Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[CH3:22][C:23]1[O:27][C:26]([CH2:28][NH2:29])=[CH:25][CH:24]=1>>[CH3:22][C:23]1[O:27][C:26]([CH2:28][NH:29][C:20]2[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(CN)o1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Product: Cc1ccc(CNC2=Nc3ccc([N+](=O)[O-])cc3CO2)o1
Yield: 79.1 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (2.0 g, 6.16 mmol; HPLC: 4.446 min) and 5-methyl-2-furanmethanamine (CAS 14003-16-8) (0.685 g, 6.163 mmol) according to the procedure described for Example 1. Obtained the title compound as a yellow solid (1.40 g, 79%, HPLC 1.624 min), MS (ISP) m/e=326.2 [(M+H)+].
Reaction SMILES: F[B-](F)(F)F.[CH:6](=[N:13][N+:14]1[CH:18]=[CH:17][N:16](N=CC2C=CC=CC=2)[C:15]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-]#N.[K+]>CO.O>[CH:6](=[N:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C(=Nn1cc[n+](N=Cc2ccccc2)c1N1CCOCC1)c1ccccc1
Agent: F[B-](F)(F)F
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Product: C(=Nn1ccnc1N1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4.47 g of 1,3-bis(benylideneamino)-2-morpholinoimidazolium tetrafluoroborate are suspended in 50 ml of methanol. A solution of 1.3 g of potassium cyanide in 20 ml of water is added dropwise within 15 minutes while cooling in an ice-bath, whereby a yellow solution results. The solution is stirred at room temperature for an additional 15 minutes, 150 ml of water are added and the mixture is extracted three times with 30 ml of methylene chloride each time. The combined methylene chloride extracts are dried over sodium sulfate, filtered and evaporated in a vacuum. The yellow oil which remains behind as the residue is treated with 70 ml of ice-cold water. Then the mixture is acidified (pH about 1) with 2N hydrochloric acid and subsequently extracted three times with diethyl ether. The colorless, acidic-aqueous phase is treated with 2N sodium hydroxide solution up to an alkaline reaction (pH about 8-9). The resulting pale yellow precipitate is removed by filtration and reprecipitated from methanol/water. There is obtained 1-benzylideneamino-2-morpholinoimidazole of m.p. 59°-61°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14].C(N(CC)CC)C>C(O)CCC>[NH2:14][CH2:13][CH2:12][NH:15][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: NCCN
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: NCCNc1nc(Cl)nc2[nH]ccc12
Yield: 39.5 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (160 mg, 0.85 mmol), ethylenediamine (0.170 mL, 2.55 mmol) and triethylamine (0.100 mL, 0.72 mmol) in nBuOH (4 mL) was stirred at 70° C. for 4 h. It was then purified by HPLC to give N-(2-aminoethyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (71 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1])[CH3:16]
Reactant: CCO
Reactant: O=C(O)c1cccnc1Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cccnc1Cl

Procedure:
To a solution 2-Chloro-nicotinic acid (12.5 g) in Ethanol (250 ml) was added thionyl chloride (5.77 ml) dropwise and refluxed for 1.5 hours. The mixture was concentrated to remove ethanol and diluted with 300 ml water. Solid sodium bicarbonate was added to adjust the solution to pH 8.0. This was extracted with ethyl acetate, washed with water, saturated bicarbonate solution, water and brine, dried over Na2SO4, filtered and concentrated to a yellow liquid (10.0 g). MW 185.61; MS (m/e) 185 (M+).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[C:11]2[C:16](=[C:17](Br)[C:18]=1[O:19][CH3:20])[CH2:15][N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@:13]([CH3:32])([C:29]([OH:31])=[O:30])[CH2:12]2>CO.[Pd]>[C:25]([O:24][C:22]([N:14]1[C@@:13]([CH3:32])([C:29]([OH:31])=[O:30])[CH2:12][C:11]2[C:16](=[CH:17][C:18]([O:19][CH3:20])=[CH:9][CH:10]=2)[CH2:15]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1c(Br)cc2c(c1Br)CN(C(=O)OC(C)(C)C)[C@@](C)(C(=O)O)C2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@@](C)(C(=O)O)C2
Reaction time: 1.5 h

Procedure:
Triethylamine (303 mg, 3 mmol) and 10% Pd—C (20 mg) were added to Compound 2.7 (500 mg, 1.05 mmol) in MeOH (5 mL) and the mixture was hydrogenated on a Parr shaker at 40 PSI for 90 min. The mixture was filtered through Celite and concentrated. The product was used in the next step.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:7]=2[C:8](N(C)OC)=[O:9])[CH2:3][CH2:2]1.[CH2:20]([Mg]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH:1]1([C:4]#[C:5][C:6]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:7]=2[C:8](=[O:9])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(C(=O)N(C)OC)c(C#CC2CC2)c1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2ccccc2)c(C#CC2CC2)c1
Yield: 89 %

Procedure:
2-(Cyclopropylethynyl)-N-methyl-N,4-bis(methyloxy)benzamide (150) (0.47 g, 1.82 mmol) was treated with benzylmagnesium chloride in THF to give 0.47 g (89%) of the title compound (151) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.80-0.95 (m, 4H), 1.45-1.55 (m, 1H), 3.82 (s, 3H), 4.41 (s, 2H), 6.80 (dd, J1=8.8 Hz, J2=2.6 Hz, 1H), 6.94 (d, J=2.5 Hz, 1H), 7.20-7.26 (m, 3H), 7.27-7.33 (m, 2H), 7.65 (d, J=8.8 Hz, 1H). LCMS (ESI): m/z 291 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.I[CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:11]([N:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CI
Reactant: c1ccc2[nH]nnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1nc2ccccc2n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A mixture of benzotriazole (11.91 g, 100 mmol), 1-iodo-2-methylpropane (13.8 mL, 120 mmol), potassium carbonate (41.46 g, 300 mmol), and dimethylformamide (200 mL) was stirred and heated under argon at 40° C. for 2 days. The reaction mixture was poured into ice/water (1 L) and extracted with toluene/hexanes (2:1, 2×500 mL). The extract was washed with 1 N HCl (2×200 mL) followed by brine (100 mL), dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was triturated with hexane (200 mL) and set aside at room temperature for 2 hours. The precipitate was separated and discarded, and the solution was filtered through a layer of silica gel (200 g). The silica gel was washed with hexane/dichloromethane/ethyl acetate (37:50:3, 2 L). The filtrate and washings were combined, and the solvent was removed under reduced pressure to give 2-isobutyl-2H-benzo[d][1,2,3]triazole (8.81 g, 50% yield) as an oily product. 1H NMR (400 MHz, CDCl3): δ 7.86 (m, 2H, benzotriazole), 7.37 (m, 2H, benzotriazole), 4.53 (d, J=7.3 Hz, 2H, i-Bu), 2.52 (m, 1H, i-Bu), 0.97 (d, J=7.0 Hz, 6H, i-Bu).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:14][C@@H:15]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([OH:26])=[O:25])[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[S:17][CH2:16]1)[C:9]([O:11]CC)=[O:10].[C:31]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C([BH3-])#N.[Na+]>C(O)C>[C:9]([C@@H:8]([NH:14][C@@H:15]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([OH:26])=[O:25])[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[S:17][CH2:16]1)[CH2:7][CH2:6][CH2:5][CH2:4][NH:3][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)([OH:11])=[O:10]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)[C@H](CCCCN)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCNC2CCCCC2)C(=O)O)CSc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A mixture of 3(R)-[5-amino-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrochloride (0.2 g) obtained in Example 59, ethanol (10 ml), cyclohexanone (2 g) and sodium cyanoborohydride (0.3 g) is allowed to stand overnight at room temperature. To the residue, after evaporation of ethanol, is added 1N aqueous sodium hydroxide (4 ml). The resulting mixture is stirred at room temperature for 1 hour, diluted with water (20 ml) and extracted 3 times with ethyl acetate (20 ml each). The aqueous layer is slightly acidified with acetic acid (1 ml) and subjected to Amberlite XAD-2 column chromatography eluting with methanol-water (1:1). The eluate is concentrated under reduced pressure and lyophilized to give 3(R)-[1(S)-carboxy-5-cyclohexylaminopentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (0.12 g) as colorless powder.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][C:7]2([C:13]1[NH:14][CH2:15][CH2:16][N:17]=1)[CH3:12].C([Li])(C)(C)C.[CH3:23][C:24]([CH3:28])([CH3:27])[CH:25]=[O:26]>C1COCC1.CCCCC>[NH:14]1[CH2:15][CH2:16][N:17]=[C:13]1[C:7]1([CH3:12])[C:8]2[C:3](=[C:2]([CH:25]([OH:26])[C:24]([CH3:28])([CH3:27])[CH3:23])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][O:6]1
Reactant: CC1(C2=NCCN2)OCCc2c(Br)cccc21
Reactant: CC(C)(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1(C2=NCCN2)OCCc2c(C(O)C(C)(C)C)cccc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(5-bromo-1-methylisochroman-1-yl)-4,5-dihydro-1H-imidazole (Example 2, 0.075 g) in 2 ml of THF was added 0.33 ml of tert-butyl lithium solution in pentane (1.7M) at −78° C. followed by addition of 1.2 ml of 20.8M solution of trimethylacetaldehyde in THF. After stirring at −78° C. for 15 min, the reaction was quenched with ice. The title compound was isolated with separation methods A and G. (Yield 0.003 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:6][C:5]=2[NH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:6][C:5]2[NH:4][CH:3]=[C:2]([CH3:1])[C:10]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1ccccc1C1CC(=O)c2c(C)c[nH]c2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)c[nH]c2C1
Yield: 4.1 %

Procedure:
A mixture of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindol-4-one (0.70 g), aminoguanidine hydrochloride (0.34 g), concentrated hydrochloric acid (0.44 ml), water (0.44 ml) and ethanol (50 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated. To the residue was added sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/MeOH/Et3N). The resulting oil was dissolved in ethanol, and to the solution was added 1N hydrochloric acid. The solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindole hydrochloride (Compound 6) (0.04 g) as colorless crystals.
Reaction SMILES: [O-:1][O-:2].[Na+].[Na+].[C:5]([N:9]=[N:10][C:11]1(Cl)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([N:9]=[N:10][C:11]1([O:1][O:2][C:11]2([N:10]=[N:9][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: [O-][O-]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)N=NC1(OOC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Yield: 100.1 %

Procedure:
To a solution of 0.78 grams (.01 moles) of sodium peroxide in 30 ml. of methanol, cooled to 10° C in a 50 ml. erlenmeyer flask immersed in a cold water bath was added 4.3 grams (.0213 moles) of 1-t-butylazo-1-chlorocyclo-hexane dropwise and with rapid stirring holding the temperature at 10°-15° C. After the addition was complete, the reaction was stirred for 1 hour at 5° C. It was then poured in 250 ml. of ice cold water and the product extracted with pentane. The pentane layer was separated, washed with saturated (NH4)2SO4, water, saturated NaHCO3, water, dried, filtered and the pentane evaporated under reduced pressure to give 3.67 grams (85% yield) of crude di[1-(t-butylazo)cyclohexyl] peroxide. The infrared spectrum indicated the product was contaminated to a small extent by 1-t-butylazo-1-methoxy-cyclohexane which resulted from the chloro compound reacting to a small extent with the methanol solvent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C@H:13]1[CH2:18][NH:17][C@H:16]([CH3:19])[CH2:15][N:14]1[C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23].C(N(CC)CC)C>CCOC(C)=O>[CH3:12][C@H:13]1[CH2:18][N:17]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C@H:16]([CH3:19])[CH2:15][N:14]1[C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:23])[F:24]
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(F)cc1
Yield: 56 %

Procedure:
A solution of 4-fluorobenzene sulphonyl chloride (234 mg, 1.2 mmol) in EtOAc (10 ml) was added to a stirred mixture of (R)-[(2S,5R)-2-methyl-5-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (J. Med. Chem., 1999, 42, 2741-2746) (254 mg, 1.0 mmol) and triethylamine (0.17 ml, 1.2 mmol) in EtOAc (15 ml). The resultant mixture was stirred at ambient temperature for 2 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was recrystallized from EtOAc/hexane to give the title compound as a solid (230 mg, 0.56 mmol). Mp: 174-175° C.; NMR: 0.95 (d, 3H), 1.25 (d, 3H), 1.75 (s, 3H), 3.25 (dd, 1H), 3.35 (d, 1H), 3.5 (dd, 1H), 4.15 (m, 2H), 4.3 (s, 1H), 4.75 (s, 1H), 7.2 (d, 2H), 7.8 (d, 2H); m/z 411.
Reaction SMILES: Cl[C:2]([N:4]=[C:5]=[O:6])=[O:3].[CH2:7]([C:14]1[C:18]2[CH:19]=[CH:20][C:21](/[C:23](/[CH2:28][CH3:29])=[CH:24]\[CH2:25][NH:26][OH:27])=[CH:22][C:17]=2[O:16][C:15]=1[CH2:30][CH3:31])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1COCC1>[CH2:7]([C:14]1[C:18]2[CH:19]=[CH:20][C:21](/[C:23](/[CH2:28][CH3:29])=[CH:24]\[CH2:25][N:26]3[C:5](=[O:6])[NH:4][C:2](=[O:3])[O:27]3)=[CH:22][C:17]=2[O:16][C:15]=1[CH2:30][CH3:31])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC/C(=C/CNO)c1ccc2c(Cc3ccccc3)c(CC)oc2c1
Reactant: O=C=NC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC/C(=C/Cn1oc(=O)[nH]c1=O)c1ccc2c(Cc3ccccc3)c(CC)oc2c1
Temperature: -7.5 °C
Reaction time: 1 h

Procedure:
A solution of chlorocarbonyl isocyanate (0.31 mL; 3.88 mmol) in THF (5 mL) was added dropwise to the solution of Z-N-[3-(3-Benzyl-2-ethyl-benzofuran-6-yl)-pent-2-enyl]-hydroxylamine (1.3 g; 3.88 mmol) in THF (25 mL) at −10° C. The mixture was stirred for 1 hour at −10 to −5° C., and at 0° C. for 30 minutes, then poured over cold 1N HCl solution and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, dried over anhydrous magnesium sulfate and solvent evaporated. The residue was purified by flash chromatography over acid-treated silica gel using 2-5% ethyl acetate in hexane as an eluent. The title compound was obtained (0.82 g) as a white solid. mp: 118-120° C. Mass spectrum (APCI, [M+H]+) m/z 405. 1HNMR (400 MHz, DMSO-d6): δ 0.88 (t, 3H, J=7.32 Hz), 1.23 (t, 3H, J=7.56 Hz), 2.42 (q, 2H, J=7.80 Hz), 2.87 (q, 2H, J=7.32 Hz), 3.98 (s, 2H), 4.12 (d, 2H, J=6.83 Hz), 5.51 (t, 1H, J=6.59 Hz), 6.96 (dd, 1H, J=8.05, 1.46 Hz) 7.14-7.19 (m, 1H), 7.24-7.28 (m, 3H), 7.30 (d, 1H, J=1.0 Hz), 7.37 (d, 1H, J=7.81 Hz), 12.3 (s, 1H). Elemental Analysis for C24H24N2O4: Calculated: C, 71.27; H, 5.98, N, 6.93. Found: C, 71.17; H, 6.14, N, 6.83.
Reaction SMILES: CCN(CC)CC.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=1.Cl[CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>O1CCCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][CH2:19][CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: O=C(CCCl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](NCCC(=O)c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NEt3 (60 mL) followed by (S)-1-(4-chloro-phenyl)-ethylamine (20.5 g) was added to a solution of 3-chloro-1-phenyl-propan-1-one (23.2 g) in tetrahydrofuran (200 mL). The resulting mixture was stirred at room temperature overnight. Then, the solution was concentrated, water (100 mL) was added to the residue, and the resulting mixture was extracted with tert-butyl methyl ether. The combined organic extracts were washed with water and brine and dried (MgSO4). The title compound was obtained after removal of the solvent.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([O-:31])=[O:30]>>[CH:18]([N:13]1[C:12]([C:35]2[CH:36]=[CH:37][C:32]([N+:29]([O-:31])=[O:30])=[CH:33][CH:34]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: CC(C)n1nc2c(c1-c1ccc([N+](=O)[O-])cc1)CCNCC2
Yield: 17.7 %

Procedure:
The title compound (34 mg) was prepared according to Example 189 using 274 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 321 mg of 4-nitrophenylboronic acid. MS (ESI): exact mass calculated for C16H20N4O2, 300.16; found, m/z 301.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.42-8.40 (m, 2H), 7.62-7.60 (m, 2H), 4.37 (m, 1H), 3.43-3.41 (m, 2H), 3.21-3.18 (m, 2H), 2.82-2.79 (m, 2H), 1.41 (d, J=8.2 Hz, 6H).
Reaction SMILES: [OH-:1].[Na+].S(=O)(=O)(O)O.[C:8]([OH:11])(=O)[CH3:9]>>[OH:1][CH2:9][C:9]([C@@H:8]([C@H:8]([C@H:9]([CH2:8][OH:11])[OH:1])[OH:11])[OH:11])=[O:1]
Reactant: [OH-]
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(CO)[C@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Compound 10 was stirred in 30% acetic acid at 55° C. for 5 hours. The solution was brought to pH of about 10 with 10N sodium hydroxide and heated at 40° C. for 3 hours. The reaction mixture was acidified with 10N sulfuric acid and heated at 80° C. with stirring for 30 minutes. The reaction mixture was neutralized with 10N sodium hydroxide and the salt was removed by repeated precipitation with ethanol. After filtration, the filtrate was concentrated to give L-fructose as a syrup in more than 85% yield.
Reaction SMILES: [N:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]2[C:13]=1[CH2:14][CH2:15][C:16](=[O:24])[NH:17]2)=[O:2].[ClH:25].O>CO.[C].[Pd]>[OH2:2].[ClH:25].[NH2:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]2[C:13]=1[CH2:14][CH2:15][C:16](=[O:24])[NH:17]2.[NH2:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]2[C:13]=1[CH2:14][CH2:15][C:16](=[O:24])[NH:17]2.[ClH:25]
Reactant: COc1ccc(-c2nc3ccccn3c2N=O)c2c1NC(=O)CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc3ccccn3c2N)c2c1NC(=O)CC2

Procedure:
To a suspension of 5-(3-nitrosoimidazo[1,2-a]-pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril (20.85 g) in methanol (500 ml) was added 12 ml of concentrated hydrochloric acid to render the suspension acidic. 10% Palladium-carbon (2 g), was added to the suspension, and catalytic reduction was carried out at room temperature under atmospheric pressure. After completion of reaction, water was added to the reaction mixture to dissolve and the resulting mixture was heated. After removing the catalyst by filtration, the filtrate was concentrated to dryness. Acetone was added to the residue, and crystals which precipitated were collected by filtration and recrystallized from water to give 21.20 g of 5-(3-aminoimidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril monohydrochloride hemihydrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.Cl.[CH2:15]([O:17][C:18]([N:20]1[C:24]([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[N+:40]([O-:42])=[O:41])=[C:23]2[CH2:44][NH:45][C:46]([CH3:48])([CH3:47])[C:22]2=[N:21]1)=[O:19])[CH3:16].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:15]([O:17][C:18]([N:20]1[C:24]([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[N+:40]([O-:42])=[O:41])=[C:23]2[CH2:44][N:45]([S:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)(=[O:11])=[O:10])[C:46]([CH3:47])([CH3:48])[C:22]2=[N:21]1)=[O:19])[CH3:16]
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1[N+](=O)[O-])CNC2(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1[N+](=O)[O-])CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Reaction time: 4 h

Procedure:
3,5-difluoro-benzenesulfonyl chloride (1 eq., 3.9 g, 18.4 mmol) was added portion-wise to a stirred solution of 6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester dihydrochloride (10 g, 18.4 mmol) and N,N-diisopropylethylamine (6 eq, 19.3 mL, 110.4 mmol) in dry dichloromethane (100 mL) at room temperature. Stirring was continued for about 4 hours. The reaction mixture was diluted with dichloromethane (100 mL) then washed with saturated sodium hydrogen carbonate (150 mL), dried over sodium sulphate, evaporated to dryness and purified by flesh chromatography on silica gel using acetone as the eluant. The title compound was obtained as yellow solid (9 g, 65% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:19][CH2:18][CH2:17][CH:13]([C:14]([OH:16])=O)[CH2:12]1)=[O:4].Cl.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:14]([CH:13]3[CH2:17][CH2:18][CH2:19][N:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[C:3]([O:2][CH3:1])=[O:4])[CH2:12]3)=[O:16])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: NCc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COC(=O)c1ccccc1N1CCCC(C(=O)O)C1
Agent: Cl
Product: COC(=O)c1ccccc1N1CCCC(C(=O)NCc2ccc(-c3ccc(Cl)cc3)cc2)C1
Yield: 86.7 %

Procedure:
Using 1-[2-(methoxycarbonyl)phenyl]nipecotic acid (77.5 mg, 0.294 mmol) and (4′-chlorobiphenyl-4-yl)methylamine hydrochloride (72.2 mg, 0.284 mmol), the same procedure was followed as in Step 3a of Example 3 to give 114 mg (87%) of the desired compound as a colorless amorphous product.