Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][C:7]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8]1)(=O)=O.[Br:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:5][CH2:6][C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1(COS(C)(=O)=O)CCC1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2ccc(Br)cc2)CCC1
Temperature: 135 °C
Reaction time: 6 h
Yield: 46.6 %

Procedure:
The mixture of ethyl 1-{[(methylsulfonyl)oxy]methyl}cyclobutanecarboxylate (1.50 g, 6.3 mmol), 4-bromophenol (1.2 g, 7.0 mmol), and caesium carbonate (4.13 g, 7.0 mmol) in DMF (15 ml) was stirred for 6 hours at 135° C. After dilution with EtOAc and H2O, the organic layer was washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane:EtOAc=100:0-70:30) to give ethyl 1-[(4-bromophenoxy)methyl]cyclobutanecarboxylate (919 mg).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].[CH:17](=[C:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH:17](=[C:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCC=C1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)CSc2ccccc21
Solvent: CC#N
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)CSc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 96 h
Yield: 59.6 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one (108LM37-34) (0.432 g, 1.25 mmol) and 4-butylidenepiperidine (111MF05) (0.208 g, 1.49 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 60° C. for 4 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:20) to give the title compound (108LM50-47) (0.267 g, 60%). 1H NMR (CDCl3) δ 7.35 (d, J=7.5 Hz, 1H), 7.26-7.18 (m, 2H), 6.98 (t, J=7.5 Hz, 1H), 5.10 (t, J=7.4 Hz, CH), 4.17-4.03 (m, 2H), 3.36 (s, CH2), 2.43-2.33 (m, 2H), 2.30-2.08 (m, 8H), 2.00-1.90 (m, 3H), 1.28-1.38 (m, 2H), 0.90-0.80 (m, 6H); 13C NMR (CDCl3) δ 166.0, 139.2, 136.4, 128.8, 127.1, 124.8, 123.5, 122.7, 118.8, 63.4, 56.4, 55.6, 47.7, 36.4, 32.1, 29.5, 29.4, 28.6, 23.4, 16.7, 14.0; HPLC-MS (ammonium acetate) [M+H]+=359.3.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:9]1([CH2:15][O:16][C:17]([NH:19][C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][OH:23])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CN=C1.CO>CN(C)C=O>[C:9]1([CH2:15][O:16][C:17]([NH:19][C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][O:23][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])=[O:18])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
[(1,1-Dimethylethyl)dimethylsilyl]chloride (37.5 g., 249 mmol.) was added to a solution of N-[(phenylmethoxy)carbonyl]-L-homoserine [prepared as described in Example 6(a), 41.56 mmol.] in dimethylformamide (125 ml.), followed by imidazole (33.95 g., 498 mmol.). The resulting light yellow solution was stirred at room temperature for 22 hours. Methanol (500 ml.) was added, the reaction mixture was stirred for an additional 6 hours, and then the methanol and most of the dimethylformamide were removed in vacuo. The remaining residue was taken up into ethyl acetate (800 ml.), washed with 10% citric acid (2×300 ml.), and the combined aqueous phase was extracted with ethyl acetate (300 ml.). The combined ethyl acetate phase was washed with water and brine, dried (sodium sulfate), concentrated, and the residue was evaporated with hexane to form a white powder. This powder was dried in vacuo to give 12.942 g. of title product.
Reaction SMILES: CS(O[N:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[N:8]=[C:7]1[C:16]([F:19])([F:18])[F:17])(=O)=O.[I-].[Na+].CCOCC.C(=O)(O)[O-]>CC(C)=O>[Cl:15][C:12]1[CH:13]=[C:14]2[NH:6][C:7]([C:16]([F:17])([F:18])[F:19])=[N:8][C:9]2=[N:10][CH:11]=1
Reactant: CS(=O)(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: FC(F)(F)c1nc2ncc(Cl)cc2[nH]1
Yield: 71.2 %

Procedure:
1-(Methylsulfonyloxy)-6-chloro-2-(trifluoromethyl)-1H-imidazo [4,5-b] pyridine (20 milligrams) in 0.5 milliliter of acetone was treated with 0.1 gram of sodium iodide in 0.5 milliliter of acetone. The reaction mixture was shaken with ether and bicarbonate solution. The ether portion was dried over magnesium sulfate and evaporated, yielding 10 milligrams (about 73 percent) of 6-chloro-2-(trifluoromethyl)-1H-imidazo [4,5-b] pyridine.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)=O.[NH3:16]>>[NH2:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[CH:14][C:5]([C:3]([NH2:16])=[O:2])=[N:6]2
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Reactant: N
Product: NC(=O)c1ccc2c(N)cccc2n1
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
840 mg (4.16 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester is dissolved in 70 ml of a 7N methanolic ammonia solution. It is stirred for 3.5 hours at 40° C., then for 20 hours at room temperature. After the solvent is removed in a vacuum, the purification is carried out on silica gel with hexane-ethyl acetate (0–100%) as well as with ethyl acetate-methanol (0–10%). 690 mg (88% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:8]3[CH:17]=[C:16]4[O:18][CH2:19][O:20][C:15]4=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]=O)=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:24]=1.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:8]3[CH:17]=[C:16]4[O:18][CH2:19][O:20][C:15]4=[CH:14][C:9]=3[S:10][C:11]=2/[CH:12]=[C:29](\[C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:4][CH:3]=1
Reactant: O=Cc1sc2cc3c(cc2c1Oc1ccc(Cl)cc1)OCO3
Reactant: CCOC(=O)Cc1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)/C(=C/c1sc2cc3c(cc2c1Oc1ccc(Cl)cc1)OCO3)c1ccncc1
Temperature: 100 °C

Procedure:
A solution containing 85 mmol of the product obtained in Step E, 127 mmol of ethyl 4-pyridylacetate and 75 ml of acetic anhydride is heated at 100° C. for 18 hours. After returning to ambient temperature, the reaction mixture is hydrolysed by saturated NaHCO3 solution and extracted with ethyl acetate. The organic phases are then washed with water and then with NaCl solution, dried over calcium sulphate, filtered and concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethanol : 98/2) allows the expected product to be isolated.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]([NH2:16])=[O:15])=[N:4][C:5]([C:9]([O:11]CC)=[O:10])=[C:6]([OH:8])[N:7]=1.[OH-].[Na+].Cl>O.C(O)C>[OH:1][C:2]1[C:3]([C:14]([NH2:16])=[O:15])=[N:4][C:5]([C:9]([OH:11])=[O:10])=[C:6]([OH:8])[N:7]=1
Reactant: CCOC(=O)c1nc(C(N)=O)c(O)nc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)c1nc(C(=O)O)c(O)nc1O
Reaction time: 16 h
Yield: 61.4 %

Procedure:
In a mixture of 1.0 mL of water and 1.0 mL of ethanol is suspended 0.13 g of 3,5-dihydroxy-6-ethoxycarbonyl-2-pyrazinecarboxamide. At ambient temperature, 0.34 mL of 5 mol/mL sodium hydroxide is added to the suspension, which is then stirred for 16 hours. The reaction mixture is adjusted to pH 2 by adding 1 mol/mL hydrochloric acid. The deposited crystals are collected by filtration and washed with water to obtain 0.07 g of 3,5-dihydroxy-6-carboxy-2-pyrazinecarboxamide.
Reaction SMILES: [NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33](C(F)(F)F)[CH:32]=3)[C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][N:18]=[C:13]2[CH:12]([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:53](Br)[CH:54]=[CH:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C1COCC1>[NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:17][N:18]=[C:13]2[C@:12]([CH3:42])([CH2:53]/[CH:54]=[CH:55]/[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Reactant: BrCC=Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@]1(C/C=C/c2ccccc2)C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1ccccc1)C(=O)OCc1ccccc1)c2=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a solution of 12c (32 mg, 0.063 mmol) in 1 mL THF at −78° C., was added LiHMDS (157 μL, 0.157 mmol). The mixture was stirred at −78° C. for 10 min, then cinnamyl bromide (18.6 mg, 0.095 mmol) in 250 μL THF was added. The reaction was stirred at −78° C. for 1.5 h, then quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with sat NH4Cl and brine, dried (Na2SO4), and concentrated. The crude mixture was purified by flash chromatography (35% EtOAc/hexanes) to afford 26.0 mg (66%) of 116a. 1H NMR (300 MHz, CDCl3) δ9.57 (br s, 1H), 7.74 (br s, 1H), 7.47 (d, J=8.1, 2H), 7.29-7.23 (m, 17H), 7.07 (t, J=7.5, 1H), 6.47 (d, J=15.7, 1H), 6.02-5.97 (m, 1H), 5.20-5.17 (m, 3H), 4.80 (br s, 1H), 2.70-2.41 (m, 4H), 1.48 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:13])=[N:4][C:5]([C:9]([F:12])([F:11])[F:10])=[C:6]([Br:8])[N:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:6]1[N:7]=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[C:3]([NH2:13])=[N:4][C:5]=1[C:9]([F:12])([F:11])[F:10]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1nc(C(F)(F)F)c(Br)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
To a mixture of 6.08 g 3,5-dibromo-6-trifluoromethyl-pyrazin-2-ylamine, 3.25 g 4-chlorophenylboronic acid and 1.095 g tetrakis(triphenylphosphine)palladium(0) in 60 ml 1,2-dimethoxyethane was added a solution of 4.016 g sodium carbonate in 22.74 ml water and the mixture was heated to reflux for 18 h. The reaction mixture was cooled to room temperature and partitioned between 10% aqueous citric acid and ethyl acetate, the phases were separated and the organic phase was purified by chromatography on silica gel with a gradient of 9:1 heptane: dichloromethane to 1:1 heptane: dichloromethane to yield 4.45 g of the title compound as white solid. MS (M−H) at 352.0 and 350.1.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[N:6][CH:5]=1.[BH4-].[Na+]>CCO>[Br:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
A suspension of 5-bromo-nicotinic acid methyl ester (example 26d) (10 g, 46.29 mmol) in anhydrous EtOH (100 ml) was cooled to 0° C. and NaBH4 (4.03 g, 106.47 mmol) was added in portions within 15 min. After stirred at 0° C. for 1 hour the ice bath was removed and stirring was continued at room temperature for 3 hours, then the reaction mixture was heated to reflux overnight. The solvent was evaporated and acetone (50 mL) was added and the solution stirred for 30 minutes then the acetone was evaporated. Saturated aqueous K2CO3 (50 mL) was added and the mixture was refluxed for 1 hour then diluted with water (100 mL) and extracted with DCM. The organic phase was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (5% MeOH in DCM) to give 4.78 g of pure (5-bromopyridin-3-yl)methanol as a light yellow oil. Yield 55%. 1H NMR (400 MHz, CDCl3): 2.60 (t, 1H); 4.73-4.74 (d, 2H), 7.90 (s, 1H,), 8.47 (s, 1H), 8.57 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=O)[CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].B.C1COCC1>C1COCC1>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)OCCN2
Yield: 81.4 %

Procedure:
Using 7-nitro-4H-benzo[1,4]oxazin-3-one (2.9 g, 15 mmol) and borane-THF (45 ml of a 1M solution in THF, 45 mmol) in THF (40 mL) to yield the title compound as an orange solid (2.2 g, 83%). δH (CDCl3) 3.48-3.60 (2H, m), 4.20-4.32 (2H, m), 6.52 (1H, d, J 8.9 Hz), 7.69 (1H, d, J 2.4 Hz), 7.74 (1H, dd, J 8.9, 2.4 Hz). LCMS (ES+) 181 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][N:21]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCNC1
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCN(S(C)(=O)=O)C1
Yield: 67 %

Procedure:
Using a similar procedure to that described in Example 29, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(pyrrolidin-3-ylmethoxy)quinazoline hydrochloride (300 mg) was reacted with methane sulfonyl chloride to give the title product (200 mg, 67%); 1H-NMR Spectrum: (DMSO d6+CD3COOD) 1.75-1.89 (m, 1H); 2.08-2.18 (m, 1H); 2.77-2.86 (m, 1H); 2.91 (s, 3H); 3.12-3.18 (m, 1H); 3.25-3.43 (m, 2H); 3.47-3.52 (m, 1H); 3.94 (s, 3H; 4.06-4.09 (m, 2H); 7.15-7.30 (m, 2H); 7.43-7.53 (m, 2H): 7.81 (s, 1H); 8.38 (s, 1H); Mass Spectrum: (M+H)+ 481.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([C:16]2[O:15][C:14]([C:12]([NH:11][C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:20])[CH:10]=[CH:9][CH:8]=3)=[O:13])=[CH:18][CH:17]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: O=C(O)Cc1cccc(NC(=O)c2ccc(-c3cc(F)cc(F)c3)o2)c1

Procedure:
The furyl bromide (16)(100 mg, 0.30 mmol) was coupled to 3,5-difluoro-phenylboronic acid (48 mg, 0.30 mmol) using Method E. During this reaction, hydrolysis occurred. The residue was extracted using Work-up E1 to give the acid. The residue was purified by column chromatography eluting with 20% heptane:75% EtOAc:5% AcOH to give the title compound.
Reaction SMILES: [F:1][C:2]1([CH2:26][NH2:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[F:1][C:2]1([CH2:26][NH:27][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CN)CC3)c(F)c2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CNS(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Yield: 75 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-fluoro-4-aminomethyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.30 mmol) with methane sulfonyl chloride (1.40 mmol) and triethylamine (2.08 mmol) in dichloromethane (10 ml) at a temperature 25° C. for 2 hours followed by purification of the compound using silica gel column chromatography in 75% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)[CH:7]=1.C([O-])(O)=O.[Na+].Cl[C:30]([O:32][C:33]([CH3:35])=[CH2:34])=[O:31]>CCOC(C)=O>[Cl:18][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:8]([C:6]3[C:5]([CH3:22])=[CH:4][C:3]([F:23])=[C:2]([NH:1][C:30](=[O:31])[O:32][C:33]([CH3:35])=[CH2:34])[CH:7]=3)[C:9](=[O:21])[N:10]2[CH2:19][CH3:20])=[CH:15][N:14]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(Cl)cc3n(CC)c2=O)c(C)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A suspension of Example A6 (0.161 g, 0.485 mmol) in EtOAc (2.5 mL) was treated with satd. NaHCO3 (2.5 mL) followed by isopropenyl chloroformate (0.080 mL, 0.728 mmol) and the bi-phasic mixture stirred vigorously at RT for 2 h. The layers were separated, the organic layer washed with brine dried over MgSO4 and concentrated to dryness to afford prop-1-en-2-yl (5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)carbamate (100% yield assumed). MS (ESI) m/z: 416.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[K].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([SH:27])[CH:22]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: Sc1cccnc1
Reactant: COC(=O)c1ccc(CCl)cc1-c1ccccc1C
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CSc2cccnc2)cc1-c1ccccc1C
Reaction time: 0.5 h

Procedure:
To a solution in DMF (2 mL) of 4-chloromethyl-2-(2-methylphenyl)benzoic acid methyl ester (275 mg, 1.0 mmol) was added 3-pyridinethiol potassium salt (224 mg, 1.5 mmol). The reaction mixture was stirred for 30 minutes and then was poured into water. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine, dried, filtered and concentrated in vacuo. Chromatography on silica gel (40% ethyl acetate-hexanes) gave 4-(3-pyridylthiomethyl)-2-(2-methylphenyl)benzoic acid methyl ester which was converted to the title compound by saponification of the methyl ester, coupling with methionine methyl ester hydrochloride, and saponification as described in Examples 319I-J. 1H NMR (300 MHz, DMSO-d6) δ 12.53 (bs, 1H), 8.49 (d, 1H), 8.38 (dd, 1H), 8.11 (d, 1H), 7.79 (dt, 1H), 7.43 (s, 2H), 7.31 (dd, 1H), 7.19 (m, 2H), 7.11 (m, 2H), 7.05 (m, 1H), 4.36 (s, 2H), 4.20 (m, 1H), 1.92-2.23 (m, 8H), 1.66-1.90 (m, 2H). MS (CI, NH3) m/e 467, 449. Anal calcd for C25H26N2O3S2: C, 64.35; H, 5.62; N, 6.00. Found: C, 64.00; H, 5.62; N, 5.89.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][O:12][CH3:13].C([Li])CCC.CN(C)[CH:21]=[O:22].O>O1CCCC1>[Cl:1][C:2]1[C:3]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:4][CH:5]=[C:6]([F:8])[C:7]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COCCOc1ccc(F)cc1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1ccc(F)c(C=O)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 2-chloro-4-fluoro-1-(2-methoxy-ethoxy)-benzene (122, 1.50 g, 7.33 mmol) in tetrahydrofuran (44.0 mL), under an atmosphere of nitrogen at −78° C., n-butyllithium (2.50 M in hexane, 3.08 mL) was added slowly. After 15 minutes, N,N-dimethylformamide (0.681 mL, 8.80 mmol) was added to the reaction. After 30 minutes, the reaction was allowed to warm to room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a light yellow solid (123, 1.20 g, 70.4%).
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][O:3][CH2:4][C:5](Cl)=[O:6].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[NH2:15]>C1C=CC=CC=1>[F:10][C:11]([F:22])([F:23])[C:12]1[CH:13]=[C:14]([NH:15][C:1](=[O:8])[CH2:2][O:3][CH2:4][C:5]([NH:15][C:14]2[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:12]([C:11]([F:10])([F:22])[F:23])[CH:13]=2)=[O:6])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C(Cl)COCC(=O)Cl
Solvent: c1ccccc1
Product: O=C(COCC(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
Reflux a mixture of 11.97 g (0.07 mole) of diglycolic acid dichloride and 28.84 g (0.14 mole) of 3-trifluoromethyl-4-nitroaniline in 250 ml of benzene for 1 hour. Isolate the solid product of this example by filtration and obtain analytically pure material by recrystallization from benzene-methanol followed by crystallizatin from pure methanol, mp 137°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:24][C:25](=[C:36]([C:39]#[N:40])[C:37]#[N:38])SCC2C=CC(OC)=CC=2)=[CH:19][CH:18]=1>C(O)(C)C>[NH2:40][C:39]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:25]([S:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[C:36]=1[C:37]#[N:38]
Reactant: COc1ccc(CSC(SCc2ccc(OC)cc2)=C(C#N)C#N)cc1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CC(C)O
Product: COc1ccc(CSc2nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c(N)c2C#N)cc1

Procedure:
A solution of 2,6-dichloro-4-trifluoromethyl phenyl hydrazine (245 mg, 1.0 mmol) and {bis[(4-methoxyphenyl)methylthio]methylene}methane-1,1-dicarbonitrile (101, 382 mg, 1.0 mmol) in isopropyl alcohol (15 mL) was heated at reflux for 16 h. The solvent was removed under reduced pressure and the desired product 102 obtained after chromatographic separation (silica gel) using ethyl acetate-hexanes (331 mg, 70%). NMR (δ, CDCl3): 7.7 (2H, s); 7.2 (2H, d, J=8.7 Hz); 6.8 (2H, d, J=8.7 Hz); 4.41 (2H, broad); 4.23 (2H, s). MS: M+1=473 (calc.: 473).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:12][C:11]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8].[F-:21].[K+].S1(CCCC1)(=O)=O>O>[F:21][C:2]1[N:3]=[C:4]2[S:12][C:11]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CCCCCCCSc1nn2c(=O)c(C)c(Cl)nc2s1
Reactant: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CCCCCCCSc1nn2c(=O)c(C)c(F)nc2s1
Yield: 63 %

Procedure:
A solution of 8.6 g of the thus obtained 7-chloro-2-heptylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, 3.0 g of spray dry potassium fluoride and 32 ml of sulfolane was heated at 205°~225° C. in a stream of nitrogen for 1 and half hours. After cooling, water was added to the mixture, and the mixture was extracted with toluene. The toluene layer was collected and washed with water. The toluene phase was dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by column chromatography on a silica gel column with an ethyl acetate/n-hexane (1:3) mixture as an eluent. After the solvent was distilled off, 5.2 g of 7-fluoro-2-heptylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 78°~91° C. Yield 63%.