Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:17]([N:24]1[C@@H:29]([CH3:30])[CH2:28][C:27](=O)[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(C(F)(F)F)=O>[CH2:17]([N:24]1[C@H:29]([CH3:30])[CH2:28][CH:27]([NH:1][C:2]2[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H]1CC(=O)C[C@H](C)N1Cc1ccccc1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C(F)(F)F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@H](C)C2)c1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (400 mg, 1.72 mmol) in THF (15 mL) and TFA (491 uL) was added (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (410 mg, 1.89 mmol) at 0° C. The mixture was stirred at 60° C. for 1 hour under nitrogen atmosphere. Then the mixture was cooled to 0° C. in an ice bath, sodium triacetoxyborohydride (765 mg, 3.43 mmol) was added. The reaction mixture was stirred at 23° C. for 2 hours. Then aq. NaHCO3 was added at 0° C. until pH8-9, and the content was extracted with ethylacetate. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=3/1) to give the titled compound as a colorless oil. (278 mg, 37% yield). 1H-NMR (400M Hz, CDCl3) δppm; 7.21-7.40 (m, 6H), 6.90 (s, 1H), 3.95 (d, J=14.0 Hz, 1H), 3.90 (s, 3H), 3.60-3.73 (m, 2H), 3.46 (d, J=14.0 Hz, 1H), 3.08-3.12 (m, 1H), 2.98-3.03 (m, 1H), 2.30 (s, 3H), 2.02-2.08 (m, 1H), 1.83-1.88 (m, 1H), 1.52-1.60 (m, 1H), 1.17-1.26 (m, 1H), 1.11 (d, J=6.8 Hz, 3H), 1.13 (d, J=6.4 Hz, 3H).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[Br:28]C1C=C(C=CC=1)C=O>>[Br:28][C:16]1[CH:15]=[C:14]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][I:1])[N:4]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2cccc(Br)c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 3-bromobenzaldehyde gave 2-(3-bromophenyl)-4-iodomethyl-5-methyloxazole.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].[CH:6]1([CH:11]([C:17](OCC)=[O:18])[C:12](OCC)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(O)C>[CH:6]1([CH:11]2[C:12](=[O:13])[NH:5][C:3](=[O:4])[NH:2][C:17]2=[O:18])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCC1
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: O=C1NC(=O)C(C2CCCC2)C(=O)N1

Procedure:
To a solution of 3.48 g (151 mmol) of sodium in 50 mL absolute ethanol was added 3.02 g (50 mmol) urea and 10 g (44 mmol) of the diethyl cyclopentylmalonate prepared above. The thick white slurry which formed was refluxed for 12 hours. Most of the ethanol was removed via rotary evaporation, and the residue was diluted with 100 mL of water and acidified with 10 mL of 98% H2SO4. The resulting white solid which formed was collected by filtration and dried on a pump. The solid was recrystallized from water, and recrystallized a second time from 5% water/ethanol to obtain 7.006 g of colorless platelike crystals with a melting point of 222-223° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:11]=3)[NH:7][C:6]=2[CH:24]=1.C(N(C(C)C)CC)(C)C.[CH3:34][Si:35]([CH3:42])([CH3:41])[CH2:36][CH2:37][O:38][CH2:39]Cl.O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:11]=3)[N:7]([CH2:39][O:38][CH2:37][CH2:36][Si:35]([CH3:42])([CH3:41])[CH3:34])[C:6]=2[CH:24]=1
Reactant: Cc1ccc(Cn2nc(-c3nc4ccc(Br)cc4[nH]3)cc2C)cc1
Reactant: C[Si](C)(C)CCOCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(-c3nc4ccc(Br)cc4n3COCC[Si](C)(C)C)cc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of 6-bromo-2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1H-benzimidazole (Example 37, 600 mg, 1.57 mmol) in dichloromethane (20 mL) were added diisopropylethylamine (0.82 mL, 4.72 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.36 mL, 2.36 mmol) and the resulting mixture was stirred at rt for 16 h. Water was then added and the mixture was extracted with dichloromethane (1×50 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was then purified with an ISCO CombiFlash Companion using gradient elution from 0% to 30% EtOAc in hexanes to afford the title compound as a white solid (560 mg, 70%, mixture of two regioisomers): Isomer 1 (less polar): 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 1H), 7.78 (d, 1H), 7.60-7.63 (dd, 1H), 7.31-7.36 (m, 4H), 6.95 (s, 1H), 6.34 (s, 2H), 5.57 (s, 2H), 3.61 (t, 2H), 2.50 (s, 3H), 2.46 (s, 3H), 0.91 (t, 2H), 0.00 (s, 9H); ES-MS m/z 512.21, HPLC RT (Method C) 4.05 min. Isomer 2 (more polar): 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 1H), 7.79 (d, 1H), 7.59-7.62 (dd, 1H), 7.31-7.34 (m, 4H), 6.94 (s, 1H), 6.35 (s, 2H), 5.57 (s, 2H), 3.61 (t, 2H), 2.50 (s, 3H), 2.47 (s, 3H), 0.92 (t, 2H), 0.00 (s, 9H); ES-MS m/z 512.11, HPLC RT (Method B) 4.03 min.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]([CH2:11][CH3:12])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCl>[Br:1][CH:11]([CH3:12])[C:4](=[O:3])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: BrBr
Reactant: CCOC(=O)CC(=O)CC
Agent: CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)CC(=O)C(C)Br
Temperature: 0 °C

Procedure:
277 g of bromine are added dropwise to a solution of 250 g of ethyl 3-oxovalerate and 0.5 g of p-toluenesulphonic acid in 55 ml of methyl chloride at room temperature, while stirring. The mixture is subsequently stirred at 30° C. for one hour, ice-water is added and the organic phase is separated off. The aqueous phase is extracted once more with methylene chloride and the combined organic phases are then dried over magnesium sulphate and evaporated. The product is further processed in the crude form.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1.O>ClCCl>[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
Cyanuric chloride (85 mg, 0.46 mmol) was added to N,N-dimethylformamide (0.036 mL, 0.46 mmol) at room temperature. After the formation of a white solid (10 minutes), methylene chloride (2 mL) was added, followed by 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (115 mg, 0.330 mmol, from Example 11, step 3). After the addition, the mixture was stirred at room temperature overnight. Water was added, and then diluted with dichloromethane. The organic phase was washed with sat. NaHCO3 solution, water and brine, then dried over MgSO4, concentrated. The residue was purified on silica gel (eluting with 0 to 80% EtOAc in hexanes) to give the desired product (76 mg, 63%). LCMS calculated for C18H21Cl2N2O2 (M+H)+: m/z=367.1; Found: 367.0.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11](=[O:16])[CH2:12][C:13]([OH:15])=[O:14].[CH2:17](OC(OCC)OCC)C.C(OC(=O)C)(=O)C.[CH:34]1([NH2:37])[CH2:36][CH2:35]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH:34]1([N:37]2[C:2]3[C:3](=[CH:4][C:5]([F:10])=[C:6]([F:9])[C:7]=3[F:8])[C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:17]2)[CH2:36][CH2:35]1
Reactant: O=C(O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CCOC(OCC)OCC
Reactant: NC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To 17.6 g (66.6 mmol) of the 2,3,4,5-tetrafluoro-β-oxo-benzenepropanoic acid was added 14.6 g (~1.5 equivalents) of triethylorthoformate and 16.19 g (2.38 equivalents) of acetic anhydride. The mixture was refluxed for two hours at 120° (and was then cooled to 80° C. and concentrated in vacuo. The mixture was diluted with t-butanol, cooled to 10° C., and 3.8 g (1.05 equivalents) of cyclopropylamine in 120 ml of t-butanol was added. The mixture was stirred at 20° C. for 30 minutes and then warmed to 50° C. overnight. At this temperature 7.5 g of potassium t-butoxide was added in 50 ml of t-butanol and the mixture was stirred for four hours. It was filtered and the solids dissolved in 250 ml of hot acetic acid and 200 ml of 3N hydrochloric acid was added in portions over four hours at 100° C. The mixture was cooled and the solids collected to give 15.44 g (82%) of the 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 226°-228° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10](N)=[N:9][N:8]=2)[CH:2]=1.C(O)(=O)C.[ClH:17].N([O-])=O.[Na+]>O.[Cu]>[Cl:17][C:10]1[S:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8][N:9]=1
Reactant: Cl
Reactant: Nc1nnc(-c2cccnc2)s1
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1nnc(-c2cccnc2)s1
Temperature: 23 °C
Yield: 72 %

Procedure:
To a mixture of 5-pyridin-3-yl-[1,3,4]thiadiazol-2-ylamine (5.5 g, 30.9 mmol) and copper powder (0.335 g, 5.27 mmol), in a mixture of glacial acetic acid (93 mL) and concentrated hydrochloric acid (19 mL) at 0° C., was added dropwise a solution of sodium nitrite (10.67 g, 154.6 mmol) dissolved in water (13 mL). The reaction mixture was then allowed to warm to 23° C. overnight. The reaction mixture was diluted with 300 g of ice, resulting in an emulsion, and extracted with dichloromethane (3×200 mL). The emulsion was then passed through a medium porosity scintered glass funnel containing celite. The cake was stirred and washed well with chloroform. The filtrate was combined with the organic extracts. The organic phase was dried over MgSO4 and concentrated to dryness to give the title compound as a yellow solid (4.42 g, 72%): 1H NMR (300 MHz, CDCl3) δ 9.08 (br s, 1H), 8.78 (br s, 1H), 8.29 (dt, J=8, 2 Hz, 1H), 7.49 (dd, J=8, 5 Hz, 1H).
Reaction SMILES: NC[C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:6][C:7]=1[C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C([N:27](CC)CC)C.[Cl-].[NH4+]>ClCCl>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[O:6][C:7]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)=[C:3]([NH:27][S:21]([CH3:20])(=[O:23])=[O:22])[N:4]=2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CS(=O)(=O)Nc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-aminomethyl-2-(4-fluorophenyl)-5-(3-thienyl)oxazole (110 mg) in dichloromethane (5 ml) were successively added dropwise under acetone-ice cooling methanesulfonyl chloride (0.036 ml) and triethylamine (0.15 ml) The reaction mixture was stirred at 0° C. for one hour, and further stirred at room temperature for 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution and extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform:methanol=100:0→95:5) to obtain a crude product of N-[2-(4-fluorophenyl)-5-(3-thienyl)oxazol-4-yl]-methanesulfonamide (140 mg).
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=1.C1(CBr)CC1.CN(C)C=O>O1CCCC1.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:1][CH:2]2[CH2:4][CH2:3]2)[CH:13]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1ccc(Br)cn1CC1CC1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
KOtBu (0.68 g) was added to a solution of 5-bromo-1H-pyridin-2-one (1.00 g) in tetrahydrofuran (20 mL) at room temperature. After stirring for 30 min, cyclopropylmethyl bromide (0.77 mL) and dimethylformamide (3 mL) were added to the suspension and the resulting mixture was warmed to 70° C. After stirring the mixture at 70° C. for 2 h, the reaction was complete. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (2×20 mL) and brine (20 mL). Then, the solution was dried (MgSO4) and the solvent was removed to give the title compound as a colorless oil. Yield: 1.18 g (90% of theory). Mass spectrum (ESI+): m/z=228/230 (Br) [M+H]+
Reaction SMILES: Cl[Si](C)(C)C.[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2[CH2:20][S:21][CH2:22][C:8]1=2.[Cl:23]N1C(=O)CCC1=O>N1C=CC=CC=1.O>[Cl:23][C:20]1[S:21][CH:22]=[C:8]2[C:7](=[O:6])[N:12]3[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]3=[N:10][C:9]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccc2nc3c(Cl)scc3c(=O)n2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (0.4 ml, 0.03 mol) is added to a cooled (ice bath) solution of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno-[3,4-d]pyrimidine-7-carboxylic acid (0.75 g., 0.03 mol) in pyridine (5 ml) under nitrogen. The mixture is stirred at ice bath temperatures for one hour and then allowed to warm to room temperature. N-Chlorosuccinimide (0.8 g., 0.06 mol) is addd and the mixture is heated at 95° C. for 20 minutes. The mixture is cooled, diluted with water (3 ml) and stirred for 15 minutes. The precipitate is filtered off, dried and recrystallized from ethanol to give the product (0.5 g.), mp 285° C. (dec).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH:10](=O)C1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:10][NH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1
Reactant: NC1CN2CCC1CC2
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CNC1CN2CCC1CC2
Temperature: 0 °C

Procedure:
A mixture of 50 g of 3-amino quinuclidine and 40 ml of benzaldehyde in 1000 ml of toluene is brought to reflux for 45 minutes, while eliminating the water formed. Then the solvent is evaporated, the residue is dissolved in 800 ml of methanol and 15 g of potassium borohydride are added within 3 hours while maintaining the temperature at 0° C. Then the solvent is evaporated, the residue is taken up in water, the mixture obtained is extracted with ethyl acetate (or with chloroform), dried on sodium (or magnesium) sulfate, filtered and the filtrate is evaporated. Thus 85 g (yield ≃100%) of the pure expected product are obtained (one spot in TLC) which is in liquid form.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32](Cl)=O)[CH:28]=[CH:29][CH:30]=1.[O-]CC.[Na+]>C(O)C>[Cl:15][C:8]1[CH:9]=[C:10]([Cl:14])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]2=[N:1][C:32]([CH2:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=3)=[N:22][C:20](=[O:21])[C:3]2=[C:4]([C:16]([F:19])([F:18])[F:17])[NH:5]1
Reactant: NC(=O)c1c(C(F)(F)F)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Reactant: COc1cccc(CC(=O)Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(F)(F)F)c-3c(=O)n2)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 91.3 %

Procedure:
To a stirred solution of 186 mg (0.50 mmol) of 5-amino-3-trifluoromethyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 555 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.26 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 23 h at reflux, and the heating mantle was then removed. The reaction was treated with 10 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:3 ether-hexanes. The off-white solid was briefly air-dried to give 230 mg (91%) of 1-(2,4,6-trichlorophenyl)-3-trifluoromethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one. Mass spec.: 503 (M+H)+.
Reaction SMILES: [N+]([O-])(O)=O.Cl[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[CH:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+].C(O)CCCC>O>[CH3:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: Cc1cc(Cl)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCCCO
Solvent: O=[N+]([O-])O
Product: Cc1cc(N2CCNCC2)ccn1
Yield: 60.2 %

Procedure:
A mixture of 4-chloro-2-methylpyridine nitrate (5.00 g), piperazine (9.00 g), anhydrous sodium bicarbonate (6.60 g) and amyl alcohol (60 ml) was heated under reflux for 18 hours. The mixture was cooled and water was added to dissolve inorganic material. The organic layer was washed four times with brine and all the aqueous extracts were combined and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulphate and evaporated. The residue was crystallised from ethyl acetate/hexane to give 1-(2-methylpyrid-4-yl)piperazine (2.80 g), m.p. 93°-94° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[N:15][C:16]2[CH:17]([S:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])[CH2:18][CH2:19][CH2:20][C:21]=2[CH:22]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:12][C:13]1[CH:14]=[N:15][C:16]2[CH:17]([S:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:9])=[O:24])[CH2:18][CH2:19][CH2:20][C:21]=2[CH:22]=1
Reactant: Cc1cnc2c(c1)CCCC2S(=O)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc2c(c1)CCCC2S(=O)(=O)c1ccccc1

Procedure:
A solution of m-chloroperbenzoic acid (1.4g) in dichloromethane (25ml) was added to a stirred solution of 5,6,7,8-tetrahydro-3-methyl-8-phenylsulphinylquinoline (1.87g) and trifluoroacetic acid (1.2ml) in dichloromethane (25ml). After stirring at ambient temperature for 1h, the reaction mixture was washed with 2M sodium hydroxide, dried over magnesium sulphate and evaporated to a solid. After chromatography on silica eluting with ether the product was recrystallised from diisopropylether affording white crystals, mp 84°-86° C.
Reaction SMILES: CS(C1C=CC(CCC)=C(C=1)N)(=O)=O.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:31]([O-])=O.CS(C1C=CC(Br)=CC=1)(=O)=O>CO.CCOC(C)=O>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[NH2:31]
Reactant: Cc1ccc(S(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: CCCc1ccc(S(C)(=O)=O)cc1N
Agent: CS(=O)(=O)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)c2ccccc2)cc1N
Yield: 94 %

Procedure:
Following the general method as outlined in Intermediate 61 using MeOH and EtOAc as solvents, starting from 1-methyl-2-nitro-4-(phenylsulfonyl)benzene (Intermediate 112) and 4-bromophenyl methyl sulfone, the title compound was obtained as a beige solid in 94% yield.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([O:11][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: OC1CCCCc2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Brc1ccc2c(c1)C(OC1CCCCO1)CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.88 g (7.8 mmol) of (±)-3-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol, 1.07 mL (11.7 mmol, 1.5 equiv) of 3,4-dihydro-2H-pyran, and 0.20 g (0.80 mmol, 0.1 equiv) of pyridinium p-toluenesulfonate in 38 mL of methylene chloride was stirred under nitrogen at ambient temperature overnight. The mixture was diluted with 115 mL of ether, washed with 45 mL of half-saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to give 2.8 g of a cloudy oil. Purification by flash chromatography (5-30% ethyl acetate in hexanes) gave the product as a colorless oil. MS (m+1)=327.0; 1H NMR (400 MHz, CDCl3) 7.68 (s, 0.5H), 7.39 (d, 0.5H, J 2 Hz), 7.25 (m, 1H), 6.95 (m, 1H), 4.90 (t, 0.5H, J 3 Hz), 4.80 (m, 1H), 4.48 (t, 0.5H, J 3 Hz), 3.95 (m, 0.5H), 3.67 (m, 0.5H), 3.52 (m, 0.5H), 3.42 (m, 0.5H), 2.85 (m, 1H), 2.67 (m, 1H), 2.10-1.83 (m, 3.5H), 1.82-1.52 (m, 8H), 1.43 (m, 0.5H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][CH:18]([CH3:26])[CH2:19][C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23]>>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:22]([CH3:23])[C:21]([C:20](=[O:25])[CH2:19][CH:18]([CH3:26])[CH3:17])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)CC(C)C
Product: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)CC(C)C
Yield: 55 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 6-methyl-2,4-heptanedione according to the procedure of example 1. Yield: 55%. MS: m/z=381 (M).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13]CC)=[O:12].Cl>>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:4]([CH3:3])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1cccc(OCc2c(C)cccc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C)c1COc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1N NaOH (86 ml) was added to a stirred solution of Ethyl 3-(2,6-dimethylbenzyloxy)benzoate (Step A, 16.31 g, 57.4 mmol) in absolute alcohol (150 ml). After 3 hours of stirring at room temperature, the reaction mixture was acidified with 1M HCl and concentrated in vacuuo. The organic residue was taken into chloroform and washed with 0.1N HCl, dried over Na2SO4, filtered, concentrated and purified by flash chromatography using chloroform:methanol (95:5 spiked with acetic acid) as elutent.