Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)CC(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: COC(=O)CC(C(=O)OC)c1ccc(N)cc1
Reaction time: 1 h
Yield: 98348.4 %

Procedure:
Compound 8 (0.73 g/0.0027 mmol) was then dissolved in 20 ml absolute methanol/2 ml THF and placed in a 500 ml Parr bottle. The bottle was flushed with nitrogen gas and then ˜200 mg 5% Pd—C added as catalyst. The resultant mixture was hydrogenated in a Parr Hydrogenator for 1 hour at ˜40 psi hydrogen. The initial uptake of hydrogen was rapid. The excess catalyst was removed by suction filtration through Celite, the filter cake washed with methanol and the filtrate evaporated in vacuo. The product crystallizes to afford 0.63 g of an off-white solid (97% yield). This compound was used without further purification. 1H NMR (d6-DMSO): δ 6.9 (d, J=4.4 Hz, 2H), 6.49 (d, J=4.4 Hz, 2H), 5.02 (s, 2H, —NH2), 3.81 (dd, J=11 Hz, 6 Hz, 1H), 3.56 (s, 3H), 3.55 (s, 3H), 2.99 (dd, J=11 Hz, 17 Hz, 1H), 2.59 (dd, J=17 Hz, 6 Hz, 1H). NP-TLC (CH2Cl2): Rf˜0.1; NP-TLC (1% CH3OH in CH2Cl2): Rf˜0.6; RP-TLC (1:1 CH3OH—H2O): Rf˜0.5.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[O:15][CH2:16][CH3:17])=[N+:2]=[N-:3].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[C:19]#[CH:20]>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:5]1[CH:6]=[C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])[CH:13]=[CH:14][C:4]=1[N:1]1[CH:20]=[C:19]([C:18]([O:22][CH2:23][CH3:24])=[O:21])[N:3]=[N:2]1)[CH3:17]
Reactant: C#CC(=O)OCC
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])c(OCC)c1
Solvent: Cc1ccccc1
Product: CCNC(=O)c1ccc(-n2cc(C(=O)OCC)nn2)c(OCC)c1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 4-azido-3-ethoxy-N-ethylbenzamide (0.70 g) obtained in Example 131d) in toluene (30 ml) was added ethyl propiolate (0.61 ml), and the mixture was heated under reflux overnight under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a white powder (0.59 g, 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]#[N:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl-].[NH4+].[N-:14]=[N+:15]=[N-:16].[Na+].Cl>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:14]=[N:15][NH:16][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#Cc1cccc([N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-c2nn[nH]n2)c1
Temperature: 125 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
m-Nitrocyanobenzene (10 g, 67.5 mmol) was dissolved in DMF and ammonium chloride (7.2 g, 135 mmol) and sodium azide (8.8 g, 135 mmol) were added and the. resulting mixture was stirred at 125° C. for 16 hours. After cooling to room temperature, the mixture was poured into water (1 L), acidified with 1 N hydrochloric acid and filtered immediately. The mother liquor was left for 1 hour and filtered and the solid was washed with water and dried by suction to afford 9.3 g (72%) 5-(3-nitrophenyl)-2H-tetrazole.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>CN(C)C=O>[N:13]1([CH2:2][C:3]2[CH:12]=[CH:11][C:6]3[NH:7][C:8](=[O:10])[NH:9][C:5]=3[CH:4]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1c[nH]cn1
Reactant: O=c1[nH]c2ccc(CCl)cc2[nH]1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(Cn3ccnc3)cc2[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A mixture of 6.35 parts of 5-(chloromethyl)-1,3-dihydro-2H-benzimidazol-2-one, 11.9 parts of 1H-imidazole and 135 parts of N,N-dimethylformamide was stirred overnight at 80° C. The whole was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (80:20 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. After standing over weekend at room temperature, the residue was solidified. The product was pulverized and stirred in acetonitrile. The product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (87:13 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was dried in a dry-pistol at 130° C., yielding 0.75 parts (10%) of 1,3-dihydro-5-(1H-imidazol-1-ylmethyl)-2H-benzimidazol-2-one; mp. 254.5° C. (compound 24).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]([F:47])([F:46])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[C:33]([O:39][CH3:40])=[N:34][CH:35]=[C:36]([Cl:38])[CH:37]=4)=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=3)[C@H:20]2[CH3:45])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1>C1COCC1>[F:47][C:8]([F:7])([F:46])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[C:33]([O:39][CH3:40])=[N:34][CH:35]=[C:36]([Cl:38])[CH:37]=4)=[CH:30][N:29]=[C:28]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:27]=3)[C@H:20]2[CH3:45])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1
Reactant: C1COCCN1
Reactant: COc1ncc(Cl)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: C1CCOC1
Product: COc1ncc(Cl)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Morpholine (0.217 mL, 2.488 mmol) was added to a THF (1 mL) solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Step A, 311 mg, 0.498 mmol). This was then stirred for 30 minutes at 120° C. in a microwave reactor. LCMS showed >90% conversion to product. The reaction was concentrated on rotary evaporator. The crude isolate was purified by silica gel chromatography, eluting with a 0-50% isopropyl acetate/hexanes linear gradient followed by isocratic elution with 50% isopropyl acetate/hexanes for 10 minutes to give the titled compound as a white foam. LCMS (M+H)+: 632.3. 1H NMR (CDCl3, 500 MHz): δ 8.19 (d, J=2.5 Hz, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.75 (s, 2H), 7.48 (d, J=2.5 Hz, 1H), 5.66 (d, J=8.5 Hz, 1H), 4.72 (d, J=17.1 Hz, 1H), 4.31 (m, 1H), 3.96 (s, 3H), 3.89 (m, 4H), 3.83 (m, 4H), 0.73 (d, J=6.5 Hz, 3H). SPA IC50: 671 nM.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[F:13].[NH2:15][C:16]1[S:17][C:18](Br)=[CH:19][N:20]=1>O1CCCC1>[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([O:12][CH:18]2[S:17][CH:16]([NH2:15])[N:20]=[CH:19]2)[CH:9]=[CH:8][C:7]=1[F:13]
Reactant: Nc1ncc(Br)s1
Reactant: COC(=O)c1cc(O)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC2C=NC(N)S2)ccc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of sodium hydride (1.7 g, 44.11 mmol) in tetrahydrofuran (50 mL) was added solution of 2-fluoro-5-hydroxy benzoic acid methyl ester (5 g, 29.41 mmol) in tetrahydrofuran (50 mL) under argon atmosphere and stirred for 15 minutes. A solution of 2-amino-5-bromothiazole (5.2 g, 29.41 mmol) in tetrahydrofuran (47 mL) was added dropwise over a period of 30 min and stirred at room temperature for 4 hrs. Reaction mixture was poured into ice cold water (300 mL) extracted with ethyl acetate (3×200 mL), combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Crude compound was purified by silica gel column chromatography using 40% ethyl acetate in hexane as eluent to afford pure 5-[(2-amino-5H-thiazol-5-yl)oxy]-2-fluoro-benzoic acid methyl ester. (2.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-])=O)[C:3]=1[CH3:17].O.O.[Sn](Cl)Cl>C(O)C>[NH2:14][C:4]1[C:3]([CH3:17])=[C:2]([Cl:1])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2
Reactant: Cc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1N
Temperature: 25 °C

Procedure:
A suspension of 7-chloro-1,4-dihydro-6-methyl-5-nitroquinoxaline-2,3-dione (0.050 g, 0.20 mmol) and tin (II) chloride dihydrate (0.133 g, 0.60 mmol) in ethanol (1.0 mL) was refluxed for 6 h. The suspension was then cooled to room temperature and the solid was collected by vacuum filtration, washed with ethanol (1 mL), and dried further under vacuum to obtain 0.036 g (82%) pure (HPLC) title compound as an off-white solid; mp-darkens at 323° C.; 1H NMR (DMSO-d6) δ 2.09 (s, 3H), 5.47 (s, 2H), 6.46 (s, 1H), 11.15 (s, 1H), 11.72 .(s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[C:4]([O:14][CH3:15])=[C:3]1[C:16]([O:18]CC)=[O:17].[OH-].[Na+].C(O)C>O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[C:4]([O:14][CH3:15])=[C:3]1[C:16]([OH:18])=[O:17]
Reactant: C=CCOC(=O)Nc1cn(C)c(C(=O)OCC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOC(=O)Nc1cn(C)c(C(=O)O)c1OC
Temperature: 25 °C
Reaction time: 120 h
Yield: 71.5 %

Procedure:
A mixture of 0.93 g (3.3 mmol) of ethyl 1-methyl-4-[(allyloxycarbonyl)amino]-3-methoxy-1H-pyrrole-2-carboxylate (prepared according to the method described in K. Narkunan, M. A. Ciufolini, Synthesis, 2000, 673–676), 3.3 ml of a 2 molar sodium hydroxide aqueous solution and 3.3 ml of ethanol is stirred at room temperature for 5 days. Water is added and the ethanol is evaporated. After extraction with diethyl ether, the aqueous phase is acidified to pH 2 with concentrated hydrochloric acid. Extraction with ethyl acetate, drying and concentration give 0.6 g (71% yield) of a light brown solid. (M−1=253).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].Cl[O:12]C(C)(C)C.CC(C)([O-])C.[K+].S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>C(O)(C)(C)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OCl
Reactant: N#Cc1ccc(CN)cc1
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
13.2 g of p-cyanobenzylamine and 300 ml of t-butyl alcohol were mixed and 11.9 g of t-butyl hypochlorite was added dropwise at 50° C. over 30 minutes while stirring. After cooling the mixture to room temperature, 12.3 g of potassium t-butoxide was added and stirred at 60° C. for 3 hours. After cooling the mixture to room temperature, 60 g of 10% by weight sulfuric acid was added dropwise over 1 hour and the mixture was stirred for additional 1 hour. The reaction mixture was adjusted to pH 6 by addition of sodium acetate and the solvent was distilled off under reduced pressure. The residue was extracted with toluene and the toluene layer was washed with water. After distilling off the toluene, evaporation under reduced pressure (135° C./15 mmHg) afforded 7.3 g (yield: 56%) of p-cyanobenzaldehyde. The obtained p-cyanobenzaldehyde had a purity of 98% by the analysis of high performance liquid chromatography.
Reaction SMILES: C1(C2N(S[CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH2:26][CH3:27])[S:15]3(=[O:17])=[O:16])N=NN=2)C=CC=CC=1.[Na].[C:29]1([N:35]2[C:39]([SH:40])=[N:38][N:37]=[N:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[C:29]1([N:35]2[C:39](=[S:40])[N:38]([CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH2:26][CH3:27])[S:15]3(=[O:16])=[O:17])[N:37]=[N:36]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCc1cccc2c1C(=O)N(CSn1nnnc1-c1ccccc1)S2(=O)=O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cccc2c1C(=O)N(Cn1nnn(-c3ccccc3)c1=S)S2(=O)=O
Yield: 60 %

Procedure:
A solution of 2-(5-phenyl-1-tetrazolyl)thiomethyl-4-ethylsaccharin (Example 30AE, 0.020 g) and 1-phenyltetrazol-5-thiol sodium salt (0.0026 g) in dimethylformamide (1 mL) was heated at 100° C. for three days, then poured into water. Recrystallization of the resulting solid from ethanol-water afforded 2-(4-phenyl-5-thioxo-1-tetrazolyl)methyl-4-ethylsaccharin, 0.012 g, 60% yield, mp 127°-129° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[C:13]1([C@@H:19]2[C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:22][C:21]3([CH2:34][CH2:33][CH2:32][C@H:31]([CH2:35][NH2:36])[CH2:30]3)[O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)C.CO>[C:13]1([C@@H:19]2[C@@H:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:22][C:21]3([CH2:34][CH2:33][CH2:32][C@H:31]([CH2:35][NH:36][C:2]4[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=4[N+:10]([O-:12])=[O:11])[C:5]#[N:6])[CH2:30]3)[O:20]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC[C@H]1CCCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: N#Cc1ccc([N+](=O)[O-])c(NC[C@H]2CCCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 88 %

Procedure:
A mixture of 3-fluoro-4-nitrobenzonitrile (55.5 g, 334 mmol), 1-[(2R,3R,7S)-2,3-diphenyl-1,4dioxaspiro[4.5]dec-7-yl]methanamine (103 g, 318 mmol) and potassium carbonate (88 g, 637 mmol) in acetonitrile (2654 mL) was stirred at RT for 5 days (˜200 mL DCM was added to help with solubility). The resulting solution was filtered and the solids washed with MeCN. The resulting solution was concentrated to give the crude product that was dissolved in MeOH (500 mL) and allowed to crystallize with stirring. The slurry was allowed to stir at RT overnight, filtered and the solids dried under reduced pressure to give 3-({[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-7-yl]methyl}amino)-4-nitrobenzonitrile (131.41 g, 88% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=O)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([SH:15])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: O=S(=O)(O)O
Agent: [Zn]
Product: Sc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Zinc dust (13.1 g) was added to a mixture of 4-Benzyloxy-benzenesulfonyl chloride (I) (10 g, 35.2 mmoles), sulfuric acid (26.2 g) and ice (78.6 g) at 0° C. The mixture was warmed to ambient temperature, stirred for 1 hour, refluxed for 2 hours and then cooled to ambient temperature. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound. 1H NMR (CDCl3, 400 MHz) δ 5.03 (s, 2H), 6.89 (d, J=8.92 Hz, 2H), 7.38 (d, J=8.93 Hz, 2H), 7.3-7.4 (m, 5H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([CH:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH:60][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]=[C:3]([CH3:2])[CH:4]=3)[S:57][C:47]=2[C:48]([CH:51]2[CH2:52][CH2:53][O:54][CH2:55][CH2:56]2)=[N:49][CH:50]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: COc1cnc(C2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(C2CCOCC2)c2sc(NC(=O)c3ccnc(C)c3)nc12

Procedure:
From 2-methyl-isonicotinic acid hydrochloride, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([C:10]1[S:14][C:13]([C:15]([NH2:17])=[O:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].Cl[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>O1CCCC1>[C:15]([C:13]1[S:14][C:10]([N+:7]([O-:9])=[O:8])=[C:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=1)(=[O:16])[NH2:17]
Reactant: NC(=O)c1ccc([N+](=O)[O-])s1
Reactant: CCOC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc(C(N)=O)sc1[N+](=O)[O-]
Temperature: -50 °C
Reaction time: 16 h
Yield: 121.8 %

Procedure:
Potassium tertiary-butoxide (1.96 g, 17.4 mmol) was dissolved in tetrahydrofuran (45 ml) and the solution cooled to −50° C. A solution of 5-nitrothiophene-2-carboxamide (1 g, 1.94 mmol) and ethyl chloroacetate (0.5 ml, 5.81 mmol) was added dropwise in dry tetrahydrofuran (12 ml) over 5 minutes. The reaction mixture was stirred at −50° C. for 16 hours then quenched with acetic acid (3 ml), then washed with water (20 ml). The aqueous phase was extracted with ethyl acetate and the combined organic fractions were washed with saturated brine solution. The organic phase was dried over magnesium sulfate, evaporated to dryness and the residue chromatographed on silica gel using hexane/ethyl acetate (4:1) as eluent to give 610 mg of ethyl 5-carbamoyl-2-nitrothiophene-3-acetate as a yellow/brown oil. MS(ES): m/e 259 [M+H].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:12])=O)=[CH:2]1.C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([Cl:16])=[O:12])=[CH:2]1
Reactant: O=C(O)c1coc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1coc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzofuran-3-carboxylic acid (1.00 g, 6.17 mmol) was suspended in methylene chloride (20 mL), and oxalyl chloride (1.08 mL, 12.34 mmol) was added dropwise. To this reaction liquor, a catalytic amount of DMF (one drop) was added, and the reaction liquor was stirred for one hour at room temperature. The solvent was distilled off under reduced pressure, to obtain benzofuran-3-carboxylic acid chloride as a solid. The obtained acid chloride was suspended in 1,2-dichloroethane (20 mL), and (4-amino-3-chlorophenyl)acetic acid ethyl ester hydrochloride (1.54 g, 6.17 mmol) was added. The mixture was heated and stirred for 20 hours. The mixture was left to cool naturally to room temperature, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography (Flash Chromatography System from Biotage AB, column size: 40S, elution solvent: n-hexane:ethyl acetate=95:5 to 75:25), to obtain the title compound (2.08 g, 94%) as a solid.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31](=[O:33])[CH3:32])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31](=[O:33])[CH3:32])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Product: CCCCN1C(=O)C(Nc2ccc(S(=O)(=O)NC(C)=O)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and N-[(4-aminophenyl)sulfonyl]acetamide in a similar manner as described for e.g. Examples 6-9, 22-25, 28 and 32-35. 1H NMR (500 MHz, CD3CN): δ 1.00 (t, 3H), 1.43-1.52 (m, 2H), 1.78-1.85 (m, 2H), 1.94 (s, 3H), 3.76 (t, 2H), 6.88-6.92 (m, 2H), 7.16-7.24 (m, 4H), 7.29-7.34 (m, 1H), 7.54-7.57 (m, 2H), 8.03 (bs, 1H), 9.26 (bs, 1H).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:2]1([C:1]2[O:21][C:17]([CH:18]([CH3:19])[CH3:20])=[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(-c2ccccc2)oc1C(C)C
Yield: 82 %

Procedure:
6.5 g of ethyl 3-benzoylamino-3-isobutyrylpropionate, 30 ml of dimethylformamide and 4.8 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 5.0 g of ethyl 2-(2-phenyl-5-isopropyl-4-oxazoly)acetate are thereby obtained. Yield: 81.4%.
Reaction SMILES: [C:1]([N:8]([C:13]12[CH2:22][C:17]3([CH3:23])[CH2:18][CH:19]([CH2:21][C:15]([CH3:24])([CH2:16]3)[CH2:14]1)[CH2:20]2)[CH2:9][C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O-:25][Mn](=O)(=O)=O.[K+].Cl>[OH-].[K+].O.CCOC(C)=O>[C:1]([N:8]([C:13]12[CH2:14][C:15]3([CH3:24])[CH2:16][C:17]([CH3:23])([CH2:18][C:19]([OH:25])([CH2:21]3)[CH2:20]1)[CH2:22]2)[CH2:9][C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC12CC3CC(C)(C1)CC(N(CC(=O)O)C(=O)OC(C)(C)C)(C3)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC12CC3(C)CC(O)(C1)CC(N(CC(=O)O)C(=O)OC(C)(C)C)(C2)C3
Temperature: 90 °C
Yield: 102 %

Procedure:
To a solution of N-BOC-(3,5-dimethyladamantan-1-yl)-glycine (1.79 g, 5.3 mmol) in 2% KOH/water (75 mL) at rt was added KMnO4 (1.0 g, 6.3 mmol). The reaction was heated to 90° C. for 2 h. An additional portion of KMnO4 (0.3 g, 1.9 mmol) was added and the reaction was heated at 90° C. for an additional 1.5 h. The reaction was then diluted with EtOAc (150 mL) and with vigorous mixing the pH was addjusted to ˜3 with 1N HCl. The EtOAc layer was separated and set aside. The aqueous layer was then extracted once more with EtOAc and twice with dichloromethane. The combined organics were dried over MgSO4, filtered and concentrated to give N-BOC-(3-hydroxy-5,7-dimethyladamant-1-yl)-glycine (1.91 g). MS m/e (M+H)+=354.2
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)CC=[C:12]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=1[O:26][CH3:27].F[C:29](F)(F)[C:30]([OH:32])=[O:31]>ClC(Cl)(Cl)Cl.O.[Ru](Cl)(Cl)Cl.C(#N)C>[Cl:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:29][C:30]([OH:32])=[O:31])=[C:11]([CH2:12][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[O:26][CH3:27])[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc(C2=CCc3ccc(Cl)cc32)c1OC
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(Cc2cc(Cl)ccc2CC(=O)O)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
701.6 mg of sodium periodate (3.28 mol) and 3.6 mg of ruthenium(III) chloride monohydrate (0.02 mol) are introduced into 3 ml of water. 229.4 mg of the compound from Example 24A (0.80 mol) dissolved in 2 ml of tetrachloromethane are added and, after addition of 2 ml of acetonitrile, the reaction mixture is stirred at room temperature for 16 h. For working up, the mixture is poured into 20 ml of a 5% strength aqueous trifluoroacetic acid solution and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate, and the solvent is removed in a rotary evaporator. The residue is stirred with 5 ml of ethyl acetate and 2 ml of n-heptane and stored at 5° C. for 3 h. The deposited product is filtered off, washed with m-pentane and dried under high vacuum. 119.0 mg (44% of theory) of the title compound are obtained.