Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:12]([N+:23]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1>CO.[Ni]>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:31](=[O:32])[NH:23][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)nc1Nc1ccccc1Cl
Agent: [Ni]
Solvent: CO
Product: O=c1[nH]c2ccc(OCc3ccccc3)nc2n1-c1ccccc1Cl
Reaction time: 8 h
Yield: 121.9 %

Procedure:
To a solution of 6-(benzyloxy)-N-(2-chlorophenyl)-3-nitropyridin-2-amine (750 mg, 2.11 mmol) in MeOH (20 mL) was added Raney nickel (300 mg). The reaction mixture was stirred overnight under H2 (1 atm), filtered through Celite® and concentrated. The residue was dissolved in DCM (40 mL) and CDI (410 mg, 2.53 mmol) was added. The mixture was stirred at room temperature for 4 h, washed with saturated NaHCO3 and water, dried over MgSO4 and concentrated to give the title compound (905 mg). LCMS m/z=352.3, [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][OH:28])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(NC(=O)C(CO)NS(=O)(=O)c2ccc(Cl)cc2)c1
Reactant: CS(=O)(=O)Cl
Product: CCOC(=O)c1cccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-hydroxypropanamide (1 g) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (763 mg). Recrystallization from CHCl3 was carried out.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[N:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15].CN(C)[CH:25]=[O:26].Cl>CC1CCCO1>[Cl:11][C:12]1[C:13]2[C:14](=[O:15])[NH:16][CH:25]([OH:26])[C:17]=2[C:18]([F:22])=[C:19]([F:21])[N:20]=1
Reactant: NC(=O)c1cc(F)c(F)nc1Cl
Reactant: CN(C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CC1CCCO1
Product: O=C1NC(O)c2c(F)c(F)nc(Cl)c21
Temperature: 2.5 °C
Yield: 87.9 %

Procedure:
To an inert 250 mL 3-neck round bottom flask with magnetic stirring was added LiHMDS (1M in THF, 57.3 mL, 57.3 mmol). The solution was cooled in an ice/brine bath to achieve an internal temperature of −4° C. To the cooled LiHMDS solution was added dropwise a solution of 2-chloro-5,6-difluoronicotinamide (4.41 g, 22.9 mmol) dissolved in 2-methyltetrahydrofuran (22 mL) and N,N-dimethylformamide (8.87 mL, 115 mmol) while maintaining the internal temperature between +1° C. to −3° C. The reaction mixture was stirred for 30 minutes at a temperature of about 0° C. The reaction was quenched by adding it dropwise to a cooled (0-5° C.) stirred mixture of 2M aqueous HCl (74.4 mL, 149 mmol) and IPAc (75 mL) while maintaining an internal temperature <10° C. Once the transfer was completed, the biphasic solution was transferred to a separatory funnel and the lower aqueous layer was removed and extracted with IPAc (75 mL). The organic layers were combined, washed with water (25 mL), dried over sodium sulfate, and concentrated on a rotary evaporator. The resulting solid was suspended in heptane (20 mL), and the mixture was stirred for 90 minutes and filtered. The filter cake was washed with heptane (20 mL) and dried to give the title compound as an off-white solid (4.442 g, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.11-6.14 (m, 1H), 6.98 (d, J=8 Hz, 1H), 9.5 (s br, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]12[O:19][CH:15]([CH2:16][NH:17][CH2:18]1)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]2.C(N(C(C)C)CC)(C)C>C(O)C>[CH3:7][N:6]1[C:2]([N:17]2[CH2:18][CH:11]3[O:19][CH:15]([CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]3)[CH2:16]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CC2CN(C(=O)OC(C)(C)C)CC(C1)O2
Yield: 65 %

Procedure:
To a microwave reaction vial was added 5-chloro-1-methyl-4-nitro-1H-pyrazole (141 mg, 0.88 mmol), tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (200 mg, 0.88 mmol). Ethanol (8 mL) and diisopropylethylamine (0.92 mL, 5.25 mmol) were added and the mixture was irradiated with a microwave for 60 min at 130° C. The mixture was cooled, concentrated and purified via flash chromatography, ethyl acetate/heptane 0% to 100% to afford yellow oil tert-butyl 7-(2-methyl-4-nitro-pyrazol-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (202 mg, 65%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:20]3[N:21]([CH:24]4[CH2:26][CH2:25]4)[CH:22]=[CH:23][C:19]=3[C:18](=[O:27])[N:17]2[C:28]2[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=2)=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:8][C:22]1[N:21]([CH:24]2[CH2:26][CH2:25]2)[C:20]2[CH:16]([C:13]3[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=3)[N:17]([C:28]3[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=3)[C:18](=[O:27])[C:19]=2[CH:23]=1
Reactant: Cc1cc(N2C(=O)c3ccn(C4CC4)c3C2c2ccc(Cl)cc2)cn(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(N2C(=O)c3cc(Br)n(C4CC4)c3C2c2ccc(Cl)cc2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 70.9 %

Procedure:
NBS (0.497 g, 2.79 mmol) was added to a mixture of 6-(4-chlorophenyl)-1-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (Step 240.2) (1.1 g, 2.79 mmol) in CCl4 (40 mL) at 0° C. The reaction mixture was stirred for 40 h at rt, concentrated, diluted with EtOAc/water, and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by silica gel column chromatography (CH2Cl2/MeOH 95:5) to afford a white solid and mixed fractions. The mixed fractions were purified by SFC (column 2-EP 250×30 mm, 5 μm, 60 Å, Princeton; flow 100 mL/min; gradient: isocratic 5% B for 25 min; A: scCO2, B: MeOH) to afford a white solid. Both solids were dissolved in CH2Cl2 and concentrated to afford the title compound (935 mg, 70.8% yield) as a white solid. tR: 1.07 min (LC-MS 6); ESI-MS: 472.1/474.1 [M+H]+ (LC-MS 6); TLC (CH2Cl2/MeOH 95:5): Rf=0.27.
Reaction SMILES: [N+]([N:4](CCCC)[C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[NH:4][CH2:5][CH2:18][CH2:17][CH3:16])[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: CCCCN(c1cccc(C(=O)c2ccccc2)c1)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCNc1ccc(C(=O)c2ccccc2)cc1N
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of 3-(nitro-4-n-butylamino)-benzophenone (5.96 g.; 0.02 mole) in ethanol (200 ml.) is added palladium on charcoal (5%; 0.1 g.). The mixture is hydrogenated until theoretical uptake of hydrogen has occurred (about 3 hours) and then let stand at room temperature overnight. The reaction mixture is filtered to remove the catalyst and the filtrate concentrated under vacuum to afford 4.75 g. (88.6% yield) of 3-amino-4-n-butylaminobenzophenone.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].[CH:8]1([O:14][C:15](Cl)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([O:14][C:15]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COP(OC)OC
Reactant: O=C(Cl)OC1CCCCC1
Product: COP(=O)(OC)C(=O)OC1CCCCC1

Procedure:
From 24.8 g (0.20 mole) of trimethylphosphite and 32.1 g (0.20 mole) of cyclohexylchloroformate. (Y. Iwakura and A. Nabeya, J. Org. Chem. 25 (1960) 1118; M. E. Fourneau et al. Chem. Abstr. 16 (1922) 240; J. H. Saunders et al. J. Am. Chem. Soc. 73 (1951) 3797). (100° C., 2 hours). Yield 30 g (64%). Bp1.4-1.8 148°-151° C. nD21 1.4543.
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][CH2:25]2)[CH:9]=1.[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][CH2:25]2)[CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To 10-20 mL microwave flask was added ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (Int-5m, 500 mg, 741 μmol), phenylboronic acid (181 mg, 1.48 mmol), K3PO4 (314 mg, 1.48 mmol), Pd(PPh3)4 (86 mg, 74 mol) and 3:1 1,4-dioxane:H2O (8 mL). The flask was flushed with argon and sealed. The reaction was stirred in a microwave at 150° C. for 30 minutes. After 30 minutes, the reaction was diluted with DCM and washed with H2O. The aqueous was extracted with DCM (x2) and the combined organic layers were dried over Na2SO4. The solvent was reduced in vacuo and the title compound was purified via silica gel chromatography.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]([O:10][CH2:11][O:12][CH3:13])=[CH:4][C:3]=1[CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[C:21]1(C)C=CC=CC=1>CN(C=O)C>[OH:20][CH:14]([C:3]1[C:2]2[O:1][CH2:21][O:8][C:7]=2[C:6]([CH3:9])=[C:5]([O:10][CH2:11][O:12][CH3:13])[CH:4]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(O)c1cc(OCOC)c(C)c(O)c1O
Reactant: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)c1cc(OCOC)c(C)c2c1OCO2
Temperature: 25 °C

Procedure:
Into a clean and dry 2 L, 4-necked RB flask was charged 400 ml of N,N-dimethylformamide under nitrogen atmosphere at RT. Cesium carbonate (171 g) was added to the reaction mass under stirring at room temperature. Bromochloromethane (226 g) was added to the reaction mass under stirring at RT. Reaction mass was heated to 30-35° C. Ethyl 2-(2,3-dihydroxy-5-(methoxymethoxy)-4-methylphenyl)-2-hydroxyacetate (50 g) was dissolved in 100 ml of DMF and slowly added to the reaction mass under stirring at 30-35° C. Reaction mass was maintained at 30-35° C. for 2.5 h under stirring. Reaction mass was poured into 1 L toluene and stirred for 1.0 h at RT. Reaction mass was filtered through hyflow bed, and the bed washed with 600 mL of toluene. Filtrate was washed with 2.0 L of DM water. Aqueous layer was extracted with 2×500 mL of toluene. Combined organic layer was washed with 2×600 mL of saturated sodium chloride solution and treated with 7.5 g of activated carbon at 45-50° C. Reaction mass was filtered and distilled of solvent under vacuum at 45-55° C. to get 40 g of crude title compound as syrup. HPLC purity of the crude compound is 92.5%. The crude compound was directly used in next step. A small sample was purified by column chromatography to compare its spectral data with the literature values.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:20])[CH:14]=1.C1N2CCN(CC2)C1>ClCCl>[OH:20][CH:19]([C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)[C:2](=[CH2:3])[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:4]
Reactant: C=CC(=O)Oc1ccc(Cl)cc1
Reactant: O=Cc1cccnc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: C=C(C(=O)Oc1ccc(Cl)cc1)C(O)c1cccnc1
Reaction time: 1 h
Yield: 18 %

Procedure:
A mixture of 37 mg (0.20 mmol) of 4-chlorophenyl acrylate, 22 mg (0.22 mmol) of pyridine-3-carboxaldehyde, and 22 mg (0.20 mmol) of DABCO was thoroughly shaken on a Vortex mixer. After 1 hr at room temperature, the mixture was diluted with dichloromethane. The DCM solution was washed with dilute aqueous acetic acid, and the DCM removed by rotoevaporation. The residue was purified by preparative HPLC to give 10 mg (0.035 mmol, 18% yield) of the desired Baylis-Hillman adduct, 4-chlorophenyl β-hydroxy-α-methylene-3-pyridinepropanoate. 1H NMR (CDCl3): δ 5.70 (1H), 6.14 (1H), 6.64 (1H), 7.76 (d of t, 1H), 8.55 (d of d, 1H), and 8.64 ppm (d, 1H). MS m/z: 290.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](O)=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1.C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.CCN(CC)CC>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:29]=[N+:30]=[N-:31])=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COc1cc(F)ccc1/C=C/C(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(F)ccc1/C=C/C(=O)N=[N+]=[N-]
Reaction time: 16 h
Yield: 76.5 %

Procedure:
(E)-3-(4-fluoro-2-methoxyphenyl)acrylic acid (1.22 g, 6.22 mmol), diphenylphosphinyl azide (1.273 mL, 5.91 mmol), and Et3N (1.734 mL, 12.44 mmol) were dissolved in benzene and stirred for 16 h. The solution was concentrated under vacuum and the residue was purified by silica gel chromatography using 20% EtOAc/Hexanes to give (E)-3-(4-fluoro-2-methoxyphenyl)acryloyl azide (1.0 g, 73% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[N:34]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(CC)CC)C>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:39]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:41])=[O:40])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: Oc1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Reactant: O=S(=O)(Cl)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(N1CCCC1)N1CCC(Nc2cc(O)nc3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 8-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol (70 mg, 0.15 mmol, 1.00 equip), dichloromethane (3 mL), pyrrolidine-1-sulfonyl chloride (37.2 mg, 0.22 mmol, 1.50 equip), and triethylamine (44.6 mg, 0.44 mmol, 3.01 equip). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[[1-(pyrrolidine-1-sulfonyl)piperidin-4-yl]amino]quinolin-2-ol as an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][C@@:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O.CCOC(C)=O>[N:15]([CH2:2][CH2:3][C@@:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:16]=[N-:17]
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@](C)(CCN=[N+]=[N-])S(C)(=O)=O
Temperature: 80 °C

Procedure:
To a solution of ethyl (2R)-4-bromo-2-methyl-2-(methylsulfonyl)butanoate (4.5 g, 15.7 mmol, 1 eq) in DMSO (5 mL) was added sodium azide (1.02 g, 15.7 mmol, 1 eq). The mixture was heated at 80° C. for 3 h. The mixture was then diluted with EtOAc and washed with water. The organic layer was dried (MgSO4), filtered and concentrated to give ethyl (2R)-4-azido-2-methyl-2-(methylsulfonyl)butanoate which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([C:20]([OH:23])([CH3:22])[CH3:21])[CH2:15]1)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][CH:25]([CH2:28][CH3:29])[CH2:26][NH2:27]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[C@@H:14]([OH:18])[CH2:15][C@@H:16]([C:20]([OH:23])([CH3:22])[CH3:21])[C:17]([NH:27][CH2:26][CH:25]([CH3:24])[CH2:28][CH3:29])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C)CN
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1C[C@@H](C(C)(C)O)C(=O)O1
Product: CCC(C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(C)(C)O
Temperature: 100 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Following a procedure similar to that described in Preparation 7, 250 mg (0.76 mmoles) of (3S, 5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-3-methylbutyl]-3-(1-hydroxy-1-methylethyl)dihydrofuran-2(3H)-one (prepared as described in Preparation 9) were dissolved in 500 mg (5.75 mmoles) of 2(RS)-methylbutylamine, and the solution was stirred at 100° C. for 3 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent). to give 270 mg (yield 85%) of the title compound as an amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:30][CH2:31][CH3:32])=[N:25][C:26]([CH3:29])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:44])[C:35](=[O:43])[CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:40]3[CH2:39][CH2:38][N:37]([CH2:36][C:35]([N:34]([CH3:44])[CH3:33])=[O:43])[CH2:42][CH2:41]3)=[O:21])[C:10]([C:23]3[C:24]([O:30][CH2:31][CH3:32])=[N:25][C:26]([CH3:29])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: CCOc1nc(C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 16) was reacted with N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C31H36N7O3Cl2 [(M+H)+] 624.2251, observed 624.2253.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C[O-].[Na+].Cl[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)=[CH:12][C:13]#[N:14]>CO>[CH3:6][O:5][C:1]([C:2]1[S:3][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:12][C:13]=1[NH2:14])=[O:4]
Reactant: COC(=O)CS
Reactant: N#CC=C(Cl)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc(-c2cccc(Cl)c2)cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium pellets were slowly added to methanol solution to form NaOMe in situ, then methyl thioglycolate was added over a period of 20 minutes to the methanol solution. A solution of 3-Chloro-3-(3-chloro-phenyl)-acrylonitrile in methanol was added slowly and was brought to reflux for 1 hour. The reaction mixture was cooled to room temperature and methanol was concentrated to 100 mL and 200 mL of water was added, stirred for 30 min and the yellow precipitate was collected and washed with water several times to yield a yellow crystalline compound, mp 92-95° C. 1H NMR (DMSO-d6) δ1.60 (s, 6H), 7.30 (d, 1H, J=8.41 Hz), 7.41 (d, 1H, J=8.41 Hz), 10.47 (s, 1H); MS (+APCI) m/z 213(M+H); Anal. Calc. For C9H9ClN2O2: C, 50.84; H, 4.27; N, 13.17. Found: C, 50.99; H, 4.28; N, 12.98.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[NH:12][C:13](=[O:20])[C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:10]=3[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:23][N:24]1[C:28]([CH2:29]Cl)=[N:27][CH:26]=[N:25]1.O>CN(C=O)C>[C:1]1([N:7]2[C:11]3=[N:12][C:13]([O:20][CH2:29][C:28]4[N:24]([CH3:23])[N:25]=[CH:26][N:27]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:15]=[C:10]3[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1ncnc1CCl
Reactant: COC(=O)c1cc2nnn(-c3ccccc3)c2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2nnn(-c3ccccc3)c2nc1OCc1ncnn1C
Temperature: 25 °C
Yield: 26.6 %

Procedure:
A mixture of 3-phenyl-5-oxo-6-methoxycarbonyl-4H-1,2,3-triazolo[4,5-b]pyridine (0.10 g, 0.37 mmol) and sodium hydride (55% in oil, 0.018 g, 0.40 mmol) in dry DMF (2 ml) was stirred at room temperature under nitrogen until all effervescence had ceased. A solution of 2-methyl-3-chloromethyl-1,2,4-triazole (0.065 g, 0.50 mmol) in dry DMF (0.5 ml) was added and the mixture was stirred for 4 days. Water was added and the aqueous solution was extracted with dichloromethane. The extracts were dried (Na2SO4), filtered and concentrated. Preparative thin-layer chromatography on silica gel, eluting with 5% methanol-dichloromethane, gave the alkylation product which was washed with hot ethyl acetate to give 3-phenyl-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-methoxycarbonyl-1,2,3-triazolo[4,5-b]pyridine (0.036 g, 27%) as an off-white, crystalline solid, m.p. 188-190° C. Found: C, 55.97; H, 4.17; N, 26.93. C17H15N7O3 requires C, 55.89; H, 4.14; N, 26.84%. δH (360 MHz; CDCl3) 3.96 (3H, s), 4.08 (3H, s), 5.76 (2H, s), 7.50 (1H, t, J=7.5), 7.63 (2H, dd, J=7.5 and 7.5), 7.89 (1H, s), 8.23 (2H, d, J=7.5) and 8.96 (1H, s); m/z (ES+) 366 (M+H+).