])=[C:4]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5](=[O:13])[NH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])O.[K+].CN(C)C=O.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][C:5]([O:13][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:4]([CH2:14][CH:15]([CH3:17])[CH3:16])[N+:3]=1[O-:18]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]c(=O)c(CC(C)C)[n+]([O-])c1N
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(OCc2ccccc2)c(CC(C)C)[n+]([O-])c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
There were mixed 1.00 g of 5-amino-6-ethoxycarbonyl-3-isobutyl-1,2-dihydropyrazin-2-one 4-oxide, 1.18 g of potassium hydrogencarbonate (powder), 20 ml of dry dimethylformamide and 932 μl of benzyl bromide. The mixture was stirred for 16 hours at room temperature to effect a reaction. After completion of the reaction, the reaction mixture was poured into 50 ml of ethyl acetate. The resulting mixture was washed with 30 ml of water three times. The aqueous layer was extracted with 30 ml of ethyl acetate twice. The extract was combined with the above ethyl acetate layer. The combined solution was washed with 30 ml of water twice, and dried over magnesium sulfate. The solvent was removed by evaporation. The residue was recrystallized from ethanol to obtain 1.06 g of 2-amino-5-benzyloxy-3-ethoxycarbonyl-6-isobutylpyrazine 1-oxide (Compound B-10) as pale yellow fine needle-like crystals having a melting point of 114.5°-115.5° C.
Reaction SMILES: [H-].[Na+].[NH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:4]([CH3:6])=[O:5].[N+:14]([O:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])([O-:16])=[O:15]>C1COCC1>[N+:14]([O:17][CH2:18][CH2:19][CH2:20][C:21]([O:13][C:10]1[CH:11]=[CH:12][C:7]([NH:3][C:4](=[O:5])[CH3:6])=[CH:8][CH:9]=1)=[O:22])([O-:16])=[O:15]
Reactant: O=C(Cl)CCCO[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OC(=O)CCCO[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 40 %

Procedure:
Sodium hydride (270 mg of 60% NaH, 6.8 mmol) was added under argon and under magnetic stirring to a solution of 4-acetaminophenol (840 mg, 5.6 mmol) in dry THF (20 ml) kept at 0° C. The reaction mixture was stirred at 0° C. for 40 minutes. A solution of crude 4-(nitrooxy)butanoyl chloride in dry THF (10 ml), was then added dropwise to the reaction mixture kept at 0° C. The reaction temperature was allowed to rise to r.t. and the mixture was stirred for 18 hours. The unreacted 4-acetaminophenol was removed by washing the solution with 2M NaOH solution (75 ml). The resulting mixture was extracted with CH2Cl2 (3×75 ml). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. Purification of the residue by silica gel column chromathography by using petroleum ether/ethyl acetate=30/70 mixture as eluent provided 300 mg (1.1 mmol, 40% yield on converted paracetamol) of pure 4-(acetylamino)phenyl 4-(nitrooxy)butanoate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([N:18]1[C@@H:30]2[C@@H:21]([C@H:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=32)[CH2:20][CH2:19]1)=[O:17])=[O:8].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N:37]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[C:16]([N:18]2[C@@H:30]3[C@@H:21]([C@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=43)[CH2:20][CH2:19]2)=[O:17])=[O:8])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: O=C(CCCCCBr)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(CCCCCN1CCOCC1)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Yield: 91.3 %

Procedure:
6-Bromo-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexyl)hexaneamide (166 mg, 0.30 mmol), morpholine (28 μl, 0.331 mmol) and potassium carbonate (207 mg, 1.5 mmol) were heated under reflux for 6 hrs. in acetonitrile (3 ml). Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel column chromatography and eluted with ethyl acetate to give the title compound (153 mg, 91%) as a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(OC([NH:42][C@H:43]([C:50]([OH:52])=O)[CH2:44][N:45]1[CH:49]=[CH:48][CH:47]=[N:46]1)=O)C1C=CC=CC=1.[NH2:53][C@@H:54]([CH2:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)[C@@H:55]([OH:61])[C@H:56]([CH:58]1[CH2:60][CH2:59]1)[OH:57]>C(#N)C>[NH2:42][C@@H:43]([CH2:44][N:45]1[CH:49]=[CH:48][CH:47]=[N:46]1)[C:50]([NH:53][C@@H:54]([CH2:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)[C@@H:55]([OH:61])[C@H:56]([CH:58]1[CH2:60][CH2:59]1)[OH:57])=[O:52]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: O=C(N[C@@H](Cn1cccn1)C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N[C@@H](Cn1cccn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 2 h

Procedure:
1.03 g (2.83 mmol) of HBTU and 0.39 ml (2.83 mmol) of triethylamine were added to a solution of 820 mg (2.83 mmol) of N-[(benzyloxy)carbonyl]-3-(pyrazol-1-yl)-L-alanine [J. Am. Chem. Soc. 107, 7105 (1985)]and 644 mg (2.83 mmol) of (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol in 28 ml of acetonitrile and the mixture was stirred at room temperature overnight. The crystals obtained after filtration were dissolved in 30 ml of ethanol and hydrogenated at 400 for two hours. Filtration over diatomaceous earth and evaporation under reduced pressure yielded 670 mg of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(pyrazol-1-yl)propionamide, MS: 365 (M+H)+, as a colourless foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[S:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1)[NH2:22]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:23]=[CH:24][C:25]=1[S:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Product: COc1cc2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2cc1OC

Procedure:
In the manner of Example 141 reaction of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile with 3-chloro-4-(1-methyl-2-imidazolylthio)aniline (WO-9615118) gave the title compound as a white solid, mp 302-307° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Reactant: Cc1ccc(O)c(B(O)O)c1
Product: COc1cccc(-c2cccc(-c3cccc(-c4cc(C)ccc4O)n3)n2)c1O
Yield: 20 %

Procedure:
6-(3-methoxyphenyl)-6′-(2-hydroxy-5-methyphenyl)-2,2′-was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-5-methylphenyl boronic acid in 20% yield using method F; δH [2H6]-DMSO 13.57,(1H, b), 13.09,(1H, b), 8.33,(2H, t), 8.24,(2H, m), 8.15,(2H, m), 7.95,(1H, s), 7.70,(1H, d), 7.18,(1H, d), 7.10,(1H, d), 6.91,(2H, m), 3.84,(3H, s), 2.35,(3H, s), 385 (MH)+; HPLC retention time (system 1) 4.17 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]2[N:21]=[CH:22][CH:23]=[CH:24][C:4]=2[N:3]=1.[Br:25]N1C(=O)CCC1=O>C1C=CC=CC=1.COC(C)(C)CC(C)C#N>[Br:25][CH2:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]2[N:21]=[CH:22][CH:23]=[CH:24][C:4]=2[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cccnc2n(-c2cccc(-c3ccccc3)c2)c1=O
Agent: COC(C)(C)CC(C)C#N
Solvent: c1ccccc1
Product: O=c1c(CBr)nc2cccnc2n1-c1cccc(-c2ccccc2)c1
Yield: 23.5 %

Procedure:
The mixture of 2-methyl-4-(3-biphenylyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (17 g), N-bromosuccinimide (10.6 g) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile (167 mg) in benzene (200 ml) was refluxed for 2 hours. The mixture was washed with water and evaporated. The crude products was purified by column chromatography to obtain 2-bromomethyl-4-(3-biphenylyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (5 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:78])([F:77])[C:49]1[CH:50]=[C:51]([C:59]([CH3:76])([CH3:75])[C:60]([N:62]([CH3:74])[C@H:63]2[C@H:67]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:66][NH:65][CH2:64]2)=[O:61])[CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1>C1COCC1>[F:77][C:48]([F:47])([F:78])[C:49]1[CH:50]=[C:51]([C:59]([CH3:75])([CH3:76])[C:60]([N:62]([C@H:63]2[C@H:67]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:66][N:65]([C:10]([CH:7]3[CH2:6][CH2:5][CH:4]([CH2:3][O:2][CH3:1])[CH2:9][CH2:8]3)=[O:12])[CH2:64]2)[CH3:74])=[O:61])[CH:52]=[C:53]([C:55]([F:56])([F:57])[F:58])[CH:54]=1
Reactant: COCC1CCC(C(=O)O)CC1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC1CCC(C(=O)N2C[C@@H](N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccccc3)C2)CC1
Reaction time: 48 h
Yield: 48.2 %

Procedure:
To a stirred solution of 4-methoxymethyl-cyclohexanecarboxylic acid (described in JP60258141) (7.4 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 12.7 mg (48%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH2:7][C@@H:8]([N:12]1[CH:16]=[C:15]([C:17]([NH2:19])=[O:18])[N:14]=[CH:13]1)[C@@H:9]([OH:11])[CH3:10].[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:23]1[C:24]([C:2]2[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=2)[O:5][CH2:6][CH2:7][C@@H:8]([N:12]2[CH:16]=[C:15]([C:17]([NH2:19])=[O:18])[N:14]=[CH:13]2)[C@@H:9]([OH:11])[CH3:10])=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]1=2
Reactant: C[C@H](O)[C@@H](CCOc1cccc(Br)c1)n1cnc(C(N)=O)c1
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C[C@H](O)[C@@H](CCOc1cccc(-c2cc3ccccc3s2)c1)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.6 %

Procedure:
To a solution of 1-[(2S,3R)-5-(3-bromophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide in DME (5 ml) was added Pd(PPh3)4 (29.3 mg, 0.025 mmol)at ambient temperature under N2. After stirring for 20 min., benzothiophene-2-boronic acid (54.2 mg, 0.304 mmol) and a solution of Na2CO3 (40.3 mg, 0.38 mmol) in H2O (1 ml) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and partitioned between ethyl acetate (20 ml) and H2O. The organic layer was washed successively with saturated NaHCO3 aqueous solution, H2O and then brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with chloroform/methanol (100:1 to 20:1) to give 1-{(2S,3R)-5-[3-(2-benzo[b]thiophenyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide (41) (66.9 mg, 62.6%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:10]([S:11][CH3:12])=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:8]=[C:7](Cl)[N:6]=1.CC1(C)C(C)(C)OB([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:10]([S:11][CH3:12])=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:8]=[C:7]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[N:6]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COC(=O)Cc1nc(Cl)nc(N2CCOCC2)c1SC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)Cc1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1SC
Temperature: 90 °C
Reaction time: 12 h

Procedure:
A mixture of (2-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-4-yl)-acetic acid methyl ester (420 mg, 1.47 mmol.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-aniline) (357 mg, 1.62 mmol.), (PPh3)4Pd (170 mg, 0.07 mmol.), 2M Na2CO3 (2.2 ml, 4.14 mmol, 3.0 eq.) and dioxane (10 ml) was added a reaction vessel which was flushed with argon. The reaction mixture was stirred at 90° C. for 12 hr then dried, and the solvent was evaporated. The reaction mixture was partitioned between EA and water, the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Hexane/EtOAc 3:2) to give a pale yellow solid of 424 mg (43.8%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:17]([C:26]([O:28][CH2:29][CH:30]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[C@H:18]([C:23](O)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.C1C=CC2N(O)N=NC=2C=1>[NH:17]([C:26]([O:28][CH2:29][CH:30]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[C@H:18]([C:23]([NH:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
The obtained wet crystals of Leu-OBzl (2-MeO-4-OC12OC22) were dissolved in chloroform (13 mL), Fmoc-Leu-OH (373 mg, 1.06 mmol) and HOBt (14.3 mg, 106 μmol) were added at room temperature, and EDC.HCl (223 mg, 1.16 mmol) was further added under ice-cooling. The mixture was warmed to room temperature, stirred overnight, and concentrated under reduced pressure. Methanol (10 mL) was added to the residue, and the precipitate was collected by filtration to give Fmoc-Leu-Leu-OBzl (2-MeO-4-OC12OC22) (1.02 g, 93% yield relative to Bzl (2-MeO-4-OC12OC22)OH).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:18][CH:17]=2)[C:13](=[O:35])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:36]([O-])=O)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>CO.[Pd]>[NH2:36][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:14]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:18][CH:17]=1)[C:13]2=[O:35]
Reactant: [H][H]
Reactant: CCCCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
0.11 g (0.21 mmol) of 2-butyl-3-[(2'-(t-butoxycarbonyl)biphen-4-yl)methyl]-6-nitroquinazolin-3(1H)-one (Example 27) was suspended in 7.5 mL of MeOH and hydrogenated over 55 mg of 10% Pd/C under an atmospheric pressure hydrogen blanket. After 1 hour the reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with 50% EtOAc/hexane to give a white foam. 1H-NMR (CDCl3): 0.94 (t, 3H, J=7. Hz), 1.23 (s, 9H), 1.41 (m, 2H), 1.79 (m, 2H), 2.74 (3 line m, 2H, J=7.7 Hz), 5.44 (bs, 2H), 7.05-7.57 (m, 10H), 7.77 (d, J=7.5 Hz).