Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.FF.B(F)(F)F.CCOCC>C(#N)C>[CH2:9]1[CH:10]2[CH:5]([CH2:4][CH2:3][CH2:2][CH2:1]2)[CH2:6][CH2:7][CH2:8]1
Reactant: C1CC[C@H]2CCCC[C@H]2C1
Agent: FB(F)F
Agent: FF
Solvent: CC#N
Solvent: CCOCC
Product: C1CCC2CCCCC2C1
Temperature: 82 °C
Yield: 31.3 %

Procedure:
Using a similar procedure to that described above (Method 2), cis-decalin (2.2 g, 16 mmol), elemental fluorine (65 mmol), boron trifluoride etherate (2.3 g, 16 mmol), and anhydrous acetonitrile (120 cm3) gave, after heating (82° C.) and the work-up as detailed above, a crude product mixture which was distilled to give decalin (0.7 g, 5 mmol); bp 55° C./10 mmHg. The brown solid which remained gave, after recrystallisation, N-(trans-9-decalyl)acetamide (0.8 g, 49%, 67% conv.) as a white solid; mp 183-184° C. (from acetonitrile) (Found C, 73.6; H, 10.9; N, 7.3. C12H21NO requires: C, 73.8; H, 10.9; N, 7.2%); δH (400 MHz) 0.85-1.68 (18 H, m), 2.57 (1 H, s), 2.62 (1 H, s), 4.89 (1 H, br s, NH); δC (101 MHz) 21.6 (s, CH2), 24.6 (s, CH3), 26.1 (s, CH2), 28.6 (s, CH2), 34.4 (s, CH2), 45.2 (s, CH), 55.9 (CNHCO), 169.2 (s, CO); m/z (EI+) 195 (M+, 1%), 152 (18), 136 (100), 121 (141).
Reaction SMILES: [CH2:1]([O:8][P:9]([O:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23](O)=[O:24])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:36])=O>ClCCl>[P:9]([O:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([Cl:36])=[O:24])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(CCOP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(CCOP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)Cl

Procedure:
To a solution of the product from Example 11B (0.211 g, 0.538 mmol) in dichloromethane (1.35 mL) at 0° C. were added DMF (4 μL) and a solution of oxalyl chloride in dichloromethane (2M, 0.538 mL) and the mixture was stirred for 45 minutes at 0° C. The solvent was evaporated under reduced pressure and the residue was used without further purification.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([Cl:15])[C:9]=2[S:8][CH:7]=1)(=O)C.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:15][C:14]1[C:9]2[S:8][CH:7]=[C:6]([CH2:5][OH:4])[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: CC(=O)OCc1csc2c(Cl)ncnc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1csc2c(Cl)ncnc12
Reaction time: 0.5 h

Procedure:
(4-Chlorothieno[3,2-d]pyrimidine-7-yl)methyl acetate (3.12 g, 12.06 mmol) was dissolved in THF (240 mL) and then 1N NaOH solution (100 mL) was added thereto at room temperature. The reaction mixture was stirred for 30 minutes, diluted with ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered and concentrated to obtain the title compound as a white solid without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20][CH2:21]OS(C)(=O)=O)[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].O1CCOCC1>C1COCC1>[CH2:27]([N:29]([CH2:30][CH3:31])[CH2:21][CH2:20][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[O:12]1)[CH3:28]
Reactant: CS(=O)(=O)OCCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reactant: CCNCC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCN(CC)CCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A solution of methanesulfonic acid 2-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-ethyl ester (50 mg, 0.135 mmol) and diethylamine (279 μl, 2.7 mmol) in THF (0.8 ml) was heated at 60° C. After 3 hours, dioxane (0.3 ml) was added to give a solution and the reaction continued at 60° C. for 24 h. The reaction was partitioned between EtOAc and water. The EtOAc layer was washed with water, brine, dried with anhydrous Na2SO4 and rotary evaporated to give brown oil. The brown oil was chromatographed (CHCl3 to 2% MeOH/CHCl3 gradient) to yield 3-[3-(2-diethylamino-ethyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow-green solid (33 mg, 71%).
Reaction SMILES: [Na].[N+]([C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[CH:6]=1)([O-])=O.[C:13](O)(=[O:15])C.C([O-])(O)=O.[Na+]>CO.O>[CH3:13][O:15][C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COc1cc[n+]([O-])c(C)c1
Temperature: 25 °C

Procedure:
With stirring, sodium pellets (3.95 g, 0.172 mol), maintained dry under hexane, were added to 540 ml dry methanol, under N2. Following dissolution, the mixture was diluted with 900 ml methanol, 4-nitro-2-methylpyridine N-oxide (26.0 g, 0.169 mol) was added, and the mixture heated at reflux for 1 hour, cooled to room temperature and acidified with 18 ml glacial acetic acid. After stirring 15 minutes, the reaction mixture was stripped of solvent, the orange residue taken up in 300 ml of H2O, neutralized with saturated NaHCO3, reconcentrated to dryness, and the residue triturated 5×50 ml of ethanol. The ethanol triturates were combined, stripped to dryness, and the residue restripped 3×50 ml toluene to yield solids (36.1 g) which were chromatographed on silica gel using 6:1 CH2Cl2 :CH3OH as eluant to yield purified title product, 21.14 g; MS 139 (M+).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]2)[CH:5]=1)=[O:3].[Cu](C#N)[C:26]#[N:27]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH2:1][C:2]([C:4]1[CH:9]=[C:8]([C:26]#[N:27])[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]2)[CH:5]=1)=[O:3]
Reactant: N#C[Cu]C#N
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=O)cc(Cl)n2)CC1
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=O)cc(C#N)n2)CC1
Temperature: 100 °C
Yield: 62.6 %

Procedure:
tert-Butyl {1-[4-(aminocarbonyl)-6-chloropyridin-2-yl]piperidin-4-yl}carbamate (Intermediate 16) (100 mg, 0.282 mmol), copper cyanide (101 mg, 1.13 mmol), Pd(dba) (103 mg, 0.11 mmol) and Dppf (250 mg, 0.45 mmol) were placed in anhydrous dioxane (5 ml) under argon. The mixture was heated at 100° C. for 5 h, then diluted with EtOAc (20 ml) and filtered through celite. The mixture was washed with sodium bicarbonate (2×20 ml), brine (20 ml), dried over sodium sulphate and concentrated in vacuo. The brown residue was purified by flash chromatography eluting with DCM and MeOH mixtures to give the title compound as a brown solid (61 mg).
Reaction SMILES: [CH2:1]([NH2:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[O:16]=[C:12]([CH3:11])[CH2:13][C:14]([NH:10][CH2:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15]
Reactant: C=C1CC(=O)O1
Reactant: NCC=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)NCC=Cc1ccccc1

Procedure:
3.06 g (23.0 mmol) of cinnamylamine, 2.32 ml (30.1 mmol) of ketene dimer and 0.321 ml (2.30 mmol) of triethylamine were heated at 70° C. under stirring in 23 ml of toluene for 3 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[S:10][C:9]=1[C:20](=[O:22])[NH2:21])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[S:10][C:9]=1[C:20]([NH2:21])=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2ccc(Cl)cc2)sc1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1sc(-c2ccc(Cl)cc2)cc1N

Procedure:
To a solution of 1c (250 mg, 0.71 mmol) in CH2Cl2 (10 mL) was added TFA (1 mL). The resultant solution was stirred for 1 h, then mixed with saturated NaHCO3 solution (60 mL), and extracted with ethyl acetate (50 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 1:1) then provided compound 1d as a yellow solid: MS (ES) 253 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoate (Novabiochem), the title compound was prepared as a solid. The action was monitored by tlc (Rf=0.2 in 95:5 CHCl3/MeOH) and the product was purified by flash column chromatography using 95:5 CHCl3/MeOH as the eluent.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH2:8][C:7](=O)[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:5]2=[O:21])[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:24])=O>O>[Cl:24][C:7]1[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5](=[O:21])[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:9](=[O:10])[CH:8]=1
Reactant: O=C1CC(=O)N(C2CC2)C(=O)N1c1cccc([N+](=O)[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=c1cc(Cl)n(-c2cccc([N+](=O)[O-])c2)c(=O)n1C1CC1
Temperature: 110 °C
Yield: 34 %

Procedure:
To 1-cyclopropyl-3-(3-nitrophenyl)pyrimidine-2,4,6-trione 5 (28 g) obtained in Step 2 was added water (3 ml), phosphorus oxychloride (72 ml) was added dropwise by small portions with stirring, and the mixture was stirred with heating at 110° C. for 1 hr. The reaction mixture was poured into ice water by small portions, and the precipitated solid was filtered by suction. The filtrate was dissolved in chloroform (300 ml), washed with water (30 ml) and brine (30 ml), and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:acetone=9:1) to give a 2:1 mixture (10 g, 34%) of 6-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 6 and 4-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,6-dione 7 as a white solid.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])=[C:19]([OH:21])[CH:20]=1.N1C=CC=CC=1>ClCCl>[C:22]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:11]([CH:2]2[CH2:3][NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:1]2)=[O:13])=[CH:20][C:19]=1[OH:21])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(O)C1CNc2ccccc2S1
Reactant: CC(C)(C)c1ccc(N)cc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)C2CNc3ccccc3S2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A solution of 3,4-dihydro-2H-1,4-benzothiazine-2-carboxylic acid (80 mg, 0.41 mmol) and 5-amino-2-tert-butyl-phenol (67 mg, 0.41 mmol) in dichloromethane (3 mL) was treated with propane phosphonic acid anhydride (610 μL of 50% w/w in ethyl acetate, 1.02 mmol) and pyridine (99 μL, 1.2 mmol) and stirred for 30 min at room temperature. The reaction was washed with water, dried over Na2SO4, and concentrated in vacuo. HPLC purification (20-99% CH3CN/0.05% TFA) provided N-(4-tert-butyl-3-hydroxy-phenyl)-3,4-dihydro-2H-1,4-benzothiazine-2-carboxamide (51 mg, 36% yield). LC/MS m/z 343.2 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.38 (s, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.93 (dd, J=1.1, 7.7 Hz, 1H), 6.88-6.83 (m, 2H), 6.58 (d, J=7.5 Hz, 1H), 6.51-6.47 (t, J=7.5, 1H), 3.92 (dd, J=3.0, 8.0 Hz, 1H), 3.72 (dd, J=3.0, 12.3 Hz, 1H), 3.53 (dd, J=8.1, 12.3 Hz, 1H), 1.31 (s, 9H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.[H-].[Na+].[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br)([O-:20])=[O:19].O>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2ncn(Cc3cccc([N+](=O)[O-])c3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
An ice-cold solution of 6-(2-furyl)1H-purine-2-amine (201 mg, 1 mmol) in DMF (6 mL) was treated with NaH (44 mg, 1.1 mmol), stirred for 30 min, treated with 3-nitrobenzyl bromide (238 mg, 1.1 mmol), stirred at room temperature for 3 h, treated with water and the resulting solid filtered, suspended in methanol, stilled for 30 min, and filtered to give the title compound (201 mg, 60%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>C1COCC1>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: O=C=Nc1ccccc1Br
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Br
Reaction time: 3 h
Yield: 113.5 %

Procedure:
To a stirred mixture of tert-butyl 4-amino-3-methylphenylacetate (780 mg, 3.30 mmol), 2-bromo phenyl isocyanate (0.41 ml, 3.30 mmol) in THF (7 ml) was added Et3 N (0.092 ml, 0.66 mmol) at room temperature. After 3 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2-bromophenyl) ureido]-3-methylphenylacetate (1.57 g, 93%) as a pale yellow powder. mp 138–145° C. (dec.); 1H-NMR (CDCl3) δ 1.44 (s, 9H), 2.33 (s, 3H), 3.51 (s, 2H), 6.90 (dt, J=9.0, 1.4 Hz, 1H), 6.98 (br, 1H), 7.18–7.31 (m, 4H), 7.39 (dd, J=8.1, 2.9 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 8.22 (d, J=8.3 Hz, 2H); Anal. Calcd for C20H22BrN2O3.0.2H2O: C, 56.80; H, 5.58; N, 6.62. Found: C, 56.85; H, 5.42; N, 6.62.
Reaction SMILES: C(OC([N:8]([CH2:16][C@H:17]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[O:25][CH2:26][CH2:27][O:28][C:20]=12)[CH3:18])C(=O)OC(C)(C)C)=O)(C)(C)C.[ClH:29].CC(O)C>CCO>[ClH:29].[ClH:29].[O:28]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][C:19]=2[C@H:17]([CH3:18])[CH2:16][NH2:8])[O:25][CH2:26][CH2:27]1
Reactant: C[C@H](CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1ccnc2c1OCCO2
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: C[C@H](CN)c1ccnc2c1OCCO2
Reaction time: 16 h
Yield: 100 %

Procedure:
As shown in step 7-iv of Scheme 7, (S)-tert-butyl N-tert-butoxycarbonyl-N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl]carbamate (7.74 g, 39.8 mmol) was dissolved in EtOH, HCl in IPA (60 mL of 4 M solution, 240 mmol) was added and the reaction mixture was refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure to a minimum volume, Et2O was added, and the resulting suspension stirred for 16 hours. The solid was collected by filtration and dried under high vacuum to provide (S)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propan-1-amine, dihydrochloride as a yellowish solid (Compound 2025, 10.55 g, 100% yield): 1H NMR (300 MHz, CDCl3) δ 7.80 (d, 1H), 7.10 (d, 1H), 4.50 (m, 2H), 4.40 (m, 2H), 3.40 (m, 1H), 3.00 (m, 2H), 1.25 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11](#[N:13])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:10][C:11]([CH3:12])=[N:13][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: CC(=O)c1cccc(Cl)c1
Product: Cc1ncc(-c2cccc(Cl)c2)o1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of Tl(OAc)3 (4.2 g, 11.1 mmol) in acetonitrile (80 ml), trifluoromethanesulfuric acid (5 g, 33.3 mmol) was added dropwise at room temperature and stirred for 15 min. The reaction mixture was then heated to 80° C. and 1-(3-chloro-phenyl)-ethanone (1.14 g, 7.4 mmol) in acetonitrile (40 ml) was added. After one h, the reaction was quenched with dichloromethane and saturated sodium bicarbonate. The organic layer was dried, purified by column chromatography with 5˜19% ethyl acetate in hexanes to give 1.2 (83.9%) g of 5-(3-chloro-phenyl)-2-methyl-oxazole as yellow oil. 1H-NMR(CDCl3) d(ppm): 7.60 (s, 1H), 7.48 (d, 1H), 7.29 (m, 2H), 7.23 (s, 1H) and 2.34 (s, 3H). Step 2: 2-Bromomethyl-5-(3-chloro-phenyl)-oxazole: 5-(3-chloro-phenyl)-2-methyl-oxazole (580 mg, 3 mmol) was mixed with NBS (531 mg, 3 mmol) and BPOA (36.3 mg, 0.15 mmol) in CCl4 at room temperature. The reaction mixture was heated at 75° C. for 2 h and then quenched with water and dichloromethane. The organic layer was dried, concentrated, purified by column chromatography with 2˜5% ethyl acetate in hexanes to give 562 mg (68.3%) of 2-bromomethyl-5-(3-chloro-phenyl)-oxazole as yellow oil. 1H-NMR(CDCl3) d(ppm): 7.67 (s, 1H), 7.54 (d, 1H), 7.35(m, 3H) and 4.56 (s, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[SH:17])=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[SH:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCn2ccnc2S)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(CCCn2ccnc2S)cc1

Procedure:
A solution of 1.75 g (0.007 mole) of 1-[3-(4methoxyphenyl)propyl]-2-mercaptoimidazole in 60 ml of CH2Cl2 was deprotected by treatment with a solution of 7.0 g (0.028 mole) of BBr3 in 10 ml of CH2Cl2. After 1 5 hr, the reaction mixture was cooled to 0° , and methanol was cautiously added. After a vigorous reaction subsided, the solvents were evaporated. The residue was recrystallized from ethanol to give 1-[3-(4-hydroxyphenyl)-propyl]-2-mercaptoimidazole, 1.02 g (67%), mp 185° .
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([F:15])[C:3]=1[CH:16]([O:31][CH3:32])[C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[NH:30])[NH:28]O)=[CH:23][CH:22]=1)=[O:18].C([OH:35])C>C(O)(=O)C.[Ni]>[C:16]([OH:31])(=[O:35])[CH3:17].[C:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:17](=[O:18])[CH:16]([C:3]2[C:4]([F:15])=[CH:5][CH:6]=[C:7]([NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:2]=2[F:1])[O:31][CH3:32])=[CH:26][CH:25]=1)(=[NH:28])[NH2:30]
Reactant: COC(C(=O)NCc1ccc(C(=N)NO)cc1)c1c(F)ccc(Nc2ccccc2)c1F
Reactant: CCO
Agent: [Ni]
Solvent: CC(=O)O
Product: COC(C(=O)NCc1ccc(C(=N)N)cc1)c1c(F)ccc(Nc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a stirred solution of (RS)-2-(2,6-difluoro-3-phenylamino-phenyl)-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-2-methoxy-acetamide (106 mg) at rt in ethanol (5 ml) under an argon atmosphere were added 5 drops of acetic acid and and a catalytic amount of Raney-Nickel. The mixture was then stirred at rt under a hydrogen atmosphere for 23 h. The catalyst was filtered off and the filtrate was concentrated. The crude product was purified using flash chromatography (EtOAc/acetone/H2O/HOAc 6:2:1:1) to give (RS)-N-(4-carbamimidoyl-benzyl)-2-(2,6-difluoro-3-phenylamino-phenyl)-2-methoxy-acetamide acetate (92 mg) as on off-white solid. MS 425.5 ([M+H]+)
Reaction SMILES: [Cs].[CH3:2][CH:3]([CH3:15])[CH2:4][CH2:5][CH:6]1[N:10]([CH3:11])[S:9](=[O:13])(=[O:12])[NH:8][C:7]1=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].[C:22]1([S:28][CH2:29]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO.CN(C=O)C>[C:22]1([S:28][CH2:29][N:8]2[C:7](=[O:14])[CH:6]([CH2:5][CH2:4][CH:3]([CH3:15])[CH3:2])[N:10]([CH3:11])[S:9]2(=[O:13])=[O:12])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCSc1ccccc1
Reactant: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Cs]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)CCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Temperature: 85 °C
Yield: 70.6 %

Procedure:
A mixture of 4-(3-methylbutyl) -5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide cesium salt (prepared by reacting 7.7 g (34.95 retool) of the 1,1-dioxide in methanol with 5 5.13 g of Cs2CO3 followed by removal of the solvent) and phenylthiomethyl chloride (6.65 g, 41.94 mmol) suspended in DMF was heated at 85° C. for 17 hours. The mixture was cooled, and poured into 300 ml of ice/water. The reaction mixture was extracted with ethyl acetate (3×) and the organic layer was washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated in vacuo and the residue was purified by silica column chromatography (10% ethyl acetate in hexane) to afford 8.15 g (70.6%) of 2-phenylthiomethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =(CH2)2CH(CH3)2 ; R3 =CH3) as an oil.
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH3:2].N1C=CC=CC=1.C(N(CC)[CH2:20][CH2:21][C:22](=[O:34])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)C.COC1C=C(CCCC(=O)C=C)C=CC=1>C1C=CC=CC=1>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][CH2:23][C:22](=[O:34])[CH2:21][CH2:20][C:3]2([CH2:1][CH3:2])[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]2=[O:10])[CH:31]=[CH:30][CH:29]=1
Reactant: CCC1C(=O)CCCC1=O
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC)c1
Agent: C=CC(=O)CCCc1cccc(OC)c1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCC1(CCC(=O)CCCc2cccc(OC)c2)C(=O)CCCC1=O

Procedure:
Reflux 2-ethylcyclohexane-1,3-dione (30.6 g), pyridine (20 cc), benzene (372 cc) and a mixture of 1-diethylamino-6-m-methoxyphenylhexan-3-one and 6-m-methoxyphenylhex-1-en-3-one (40.3 g, produced by the distillation of the former substance) for 15 hours. Wash the cooled reaction mixture with water, 10% aqueous sulfuric acid, water, 10% aqueous sodium carbonate, water and brine, and filter. Evaporate the solvent to leave as residue 2-(6-m-methoxyphenyl-3-oxohexyl)-2-ethylcyclohexane-1,3-dione, 38.1 g, 56.2%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[O:5][CH2:6][CH2:7][OH:8]>CO.O1CCCC1.[Pd]>[OH:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][C:11]([NH2:12])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(OCCO)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCCO)ccc1N
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, 2-(3-methyl-4-nitrophenoxy)ethanol (1.0 g, 5.3 mmol) was dissolved in methanol/tetrahydrofuran (30 mL/30 mL) and 10% palladium on carbon (0.37 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere for 4 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure to afford 4-(2-hydroxyethoxy)-2-methylaniline as solid (0.80 g, y. 90%).