Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][S:6]([C:9]2[CH:26]=[CH:25][C:12]3[N:13]([CH2:21][CH:22]4[CH2:24][CH2:23]4)[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)(=[O:8])=[O:7])[CH2:2]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH:22]1([CH2:21][N:13]2[C:12]3[CH:25]=[CH:26][C:9]([S:6]([CH2:5][CH:3]4[CH2:2][N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:4]4)(=[O:8])=[O:7])=[CH:10][C:11]=3[N:15]=[C:14]2[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CNC3)ccc2n1CC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CN(S(C)(=O)=O)C3)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of 5-(azetidin-3-ylmethylsulfonyl)-1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazole (STEP F of Example 3, 350 mg, 0.780 mmol) and triethylamine (395 microL, 2.81 mmol) in dichloromethane (10 mL) was added methanesulfonyl chloride (67.0 microL, 0.819 mmol) and stirred for 3 h at room temperature. The reaction mixture was concentrated in vacuo, extracted with ethyl acetate (15 mL) and water (30 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography (dichloromethane-methanol=100:0 to 100:6). T he resulting product was recrystallized with ethanol (6 mL)-ethyl acetate (1 mL) to give the title compound (212 mg) as pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:10]=C)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.[O:29]=O.CSC>C(OCC)(=O)C.CO>[C:1]([O:5][C:6]([N:8]([CH2:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:10]=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCN(CC(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=O
Solvent: CSC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CC=O)CC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 5.5 h

Procedure:
Combine N-t-butoxycarbonyl-N-allyl-2,2-bis-phenyl-ethylamine (0.23 g, 0.68 mmol) and dichloromethane (10 mL) and methanol (0.5 mL). Cool the -78° C. Pass ozonized oxygen through the solution until a persistent light blue color is obtained. Pass nitrogen through the solution until the blue color dissipates. Add dimethyl sulfide (2.0 mL). Allow the reaction mixture to warm to ambient temperature and stir for 5.5 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:11]2[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[C:33](=[O:34])[C:10]=12)C1C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1CC1N2CCN(C)C(=O)C2=C(O)C(=O)N=1>>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:12]1[N:11]2[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[C:33](=[O:34])[C:10]2=[C:9]([OH:8])[C:14](=[O:15])[N:13]=1
Reactant: CC(C)N1CCN2C(Cc3ccccc3-c3ccccc3Cl)=NC(O)C(OCc3ccccc3)=C2C1=O
Agent: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(O)c2C1=O
Product: CC(C)N1CCn2c(Cc3ccccc3-c3ccccc3Cl)nc(=O)c(O)c2C1=O
Yield: 37 %

Procedure:
6-(2′-Chloro-biphenyl-2-ylmethyl)-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (12-04) (107 mg, 37.07%) was synthesized as an off-white solid from 9-benzyloxy-6-(2′-chloro-biphenyl-2-ylmethyl)-8-hydroxy-2-isopropyl-3,4-dihydro-2H,8H-pyrazino[1,2-c]pyrimidin-1-one (11-04) (350 mg, 0.682 mmol) following the procedure as described for 6-biphenyl-2-ylmethyl-9-hydroxy-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (12-01).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:30][CH2:31][CH2:32][OH:33]>O1CCOCC1.O>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:30][CH2:31][CH2:32][OH:33])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: OCCCBr
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: OCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 17 h

Procedure:
To 1-benzhydrylpiperazine (64 mmol) and diisopropylethylamine (77 mmol) in dioxane/H2O (9:1, 100 mL) is added 3-bromo-1-propanol (64 mmol) while stirring. After about 17 hours, the solution is concentrated in vacuo, and the residue is taken up in EtOAc (250 mL) and washed with 1N NaOH (2×100 mL), and brine (2×). The organic phase is dried over Na2SO4 (s), concentrated in vacuo and recrystallized from hot EtOAc to afford white crystalline product.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[CH:28]([NH:31][C:19](=[O:20])[C:18]1[C:22]([C:24]([F:27])([F:25])[F:26])=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:30])[CH3:29]
Reactant: CC(C)N
Reactant: Cc1onc(-c2ccccc2)c1COc1cc(C(F)(F)F)c(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(F)(F)F)c(C(=O)NC(C)C)cn1
Yield: 27 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-4-trifluoromethyl-nicotinic acid (200 mg, 0.53 mmol) instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was converted using isopropylamine instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, ethyl acetate:dichloromethane=100:0 to 50:50, 60 mg, 27%) which was obtained as an off white solid. MS: m/e=420.1 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[C:15]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH3:30])[C:25](=[O:31])[CH2:24][CH2:23]4)[CH:16]=[N:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)(C)(C)C.[ClH:33].O1CCOCC1>CO>[ClH:33].[NH2:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[C:15]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH3:30])[C:25](=[O:31])[CH2:24][CH2:23]4)[CH:16]=[N:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCCN4CCNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCCN4CCN)ccc21
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of {2-[5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-3,4-dihydro-2H-[1,7]naphthyridin-1-yl]-ethyl}-carbamic acid tert-butyl ester (example 11, 0.06 g, 0.137 mmol) in MeOH (1 mL) was added 4M HCl in dioxane (0.137 mL, 0.550 mmol) and the reaction mixture was stirred at room temperature over night. Then, the reaction mixture was evaporated to dryness and the solid residue was triturated in diethyl ether, filtered off and further dried on the high vacuum to give the title compound (0.040 g, 70%) as an orange solid. MS: 337.3 (M+H+).
Reaction SMILES: C([Zn]CC)C.[C:6](O)([C:8](F)(F)F)=[O:7].IC.[CH3:15][C:16]([CH3:35])([CH3:34])[CH2:17][N:18]1[C:26]2[C:21](=[N:22][C:23](/[CH:27]=[CH:28]/[CH2:29]CO)=[CH:24][CH:25]=2)[N:20]([CH3:32])[C:19]1=[O:33]>C(Cl)Cl>[CH3:35][C:16]([CH3:15])([CH3:34])[CH2:17][N:18]1[C:26]2[C:21](=[N:22][C:23]([C@@H:27]3[CH2:28][C@H:29]3[CH2:8][CH2:6][OH:7])=[CH:24][CH:25]=2)[N:20]([CH3:32])[C:19]1=[O:33]
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(/C=C/CCO)nc21
Agent: CC[Zn]CC
Solvent: ClCCl
Solvent: CI
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CCO)nc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diethyl zinc (0.53 mL, 0.53 mmol, 2.0 equiv, 1M in hexanes) was added to anhydrous DCM (0.53 mL) and cooled to 0° C. To this solution was added TFA (41 μL, 0.53 mmol, 2.0 equiv) in anhydrous DCM (0.27 mL), and the resulting mixture was stirred at 0° C. for 15 min. Following this duration, iodomethane (43 μL, 0.53 mmol, 2.0 equiv) in anhydrous DCM (0.27 mL) as added and the resulting reaction mixture was stirred for and additional 20 min. 1-(2,2-Dimethylpropyl)-5-[(1E)-4-hydroxybut-1-en-1-yl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (32-3, 77 mg, 0.27 mmol, 1.0 equiv) in anhydrous DCM (0.27) as then added. After 1 h, the reaction vessel was removed from the 0° C. bath and allowed to gradually warm to RT. After 2.5 h, LCMS showed consumption of 32-3. The reaction was quenched with saturated NH4Cl (5 mL) and extracted with ethyl acetate (3×5 ml). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give 32-4 as a white solid. Since the material was determined to be of >95% purity by 1H NMR, further purification was deemed unnecessary. MS m/z (M+H): calculated=303.4; observed=304.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17](=[CH:18][C:19](=[O:30])[C@@H:20]5[O:29][C@@H:21]53)[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.[BH4-].[Na+].Cl>C(O)C.O>[CH3:31][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17](=[CH:18][C@H:19]([OH:30])[C@@H:20]5[O:29][C@@H:21]53)[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=C[C@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
In 200 ml of ethanol was dissolved 13.0 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one, followed by addition of 1.0 g of sodium borohydride under ice-cooling. The mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was neutralized with diluted hydrochloric acid under ice-cooling, diluted with water and extracted with methylene chloride. The extract was washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure to recover 12.1 g of a crude product. Purification of this crude product by silica gel chromatography gave 10.6 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3α-ol (yield: 81%) having the following physical properties.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.F[C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[C:18](=[O:26])[NH:19][CH:20]=[N:21]2>>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18](=[O:26])[NH:19][CH:20]=[N:21]3)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=c1[nH]cnc2cccc(F)c12
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc3nc[nH]c(=O)c23)CC1
Yield: 103 %

Procedure:
Thus, tert-butyl 4-hydroxypiperidine-1-carboxylate (0.33 g) was reacted with 5-fluoro-3,4-dihydroquinazolin-4-one (0.18 g) to give 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one (0.39 g); NMR Spectrum: (CDCl3) 1.5 (s, 9H), 1.9-2.0 (m, 4H), 3.52 (m, 2H), 3.7 (m, 2H), 4.72 (m, 1H), 6.95 (d, 1H), 7.32 (d, 1H), 7.65 (m, 1H), 7.95 (s, 1H), 10.22 (br s, 1H); Mass Spectrum: M+H+ 346;
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.FC(F)(F)C(O)=O.CO[CH2:16][N:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[CH2:18][Si](C)(C)C>ClCCl>[F:31][C:30]([F:32])([F:33])[C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:17]1[CH2:18][CH:2]2[C:1](=[O:6])[CH2:5][CH2:4][CH:3]2[CH2:16]1
Reactant: COCN(Cc1cccc(C(F)(F)F)c1)C[Si](C)(C)C
Reactant: O=C1C=CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12

Procedure:
Cyclopent-2-enone (3.31 g, 40.4 mmol), and trifluoroacetic acid (0.031 mL, 0.404 mmol) were combined in dichloromethane (40 mL). Then 1-methoxy-N-(3-(trifluoromethyl)benzyl)-N-((trimethylsilyl)methyl)methanamine (Example 56B, 12.33 g, 40.4 mmol) was added as a solution in dichloromethane (10 mL) dropwise via addition funnel over 45 minutes at room temperature under nitrogen. The reaction was quenched with aqueous bicarbonate solution and extracted with dichloromethane (2×100 mL). The organics were combined and washed with brine, and the solvent was removed in vacuo to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.54-7.34 (m, 4H), 3.66 (d, J=13.4, 1H), 3.52 (d, J=13.4, 1H), 3.04 (dd, J=1.8, 8.9, 1H), 2.91 (ddd, J=2.8, 7.4, 11.7, 1H), 2.72-2.65 (m, 1H), 2.62 (d, J=8.9, 1H), 2.52-2.23 (m, 4H), 2.15 (ddd, J=8.1, 12.9, 17.1, 1H), 1.85-1.70 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.[NH2:35][C:36]1[CH:46]=[CH:45][C:44](Br)=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39].C(#N)C.C(=O)(O)[O-].[Na+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O.ClCCl>[NH2:35][C:36]1[CH:46]=[CH:45][C:44]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])[C:12]3=[N:13][CH:14]=2)=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39]
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Yield: 33.3 %

Procedure:
650 mg (1.35 mmol) of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine, 395 mg (1.62 mmol) 2-amino-5-bromo-N,N-dimethyl-benzamide and 55 mg (67 μmol) of dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct were placed in a vial. 8 mL of acetonitrile and 8 mL of a saturated aqueous solution of sodium bicarbonate were added. The vial was closed and the mixture irradiated in a Personal Chemistry® Optimizer to 100° C. for 15 min. The crude mixture was distributed between dichloromethane and water. The aqueous layer was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. The crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate containing 15% of methanol in hexanes to afford 288 mg (0.45 mmol, 33%) of 2-amino-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a pale beige solid. MS: m/z 518.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)[C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)Cc1cc(Cl)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(=O)C(Cc1ccc(Cl)cc1)c1cc(Cl)cc(Br)c1

Procedure:
To a vigorously stirred solution of (3-bromo-5-chlorophenyl)acetone (4.0 g, 17 mmol) and 4-chlorobenzyl chloride (2.2 g, 14 mmol) in 60 mL of acetonitrile at 0° C. was added cesium carbonate (11 g, 35 mmol), and the reaction was allowed to warm to room temperate overnight. The reaction mixture was partitioned between ethyl acetate (200 mL) and saturated aqueous ammonium chloride (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.21 (s, 1H), 7.19 (d, 2H), 7.04 (d, 2H), 6.97 (d, 1H), 6.87 (d, 1H), 4.16 (dd, 1H), 3.25 (dd, 1H), 2.86 (dd, 1H), 2.03 (s, 3H).
Reaction SMILES: [C:1]([CH:5]([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[OH:10])[C:6]([OH:8])=O)([CH3:4])([CH3:3])[CH3:2].[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19]>O1CCCC1>[C:1]([CH:5]([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[O:10][C:18]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19])[C:6]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C(C(=O)O)C(O)c1ccc(Cl)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)C(C(=O)n1ccnc1)C(OC(=O)n1ccnc1)c1ccc(Cl)cc1
Yield: 39 %

Procedure:
83.3 Grams (0.324 mole) of 2-tert-butyl-3-(4-chlorophenyl)-3-hydroxypropionic acid and 125 g (0.77 mole) of 1,1'-carbonyldiimidazole were mixed with 700 ml of tetrahydrofuran, and the mixture was heated under reflux for 3 hours with stirring. After concentrating the reaction solution under reduced pressure, water and then diethyl ether were added to the residue which was then washed with water. The ether layer was separated and concentrated to form crystals with a small amount of ether left in the system. The crystal was filtered off and washed with a small amount of ether to obtain 50.6 g (38.5%) of N-{2-tert-butyl-3-(4-chlorophenyl)-3-(1-imidazolylcarbonyloxy)propanoyl}-imidazole. m.p., 69°-71° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:6][CH2:5]1)[CH3:3].Cl[C:18]1[N:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:18]3[N:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[N:22][CH:23]=3)[CH2:15][CH2:16]2)[CH2:6][CH2:5]1)[CH3:1]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC(C)N1CCC(CC2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCC(CC3CCN(C(C)C)CC3)CC2)cn1
Temperature: 120 °C
Yield: 102.7 %

Procedure:
1-(1-Methylethyl)-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 4) (0.50 g), methyl 5-chloro-2-pyrazinecarboxylate (0.575 g) and potassium carbonate (0.615 g) were dissolved in acetonitrile (5 ml) and heated at 120° C. for 5 min in the microwave reactor. The crude mixture was passed through an SCX column (10 g, eluting with methanol [80 ml] then 2 N NH3 in methanol [80 ml]). The basic fractions were evaporated to give the title compound (E2) as a yellow crystalline solid (0.825 g). MS electrospray (+ion) 361 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=O.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:5](=[O:7])[C:4]2[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([Br:11])[CH:8]=2)[CH:18]=1)[CH3:13]
Reactant: O=C(O)c1cc(F)cc(Br)c1
Reactant: CCOC(=O)Cc1cccc(N)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(F)cc(Br)c2)c1

Procedure:
3-Fluoro-5-bromobenzoic acid (123 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[CH:13]=[C:12]2[CH3:22])[CH:18]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)=O.[N+:32]([O-])([O-:34])=[O:33].[K+]>O>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[C:13]([N+:32]([O-:34])=[O:33])=[C:12]2[CH3:22])[CH:18]=1)([OH:8])[C:2]([F:1])([F:23])[F:24]
Reactant: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)CC2
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([N+](=O)[O-])c(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To a stirred mixture of 7.0 g (0.02 mole) of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one and 70 ml of trifluoroacetic acid is added 4.2 g (0.042 mole) of potassium nitrate. The mixture is stirred for 16 hours at room temperature and then is refluxed for 30 minutes. The mixture is poured into 300 ml of water. The solid is filtered off, washed with water, and dried. Recrystallization from 250 ml of acetonitrile gives 3.3 g (42%) of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-6-methyl-5-nitro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, m.p. 289°-290° (dec).
Reaction SMILES: C(=[N:8][CH:9]([P:22]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:23])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:11])C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.NC(P(O)(ON(CC)CC)=O)C(OCC1C=CC(OC)=CC=1)=O>CCOCC>[NH2:8][CH:9]([P:22]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:23])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:11]
Reactant: CCOP(=O)(OCC)C(N=Cc1ccccc1)C(=O)OCc1ccc(OC)cc1
Agent: CCN(CC)OP(=O)(O)C(N)C(=O)OCc1ccc(OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(N)C(=O)OCc1ccc(OC)cc1

Procedure:
A solution of 16.4 g. of p-methoxybenzyl N-benzylidene-α-amino-diethylphosphonoacetate in 100 ml. of ether is added over 30 minutes with stirring to a solution of 8.25 g. of p-toluenesulfonic acid monohydrate in 150 ml. of ether. To the reaction mixture is added 60 ml. of cyclohexane and the solvent layer is separated by decantation. The residue is washed with additional 2:1 ether-cyclohexane and is again decanted. The resulting oil is dissolved in about 25 ml. of 1 M dipotassium phosphate (final pH about 7), and this solution is extracted 4 times with methylene chloride. The methylene chloride solution is then dried with magnesium sulfate, filtered and evaporated to give 12 g. of p-methoxybenzyl α-amino-diethylaminophosphonoacetate as an orange oily product. ir (neat) μ: 2.95 (NH), 5.75 (C=O), and 9.75 (P--O); nmr (CDCl3) τ: 8.73 (t, 6, J=7Hz, CH2CH3), 8.12 (s, 2, NH2), 6.18 (s, 3, ArOCH3), 6.03 (d, 1, J=21Hz, CH), 5.86 (p, 4, J=7Hz, CH2CH3), 4.80 (s, 2, ArCH2), 3.11 (d, 2, J=8Hz, arH), and 2.64 (d, 2, J=8Hz, ArH).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][CH:9]=1)[CH3:3].[H][H]>C(O)C.[Pd]>[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1ccc(C(=O)OCC)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(C(C)C)cn1
Yield: 99 %

Procedure:
10% palladium-activated carbon (5.8 g) was added to a solution of ethyl 5-(prop-1-en-2-yl)pyridine-2-carboxylate (10 g) in ethanol (100 mL), and the mixture was stirred in a hydrogen gas stream at room temperature overnight. The reaction solution was filtered through celite, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) to give ethyl 5-isopropylpyridine-2-carboxylate as a colorless oil (10 g, 95%).