Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]=1[C:17]1[S:21][C:20]([N:22]2[CH2:25][C:24]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[CH2:23]2)=[N:19][N:18]=1.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[S:21][C:20]([N:22]2[CH2:25][C:24]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:27][CH2:26]3)[CH2:23]2)=[N:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(OS(=O)(=O)C(F)(F)F)c(F)c3F)s1)C2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(-c4cn[nH]c4)c(F)c3F)s1)C2
Temperature: 120 °C
Yield: 18.9 %

Procedure:
A mixture of tert-butyl 2-(5-(2,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (68 mg, 0.119 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (35 mg, 0.179 mmol) in dioxane (1 mL) was stirred under nitrogen atmosphere. To this suspension was added Pd(PPh3)4 (7 mg, 0.006 mmol) followed by a solution of Na2CO3 (38 mg, 0.358 mmol) in water (0.25 mL). The reaction mixture was sealed and heated at 120° C. for 1 hour under microwave irradiation. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The organic phase was separated and concentrated in vacuo to afford the crude product as an off-white solid. The crude material was purified by UV directed preparative HPLC under basic conditions (NH4OH modified) to afford he title compound as a white solid (11 mg, 19% yield). MS m/z 489.1 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 8.18 (s, 2H), 7.85 (ddd, J=8.6, 6.7, 1.8 Hz, 1H), 7.70 (ddd, J=8.7, 7.0, 1.8 Hz, 1H), 3.91 (s, 4H), 3.28-3.31 (m, 4H), 1.74 (t, J=5.6 Hz, 4H), 1.40 (s, 9H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][C:17]([F:23])=[C:18]([OH:22])[CH:19]=2)[C:14]1=[O:24])[CH2:10][CH2:11][CH3:12]>CN(C)C=O>[Br:1][C:19]1[C:18]([OH:22])=[C:17]([F:23])[CH:16]=[C:15]2[C:20]=1[CH2:21][CH:13]([CH2:9][CH2:10][CH2:11][CH3:12])[C:14]2=[O:24]
Reactant: CCCCC1Cc2cc(O)c(F)cc2C1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCC1Cc2c(cc(F)c(O)c2Br)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
N-Bromosuccinimide (1.41 g, 7.93 mmol) was added to a solution of 2-butyl-6-fluoro-5-hydroxy-1-indanone (1.76 g, 7.93 mmol) in anhydrous N,N-dimethylformamide (15 mL). The resulting solution was stirred at room temperature for two hours. The solvent was evaporated under vacuum and the residue was partitioned between EtOAc (100 mL) and water (100 ml). The organic phase was washed with water (4×100 mL) and brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to provide crude 4-bromo-2-butyl-6-fluoro-5-hydroxy-1-indanone (2.17 g) as an oil.
Reaction SMILES: C(NC1C=CC=C2C=1CCC(N)C2)(=[O:3])C.Cl.[C:17]([NH:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][CH:25]([NH:31][CH2:32][C:33]1[CH:38]=CC=CC=1)[CH2:26]2)(=[O:19])[CH3:18]>>[C:17]([NH:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][CH:25]([NH:31][C:32](=[O:3])[CH2:33][CH3:38])[CH2:26]2)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cccc2c1CCC(NCc1ccccc1)C2
Reactant: CC(=O)Nc1cccc2c1CCC(N)C2
Agent: Cl
Product: CCC(=O)NC1CCc2c(cccc2NC(C)=O)C1

Procedure:
Starting from 12.3 g (0.06 mol) of 5-acetylamino-2-amino-tetraline (known substance prepared by debenzylation of 5-acetylamino-2-benzylamino-tetraline (Example 4.1.16) analogously to Example 4.4.1) the title compound is obtained by propionylation analogously to Example 4.5.1 a) in a yield of 13.5 g (86.3% of theory).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][N:4]=1.[CH3:13]COCC>>[F:12][C:2]([F:1])([F:11])[C:3]1[N:4]=[CH:5][C:6]([CH:9]([OH:10])[CH3:13])=[CH:7][N:8]=1
Reactant: O=Cc1cnc(C(F)(F)F)nc1
Reactant: CCOCC
Product: CC(O)c1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
To a magnetically stirred solution of methyl Grignard (19.9 mL of a 3 M solution in ether (Et2O), 59.7 mmol) in Et2O (167 mL) was added a solution of 2-trifluoromethylpyrimidine-5-carbaldehyde (9.56 g, 54.3 mmol) in Et2O (50 mL) at 0° C., and the resulting pale yellow solution was warmed to room temperature (RT) and stirred for 2.5 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride (NH4Cl) (50 mL) at 0° C., and the mixture was warmed to RT. The phases were separated and the organic phase was dried over Na2SO4, filtered, and concentrated to give a light yellow oil (9.32 g crude). The oil was purified by flash chromatography (330 g SiO2, 0→100% EtOAc/hexanes gradient) to give 1-(2-trifluoromethylpyrimidin-5-yl)ethanol (E) (8.87 g, 85%) as a light yellow solid: mp 43-45° C.; 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 2H), 5.15-5.07 (m, 1H), 2.26 (d, J=4.0 Hz, 1H), 1.62 (d, J=6.5 Hz, 3H); MS (EI) m/z 192 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)cc1
Reaction time: 18 h
Yield: 99 %

Procedure:
A mixture of ethyl 3-(4-aminophenyl)acrylate(1.5 g) and 10% Pd on activated carbon (0.3 g) in ethanol (20 ml) was hydrogenated at 30 psi for 18 h and filtered over Celite. Removal of the volatiles in vacuo provided ethyl 3-(4-aminophenyl)propionate (1.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:22]([CH3:24])=[CH2:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].[H][H]>[Pd].O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:22]([CH3:24])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2]
Reactant: [H][H]
Reactant: C=C(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)OC)cc3)oc12
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1
Yield: 99.1 %

Procedure:
To a 5-gallon reaction vessel was added methyl 4-(5-cyano-7-isopropenyl-1,3-benzoxazol-2-yl)benzoate (40.6 g, Step A), tetrahydrofuran (4 L), and 10% palladium on carbon (8 g). The reaction mixture was heated to 60° C. under 10 psi of hydrogen for 3 h, and then filtered through Celite, washing generously with dichloromethane. Concentration of the eluent in vacuo provided 40.5 g (99%) of the title compound. Mass spectrum (ESI) 321.1 (M+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH2:21][C:22]([O:24]C)=[O:23].[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2c(CC(=O)O)c(C)nc3sc4c(c23)CCC4)cc1
Temperature: 60 °C
Yield: 63.1 %

Procedure:
To a solution of methyl [2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate (0.071 g; 0.202 mmol) in dioxane (4 mL) and water (1 mL) was added a 1N lithium oxide solution (1 mL; 1 mmol). The reaction mixture was heated at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphatesulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.043 g (63%) of the title compound as a beige powder.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]([F:35])([F:34])[O:20][C:21]1[CH:33]=[CH:32][C:24]([O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[N+:15]([C:13]1[N:12]=[C:9]2[N:8]([CH:14]=1)[CH2:7][C@H:6]([NH:5][C:3](=[O:4])[CH2:2][N:29]1[CH2:30][CH2:31][CH:26]([O:25][C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:34])[F:35])=[CH:33][CH:32]=3)[CH2:27][CH2:28]1)[CH2:11][O:10]2)([O-:17])=[O:16]
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Product: O=C(CN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 56 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(trifluoromethoxy)phenoxy)piperidine (275 mg, 1.0 mmol) as crude materials, title compound as 140 mg yellow powder was generated and yield was 56%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]2[N:18]=[CH:19][C:20]([C:22]4[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=4)=[CH:21][C:12]3=2)=[CH:5][CH:4]=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]2[N:18]=[CH:19][C:20]([C:22]4[CH:23]=[C:24]([NH:28][S:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)(=[O:37])=[O:36])[CH:25]=[CH:26][CH:27]=4)=[CH:21][C:12]3=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3[nH]c4ncc(-c5cccc(N)c5)cc4c3c2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(-c2ccc3[nH]c4ncc(-c5cccc(NS(=O)(=O)c6ccccc6)c5)cc4c3c2)cc1
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of 3-(6-(4-methoxyphenyl)-9H-pyrido[2,3-b]indol-3-yl)benzenamine (23 mg, 0.06 mmol, 1 equiv.), in anhydrous pyridine (0.300 ml), benzenesulfonyl chloride (0.009 ml) is added under argon. The reaction is carried out at room temperature for 3 hours and is then quenched with H2O (5 ml). The aqueous layer is extracted with AcOEt (3×5 ml) and CH2Cl2 (5 ml). The organic layers are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified over silica gel chromatography (eluant CH2Cl2/AcOEt 7:3) to afford the product as a white solid (15 mg, 0.03 mmol) in 50% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:21]1[CH:22]=[N:23][C:24]([O:27]C)=[CH:25][CH:26]=1.B(Br)(Br)Br.ClCCl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:18])[F:19])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[N:23][CH:22]=1
Reactant: COc1ccc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)cn1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1COCCO1
Product: Oc1ccc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)cn1
Yield: 31 %

Procedure:
A solution of 3-[4-fluoro-3-(6-methoxypyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (30 mg, 0.077 mmol) in 1,4-dioxane (2 ml) was treated with a 1M solution of boron tribromide in dichloromethane (0.77 ml, 0.77 mmol) and heated at reflux for 72 h. The mixture was partitioned between dichloromethane and water and the aqueous layer adjusted to pH 7. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated in vacuo. 5-[2-Fluoro-5-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)phenyl]pyridin-2-ol was obtained in 31% yield after purification on silica gel: δH (400 MHz, DMSO) 6.46 (1H, d, J 9), 7.48-7.55 (2H, m), 7.72 (1H, ddd, J 8, 5 and 2), 7.76-7.82 (1H, m), 7.90 (1H, dd, J 8 and 2), 8.30 (1H, s), 9.35 (1H, d, J 7), 11.97 (1H, br); m/z (ES+) 375 (M++H).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: O=C(O)c1ccccn1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(-c3ccccn3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 2-pyridinecarboxylic acid, the title compound was obtained in 82% purity by HPLC. MS(ESI+): m/z=440.2.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH:5]([CH2:7]O)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([Cl:49])[C:37]=1[CH:38]([O:41][Si:42]([CH2:47][CH3:48])([CH2:45][CH3:46])[CH2:43][CH3:44])[CH2:39][NH2:40].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([Cl:49])[C:37]=1[CH:38]([O:41][Si:42]([CH2:45][CH3:46])([CH2:47][CH3:48])[CH2:43][CH3:44])[CH2:39][NH:40][CH2:7][CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[O:6]1
Reactant: CC1CCC(CO)O1
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cncc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(CNCC1CCC(C)O1)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of 5-methyltetrahydrofuran-2-methanol in DCM was added Dess-Martin periodinane (1.2 eq.). The mixture was stirred at room temperature overnight. The crude mixture was directly added to a solution of 2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethanamine (1 eq.) in DCM followed by AcOH (1.2 eq.) and NaBH(OAc)3 (1.5 eq.). The reaction mixture was stirred at room temperature. After 2 h, the mixture was quenched with saturated aqueous Na2S2O3 and saturated NaHCO3. The reaction mixture was extracted with DCM. The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 25% EtOAc in heptane to provide 2-(3,5-dichloropyridin-4-yl)-N-((5-methyltetrahydrofuran-2-yl)methyl)-2-((triethylsilyl)oxy)ethanamine (A281) as a light-yellow syrup. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (2H, s), 5.34-5.46 (1H, m), 3.71-3.90 (2H, m), 3.10 (1H, dt, J=12.5, 8.1 Hz), 2.90 (1H, td, J=12.1, 6.0 Hz), 2.52-2.67 (2H, m), 1.71-2.07 (3H, m), 1.47-1.64 (1H, m), 1.19-1.38 (1H, m), 1.11 (3H, t, J=6.3 Hz), 0.77-0.89 (9H, m), 0.40-0.62 (6H, m); LCMS (ESI) m/z 419.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]O.[Br-:14].[C:15]1([PH+:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[Br-:14].[C:28]1([P+:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3][C:2]([F:13])([F:12])[F:1])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: OCc1ccccc1OC(F)(F)F
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CC#N
Product: FC(F)(F)Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
5 g (26 mmol) of 2-trifluoromethoxybenzyl alcohol and 8.5 g (24.7 mmol) of triphenylphosphonium bromide are heated under reflux in 100 ml of acetonitrile for 3 h. After cooling, the resulting precipitate is filtered off with suction and dried. 13.5 g (quant.) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19][NH2:20]>>[CH3:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19]/[N:20]=[C:10](/[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=1)\[CH3:11]
Reactant: Cc1cccc(CON)c1
Reactant: COc1ccc(C(C)=O)cc1O
Agent: Cl
Product: COc1ccc(/C(C)=N/OCc2cccc(C)c2)cc1O
Yield: 90.8 %

Procedure:
Acetophenone 12 (50 mg, 0.301 mmol) was condensed with O-(3-methylbenzyl)hydroxylamine hydrochloride (28) (57 mg, 0.328 mmol) according to the general procedure II-B defined above. After being heated for 15 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing residue was dissolved in CH2Cl2 (15 mL), washed with H2O (2×10 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The oil thus obtained was subjected to flash chromatography (1:19 v/v ethyl acetate/hexane elution) to afford the title compound CP30264 (78 mg, 91%) as a pale-orange oil, Rf 0.6 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H]1COS(C)(=O)=O
Temperature: 0 °C
Yield: 37.5 %

Procedure:
A mixture of (2R)-1-Boc-2-(hydroxymethyl)azetidine (1.5 g, 8.0 mmol; see Tetrahedron Asym. 1998, 9, 2791) and triethylamine (3.5 g, 35 mmol; Spectrum) in dry THF (20 mL) was cooled to 0° C., and methanesulfonyl chloride (0.75 mL, 9.7 mmol; Aldrich) was added slowly with stirring. The reaction mixture was allowed to warm to room temperature and stir for 1 hour, then the solid was removed by filtration and the organic phase was concentrated. The residue was dissolved in dichloromethane (40 mL), washed with water (20 mL), and then concentrated to afford the title compound (800 mg, 3.0 mmol; 38% yield). MS (DCl/NH3): 266 (M+1)+, 283 (M+18)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:15])[CH2:13]Br)=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:19][NH:20][CH3:21]>C(O)C>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:15])[CH2:13][N:20]([CH3:21])[CH3:19])=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CNC
Reactant: CCCCc1ccc(NC(=O)CBr)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCCCc1ccc(NC(=O)CN(C)C)c([N+](=O)[O-])c1

Procedure:
A suspension of N-(4-n-butyl-2-nitrophenyl)-2-bromoacetamide (41 g) in ethanol (200 ml) was treated with a solution of dimethylamine in ethanol (90 ml of 20% w/w). The mixture was refluxed for one hour and the ethanol was evaporated off. Water (100 ml) was added and the mixture extracted with diethyl ether (3 × 200 ml). The extract was dried over magnesium sulphate, filtered and evaporated to give N-(4-n-butyl-2-nitrophenyl)-2-dimethylaminoacetamide as a yellow oil which was used without further purification in the next stage.
Reaction SMILES: [CH2:1]([O:8][P:9]([CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:18])[O:10]CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.O>[CH2:1]([O:8][P:9]([CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:10])[OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P(CCOCc1ccccc1)(OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=P(O)(CCOCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-benzyloxy-ethyl)-phosphonic acid dibenzyl ester (0.200 g, 0.543 mmol) in THF was added a solution of NaOH (1.36 mL, 1M) in water. The reaction mixture was stirred at room temperature for 3 hours. Most of THF was removed in vacuo and the residue was dissolved in water. The aqueous solution was washed with ethylacetate three times then acidified with 1N HCl (to pH=1) then extracted with ethylacetate. The organic phase was dried (MgSO4), concentrated and co-evaporated with toluene in vacuo to afford the mono-acid, (2-benzyloxy-ethyl)-phosphonic acid monobenzyl ester, 173 (0.160 g. 100%) as an oil with no further purification: 1H NMR (CDCl3) δ 9.25 (bs, 1H), 7.4-7.1 (m, 10H), 4.5 (s, 2H), 3.8 (m, 2H), 2.25 (m, 2H); 31P NMR (CDCl3) δ 28.63.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:6][N:7]=1.[CH2:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:27]([NH:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:28])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(N)c2)cnc1N
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)c1nc(-c2cccc(NC(=O)NCc3ccccc3)c2)cnc1N
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of 3-amino-6-(3-aminophenyl)-N-methylpyrazine-2-carboxamide (0.25 g, 1.03 mmol) in dry tetrahydrofuran (2 mL) was added benzyl isocyanate (0.15 g, 1.12 mmol). The mixture was allowed to stir overnight. The solid product was filtered from the reaction mixture and triturated with hexane/ethyl acetate (9:1). The solid was collected by filtration and dried to afford 3-amino-N-methyl-6-[3-({[(phenylmethyl)amino]carbonyl}amino)phenyl]pyrazine-2-carboxamide (0.26 g, 70% yield) as light yellow solid. 1H NMR (400 MHz, d6-DMSO): 8.80 (m, 1H), 8.64 (s, 1H), 8.02 (s, 1H), 7.68 (d, 1H), 7.58 (d, 1H), 7.30 (m, 8H), 4.30 (d, 2H), 2.80 (d, 3H); MS (EI) for C20H20N6O2: 377 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C@@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][C@@H:18]([CH:32]([CH3:34])[CH3:33])[C:19]([NH:21][C@@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:23][O:24][CH3:25])=[O:20]>>[CH3:25][O:24][CH2:23][C@@H:22]([NH:21][C:19]([C@@H:18]([NH:17][C:9]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:15])=[O:11])[CH:32]([CH3:33])[CH3:34])=[O:20])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC[C@@H](NC(=O)[C@@H](N)C(C)C)c1ccccc1
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](COC)c1ccccc1)C(C)C
Yield: 80 %

Procedure:
According to the method of Preparation 2, (2R)-2-[2-(tert-butoxy)-2-oxoethyl]pent-4-enoic acid (646 mg, 3.02 mmol) was reacted with (2S)-amino-N-[(1S)-2-methoxy-1-phenylethyl]-3-methylbutanamide hydrochloride (from b) above)(908 mg, 3.17 mmol) for 1 h at 4° C. and then 18 h at 20° C. The mixture was concentrated under reduced pressure, and partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The layers were separated and aqueous layer extracted again with ethyl acetate (100 mL). The combined organic layers were dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane:methanol 98:2) to give tert-butyl (3R)-3-({[({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)-(1S)-2-methyl-1-propyl]amino}carbonyl)hex-5-enoate (1.08 g, 80%), as a white solid.