Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[C:3]=1[CH2:11][CH3:12].[N:13]#[C:14]Br.O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[C:3]([CH2:11][CH3:12])=[C:4]([CH3:10])[C:5]2[N:6]([C:14]([NH2:13])=[N:9][N:8]=2)[N:7]=1
Reactant: CCc1c(Cl)nnc(NN)c1C
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCc1c(Cl)nn2c(N)nnc2c1C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
(6-Chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine (W3.007; 340 mg) was dissolved in ethanol/water (10/2 ml) at RT while stirring. Thereafter, cyanogen bromide (386 mg, dissolved in 5 ml of ethanol and 1 ml of water) was cautiously added dropwise. After stirring at RT for 5 h, the mixture was left to stand overnight and then the solvent was drawn off, and the residue was admixed with water. Once the residue had been alkalized with saturated potassium carbonate solution, it was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after filtering off the desiccant, dried under reduced pressure. 385 mg of the title compound were obtained. LC-MS rt: 0.62 min [M+H]+: 212.1 (met. b)
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([CH3:11])/[C:6](=[CH:12]\[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)/[C:5]1=[O:21])(=O)C.[H-].[Na+].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[CH:24](=[C:9]1/[C:8](=[O:10])[N:7]([CH3:11])/[C:6](=[CH:12]\[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)/[C:5](=[O:21])[NH:4]/1)\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(/C=C2/C(=O)N(C(C)=O)CC(=O)N2C)cc1
Reactant: O=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(/C=c2/c(=O)[nH]/c(=C\c3ccccc3)c(=O)n2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.8 %

Procedure:
A mixture of (3Z)-1-Acetyl-3-(4-methoxybenzylidene)-4-methyl-2,5-piperazinedione (10) (200 mg, 0.69 mmol) and sodium hydride (60% dispersion in oil, 28 mg, 0.69 mmol) in dry DMF (10 ml) was stirred at room temperature for 18 h. Benzaldehyde (71 μl, 0.69 mmol) was then added and the reaction mixture stirred at room temperature for 18 h. It was then diluted with ethyl acetate (100 ml) and washed with brine (4×50 ml) . The organic phase was separated, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, dichloromethane containing 1% MeOH) to give 48 mg (21%) of a yellow solid.
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]3[N:29]=[C:30]([CH2:32]O)[CH:31]=[C:25]3[C:24]2=[O:34])=[N:21][CH:22]=1.FC1C=CC(N2CCN3N=C(COC4C=CC(C)=CC=4)C=C3C2=O)=CC=1>>[C:5]([Si:2]([CH3:4])([CH3:3])[O:1][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:32][C:30]2[CH:31]=[C:25]3[C:24](=[O:34])[N:23]([C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:22][N:21]=4)[CH2:28][CH2:27][N:26]3[N:29]=2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: O=C1c2cc(CO)nn2CCN1c1ccc(F)cn1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Agent: Cc1ccc(OCc2cc3n(n2)CCN(c2ccc(F)cc2)C3=O)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCc2cc3n(n2)CCN(c2ccc(F)cn2)C3=O)cc1

Procedure:
The compound was prepared from 4-(tert-butyldimethylsiloxy)phenol and 5-(5-fluoro-pyridin-2-yl)-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one using the method described in the preceding example 55 (5-(4-fluorophenyl)-2-(p-tolyloxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-])=O)[CH:3]=1>[Zn]>[NH2:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Zn]
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N

Procedure:
The title compound was prepared from the tert-butyl 4-chloro-2-nitrophenylcarbamate (Example A5; 3 mmol) by reduction with zinc according to the general procedure B. Obtained as a yellow solid (85%), MS (EI) 243 [(M+1)+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:34]=[C:33]([C:35](O)=[O:36])[CH:32]=[N:31][CH:30]=2)=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:35]([C:33]4[CH:32]=[N:31][CH:30]=[C:29]([C:26]5[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=5)[N:34]=4)=[O:36])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cncc(-c2ccc(F)cc2)n1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cncc(-c3ccc(F)cc3)n2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Yield: 90.2 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl4-carboxamide (75 mg, 0.27 mmol), 6-(4fluorophenyl)pyrazine-2-carboxylic acid (58.4 mg, 0.27 mmol), HATU (101.5 mg, 0.27 mmol), HOBT (36 mg, 0.27 mmol) and DIPEA (140 μl, 0.80 mmol) in DMF (3 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with hydrochloric acid (0.5M, 2×20ml), aqueous sodium hydrogen carbonate (20 ml) and dried (magnesium sulphate). Evaporation of the solvents under vacuum gave N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-6-(4-fluorophenyl)pyrazine-2-carboxamide (117 mg, 91%). NMR; δH [2H6]—DMSO 10:64,(1H, s), 9.52,(1H, s), 9.20,(1H, s), 8.63,(1H, t), 8.54,(2H, m), 7.95,(2H, d), 7.88,(1H, dd), 7.78,(1H, d), 7.48,(2H, d), 7.42,(2H, t), 7.35,(1H, d), 3.17,(2H, t), 2.23,(3H, s), 1.05,(1H, m), 0.24,(2H, m). LCMS: retention time 3.65 min, MH+481.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C:18]23[C:24]([CH3:26])([CH3:25])[C:21]([CH3:27])([CH2:22][CH2:23]2)[C:20](=[O:28])[CH2:19]3)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.C(O)C.[BH4-].[Na+]>>[Cl:1][C:2]1[C:3]([NH:17][C@@:18]23[C:24]([CH3:25])([CH3:26])[C:21]([CH3:27])([CH2:22][CH2:23]2)[CH:20]([OH:28])[CH2:19]3)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cn1cc(-c2nc3c(NC45CCC(C)(C(=O)C4)C5(C)C)c(Cl)cnc3[nH]2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cn1cc(-c2nc3c(N[C@@]45CCC(C)(C(O)C4)C5(C)C)c(Cl)cnc3[nH]2)cn1
Temperature: 60 °C
Yield: 45.9 %

Procedure:
To a suspension of 4-(6-chloro-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-ylamino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (Compound CXCIX) (90 mg, 0.228 mmol) in ethanol NaBH4 (85 mg, 2.26 mmol) was added and the reaction mixture was heated at 60° C. for 16 h when LCMS confirmed consumption of staring material and formation of desired product. The reaction mixture was allowed to come to rt and acidified to pH 5. Solvent was then removed and the residue was suspended in water and filtered. The residue was triturated with ether to afford the desired product (42 mg, 46%) as a white solid. NMR: δ (1H, 400M Hz, DMSO-d6): 0.88 (3H, s), 0.91 (3H, s), 1.09 (3H, s), 1.10-1.60 (4H, m), 2.75-2.90 (1H, m), 3.60-3.75 (1H, m), 3.94 (3H, s), 4.77 (1H, d, J=4.4 Hz), 5.21 (1H, s), 7.95 (1H, s), 8.03 (1H, s), 8.28 (1H, s), 12.99 (1H, s). LCMS (254 nm): [M+H]+ 401.05 (96.59%). HPLC: 93.58% (220 nm)
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH2:11][CH2:10]2)(=[O:6])=[O:5].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[CH:35]=[C:34](Cl)[N:33]=[CH:32][N:31]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.[Cl-].[Na+].O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[CH:35]=[C:34]([N:12]3[C:13]4[C:9](=[CH:8][C:7]([S:4]([CH3:3])(=[O:6])=[O:5])=[CH:15][CH:14]=4)[CH2:10][CH2:11]3)[N:33]=[CH:32][N:31]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ncn2)CC1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of NaH (0.62 g, 15.5 mmol, 60% NaH) in 40 mL of DMF, 5-methanesulfonyl-2,3-dihydro-1H-indole (1.9 g, 9.63 mmol) was added and the mixture was stirred at room temperature for 30 minutes. 17a (3.09 g, 9.88 mmol) was added in DMF and the mixture was heated at 85° C. for 17 h. After cooling to room temperature, brine was added (200 mL) and the mixture was extracted with DCM (200 mL then 3×500 mL). The combined extracts were washed with brine (3×100 mL), dried, filtered and evaporated. The residue was purified by flash chromatography (eluent: 25 to 100% EtOAc in hexane with 0.1% triethylamine) to afford 2.83 g (62%) of 17b.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:5][C@H:4]2[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:18](=[O:20])[O:19][C@H:3]12>CO.[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:6]1[CH2:7][C@H:2]([CH3:1])[C@H:3]2[O:19][C:18](=[O:20])[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:4]2[CH2:5]1
Reactant: C[C@H]1CN(c2ccncc2[N+](=O)[O-])C[C@@H]2[C@@H]1OC(=O)N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2N)C[C@@H]2[C@@H]1OC(=O)N2C(=O)OC(C)(C)C
Reaction time: 14 h

Procedure:
To a solution of (3aR,7S,7aR)-tert-butyl 7-methyl-5-(3-nitropyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate (1.0 equiv.) in methanol, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 14 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding (3aR,7S,7aR)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate. LCMS (m/z): 349.1 (MH+); LC Rt=2.18 min.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:11][CH2:12][C:13](Cl)=[O:14].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][CH2:12][C:13]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:14]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCCc2ccccc21
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinolin (3) (2.00 g, 15.0 mmol) in dry CH2Cl2 (30 mL) at 0° C. was added chloroacetyl chloride (1.27 mL, 16.0 mmol) followed by drop wise addition of triethylamine (2.50 mL, 18.03 mmol). The reaction was stirred overnight under N2. The reaction mixture was then diluted with CH2Cl2 (50 mL), washed with 5% HCl (15 mL), H2O (2×15 mL) and brine. Dried over MgSO4, filtered and concentrated to give 3.05 g of 4. This crude material was used in subsequent reactions without further purification.
Reaction SMILES: [NH3:1].[N:2]1([C@@H:7]([CH2:12][CH3:13])[C:8](OC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1>O>[N:2]1([C@@H:7]([CH2:12][CH3:13])[C:8]([NH2:1])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC[C@@H](C(=O)OC)N1CCCC1
Reactant: N
Solvent: O
Product: CC[C@@H](C(N)=O)N1CCCC1
Temperature: 5 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
11.3 g of ammonia gas was condensed in 13.2 ml of water at approximately 0° C. and the temperature was maintained at 0–5° C. Then 20 g of (S)-PBM (26) was added dropwise over a period of 10 min and reaction mixture was maintained at 5° C. and stirred for minimum 8 hrs (reaction was complete as indicated by TLC). The reaction mixture was then evaporated to dryness under vacuum and dried by means of toluene (2×50 ml) to give minimum 17 g (92%) of crude (S)-pyrrolidinobutyramide (crude Levetiracetam) as an off-white to beige solid.
Reaction SMILES: C1(CC(CC(N2CCCCC2)=O)C(N(C(=O)[C@H](CC2N=CNC=2)N)N)=O)C2C(=CC=CC=2)C=CC=1.Cl.N(OCCC(C)C)=O.[C:45]1([CH2:55][CH:56]([CH2:72][C:73]([N:75]2[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]2)=[O:74])[C:57]([NH:59][C@H:60]([C:67]([N:69]=[N+]=[N-])=[O:68])[CH2:61][C:62]2[N:66]=[CH:65][NH:64][CH:63]=2)=[O:58])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1.[N-]=[N+]=[N-].Cl.N[C@@H:86]([CH2:95][CH:96]([CH3:98])[CH3:97])[CH:87]([OH:94])[C:88]([O:90][CH:91]([CH3:93])[CH3:92])=[O:89]>CN(C)C=O.C(N(CC)CC)C>[C:45]1([CH2:55][CH:56]([CH2:72][C:73]([N:75]2[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]2)=[O:74])[C:57]([NH:59][C@H:60]([C:67]([NH:69][C@@H:86]([CH2:95][CH:96]([CH3:98])[CH3:97])[CH:87]([OH:94])[C:88]([O:90][CH:91]([CH3:92])[CH3:93])=[O:89])=[O:68])[CH2:61][C:62]2[N:66]=[CH:65][NH:64][CH:63]=2)=[O:58])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)N1CCCCC1)Cc1cccc2ccccc12
Reactant: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Agent: CC(C)CCON=O
Agent: Cl
Agent: N[C@@H](Cc1c[nH]cn1)C(=O)N(N)C(=O)C(CC(=O)N1CCCCC1)Cc1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)N1CCCCC1)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C

Procedure:
To a suspension of 240 mg of N-[2-(1-naphthylmethyl)-3-(piperidinocarbonyl)propionyl]-L-histidine hydrazide in 3 ml of dry N,N-dimethylformamide were added successively 0.32 ml of a dry 5.1N-hydrogen chloride in N,N-dimethylformamide solution and 0.08 ml of isoamyl nitrite at -20° C. with stirring. After disappearance of hydrazide compound, the reaction mixture was cooled to -30° C. and neutralized with 0.23 ml of triethylamine to prepare a solution of N-[2-(1-naphthylmethyl)-3-(piperidinocarbonyl)propionyl]-L-histidine azide. The cold azide solution was added dropwise to a solution of 120 mg of isopropyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride and 0.07 ml of triethylamine in 2 ml of dry N,N-dimethylformamide under ice-cooling with stirring, and the mixture was stirred for 16 hours. The reaction mixture was evaporated under reduced pressure. A 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was separated by silica gel flash column chromatography (eluent: chloroform/methanol=20/1 by volume), and fraction containing desired product which has Rf1 value of 0.63 was combined and purified to obtain 18 mg of isopropyl (2RS, 3S)-3-{N-[ 2-(1-naphthylmethyl)-3-(piperidinocarbonyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][N:12]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.Br[CH2:22][C:23]([O:25]C(C)(C)C)=[O:24]>>[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([S:8]([N:7]([CH2:22][C:23]([OH:25])=[O:24])[C:4]2[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=2)(=[O:10])=[O:9])=[N:12][CH:13]=1)([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cc1

Procedure:
prepared by reaction of 5-isopropyl-pyridine-2-sulfonic acid p-tolylamide with tert-butyl bromoacetate
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=O)[C:19]3=[O:26])(=[O:15])=[O:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:28][C:29]1([C:34]#[N:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:1]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:13]([C:16]2[CH:24]=[CH:23][C:22]3[N:21]4[CH2:28][C:29]5([CH2:33][CH2:32][CH2:31][CH2:30]5)[CH2:34][N:35]=[C:20]4[C:19](=[O:26])[C:18]=3[CH:17]=2)(=[O:14])=[O:15])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#CC1(CCl)CCCC1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3CN3CCOCC3)cc2C1=O
Product: O=C1C2=NCC3(CCCC3)CN2c2ccc(S(=O)(=O)N3CCC[C@H]3CN3CCOCC3)cc21

Procedure:
The title compound was prepared as a orange solid from 5-{[(2S)-2-(morpholin-4-ylmethyl)pyrrolidin-1-yl]sulfonyl}-1H-indole-2,3-dione and 1-chloromethyl-cyclopentanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 471 [M−H]. m.p.: 162.9-163.6° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][CH:24]([CH3:26])[N:23]([CH3:27])[C:20]4=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH:32]=[C:31]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:30][CH2:29]1>CS(C)=O.C(OCC)(=O)C>[NH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([C:31]2[CH2:32][CH2:33][N:28]([CH2:12][CH:13]3[O:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]5[NH:25][CH:24]([CH3:26])[N:23]([CH3:27])[C:20]5=4)[O:15][CH2:14]3)[CH2:29][CH:30]=2)=[CH:35]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)N(C)C(C)N4)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1Nc2ccc3c(c2N1C)OC(CN1CC=C(c2c[nH]c4ccccc24)CC1)CO3
Temperature: 95 °C
Yield: 12 %

Procedure:
A mixture of 0.69 g (1.8 mmole) of [(8R)-1,2-dimethyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl 4-methylbenzenesulfonate and 1.0 g (5.0 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10.0 mL of DMSO was heated at 90-100° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 0-3% methanol in chloroform as eluant and the product fractions concentrated in vacuum to give 0.090 g of the desired compound as the free base. Recrystallization from ethanol with the addition of 0.025 g of fumaric acid gave the (S)-enantiomer of the title compound as a yellow solid, m.p. 186-188° C.
Reaction SMILES: C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1OC=CCC)(=O)C.C(S)C1C=CC=CC=1.C([O:40][C@@H:41]1[C@@H:59]([O:60]C(=O)C)[C@H:58]([O:64]C(=O)C)[C@@H:57]([CH2:68][O:69]C(=O)C)[O:56][C@H:42]1[O:43][CH2:44][CH2:45][CH2:46][CH2:47][S:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=O)C.C[O-].[Na+]>O1CCOCC1.CC(N=NC(C#N)(C)C)(C#N)C.CO>[O:43]([CH2:44][CH2:45][CH2:46][CH2:47][S:48][CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C@@H:42]1[O:56][C@H:57]([CH2:68][OH:69])[C@@H:58]([OH:64])[C@H:59]([OH:60])[C@H:41]1[OH:40]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCCCSCc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCC=CO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Solvent: C1COCCO1
Solvent: CO
Product: OC[C@H]1O[C@@H](OCCCCSCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
4-benzylthiobutyl β-D-glucopyranoside was synthesized by the following reactions from β-D-glucopyranose. Thus, acetyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside was prepared by exhaustive acetylation of the hydroxyl groups in β-D-glucopyranose by the action of sodium acetate in acetic anhydride. The acetyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside was subsequently reacted with 3-buten-1-ol under catalysis by boron trifluoride diethyl etherate to give butenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside. The butenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside was mixed with benzyl thiol in dioxane and AIBN was added as radical initiator; reaction then gave 4-benzylthiobutyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside. Deacetylation of the 4-benzylthiobutyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside by reaction with sodium methoxide in methanol gave 4-benzylthiobutyl β-D-glucopyranoside:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[CH2:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN1CCCC1=O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH:16]=[CH:15][CH2:14][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:18][CH:19]=1
Reactant: BrCC=Cc1ccc(Br)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCC=Cc1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 96 h
Yield: 86.8 %

Procedure:
18.5 g (0.11 mol) of N-hydroxyphthalimide and 31.4 g (0.11 mol) of 1-bromo-3-(4-bromophenyl)-prop-2-ene were added in succession to 350 ml of dry N-methylpyrrolidone, and 12.1 g (0.12 mol) of triethylamine were then added dropwise at room temperature. The reaction mixture was stirred for four days at 20° C. and then poured onto 1.5 l of ice water, and the product was filtered off and washed with water and isopropanol. Yield: 86.8%; m.p.: 161°-162° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][NH:12][C:13]=1[C:14]([O:16]C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>CN(C)N.O>[CH2:1]([O:8][C:9]1[C:13]([C:14]([OH:16])=[O:15])=[N:12][NH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1OCc1ccccc1
Agent: CN(C)N
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1[nH]nc(C(=O)O)c1OCc1ccccc1
Temperature: 35 °C

Procedure:
Dimethyl 4-benzyloxy-1H-pyrazole-3,5-dicarboxylate (25 g, 86 mmol) was dissolved in N,N-dimethylhydrazine (75 mL) and the stirred mixture heated to reflux under nitrogen atmosphere for 30 hours. The solvent was removed in vacuo to give a white solid. The residue was dissolved in water (200 mL), 1N HCl (75 mL), and ethyl acetate (100 mL). The mixture was stirred and warmed to 35° C. until all the solids had dissolved. The layers were then separated and the aqueous layer was extracted with more ethyl acetate (3×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the product as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 13.2 (br s, 1H), 7.3-7.45 (m, 5H), 5.09 (s, 2H), 3.81 (s, 3H); ES MS (M+1)=277.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[CH:26]1([NH2:29])[CH2:28][CH2:27]1.O>CCO>[CH:26]1([NH:29][C:3]([C:5]2[N:6]=[C:7]([C:24]#[N:25])[C:8]3[C:9](=[O:23])[N:10]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:4])[CH2:28][CH2:27]1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NC1CC1
Solvent: CCO
Solvent: O
Product: N#Cc1nc(C(=O)NC2CC2)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 80 °C
Yield: 61.7 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (27 mg, 0.081 mmol) and cyclopropylamine (0.060 mL, 0.81 mmol) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After cooling to r.t., water (3 mL) were added. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-15% EtOAc/CH2Cl2) to give 18 mg of the title compound as a white solid. MS: (−) m/z 358.99 (M−1).