Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:30])([OH:29])[OH:28])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Ca+2:40].[OH-]>C(O)C.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:28])([O-:29])[O-:30])(=[O:24])=[O:25])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Ca+2:40]
Reactant: O=P(O)(O)NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=P([O-])([O-])NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a suspension of ((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonyl)phosphoramidic acid (2) (0.200 g, 0.365 mmol) in ethanol (5 mL) was added calcium hydroxide (0.041 g, 0.55 mmol) in 2 mL of water. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The reaction mixture was concentrated to dryness and the residue was washed with ethyl acetate (2×10 mL), acetone (2×10 mL) and acetonitrile (2×15 mL) to afford calcium (5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonylphosphoramidate (7) (0.195 g, 0.322 mmol, 88.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 4.77 (d, J=4.27 Hz, 2H), 6.92 (t, J=4.14 Hz, 1H), 7.26-7.35 (m, 2H), 7.39 (d, J=8.03 Hz, 1H), 7.50-7.60 (m, 5H), 7.79 (td, J=7.65, 1.76 Hz, 1H), 7.83-7.89 (m, 1H), 7.91-7.96 (m, 1H), 8.30 (d, J=4.27 Hz, 1H), 9.10 (s, 1H), 9.25 (t, J=2.13 Hz, 1H), 9.73 (d, J=2.01 Hz, 1H); LCMS Method I: retention time 1.66 min, [M−1]=547. HPLC Method B: Purity 94.3%, retention time 6.17 min, HPLC Method C: Purity 94.45%, retention time 5.97 min. Elemental analysis: Compound was hygroscopic, elemental analysis not obtained.
Reaction SMILES: [NH2:1][C:2](=[N:37]O)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][CH2:19][C@H:20]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:36])[CH2:10]2)=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C.C>C(O)(=O)C.O.[Pd]>[C:21]([OH:23])(=[O:22])[CH3:20].[NH2:37][C:2](=[NH:1])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][CH2:19][C@H:20]([NH:26][S:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)(=[O:29])=[O:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:36])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)[C@H](CNC(=O)CN1CCN(c2ccc(C(N)=NO)cc2)CC1=O)NS(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)[C@H](CNC(=O)CN1CCN(c2ccc(C(=N)N)cc2)CC1=O)NS(=O)(=O)c1ccccc1
Reaction time: 3 h
Yield: 160.1 %

Procedure:
Ethyl (2S) -3-{[2- (4-{4-[amino(hydroxyimino)methyl]phenyl}-2-oxopiperazino)acetyl]amino}-2-[(phenylsulphonyl)amino]propanoate (Example 1) (1.5 g, 2.75 mmol) is dissolved in 50 ml of acetic acid. 600 mg of acetic anhydride (5.6 mmol) and 0.76 g of 10%; palladium-on-charcoal are added. The hydrogenolysis is carried out at room temperature under 50 psi for 3 hours. The catalyst is filtered off and the solution is evaporated to dryness. The solid obtained is dissolved in 150 ml of water and treated with charcoal. The solution is filtered. The filtrate is freeze-dried to give 1.3 g of a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][C:5]([OH:12])([CH2:9][CH:10]=[CH2:11])[CH2:6]C=C.[Cl-].OC[P+](CO)(CO)CO>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(O)(C)C.[OH-].[Na+].O>[CH3:14][O:13][CH:3]([O:2][CH3:1])[CH2:4][C:5]1([OH:12])[CH2:6][CH:11]=[CH:10][CH2:9]1
Reactant: C=CCC(O)(CC=C)CC(OC)OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: OC[P+](CO)(CO)CO
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: COC(CC1(O)CC=CC1)OC
Reaction time: 15 h

Procedure:
A solution of 4-(2,2-dimethoxyethyl)hepta-1,6-dien-4-ol (28 g, 140 mmol) in DCM (2L) was charged to a 3 L RB flask. Dry argon was bubbled through the solution for 30 minutes. Grubbs second generation catalyst (5.9 g, 7.0 mmol) was added and the reaction was allowed to stir under argon for 15 hours. The reaction was quenched with a solution of tetrakis-(hydroxymethyl)phosphonium chloride (27 g, 140 mmol) in isopropanol (200 mL) and 10 N NaOH (14 mL), and stirred for 15 hours. The reaction was diluted with water (1 L) and poured into a seperatory funnel. The DCM layer was separated and the aqueous was extracted with DCM (3×100 mL). The combined organics were concentrated to a dark oil which was purified by flash chromatography on a 330 g ISCO column eluting by gradient hexanes to 20% EtOAc/ hexanes over a 50 minute period. Product fractions were combined to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C(N(CC)CC)C.[CH:17]1([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:24][CH2:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nc(Cl)cc(NCC2CCCCC2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (1.64 g, 10 mmol) in CH3OH (20 mL) were added triethylamine (2.02 g, 20 mmol) and cyclohexylmethanamine (1.36 g, 12 mmol), and the reaction mixture was stirred for 3 hours at 60° C. The mixture was evaporated under vacuum, and the resulting residue was subjected to SiO2 chromatography (gradient: EtOAc/petroleum ether 1:4 to 1:2) to afford the title compound (1.6 g, 66%) as light yellow solid. LC-MS (ES) m/z=241, 243 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[N:6]([CH2:8][CH2:9][O:10]C2CCCCO2)[CH:7]=1)[CH3:2].[Cl:30]CCl.[ClH:33]>CO>[ClH:30].[ClH:33].[CH2:1]([C:3]1[N:4]=[C:5]([CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=1)[CH3:2]
Reactant: CCc1cn(CCOC2CCCCO2)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: CCc1cn(CCO)c(C2CCNCC2)n1
Reaction time: 8 h
Yield: 100 %

Procedure:
Combine tert-butyl 4-(4-ethyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (4.70 g, 11.53 mmol), dichloromethane (100 mL), and methanol (50 mL). Add hydrogen chloride (20 mL) (4 M in dioxane) slowly. Stir overnight under nitrogen. Concentrate in vacuo to give the title compound (3.40 g, 100%). MS (ES) m/z=224 [M]+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH:5]1[CH:6]=[CH:7][C:8]2N[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:9]=2[CH:10]=1.[S:20](=[O:24])(=[O:23])([OH:22])[OH:21]>C(O)(=O)C.O>[CH:5]1[CH:6]=[CH:7][C:8]2[N:1]([C:2]([NH2:4])=[O:3])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:9]=2[CH:10]=1.[S:20](=[O:22])(=[O:21])([OH:24])[OH:23]
Reactant: NC(N)=O
Reactant: C1=Cc2ccccc2Nc2ccccc21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 27.5 °C

Procedure:
To a suspension of urea (400 g, 6.66 mols) in acetic acid (500 ml), sulphuric acid (15 ml) was added, followed by iminostilbene (100 g, 0.518 mols), under stirring at 25-30° C. The resulting reaction mixture was heated to 80-85° C. and maintained for a period of 7-8 hours, and the reaction was monitored by thin layer chromatography (TLC). The reaction mass was diluted with water, and the resulting carbamazepine product (m.p. 188-189° C.) separated by filtration, washed with water until neutral and dried at 90-100° C. until constant weight. The identity of the product was further verified by tlc (toluene/methanol 18/03, uv=254 nm) to be identical to the reference compound and by infra-red spectroscopy (KBr) Vmax=3466, 1677, 1605, 1595 cm−1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[NH:18][C:19](=[O:21])[CH3:20])[C:3]1=[O:22].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.C(N(CC)CC)C.O.[OH-].[Na+]>C(O)(C)C.ClCCl>[CH:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([NH:18][C:19](=[O:21])[CH3:20])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])[CH3:16]
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexyl)acetamide (˜35 g, 0.115 mol) in isopropanol (600 mL) was added 4-chloro-6-(trifluoromethyl)quinazoline (32 g, 0.138 mol, 1.2 eq, see: P. H. Carter et al., PCT application WO 2005/021500). The mixture was stirred at room temperature overnight before being charged with triethylamine (46 g, 0.46 mol, 4 eq). The mixture was stirred at 60° C. for 10 h. The solvent was removed under reduced pressure to give an oil. Azeotropic distillation with isopropanol was performed twice. The residue was dissolved in dichloromethane (600 mL) and extracted with water (250 mL, containing 4 eq acetic acid). Dichloromethane (600 mL) was added to the combined aqueous washes, and the mixture was cooled to 0° C. Aqueous NaOH (50% by weight) was added with stirring until the pH reached 11. The water layer was extracted with dichloromethane twice (2×600 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give the amorphous free base of the title compound (99% purity by HPLC). LC/MS found [M+H]+=507.3. 1H-NMR (400 MHz, d4-MeOH): δ 8.82 (s, 1H), 8.59 (s, 1H), 8.05 (dd, J=8.8, 1.8 Hz, 1H), 7.9 (d, J=8.7 Hz, 1H), 5.28 (t, J=8.6 Hz, 1H), 4.58 (br s, 1H), 4.06 (m, 1H), 3.52-3.68 (m, 2H), 3.43 (m, 1H), 2.76 (br s, 1H), 2.55 (m, 1H), 2.28 (s, 3H), 2.1-2.3 (m, 3H), 2.0 (s, 3H), 2.0 (m, 1H), 1.65-1.8 (m, 3H), 1.09 (app. dd, J=24, 6.4 Hz, 6 H).
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[N:5]=[N:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1>>[NH:1]([C:4]1[N:5]=[N:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[NH2:2]
Reactant: Clc1ccc(-c2ccncc2)nn1
Reactant: NN
Product: NNc1ccc(-c2ccncc2)nn1

Procedure:
The reaction of hydrazine with 3-chloro-6-(4-pyridinyl)pyridazine to produce 3-hydrazino-6-(4-pyridinyl)-pyridazine is carried out by heating the reactants at about 60° C. to 100° C. in a suitable solvent, preferably but optionally under an inert atmosphere. The reaction is preferably run at about 75° C. to 85° C. and is conveniently and preferably run by heating the reactants in refluxing isopropyl alcohol, preferably under nitrogen. Other suitable solvents include dioxane, ethanol, 2-methoxyethanol, or the like. Optionally, the reaction can be run in the absence of a solvent.
Reaction SMILES: [CH:1]1([C@H:4]([NH:8]C(=O)[O-])[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1.[ClH:12]>CCO.C(Cl)(Cl)Cl.O1CCOCC1.[Pd]>[ClH:12].[CH:1]1([C@H:4]([NH2:8])[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1
Reactant: COC[C@@H](NC(=O)[O-])C1CC1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COC[C@@H](N)C1CC1
Yield: 100 %

Procedure:
To a solution of (S)-1-cyclopropyl-2-methoxyethylcarbamate (4.36 g, 17.5 mmol) in EtOH (80 ml) and CHCl3 (3 mL) in a Parr bottle was added 4 N HCl in dioxane (5 mL) and Pd/C (476 mg, 10%, wet, Degussa type). The mixture was placed on a Parr shaker under H2 atm at 45 psi for 16 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated then reconcentrated from hexanes (2×) to afford (S)-1-cyclopropyl-2-methoxyethanamine hydrochloride (2.65 g, 100% yield) as a white solid: mp 190-192° C.; [α]25D+14.3 (c 0.446, MeOH); 1H NMR (400 MHz, CDCl3) δ 8.41 (s br, 3H), 3.68 (d, J=5.6 Hz, 2H), 3.39 (s, 3H), 2.64-2.60 (m, 1H), 1.20-1.13 (m, 1H), 0.71-0.58 (m, 3H), 0.32-0.28 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 72.1, 59.2, 57.5, 10.7, 4.2, 4.1; LRMS (ESI m/e 231.2 [(2M+H)+, calcd for C12H27N2O2 231.2].
Reaction SMILES: CS[C:3]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=O)[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=[O:5].C(Cl)Cl.O>C(O)(=O)C.[Zn].S([O-])([O-])(=O)=O.[Cu+2]>[O:24]=[C:15]1[C:16]2[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][N:14]1[C:11]1[CH:12]=[CH:13][C:8]([CH:3]([CH3:7])[C:4]([OH:6])=[O:5])=[CH:9][CH:10]=1
Reactant: CSC(C)(C(=O)O)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 97.7 %

Procedure:
α-Methylthio-α-(p-phthalimidophenyl)propionic acid (123 mg), 300 mg of zinc powder and 16 mg of anhydrous copper sulfate were stirred in 1.5 ml of acetic acid at the refluxing temperature for 5 hours. After cooling, 30 ml of methylene chloride and 20 ml of water were added, and the insoluble precipitate was separated by filtration. The filtrate was adjusted to pH 1 with conc. hydrochloric acid, and extracted three times with 20 ml of methylene chloride. The organic layer was washed with 10 ml of water, and dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure to afford 99 mg of α-[p-(1-oxo-2-isoindolinyl) phenyl]propionic acid in a yield of 98%.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:16][CH2:17][C:18]2[S:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=2)=[CH:4][C:5]([NH:8]C(=O)OC(C)(C)C)=[N:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([CH2:16][CH2:17][C:18]2[S:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(C)c1csc(CCc2cc(NC(=O)OC(C)(C)C)ncc2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1csc(CCc2cc(N)ncc2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
The tert-butyl N-{5-fluoro-4-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-pyridyl}-carbamate (393 mg, 1.08 mmol) obtained in (G) was dissolved in methylene chloride (10 ml), added with trifluoroacetic acid (10 ml) under ice cooling, and stirred overnight at room temperature. The reaction mixture was concentrated, and the resulting residue was dissolved in chloroform and washed with 1 N aqueous sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:2) to obtain the title compound (40.0 mg, 33%) as an oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH:20][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: COc1cccc(CN)c1
Solvent: CN(C)C=O
Product: COc1cccc(CNC(=O)c2ccc3cnccc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (10 mL) at room temperature was added sequentially 1-hydroxyhenzotriazole hydrate (42.7 mg, 0.316 mmol), 3-methoxybenzylamine (56.6 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a clear oil (79.1 mg, 94%).
Reaction SMILES: [NH2:1][CH:2]([CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[C:3]([O:5][CH2:6][C@@H:7]([C:15]([OH:17])=[O:16])[NH:8]C(=O)C(F)(F)F)=[O:4].ClCC(O)=O.[N:29]([O-])=O.[Na+]>O>[N+:1](=[C:2]([CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[C:3]([O:5][CH2:6][C@@H:7]([C:15]([OH:17])=[O:16])[NH2:8])=[O:4])=[N-:29]
Reactant: NC(C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O)C(O)C(F)(F)F
Reactant: O=N[O-]
Agent: O=C(O)CCl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=C(C(=O)OC[C@H](N)C(=O)O)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To a solution of O-(2-amino-3-hydroxy-4,4,4-trifluoro-1-oxobutyl)-N-trifluoroacetyl-L-serine (685 mg) and chloroacetic acid (0.04 ml) in water (7 ml) was added sodium nitrite (227 mg) at room temperature. After stirring for 30 minutes at room temperature, the reaction mixture was neutrized with 2M tris buffer solution to pH 7.0 to 7.3 and then Acylase I (acylase, Sigma A-7264, made by Sigma Chemicals) (140 mg) was added. The mixture was stirred for 6 hours at room temperature and chromatographed on carbon (60 ml) eluting successively with water and a 9:1 mixture of water and acetone to give a crude product, which was chromatographed on preparative thin layer chromatography eluting with a 65:35:4 mixture of chloroform, methanol and water, and lyophilized to give O-(2-diazo-3-hydroxy-4,4,4-trifluoro-1-oxobutyl)-L-serine (113 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[O:21][C:22]([CH2:25][N:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:29])[N:3]=1.B([C:33]1[CH:44]=[CH:43][C:36]([CH2:37][C@@H:38]([C:40]([OH:42])=[O:41])[NH2:39])=[CH:35][CH:34]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:39][C@@H:38]([CH2:37][C:36]1[CH:43]=[CH:44][C:33]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[O:21][C:22]([CH2:25][N:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:29])[N:3]=2)=[CH:34][CH:35]=1)[C:40]([OH:42])=[O:41]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: CN(C)Cc1ccc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN(C)Cc1ccc(-c2ccccc2C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)o1
Temperature: 150 °C
Yield: 33.1 %

Procedure:
In a microwave vial, 4-chloro-6-{1-[2-(5-dimethylaminomethyl-furan-2-yl)-phenyl]2,2,2-trifluoro-ethoxy}-pyrimidin-2-ylamine (37 mg, 0.087 mmol), 4-borono-L-phenylalanine (22 mg, 0.10 mmol), 1 ml of actonitrile and 0.7 ml of water were mixed. Then, 0.3 ml of 1N aqueous sodium carbonate was added, followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 16 mg of (S)-2-amino-3-[4-{2-amino-6-{1-[2-(5-dimethylaminomethyl-furan-2-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl]-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 7.88 (d, J=8.4 Hz, 2H), 7.71 (d, J=7.6 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.42 (m, 2H), 7.40 (d, J=1.6 Hz, 2H), 7.34 (d, J=8.4 Hz, 1H), 6.89 (q, J=3.6 Hz, 2H), 6.66 (s, 1H), 4.54 (s, 2H), 4.20 (q, J=6 Hz, 1H), 3.3 (m, 1H), 3.14 (m, 1H), 2.84 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.C1C(C(OO)=[O:18])=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]2[O:18][CH:9]2[CH:8]=[CH:7][CH:6]=1
Reactant: CC=CCc1ccccc1
Reactant: O=C(OO)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC=CCC1=CC=CC2OC12
Reaction time: 8 h
Yield: 19 %

Procedure:
To 5.3 g of m-methylallylbenzene was added 85 ml of chloroform solution containing perbenzoic acid and the mixture was allowed to stand at room temperature overnight. The resulting solution was washed with sodium hydroxide solution, Mohr's salt solution and then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was distilled under reduced pressure to give 1.1 g (yield 19%) of m-methylallylbenzene oxide having a boiling point of 90° C/7 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.O>ClCCl>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][S:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)(=[O:10])=[O:9])=[CH:24][CH:23]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCc1ccc(F)cc1)c1cncc(Br)c1
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-3-pyridinesulfonyl chloride (CAS#65001-21-0, 256 mg, 1.0 mmol) in dichloromethane (8 mL) at 0° C. was added diisopropylethylamine (0.350 mL, 2.0 mmol) followed by 4-fluorobenzylamine (CAS#140-75-0, 0.11 mL, 0.95 mmol). The reaction was put at room temperature and stirred for 15 minutes. The reaction was then poured into water and diluted with dichloromethane. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to furnish 5-bromo-pyridine-3-sulfonic acid 4-fluoro-benzylamide without the need for further purification. MS: (ES+) m/z 344.8 (M+H)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.Cl.O1CCOCC1>C(O)C>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: Clc1ncc(CCc2cccnc2)c2ccccc12
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Clc1ccc(Nc2ncc(CCc3cccnc3)c3ccccc23)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere, 250 mg (0.93 mmol) of 1-chloro-4-(2-pyridin-3-yl-ethyl)-isoquinoline in 2.9 ml of abs. ethanol are mixed with 131 mg (1.02 mmol) of 4-chloro-aniline and 0.23 ml of 4 N HCl/dioxane, and stirred for 8 h at 80° C. The mixture is cooled to RT, filtered and the residue washed with acetonitrile. The residue is dissolved in 4 ml of water, then 0.9 ml of sat. NH3 solution are added, stirring is effected for 10 min, the precipitate is filtered off and washed with water. Recrystallisation from acetonitrile yields 1-(4-chloroanilino)-4-[2-(pyridin-3-yl)-ethyl]-isoquinoline; m.p.157-158° C.