Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=O.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:23](=[O:24])[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[S:20]2(=[O:30])=[O:29])[CH2:15][CH2:14]1>CO>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:1][N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[S:20]3(=[O:29])=[O:30])[CH2:17][CH2:18]2)=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: C=O
Reactant: O=C1c2ccccc2S(=O)(=O)N1C1CCNCC1
Agent: Cl
Solvent: CO
Product: O=C1c2ccccc2S(=O)(=O)N1C1CCN(Cc2c[nH]c3ccccc23)CC1

Procedure:
Formaldehyde (0.4 cm3, 40% aqu.soln.) was added to a mixture of indole (0.6 g, 0.005 mol), 2-(piperid-4-yl)-1,2-benzisothiazoline-3-one-1,1-dioxide, hydrochloride (1.5 g, 0.005 mol) and methanol (10 cm3). The mixture was warmed sufficiently to give a clear solution and then allowed to stand without further heating for 2 hours. The clear solution was then evaporated, and the residual water removed by successive evaporation of the residue with ethanol to give a gum. The gum was dissolved in methanol and allowed to stand in ice whereupon the crystalline title compound separated (1.7 g, 79%) as the hydrochloride. Recrystallisation twice from aqueous methanol (80% methanol) gave 1.3 g of the title compound as the hydrochloride hemihydrate, m.p. 214°-215° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([C:32]#[N:33])[CH:23]=4)[O:19][N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(=[O:3])[CH3:2].[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][N:7]([C@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([C:32]#[N:33])[CH:23]=4)[O:19][N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[S:35]([CH3:34])(=[O:37])=[O:36])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OCCN[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCN([C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.6 %

Procedure:
Prepared using General Procedure 12. To a stirred solution of (R)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)ethyl acetate (20 mg, 0.04 mmol) in DCM (1 mL) was added methanesulfonyl chloride (10.2 mg, 0.08 mmol) followed by triethylamine (9.08 mg, 0.08 mmol)) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water (1 mL), extracted with DCM (2×1 mL), and the combined extracts were dried over MgSO4. The organic layers were concentrated to give 23 mg (50%) of (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)methylsulfonamido)ethyl acetate which was used in the next step without purification. LCMS-ESI (m/z) calculated for C26H28N4O6S: 524.2. found 547.1 [M+Na]+, tR=3.82 min.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:21]1([C:27]2[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[C:27]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:28]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Oc1cccc(-c2ccccc2)c1
Solvent: CO
Product: COC(=O)C(Oc1cccc(-c2ccccc2)c1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
In a similar manner as in Example 39, 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate is reacted with 4.25 g of 3-phenylphenol in methanol to give a yellow oil, which is subjected to fractional bulb-to-bulb distillation (175°-178° C. @ 0.02 mm) to remove volatile impurities. The glassy residue is subjected to filtration through 200 g of silica gel (benzene) and concentration to yield the product as an orange foam.
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C@@H:15]2[CH2:19][C:18](=[N:20][O:21][CH3:22])[CH2:17][N:16]2[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)=[O:24])[N:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].[N:53]1([CH2:59][CH2:60]C(O)=O)[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[C:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][C:25]([C:23]([N:16]2[CH2:17][C:18](=[N:20][O:21][CH3:22])[CH2:19][C@H:15]2[C:12]2[N:11]=[C:10]([CH2:9][NH:8][C:6](=[O:5])[CH2:60][CH2:59][N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[O:14][N:13]=2)=[O:24])=[CH:30][CH:29]=1
Reactant: CON=C1C[C@@H](c2noc(CNC(=O)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C(O)CCN1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON=C1C[C@@H](c2noc(CNC(=O)CCN3CCCCC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
4-{[(2S,4EZ)-2-(5-{[(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl (Example 50) was treated with a 25% TFA/DCM solution at 0° C. The reaction was monitored by LC/MS and stopped after completion. The reaction was then made basic with sodium carbonate solution (10%) and extracted with DCM. The combined organic phases were dried over magnesium sulfate. Solvent removal afforded a crude product, which was used without purification in the next step. The residue was dissolved in DCM at room temperature, DMAP (1.1 equivalent) and 3-(1-piperidinyl)propanoic acid (1 equivalent) were added. The reaction mixture was then cooled down to 0° C. and EDC (1.1 equivalent) was added portion-wise. After stirring for 1 hour at 0° C., the reaction mixture was allowed to warm to room temperature. The reaction was monitored by TLC and LC/MS. Usually after 12 hours stirring at RT, the reaction mixture was hydrolyzed, washed with sodium carbonate solution (10%), dried over MgSO4, and evaporated in vacuo to give a crude product. Flash chromatography on silica gel, eluting with 60% EtOAc in hexane, gave the title compound as a mixture of E- and Z-isomers in 50% yield (87.4% purity by HPLC).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15]O)[CH3:13])[CH3:8])[CH3:3].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:41]I>C1(C)C=CC=CC=1.CCCCCC>[CH3:13][CH:12]([CH2:11][CH2:10][CH2:9][CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:14][CH2:15][I:41]
Reactant: II
Reactant: CC(C)CCCC(C)CCCC(C)CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)CCCC(C)CCCC(C)CCI
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a stirring solution of 44 (1.5 g, 6.6 mmol), imidazole (1.13 g, 16.6 mmol, 2.5 equ) and triphenylphosphine (4.40 g, 16.8 mmol, 2.5 equ) in toluene (250 ml) under nitrogen was added iodine (3.26 g, 12.8 mmol, 1.9 equ). The reaction mixture was stirred for one hour then filtered. The filtrate was washed with 8% sodium thiosulphate solution (250 ml) and brine (100 ml) then dried (Na2SO4) and concentrated in vacuo to give a white solid. This solid was taken up in hexane, cooled and filtered. The filtrate was then concentrated in vacuo to give 46 (1.1 g, 61%) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:22])[N:13]([CH3:21])[CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:6]=1>O1CCCC1.CO.[Pd]>[NH2:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:22])[N:13]([CH3:21])[CH:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH:6]=2)=[C:2]([F:1])[CH:26]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reaction time: 3 h
Yield: 77.8 %

Procedure:
3-[4-(2-Fluoro-4-nitrophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (243 mg) was dissolved in tetrahydrofuran (6 ml)-methanol (6 ml), and 10% palladium on carbon (128 mg) was added thereto, followed by stirring under a hydrogen atmosphere for 3 hr. The atmosphere in the reaction vessel was replaced with nitrogen, and the catalyst was removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) and concentrated under reduced pressure to provide the titled compound as pale yellow powder (175 mg, 78.0%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]4[C:15]3=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[I-:27].[Na+].CNC1CCCCC1NC>[Cu]I.O1CCOCC1>[I:27][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]4[C:15]3=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: Brc1cccc(-c2cccc(-n3c4ccccc4c4ccccc43)c2)c1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: Ic1cccc(-c2cccc(-n3c4ccccc4c4ccccc43)c2)c1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
9-(3′-bromo-[1,1′-biphenyl]-3-yl)-9H-carbazole (9.50 g, 23.85 mmol), sodium iodide (7.15 g, 47.7 mmol), copper(I) iodide (1.363 g, 7.16 mmol), and dioxane (239 ml) were added into a 500 mL 3-necked flask. N1,N2-dimethylcyclohexane-1,2-diamine (1.881 ml, 11.93 mmol) was added. The reaction mixture was heated and refluxed overnight. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was filtered through a pad of Celite® and washed several times with DCM. The solvent are evaporated in vacuum. The crude material was purified by column chromatography using hexane and DCM (75/25) and gradually increasing DCM to a ratio of hexane/DCM 50/50. The product was further purified by trituration from methanol. 9-(3′-iodo-[1,1′-biphenyl]-3-yl)-9H-carbazole (10.2 g, 22.91 mmol, 96% yield) was obtained as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:19][CH3:20])[CH:10]=1)C1C=CC=CC=1.O1CCCC1>CO.[C].[Pd]>[OH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:19][CH3:20])[CH:10]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)cc1OC
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of methyl 4-benzyloxy-2-methoxybenzoate (3.08 g) in methanol (5 mL)/tetra hydrofuran (7.5 mL) was added 10% palladium-carbon (0.3 g) at room temperature under an atmosphere of argon, and the mixture was stirred at that temperature for 2 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to afford the title compound (2.02 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][N:17]1[C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=[N:18]1>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>[CH3:16][N:17]1[C:21]([C:2]2[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=2)=[CH:20][CH:19]=[N:18]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(O)c1cc(Br)cs1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1csc(C(=O)O)c1
Temperature: 85 °C

Procedure:
To a solution of 4-bromo-2-thiophenecarboxylic acid (3.91 g, 18.9 mmol) in dioxane/H2O (4:1, 100 mL) was added Cs2CO3 (21.7 g, 66.6 mmol), tetrakistriphenylphosphine Pd(0) (1.1 g, 0.95 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.94 g, 18.94 mmol) [prepared according to the procedure of Preparation 7]. The reaction mixture was heated to 85° C. in a sealed tube for 12 hours and partitioned between H2O and CHCl3. The pH of the aqueous phase was adjusted to ˜3 with 6N HCl and washed several times with CHCl3. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (2.84 g, 13.64 mmol, 72%): LC-MS (ES) m/z=209 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH:6]1([NH:9][C:10](=[O:40])[C:11]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][C:29](OC)=[O:30])=[O:22])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1>CO.C(Cl)Cl.O>[CH:6]1([NH:9][C:10](=[O:40])/[C:11](/[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16]([CH:19]=[CH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:2][OH:3])=[O:30])=[O:22])=[CH:17][CH:18]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)C=CCCCNC(=O)/C=C/c1ccc(C=C(C(=O)NC2CC2)c2ccc(F)cc2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(C=Cc1ccc(/C=C(/C(=O)NC2CC2)c2ccc(F)cc2)cc1)NCCCCCC(=O)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
Hydroxylamine hydrochloride (0.63 g, 9 mmol) in methanol (3 mL) was mixed with KOH (0.51 g, 12.3 mmol) in methanol (3 mL) at 0° C., and sonicated for. 2 minutes and the white precipitate formed was filtered. The filtrate was added to the methyl 6-(3-(E)-(4-(3-(cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-1-en-1-yl) phenyl)acrylamido)hexenoate (0.24 g, 0.5 mmol) in DCM (1.5 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (1×200 mL). The ethyl acetate layer was washed with water (100 mL), dried over anhydrous Na2SO4 and concentrated to obtain a sticky compound, subsequently triturated with DCM (15 mL), to obtain a solid. The solid obtained was filtered and washed with DCM (5 mL) to afford the title compound (0.075 g, 32% yield). 1H NMR (DMSO-d6) δ (ppm): 0.51 (2H, m, —CH2), 0.62-0.64 (2H, t, —CH2), 1.24 (2H, m, —CH2), 1.40-1.49 (4H, m, —CH2), 1.91-1.93 (2H, d, —CH2), 2.74-2.76 (1H, m, —CH), 3.12-3.13 (2H, d, —CH2) 6.53-6.57 (1H, d, ═CH), 6.99-7.01 (2H, d, Ar—H), 7.18-7.22 (4H, m, Ar—H), 7.27 (1H, s, ═CH), 7.28-7.32 (1H, d, ═CH), 7.37-7.39 (2H, d, Ar—H), 7.82-7.83 (1H, d, —NH), 8.06 (1H, s, —NH), 8.67 (1H, s, —OH), 10.34 (1H, s, —NH). MS m/z: 480.3 (M++1).
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][C:7]([CH3:18])([CH3:17])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:9].N1(C=O)CC[O:22][CH2:21]C1.O>C(OCC)C.O1CCCC1>[CH:21]([C:16]1[C:11]([NH:10][C:8](=[O:9])[C:7]([CH3:18])([CH3:17])[CH3:6])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:22]
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: O=CN1CCOCC1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncccc1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a mixture solution of tert-butyl lithium (1.5M pentane solution, 10 mL, 15 mmol) and diethyl ether (50 mL) was added a solution of 2,2-dimethyl-N-pyridin-2-yl-propionamide described in Preparation Example J-1 (900 mg, 5.0 mmol) in diethyl ether (10 mL) dropwise at −78° C., and the solution was stirred for 90 minutes at the same temperature. At the same temperature, morpholine-4-carbaldehyde (1.0 mL, 10 mmol) was added dropwise, and the solution was warmed gradually to room temperature. Water and tetrahydrofuran were added to the reaction mixture for extraction, the organic layer was washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4), and the title compound (880 mg, 4.3 mmol, 85%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[C:11]1([S:17]([NH:1][C:2]2[C:7]([I:8])=[CH:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CSc1cnc(N)c(I)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 56.6 %

Procedure:
2-Amino-5-methylthio-3-iodo-pyridine (2.95 g) and benzenesulfonyl chloride (2.35 g) were dissolved in pyridine (11.1 ml) and the solution was stirred at 60° C. for 15 hours. The reaction solution was poured into water, extracted with chloroform, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (chloroform:methanol=50:1) to obtain 2.55 g of the desired product as a pale yellow crystal.
Reaction SMILES: C(O)C.[CH3:4][N:5]([CH2:7][C:8]1[S:12][C:11]([CH2:13][S:14][CH2:15][CH2:16][NH:17][C:18](SC)=[CH:19][N+:20]([O-:22])=[O:21])=[CH:10][C:9]=1[CH3:25])[CH3:6].[Br:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:36])[CH2:34][NH2:35])[CH:30]=[CH:31][CH:32]=1.C(O)(C)C>C(OCC)C>[Br:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:36])[CH2:34][NH:35][C:18]([NH:17][CH2:16][CH2:15][S:14][CH2:13][C:11]2[S:12][C:8]([CH2:7][N:5]([CH3:4])[CH3:6])=[C:9]([CH3:25])[CH:10]=2)=[CH:19][N+:20]([O-:22])=[O:21])[CH:30]=[CH:31][CH:32]=1
Reactant: NCC(O)c1cccc(Br)c1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1cc(C)c(CN(C)C)s1
Solvent: CC(C)O
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(CSCCNC(=C[N+](=O)[O-])NCC(O)c2cccc(Br)c2)sc1CN(C)C
Yield: 65 %

Procedure:
With 7.5 ml of ethanol were mixed 4.5 g of 1-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethylamino}-1-methylthio-2-nitroethene and 3.5 g of DL-[2-(3-bromophenyl)-2-hydroxyethyl]amine, and the resulting mixture was subjected to reaction at room temperature for 30 hours. Thereto were added 5 ml of isopropanol and 30 ml of diethyl ether, and the mixture thus obtained was stirred, after which the crystals formed were collected by filtration. The crystals were recrystallized from 40 ml of isopropanol to obtain 4.3 g (yield 65%) of N-[2-(3-bromophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine having a melting point of 104°-106° C.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>N1C=CC=CC=1>[F:27][C:13]([F:12])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[N:24]([C:30]([N:29]([CH3:33])[CH3:28])=[O:31])[C:23](=[O:25])[O:22][N:21]=2)[CH:15]=1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CN(C)C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 20 h
Yield: 63.7 %

Procedure:
To 1 ml of pyridine were added 0.26 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.18 g of N,N-dimethylcarbamoyl chloride was added at room temperature. After stirring for 20 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.25 g of 3-(4-trifluoromethylpyridin-2-yl)-N,N-dimethyl-1,2,4-oxadiazol-5-one-4-carboxamide (present compound (14)).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[O:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2oc3ncccc3c2n1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2oc3ncccc3c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of 4 (64 mg, 0.27 mmol) in dry methanol (10 mL) was added morpholine (55 μL, 0.62 mmol) dropwise, and the resulting reaction was stirred for 2 h at rt. The resulting precipitate was then filtered, washed with water and then a mixture of 5:1 methanol/water, and the remaining solid was dried in vacuo to furnish 5 (50 mg, 0.17 mmol, 64%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:5]=1[NH:6][CH2:7][CH:8](C)C#N)([O-:3])=[O:2].OS(O)(=O)=O.[C:23]([O-:26])([O-])=[O:24].[Na+].[Na+].[C:29](O)(=O)C>O>[CH3:29][C:7]([NH:6][C:5]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:8])[C:23]([OH:26])=[O:24]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(NCC(C)C#N)c([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1ccc(NC(C)(C)C(=O)O)c([N+](=O)[O-])c1

Procedure:
47 g (mol/5 ) of 2-nitro-4-methoxy-(2'-methyl-2'-cyanoethyl)-aniline, 36 ml of H2O, 36 ml of acetic acid and 36 ml of H2SO4 are heated under reflux for 25 minutes. The reaction mixture is poured into iced water and is made alkaline with an Na2CO3 solution. 4.5 G of solid are eliminated by filtration. The solution is washed first of all with ethyl acetate and then acidified. The formed crystals are water extracted. Yield: 23.8 g = 47.7% (theoretical yield = 50.8 g) of a deep red solid of melting point 119°-121° C. After recrystallisation (ethylacetate plus decoloring carbon) a red solid, m.p. = 124°-126° C. is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:8]1[CH:7]=[C:6]([B:10]([OH:12])[OH:11])[CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:9]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(B(O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred slurry of m-carboxyphenylboronic acid (5 g, 0.03 mol) in concentrated sulfuric acid (15 ml) was added fuming nitric acid (15 ml, d=1.54). The reaction mixture was stirred at room temperature for 45 minutes and poured on ice (150 g). The nitro acid formed was filtered, washed with water and dried. M.P. 235°-37° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[CH3:1][O:2][C:3]1[C:4]([NH:10][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])(=[O:20])=[O:19])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: COc1nc(C)cnc1N
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1F

Procedure:
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and 2-fluorobenzenesulphonyl chloride.