Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]1[C:17]([O:19]CC)=[O:18].O=C1C2C(=CC=CC=2)C(C2C=CC=CC=2)=C1C(OCC)=O.C1OC2C=CC([Mg]Br)=CC=2O1>C1COCC1>[CH2:29]1[O:28][C:25]2[CH:26]=[CH:27][C:22]([CH:2]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:3]3[C:17]([OH:19])=[O:18])=[CH:23][C:24]=2[O:30]1
Reactant: CCOC(=O)C1C(c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: Br[Mg]c1ccc2c(c1)OCO2
Agent: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Solvent: C1CCOC1
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Ethyl (1RS)-1-Hydroxy-1-(3,4-methylenedioxyphenyl)-3-phenylindane-2-carboxylate. To a solution of ethyl 1-oxo-3-phenylindene-2-carboxylate (1.0 g, 3.6 mmol) in THF (35 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 3,4-methylenedioxyphenyl magnesium bromide (5.4 mmol). After stirring for 30 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to afford the title compound (1.03 g, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][NH:31]C(OC(C)(C)C)=O)([CH3:7])[CH3:6])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][NH2:31])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CN
Reaction time: 2.5 h
Yield: 133.7 %

Procedure:
A solution of 2-{2-(tert-butoxycarbonylamino-methyl)-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester (350 mg, 0.650 mmol) in CH2Cl2 (10 mL) was treated at ambient temperature with TFA (4 mL) and stirred for 2.5 h. The solution was concentrated and co-evaporated with CCl4 (3×) to yield the title compound as a foam (381 mg, quantitative).
Reaction SMILES: [N+:1]([CH:4]([CH2:13][CH3:14])[CH:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:6])([O-])=O>C(O)C.[Ni]>[NH2:1][CH:4]([CH2:13][CH3:14])[CH:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:6]
Reactant: CCC(C(O)c1cccnc1)[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCC(N)C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.4 %

Procedure:
A solution of 2-nitro-1-pyridin-3-yl-butan-1-ol (1.0 g, 4.44 mmol) in ethanol (20 mL) was purged with argon, and 100 mg of Raney-Nickel was added at room temperature. The reaction mixture was three times evacuated and refilled with hydrogen. The reaction was stirred for 16 hours at room temperature. Raney-Nickel was then filtered over Hyflo, and the Hyflo washed with EtOH. The filtrate was then concentrated. The residue was purified by column chromatography (40 g of SiO2) using MeOH in CH2Cl2 from 0% to 100% in order to give the title compound as a yellow oil (180 mg, 21%). LC-MS: [M+H] 167.1; Rt 0.21 min; (LCMS method 1).
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH3:13][N:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]>C1C=CC=CC=1.[Al].CCOCC.CO>[CH3:13][NH:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: CN=C(C)c1ccccc1
Agent: [Al]
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: CO
Solvent: CCOCC
Solvent: c1ccccc1
Product: CNC(C)c1ccccc1
Reaction time: 20 h
Yield: 50.6 %

Procedure:
(R,R)-Ethylene-1,2-bis(η5 -4,5,6,7-tetrahydroindenyl) titanium (R)-1,1'-binaphth-2,2'-diolate (53 mg, 0.089 mmol) was dissolved in 4 mL of dry benzene in a Schlenk tube under a nitrogen atmosphere. The tube was wrapped in aluminum foil. A solution of n-butyllithium (72 μL, 0.12 mmol, 1.6M in hexane) was added and the mixture was shaken until it turned a dark red brown color. After 5 min. phenylsilane, (164 μL, 1.33 mmol) was added and the reaction mixture turned blue, then brown, in color. After 10 minutes acetophenone N-methyl imine (119 mg, 0.89 mmol) was added. The tube was shaken and left for about 20 hours at room temperature. The resulting solution was diluted with 15 mL of ether and 3 mL of methanol and allowed to stir for 2 hours. The reaction mixture was then washed with 10 mL of water and extracted with 1M HCl (2×10 mL). The aqueous layer was separated, basified with 5M NaOH (until strongly basic to pH paper), and extracted with ether (3×20 mL). The ether solution was dried over anhydrous sodium sulfate and concentrated to yield 60 mg (0.45 mmol, 50% yield) of N-methyl-1-phenylethylamine as a yellow oil. The yield for repeated experiments ranged from 50 to 80%.
Reaction SMILES: [C:1]([C:3](=[C:25]1[CH2:29][CH2:28][CH2:27][O:26]1)[C:4]1[C:5]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].FC(F)(F)S([Cl:45])(=O)=O.Cl>C(OCC)(=O)C.C1COCC1>[F:15][CH:14]([F:16])[C:7]1[C:6]([C:17]([O:19][CH3:20])=[O:18])=[C:5]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:4]([C:3](=[C:25]2[CH:29]([Cl:45])[CH2:28][CH2:27][O:26]2)[C:1]#[N:2])=[C:9]([C:10]([F:12])([F:11])[F:13])[N:8]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2CCCO2)c1CC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2OCCC2Cl)c1CC(C)C
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 25.9 %

Procedure:
A 100 mL round-bottomed flask was charged with 1.2 g (2.9 mmol) of the compound of Example 2 and 30 mL anhydrous THF and cooled to -70° C. Then 2.9 mL sodium bis(trimethylsilyl)amide (1.0 M solution in THF) was added. After 5 minutes, 0.48 g (2.9 mmol) trifluoromethanesulfonyl chloride was added. To the reaction mixture was added 0.25 g additional trifluoromethanesulfonyl chloride. The reaction mixture was poured into dilute HCl and extracted with ethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 1.3 g of crude product. Chromatography using 15% ethyl acetate in hexanes yielded 0.34 g of the desired product, as a yellow oil, a 27% yield. nD25 1.4860.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1B(O)O.C(Cl)Cl>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:2]1[N:3]=[C:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: Cc1nc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(-c2c(F)cccc2F)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
A suspension of 2-bromo-6-methyl-5-nitropyridine (3 g, 13.82 mmol, Matrix Scientific), 2,6-difluorobenzeneboronic acid (4.37 g, 27.6 mmol, Alfa Aesar) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (0.564 g, 0.691 mmol, Strem) in Dioxane (60 mL) (degassed with argon for 30 min) and Na2CO3, 2.0 M (20.74 mL, 41.5 mmol) was heated to 100° C. under N2. After 3 h, 2,6-difluorobenzeneboronic acid (4.37 g, 27.6 mmol) was further added. After a total of 7 h, 2,6-difluorobenzeneboronic acid (2.18 g, 13.8 mmol) was further added. After a total of 9 h, the reaction mixture was cooled to 23° C., diluted with EtOAc (400 ml) and washed with brine (200 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 5-10% EtOAc/hexane), affording 6-(2,6-difluorophenyl)-2-methyl-3-nitropyridine (1.931 g, 56%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(O)(=O)C[C:12](CC(O)=O)(C(O)=O)[OH:13]>C(OC=O)C.C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH:12]=[O:13])[C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(=O)C(C=O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of K. tert.-butylate (24.5 g, 109 mmol, 50% solution in tert.-butanol) in THF (700 mL) ethylformate (120 mL, 123 mmol) is slowly added. The mixture is stirred at it for 30 min before a solution of 4,4-dimethyl-cyclohexanone (50 g, 396 mmol) in ethylformate (50 mL) and THF (70 mL) is added over a period of 20 min. Upon complete addition, stirring is continued at 15-20° C. for 30 min. The orange suspension is poured onto 10% aq. citric acid solution (200 mL) and brine (200 mL) and extracted with EA (2×200 mL). The organic extracts are washed with 0.2 N aq. NaOH and brine, dried over Na2SO4 and evaporated to dryness to give 5,5-dimethyl-2-oxo-cyclohexanecarbaldehyde (52 g) as a yellow oil; LC-MS: tR=0.89 min, [M+1+CH3CN]+=196.15.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16](N)=[CH:15][C:14]=2[F:20])=[CH:10][CH:9]=[C:8]([CH3:21])[N:7]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.[BrH:34]>O.[Cu]Br>[Br:34][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:11]2[C:6]([CH3:5])=[N:7][C:8]([CH3:21])=[CH:9][CH:10]=2)=[C:14]([F:20])[CH:15]=1
Reactant: Br
Reactant: Cc1ccc(Oc2ccc(N)cc2F)c(C)n1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Oc2ccc(Br)cc2F)c(C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A solution of sodium nitrite (4.57 g, 66.3 mmol) in water (75 ml) was added dropwise (over 45 minutes) to a cooled (at 0° C.) solution of intermediate D15 (7.7 g, 33.2 mmol) in 48% aqueous HBr (75 ml). The reaction mixture was warmed to room temperature and further stirred for 15 minutes, after which it was cooled again to 0° C. and copper(I) bromide (7.31 g, 49.8 mmol) was added portionwise. The mixture was allowed to reach room temperature, stirred for 15 minutes and finally it was heated at 140° C. for 1.5 hours. The reaction mixture was cooled to room temperature and neutralized with an aqueous saturated solution of potassium carbonate. EtOAc was added, the organic layer was separated and washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; 0-10% EtOAc/heptane as eluent). The desired fractions were collected and evaporated in vacuo to yield D16 (8.75 g, 89%) as a pale brown oil.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[C:6]([NH:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20]C)=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7]>C(O)C.O>[CH3:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[C:6]([NH:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1C)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=O)N[C@@H]1CCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
KOH (1 mol/laq) (2 eq.) was added to a suspension of (R)-methyl 3-(2-methylbenzamido)-2,3-dihydro-1H-indene-5-carboxylate (B-09) (0.61 mmol, 1 eq.) in a mixture of ethanol (3.6 ml) and water (0.8 ml). The reaction mixture was stirred at room temperature overnight. Ethanol was removed in vacuo and the aqueous residue was diluted with diethyl ether and dist. water. The phases were separated and the aqueous phase was acidified with 1N HCl to pH 3 and then extracted 4× with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated in vacuo to yield the desired product (E-09). Yield: 88%
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16](=[N:18]O)[CH3:17])[C:10]=2[N:9]=[CH:8]1.[NH4+].[Cl-]>CO.CC(O)=O.[Zn]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH:16]([NH2:18])[CH3:17])[C:10]=2[N:9]=[CH:8]1
Reactant: CC(=NO)c1cccc2c1ncn2C1CCCCO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)c1cccc2c1ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)ethanone oxime (538 mg, 1.02 mmol), Zn (651 mg, 10.2 mmol), and NH4Cl (541 mg, 10.2 mmol) in MeOH (20 mL) and HOAc (5 mL) was stirred at 80° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added an aqueous NH4OH (50 mL) and the resulting mixture extracted with DCM (50 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH/TEA (10:1:0.2) to afford 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)ethanamine (103) as a yellow solid (458 mg, yield, 90.1%). MS (ESI): m/z=246.1[M+1]+.
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[N:5]=1.[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(Cl)Cl>C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.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>[Br:10][C:6]1[N:5]=[C:4]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccncc2)n1

Procedure:
Dry N2 was bubbled through a stirred solution of 2,6-dibromopyridine (1.6 gm, 6.7 mmole), pyridine-4-boronic acid (317 mg, 2.6 mmol), and Pd(PPh3)4 (160 mg) in aqueous 2M Na2CO3 (8 mL) and toluene (8 mL) at rt for 20 min. The reaction mixture was then heated to reflux for 10 hr. After cooling to rt CH2Cl2 (100 mL) was added and the mixture was washed with brine and dried (Na2SO4). Purification (Sio2, CH2Cl2/MeOH/NH4OH: 100/11/8) gave 6-bromo-[2,4′]bipyridine. MS (m/z): Calcd. C10H7N2Br (M+): 235, found: 234.9.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([O:20][CH2:21][CH2:22][CH3:23])[C:6]2[N:11]=[C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[Cl:19])[O:9][C:7]=2[N:8]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.ClCCl>[Cl:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[C:10]1[O:9][C:7]2[N:8]=[C:3]([CH2:2][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:4]=[C:5]([O:20][CH2:21][CH2:22][CH3:23])[C:6]=2[N:11]=1
Reactant: CCCOc1nc(CBr)nc2oc(-c3cc(F)ccc3Cl)nc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCCOc1nc(CN2CCOCC2)nc2oc(-c3cc(F)ccc3Cl)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.5 %

Procedure:
A mixture of 130 mg of 5-bromomethyl-2-(2-chloro-5-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine, 33.9 mg of morpholine and 135 mg of potassium carbonate in 3 ml of dimethylformamide was stirred at room temperature for 4 h. Then 50 ml water and 50 ml of dichloromethane were added. The phases were separated and the aqueous layer was extracted with 50 ml of dichloromethane. The combined organic layers were dried with sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by preparative HPLC (Method HPLC1) to give 72 mg of the title compound in the form of 2-(2-chloro-5-fluoro-phenyl)-5-morpholin-4-ylmethyl-7-propoxy-oxazolo[5,4-d]pyrimidine trifluoroacetic acid salt.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][NH:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH2:14][C@H:15]([CH3:17])[CH2:16][C@H:11]([CH3:10])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C[C@@H]1CNC[C@@H](C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](C)CN(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
A suspension of 4-bromobenzyl bromide (4.0 g, 16.0 mmol), cis, trans-(3,5-dimethylpiperidine) (1.81 g, 16.0 mmol) and potassium carbonate (2.65 g, 19.2 mmol) in THF (160 mL) was heated under reflux for 24 h. The reaction mixture was allowed to cool to ambient temperature, the solid removed by filtration and the filtrate evaporated in vacuo. The resultant residue was loaded onto a 50 g SCX-2 cartridge which was washed with methanol then eluted with 2N ammonia in methanol. Concentration of the combined basic fractions in vacuo followed by flash chromatography of the resultant residue (silica, 330 g column, ISCO, 0-25% ethyl acetate in pentane) afforded cis-1-(4-bromobenzyl)-3,5-dimethylpiperidine (1.60 g, 35%) as a colourless oil. 1H NMR (CDCl3, 300 MHz): 7.47-7.39 (m, 2H); 7.20 (d, J=8.0 Hz, 2H); 3.42 (s, 2H); 2.82-2.71 (m, 2H); 1.76-1.61 (m, 4H); 1.51-1.37 (m, 2H); 0.82 (d, J=6.4 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl)([O-])=O.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)C>C(O)(=O)C>[N+:10]([C:6]1[C:5]2[C:4](=[N:1][N:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:21]=2)[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=[N+]([O-])c1cccc2nn(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 17.7 %

Procedure:
A solution of 40.6 grams of 2,6-dinitrochlorobenzene, 21.6 grams phenylhydrazine and 350 milliliters of 95% ethanol is heated at the reflux temperature for 22 hours. Then the solvent is evaporated to yield a dark oil. To the oil is added 70 milliliters of acetic acid and the mixture is heated to reflux for 6 hours. After cooling to room temperature, the crude product is collected by filtration, washed with petroleum ether and then washed with hot methanol to yield 8.5 grams (18%) of product m.p. 155°-156° C. The analytical sample is recrystallized from methanol, m.p. 155°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9](S(C)(=O)=O)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH3:25])[C:17]=2[F:26])[N:6]=1)=[O:4].[NH3:27].CO>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:27])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH3:25])[C:17]=2[F:26])[N:6]=1)=[O:4]
Reactant: CCOc1c(Cl)ccc(-c2nc(C(=O)OC)c(Cl)c(S(C)(=O)=O)n2)c1F
Reactant: N
Solvent: CO
Solvent: C1COCCO1
Product: CCOc1c(Cl)ccc(-c2nc(N)c(Cl)c(C(=O)OC)n2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
5-Chloro-2-(4-chloro-3-ethoxy-2-fluorophenyl)-6-methane-sulfonylpyrimidine-4-carboxylic acid methyl ester (350 mg, 0.83 mmol) was dissolved in 10 mL p-dioxane and 7N ammonia in methanol (0.43 mL, 3 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was partitioned between ethyl acetate and water and the organic phase was dried and concentrated. The product was purified by column chromatography to yield 6-amino-5-chloro-2-(4-chloro-3-ethoxy-2-fluorophenyl)-pyrimidine-4-carboxylic acid methyl ester (160 mg, 54% yield): 1H NMR (CDCl3): δ 7.65 (dd, 1H), 7.24 (dd, 1H), 5.67 (br s, 2H), 4.22 (q, 2H), 4.03 (s, 3H), 1.46 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-])=O.[N:12]#[C:13]Br>CO.[Pd].O>[NH2:12][C:13]1[O:6][C:5]2[C:4](=[C:10]([OH:11])[CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: N#CBr
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Nc1nc2c(O)cccc2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
To a stirred solution of 30 g (193 mmol) 2-nitroresorcinol in 900 ml methanol was added 2.00 g 10% palladium on charcoal, and the mixture was then stirred for 18 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered and the filtrate, which contained 2-aminoresorcinol, added dropwise to a stirred solution of 22.5 g (213 mmol) cyanogen bromide in 230 ml methanol and 100 ml water. Stirring was continued for 2 h at room temperature, and then the mixture was concentrated in vacuo. To the residue was added aqueous sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (ethyl acetate) followed by trituration in ether afforded 27.0 g (93%) 2-amino-benzooxazol-4-ol as a beige crystalline solid. EI-MS m/e (%): 150 (M+, 100), 107 (28).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[CH3:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: Cc1ccc(B(O)O)cc1Cl
Product: Cc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 94.1 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 2.49 g (7.17 mmol) of 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 1.59 g (9.33 mmol) of 3-chloro-4-methylphenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (1:5) gave 2.65 g (94%) of 1-(3-chloro-4-methylphenyl)-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 138.0-139.0° C.; NMR (CDCl3) δ 2.34 (s, 3H), 3.05 (s, 3H), 6.75 (dd, J=2, 8 Hz, 1H), 7.03-7.10 (m, 2H), 7.18-7.26 (m, 2H), 7.29 (d, J=8 Hz, 2H), 7.83 (d, J=8 Hz, 2H). MS (FAB): m/e 399 (M+Li). Anal. Calc'd for C20H15ClF2O2S: C, 61.15; H, 3.85. Found: C, 61.12; H, 3.82.
Reaction SMILES: [OH-:1].[Na+].[O-2].[Ca+2].[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C(C)=O)C>[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][CH:6]([CH3:5])[C:13](=[O:1])[CH3:12]
Reactant: [OH-]
Reactant: Cc1cccc(CCl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Ca+2]
Solvent: CCC(C)=O
Product: CC(=O)C(C)Cc1cccc(C)c1
Yield: 86 %

Procedure:
256 g of methyl ethyl ketone, 80 g of powdered NaOH, 28 g of calcium oxide and 10 g of tetrabutylammonium bromide were warmed with stirring. 141 g of 3-methylbenzyl chloride were added dropwise in the course of 90 minutes at 70° C. The mixture was then boiled under reflux for 1 hour, cooled, filtered and washed with methyl ethyl ketone, and the filtrate was concentrated and distilled through a 30-cm long column containing steel helices. 86% pure 3-(3-methylbenzyl)-butanone was obtained at a boiling point of 80° C. at 0.4 mbar in 40% yield.