Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:4][NH:5][C:6]=1[S:7][CH3:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]([CH2:23][C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)=[O:25])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CSc1[nH]nc(-c2ccc(F)cc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CSc1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(-c2ccc(F)cc2)c1Cl

Procedure:
Protocol T was followed using 4-Chloro-3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.82-7.88 (m, 2H), 7.06-7.12 (m, 2H), 6.96-7.1 (m, 2H), 6.88-6.92 (m, 2H), 5.2 (s, 2H), 3.68-3.84 (m, 4H), 3.06-3.18 (m, 4H), 2.4 (s, 3H). 13C NMR (400 MHz, CDCl3): 164.8, 158, 147, 135, 127.4, 127, 119, 112.4, 112.2, 110, 108.8, 52.8, 52, 51.8, 45.4, 42.2, 18.6.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]2[N:9]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[NH:12]3)=[CH:4][CH:3]=1.[CH2:33](I)[CH:34]([CH3:36])[CH3:35].IC1CCCC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[N:9]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=3)[N:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]3[CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:31][CH:32]=1
Reactant: Cn1c(=O)[nH]c2nn(Cc3ccc(C(F)(F)F)cc3)c(NCc3ccc(F)cc3)c2c1=O
Reactant: CC(C)CI
Agent: IC1CCCC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(NCc3ccc(F)cc3)n(Cc3ccc(C(F)(F)F)cc3)nc21

Procedure:
The synthesis method is analogous to example 7 wherein 3-(4-fluorobenzylamino)-5-methyl-2-(4-(trifluoromethyl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione is used instead of 5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione, and isobutyl iodide is added instead of iodocyclopentane. MS (ESI) m/z 490.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[NH:7][C:6]=2[CH:5]=[C:4]([Cl:15])[CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[CH:44]1[O:56][C@H:55]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[C@@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@H:45]1[O:46][C:47](=[O:49])[CH3:48])(=O)C>ClCCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:13])[CH3:14])[N:7]([C@H:44]3[O:56][C@@H:55]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[C@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@@H:45]3[O:46][C:47](=[O:49])[CH3:48])[C:6]=2[CH:5]=[C:4]([Cl:15])[CH:3]=1
Reactant: CC(C)Nc1nc2c(Cl)cc(Cl)cc2[nH]1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)OC[C@@H]1O[C@H](n2c(NC(C)C)nc3c(Cl)cc(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 36.9 %

Procedure:
4,6-Dichloro-2-(isopropylamino)-1H-benzimidazole (0.83 g, 3.40 mmol), N,O-bis(trimethylsilyl)acetamide (0.88 mL, 0.72 g, 3.56 mmol), trimethylsilyl trifluoromethanesulfonate (0.43 mL, 0.49 g, 2.20 mmol), 1,2,3,5-tetra-O-acetyl-ribofuranose (1.31 g, 4.12 mmol) and 1,2-dichloroethane (10 mL) were used according to general procedure II. The product was purified by silica gel chromatography using 60:1 dichloromethane/methanol to afford 0.63 g (37%) of a white foam. MS (CI): m/z 502.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[Si:19]([O:26][CH2:27][C@H:28]([OH:34])[CH2:29][O:30][CH:31]([CH3:33])[CH3:32])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[H-].[Na+]>C1COCC1>[Si:19]([O:26][CH2:27][C@@H:28]([CH2:29][O:30][CH:31]([CH3:33])[CH3:32])[O:34][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: CC(C)OC[C@@H](O)CO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)OC[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (product of example 1 step ii) (0.46 g), (2R)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-isopropoxypropan-2-ol (product of step (0.66 g), THF (5 mL) and 60% sodium hydride (80 mg), to give the subtitle compound as a colourless oil. Yield: 0.56 g
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)O1>>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccc([N+](=O)[O-])cc3)nc2c1
Yield: 25.1 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (144.4 mg, 0.58 mmol, 2.00 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) afforded 27 mg (24%) of 3-(4-nitrophenyl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1]([NH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].C1COCC1.Br[CH2:19][C:20]([N:22]([CH2:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)=[O:29])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>CN(C=O)C.CC(C)([O-])C.[K+]>[CH2:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:38][CH2:39][N:30]1[C:28](=[O:29])[CH2:27][N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:20]([CH2:19][N:3]([C:1]#[N:2])[C:4](=[O:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:21]
Reactant: CC(C)CN(CC(=O)N1CCc2ccccc2C1)C(=O)CBr
Reactant: N#CNC(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CN(CC(=O)N1CCc2ccccc2C1)C(=O)CN(C#N)C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 12.2 %

Procedure:
To a stirred solution of N-cyano-2-phenyl-acetamide (0.15 g, 0.9 mmol) (see Example 1) in DMF (5.0 mL), potassium tert-butoxide (0.9 mL of a 1.0 M THF solution, 0.9 mmol) was added dropwise at 0° C., under argon. The resulting mixture was stirred at 0° C. for 20 min, then at ambient temperature for 15 min. After this time, the resulting anion was added dropwise to a stirred solution of the 2-bromo-N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-N-isobutyl-acetamide (0.34 g, 0.9 mmol) from above in DMF (5.0 mL) at room temperature, under argon. Upon complete addition, the reaction was stirred at room temperature for 1.5 h, then warmed to 40° C. for 6 h. The reaction was cooled to room temperature and stirred for 48 h after which time it was concentrated to dryness. The resulting residue was dissolved in EtOAc and washed with 5% citric acid (aqueous). The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via reverse phase HPLC (C18 column, 20-100% CH3CN/H2O over 20 min at a flow rate of 20 mL/min, UV detection was at 220 nm). Retention time of the product was 16 min. Product-containing fractions were concentrated to give 49 mg (12%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[S:10][C:6]=2[CH:5]=1)([O-])=O>CS(C)=O.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[S:10][C:6]=2[CH:5]=1
Reactant: O=C(Nc1nc2ccc([N+](=O)[O-])cc2s1)c1cccnc1
Agent: [Pd]
Solvent: CS(C)=O
Product: Nc1ccc2nc(NC(=O)c3cccnc3)sc2c1
Reaction time: 5.5 h
Yield: 100 %

Procedure:
N-(6-Nitrobenzothiazol-2-yl)nicotinamide (0.50 g, 1.67 mmol) was dissolved in dimethylsulfoxide (50 mL) by warming. After addition of palladium on charcoal (0.089 g, 10% Pd, 0.08 mmol Pd), the rntrre ,shydrogened for 5.5 h at 80° C. The palladium was removed by hot filtration through a pad of silica. After removal of the solvent, N-(6-aminobenzothiazol-2-yl)nicotinamide (0145 g, 1.67 mmol, 100%) was obtained as a brownish solid. LC/ESI-MS: m/z=271 [M+H]+; m/z=269 [M−H]−; Rt=1.67 min.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.CN(C)C=O>[Ni].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:22][CH:23]=1
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Ni]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1

Procedure:
A 19.2 g portion of 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one was dissolved in a mixed solvent consisting of 200 ml of dimethylformamide and 100 ml of methyl alcohol, and 3 ml of Raney nickel was added to the resulting solution to carry out hydrogenation at normal pressure. After completion of the hydrogen absorption, the reaction solution was filtered and concentrated. The thus obtained residue was dissolved in dichloromethane and then washed with a saturated sodium bicarbonate aqueous solution. The resulting dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The thus obtained residue was recrystallized from methyl alcohol to obtain 15.5 g of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]([OH:22])[C@H:12]1[O:17]C(O)[C@H:14]([OH:18])[C@H:13]1[N:19]=[N+:20]=[N-:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+].C([O-])(O)=O.[Na+]>>[C:1]([O:9][CH2:10][C@H:11]1[O:22][CH:14]([OH:18])[C@@H:13]([N:19]=[N+:20]=[N-:21])[C@@H:12]1[OH:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=N[C@H]1[C@@H]([C@H](O)COC(=O)c2ccccc2)OC(O)[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: [N-]=[N+]=N[C@@H]1C(O)O[C@H](COC(=O)c2ccccc2)[C@H]1O
Reaction time: 3 h

Procedure:
Benzoylation of 1,2-O-isopropylidene-3-azido-3-deoxy-α-D-glucofuranose with 1.05 molar equivalent of benzoyl chloride gives a greater than 90% yield of 1,2-O-isopropylidene-6-O-benzoyl-3-azido-3-deoxy-α-D-glucofuranose (1). A sample of 1 is purified on silica gel (CHCl3 -ether; 3:1), NMR (CDCl3, TMS internal standard) 7.36-8.18 (2m, 5, aromatic), 5.93 (d, l, J1,2 =3.5 Hz, H-1), 4.67 (d, l, J1,2 =3.5 Hz, H-2), 4.25-4.80 (m, 5, H-3,4,5,6), 1.50, 1.33 (2s, 6, 2CH3). Crude 1, which contains a small amount of 5,6-di-O-benzoate and a trace of 5-O-benzoate derivatives, is hydrolyzed in dioxane-water (1:1) with Dowex 50 [H+ ] ion exchange resin to give 6-O-benzoyl-3-azido-3-deoxy-D-glucofuranose (2). Compound 2, which gives a poorly resolved NMR spectrum, is oxidized with sodium metaperiodate at 22-28 degrees C. for 3 hr., followed by treatment with NaHCO3 (to hydrolyze the formyl group) overnight to give 5-O-benzoyl-2-azido-2-deoxy-D-arabinofuranose (3), which is purified by silica gel chromatography (CH2Cl2 -ether; 3:1).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][C:5]#[CH:6])[CH3:2].[CH2:9]=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCOCC1>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][C:5]#[C:6][CH2:9][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:2]
Reactant: C#CCN(CC)CC
Reactant: C=O
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: CCN(CC)CC#CCN1CCCC1
Reaction time: 8 h

Procedure:
Following the procedure given in Example 1B, 7.8 g. (0.07 mole) of diethylpropargylamine, 3.8 g. of paraformaldehyde, 5.7 g. (0.08 mole) of pyrrolidine, and a trace of cuprous chloride in 80 ml. of dioxane was refluxed for 4 hours and allowed to stand overnight. After distillation and redistillation, the product, 1-[4-(diethylamino)-2-butynyl]pyrrolidine was obtained as a clear oil boiling at 68.0° C. at 0.05 mm.; ND25 = 1.4770.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[CH:11][NH:10][N:9]=1.[Br:13]Br>C(O)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([Br:13])=[CH:11][NH:10][N:9]=1
Reactant: Clc1ccccc1-c1cc[nH]n1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccccc1-c1n[nH]cc1Br
Temperature: 25 °C
Yield: 65.3 %

Procedure:
3.5 g of 3-(2-chlorophenyl)-1H-pyrazole, prepared as in Example 9, are dissolved, at room temperature and with stirring, in 20 ml of acetic acid. A solution of 3.76 g (0.0235 mol) of bromine in 20 ml of acetic acid is then run dropwise into the reaction mixture. Stirring is maintained for 1 hour at room temperature and then the acetic acid and the excess bromine are driven off under reduced pressure. The residue is taken up in methylene chloride and this organic solution is washed with an aqueous bicarbonate solution, then with water and then dried over MgSO4 before being concentrated to dryness. The residue is recrystallised from pentane. 3.3 g (0.0128 mol) of 3-(2'-chlorophenyl)-4-bromo-1H-pyrazole are obtained, which melts at 80° C. (yield 65%) (compound 94)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)=CC=1.[N:22]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[C:23]=[O:24]>>[C:25]1([N:22]2[CH2:12][CH2:13][C@H:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:21][C:23]2=[O:24])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H](O)c2ccccc2)cc1
Reactant: O=C=Nc1cccc2ccccc12
Product: O=C1O[C@@H](c2ccccc2)CCN1c1cccc2ccccc12

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 2 using (R)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate and 1-isocyanatonaphthalene. LC-MS (10-80) tR=2.625 min, m/z=304; 1H NMR (CDCl3) δ 2.44-2.55 (m, 3H), 3.64-3.69 (m, 1H), 3.84-3.91 (m, 1H), 5.62-5.72 (m, 1 H), 7.38-7.61 (m, 9H), 7.86-7.93 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[C@H:14]([CH3:25])[CH2:13]2)(=[O:11])=[O:10])=[C:5]([CH3:26])[CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[CH3:26][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[S:9]([N:12]1[CH2:17][CH2:16][NH:15][C@H:14]([CH3:25])[CH2:13]1)(=[O:11])=[O:10])[C:1]#[N:2]
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN[C@H](C)C1
Yield: 95.7 %

Procedure:
A solution of 1,1-dimethylethyl (2R)-4-[(4-cyano-2-methylphenyl)sulfonyl]-2-methyl-1-piperazinecarboxylate (may be prepared as described in Description 19) (3.24 g, 8.54 mmol) and TFA (7.00 ml, 91.0 mmol) in dry DCM (10 ml) was stirred at rt for 1 h, then concentrated under vacuum, azetroping with toluene (25 ml) to give an orange oil. This was redissolved in MeOH (10 ml) then applied to an SCX-2 cartridge (50 g), washing with MeOH. The product was eluted with 2M NH3 in MeOH; concentration under vacuum gave the title compound as a pale orange oil (8.17 mmol).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:17]1[C:22]([NH2:23])=[CH:21][N:20]=[CH:19][N:18]=1>O1CCCC1>[NH2:23][C:22]1[C:17]([O:15][CH:12]2[CH2:13][CH2:14][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11]2)=[N:18][CH:19]=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Nc1cncnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncncc2N)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
At room temperature, NaH (71 mg, 2.94 mmol) was added to a solution of tert-butyl-3-hydroxypyrrolidine-1-carboxylate (1B2) (500 mg, 2.67 mmol) in THF (tetrahydrofuran) (10 mL) and stirred for 1 hour. 4-chloropyrimidin-5-amine (H) (348 mg, 2.67 mmol) was then added. The reaction mixture was then heated to 100° C. under nitrogen and stirred for 4 hours, cooled to room temperature (20-30° C.) and concentrated in vacuo. The residue was purified with flash column (eluent: 10-30% ethyl acetate/petroleum ether) to obtain the product 1D3 (336 mg, 1.2 mmol).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9](=[NH:12])[CH2:10][SH:11])[CH2:4]1.C1(S([C:21]2[CH:22]([CH3:45])[C@@H:23]3[C@@H:40]([C@H:41]([OH:43])[CH3:42])[C:39](=[O:44])[N:24]3[C:25]=2[C:26]([O:28]CC2C=CC([N+]([O-])=O)=CC=2)=[O:27])=O)C=CC=CC=1.C(OCC)C>CS(C)=O.C(#N)C>[O:2]=[C:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9](=[NH:12])[CH2:10][S:11][C:21]2[C@H:22]([CH3:45])[C@@H:23]3[C@@H:40]([C@H:41]([OH:43])[CH3:42])[C:39](=[O:44])[N:24]3[C:25]=2[C:26]([OH:28])=[O:27])[CH2:4]1
Reactant: N=C(CS)N1CCNC(=O)C1
Reactant: CC1C(S(=O)c2ccccc2)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Agent: Cl
Solvent: CC#N
Solvent: CS(C)=O
Solvent: CCOCC
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCC(=N)N3CCNC(=O)C3)[C@H](C)[C@H]12
Reaction time: 0.5 h

Procedure:
A suspension of 108 mg of 2-(3-oxopiperazin-1-yl)-2-iminoethylmercaptan hydrochloride in 0.8 ml of dimethyl sulfoxide was added, under ice-cooling, to a solution of 130 mg of p-nitrobenzyl (1RS,5S,6S)-2-phenylsulfinyl-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate in 1.4 ml of acetonitrile, and the mixture was stirred for 30 minutes. The reaction mixture was then poured into 50 ml of anhydrous diethyl ether, and the solvent was decanted off. The oily residue was dissolved in a mixture of 8 ml of tetrahydrofuran, 2.7 ml of water and 9.4 ml of 0.1M phosphate buffer solution (pH 7.0), and the resulting solution was subjected to catalytic hydrogenation at room temperature for 2 hours in the presence of 160 mg of palladium-carbon. The insolubles were filtered off over "Celite" (Trade Mark) filter aid, and the filtrate was extracted twice with 30 ml portions of diethyl ether. The aqueous phase was concentrated by evaporation under reduced pressure and the residue was purified through a Lobar column (Merck "LiChloprep RP-8", size B, two columns), eluted with 5% aqueous methanol, to give the title compound having the same properties as those of the product obtained in Example 13.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1[N:20]=CC(COP(O)(O)=O)=C(C=O)C=1O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC1CCN(Cc2ccccc2)C1

Procedure:
In the same manner as in Example 12, a cell-dispersion solution was prepared. Into a flask in which substrates, that is, 900 mg of 1-benzyl-3-pyrrolidinone and 928.2 mg of (S)-α-phenethylamine were added in advance, 3 ml of the cell-dispersion solution, 3.7 mg of pyridoxal phosphate, and 3 mL of a 1M potassium phosphate buffer (pH 6.8) were introduced. The whole volume was adjusted to 30 mL by adding deionized water therein. This was reacted at 30° C. for 16 hours with stirring. After the reaction is completed, 1-benzyl-3-aminopyrrolidine thus produced in the reaction mixture was analyzed via HPLC with the conditions described below. This showed that 1-benzyl-3-aminopyrrolidine was produced with a conversion rate of 75.1%, and it had a (S) configuration and optical purity of 79.2% e.e.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[F:28][C:29]([F:34])([F:33])[C:30](=[O:32])[CH3:31]>C1COCC1>[F:28][C:29]([F:34])([F:33])[C:30]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)([OH:32])[CH3:31]
Reactant: O=S(=O)(c1ccccc1)N1CCN(c2ccc(Br)cc2)CC1
Reactant: CC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3ccccc3)CC2)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
A 250 ml, round-bottomed flask was charged with 1-(4-bromophenyl)-4-(phenylsulfonyl)piperazine (0.50 g, 1.31 mmol) and 20 mL of THF. After cooling to −78° C., n-BuLi (0.603 mL, 2.5 M in hexanes, 1.51 mmol) was slowly added. The mixture was stirred at −78° C. for 30 min, then 1,1,1-trifluoro-2-propanone (0.441 g, 3.93 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. The reaction was stirred at −78° C. for 1 h, and then quenched with saturated aqueous NH4Cl (15 mL). The organics were extracted with EtOAc (2×50 mL), dried (MgSO4), and concentrated to give an oil. Purification via column chromatography (40 g of silica, 0 to 40% EtOAc in hexanes) produced 1,1,1-trifluoro-2-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.215 g) as a mixture of two enantiomers.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:27][C:26]=2[F:45])[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(O)C>C(OCC)(=O)C>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]([C:19]([F:20])([F:22])[F:21])=[C:10]([N:8]2[C:7](=[O:23])[N:6]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[S:37](=[O:43])(=[O:44])[NH:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[CH:27][C:26]=3[F:45])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9]2)[CH:15]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 91 %

Procedure:
Hydrogenation of 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluoro-biphenyl-4-yl]methyl]-2,4-dihydro-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 84, Step D) was carried out according to the procedure of Example 75, Step D, except that a 4:1 ratio of ethanol and ethyl acetate was used as solvent. The title compound was obtained in 91% yield oas an off-white foam, suitable for use without further purification; nearly homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 626 (M+Li)+.