Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([C:27]2([OH:31])[CH2:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([C:27]2([OH:31])[CH2:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[C:25]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: OC1(c2cc(F)cc(F)c2)CCC1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(C3(O)CCC3)cc2F)OC1(C)C
Yield: 100 %

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 equiv.), butyllithium (2.4 equiv.) and 1-(3,5-difluorophenyl)cyclobutanol (1.0 equiv.) to give 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol in 100% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.23-1.25 (m, 12H), 1.69-1.82 (m, 1H), 2.05-2.12 (m, 1H), 2.37 (br. s., 2H), 2.47 (br. s., 2H), 7.00 (d, J=8.80 Hz, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CO>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)[C:3]=1[C:4]#[N:5]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cn(-c2cccc(F)c2C#N)cn1

Procedure:
In analogy to example 5a, 2,6-difluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After extractive workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 98:2) the title compound was obtained as an off-white solid (yield: 29%). 1H-NMR (300 MHz, DMSO): δ=2.19 (d, J=0.8 Hz, 3H), 7.39 (s with fine splitting, 1H), 7.56-7.64 (m, 2H), 7.92 (mc, 1H), 8.04 (d, J=1.2 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)C>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OC1CCNCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Reaction time: 16 h
Yield: 71.5 %

Procedure:
1-tert-Butoxycarbonyl-4-piperidone (4 g, 0.0201 mol, 1.3 eq) and 4-hydroxypiperidine (1.56 g, 0.054 mol, 1 eq) were stirred at room temperature in ethanol (20 ml) and acetic acid (2 ml) for 3 hours. To the solution was added 0.56 g of 5% palladium on carbon type 440 Johnson Matthey catalyst. The reaction was then hydrogenated under a pressure of 3 bar at room temperature for 16 hours. The catalyst was filtered off through CELITE™, washed with ethanol (40 ml) and evaporated in vacuo to an oil. The oil was dissolved in water (25 ml) and the aqueous washed twice with dichloromethane (2×20 ml). The aqueous was basified (5M aqueous sodium hydroxide, 12 ml) and the aqueous washed twice with dichloromethane (2×30 ml). The combined organics were dried (magnesium sulphate). The solution was filtered and evaporated in vacuo to give 4-(hydroxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester as a yellow oil (3.13 g, 71.5% yield, 95.4% purity HPLC area %).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:32])=[C:18]([C@:20]23[CH2:28][O:27][C@H:26]([CH2:29][F:30])[C@H:25]2[CH2:24][S:23][C:22]([NH2:31])=[N:21]3)[CH:19]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[NH4+]>CCOC(C)=O.O>[NH2:31][C:22]1[S:23][CH2:24][C@@H:25]2[C@@H:26]([CH2:29][F:30])[O:27][CH2:28][C@:20]2([C:18]2[CH:19]=[C:14]([NH:13][C:9]([C:6]3[CH:5]=[N:4][C:3]([CH:2]([F:1])[F:12])=[CH:8][N:7]=3)=[O:11])[CH:15]=[CH:16][C:17]=2[F:32])[N:21]=1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Reactant: NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](CF)[C@H]2CS1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(C(F)F)cn4)ccc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
5-(Difluoromethyl)pyrazine-2-carboxylic acid (30.0 g, 1.05 equiv) and (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (49.2 g, 1.00 equiv.) were charged to a reactor and EtOAc (443 mL) was added to the mixture to give a suspension. A solution of ®T3P (105 g, 1.10 equiv, 50 wt % in EtOAc) (Archimica, Germany) was added at ambient temperature while controlling the internal temperature below 30° C. The reaction mixture was stirred at 40-45° C.>3 hours and monitored by HPLC. The reaction mixture was cooled to ambient temperature and water (98 mL) was charged. After 10-15 minutes charged 28% ammonium hydroxide (137 mL) while controlling the temperature below 30° C. Additional EtOAc (172 mL) was added and the reaction mixture was stirred for 30 minutes at ambient temperature. The aqueous phase was separated and back-extracted with EtOAc (246 mL). The organic phases were combined and washed with 15% aq. NaCl (98 mL) and water (98 mL). The organic layer was filtered over Celite (0.5 Wt) and concentrated under vacuum to obtain a beige solid (quantitative crude yield) which was recrystallized from 1-propanol to afford N-(3-((4aS,5S,7aS)-2-amino-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(difluoromethyl)pyrazine-2-carboxamide as a tan solid (54.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[N:12]\[OH:13])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][S:22]([O:13]/[N:12]=[C:9]1\[CH2:8][CH2:7][C:6]2[C:10]\1=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:24])=[O:23]
Reactant: COc1ccc2c(c1)/C(=N/O)CC2
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)/C(=N/OS(C)(=O)=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 7750 %

Procedure:
To the solution of intermediate 16 (6.6 g, 37.2 mmol) in CH2Cl2 (120 mL) was added Et3N (20.6 mL, 149 mmol), DMAP (455 mg, 3.73 mmol) and MsCl (4.35 mL, 55.87 mmol). The mixture was stirred at rt overnight. The reaction mixture was washed successively with water, saturated aq NH4Cl, brine, dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel column (elution with PE/CH2Cl2=1:1) to give (E)-6-methoxy-2,3-dihydro-1H-inden-1-one O-methylsulfonyl oxime (intermediate 17) (736 g, 82%) as a white solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:34])([F:33])[O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([NH:22][C:23]3[CH:28]=[C:27]([F:29])[C:26]([C:30]#[N:31])=[CH:25][C:24]=3[F:32])=[N:20][N:19]=[N:18]2)=[CH:13][CH:12]=1.S(=O)(=O)(O)O>>[F:34][C:9]([F:8])([F:33])[O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]([N:22]([C:1](=[O:3])[CH3:2])[C:23]3[CH:28]=[C:27]([F:29])[C:26]([C:30]#[N:31])=[CH:25][C:24]=3[F:32])=[N:20][N:19]=[N:18]2)=[CH:15][CH:16]=1
Reactant: N#Cc1cc(F)c(Nc2nnnn2-c2ccc(OC(F)(F)F)cc2)cc1F
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)N(c1cc(F)c(C#N)cc1F)c1nnnn1-c1ccc(OC(F)(F)F)cc1

Procedure:
A mixed solution of acetic anhydride (15 ml), 1-(4-trifluoromethoxyphenyl)-5-(4-cyano-2,5-difluoroanilino)tetrazole (1.5 g) and concentrated sulfuric acid (1 ml) was stirred at 70 to 80° C. for 1 hour. After unreacted acetic anhydride was distilled off under reduced pressure, the residue was washed with water and n-hexane to obtain 1-(4-trifluoromethoxyphenyl)-5-(4-cyano-2,5-difluoro-N-acetylanilino)tetrazole (1.55 g).
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.[CH3:14][C:15]([S:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>C1COCC1>[C:15]([S:18]([N:20]=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1)=[O:19])([CH3:17])([CH3:16])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Reactant: CC(C)(C)S(N)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC(=NS(=O)C(C)(C)C)C1
Temperature: 55 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A mixture of tert-butyl 3-oxocyclobutylcarbamate (2.2 g, 11.9 mmol), 2-methylpropane-2-sulfinamide (1.6 g, 13.1 mmol), Ti(OEt)4 (5.5 g, 24 mmol) in 20 mL of THF was stirred at 50-60° C. overnight. The mixture was cooled to room temperature and then quenched with saturated NH4Cl solution. The formed solid was removed by filtration. The filtrate was evaporated to dryness and the crude residue was purified by silica gel chromatography (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1)) to give tert-butyl 3-(tert-butylsulfinylimino)cyclobutylcarbamate as clear oil (2.0 g, 58%). MS: (M+H)+=289.1; 1H NMR (300 MHz, CDCl3): δ 5.08 (m, 1H), 4.29 (s, 1H), 3.42-3.00 (m, 4H), 1.43 (s, 9H), 1.22 (s, 9H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]2[C:8]=1[C@@:9]1([CH3:30])[C@H:18]([CH2:19][S:20]2)[C@:17]2([CH3:27])[C@H:12]([C:13]([CH3:29])([CH3:28])[CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10]1)(=O)=O.[CH3:33]B1OB(C)OB(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH3:26][O:25][C:23]1[CH:22]=[C:21]2[C:8]([C@@:9]3([CH3:30])[C@H:18]([CH2:19][S:20]2)[C@:17]2([CH3:27])[C@H:12]([C:13]([CH3:29])([CH3:28])[CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10]3)=[C:7]([CH3:33])[CH:24]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
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
Product: COc1cc(C)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 100 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
In a sealed tube was placed (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl trifluoromethanesulfonate (Compound No. 32) (0.098 g, 0.20 mmol), trimethylboroxine (0.050 g, 0.40 mmol), K3PO4 (0.085 g, 0.40 mmol), Pd(Ph3P)4 (0.046 g, 0.04 mmol) and dioxane (4 mL). The vessel was degassed for 5 min, then sealed and stirred at 100° C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc and washed with brine. The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 95:5) gave (1R,10R,11S,16S)-5-methoxy-1,3,11,15,15-pentamethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 33) (0.060 g, 83%) as a white foam. 1H NMR (CDCl3): δ 6.46 (m, 1H), 6.39 (m, 1H), 3.71 (s, 3H), 2.98-2.80 (m, 3H), 2.50 (s, 3H), 1.95-1.37 (m, 8H), 1.37 (s, 3H), 1.20-1.00 (m, 2H), 0.94 (s, 3H), 0.90 (m, 1H), 0.86 (s, 3H), 0.84 (s, 3H). MS m/z 359 (C23H34OS+H+).
Reaction SMILES: [C-:1]#[N:2].[Na+].C(Cl)(Cl)Cl.[Br:8][C:9]1([C:15]2[O:16][C:17]3[C:25]([CH2:26]Br)=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[Br:8][C:9]1([C:15]2[O:16][C:17]3[C:25]([CH2:26][C:1]#[N:2])=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=c1cc(C2(Br)CCCCC2)oc2c(CBr)cccc12
Reactant: [C-]#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#CCc1cccc2c(=O)cc(C3(Br)CCCCC3)oc12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 72.2 %

Procedure:
NaCN (3.88 g, 0.075 mole) was dissolved in water (11 ml) and to the solution was added benzyltrimethylammonium chloride (13.9 g, 0.075 mole). After stirring at 50° C. for 15 minutes, chloroform (120 ml) was added and further 2 -(1-bromocyclohexyl)-8-bromomethyl-4-oxo-4H-[1]-benzopyran (12 g, 0.03 mole) was added. The mixture was stirred for 4 hours. The chloroform layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure to obtain crystals. The crude crystals were recrystallized from ethyl acetate to obtain the title compound (7.5 g) as prisms, m.p. 143°-144° C., yield 72.2%. IR and NMR spectra of this compound were identical with those of the compound obtained in Reference Example 20.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[N:7]([CH3:20])[CH:6]=1)=[O:4].B1([O-])O[O:22]1.O.O.O.O.[Na+]>CC(O)=O>[Cl:1][CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:18])=[O:22])=[CH:13][CH:12]=2)[N:7]([CH3:20])[CH:6]=1)=[O:4]
Reactant: CSc1ccc(C(=O)c2cc(C(=O)CCl)cn2C)cc1
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(C(=O)CCl)cc1C(=O)c1ccc(S(C)=O)cc1
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A mixture of 2.5 g (0.008 mole) of 2-chloro-1-[1-methyl-5-(4-(methylthio)benzoyl]-1H-pyrrol-3-yl]-ethanone, 1.2 g of sodium perborate tetrahydrate and 50 mL of HOAc was stirred for 3 h. The solvent was evaporated in vacuo and the residue partitioned between CH2Cl2 and NaHCO3. The organics were separated off and washed again with NaHCO3, water, brine and dried (Na2SO4). The solvent was evaporated in vacuo. The residue was passed through a Biotage flash 40 L column (silica gel 9:1 CH2Cl2: MeOH) to give 2.2 g (85%) of 2-chloro-1-[1-methyl-5-(4-(methylsulfinyl)benzoyl]-1H-pyrrol-3-yl]-ethanone. CIMS m/z=324 (MH+). HNMR (CDCl3) δ8.0 (d, 2H); 7.75 (d, 2H); 7.6 (s, 1H); 7.15 (s, 1H); 4.4 (s, 2H); 4.1 (2, 3H); 2.8 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][CH:20]=[CH:21][C:22]=3[NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:14][CH:13]=2)=[C:8]([O:30][CH2:31][CH3:32])[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH2:31]([O:30][C:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:11]=[CH:10][C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH:23][S:24]([CH:27]([CH3:28])[CH3:29])(=[O:26])=[O:25])=[CH:14][CH:13]=1)[CH3:32]
Reactant: CCOC(=O)c1ccc(-c2ccc(-c3sccc3NS(=O)(=O)C(C)C)cc2)c(OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cc(C(=O)O)ccc1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
The resultant ester may be hydrolyzed in the following manner: Mix 2-ethoxy-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-4-carboxylic acid ethyl ester (38 g, 80 mmol), in ethanol (100 mL) and NaOH 2 M in water (400 mL) and stir the reaction mixture for one hour at RT. Evaporate the ethanol and wash the aqueous mixture with 200 mL of EtOAc. Acidify the aqueous mixture to pH 2 using HCl 1N. Extract the desired product with EtOAc. Dissolve the crude in warmed acetone (500 ml) and add water (600 ml), maintaining the temperature at 55° C. Stir the mixture at 60° C. for 1 hour and then to RT. overnight. Filtrate the precipitate and dry under vacuum at 45° C. overnight. Yield 28 g, 78%. 1H NMR (300 MHz, DMSO): δ 1.14 (d, J=7.0 Hz, 6H), 1.31 (t, J=7.0 Hz, 3H), 3.06 (sept, J=7.0 Hz, 1H), 4.13 (q, J=7.0 Hz, 2H), 7.10 (d, J=5.3 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.54 (d, J=5.3 Hz, 1H), 7.58-7.68 (m,4H), 7.72 (d, J=8.4 Hz, 2H), 9.22 (bs, 1H), 13.04 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[S:18](Cl)(=[O:20])=[O:19]>>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[S:18]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:20]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Product: Cc1cc(C)c(S(=O)(=O)Nc2onc(C)c2Br)c(C)c1
Yield: 64 %

Procedure:
2,4,6-Trimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,4,6-trimethylbenzenesulfonyl chloride according to the procedures described in Example 1 b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a pink solid, m.p. 92°-95° C., yield 64%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Clc1ccncn1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccncn1

Procedure:
The title compound, MS: m/e=294.1/296.1 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 4-chloro-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.CN([CH:19]=[O:20])C>C(OCC)C>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([CH:19]=[O:20])=[C:3]([F:10])[CH:4]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cc(F)c(Br)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 2,5-dibromo-1,4-difluorobenzene (10.0 g, 36.77 mmol) in diethyl ether (150 mL) at −78° C. was added n-butyl lithium (2.5 M in Hexanes, 14.86 mL, 37.15 mmol) dropwise under nitrogen. The reaction mixture was stirred at −78° C. for 30 min. Dry DMF (3.13 mL, 40.46 mmol) in diethyl ether (10 mL) was added dropwise and reaction was slowly warmed to room temperature over 2 h. The reaction was quenched with aqueous saturated ammonium chloride solution (25 mL) and extracted with diethyl ether. The organic phase was washed with saturated brine solution, dried (Na2SO4), filtered, and concentrated under reduced pressure (Note: Product is highly volatile). The crude product was purified by flash chromatography (SiO2, eluting with 2-20% ethyl acetate in hexanes) to provide the title compound as a pale yellow solid (7.0 g, 86%): 1H NMR (400 MHz, CDCl3): δ 7.50 (dd, J=5.08, 8.92 Hz, 1H), 7.62 (dd, J=5.80, 7.68 Hz, 1H), 10.30 (d, J=2.76 Hz, 1H).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]([CH2:17][C:18](=[O:35])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:18](=[O:35])[CH2:17][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[C:8]2[C:6]([OH:7])=[O:5])=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCc1ccc(OCC(=O)Cn2c(C(=O)OC(C)(C)C)cc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCc1ccc(OCC(=O)Cn2c(C(=O)O)cc3ccccc32)cc1
Temperature: 25 °C

Procedure:
0.046 g (0.096 mmol) tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-2-carboxylate is dissolved in 10 ml absolute dichloromethane and mixed with 1.49 g (13.6 mmol) trifluoroacetic acid. Having stirred at room temperature for 1½ hours, concentration to dryness is carried out on the rotary evaporator. Two dissolution steps in toluene and respective concentration on the rotary evaporator leave as a crude product a yellowish solid which is recrystallized from petroleum ether/ethyl acetate (67:33) and yields the product as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@H:16]2[OH:28])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:28][C@H:16]1[C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(OCc3ccccc3)cc2)[C@H](O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)cc2)[C@H](O)C1
Reaction time: 16 h

Procedure:
A solution of (3S,4S)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (26 g, 67.8 mmol, intermediate C) in 260 mL of methanol was treated with 1.6 grams of 10% palladium on carbon (13.6 mmol) in a pressure bottle. Hydrogen at 50 psi was introduced, and the reaction mixture was stirred for 16 h.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21]([OH:23])[CH3:22].Cl>CN(C=O)C.O>[CH2:21]([O:23][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])[CH3:22]
Reactant: O=C(O)c1cc(F)c([N+](=O)[O-])cc1F
Reactant: CCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 110 %

Procedure:
2,5-difluoro-4-nitrobenzoic acid (Fluorochem; 1 g, 4.92 mmol) was stirred and dissolved in DMF (10 mL) and caesium carbonate (4.8 g, 14.7 mmol) was added followed by ethanol (2.3 g, 49.9 mmol). The resulting white mixture was stirred at ambient temperature for 3 hours, diluted with water, acidified to pH1 with 2N HCl (aq), extracted with EtOAc (×3). Combined extracts were washed with water, dried (MgSO4), filtered and evaporated to yield the title compound as a yellow solid (1.24 g, 100%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10]Br)([CH3:4])[CH3:3].[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Nc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCNc1nccs1
Temperature: 85 °C
Yield: 23.3 %

Procedure:
To a solution of (3-bromopropyl)-carbamic acid 1,1-dimethylethyl ester (1.2 g, 5.0 mmol) and 2-aminothiazole (1.0 g, 10 mmol, 2 equiv.) in DMF 20 (mL) was added Cs2CO3 (2.5 g, 7.7 mmol, 1.5 equiv.). The resulting mixture was heated at 85° C. under N2 overnight. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3×200 mL), and brine (200 mL). The organic phase was dried over Na2SO4, then concentrated in vacuo to afford an oil. The crude product was purified by chromatography (SiO2) using hexane/ethyl acetate to afford the title compound as a light yellow solid (300 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33])[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: N#CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
1,4,5-TriphenylimidazoI-2-one was treated with 7-bromo-heptanonitrile and potassium carbonate in bumone to give after chromatographic work-up 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)heptanonitrile, m.p. 100°-101° C., Found: C, 79.7; H, 6.6; N, 9.8%; C28H27N3O requires: C, 79.9; H, 6.4; N, 10.0%; and 7-(1,4,5-triphenylimidazol-2-yloxy)heptanonitrile, m.p..93°-94° C., Found: C, 79.5; H, 6.6; N, 9.7%; C28H27N3O requires: C, 79.9; H, 6.4; N, 10.0%.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([CH3:3])[CH3:2].Cl.Cl.[CH:20]12CCC(NC1)CN2>>[CH:1]([N:4]1[CH2:9][CH:8]2[CH2:20][CH2:10][CH:5]1[CH2:6][N:7]2[C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)([CH3:2])[CH3:3]
Reactant: C1CC2CNC1CN2
Reactant: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(N)cc1
Agent: Cl
Product: CC(C)N1CC2CCC1CN2c1ccc(N)cc1

Procedure:
This compound is prepared according to the same procedure as described for Intermediate 7 using 2,5-diazabicyclo[2.2.2]octane dihydrochloride (J. Heterocycl. Chem, 1974, 11, 449-451).