Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:43])([CH3:42])[C@H:3]([NH:14][C:15]([C@H:17]([CH2:26]/[CH:27]=[CH:28]/[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:31]([CH3:41])[CH:30]=1)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:4]([O:6]CC1C=CC=CC=1)=[O:5]>C(O)C.O.[Pd]>[CH3:1][C:2]([CH3:43])([CH3:42])[C@H:3]([NH:14][C:15]([C@H:17]([CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:31]([CH3:41])[CH:30]=1)[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:16])[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(/C=C/C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc2ccccc2)C(C)(C)C)ccc1-c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Cc1cc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)C(C)(C)C)ccc1-c1ccccc1
Yield: 97 %

Procedure:
A solution of tert-butyl (3R,5E)-3-({[(1S)-2,2-dimethyl-1-(benzyloxycarbonyl)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hex-5-enoate (2.205 g, 3.78 mmol) in ethanol/water=10:1 (44 mL) was hydrogenated over 10% palladium on charcoal at 3 bar and room temperature for 6 h. The mixture was filtered through Arbocel filter aid, washing well with ethanol. The filtrate was concentrated under reduced pressure. The residue was dissolved in toluene and evaporated (three times), dissolved in ether and evaporated (twice), and finally dissolved in ether and precipitated as an oil by the addition of hexane. Removal of the solvent under reduced pressure gave tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-(carboxy)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hexanoate (1.817 g, 97%) as a colourless foam, m.p. 51-56° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][C:17]2=[O:30])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[CH2:1]([NH:8][C:9]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]2=[O:30])[CH:11]=1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)c1ccnc(-n2ccc(OCc3ccccc3)cc2=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NCc1ccccc1)c1ccnc(-n2ccc(O)cc2=O)c1
Yield: 49.4 %

Procedure:
A solution of N-benzyl-2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)isonicotinamide (0.88 g, 2.14 mmol) and 20 weight % palladium on activated carbon (0.10 g) in methanol (50 mL) was stirred in atmospheric pressure of hydrogen for 2 hours. The resulting solution was filtered and concentrated in vacuo. The residue was recrystallized from methanol (10 mL) to give 4-hydroxy-2-oxo-2H-[1,2′]bipyridinyl-4′-carboxylic acid benzylamide as a colorless solid (0.34 g, 50%): mp 102-105° C. (methanol); 1H NMR (300 MHz, CD3OD) δ 8.66 (d, J=5.1 Hz, 1H), 8.05 (s, 1H), 7.81-7.78 (m, 2H), 7.36-7.24 (m, 5H), 6.20-6.17 (m, 1H), 5.86 (s, 1H) 4.57 (s, 2H); 13C NMR (75 MHz, CD3OD) δ 167.6, 164.0, 162.9, 150.8, 147.9, 142.4, 136.5, 135.9, 126.6, 125.7, 125.4, 119.5, 117.9, 100.9, 96.8, 41.8; MS (ES+) m/z 322.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:14])=[O:23]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: Cc1ccccc1N=C=O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(Cl)c1
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-methylphenyl isocyanate (0.60 ml, 5.01 mmol) in THF (20 ml) was added Et3 N (0.14 ml, 1.00 mmol) at room temperature. After 1 day stirring, 2-methylphenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 17 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-chloro-4-[N′-(2-methylphenyl) ureido]phenylacetate (1.23 g, 74%) as a colorless powder. 1H-NMR (CDCl3) δ 2.34 (s, 3H), 3.54 (s, 2H), 3.68 (s, 3H), 6.24 (br, 1H1), 6.99 (br, 1H), 7.15 (dd, J=8.3, 2.0 Hz, 1H), 7.21–7.31 (m, 5H), 7.44 (d, J=7.6 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H); MS (ESI) m/z 333 (M++1), 335 (M++3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[CH:8]=[N:7][CH:6]=1)[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:10]2[N:11]=[C:18]([C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15]([F:14])([F:24])[F:25])[NH:12][C:9]=2[CH:8]=[N:7][CH:6]=1)=[O:13])[CH3:2]
Reactant: CCOC(=O)c1cncc(N)c1N
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cncc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Temperature: 120 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
A mixture containing 4,5-diamino-nicotinic acid ethyl ester (79; 1.81 g, 10 mmol), 2-trifluoromethylbenzaldehyde (1.9 g, 11 mmol), Na2S2O5 (9.5 g, 50 mmol) in 50 mL of DMF was stirred at 120° C. for 18 h. Upon cooling to room temperature, the reaction mixture was poured into 100 mL of cold water. The resulting solids were collected by filtration, washed with water, and dried to provide 2-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine-7-carboxylic acid ethyl ester 80 (2.35 g, 70%)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][CH:10]([NH2:12])[CH3:11]>C1COCC1>[Cl:8][C:7]1[C:2]([NH:12][CH:10]([CH3:11])[CH3:9])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CC(C)N
Reactant: Clc1nccnc1Cl
Solvent: C1CCOC1
Product: CC(C)Nc1nccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
2,3-dichloropyrazine (10 g, 67.1 mmol), propan-2-amine (11.90 g, 201 mmol), and 50 mL of THF were mixed in a three-neck flask and stirred at room temperature overnight. The reaction was brought to reflux overnight. The reaction was cooled and the solvent was evaporated. The residue was dissolved in dichloromethane and the salt was filtered. The solvent was then evaporated and the residue was purified by column using dichloromethane as solvent to give 3-chloro-N-isopropylpyrazin-2-amine (6.2 g, 53.8%).
Reaction SMILES: [CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][C:22](N)=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].N([O-])=[O:34].[Na+].[OH-].[Na+]>>[CH2:1]([C@@:4]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22](=[O:34])[NH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=N[O-]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(N)nc3)cc2)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)[nH]c3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (1.5 g, 3.47 mmol.) in 3.5 MH2SO4 (25 mL) was added 2 M NaNO2 (15 mL) at 0° C. The reaction mixture was stirred at rt overnight. The reaction was treated with aqueous NaOH solution (8%), and the mixture was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give crude product, which was purified by preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (891 mg, 59%). 1H NMR (CDCl3): δ=1.52 (d, 3H), 2.15-2.38 (m, 3H), 2.51-2.60 (m, 2H), 2.94 (m, 1H), 4.99-5.11 (m, 2H), 5.65-5.74 (m, 2H), 6.67 (m, 1H), 6.89 (d, 2H), 7.00 (t, 2H), 7.13-7.20 (m, 2H), 7.20-7.27 (d, 2H), 7.33 (m, 1H), 7.46 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.Br[C:17]1[N:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:17]2[N:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]3)=[CH:19][CH:18]=2)=[CH:9][CH:8]=1
Reactant: COCCCSc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCCCSc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cn2)cc1
Yield: 86.4 %

Procedure:
1,1-Dimethylethyl 4-({[6-(4-{[3-(methoxy)propyl]thio}phenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate (0.384 g, 86%) was prepared as a yellow solid from (4-{[3-(methoxy)propyl]thio}phenyl)boronic acid (0.27 g, 1.13 mmol), 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 76, Step 1, 0.35 g, 0.94 mmol), 2M Na2CO3 (5 mL) and PdCl2(PPh3)2 (68 mg, 0.09 mmol) in DME (6 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 8.34 (d, 1H, J=2.2 Hz), 7.84 (d, 2H, J=8.3 Hz), 7.63 (d, 1H, J=8.8 Hz), 7.39 (d, 2H, J=8.3 Hz), 7.25-7.20 (m, 1H), 4.17 (bs, 2H), 3.88 (d, 2H, J=6.3 Hz), 3.48 (t, 2H, J=6.0 Hz), 3.32 (s, 3H), 3.04 (t, 2H, J=7.2 Hz), 2.85-2.70 (m, 2H), 2.05-1.80 (m, 5H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 473 (M+H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C@:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:35]5[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
The compound (255 mg, 0.55 mmol) obtained in Example 4-2), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (126 mg, 0.60 mmol), tris(dibenzylideneacetone)dipalladium (25 mg, 0.03 mmol), tricyclohexylphosphine (29 mg, 0.07 mmol), and tripotassium phosphate (205 mg, 0.93 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (1 mL), and the mixture was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, then diluted with methylene chloride (60 mL), and separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (20 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 20%) to obtain the title compound (283 mg, quant.) in a colorless solid form.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1COCC1.O>[C:3]([C@H:2]([O:1][S:15]([CH3:14])(=[O:17])=[O:16])[CH3:6])(=[O:4])[NH2:5]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)C(N)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](OS(C)(=O)=O)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71233.6 %

Procedure:
Alternatively, to a solution of (R)-2-hydroxy-propionamide (10 g, 0.11 mmol) and triethylamine (17.2 mL, 0.12 mmol) in THF (130 mL) at 0° C. was added dropwise, methanesulfonyl chloride (9.56 mL, 0.12 mmol) causing a thick white precipitate to form. The reaction mixture was stirred at RT for 2 hours. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was triturated with TBME to yield methanesulfonic acid (R)-1-carbamoyl-ethyl ester as a white solid (13.1 g, 70%). 1H NMR (400 MHz, d6-DMSO) 7.56 (1H, br s), 7.41 (1H, br s), 4.91 (1H, t, J=6.6 Hz), 3.23 (3H, s), 1.44 (3H, d, J=6.6 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[Br:12][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nccnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: BrCc1ccc2nccnc2c1

Procedure:
A mixture of 6-methylquinoxaline (1.5 g, 10.4 mmol), N-bromosuccinimide (2.2 g, 12.5 mmol) and benzoylperoxide (0.30 g, 1.25 mmol) in benzene (35 mL) was stirred rapidly and heated to reflux for 5 h. Upon cooling, the mixture was diluted with ethyl acetate (25 mL), washed with IN sodium hydroxide solution (50 mL) and saturated sodium chloride solution (50 mL). The organic layer was dried (MgSO4) and evaporated to a crystalline solid (2.5 g, 77% desired product, 23% α,α-dibrominated product as determined by 1H NMR). The mixture was used in subsequent reactions.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[N:16][CH:15]=[CH:14]3)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:22]C1C=CC=C(C(OO)=O)C=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:22][C:17]1[C:18]2[C:13](=[CH:12][C:11]([NH:10][S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:21])=[CH:6][CH:5]=3)(=[O:8])=[O:9])=[CH:20][CH:19]=2)[CH:14]=[CH:15][N:16]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc3cnccc3c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Nc2ccc3c(Cl)nccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
6-(4-Toluenesulfonylamino) isoquinoline (3.0 g, Production Example 21b) was dissolved in chloroform (100 ml). Under ice-cooling, m-chloroperbenzoic acid (2.57 g) was added thereto, followed by stirring at room temperature overnight. The solvent was evaporated, and the resulting crystals were washed with diethyl ether, collected by filtration and dried, to give pale yellow crystals. The crystals were suspended in chloroform (83 ml) and phosphorous oxychloride (19 ml) was added thereto, followed by heating under reflux for 5 hours. After cooling, the solvent was evaporated. The residue was basified by adding an aqueous saturated sodium bicarbonate in an ice bath, and then the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column, to give crude crystals of the title compound (1.630 g, 49.40%). The crystals were recrystallized from ethanol, to give the title compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C([Li])CCC.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=[N:26][CH3:27]>O1CCCC1.CCCCCC.C1(C)C=CC=CC=1>[CH3:27][NH:26][CH:25]([C:21]1[S:20][CH:24]=[CH:23][CH:22]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: CN=Cc1cccs1
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1cccs1
Temperature: -6 °C
Reaction time: 2.3 h
Yield: 36.7 %

Procedure:
A stirred, chilled (-10° C.) solution of 19.3 g of N-[(2-methyl)phenyl]-2,2-dimethylpropanamide in 150 ml of tetrahydrofuran was treated over 43 min with 140 ml of a 1.6M solution of n-butyllithium in hexane, while maintaining the temperature at or below 0° C. Stirring for 2.3 hours with cooling afforded a suspension. The stirred, cooled (-6° C.) suspension was treated over 13 min with a solution of 15.02 g of N-(2-thienylmethylene)methanamine in 30 ml of toluene. The reaction mixture was stirred with cooling (1° C.) for 1.5 hours, quenched by the addition of 120 ml of water and concentrated. The concentrate was extracted with dichloromethane (2×200 ml), and the combined extract was dried over anhydrous sodium sulfate, filtered, and evaporated to an oil. Preliminary purification of the oil was achieved by preparative high pressure liquid chromatography (hereinafter "HPLC") separations utilizing a Water's Model 500A High Pressure Liquid Chromatograph (silica gel; eluting with 10% methanol in ethyl acetate). The appropriate fractions from each separation were combined and concentrated to an oil. The purification procedure was repeated utilizing 5% methanol in ethyl acetate as the eluent to yield 11.71 g of N-[2-[2-methylamino-2-(2-thienyl)ethyl]phenyl]-2,2-dimethylpropanamide as a solid, mp 78.5°-82° C.
Reaction SMILES: [Cl:1][C:2]1([S:8](Cl)(=[O:10])=[O:9])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>>[CH2:12]([NH:15][S:8]([C:2]1([Cl:1])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1)(=[O:10])=[O:9])[CH:13]=[CH2:14]
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Reactant: C=CCN
Product: C=CCNS(=O)(=O)C1(Cl)NC(Cl)=CS1

Procedure:
In analogy to Example 2, the N-allyl-2,4-dichlorothiazole-sulphonamide was prepared by reacting 2,4-dichlorothiazolesulphonyl chloride from Example 1 with anhydrous allylamine. Following recrystallization from petroleum ether/acetone (6:1), 7.6 g of product were obtained (28% of the theoretical yield), m.p.: 80°-81° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:5][N:4]=[CH:3]1.C(O)(C(F)(F)F)=O.[Br:28][C:29]1C(Cl)=[C:31]([N+:36]([O-:38])=[O:37])[C:32]([NH2:35])=[N:33][CH:34]=1>C(Cl)Cl>[Br:28][C:29]1[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)[CH2:13][CH2:12]2)=[C:31]([N+:36]([O-:38])=[O:37])[C:32]([NH2:35])=[N:33][CH:34]=1
Reactant: Cn1cncc1CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reaction time: 1 h
Yield: 36.1 %

Procedure:
tert-Butyl 4-((1-methyl-1H-imidazol-5-yl)methyl)piperazine-1-carboxylate (0.150 g, 0.54 mmol, 1.1 eq) was dissolved in DCM (1.7 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (1.7 mL). Stirring was continued at this temperature for 1 h and the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 1-((1-methyl-1H-imidazol-5-yl)methyl)piperazine (supposedly 0.097 g, 0.54 mmol, 1 eq) was suspended in iPrOH (1.6 mL) and DIPEA (0.42 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.120 g, 0.49 mmol, 1 eq) was added and the mixture heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.070 g, 33%); 1H-NMR (500 MHz, DMSO-d6): δ 3.03 (br s, 4H, piperazine N(CH2)2), 3.49 (s, 2H, NCH2), 3.62 (s, 3H, imidazole Me), 6.76 (s, 1H, imidazole H-4), 6.96 (s, 2H, NH2), 7.54 (s, 1H, imidazole H-2), 8.16 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=1.56 min—396/398 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([C:26]([CH:28]=[CH2:29])=[O:27])[CH3:25].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:25]=[CH:24]/[C:26](=[O:27])[CH2:28][CH3:29])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CC(=O)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 100 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (160 mg, 0.36 mmol), ethylvinyl ketone (50 mg, 0.43 mmol) and Pd(OAc)2 (8 mg) in MeCN (2 mL) is added triethylamine (0.5 mL, 3.6 mmol) and the mixture is heated at 100° C. in a pressure vessel for 4 h. The mixture is filtered and the solvent removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][NH:12][C:13]([O-:15])=[O:14])[CH2:8]2.C(=O)([O-])O.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24].O>ClCCl>[Cl:21][CH2:22][C:23]([N:11]([CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)[NH:12][C:13]([O:15][CH2:10][C:1]1[CH:8]=[CH:7][CH:9]=[CH:3][CH:2]=1)=[O:14])=[O:24]
Reactant: O=C([O-])NNC1C2CC3CC(C2)CC1C3
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(NN(C(=O)CCl)C1C2CC3CC(C2)CC1C3)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 144.8 %

Procedure:
Under an argon atmosphere, a solution of 2-(adamantan-2-yl)hydrazinecarboxylate (800 mg, 2.66 mmol) in dichloromethane (30 mL) was added with sodium hydrogen carbonate (450 mg, 5.40 mmol) and chloroacetic acid chloride (300 mg, 2.66 mmol) were added at 0° C., and the resultant was stirred at room temperature for 3 hours. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and benzyl 2-(2-chloroacetyl)-2-(adamantan-2-yl)hydrazinecarboxylate (726 mg, 72.4%) was obtained as a white crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12]1>>[CH:11]1([C:15]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:16])[CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CCC1
Reactant: Nc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(NC(=O)C2CCC2)cc1

Procedure:
4-Cyclobutanecarbonylamino-benzoic acid was prepared as described in Example 3 from 7.05 g (0.0514 mol) of p-aminobenzoic acid (PAB) and 6.4 g (0.054 mol) of cyclobutanecarboxylic acid chloride.