Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=1[OH:30])(=[O:21])=[O:20])C.O.[NH2:33][NH2:34]>C(O)C>[C:28]([C:26]1[CH:25]=[CH:24][C:23]([OH:30])=[C:22]([S:19]([NH:18][CH2:17][CH2:16][C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:15])[CH3:14])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([NH:33][NH2:34])=[O:31])(=[O:21])=[O:20])[CH:27]=1)#[N:29]
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)NN)c1

Procedure:
Ethyl[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate (0.266 g) was dissolved in 5 mL of ethanol. To the solution was added 0.087 mL of hydrazine monohydrate at room temperature, and the mixture was refluxed for 1 hour. The solvent was removed under reduced pressure to give 0.258 g of 5-cyano-N-[2-(2-hydrazinocarbonylmethoxy-4-isopropylphenyl)ethyl]-2-hydroxybenzenesulfonamide.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C=O)C.N1C=CC=CC=1>CCOC(C)=O.O>[C:10]1([C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:1]2[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 8 h
Yield: 94.1 %

Procedure:
1-(Triphenylmethyl)-1H-imidazole-4-carboxylic acid was prepared as described in J. Med. Chem. 2001, 44, 1268. 1H-Imidazole-4-carboxylic acid (0.50 g, 4.5 mmol) and trityl chloride (1.35 g, 4.9 mmol) were added to a solution of DMF (30 mL) and pyridine (15 mL) and stirred overnight. Water and EtOAc were added. The layers were separated and the aqueous layer extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with water and brine, dried over Na2SO4, filtered and evaporated. The oil was triturated with EtOAc to afford the title compound (1.5 g, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.40 (br. s., 1H), 7.42 (t, 9H), 7.17-7.35 (m, 2H), 7.10 (d, 6H). MS: m/z 111 (M−243).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Cc1c(Cl)cccc1CBr
Reactant: O=[N+]([O-])c1cc(Br)c2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)cccc1Cn1cnc2c(Br)cc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
Into a 250 mL round bottomed flask charged with 4-bromo-6-nitro-1H-benzo[d]imidazole (5 g, 20.66 mmol) in N,N-Dimethylformamide (DMF) (100 mL) was added 1-(bromomethyl)-3-chloro-2-methylbenzene (6.80 g, 31.0 mmol) and potassium carbonate (8.57 g, 62.0 mmol The resulting reaction mixture was stirred 1 h at 60° C., cooled to room temperature and poured into water, extracted with ethyl acetate, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified on a silica gel cartridge and eluted with a gradient of 0% ethyl acetate/hexanes to 80% over 10 column volumes. The expected compound was collected and evaporated to yield 4-bromo-1-(3-chloro-2-methylbenzyl)-6-nitro-1H-benzo[d]imidazole (3.05 g, 8.01 mmol, 38.8% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3H) 5.79 (s, 2H) 6.61 (d, J=7.58 Hz, 1H) 7.16 (t, J=7.83 Hz, 1H) 7.42 (d, J=7.58 Hz, 1H) 8.34 (d, J=2.02 Hz, 1H) 8.65 (d, J=2.02 Hz, 1H) 8.73 (s, 1H); LC/MS: MS (ES+) m/e 381 [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17]>>[CH:19]([C@@H:15]1[S:11][C:10]([NH:9][CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])([CH3:21])[CH3:20]
Reactant: CC(C)C(Br)C(=O)O
Reactant: C[C@H](CNC(N)=S)c1ccccc1
Product: CC(C)[C@@H]1SC(NC[C@@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2S)-2-phenylpropyl]thiourea and 2-bromo-3-methylbutyric acid according to Method D3.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13].[Cl-].[Li+].[F-].[K+]>CN(C=O)C.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:12]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)OC)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
step 1 Methyl 6-chloronicotinate (1.51 g, 8.79 mmol) was dissolved in DMF (35 mL), vinyltributyltin (3.32 mL, 11.4 mmol), dichlorobis(tri-o-tolylphosphine)palladium (206 mg, 0.262 mmol) and lithium chloride (554 mg, 13.1 mmol) were added and the mixture was stirred at 100° C. for 2 hr. The mixture was allowed to cool to room temperature, and an aqueous potassium fluoride solution was added thereto. The mixture was filtered through Celite and the residue was washed with ethyl acetate. To the obtained filtrate was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30) to give methyl 6-vinylnicotinate (1.22 g, 85%) as a colorless transparent oil. 1H NMR (CDCl3, δppm): 3.95 (s, 3H), 5.63 (dd, J=1.1, 10.8 Hz, 1H), 6.35 (dd, J=1.1, 17.4 Hz, 1H), 6.87 (dd, J=10.8, 17.4 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 8.25 (dd, J=2.1, 8.2 Hz, 1H), 9.15-9.18(m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:11][C:12]([NH:14]C(OCC)=O)=S)=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:7]=1.Cl.NO.C([N:26](C(C)C)CC)(C)C>CO>[Br:1][C:2]1[C:3]2[N:4]([N:26]=[C:12]([NH2:14])[N:11]=2)[CH:5]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ncc(C2CC2)cc1Br
Agent: Cl
Agent: NO
Solvent: CO
Product: Nc1nc2c(Br)cc(C3CC3)cn2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-(3-bromo-5-cyclopropyl-pyridin-2-yl)-N′-ethoxycarbonyl-thiourea (1.5 g, 4.36 mmol) in dry methanol (20 mL) were added hydroxylamine hydrochloride (1.41 g, 21.8 mmol) and diisopropyl ethylamine (12.14 mL, 13.08 mmol) under an argon atmosphere and stirred at room temperature for 6 hours. Methanol was evaporated and the residue purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as off white solid (910 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:19]1([CH:25]=[CH:26][CH2:27][NH:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([N:28]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH:26]=[CH:25][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CNCC=Cc1ccccc1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CN(CC=Cc1ccccc1)C(=O)C1=C(C)NC(=O)NC1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
320 mg (1.20 mmol) of 4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid was dissolved in 2 ml of DMF. 280 mg (1.20 mmol) of methyl (3-phenyl-2-propene-1-ylamino)acetate and 276 mg (1.44 mmol) of WSC hydrochloride were added to the obtained solution, and they were stirred at room temperature overnight. After the extraction with ethyl acetate, the extract was dried over magnesium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by the silica gel chromatography (methylene chloride/methanol=200/1 to 50/1) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.CC([O-])(C)C.[K+].Cl[CH2:16][CH2:17][CH2:18][C:19]#[N:20].[NH4+].[Cl-]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]2[CH:18]([C:19]#[N:20])[CH2:17][CH2:16][O:8]2)[S:5][CH:6]=1
Reactant: N#CCCCCl
Reactant: O=Cc1cc(Br)cs1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: N#CC1CCOC1c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Addition of 4-bromo-2-thiophenecarboxaldehyde 63 (Aldrich, Wis.) (1.0 g, 5.23 mmol) to a solution of t-BuOK (1 M in THF, 5.23 mL, 5.23 mmol) at 0° C. was followed immediately by the addition of 4-chloro-butyronitrile (0.51 mL, 5.3 mmol). After 3 h, the reaction mixture was allowed to warm to the room temperature and saturated, aqueous NH4Cl solution was then added. The crude reaction mixture was then separated and the aqueous fraction extracted twice with EtOAc. The combined EtOAc extracts were dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel column chromatography (eluent: 10% to 20% gradient of EtOAc in hexane) afforded trans-86 (0.3 g) as an yellow liquid. 1H NMR (400 MHz, d6-DMSO) δ: 7.68 (d, J=1.5 Hz, 1H), 7.19 (dd, J=1.0 Hz and 1.5 Hz, 1H), 5.26 (d, J=7.0 Hz, 1H), 4.04 (m, 1H), 3.96 (m, 1H), 3.44 (m, 1H), 2.41 (m, 1H), 2.29 (m, 1H). MS (EI) m/z [(M+H+)+ (79Br)] 258 and [(M+H+)+ (81Br)] 260.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[S:9][C:10]([S:13][CH:14]([CH3:20])[C:15](OCC)=[O:16])=[CH:11][N:12]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].O>O1CCCC1>[NH2:7][C:8]1[S:9][C:10]([S:13][CH:14]([CH3:20])[CH2:15][OH:16])=[CH:11][N:12]=1
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)Sc1cnc(N)s1
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
Lithium aluminum hydride (97 mg, 2.56 mmol) was suspended in tetrahydrofuran (5 mL). Thereafter, under cooling on ice, a tetrahydrofuran (6 mL) solution of ethyl 2-((2-aminothiazol-5-yl)thio)propanoate (0.2 g, 0.85 mmol) was added to the obtained suspension, and the thus obtained mixture was then stirred for 30 minutes. Thereafter, sodium sulfate and water were added to the reaction solution, and the obtained mixture was then stirred. Insoluble matters were removed by filtration, and the filtrate was then concentrated in vacuo. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=5:1) to obtain 2-((2-aminothiazol-5-yl)thio)propan-1-ol (103 mg, 63%) in the form of a yellow oily product.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C([Li])CCC.C([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]1)(OC(C)(C)C)=O.C(I)CCC>C1COCC1.CCOC(C)=O>[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=[O:29])[CH2:24][CH2:23]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: CCCCI
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(O)C1CCNCC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.88 g (8.6 mmol) of diisopropylethylamine in 30 ml of THF at 0° C. under N2 was added dropwise 3.52 ml (8.6 mmol) of a solution of 2.5N butyl lithium in hexanes. The solution was stirred for 15 minutes, cooled to -78° C. and treated with a solution of ethyl N-BOC-4-piperidinecarboxylate (2.0 g, 8.0 mmol) in 8 ml of THF. The solution was stirred for 1 hour and then 2.16 g (8.4 mmol) of n-butyl iodide was added and the reaction mixture was allowed to warm to room temperature and was stirred over night. The solution was diluted with 100 ml of EtOAc and washed with 1N HCl (3×20 ml); saturated sodium bicarbonate solution (2×20 mL) and brine (1×20 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with 10% EtOAc/hexanes to give the desired product. 1H-NMR (CDCl3, 400 MHz): 0.86 (t, 3H); 1.25 (t, 3H); 1.93 (s, 9H); 1.1-1.8 (m, 8H); 2.08 (bd, 2H); 2.85 9bt, 2H); 3.85 (bd, 2H); 4.16 (q, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=O.[CH3:17][N:18]([CH3:24])S(=O)N(C)C>C(Cl)(Cl)Cl>[CH3:17][N:18]([CH3:24])[C:14](=[O:16])[CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:6][C:2]=1[Cl:1]
Reactant: O=C(O)Cc1nc(-c2ccccc2)sc1Cl
Reactant: CN(C)S(=O)N(C)C
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)Cc1nc(-c2ccccc2)sc1Cl

Procedure:
A mixture of 5-chloro-2-phenylthiazol-4-yl-acetic acid (1.98 g, 7.8 mmol), tetramethylsulphurous diamide (1.01 g, 9 mmol) and chloroform (dry, 30 ml) were heated under reflux for 4 hours. The reaction mixture was cooled and was concentrated under reduced pressure. The residue was taken up into chloroform (100 ml) and H2O (50 nl) and an excess of sodium bicarbonate added. After filtration the chloroform layer was washed with dilute HCl, water, dried (MgSO4), filtered and was concentrated under reduced pressure. The product was purified from hot petroleum ether (100°-126° C.) (0.47 g) m.p. 77°-79° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:20][C:21]([O:23]CC)=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([F:19])([F:18])[CH:15]([F:17])[F:16])=[CH:8][CH:7]=1)=[O:4].[NH3:26].C(O)C>>[F:18][C:14]([F:19])([CH:15]([F:17])[F:16])[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]2[CH2:20][C:21](=[O:23])[NH:26][CH2:2][C:3]2=[O:4])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CN(C(=O)CCl)c1ccc(OCC(F)(F)C(F)F)cc1
Reactant: N
Solvent: CCO
Product: O=C1CN(c2ccc(OCC(F)(F)C(F)F)cc2)C(=O)CN1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
The resulting N-chloroacetyl-N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (1.9 g) was dissolved in 20 ml of 10.5% ammonia-ethanol and the solution was stirred at 60° C. for four hours. After cooling, the crystals separated out therefrom were collected by filtration and washed with cold ethanol to give 1.5 g of 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,5-piperazinedione as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][NH:6][C:5](=[O:8])C[CH2:3]1.P(Cl)(Cl)(Cl)(Cl)Cl.S(Cl)(Cl)(=O)=O.[CH:21]([Cl:24])(Cl)[Cl:22]>>[Cl:22][C:21]1([Cl:24])[CH2:1][C:2]([CH3:9])([CH3:3])[CH2:7][NH:6][C:5]1=[O:8]
Reactant: CC1(C)CCC(=O)NC1
Reactant: ClC(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: CC1(C)CNC(=O)C(Cl)(Cl)C1
Reaction time: 0.17 h

Procedure:
To a cold (0° C.) stirred solution of 5,5-dimethyl-2-piperidone (30.2 g, 0.24 mol) in 475 mL of CHCl3, PCl5 (57.1 g, 0.26 mol) was added at such a rate that the temperature never exceeded 7° C. After the addition was complete, stirring was continued for 10 min. Sulfuryl chloride (96.6 g, 0.72 mol) was slowly added and the mixture was heated under reflux for 1 h. The solution was concentrated under reduced pressure. The residue was cooled in ice and diluted with 250 mL of ice-water. The product was then extracted with CHCl3 (6×250 mL) and the organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica-gel column chromatography, and then the column was eluted with CHCl3-MeOH (50:1). The titled compound was obtained as a white solid (41.3 g, 88.8%). (J. Med. Chem., 20, 1176 (1977))
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[N:17]4)[N:11]([CH:24]([C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=3)[CH3:25])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[N:17]4)[N:11]([CH:24]([C:26]3[CH:38]=[CH:37][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)[CH3:25])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(c1ccc(C(=O)OC(C)(C)C)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1ccc2nccnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccc(C(=O)O)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1ccc2nccnc2c1

Procedure:
The intermediate from step F (40 mg, 0.07 mmol) was dissolved in 1:1 CH2Cl2:TFA (4 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and azeotroped with toluene (3×). The resulting light yellow solid was used without further purification. LC-MS: 4.18 min. (M+H)=490.35.
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C(=O)([O-])[O-].[K+].[K+].Cl>CN1CCCC1=O>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:13]=[CH:12][C:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=2[N+:14]([O-:16])=[O:15])[CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)OC(=O)c1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1
Temperature: 150 °C
Yield: 62.9 %

Procedure:
A mixture of i-propyl 4-chloro-3-nitrobenzoate (25.88 g, 0.11 mol), 3-bromoaniline (17.36 ml, 0.16 mol) and potassium carbonate (14.63 g, 0.11 mol) in N-methyl-2-pyrrolidone (25 ml) is heated to 150° C. for 3 days. After cooling the mixture is poured into diluted hydrochloric acid (300 ml, 1 M). The precipitate is filtered off, washed with water and dried (37.4 g). This crude product is washed with hot 2-propanol to afford pure 24 (26.25 g, 65%). Mp 162-165° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCCO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
33 mg (0.10 mmol) of the compound from Example 31A, 29 mg (0.12 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 33 mg (0.39 mmol) of sodium bicarbonate are suspended in 2 ml of dry DMF. The reaction mixture is stirred at RT for 20 h. The mixture is filtered and directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[O:6][CH:7]=1.[F:15][C:16]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([F:26])[C:17]=1[C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:25][C:24]3[C:16]([F:15])=[C:17]([C:21]([F:26])=[CH:22][CH:23]=3)[C:18]([NH2:20])=[O:19])[N:4]=2)=[CH:9][CH:10]=1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2coc(-c3ccc(Cl)cc3)n2)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.2 %

Procedure:
To a solution of 4-Chloromethyl-2-(4-chloro-phenyl)-oxazole (0.20 g, 0.87 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.15 g, 0.78 mmol) and potassium carbonate (0.363 g, 2.60 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.10 g, 31%). 1H NMR (DMSO-d6, 400 MHz): δ 5.14 9s, 2H), 7.12 (t, J=9.20 Hz, 1H), 7.40 (m, 1H), 7.63 (d, J=8.40, 2H), 7.85 (br s, 1H), 8.0 (d, J=8.40 Hz, 2H), 8.13 (br s, 1H) and 8.36 (s, 1H). MS ES+ (365.13), HPLC (method I) Rt=16.36 min.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:20][CH2:19][C:13]2([C:17](=[O:18])[NH:16][CH2:15][CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([C:17](=[O:18])[N:16]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([Br:21])=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH2:19][CH2:20]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(Cc1ccc(Br)cc1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
Introduce 600 mg (14.7 mmol) of sodium hydride (60% suspension in mineral oil) in a 500 mL round bottom flask under nitrogen before adding successively 20 mL of anhydrous DMF and 2.5 g (9.8 mmol) of 1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester previously dissolved in 20 mL of anhydrous DMF. After agitating one hour at room temperature, 2.5 g (9.8 mmol) of 4-bromobenzylbromide diluted in 20 mL of anhydrous DMF were added and the reaction mixture was agitated an additional hour at room temperature. Then 100 mL of water were added and the solution was extracted with diethyl ether (2×150 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated under reduced pressure to yield 4.63 g of 2-(4-bromobenzyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7](Cl)=[O:8])=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH:21]=[CH:22][C:23]#[N:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1.N12CCN(CC1)CC2>CC(C)=O>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([S:7]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH:21]=[CH:22][C:23]#[N:24])(=[O:20])=[O:19])=[CH:16][CH:17]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)Cl)cc1
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Agent: C1CN2CCN1CC2
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)Nc2ccc(S(=O)(=O)C=CC#N)cc2)cc1
Reaction time: 0.33 h

Procedure:
17.5 g p-toluenesulfinyl chloride (obtained by treating sodium toluenesulfinate.2H2O with thionyl chloride) is dissolved in 100 ml of acetone and this solution is added at room temperature and with stirring to a solution of 20.8 g (0.1 mol) of 2-cyanovinyl 4-aminophenyl sulfone in 250 ml of acetone. Shortly thereafter a solution of 11.2 g (0.1 mol) of 1,4-diazabicyclo[2.2.2]octane in 150 ml of acetone is added over about 10 minutes and the reaction mixture is stirred for another 20 minutes. The reaction mixture is filtered, evaporated in air to about a third of its volume, and then poured into cold water. The precipitate is filtered, washed and dried to give 3-[4-(4-methylbenzenesulfinamido)benzenesulfonyl]acrylonitrile: ##SPC45##