Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C@@H:11]1[CH2:16][N:15]([C:17]([O:19][CH3:20])=[O:18])[C@H:14]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[C@@H:13]([C:35](OC)=[O:36])[CH2:12]1)=[O:9].[OH:39][NH2:40].Cl.NO.C[O-].[Na+].Cl>CO>[OH:39][NH:40][C:35]([C@H:13]1[CH2:12][C@H:11]([O:10][C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[CH2:2][OH:1])=[O:9])[CH2:16][N:15]([C:17]([O:19][CH3:20])=[O:18])[C@@H:14]1[C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:22])=[O:36]
Reactant: NO
Reactant: COC(=O)[C@H]1C[C@H](OC(=O)N2CCC[C@H]2CO)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1C[C@@H](OC(=O)N2CCC[C@H]2CO)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of dimethyl (2S,3S,5S)-5-([(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyloxy)-2-[(4-phenylpiperazin 1-yl)carbonyl]piperidine-1,3-dicarboxylate (66 mg, 0.00012 mol) in methanol (0.57 mL, 0.014 mol) was added 1.640 M of N-hydroxyamine in methanol solution (1.511 mL), made from the hydroxylamine HCl salt and sodium methoxide freshly. The mixture was stirred at rt for 1 h and acidified with 1N HCl. The resulting mixture was applied directly on RP-HPLC to yield the desired compound (61 mg, 76%). MS (ESI): (M+H)+=534.2.
Reaction SMILES: ON1[C:6]2[CH:7]=[CH:8][CH:9]=C[C:5]=2[N:4]=N1.C(N(CC)CC)C.[C:18]([O:22][C:23]([NH:25][C@H:26]([C:33]([OH:35])=O)[CH2:27][C:28]1[N:29]=[CH:30][S:31][CH:32]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([NH:25][C@H:26]([C:33]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:8]1[CH3:9])=[O:35])[CH2:27][C:28]1[N:29]=[CH:30][S:31][CH:32]=1)=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1C(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 323.1 %

Procedure:
N,N-dicyclohexylcarbodiimide (10.83 g, 52.5 mmol), N-hydroxybenzotriazole (2.03 g, 15 mmol) and triethylamine (7.7 ml, 55.2 mmol) were added to a solution (130 ml) of N-(tert-butoxycarbonyl)-3-(thiazol-4-yl)-L-alanine (1) (13.62 g, 50 mmol) obtained by the method described in literatures (J. Am. Chem. Soc. 73, 2935 (1951) and Chem. Pharm. Bull. 38, 103 (1950)) and 2(R)-2-methylpyrrolidine p-toluenesulfonic acid (2) (12.79 g, 50 mmol) obtained by the method described in a literature (Helv. Chim. Acta, 34, 2202 (1951)) in tetrahydrofuran. The mixture was stirred for 20 hours at room temperature. After the precipitates are filtered off, the obtained filtrate was concentrated under reduced pressure. Thus-obtained residue was dissolved in ethyl acetate (200 ml) and the solution were washed with an aqueous solution of sodium hydrogencarbonate and water, successively. The organic layers were dried over magnesium sulfate and concentrated under reduced pressure to give a title compound (3) (16.45 g, 100%) as oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:36])=[C:11]([C:15]#[C:16][C:17]4[CH:22]=[C:21]([CH2:23][C:24]5[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=5)[CH:20]=[C:19]([O:32][CH3:33])[C:18]=4[O:34][CH3:35])[C:12]=3[F:14])[C:7](=[O:37])[C:6]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:5]2)[CH2:3][CH2:2]1.[H][H]>CN(C)C=O.C(O)(=O)C.[Pd]>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:36])=[C:11]([CH2:15][CH2:16][C:17]4[CH:22]=[C:21]([CH2:23][C:24]5[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=5)[CH:20]=[C:19]([O:32][CH3:33])[C:18]=4[O:34][CH3:35])[C:12]=3[F:14])[C:7](=[O:37])[C:6]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(C#Cc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(CCc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Reaction time: 6 h
Yield: 79.9 %

Procedure:
A suspension of 342 mg of ethyl 1-cyclopropyl-7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (Example 12a)) and 70 mg of 10% palladium-on-charcoal in 35 ml of dimethylformamide and 35 ml of acetic acid is hydrogenated at normal hydrogen pressure. After 6 hrs. the reaction mixture is filtered and the filtrate is concentrated in a high vacuum at 50°. The yellow residue is treated with 100 ml of 1N aqueous sodium hydroxide solution and extracted three times with 50 ml of methylene chloride each time. The combined organic phases are washed with 50 ml of water, dried over magnesium sulphate and concentrated. The crude product is triturated with 10 ml of hot ethyl acetate and filtered off under suction. 275 mg (80%) of ethyl 1-cyclopropyl-7-[2-[5-(2,4-diamino-pyrimidin-5-yl-methyl)-2,3-dimethoxy-phenyl]ethyl]-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate are obtained as a yellowish solid. M.p. 218°-220°.
Reaction SMILES: Cl.[CH:2]1([C:6]([NH2:8])=[NH:7])[CH2:5][CH2:4][CH2:3]1.C(O[CH:12]=[CH:13][C:14]#[N:15])C>>[CH:2]1([C:6]2[N:8]=[C:14]([NH2:15])[CH:13]=[CH:12][N:7]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CCOC=CC#N
Reactant: N=C(N)C1CCC1
Agent: Cl
Product: Nc1ccnc(C2CCC2)n1

Procedure:
This intermediate was made according to example 2, step A] method from cyclobutanecarboxamidine hydrochloride (0.3 g, obtained from cyclobutanecarbonitrile in analogy to Synth. Commun. 12 (13), 1982, 989-993 and Tetrahedron Lett. 31 (14), 1990, 1969-1972) and 3-ethoxy-acrylonitrile (0.3 g). 2-Cyclobutyl-pyrimidin-4-ylamine was obtained as a light brown solid (0.26 g): 1H NMR (δ, DMSO-d6): 7.98 (d, 1H), 6.66 (br s, 2H), 6.21 (s, 1H), 3.35-3-37 (m, 1H), 2.33-2.23 (m, 2H), 2.19-2.12 (m, 2H), 1.99-1.88 (m, 1H), 1.82-1.74 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C[N:18]([CH:20]=[O:21])C>>[N:1]1([C:20]([NH2:18])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: C1CCNCC1
Agent: On1nnc2ccccc21
Product: NC(=O)N1CCCCC1
Reaction time: 5 h

Procedure:
Combine N-(t-butoxycarbonyl)-S-methionine (1.50 g, 6.0 mmol), piperidine (0.51 g, 6.0 mmol) and HOBT (0.91 g, 6.0 mmol) in DMF (40 ml). Add DEC (1.15 g, 6.0 mmol). Stir 5 hours, concentrate in vacuo, and partition between EtOAc and H2O. Wash with aqueous NaHCO3, dry, and concentrate to obtain the piperidine amide as a colorless oil (TLC single spot Rf =0.6 in 5% MeOH/CH2Cl2).
Reaction SMILES: Cl[CH:2]([C:6](=[O:8])[CH3:7])[C:3](=[O:5])[CH3:4].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:3]([CH:2]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=1)[C:6](=[O:8])[CH3:7])(=[O:5])[CH3:4]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(=O)C(Oc1ccc(C#N)cc1)C(C)=O
Temperature: 60 °C
Yield: 94 %

Procedure:
A mixture of commercially available 3-chloro-2,4-pentanedione (1.2 ml, 10 mmol), 4-cyanophenol (1.19 g, 10 mmol), caesium carbonate (3.25 g, 10 mmol) and acetone (50 ml) was heated at 60° C. for 4 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting oil was diluted with dichloromethane (25 ml) and washed with 1M hydrochloric acid (30 ml). The aqueous layer, at pH 1, was extracted with dichloromethane (20 ml). The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide 4-(1-acetyl-2-oxopropoxy)benzonitrile (2.06 g, 9.4 mmol) which was used crude in the next step. 2-Hydroxyethyl hydrazine (169 μL, 2.5 mmol) was added to a stirred solution of a portion of the crude 4-(1-acetyl-2-oxopropoxy)benzonitrile (500 mg, 2.3 mmol) in acetic acid (5 ml) at room temperature under nitrogen, and the mixture was stirred at room temperature for 5 hours. Water (20 ml) was then added, and a solid triturated out and filtered off. This was recrystallised from ethyl acetate to provide the title compound (154 mg, 6%).
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH:12]([CH2:14][O:15][C:16]2[CH:31]=[CH:30][C:19]([C:20]([O:22]CC3C=CC=CC=3)=[O:21])=[CH:18][CH:17]=2)[O:11][C:10]1=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.CN(C)C=O.[C].[Pd]>[C:1]([N:9]1[CH2:13][CH:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:30][CH:31]=2)[O:11][C:10]1=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1ccc(OCC2CN(C(=O)c3ccccc3)C(=O)O2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCC2CN(C(=O)c3ccccc3)C(=O)O2)cc1
Yield: 7.8 %

Procedure:
A 1.0 g quantity of 10% palladium carbon was added to a solution of 3.8 g of benzyl 4-(3-benzoyl-2-oxooxazolidin-5-yl)methoxybenzoate (compound 120) obtained in Example 5 in 50 ml of acetic acid and 25 ml of N,N-dimethylformamide. The mixture was stirred at 60° C. for 5 hours in a stream of hydrogen. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethanol was added to the obtained residue to collect the crystals by filtration. Thus, 235 mg of the title compound (compound 134) was obtained (yield 8%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7]1.Cl.[C:19]1([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[CH3:13][N:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[C:11]1=[O:12]
Reactant: CN1C(=O)C(CCCCBr)Sc2ccccc21
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1C(=O)C(CCCCN2CC=C(c3ccccc3)CC2)Sc2ccccc21
Yield: 70.3 %

Procedure:
2.4 g (=0.0076 m) of 2-(4-bromobutyl)-4-methyl-2H-1,4-benzothiazine-3(4H)-one, 1.49 g (=0.0076 m) of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and 3.09 g of triethylamine were introduced into 20 ml of toluene. The resulting suspension was heated for 10.5 hours with stirring. The mixture was worked up by cooling and introducing the suspension into 30 ml of 20% strength aqueous hydrochloric acid solution. The resulting precipitate was filtered out, and the aqueous phase was rendered alkaline and extracted with 200 ml of dichloromethane. The precipitate was introduced into an aqueous alkaline solution and extracted with 450 ml of dichloromethane. The combined dichloromethane extracts were washed, dried over sodium sulfate, and the solvent was distilled off. 2.1 g of 4-methyl-2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl]-2H-1,4-benzothiazine-3(4H)-one were obtained as a beige-colored powder.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH2:21][NH:20][CH2:19][CH2:18]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH2:21][N:20]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH2:19][CH2:18]2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: COc1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(CCc1ccc([N+](=O)[O-])cc1)C2
Reaction time: 15 h
Yield: 23 %

Procedure:
A mixture of 1-(2-bromoethyl)-4-nitrobenzene (6.4 g), 1,2,3,4-tetrahydro-6-methoxyisoquinoline (4.6 g; Daniel J. Sall and Gary L. Grunewald, J. Med. Chem. 1987, 30, 2208-2216) and potassium carbonate (9.7 g) in DMF (150 ml) was stirred at 50° for 15 h. The mixture was evaporated to dryness and the residue was extracted with dichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was then purified by column chromatography eluting with dichloromethane/methanol (98:2) to give the title compound (2 g) as an oil which solidified on standing.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31]>>[O:17]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH:12][C:30](=[O:31])[O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1
Reactant: CC(C)COC(=O)Cl
Reactant: Nc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)COC(=O)Nc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Temperature: 45 °C

Procedure:
To a 400 L glass-lined reactor containing the 4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluoroaniline/tetrahydrofuran solutions (Step 3, 12.6 kg, 48 moles, 1.0 eq) is added a 47% potassium carbonate solution (14.1 kg, 48 moles, 1.0 eq). The mixture is heated to approximately 45° C., and isobutyl chloroformate (7.2 kg, 53 moles, 1.1 eq) is added while maintaining a reaction temperature between 45° C. and 55° C. The reaction is stirred at 45°-55° C. Once complete, the reaction is quenched by slowly adding water (45 L) over 15 minutes. The reaction mixture is cooled to 25° C. and the phases are separated. The tetrahydrofuran solution is swapped to an isopropanol (150 L)/water (50 L) suspension, and the slurry is slowly cooled to 5° C. The yellow slurry is then filtered and the cake washed with cold isopropanol (2×30 L). The yellow solids are dried with 60° C. nitrogen to give the title compound, 1H NMR (CDCl3) δ 7.02 (m, 2H), 6.81 (s, 1H), 3.95 (d, 2H), 3.60 (m, 4H), 3.17 (m, 4H), 1.97 (m, 1H), 0.94 (d, 6H).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[N+:13]([C:16]1[CH:25]=[CH:24][C:19]2[O:20][CH2:21][CH2:22][NH:23][C:18]=2[CH:17]=1)([O-:15])=[O:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:1][N:2]([CH2:10][CH2:11][N:23]1[CH2:22][CH2:21][O:20][C:19]2[CH:24]=[CH:25][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][C:18]1=2)[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCO2
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(CCN1CCOc2ccc([N+](=O)[O-])cc21)C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
To an oven dried, argon purged flask fitted with a magnetic stirbar was added tert-butyl methyl(2-oxoethyl)carbamate (0.135 g, 0.777 mmol), and DCE (10 mL). At this time, stirring began, and 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.10 g, 0.555 mmol) was added, followed by acetic acid (0.064 mL, 1.110 mmol) and sodium triacetoxyborohydride (0.294 g, 1.388 mmol). The resulting mixture stirred overnight at room temperature. After 18 hours, the reaction was quenched by the addition of saturated NaHCO3 (10 mL) and extracted with CH2Cl2. The aqueous layer was extracted further, and the combined organics were washed with brine, dried (Na2SO4), and concentrated. The crude product was combined with the product of a second reaction (prepared in accordance with the above procedure, with the omission of acetic acid). The combined products were purified on silica gel eluting with 50-70% EtOAc/hexanes to yield the title compound as a yellow residue (130 mg, 34.7%). 1H NMR (DMSO-d6) δ 7.58-7.37 (m, 2H), 6.92-6.80 (m, 1H), 4.25 (t, 2H, J=4.2 Hz), 3.58-3.36 (m, 6H), 2.87-2.74 (m, 3H), 1.27, 1.18 (2×s, 9H); ESI-MS (m/z, %): 360 (MNa+, 100).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:9]=[N:10][C:4]=2[C:3]1=[O:11].C1C(=O)N([Br:19])C(=O)C1>CC#N>[Br:19][C:6]1[C:5]2[O:8][CH:9]=[N:10][C:4]=2[C:3](=[O:11])[N:2]([CH3:1])[CH:7]=1
Reactant: Cn1ccc2ocnc2c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cn1cc(Br)c2ocnc2c1=O
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To the title compound of step 4 (100 mg, 0.7 mmol) in CH3CN (5 mL) was added NBS (154 mg, 0.8 mmol) at 20° C. After 2 h, the mixture was concentrated in vacuum at 45° C. Purification by silica gel chromatography (PE: EA=5:1˜2:1) to gave the title compound (70 mg, yield: 45%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.04 (s, 1H), 7.52 (s, 1H), 3.69 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.O1CCOCC1.[N:19](OCCC(C)C)=[O:20]>C(O)C>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:19][OH:20])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C(=O)CC2
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc2c(c1)C(=O)C(=NO)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
6-Methylindan-1-one (5.00 g, 34.2 mmol) and 4N hydrochloric acid-dioxane solution (2 ml) were added to ethanol (30 ml), isoamyl nitrite (5.1 ml, (37.6 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The precipitated solid was collected by filtration and washed with diisopropyl ether to give the title compound (5.36 g, yield 89%) as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1O.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>N1C=CC=CC=1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18]
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCNC(=O)Nc1nc2ccc(Br)c(S(=O)(=O)C(F)(F)F)c2s1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea (50 mg, 0.158 mmol) in pyridine (1 mL) were added 3 portions of (CF3SO2)2O (29 μL, 0.174 mmol) about 45 minutes apart. The reaction mixture was stirred for about 3 hours at about 35° C. The solvent was then evaporated. The crude material was purified by LC/MS to give 23 mg (32%) pure 14. 1H NMR (DMSO) δ 1.09 (t, 3H, J=8 Hz CH3), 3.19 (m, 2H, CH2), 6.79 (br s, 1H, NH), 7.67 (d, 1H, J=12 Hz, ArH), 7.80 (d, 1H, J=8 Hz, ArH), 11.20 (br s, 1H, NH). HPLC retention time 3.58 minutes.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.[Br:10]Br>O1CCCC1.CCCCCC>[Br:10][C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([OH:9])=[O:8]
Reactant: BrBr
Reactant: Cc1nc(C(=O)O)cs1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc(C(=O)O)c(Br)s1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of 2-methyl-thiazole-4-carboxylic acid (2.48 g, 17.32 mmol) in tetrahydrofurane (200.00 ml) was cooled to −78° C. under argon and treated with a 1.6N solution of buthyllithium in hexanes (22.74 ml, 36.38 mmol). The reaction mixture was left to warm to room temperature over 15 min, then cooled again to −78° C. A solution of elemental bromine (3.04 g, 19.05 mmol) in hexane (2.00 ml) was added. The reaction mixture was left to warm to room temperature, then quenched by addition of 1N HCl. The mixture was extracted three times with methylene chloride, and the combined organic layers were dried over sodium sulphate and evaporated. 5-Bromo-2-methyl-thiazole-4-carboxylic acid (3.79 g, 99%) was obtained as a yellow solid, MS (ISP): m/e=220.0, 222.1 (M−H), which was used crude.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([O:21]C)[C:18]=1[O:19]C)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([SH:15])=[S:14])[CH2:9][CH2:8]1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:21][C:17]1[CH:16]=[C:5]([CH:4]=[C:3]([OH:2])[C:18]=1[OH:19])[CH2:6][N:7]1[CH2:8][CH2:9][N:10]([C:13]([SH:15])=[S:14])[CH2:11][CH2:12]1
Reactant: COc1cc(CN2CCN(C(=S)S)CC2)cc(OC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cc(CN2CCN(C(=S)S)CC2)cc(O)c1O
Temperature: -78 °C
Reaction time: 120 h
Yield: 11.4 %

Procedure:
In a nitrogen atmosphere, 1,033 mg (3.02 mmol.) of 4-(3,4,5-trimethoxybenzyl)-1-piperazinecarbodithioic acid was suspended in dry methylene chloride, and under chilling to -78° C. in a dry ice-acetone bath, to this was dropwise added 50 ml of methylene chloride solution containing 3 ml of boron tribromide. The mixture was left to slowly reach room temperature, and then stirred for 5 days at room temperature. To the reaction mixture was added water, and insolubles were removed by filtration. The insolubles were then washed with water, and thus obtained yellow solid was dissolved in methanol. The methanol solution was filtered to remove insolubles, and the solvent of the filtrate was distilled off. To the obtained yellow semi-oil was added ether, and insolubles were removed by filtration. The filtrate was dried and further purified by cellulose column chromatography (Avicel, trademark, eluent: butanol/acetic acid/water (10/1/1)). The eluate was treated to distill off the solvent (eluent). To the residue was added ether, and insolubles were removed by filtration. The solvent of the filtrate was distilled off, leaving 103 mg of the desired compound, m.p. higher than 250° C., yield 11.4%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.S(Cl)(Cl)=O>CN(C=O)C>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]#[N:7]
Reactant: NC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cl)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-chloro-2-nitrobenzamide (step 1, 1.2 g, 4.9 mmol) in DMF (8 ml) was added thionyl chloride (2 ml, 24.8 mmol) in DMF (3 ml) dropwise at room temperature. The mixture was stirred at 120° C. for 2.5 h. The mixture was poured into ice-water and extracted with ethyl acetate (200 ml). The organic layer was washed with saturated aqueous NaHCO3 (100 ml), brine (100 ml), then dried (MgSO4), and concentrated. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (3:1/1:2) to give 1 g (quant.) of the title compound as pale yellow solids.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][N:27]([C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: CNc1cccc(C)c1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N(C)C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), methyl-m-tolyl-amine (44 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 μL, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methyl-m-tolyl-amide: MS m/z: (M+H) 518.1.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(C=CC(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of 2,3-dichloro-4-methoxybenzaldehyde (158 gm., 0.77 mole), malonic acid (146 gm., 1.4 mole), pyridine (450 ml.) and piperidine (15 ml.) is heated and stirred on a steam bath for 23/4 hours. The hot reaction mixture is poured, with stirring into a mixture of concentrated hydrochloric acid (770 ml.) and crushed ice (3.1 kg.).