Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:17])(=O)=O.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:6][CH2:7][N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[NH:10][C:9]3=[O:17])[CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CS(=O)(=O)OCCn1c(=O)[nH]c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 5.6 parts of 2-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)ethyl methanesulfonate, 4.9 parts of (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride, 8 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 7 hours with water-separator. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 4.3 parts of 1-{2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 163.6° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>ClCCl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([Cl:17])=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1C(=O)Cl

Procedure:
A solution of 5-methyl-3-phenylisoxazole-4-carboxylic acid (1 g) and PCl5 (1 g) in dichloromethane (20 mL) was refluxed for one hour. Then dichloromethane and POCl3 were removed under reduced pressure to give 5-methyl-3-phenylisoxazole-4-carbonyl chloride.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]([C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:16]=[C:17]([C:21]4[CH:25]=[CH:24][S:23][C:22]=4[C:26]#[N:27])[CH:18]=[CH:19][CH:20]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1)=O>>[OH:3][N:2]=[CH:4][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:16]=[C:17]([C:21]4[CH:25]=[CH:24][S:23][C:22]=4[C:26]#[N:27])[CH:18]=[CH:19][CH:20]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: NO
Reactant: N#Cc1sccc1-c1cccc(-c2cnc3cc(C=O)ccn23)c1
Agent: Cl
Product: N#Cc1sccc1-c1cccc(-c2cnc3cc(C=NO)ccn23)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 14 using hydroxylamine hydrochloride (57 mg, 0.82 mmol) and 3-[3-(7-formylimidazo[1,2-α]pyridin-3-yl)phenyl]thiophene-2-carbonitrile (90 mg, 0.27 mmol) to afford a white crystalline solid (77 mg, 82%), essentially as a single geometric isomer, m.p. >230° C. 1H NMR (360 MHz, d6-DMSO) δH 7.27 (1H, dd, J 1 and 7), 7.70-7.82 (3H, m), 7.91 (1H, s), 8.03 (1H, s), 8.17 (1H, d, J 1), 7.90-7.95 (1H, m), 8.17 (1H, d, J 5), 8.31 (1H, s), 8.65 (1H, d, J 7), 11.53 (1H, s); m/z (ES+) 345 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22].CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc([N+](=O)[O-])cc4)c3C2=O)C(=O)N1
Yield: 74 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (2.2 g, 8.0 mmol) and 4-nitrobenzoyl chloride (3.0 g, 16.0 mmol) in THF (80 mL) was heated to reflux for 15 h. To the mixture was added methanol (20 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-nitro-benzamide as a white solid (2.5 g, 73% yield): mp, 298-300° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H, CHH), 2.49-2.65 (m, 2H, CH2), 2.83-2.98 (m, 1H, CHH), 5.18 (dd, J=5.2, 12.6 Hz, 1H, NCH), 7.73 (d, J=7.2 Hz, 1H, Ar), 7.93 (t, J=8.0 Hz, 1H, Ar), 8.19-8.22 (m, 2H, Ar), 8.42-8.47 (m, 3H, Ar), 10.65 (s, 1H, NH), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 48.99, 119.30, 119.56, 124.06, 127.49, 129.01, 131,58, 135.77, 136.23, 138.96, 149.69, 163.65, 166.57, 167.48, 169.68, 172.72; Anal Calcd for C21H14N4O7: C, 56.88; H, 3.34; N, 13.27. Found: C, 57.15; H, 3.02; N, 13.22.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F-].[Cs+]>O1CCOCC1>[C:10]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccccc1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccccc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 150 mg (0.161 mmol) of {[(t-Bu)2P(OH)]2PdCl}2 (from Experiment 7), 1.43 g (10.0 mmol) of 2-chloroanisole, 1.83 g (15.0 mmol) of PhB(OH)2 and 4.56 g (30.0 mmol) of CsF in 30.0 mL of dioxane. The resulting mixture was refluxed for 12 h until the starting material was completely consumed as judged by TLC. The reaction was cooled to room temperature, transferred to a separatory funnel, and diluted with 300 mL of diethyl ether. The layers were separated, and organic layer was washed with H2O (2×100 mL), brine (100 mL), and dried over mgSO4, filtered, and the ether and dioxane removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using 2% EtOAc/hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.66 g (90% yield) of 2-phenylanisole.
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=2)=[CH:12][N:13]=1)=O)(C)(C)C.[C:24](N1CCNCC1)(=O)C.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:24][O:23][C:21](=[O:22])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([S:14][C:11]2[S:10][C:9]([NH2:8])=[N:13][CH:12]=2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Sc2cccc(C(=O)O)c2)s1
Reactant: CC(=O)N1CCNCC1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Sc2cnc(N)s2)c1
Temperature: 55 °C
Yield: 100.1 %

Procedure:
A suspension of 2-tert-butoxycarbonylamino-5-[(3-carboxyphenyl)thio]thiazole (528 mg, 1.5 mmol), N-acetylpiperazine (239 mg, 1.87 mmol), ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (400 mg, 2 mmol), 1-hydroxy-7-azabenzotriazole (272 mg, 2 mmol) and diisopropylethylamine (560 μL, 4 mmol) in THF (20 mL) was heated to 55° C. for 2 h. The mixture was cooled to rt. and concentrated. The residue was purified using column chromatography on silica gel eluted with 2% methanol in dichloromethane followed by 5% methanol in dichloromethane to obtain the titled compound (400 mg, 58%) as a white foam. E. 4-Acetyl-1-[3-[(2-aminothiazol-5-yl)thio]benzoyl]piperazine
Reaction SMILES: CN(C=O)C.I[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([NH2:16])=[N:10][NH:11]2.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])#[CH:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[NH2:22][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[C:9]([NH2:16])=[N:10][NH:11]3)[CH:25]=[CH:24][CH:23]=1
Reactant: C#Cc1cccc(N)c1
Reactant: Nc1n[nH]c2cccc(I)c12
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1cccc(C#Cc2cccc3[nH]nc(N)c23)c1
Temperature: 60 °C

Procedure:
To 8 ml of DMF was added 4-iodo-1H-indazol-3-amine (690 mg, 2.65 mmol) and 3-ethynylaniline (480 mg, 1.5 eq., 4.1 mmol). Following that, Bis(triphenylphosphine) palladium(II) dichloride (180 mg, 0.25 mmol, 10 mol %), Copper Iodide (100 mg, 0.52 mmol, 20 mol %), Triphenylphosphine (18 mg, 0.07 mmol, 3 mol %) and 8 ml of triethylamine was added. Nitrogen was bubbled through the reaction mixture for 15 minutes. The reaction was then set with a reflux condenser, set under nitrogen atmosphere, and heated at 60° C. for 2 hours. After that, the reaction was cooled to room temperature and 40 ml of ethyl acetate was added. The organic layer was extracted with aqueous sodium bicarbonate (3×40 ml), brine (3×40 ml), dried using anhydrous sodium sulfate, loaded onto silica and columned to give 4-((3-aminophenyl)ethynyl)-1H-indazol-3-amine.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][O:8][C:9]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([O:22][CH3:23])[C:10]=1[C:11](Cl)=[O:12].O>ClCCl>[OH:4][CH2:3][C:2]([NH:1][C:11](=[O:12])[C:10]1[C:14]([O:22][CH3:23])=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:9]=1[O:8][CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: COc1cc(C(F)(F)F)cc(OC)c1C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(F)(F)F)cc(OC)c1C(=O)NC(C)(C)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of 3.7 ml (37.22 mmol) 2-amino-2-methyl-1-propanol in 42 ml dichloromethane under nitrogen at 0° C., was added dropwise a solution of 5 g (18.61 mmol) 2,6-dimethoxy-4-trifluoromethyl-benzoyl chloride in 12 ml dichloromethane. The temperature rose to 7° C. The mixture was stirred at room temperature for 4 hours. The mixture was poured onto 75 ml water. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide 5.66 g (yield: 94.6%) of the title compound as a yellow solid. MS (m/e): 322.2 (M+H').
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]([CH3:21])[CH2:9][N:10]2[C:14](=[CH:15][C:16](OCC)=[O:17])[CH2:13][S:12][C:11]=12)=[O:6])([CH3:3])[CH3:2].[CH3:22][NH2:23]>>[CH3:22][NH:23][C:16](=[O:17])[CH:15]=[C:14]1[CH2:13][S:12][C:11]2=[C:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH:8]([CH3:21])[CH2:9][N:10]12
Reactant: CCOC(=O)C=C1CSC2=C(C(=O)OC(C)C)C(C)CN12
Reactant: CN
Product: CNC(=O)C=C1CSC2=C(C(=O)OC(C)C)C(C)CN12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.2 g of ethyl (7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo[2,1-b]thiazol-3-ylidene]acetate was suspended in 25 ml of a 40% aqueous solution of monomethylamine and stirred at room temperature for 24 hours. The precipitate was collected by filtration, washed with water and recrystallized from ethanol to thereby give 1.2 g of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>C1COCC1.C1(C)C=CC=CC=1>[Br:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:16]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1cc(Br)ccc1C(=O)O
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Ethyl chloroformate (5.00 ml, 52.1 mmol) was added to a solution of 2-amino-4-bromobenzoic acid (3.75 g, 17.36 mmol) in THF (70 ml) at room temperature. The mixture was heated to 70° C. and let stir for 24 hrs. The reaction was concentrated to give an oily solid. The resulting solid was diluted with toluene (50 mL), concentrated and then triturated with 5% ether/hexanes (100 mL) to give upon filtration and subsequent washing of the solid with hexane the title compound (4.6 gm, 92%) as a solid. LCMS (ES+) m/z 287.88 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:8]=1[O:15][CH3:16])(=O)=O.CCOC(C)=O.[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:25]#[N:26])=[C:8]([O:15][CH3:16])[CH:9]=1)=[O:14]
Reactant: CN(C)C=O
Reactant: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1C#N
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 4-formyl-2-methoxyphenyl trifluoromethanesulfonate (37.0 g, 130 mmol), zinc cyanide (61.0 g, 521 mmol) and tetrakis triphenylphosphine palladium (0) (22.6 g, 19.5 mmol) in DMF (300 mL) were stirred at 110° C. for 8 h. EtOAc was added to the reaction mixture and the organic layer was washed two times with water, dried, filtered and concentrated. The crude product was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) which afforded 4-formyl-2-methoxybenzonitrile.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([Cl:14])=[O:13])[CH:6]=[CH:7][CH:8]=1.[N+:21](C1C=C(NC2C=CC=CC=2C(O)=O)C=CC=1)([O-:23])=[O:22]>>[N+:21]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([Cl:14])=[O:13])[CH:6]=[CH:7][CH:8]=1)([O-:23])=[O:22]
Reactant: O=C(Cl)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Product: O=C(Cl)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Yield: 77 %

Procedure:
The following compound is obtained using the same procedure as that used for procurement of 2-(3-trifluoromethylphenylamino)-benzoyl chloride except that an equivalent amount of 2-(3-nitrophenylamino)-benzoic acid is used in place of the 2-(3-trifluoromethylphenylamino)-benzoic acid of the reference example from 2-(3-nitrophenylamino)-benzoic acid: 2-(3-Nitrophenylamino)-benzoyl chloride ##STR9## Yield: 77% of theory, melting point: 141°-145° C.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][C:16]=1/[CH:17]=[CH:2]/[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 87 %

Procedure:
The title compound was prepared by condensing 4-acetylbenzoic acid and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)-benzaldehyde (Ex-116A) in a similar manner as described in Ex-3. Yellow solid, 87% yield, mp 157–160° C. 1H-NMR (DMSO-d6) δ 8.17 (d, J=8 Hz, 2H), 8.08 (d, J=15 Hz, 1H), 7.99–9.02 (m 3H), 7.83 (d, J=15 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.10–7.15 (m, 1H), 6.99–7.04 (m, 1H), 6.85 (s, 1H), 6.42 (s, 1H), 4.01 (s, 3H), 3.88 (s, 3H), 3.50 (s, 3H). MS m/z=442 ([M+H]+, 100%). HRMS (ES+) Calcd. for C27H23NO5: 442.1654. Found: 442.1633.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:13](Cl)=[O:14])[C:10](Cl)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].I.[CH3:17][S:18][C:19](=[NH:25])[NH:20][N:21]=[C:22]([CH3:24])[CH3:23]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:25][CH:19]([S:18][CH3:17])[N:20]([N:21]=[C:22]([CH3:24])[CH3:23])[C:10]2=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)N(C(=O)Cl)c1ccc(Cl)c(Cl)c1
Reactant: CSC(=N)NN=C(C)C
Agent: I
Solvent: CCN(CC)CC
Product: CSC1NC(=O)N(c2ccc(Cl)c(Cl)c2)C(=O)N1N=C(C)C

Procedure:
Analogously to Example 1, N-(3,4-dichlorophenyl)-bis(chlorocarbonyl)-amine and acetone-S-methyl-isothiosemicarbazone hydroiodide, with addition of triethylamine, yielded 1-(3,4-dichlorophenyl)-3-isopropylideneamino-4-methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione as a colorless powder of melting point 181°-182° C.
Reaction SMILES: CN(C=O)C.C[O:7][C:8](=O)[N:9]=[C:10](SC)[C:11]([C:25]1[CH:26]=[N:27][C:28]([O:34][CH3:35])=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.[CH2:39]([O:41][C:42]([C:44]1[S:48][CH:47]=[N:46][C:45]=1[NH:49][NH2:50])=[O:43])[CH3:40]>C(N(CC)CC)C>[CH2:39]([O:41][C:42]([C:44]1[S:48][CH:47]=[N:46][C:45]=1[N:49]1[C:8](=[O:7])[NH:9][C:10]([CH:11]([C:25]2[CH:26]=[N:27][C:28]([O:34][CH3:35])=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=2)[NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:17][CH:18]=2)=[N:50]1)=[O:43])[CH3:40]
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cnc1OC
Reactant: CCOC(=O)c1scnc1NN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cnc(OC)c(OCC)c2)[nH]c1=O
Temperature: 85 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
To 4 ml of a DMF solution containing 117 mg of {2-(5-ethoxy-6-methoxypyridin-3-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example 160a), 52 mg of 4-hydrazinothiazole-5-carboxylic acid ethyl ester and 0.038 ml of triethylamine were added. The mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was dissolved in 10 ml of methanol and 0.05 ml of acetic acid, and then 125 mg of sodium cyanotrihydroborate was further added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (65 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]3[CH2:24][O:23]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]([OH:23])[CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCNCC1
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC2CO2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC(O)CN2CCCCC2)CC1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A solution of 0.30 g (0.81 mmol) of (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one in 0.3 ml of DMA was treated with 0.19 ml (1.22 mmol) of piperidine and 0.265 g (0.81 mmol) of cesium carbonate. The reaction was stirred over night at RT, CH2Cl2 was added, filtrated and evaporated. Crystallization (CH2Cl2/Et2O) gave 0.16 g (43%) of the title compound as pink crystalline solid. MS: 454.2 (MH+, 2Cl).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][N:8]1[C:7]2=[O:21])[CH3:3].Cl[CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:24]([CH2:23][O:19][C:18]([C:16]1[CH:15]=[CH:14][C:9]2[N:8]([CH:17]=1)[C:7](=[O:21])[C:6]1[C:11](=[CH:12][CH:13]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=1)[N:10]=2)=[O:20])#[N:25]
Reactant: N#CCCl
Reactant: CC(C)c1ccc2nc3ccc(C(=O)O)cn3c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc2nc3ccc(C(=O)OCC#N)cn3c(=O)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A suspension of 20 g of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, 6.3 ml of chloroacetonitrile and 13.2 g of potassium carbonate in 100 ml of dimethylformamide was stirred 18 hours at room temperature. The reaction mixture was diluted with 200 ml of water and the precipitated product collected to give 21.63 g (95%) of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid cyanomethyl ester, mp 186°-188° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@@H:7]([CH3:18])[CH2:6][N:5]2S(C1C=CC(C)=CC=1)(=O)=O.ClCCl.S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:15])([F:14])[F:16])[C@@H:7]([CH3:18])[CH2:6][NH:5]2
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H](C)N(C(=O)C(F)(F)F)c3ccc(Br)cc32)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A 3-L, three-necked, round bottomed flask fitted with a nitrogen inlet, magnetic stir bar, and thermocouple was charged with (S)-1-(6-bromo-2-methyl-4-tosyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (106.81 g, 224 mmol), dichloromethane (1070 mL), and sulfuric acid (18 M, 119 mL, 2238 mmol). The reaction mixture stirred at rt for 1 h and was then cooled to 0° C. Water (1070 mL) was slowly added in 100 mL portions, while maintaining the internal temperature at ca. 0° C. (Note: the internal temperature rose from ca. 2.6° C. to 23.8° C. with each addition). After the final water addition, the internal temperature was 34° C., and the mixture was cooled to rt. The aqueous layer was separated extracted with dichloromethane (700 mL). The combined organic layers were washed with water (700 mL) and then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 100% dichloromethane). The product-containing fractions were combined and concentrated under reduced pressure. Further drying under vacuum (ca. 17 Torr) at rt afforded (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (71.8 g, 99%) as a brown solid. MS (ESI, pos. ion) m/z 323[M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([OH:10])=O)[S:6][CH:7]=1.S(Cl)([Cl:13])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([Cl:13])=[O:10])[S:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1csc(C(=O)O)c1
Product: COc1csc(C(=O)Cl)c1

Procedure:
24.0 g (152 mmol) 4-methoxy-2-thiophenecarboxylic acid were suspended in 250 ml thionyl chloride and heated for two hours under reflux. The excess thionyl chloride was then distilled off under vacuum. The crude product was quickly distilled off and crystallised out in the receiver.