Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][N:9]([CH2:12][C:13]#[CH:14])[CH2:8][CH2:7]1)=[O:5].C([O-])([O-])=O.[K+].[K+].C(Br)C=C>CN(C=O)C>[ClH:1].[OH:2][NH:3][C:4]([C:6]1([S:15]([C:18]2[CH:19]=[CH:20][C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][N:9]([CH2:12][CH:13]=[CH2:14])[CH2:8][CH2:7]1)=[O:5]
Reactant: C#CCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Sc3ccccc3)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: C=CCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Sc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Part A: To a solution of the amine hydrochloride salt of Example 9, part E (4.78 g, 10.8 mmol) in DMF (25 mL) were added K2CO3 (2.98 g, 21.6 mmol) and allyl bromide (0.935 mL, 10.8 mmol), and the solution was stirred for 5 hours at ambient temperature. The solution was partitioned between ethyl acetate and H2O, and the organic layer was washed with H2O and saturated NaCl, and dried over magnesium sulfate. Filtration through a pad of silica (hexane/ethyl acetate) provided the allyl amine as an oil (4.80 g, quantitative yield).
Reaction SMILES: C(O)(=O)C.N1C=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:15]=[C:14]([C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][NH2:37])=[CH:32][CH:31]=3)[N:26]=2)[CH:13]=1.COC1CCC(OC)O1>O>[CH3:11][C:12]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[N:15]=[C:14]([C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:31]=[CH:32][C:33]([CH2:36][N:37]4[CH:9]=[CH:8][CH:7]=[CH:6]4)=[CH:34][CH:35]=3)[N:26]=2)[CH:13]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(CN)cc4)no3)cc2C)cc1
Reactant: c1ccncc1
Agent: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(Cn5cccc5)cc4)no3)cc2C)cc1
Temperature: 100 °C
Yield: 32.4 %

Procedure:
To a solution of acetic acid (348 μL, 6.08 mmol) in water (194 μL) were added successively pyridine (491 μL, 6.08 mmol), 1-(4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}phenyl)methanamine (Example 139, 130 mg, 0.362 mmol) and 2,5-dimethoxytetrahydrofuran (47 μL, 0.362 mmol). The reaction mixture was heated to 100° C. for 20 h. After being cooled to rt, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the crude product was first subjected to MPLC (silica, cyclohexane/ethyl acetate 4:1) and then to preparative HPLC affording the title compound as a white solid (48 mg, 31%): NMR (400 MHz, DMSO-d6) 8.02 (d, 2H), 7.35 (d, 2H), 7.18 (d, 2H), 7.11 (d, 2H), 6.91 (s, 1H), 6.86 (t, 2H), 6.05 (t, 2H), 5.42 (s, 2H), 5.21 (s, 2H), 2.32 (s, 3H), 2.27 (s, 3H); ES-MS m/z 410, HPLC RT (Method K) 1.54 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:17]=1)=[O:6]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2cccc(F)c2)cc1
Yield: 42 %

Procedure:
In a manner similar to that described in Example 3, 3-fluorobenzoyl chloride (0.053 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol) (Example 1, Step (c)), and the resulting intermediate was hydrolyzed to give 0.0331 g of 4-[4-(3-fluoro-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; mp 239-241° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: OCCSc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CS(=O)(=O)OCCSc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 117.97 g (0.53 mole) of 2-[(3,4-dichlorophenyl)thio]ethanol (prepared by reacting 3,4-dichlorothiophenol and 2-chloroethanol) and 53.5 g (0.53 mole) of triethylamine in 500 ml of benzene was added dropwise a benzene solution of 60.9 g (0.53 mole) of methanesulfonyl chloride over a one hour period with cooling in an ice bath. The reaction mixture was stirred at room temperature overnight and filtered. Solvent was removed from the filtrate in a rotary evaporator to give an oil which crystallized. A portion was recrystallized from isopropyl ether to give white crystalline solid, m.p. 53°-55° C.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14]([C:18]1[CH:43]=[CH:42][C:21]([O:22][C:23]2[CH:32]=[C:31]3[C:26]([CH:27]=[C:28]([C:39](Cl)=[O:40])[N:29]=[C:30]3[CH2:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[CH2:6]([N:5]([CH2:4][C:3]([OH:2])=[O:13])[C:39]([C:28]1[N:29]=[C:30]([CH2:33][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)[C:31]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([O:22][C:21]1[CH:42]=[CH:43][C:18]([C:14]([CH3:16])([CH3:17])[CH3:15])=[CH:19][CH:20]=1)[CH:32]=2)=[O:40])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)Cl)nc(CC4CCCC4)c3c2)cc1
Reactant: COC(=O)CNCc1ccccc1
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N(CC(=O)O)Cc4ccccc4)nc(CC4CCCC4)c3c2)cc1
Yield: 70.8 %

Procedure:
The title compound (39 mg) was prepared following the same procedures that was described for example 432 from benzyl glycine methyl ester (17.9 mg, 0.1 mmol) and 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl chloride (46 mg, 0.1 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]([CH3:29])([CH2:16][N:17]1[N:21]=[C:20]2[C:22]([Br:28])=[CH:23][C:24]([Cl:27])=[C:25]([Br:26])[C:19]2=[N:18]1)[C:14]#[N:15]>C1COCC1>[Cl:27][C:24]1[CH:23]=[C:22]([Br:28])[C:20]2=[N:21][N:17]([CH2:16][C:13]([NH:12][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)([C:14]#[N:15])[CH3:29])[N:18]=[C:19]2[C:25]=1[Br:26]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2c(Br)cc(Cl)c(Br)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Br)cc(Cl)c(Br)c2n1)NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-cyanobenzoyl chloride (0.16 mmole) in THF was added to a solution of 2-amino-3-(5-chloro-4,7-dibromo-2H-benzotriazol-2-yl)-2-methylpropionitrile (0.075 mmole, described in Example 53) in THF mixed with TEA (3% v./v.). The reaction mixture was stirred 12 hours at room temperature then heated to 45° C. for 6 hours before solvent was evaporated under reduced pressure. The resulting crude product was dissolved in DMSO and purify by semi-preparative HPLC. The desired fractions were collected and evaporated under reduced pressure. The title compound was isolated as solid residue (10.8 mg) that was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=521, RT=0.66 min.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O[NH2:13])(=O)=O.[Br:15][C:16]1[CH:21]=[N:20][C:19]([C:22]#[C:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:18][N:17]=1.C([O-])([O-])=O.[K+].[K+].NN1C=CN=CC1>C(Cl)Cl.CN(C=O)C>[Br:15][C:16]1[N:17]=[CH:18][C:19]2[N:20]([N:13]=[C:23]([Si:24]([CH3:26])([CH3:25])[CH3:27])[CH:22]=2)[CH:21]=1
Reactant: C[Si](C)(C)C#Cc1cnc(Br)cn1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: NN1C=CN=CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[Si](C)(C)c1cc2cnc(Br)cn2n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 7.6 %

Procedure:
O-(Mesitylenesulfonyl)hydroxylamine (680 mg, 3.2 mmol) was added in one portion to a stirred solution of 2-bromo-5-trimethylsilanylethynyl-pyrazine (Step 1, 3 mmol) in CH2Cl2 (3 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes, at RT for 4 hours, then evaporated. The N-amino adduct was used without further manipulation. K2CO3 (410 mg, 3 mmol) was added to a stirred solution of the N-aminopyrazine from above in dry DMF (5 ml) at RT under nitrogen. After 6 hours the mixture was partitioned between EtOAc/H2O. The organic layer was washed with brine (×2), then evaporated. The residue was taken up in CH2Cl2 and passed through a phase separating cartridge. The filtrate was evaporated and the residue was purified by chromatography on silica (2→4% EtOAc/Petrol) to give the title compound (62 mg, oil) MS: [M+H]+ 270/272.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:6]
Reactant: Nc1cccnc1
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Nc1c(Br)cccc1C(=O)Nc1cccnc1
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of 2-amino-3-bromobenzoic acid (Aldrich; 2.00 g, 9.26 mmol) and 3-aminopyridine (Aldrich; 0.871 g, 9.26 mmol) in 10 mL EtOAc was added DIPEA (1.93 mL, 11.11 mmol) followed by 1-propanephosphonic acid cyclic anhydride (T3P) (50 wt. % solution in EtOAc; Matrix Scientific; 6.00 mL, 10.18 mmol). The reaction became warm and after 5 min a thick precipitate formed. The reaction was stirred overnight. The reaction was treated with sat'd aq. NaHCO3 and EtOAc. The organic layer was washed 1× sat'd aq. NaHCO3, 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 2-amino-3-bromo-N-(pyridin-3-yl)benzamide (2.13, 7.29 mmol, 79% yield) as a yellow solid used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (1H, s), 8.87 (1H, d, J=2.2 Hz), 8.31 (1H, dd, J=4.6, 1.5 Hz), 8.08-8.14 (1H, m), 7.71 (1H, dd, J=7.8, 1.4 Hz), 7.62 (1H, dd, J=7.8, 1.4 Hz), 7.39 (1H, dd, J=8.2, 4.7 Hz), 6.57-6.71 (1H, m), 6.36 (2H, s). m/z (ESI, +ve) 291.9/293.9 (M+H)+.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.Cl.[C:46]([O:50][C:51](=[O:54])[CH2:52][NH2:53])([CH3:49])([CH3:48])[CH3:47]>C(N(CC)CC)C>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)=[O:30])=[CH:24][CH:23]=3)[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:53][CH2:52][C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:54])[CH2:19][CH2:20]3)[N:14]=1)[CH2:4]2
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (60 mg) and glycine tert-butyl ester hydrochloride (33 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118, the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 616.9 (M+H)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[CH3:10][N:11]([CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20])[CH3:12].[Cl-].[NH4+]>CCOCC>[ClH:9].[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([C:15]2([OH:20])[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]2[CH:13]([N:11]([CH3:10])[CH3:12])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:4][CH:5]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)c1ccc(Cl)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 110.2 %

Procedure:
0.63 g (25.9 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 4.97 g (25.9 mmole) of 4-bromochlorobenzene dissolved in 30 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was boiled for a further hour at RT. 5.0 g (21.6 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 40 ml of saturated ammonium chloride solution while cooling in an ice bath, and extracted three times at RT with in each case 100 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 7.24 g of crude base (97.4% of theory) were obtained. 5.43 g of 1-(4-chlorophenyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (66.0%) of theory) were obtained from the crude base according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 175° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12]Cl)[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].C(N(CC)CC)C.O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH:27][CH2:12][CH2:11][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH2:3][CH2:2][CH2:1]2
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Reactant: ClCCOc1cccc2c1CCC2
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4c3CCC4)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 30.3 %

Procedure:
A solution of 2-(indan4-yloxy)-ethylchloride (0.58 g, 2.9 mmol), 3-(5-fluoro-1H-indol-3-yl)-propylamine (1.4 g, 7.4 mmol) and triethylamine (1 ml, 7.4 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 12 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×100 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (7% methanol-methylene choride) afforded 0.31 g (30%) of product as a brown oil.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])=O.[NH3:9]>[Co].[H][H]>[NH2:9][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].[NH2:9][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8]
Reactant: N#CCCCCC=O
Reactant: N
Reactant: [H][H]
Agent: [Co]
Product: N#CCCCCCN
Product: NCCCCCCN
Temperature: 100 °C
Reaction time: 20 h
Yield: 56 %

Procedure:
In the autoclave described in Example 1 there were placed 32 g of 5-formylvaleronitrile and 10 g of cobalt catalyst under argon. The autoclave was then sealed and 130 ml of ammonia were forced in. The mixture was stirred using a magnetic stirrer and was heated to 100° C. and the overall pressure raised to 100 bar by forcing in hydrogen and then kept at this value by continuous replenishment with hydrogen. After a period of 20 hours the autoclave was depressurized and the hydrogenation effluent analyzed by gas chromatography. The products formed comprised 56% of 6-aminocapronitrile and 6% of hexamethylene diamine (conversion 100%).
Reaction SMILES: [NH:1]1[C:9](=[O:10])[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.[O:11]=[O:12]>>[OH:11][OH:12].[NH:1]1[C:9](=[O:10])[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[NH:3][C:2]1=[O:11].[O:11]=[O:12]
Reactant: O=c1[nH]cnc2nc[nH]c12
Agent: O=O
Product: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Product: OO

Procedure:
The enzyme catalyzes the oxidation of hypoxanthine in the presence of oxygen as the acceptor to form stoichiometrically xanthine and hydrogen peroxide, and catalyzes the oxidation of xanthine in the presence of oxygen as an acceptor to form stoichiometrically uric acid and hydrogen peroxide.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.CCO.O>[Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: C[C@H]1O[C@@H](n2c(Br)nc3ccc(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
A mixture of 0.44 g (1 mmol) of 2-bromo-6-chloro-1-(2,3-di-O-acetyl-5-deoxy-β-D-ribofuranosyl)-1H-benzimidazole and 0.17 g (1.6 mmol) of sodium carbonate in 8 mL of MeOH, 8 mL of EtOH and 2 mL of water was stirred at room temperature for 6 h. The reaction mixture was concentrated and redissolved in 50 mL of EtOAc. After 2 washings with saturated brine, the EtOAc solution was dried over MgSO4. Solvent removal resulted in a crude product which was flash column chromatographed on silica gel with EtOAc/hexane (1:1) to give 0.24 g (69%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ1.4 (d, 3H, CH3), 3.8-3.9 (m, 1H, CH), 3.9-4 (m, 1H, CH), 4.45 (q, 1H, CH), 5.21 (d 1H, OH), 5.45 (d, 1H, OH), 5.8 (d, 1H, CH), 7.3 (d, 1H, aromatic), 7.6 (s,1H, aromatic), 7.62 (d, 1H, aromatic).
Reaction SMILES: [CH:1]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+:20]([C:23]1[CH:24]=[C:25]([OH:31])[C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)([O-:22])=[O:21].[CH2:32]1[O:34][C@H:33]1CO>C1COCC1>[CH3:1][O:31][C:25]1[CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][C@H:33]1[CH2:32][O:34]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: OC[C@H]1CO1
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of Ph3P (23.3 g; 88.7 mmol) in 450 mL of THF cooled to 0° C. was added a solution of di-t-butylazodicarboxylate (20.4 g; 88.7 mmol) in 50 ml of THF over 15 min. After stirring at 0° C. for 10 min 4-nitroguaiacol (10.0 g; 59.1 mmol) was added followed by (S)-glycidol (6.3 mL; 94.6 mmol) over 10 min and the mixture allowed to warm to rt and stir for 2 h. The solution was concentrated and the residue dissolved in EtOAc, washed with H2O and brine, dried over anhydrous MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, Hexanes/EtOAc; 100:0 to 1:3 gradient). Impure fractions were concentrated under reduced pressure and the residue further purified by flash chromatography (silica gel, Hexanes/EtOAc; 100:0 to 0:100 gradient). Pure fractions from both purifications were combined and concentrated under reduced pressure to afford 9.58 g (72%) of the title compound as a yellow solid. 1H NMR (CDCl3) δ 2.78-2.80 (m, 1H), 2.94-2.96 (m, 1H), 3.40-3.43 (m, 1H), 3.96 (s, 3H), 4.06-4.11 (m, 1H), 4.41-4.44 (m, 1H), 6.98 (d, J=8.79 Hz, 1H), 7.75 (d, J=2.20 Hz, 1H), 7.89 (dd, J=8.79 Hz, 2.19 Hz, 1H); 13C NMR (CDCl3) δ 28.20, 44.57, 49.75, 56.28, 70.17, 106.80, 111.71, 117.50, 141.92, 149.20, 153.38; HPLC (Method #1) 2.09 min retention time; LCMS (ES): m/z 226 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[NH2:13])=[CH:7][CH:6]=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=2)[CH:31]=[CH:30]1>>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]([NH:13][C@@H:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH2:11][C:8]3[CH:7]=[CH:6][N:5]=[CH:10][CH:9]=3)=[O:39])[CH:36]=2)[CH:31]=[CH:30]1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)Cc3ccncc3)CC2)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3ccncc3)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(4-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and indole-6-carboxylic acid (50%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([F:16])([F:15])[F:14])[CH:10]([CH:17]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([F:16])([F:15])[F:14])[CH:10]([CH2:17][N:29]2[CH2:30][CH2:31][CH:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[CH2:27][CH2:28]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1C(F)(F)F
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Fc1ccc(C2CCN(CC3CN(Cc4ccccc4)CC3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 702.8 %

Procedure:
To a solution of 1.46 g (5.6 mmol) of 1-benzyl-3-(RS)-formyl-4-(RS)-trifluoromethylpyrrolidine and 0.13 g (0.67 mmol) of 4-(4-fluorophenyl)piperidine (Example 1, Step 1) in 30 mL of dichloroethane at rt was added 2.37 g (11.2 mmol) of sodium triacetoxyborohydride. After stirring for 18 h at rt, the reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, acetone:hexanes, 1:8) to give 1.98 g of the title compound.
Reaction SMILES: [C:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([O:10][C@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>CCOC(C)=O>[Cl-:26].[O:29]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][N+:13]12[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]1)[C@H:11]([O:10][C:8](=[O:9])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12]2
Reactant: O=C(O[C@@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccccc1
Reactant: O=C(CCl)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@H](OC(=O)C(Nc1ccccc1)c1ccccc1)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
To a solution of (S)-quinuclidin-3-yl 2-phenyl-2-(phenylamino)acetate (50.0 mg, 0.15 mmol) in EtOAc (2 mL), is added 2-chloro-1-phenylethanone (23.0 mg, 0.15 mmol) and the reaction is stirred first at RT for 15 hours, then at 70° C. for 7 hours and finally at RT for 3 days. The solvent is removed and the resulting crude is triturated with i-Pr2O/Et2O (3/1) and then with i-Pr2O to achieve the title compound as a beige solid (47.7 mg, 65% yield, chloride salt, mixture of diastereoisomers).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=O)[CH2:5][Cl:6].[CH3:12][NH:13][C:14](=[S:17])[NH:15][NH2:16]>CO>[ClH:6].[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]1[CH2:5][S:17][C:14]([NH:13][CH3:12])=[N:15][N:16]=1
Reactant: O=C(CCl)c1ccccc1F
Reactant: CNC(=S)NN
Solvent: CO
Product: CNC1=NN=C(c2ccccc2F)CS1
Product: Cl
Yield: 52 %

Procedure:
8.62 g (0.05 mole) of 2 -fluorophenacyl chloride and 5.22 g of 4-methyl-thiosemicarbazide are reacted in 150 ml of methanol under the conditions of Example 2. The product is recrystallized from methanol/ethyl acetate, yielding 6.7 g of 5-(2-fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 183°-184° C.