Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:16]I)=[CH:11][C:10]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C@H:32]([CH3:47])[CH2:33][C:34]1[C:42]2[C:37](=[C:38]([C:43]([O:45][CH3:46])=[O:44])[CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:16][NH:31][C@H:32]([CH3:47])[CH2:33][C:34]2[C:42]3[C:37](=[C:38]([C:43]([O:45][CH3:46])=[O:44])[CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)=[CH:11][C:10]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: COC(=O)c1cccc2c(C[C@@H](C)N)c[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC[Si](CC)(CC)O[C@@H](CN[C@H](C)Cc1c[nH]c2c(C(=O)OC)cccc12)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Yield: 42.4 %

Procedure:
A solution of (R)-N-[2-benzyloxy-5-(2-iodo-1-triethylsilyloxy-ethyl)phenyl]methanesulfonamide (2.09 g, 3.72 mmol), methyl (R)-3-(2-aminopropyl)-1H-indole-7-carboxylate (1.00 g, 3.72 mmol), diisopropyl-ethylamine (1.9 ml, 11.2 mmol) in tetrahydrofuran (30 ml)-acetonitrile (20 ml) is stirred at 110° C. for 18 hours in a sealed vessel. After cooling, to the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform/methanol=100/1→100/4) to give the title compound (1.05 g, yield: 42%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14](O)[C:13]=2[CH:12]=[C:11]([Br:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([C:18]([F:21])([F:19])[F:20])[NH:14][C:13]=2[CH:12]=[C:11]([Br:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1c(C(F)(F)F)nc2c(OCc3ccccc3)cc(Br)cc21
Agent: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1nc2c(OCc3ccccc3)cc(Br)cc2[nH]1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a suspension of 26.1 g (67.4 mmol) 4benzyloxy-6-bromo-2-trifluoromethyl-benzimidazol-1-ol in chloroform (260 ml) were cautiously added 19 ml (202 mmol) phosphorus tribromide and the reaction was refluxed for 4 h. After cooling to room temperature, the reaction mixture was poured into water (600 ml), neutralized with sodium bicarbonate solution and extracted with dichloromethane. The organic layers were dried over magnesium sulphate and concentrated in vacuo to afford 19.8 g (79%) of the title compound as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:22]=1)=[O:16]
Reactant: NNC(=O)c1ccc(NC(=O)CCc2ccccc2)cc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: CC(=O)O
Product: O=C(CCc1ccccc1)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(Br)cc32)cc1
Temperature: 100 °C
Yield: 79 %

Procedure:
Into a suspension of 5-bromo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)phenyl]-3-phenylpropanamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 621 mg of the title compound (79%) as a yellow powder in 99.3% purity by HPLC (Rt: 4.33, gradient of 8 mm, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH:27]4[CH2:29][CH:24]3[CH2:25][O:26]4)[N:18]2[CH3:21])=[C:14]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:28][CH:27]3[CH2:29][CH:24]2[CH2:25][O:26]3)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: Cn1c(CN2CC3CC2CO3)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC4CC3CO4)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 2-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-5-oxa-2-aza-bicyclo[2.2.1]heptane were reacted to give 384. LCMS m/z: 461.2 (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[CH:10][CH:9]=2)[CH:3]=1.[ClH:18].C(=O)([O-])O.[Na+].O1CCO[CH2:26][CH2:25]1>CN(C)C=O.ICC>[ClH:18].[ClH:18].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[NH:17])[S:16][CH2:25][CH3:26])=[CH:12][CH:13]=2)[CH:3]=1
Reactant: C1COCCO1
Reactant: Cc1ccnc(-c2ccc(NC(N)=S)cc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCSC(=N)Nc1ccc(-c2cc(C)ccn2)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To a suspension of N-(4-(4-methylpyridin-2-yl)phenyl)thiourea (186 mg) in N,N-dimethylformamide(4 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.383 ml) and iodoethane (0.306 ml), and the mixture was stirred at 50° C. for 2.5 hours. After cooling, the mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.5 ml). The precipitate was collected by filtration and recrystallized from ethanol-ethyl acetate to give N-(4-(4-methylpyridin-2-yl)phenyl)-S-ethylisothiourea dihydrochloride (162 mg).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28]O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1(=[O:36])[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][N:34]3[C:30](=[O:36])[CH2:31][CH2:32][C:33]3=[O:35])[N:27]=2)[CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CO)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OC1CN(c2nc(CN3C(=O)CCC3=O)cs2)C1)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 100.3 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidine (1.50 g, 3.53 mmol) (obtained as described in Reference Example 2(2)) in tetrahydrofuran (75 ml) were added succinimide (525 mg, 5.30 mmol), triphenylphosphine (1.39 g, 5.30 mmol) and 40% diethyl azodicarboxylate in toluene solution (2.03 ml, 5.30 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred in an ice bath for 4 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (1.79 g, yield 100%) as pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH3:11][C:12]1([CH3:32])[CH:29]=[C:28]([CH3:30])[C:27]2[C:14](=[CH:15][CH:16]=[C:17]3[C:26]=2[C:25](=[O:31])[O:24][C:23]2[C:18]3=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:13]1.[NH4+].[Cl-]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[OH:24][C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:17]1[C:26]([C:25]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:31])=[C:27]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:11])([CH3:32])[CH:29]=[C:28]2[CH3:30]
Reactant: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1ccccc13
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1=CC(C)(C)Nc2ccc(-c3ccccc3O)c(C(=O)N3CCCC3)c21
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Pyrrolidine (135 μL, 1.62 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and 1.6 M hexane solution of n-butyl litium was added dropwise thereto at 0° C. After the reaction mixture was stirred at same temperature for 30 minutes, an anhydrous tetrahydrofuran solution (3 mL) of 2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference Compound No. 1-1, 80 mg, 0.27 mmol) was dropped and then the reaction mixture was stirred for 30 minutes more. After the saturated aqueous NH4Cl solution (5 mL) was added to the reaction mixture, the reaction mixture was diluted with ethyl acetate (100 mL). The whole was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (80.2 mg) as a pale yellow solid. (Yield 82%)
Reaction SMILES: CS([O-])(=O)=O.[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][NH:14][C:10](=[O:11])[CH2:9][O:8][CH2:7][C:6]([OH:12])=[O:13]
Reactant: O=C1COCC(=O)O1
Reactant: NCCO
Agent: CS(=O)(=O)[O-]
Product: O=C(O)COCC(=O)NCCO

Procedure:
methanesulfonate by (a) reacting diglycolic anhydride and 2-aminoethanol to produce [2-(2-hydroxyethylamino)-2-oxoethoxy]acetic acid, (b) heating to cyclixe the latter to obtain 4-(2-hydroxyethyl)-3,5-dioxomorpholine, (c) esterifying the latter with methanesulfonyl chloride to produce 2-(3,5-dioxomorpholino)ethyl methanesulfonate and (d) reacting the mesylate with piperidine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[O:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:22](=[O:23])[C:21]2[CH:32]=[CH:33][C:34]([Cl:35])=[C:19]([Cl:18])[CH:20]=2)=[CH:26][CH:27]=1)#[N:2]
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Temperature: 125 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
tert-Butyl 2-(3-cyano-4-fluorophenyl)acetate (2.0 g, 8.5 mmol) and the product of step A (2.9 g, 10 mmol) were diluted with DMSO (22 mL) followed by the addition of potassium carbonate (1.4 g, 10 mmol). The reaction was heated to 125° C. and stirred for 12 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and 10% aqueous sodium carbonate. The layers were separated and the organic layer was washed with 10% aqueous sodium carbonate two more times followed by water and brine. The organic material was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 40M column eluting with hexanes:ethyl acetate (8:2) to yield tert-butyl 2-(3-cyano-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)acetate (2.5 g, 59% yield) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:13]=1)[C:8](O)=O)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[Br:33]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:33][CH2:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)n1

Procedure:
Reaction Scheme 13 provides an example for the preparation of 2,6-di-tert-butylisonicotinic acid (Compound C3) which is a reagent in accordance with Formula 8 for the preparation of several preferred compounds of the present invention. Thus, 2,6-di-tert-butyl-4-methylpyridine (available commercially from Aldrich Chemical Co.) is reacted with N-bromosuccinimide and benzoyl peroxide to provide 4-bromomethyl-2,6-di-tert-butylpyridine (Compound A3). Compound A3 is reacted with base (sodium hydroxyde) to yield the coresponding hydroxymethyl compound (Compound B3), which is thereafter oxidized in a Jones oxidation reaction to give 2,6-di-tert-butylisonicotinic acid (Compound C3).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1)#[N:2].C[Si]([N:13]=[N+:14]=[N-:15])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:8][C:5]1[S:6][CH:7]=[C:3]([C:1]2[NH:15][N:14]=[N:13][N:2]=2)[N:4]=1
Reactant: Cc1nc(C#N)cs1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2nnn[nH]2)cs1

Procedure:
A mixture of 4-cyano-2-methylthiazole (5.74 g) (U.S. Pat. No. 4,010,173 1977), trimethylsilyl azide (10.64 g) and dibutyltin oxide (115 g) in toluene (300 ml) was heated at 120° C. for 24 hours. The reaction mixture was diluted with ethyl acetate and extracted with dilute aqueous sodium hydroxide solution. The combined extracts were acidified to pH 5 with 1M HCl and extracted with ethyl acetate. The extracts were dried (MgSO4) and evaporated. Yield 4.53 g.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([CH:7]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]([O:12][CH2:13][C:14]#[C:15][CH2:16]O)=[O:11])#[N:6]>N1C=CC=CC=1.CCOCC.C(Cl)Cl>[C:5]([CH:7]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]([O:12][CH2:13][C:14]#[C:15][CH2:16][Cl:3])=[O:11])#[N:6]
Reactant: N#CC(c1ccccc1)C(CC(=O)OCC#CCO)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: N#CC(c1ccccc1)C(CC(=O)OCC#CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
Thionyl chloride (3.56 g, 30.0 mmol) was added via syringe over a 5 min period to a stirred solution of 8.00 g (24.0 mmol) of 4-hydroxy-2-butynyl 4-cyano-3,4-diphenylbutyrate in 2.4 ml of pyridine at 0°. The reaction mixture was stirred at room temperature for 2 hours in a flask equipped with a Drierite tube. The mixture was diluted with 40 ml of ether and 100 ml of methylene chloride and was washed sequentially with 40 ml of hydrochloric acid, 40 ml of saturated aqueous sodium bicarbonate, three 40-ml portions of water and 40 ml of saturated aqueous sodium chloride. The organic phase was dried (MgSO4), filtered, stripped and purified by column chromatography on silica gel (hexanes/methylene chloride) to yield 2.11 g (25%) of the title compound. The infrared and nmr spectra are in accord with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1.Cl.[NH2:24][C@H:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@H:10]([C:18]([NH:24][C@H:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)=[O:20])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 73.5 %

Procedure:
In 500 ml of a mixture of chloroform-tetrahydrofuran (2:1), were dissolved 29.9 g of N-(4-methoxybenzoyl)-phenylalanine, 23.2 g of methyl tyrosinate hydrochloride, 10.1 g of trethylamine and 11.6 g of H-hydroxysuccinimide and the mixture was cooled with ice. To the cold solution was added 20.6 g of N,N'-dicyclohexylcarbodiimide. The mixture was stirred for two hours and then allowed to sit at room temperature overnight. The precipitates were removed by filtration and the filtrate was concentrated. The residue was extracted with ethyl acetate. The extract was washed with 2% hydrochloric acid, 4% sodium bicarbonate and water, then dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 35 g of methyl N-(4-methoxybenzoyl)-phenylalanyltyrosinate with a mp. 195°-197° C in a yield of 74%. Analysis, calculated for C27H28O6N2C 68.05, H 5.92, N 5.88, found C 67.84, H 5.92, N 5.57.
Reaction SMILES: C(O[CH:5]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[N:10][CH:11]=1)(C)C.C(Cl)Cl.[Si]([C:24]#[N:25])(C)(C)C>[I-].[I-].[Zn+2].O>[CH:14]([O:13][CH:5]([C:6]1[CH:11]=[N:10][C:9]([CH3:12])=[N:8][CH:7]=1)[C:24]#[N:25])([CH3:15])[CH3:16]
Reactant: Cc1ncc(C(OC(C)C)OC(C)C)cn1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: Cc1ncc(C(C#N)OC(C)C)cn1
Reaction time: 24 h

Procedure:
A solution of 5-diisopropoxymethyl-2-methyl-pyrimidine (335 mg, 1.49 mmol) in DCM (5 mL, 80 mmol) was cooled at 0° C. Zinc diiodide (47.7 mg, 0.149 mmol) TMSCN (219 uL, 1.64 mmol) were added and cooling removed. After stirring for 24 hours TLC indicated that starting materiale was present. TMSCN (60 uL, 0.45 mmol) and zinc diiodide (48 mg, 0.15 mmol) were added and the reaction was stirred for a further 3.5 hours. The reaction was poured into water (20 mL) and extracted with DCM (3×20 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography 2-Isopropoxy-2-(2-methylpyrimidin-5-yl)acetonitrile (217 mg, 76%).
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:29][C:30]([C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1)([CH3:33])[CH:31]=O.O>O1CCCC1>[Br:2]/[CH:3]=[CH:31]/[C:30]([CH3:33])([C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1)[CH3:29]
Reactant: CC(C)(C=O)c1ccc(C(F)(F)F)cc1
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(/C=C/Br)c1ccc(C(F)(F)F)cc1
Temperature: -75 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 101.0 grams (0.23 mole) of bromomethyl triphenylphosphonium bromide in 400 mL of tetrahydrofuran was cooled in a dry ice-acetone bath, and 26.0 grams (0.23 mole) of potassium tert.-butoxide was added portionwise while maintaining the reaction mixture temperature between -70° and -75° C. Upon completion of addition, the reaction mixture was stirred at -75° C. for about 90 minutes. After this time a solution of 50.0 grams (0.23 mole) of 2-methyl-2-(4-trifluoromethylphenyl)propanaldehyde (prepared in Step C of this Example) in 100 mL of tetrahydrofuran was added dropwise while maintaining the reaction mixture temperature below -65° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. The reaction mixture was then poured into 500 mL of water and extracted with two 300 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel using petroleum ether as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 40.9 grams of cis/trans-1-bromo-3-methyl-3-(4-trifluoromethylphenyl)-1-butene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH2:19][NH:20][CH:21]1[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22]1.[Cl:36][C:37]1[C:38]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:39]=2[S:40][C:41]=1[C:42](Cl)=[O:43]>>[Cl:36][C:37]1[C:38]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:39]=2[S:40][C:41]=1[C:42]([N:20]([CH2:19][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15](=[O:17])(=[O:18])[NH2:16])=[CH:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:21]1[CH2:22][CH2:23][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:25][CH2:26]1)=[O:43]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Crude biaryl amine 216 (514 mg) is treated with acid chloride 8 (327 mg, 1.22 mmol) using Method D to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[NH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: NN1CCOCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NN3CCOCC3)n2)cc1
Yield: 12 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and 4-Aminomorpholine (12 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (6 mg, 12% yield.) MS/ES+: m/z=416.