Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:21][C:22]([C:25]1[CH:26]=[N:27][CH:28]=[C:29]([CH:32]=1)[CH:30]=O)([CH3:24])[CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(O)(=O)C.CCOC(C)=O>[F:21][C:22]([C:25]1[CH:32]=[C:29]([CH2:30][NH:1][CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:28]=[N:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(F)c1cncc(C=O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cncc(C(C)(C)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
A solution of tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (297 mg, 1.06 mmol) in THF was added 5-(2-fluoropropan-2-yl)nicotinaldehyde (180 mg, 1.06 mmol) and stirred for 30 min at room temperature, NaB(OAc)3H (460 mg, 2.12 mmol) was then added portionwise in 30 min., finally 5 drops of acetic acid was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was separated and dried (MgSO4). Concentration in vacuo, followed purification with flash chromatography to give tert-butyl (2S,3R)-4-((5-(2-fluoropropan-2-yl)pyridin-3-yl)methylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate as a white solid (230 mg, 70% yield). 1H NMR (CDCl3): d: 8.776 (d, J=11.5 Hz, 2H), 7.952 (s, 1H), 7.330-7.205 (m, 5H), 4.823 (d, J=7.7 Hz, 1H), 3.900 (s, 2H), 3.842 (m, 1H), 3.586 (m, 1H), 2.995 (m, 1H), 2.856 (m, 1H), 2.762 (m, 2H), 1.363 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:12](=[O:20])[O:13][C:14]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:10]=2[C:9]2[C@@H:8]([OH:21])[CH2:7][C:6]([CH3:23])([CH3:22])[CH2:5][C:4]=2[N:3]=1.N1C(C)=CC=CC=1C.[C:32]([Si:36](OS(C(F)(F)F)(=O)=O)([CH3:38])[CH3:37])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[Si:36]([O:21][C@H:8]1[CH2:7][C:6]([CH3:23])([CH3:22])[CH2:5][C:4]2[N:3]=[C:2]([Cl:1])[C:11]3[C:12](=[O:20])[O:13][C:14]4([CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:10]=3[C:9]1=2)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O)C1)C1(CCOCC1)OC3=O
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)OC3=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1.69 g (S)-4-chloro-9-hydroxy-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3-one are dissolved in 60 ml tetrahydrofurane and cooled to 0° C., 2.05 ml 2,6-lutidine and 3.71 ml trifluoromethanesulfonic acid-tert.-butyldimethylsilylester are added dropwise and the mixture is stirred for further 18 hours while warming to room temperature. Then the reaction is quenched by addition of 0.5 ml methanol. The mixture is partitioned between 0.1 M hydrochloric acid and ethylacetate. The aqueous phase is twice extracted with ethylacetate. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 70:30).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH:7]=[N:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([O-:3])=[O:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH3:50][C:49]1([CH3:51])[CH:48]([OH:52])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:11]=2)[NH:8][CH:7]1[C:6]1[CH:19]=[CH:20][CH:21]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(C=Nc2ccc(C(F)(F)F)cc2)c1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(O)c2cc(C(F)(F)F)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.9 %

Procedure:
To a mixture of (3-nitro-benzylidene)-(4-trifluoromethyl-phenyl)-amine (5.88 g, 20 mmol) and ytterbium(III) triflate hydrate (1.24 g, 2 mmol) in dry tetrahydrofuran (50 mL) at 25° C. was added isobutyraldehyde (2 mL, 22 mmol) and water (0.36 mL, 20 mmol) dropwise. The reaction mixture was stirred at 25° C. for 72 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-(3-nitro-phenyl)-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-ol (7.1 g, 96%) as a light yellow oil: LC/MS m/e calcd for C18H17F3N2O3 (M+H)+: 367.34, observed: 349.0.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][N:14]2[C:18]3[C:19]([N+:37]([O-])=O)=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:40]([CH3:42])[CH3:41])=[CH:5][CH:4]=1)#[N:2].O.O.[Sn](Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][N:14]2[C:18]3[C:19]([NH2:37])=[C:20]([O:23][CH:24]4[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:28][CH2:29]4)[CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:40]([CH3:42])[CH3:41])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)c1nc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)c([N+](=O)[O-])c2n1Cc1ccc(C#N)c2ccccc12
Agent: Cl[Sn]Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)c1nc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(N)c2n1Cc1ccc(C#N)c2ccccc12
Temperature: 50 °C
Yield: 66.9 %

Procedure:
1-(4-Cyanonaphth-1-yl)methyl-2-isopropyl-7-nitro-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole (12 g, 21 mmoL, 1 eq.) was dissolved in 400 mL dry pyridine and to this was added tin (II) chloride dihydrate (71 g, 315 mmoL, 15 eq.) which formed a finely divided suspension. The slurry was heated to 50° C. for 14 hours. The pyridine was stripped off, and the salts triturated in 1 L ethyl acetate. The salts were removed by filtration through Celite and the filtrate was concentrated to give a brown oil. Chromatography (3/2 ethyl acetate/hexanes) gave 7.6 g (67% yield) of 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-7-amino-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole as a tan foam.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[OH:27][CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=O)=[CH:31][CH:30]=1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:33]([C:32]3[CH:36]=[CH:37][C:29]([CH2:28][OH:27])=[CH:30][CH:31]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(-c3ccc(CO)cc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 4-(hydroxymethyl)benzoic acid, the title compound was obtained in 54% purity by HPLC. MS(ESI+): m/z=469.4.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[O:31][C:30]([F:29])([F:40])[F:41])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1OC(F)(F)F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)Oc1ccccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-trifluoromethoxy benzaldehyde. MS (ESI) m/z 553.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27].O>C(#N)C>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]1
Reactant: CCCI
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of 4-[2-fluoro-3-(methylsulfonyl)phenyl]piperidine (0.4 g, 1.55 mmol) in acetonitrile (40 ml) was added potassium carbonate (0.3 g, 2.17 mmol) and 1-iodopropane (0.151 ml, 1.55 mmol) and the mixture was heated at reflux for 15 h. The mixture was cooled to ambient temperature and water (50 ml) was added. The aqueous residue was extracted with ethylacetate (3×50 ml) and the combined organic phases was dried, concentrated, and purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.37 g, 79%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 255-257° C. MS m/z (relative intensity, 70 eV) 299 (M+, 2), 271 (16), 270 (bp), 147 (9) 133 (10).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:13][C:10]1[CH:11]=[CH:12][C:2]([O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N)ccc1Oc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
A mixture of ethyl 2-fluoro-5-nitrobenzoate (1.07 g), phenol (565 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (20 mL) was stirred at 80° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=20:80→30:70). The object fraction was concentrated under reduced pressure and ethanol (20 mL) and 10% palladium on carbon (1.5 g) were added to the residue (1.54 g). The mixture was stirred overnight under a hydrogen stream. The catalyst was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=20:80→50:50) and recrystallized from diisopropyl ether-hexane to give the title compound (1.07 g) as a pale-brown powder.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: COc1ccc(-c2ccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)s2)c(OC)c1
Yield: 15.8 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 2,4-dimethoxyphenylboronic acid (11 mg, 0.06 mmol) giving 3.5 mg (16%) of the title compound. MS (ESI+) calcd for C19H17N5O4S2 443.072195, found 443.071935.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:6][C:5]=1[OH:23].[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[CH:6][C:5]=1[OH:23]
Reactant: COC(=O)c1ccc(C=CCCNCC(=O)OC(C)(C)C)cc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCCCNCC(=O)OC(C)(C)C)cc1O
Yield: 95 %

Procedure:
A solution of the compound (0.845 g) obtained in (1) above in methanol (20 ml) was vigorously stirred in the presence of 10% palladium-carbon (0.106 g) in a stream of hydrogen. After filtering through Celite, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1 v/v) to give the title compound (0.810 g, yield 95%).
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li]CCCC.[CH3:19][Se:20][Se]C.C(OCC)(=O)C>C1COCC1>[CH3:19][Se:20][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: C[Se][Se]C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Se]c1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
To a solution of 500 mg (2.0 mmol) of 2-bromo-3-nitrobenzoic acid in anhydrous THF (15 mL) was added 2.80 mL (4.47 mmol) of n-BuLi (1.6 M soln. in Hex.) slowly at −78° C. After 10 minutes, a solution of 383 mg (2.03 mmol) of dimethyl diselenide in THF (5 mL) was added. After 30 minutes, the reaction mixture was warmed to room temperature. After additional stirring for 2 hours, ethyl acetate was added. The organic layer was washed with 1 N HCl solution, dried over MgSO4, and concentrated under reduced pressure. 470 mg of crude product was obtained and used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][OH:9].C1(SSC2C=CC=CC=2)C=CC=CC=1>O>[CH:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: Nc1ccccc1
Reactant: CO
Agent: c1ccc(SSc2ccccc2)cc1
Solvent: O
Product: O=CNc1ccccc1
Temperature: 180 °C
Yield: 59 %

Procedure:
To a 200 cc Parr reactor provided with a glass liner (actual reactor volume with liner=134 cc) and a magnetic stirrer is charged, at room temperature, 1.0 gram aniline, 20 cc methanol, 0.5 gram of BaO.CoMoO4 as catalyst and 2.5 grams of phenyl disulfide (φ2S2). The reactor is sealed and then purged with gaseous nitrogen by means of a gas inlet tube and, also at room temperature, gaseous COS (2.5 grams) is pressured into the reactor following which CO is pressured into the reactor, to provide a pressure in the reactor of about 500 psig. The molar ratio of S:aniline in this example is about 2.5:1. The pressured reactor is then heated with stirring by means of an oil bath to a temperature of 180° C., which is measured externally to the reactor. This reaction temperature is maintained for six hours after which the oil bath is cooled to about 30° C. by passing cooling water through a copper tube which is immersed in the bath. The gas in the reactor is then vented and the vent gas and the liquid product mixture in the reactor are analyzed. Methyl N-phenyl carbamate ("MPC") is found to be present in a yield of about 59 percent and in a selectivity of about 95%. No detectable formanilide is formed and the diphenyl urea yield is less than 5%.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cr](O)(O)(=O)=O>CC(C)=O.S(=O)(=O)(O)O>[C:1]([N:11]1[CH2:18][C:17](=[O:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Yield: 10.7 %

Procedure:
21.5 g (0.81 mole) of N-carbobenzyloxy-4-hydroxy-L-proline is oxidized in 1.2 liters of acetone with 83 ml of 8 N chromic acid in sulfuric acid as described in J.A.C.S. 79, 189 (1957). In order to facilitate the subsequent filtration of chromium salts, 30 g of Celite (diatomaceous earth) is added to the acetone solution before introduction of the oxidizing agent. An air stirrer is employed. The reaction mixture is filtered and the acetone filtrate is concentrated to approximately 300 ml before diluting with 1 liter of chloroform. The solution is washed with 300 ml of saturated sodium chloride (four times), dried (MgSO4), filtered and the solvent evaporated to give N-carbobenzyloxy-4-keto-L-proline (22.8 g) which is crystallized from ether (50 ml)-hexane (150 ml) to obtain 17.2 g (81%) of product, m.p. 99°-101°, [α]D26 +17° (c, 1% in chloroform).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:7]2[CH2:8][CH2:9][CH:10]([C:12]([O:14]CC)=[O:13])[CH2:11][C:6]2=[N:5][N:4]=1.O[Li].O.Cl>C1COCC1.O>[F:18][C:2]([F:1])([F:17])[C:3]1[N:7]2[CH2:8][CH2:9][CH:10]([C:12]([OH:14])=[O:13])[CH2:11][C:6]2=[N:5][N:4]=1
Reactant: CCOC(=O)C1CCn2c(nnc2C(F)(F)F)C1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCn2c(nnc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (2.28 g, 8.662 mmol) in THF (17 mL) was added 4N LiOH.H2O (726.9 mg, 17.324 mmol) in water (4 mL), then the mixture was stirred at room temperature for 2 h, then acidified with 1N HCl to pH=3. The resulting mixture was extracted with EA and the aqueous phase was directly drying to give 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[C:6]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1.[C:23]([O:27][C:28](=[O:38])[CH2:29][C@H:30]([NH2:37])[C:31]([N:33]([O:35][CH3:36])[CH3:34])=[O:32])([CH3:26])([CH3:25])[CH3:24].N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:12])(=[O:11])[NH:37][C@H:30]([C:31](=[O:32])[N:33]([O:35][CH3:36])[CH3:34])[CH2:29][C:28]([O:27][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:38])=[C:6]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1
Reactant: CON(C)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N(C)OC)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
To a solution of 3-benzyloxy-4-chlorosulfonyl-benzoic acid methyl ester (9.25 g, 27.1 mmol) in dichloromethane (270 mL) was added (S)-3-amino-N-methoxy-N-methyl-succinamic acid tert-butyl ester (6.30 g, 27.1 mmol) followed by pyridine (6.59 mL, 81.4 mmol). The reaction was allowed to stir over night at room temperature. The reaction was then diluted with ethyl acetate (500 mL) and washed sequentially with 5% citric acid, saturated sodium bicarbonate, and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield an orange oil. The crude residue was chromatographed (silica gel, 40% ethyl acetate-60% hexane) to give 3-benzyloxy-4-[(S)-2-tert-butoxycarbonyl-1-(methoxy-methyl-carbamoyl)-ethylsulfamoyl]-benzoic acid methyl ester as a white foam (8.20 g, 56%). 1H NMR(300 MHz, DMSO) 7.84 (d, 1H), 7.60 (m, 1H), 7.57 (m, 2H), 7.52 (d, 2H), 7.36 (t, 2H), 7.28 (t, 1H), 5.35 (s, 2H), 4.60 (m, 1H), 3.81 (s, 3H), 3.48 (bs, 3H), 2.82 (bs, 3H), 2.46 (dd, 1H), 2.33 (dd, 1H), 1.27 (s, 9H). MS(APCI) m/z 535.2 (M−H).
Reaction SMILES: [C:1]1([O:11][C:12]2[CH:17]=[CH:16][N+:15]([O-])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:16]1[CH:17]=[C:12]([O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:14][N:15]=1
Reactant: [O-][n+]1ccc(Oc2cccc3ccccc23)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(Oc2cccc3ccccc23)ccn1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of Example 137 A (4.50 g; 19.0 mmol) in phosphoryl chloride (50 ml) is heated to reflux temperature in the course of 1.5 h and stirred at this temperature overnight. The phosphoryl chloride is stripped off in vacuo, the residue is treated with ice water and the mixture is extracted with dichloromethane. The organic phase is washed with sat. NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The residue is chromatographed on silica gel using toluene:EA (5:1).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3=[N:18][CH:19]=[C:20]([F:22])[CH:21]=[C:16]3[N:15]([CH3:23])[C:14]2=[O:24])[CH2:10]1)(C)(C)C>O1CCOCC1>[ClH:1].[NH2:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3=[N:18][CH:19]=[C:20]([F:22])[CH:21]=[C:16]3[N:15]([CH3:23])[C:14]2=[O:24])[CH2:10]1
Reactant: Cn1c(=O)n([C@H]2C[C@H](NC(=O)OC(C)(C)C)C2)c2ncc(F)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(=O)n([C@H]2C[C@H](N)C2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 104.5 %

Procedure:
Hydrogen chloride (4.0 M in 1,4-dioxane, 1.843 mL, 7.37 mmol) was added to a stirred mixture of tert-butyl(trans-3-(6-fluoro-1-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)cyclobutyl)carbamate (0.248 g, 0.737 mmol) in 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated to yield 3-(trans-3-aminocyclobutyl)-6-fluoro-1-methyl-1 h-imidazo[4,5-b]pyridin-2(3h)-one hydrochloride (0.210 g, 0.770 mmol, 104% yield) as a white solid. M+1: 237.1.
Reaction SMILES: [OH:1][NH2:2].C(O[C:6](=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(F)cc2)ccn1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1cc(-c2ccc(F)cc2)ccn1)NO
Reaction time: 23 h
Yield: 54 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (34 mg, 0.08 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 23 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:6) to furnish IV as a colourless oil (18 mg, 54%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[C:15]([N:17]=[C:18](SC)[NH:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[O:25][C:26]([CH2:29][N:30]([CH3:32])[CH3:31])=[CH:27][CH:28]=1)#[N:16]>>[C:15]([N:17]=[C:18]([NH:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[O:25][C:26]([CH2:29][N:30]([CH3:32])[CH3:31])=[CH:27][CH:28]=1)[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)#[N:16]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC(=NC#N)NCCSCc1ccc(CN(C)C)o1
Product: CN(C)Cc1ccc(CSCCNC(=NC#N)NCCSCc2ccc(CN(C)C)o2)o1
Yield: 57.1 %

Procedure:
A mixture of 5-[[(2-aminoethyl)thio]methyl]N,N-dimethyl-2-furanmethanamine (1.39 g) and N'-cyano-N-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]carbamimidothioic acid, methyl ester (2.0 g) was heated at 120° for 2 days. The oily product was subjected to column chromatography (silica-methanol) giving the title compound as a yellow oil (1.75 g).