Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.ClCCl.CN(C)C=O>[C:20]1([S:26]([N:10]2[C:7]3=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]3[CH:12]=[CH:11]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1cnc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.1 %

Procedure:
To a mixture of 5-nitro-1H-pyrrolo[2,3-b]pyridine (2.0 g, 12.3 mmol), triethylamine (2.48 g, 24.6 mmol), 4-dimethylaminopyridine (0.15 g, 1.23 mmol) in dichloromethane/N,N-dimethylformamide (1:1, 60 mL) was added benzenesulfonyl chloride (3.25 g, 18.4 mmol) at 0° C. After stirring for 48 h at room temperature, the reaction was quenched with water (50 mL) and extracted with dichloromethane (2×120 mL). The organic layer was washed with a saturated sodium bicarbonate (2×30 mL), water (2×30 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 33% dichloromethane/hexanes) to afford 1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (2.8 g, 76%) as a yellow solid: LC/MS m/e calcd for C13H9N3O4S [M+H]+ 304.30, observed 303.9.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[NH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=O.O>O1CCCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16](=[S:2])[NH2:15]
Reactant: NC(=O)c1ccccn1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
43 g of phosphorus pentasulfide were added slowly to 46.8 g of the amide of Stage A in 700 ml of tetrahydrofuran and the mixture was stirred for 4 hours at ambient temperature. The reaction mixture was poured into water and extracted with ether. The extracts were dried and the solvent was evaporated under reduced pressure. After chromatography on silica (eluant: CH2Cl2 -AcOEt 8-2), 10 g of expected product melting at 137° C. were obtained.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20][CH2:21]Br.O>CN(C)C=O>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH2:21][CH2:20][O:19][CH3:18])[C:3]=1[CH:4]=[O:5]
Reactant: COCCBr
Reactant: O=Cc1c(O)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(F)c(F)c1C=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 2,3-difluoro-6-hydroxybenzaldehyde (0.63 g) and potassium carbonate (0.83 g) in N,N-dimethyl -formamide (4 mL) was added 2-methoxyethyl bromide (0.45 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=85/15−60/40) to give 2,3-difluoro-6-(2-methoxyethoxy)benzaldehyde (0.62 g). This material was dissolved in tetrahydrofuran (6 mL). To the solution were added water (0.6 mL) and sodium borohydride (0.12 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (0.61 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]>Cl.C(O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([O:11][CH3:12])=[C:2]([F:1])[CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1F
Agent: Cl
Solvent: CCO
Product: COc1ccc(N)cc1F

Procedure:
To a cold (5°), stirred solution of 776 g. (3.44 mol) of stannous chloride dihydrate in 1500 mL of concentrated hydrochloric acid was added, dropwise, a solution of 147 g. (0.861 mol) of 2-fluoro-4-nitroanisole in 3.0 L of ethanol at such a rate that the temperature of the reaction mixture did not exceed 23°. The suspension was stirred for 6 hours at room temperature. The ethanol was removed in vacuo at temperatures below 45°, and the residue was diluted with 3.0 L of water then basified with 1.0 L of 50% sodium hydroxide. The temperature of the mixture was maintained below 23° during the dropwise addition of the base.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.CN1CCOCC1.[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[S:30](Cl)(=[O:32])=[O:31])#[N:20]>CC#N>[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[S:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1)(=[O:32])=[O:31])#[N:20]
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (2.98 g, 20 mmol) and NMM in MeCN (150 ml) was added 2-cyano-4-nitrobenzene-1-sulfonyl chloride (5.423 g, 22 mmol) at 0° C., then the solution was stirred at room temperature for overnight. The mixture was concentrated in vacuo at room temperature, and DCM and water was added to the residue. The organic layer was dried over Na2SO4 and concentrated to give the crude product. It was purified by prep. HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 25%-50%, 25 min) to give the title compound (2.0 g, 27.86%) as a yellow solid. 1H NMR: DMSO 400 MHz. δ11.05 (s, 1H), 9.22 (s, 1H), 8.88 (s, 1H), 8.62 (d, J=11.2 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.45 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.18 (d, J=10.0 Hz, 1H), 4.89 (s, 2H). ESI-MS m/z 360 (M+H, positive); HPLC purity: 93.07% (MaxPlot 190-370 nm), 98.72% (220 nm).
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([O-:9])=[O:8].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>[OH-].[Na+]>[CH2:13]([O:20][C:21]([NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([OH:12])[CH:4]=1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(C(=O)[O-])c(O)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Product: O=C(Nc1ccc(C(=O)O)c(O)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.6 %

Procedure:
To a solution of sodium-p-aminosalicylate (Aldrich)(100 g, 0.65 mol) in 10% aqueous NaOH solution (1000 ml) is added 50% wt solution of benzylchloroformate (670 g, 1.96 mol in toluene) at 0° C. The resulting mixture is stirred at rt for 48 h. The progression of the reaction is followed by NMR. The reaction mixture is cooled down to 0° C. and acidified with 10% aqueous HCl. The solid obtained is filtered and washed with cold water and dried. It is further treated with petroleum ether and filtered to give crude 4-{[(benzyloxy)carbonyl]amino}-2-hydroxy benzoic acid (128 g, 68%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:15](=O)([O-])[O-].[Na+].[Na+]>CO>[C:1]([O:9][CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccncc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
A suspension of 100 g of isonicotinic acid (0.812 mol) in 250 ml of methanol was stirred and cooled to 10°. To this mixture was added dropwise 125 ml of sulfuric acid during 15 min. keeping the temperature below 20°. The reaction mixture was allowed to come to room temperature and then heated under reflux for 4.5 hr. After standing overnight it was poured onto 1 kg of ice and made alkaline with 235 g of sodium carbonate. The solid was filtered off, washed with water and with ether, and discarded. The filtrate was extracted with 3×300 ml of ether. The combined organic extracts were washed with water and with brine, dried over sodium sulfate, and concentrated in vacuo to leave 80 g (65%) of crude product as a pale oil.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[S:6][C:7]=1[CH3:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24](=O)[CH2:25]Br)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[S:6][C:7]=3[CH3:8])[S:13][CH:25]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: COC(=O)c1cc(C(N)=S)c(C)s1
Product: COC(=O)c1cc(-c2nc(-c3ccc(OC)c(OC)c3)cs2)c(C)s1
Yield: 53 %

Procedure:
A solution of 257 mg (0.48 mmol, based on a mixture containing 60% nitrile) of methyl 4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate was reacted with 124 mg (0.48 mmol) of 2-bromo-(3′,4′-dimethoxy)-acetophenone (Example 31, step (a)) was reacted in a manner similar to Example 8, step (a) to give methyl 4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxylate (95 mg, 53%) as a solid. Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C18H17NO4S2 376.1 (M+H), found 376.3.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:3][CH:2]=1.C(OC([NH:28][C:29]1[N:34]=[CH:33][C:32]([C:35](O)=[O:36])=[CH:31][N:30]=1)=O)(C)(C)C.Cl>O1CCOCC1>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:35]([C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=3)=[O:36])[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)cn1
Reactant: Cc1ccc(CCS(=O)(=O)N2CCC(CN)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(CCS(=O)(=O)N2CCC(CNC(=O)c3cnc(N)nc3)CC2)cc1

Procedure:
The title compound was prepared from C-[1-(2-p-tolyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-tert-butoxycarbonylamino-pyrimidine-5-carboxylic acid, followed by treatment with 4N HCl in dioxane as described in EXAMPLE 192.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)=[CH:54][C:55]4[N:61]([CH3:62])[C:60](=[O:63])[CH2:59][CH2:58][NH:57][C:56]=4[N:64]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:47]=[CH:48][C:49]([C:52]3[C:53]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)=[CH:54][C:55]4[N:61]([CH3:62])[C:60](=[O:63])[CH2:59][CH2:58][NH:57][C:56]=4[N:64]=3)=[CH:50][CH:51]=2)[CH2:43][CH2:44][CH2:45]1
Reactant: CN1C(=O)CCNc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: CN1C(=O)CCNc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 119.2 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(1-methyl-2-oxo-8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-7-yl)phenyl)cyclobutyl)carbamate (21 mg, 0.04 mmol) was reacted to afford the title compound (19 mg, 72%). LCMS (Method D): RT=0.806 min, M+1=399. 1H NMR (500 MHz, MeOD): 7.65 (1H, s), 7.47 (2H, d), 7.41 (2H, d), 7.29-7.25 (3H, m), 7.20-7.19 (2H, m), 3.86-3.84 (4H, m), 3.41 (3H, s), 2.79-2.73 (4H, m), 2.61-2.55 (2H, m), 2.25-2.18 (1H, m), 1.99-1.91 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]([OH:19])=O)=[N:6][C:7]=1[S:8]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[N:6][C:7]=1[S:8]([N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)(=[O:9])=[O:10]
Reactant: C1CCNCC1
Reactant: Cc1ccc(C(=O)O)nc1S(=O)(=O)N1CCCCC1
Product: Cc1ccc(C(=O)N2CCCCC2)nc1S(=O)(=O)N1CCCCC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-methyl-6-(piperidine-1-sulfonyl)-pyridine-2-carboxylic acid and piperidine (CAN 110-89-4) as starting materials, MS (EI): 352.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([N:10]2[C:14](=N)[C:13]([CH3:17])([CH3:16])[NH:12][C:11]2=[O:18])[CH:6]=[CH:7][C:8]=1[Cl:9].Cl.[OH2:22]>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([N:10]2[C:14](=[O:22])[C:13]([CH3:17])([CH3:16])[NH:12][C:11]2=[O:18])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC1(C)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=N
Reactant: O
Agent: Cl
Product: CC1(C)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O

Procedure:
61 mg. of 1-(3-trifluoromethyl-4-chlorophenyl)-5-imino-4,4-dimethyl-2-imidazolidinone are dissolved in 4 ml. of 0.1-N aqueous hydrochloric acid, and 2 ml. of water are added. The white needles which gradually precipitate are removed by filtration after 20 hours, washed with water and dried under greatly reduced pressure at 65° for 2 hours. 3-(3-trifluoromethyl-4-chlorophenyl)-5,5-dimethylhydantoin, which melts at 156°-157.5°, is obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:26])=[CH:22][C:23]=4[F:25])[NH:18][N:17]=3)[N:14]=2)[N:9]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[H-].[Na+].Cl.Br[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:26])=[CH:22][C:23]=4[F:25])[N:18]([CH2:39][CH2:40][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:17]=3)[N:14]=2)[N:9]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: BrCCN1CCOCC1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)cc(F)c34)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN4CCOCC4)c4cc(Cl)cc(F)c34)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
2-(6-Chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (77 mg, 0.15 mmol) was dissolved in DMF (2.5 ml) and cooled in an ice bath. Sodium hydride (60% dispersion, 8 mg, 0.20 mmol) was carefully added. The mixture was stirred for 15 min then additional sodium hydride (60% dispersion, 10 mg, 0.25 mmol) and 4-(2-bromoethyl)morpholine hydrochloride (42 mg, 0.18 mmol) were added. The reaction was warmed to room temperature and stirred overnight. Water, sodium bicarbonate solution and ethyl acetate were added to the reaction. The layers were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed water and sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to give 66 mg (70%) of 2-[6-chloro-4-fluoro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([OH:17])[CH2:15][CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@@H:10]1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Ba+2].BrBr.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1.O>[CH2:1]([O:8][C@H:9]1[C@H:16]2[CH2:15][CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[C@@H:10]1[C:11]([O:17]2)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C[C@@H]1[C@@H](OCc2ccccc2)[C@H](O)CCN1C(=O)OCc1ccccc1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: C1COCCO1
Solvent: O
Product: O=C1O[C@@H]2CCN(C(=O)OCc3ccccc3)[C@H]1[C@H]2OCc1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
A solution of 1,5-imino-1,2,5-trideoxy-D-arabino-hexitol (24) (407 mg, 1.10 mmol) in a 1:3 mixture of water and 1,4-dioxan containing barium carbonate (653 mg, 3.31 mmol), was cooled to 0° C. and treated with bromine (70 μl, 221 mg, 1.37 mmol), then stirred at room temperature for 24 hours. Sodium thiosulphate solution (1M, aqueous) was added until the bromine was removed then the solution acidified with hydrochloric acid (2M, aq, 30 ml) and centrifuged. The supernatent was removed and extracted with ethyl acetate (4×20 ml). The combined organic phase was dried, filtered and evaporated. Purification by flash chromatography gave 3-O-benzyl-N-benzyloxycarbonyl-2,6-imino-2,5,6-trideoxy-D-lyxo-hexono-1,4-lactone (342 mg, 84%) as a clear oil, [α]20D -13.7° (c, 1.42 in chloroform); νmax (film) 3030, 2880, 1790 (lactone CO), 1700 (Z CO), 1425, 1260, 1170, 1060, and 700 cm-1 ; 1H NMR δ 1.80-1.93 (1H, m, H-5); 2.28-2.35 (1H, m, H-5'); 3.15-3.20 (1H, m, H-6); 3.93-4.07 (1H, m, H-6'); 4.15, 4.28 (1H, 2×dd, H-3); 4.39-4.61 (2H, m, H-2, H-4); 4.74-4.83 (2H, m, CH2Ph; 5.04-5.20 (3H, m, H-1, CH2 -Z), 7.17-7.35 (10H, m, 2×H-Ph). 13C NMR δ 26.25 (t, C-5); 35.27, 35.49 (2×t, C-6); 65.92, 66.17 (2×d, C-4); 67.38 (t, CH2 -Z); 71.45 (t, CH2Ph); 75.86 (d, C-3); 127.87, 127.98, 128.08, 128.57 (4×d, HC-Ph); 136.78, 137.73 (2×s, C-Ph); 155.15 (s, C=O-Z); 170.34 (s, C-1). m/z (CI NH3): 91 (100%), 324 (M-CO2 +H+, 60%), 385 (M+NH4+, 25%). (Found C, 68.56; H, 5.96; N, 3.51. C21H21NO5 requires C, 68.68; H, 5.76; N, 3.81).
Reaction SMILES: C([O:8][C:9](=[O:55])[CH:10]([N:25]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]([O:40]CC)=[O:39])[CH2:33][CH2:32][N:31]([CH2:43][C:44]([O:46]CC)=[O:45])[CH2:30][CH2:29][N:28]([CH2:49][C:50]([O:52]CC)=[O:51])[CH2:27][CH2:26]1)[CH2:11][CH2:12][CH2:13][N:14]1C(=O)C2C(=CC=CC=2)C1=O)C1C=CC=CC=1>Cl>[NH2:14][CH2:13][CH2:12][CH2:11][CH:10]([N:25]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]([OH:40])=[O:39])[CH2:33][CH2:32][N:31]([CH2:43][C:44]([OH:46])=[O:45])[CH2:30][CH2:29][N:28]([CH2:49][C:50]([OH:52])=[O:51])[CH2:27][CH2:26]1)[C:9]([OH:55])=[O:8]
Reactant: CCOC(=O)CN1CCN(CC(=O)OCC)CCN(C(CCCN2C(=O)c3ccccc3C2=O)C(=O)OCc2ccccc2)CCN(CC(=O)OCC)CC1
Agent: Cl
Product: NCCCC(C(=O)O)N1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Yield: 138.3 %

Procedure:
A solution of 54 g of compound obtained in stage 2 (64 ml) in 37% hydrochloric acid (1.81) is refluxed overnight in a 5-liter reactor. After cooling and filtration, the filtrate is concentrated and purified over silanized silica (elution with water). After evaporation under reduced pressure, the product is washed with ether. 45 g of product are obtained in the form of a white solid. The product is desalified by passing it over OH resin. 30 g of product are isolated in the form of white crystals (yield 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:23]([O:26][C:27](Cl)=[O:28])([CH3:25])[CH3:24]>O>[CH:23]([O:26][C:27]([NH:1][C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1)=[O:28])([CH3:25])[CH3:24]
Reactant: Nc1ccc2nc(-c3ccccc3)oc2n1
Reactant: CC(C)OC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc2nc(-c3ccccc3)oc2n1
Reaction time: 120 h

Procedure:
A mixture of 300 mg. of 5-amino-2-phenyloxazolo[5,4-b]pyridine and 3 ml. of pyridine was cooled in ice and to it was added 0.2 ml. of isopropylchloroformate. The mixture was allowed to age in the refrigerator for 5 days, and diluted with ice and water. The precipitate was collected and recrystallized from isopropanol to give 5-isopropoxycarbonylamino-2-phenyloxazolo[5,4-b]pyridine, m.p. 210°-211° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[N:27]=[C:12]3[C:13]([O:25][CH3:26])=[CH:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=4)[N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>O1CCOCC1.O>[C:23]([C:19]1[CH:18]=[C:17]([C:16]2[N:11]3[N:10]=[C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]4)[N:27]=[C:12]3[C:13]([O:25][CH3:26])=[CH:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=1)#[N:24]
Reactant: CCOC(=O)C1(c2nc3c(OC)ccc(-c4cccc(C#N)c4)n3n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(C(=O)O)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[5-(3-Cyano-phenyl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-cyclopropanecarboxylic acid ethyl ester (compound 188) (0.32 g, 0.88 mmol) was dissolved in 1,4-dioxan (10 mL) by heating. LiOH (0.06 g, 1.4 mmol) in H2O (2.5 mL) was added at RT. The suspension was stirred at RT overnight. The reaction mixture was concentrated in vacuo and H2O was added. The aqueous phase was washed with EtOAc and acidified with 4N HCl to pH 1. The aqueous phase was extracted with DCM (×2) and dried over MgSO4, filtered and concentrated in vacuo. This afforded the title compound as a solid.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]([C:17]2[CH:18]=[C:19]3[C:25]([NH2:26])=[N:24][NH:23][C:20]3=[CH:21][N:22]=2)[CH:8]=1>N1C=CC=CC=1>[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]([C:17]2[CH:18]=[CH:19][C:20]3[NH:23][N:24]=[C:25]([NH:26][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[C:21]=3[N:22]=2)[CH:8]=1
Reactant: Nc1n[nH]c2cnc(-c3cnc4ccccc4c3)cc12
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2ccc(-c3cnc4ccccc4c3)nc12)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclopropane carbonyl chloride (168 mg, 1.602 mmol) was added to a stirred solution of 5-(quinolin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-ylamine (200 mg, 0.766 mmol) in anhydrous pyridine (5 mL) and the reaction was heated under reflux for 16 hours. The solvent was then removed in vacuo and the residue re-evaporated from water (10 mL) to yield a solid. This was triturated with saturated aqueous sodium bicarbonate solution and the mixture then left to stand for 0.5 hour until the pH stabilised at pH 9–10. The resulting solid was then collected by filtration, washed with water (3×25 mL) and dried in vacuo. This material was then stirred in piperidine (3 mL) at room temperature for 2 hours. The piperidine was evaporated and the residue triturated with water (5 mL) and with methanol (5 mL) to afford the title compound as a solid.