Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5](=[CH2:8])[C:6]#N)(=O)C.[CH:9]1[CH2:14][CH2:13]C=[CH:11][CH:10]=1>C(Cl)Cl>[CH:6]12[CH2:13][CH2:14][CH:9]([CH:10]=[CH:11]1)[CH2:4][C:5]2=[O:8]
Reactant: C1=CCCC=C1
Reactant: C=C(C#N)OC(C)=O
Solvent: ClCCl
Product: O=C1CC2C=CC1CC2
Temperature: 90 °C
Reaction time: 48 h
Yield: 20.5 %

Procedure:
A mixture of 7.0 g of α-acetoxyacrylonitrile and 3.2 g of 1,3-cyclohexadiene was heated in a closed microwave tube at 90° C. for 24 h. The obtained brown oil was taken up in DCM and evaporated. The crude mixture was washed over a pad of Celite (2 cm) using 300 mL of Hept-EtOAc (9:1) and then concentrated in vacuo. The yellow oil was redissolved in 10 mL DMSO and 3.2 g of KOH, dissolved in 5 mL water, was carefully added. The resulting black mixture was stirred for 2 d at rt, diluted with water and extracted 3 times with Hept. The combined organic phases were washed 3 times with brine, dried over Na2SO4 and concentrated in vacuo to obtain 1.0 g of rac-(1R*,4R*)-bicyclo[2.2.2]oct-5-en-2-one as beige solid.
Reaction SMILES: B1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:11]=2)OC(C)(C)C(C)(C)O1.I[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[N:27][C:28]=2[NH2:30])[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=[C:21]([C:10]3[CH:11]=[C:12]([S:16]([NH2:19])(=[O:17])=[O:18])[CH:13]=[CH:14][CH:15]=3)[C:29]=12
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccc(S(N)(=O)=O)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 28 %

Procedure:
A solution of Benzenesulfonamide-3-boronic acid pinacol ester (31 mg, 0.11 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA41 (9.2 mg, 28% yield). ESI-MS (M+H)+ m/z calcd 333.1, found 333.0.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([F:14])[C:3]=1[O:15][CH2:16][O:17][CH3:18].C([Li])CCC.BrC1C=CC(F)=C(C=1)C=O>O1CCCC1>[F:14][C:4]1[C:3]([O:15][CH2:16][O:17][CH3:18])=[CH:2][CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[N:5]=1
Reactant: COCOc1c(Br)cc(C2CCOCC2)nc1F
Agent: O=Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C2CCOCC2)nc1F
Reaction time: 0.08 h
Yield: 12.1 %

Procedure:
4-Bromo-2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridine (1.62 g, 5.06 mmol) was dissolved in dry tetrahydrofuran (50 mL) under nitrogen and cooled in a dry ice bath. Butyllithium solution (2.5 M in hexanes, 2.2 mL, 5.50 mmol) was added and the reaction stirred for 5 min. A solution of 5-bromo-2-fluorobenzaldehyde (1.03 g, 5.06 mmol) in dry THF (10 mL) was added and the reaction stirred for 35 min then quenched by addition of saturated ammonium chloride (20 mL). Water (100 mL) and EtOAc (100 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave recovered starting material (0.30 g, 18%), debrominated 2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridine (0.15 g, 0.61 mmol, 12.0% yield) and the desired (5-bromo-2-fluorophenyl)(2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)methanol (0.85 g, 1.90 mmol)
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.O.CS(C)=O.[Pd](Cl)Cl>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: Cc1ccc(C)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 87.9 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of glycol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 38.66 mg of palladium(II) chloride and 1.1 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.5 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([OH:18])[C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(O)C.[OH-].[K+]>O1CCOCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([OH:18])[C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: CCOC(=O)C(O)c1ccc(-n2cccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)C(O)c1ccc(-n2cccc2)cc1
Temperature: 27 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
A mixture of ethyl 4-(1-pyrrolyl)phenylglycolate (0.49 g., 0.002 mole), ethanol (10 ml), dioxane (1.2 ml) and 2 M aqueous KOH (1.5 ml) was stirred at 27° C. for 3 hrs., and then evaporated to dryness. The residue was dissolved in H2O. The solution was acidified with acetic acid and extracted with ethyl acetate (3×15 ml). The combined extracts after washing with H2O and drying (MgSO4), evaporation and recrystallization of the residue from H2O gave 0.19 g (44%) of 4-(1-pyrrolyl)phenylglycolic acid, m.p. 168°-168.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:23](Cl)=[O:24]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:20]([Cl:19])[CH:21]=3)[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Product: O=C(NCC1CN(C(=O)c2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 15 h
Yield: 97.5 %

Procedure:
To a stirred solution of Intermediate 9 (0.05 g) was added a solution of 3,4-dichlorobenzoyl chloride (42.7 mg) in N,N-dimethylformamide (7 ml). The mixture was stirred at 22° C. for 15 h before the solvent was evaporated in vacuo. The residue was purified by eluting through a 1 g silica solid phase extraction cartridge (Varian Bondelut), eluting sequentially with dichloromethane, ether, ethyl acetate, acetone, acetonitrile and methanol, to give the title compound as a white solid (0.080 g). LC/MS (System A) Rt 3.10 min, Mass Spectrum m/z 442 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:7](Cl)=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH-:10].[K+].Cl.[Cl-].[Na+]>[Cu].COCCOCCOC>[NH2:1][C:2]1[C:7]([OH:10])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: Nc1ncc(Cl)cc1Cl
Agent: [Cu]
Agent: Cl
Agent: [Cl-]
Solvent: COCCOCCOC
Product: Nc1ncc(Cl)cc1O
Reaction time: 5 h
Yield: 70 %

Procedure:
A mixture of 20 parts of 2-amino-3,5-dichloropyridine, 160 parts of glycol, 80 parts of potassium hydroxide, 1 part of copper powder and 3 parts of diethylene glycol dimethyl ether is stirred under nitrogen for 5 hours at 150°-160° C. The cooled solution is neutralised with conc. hydrochloric acid, saturated with sodium chloride and extracted twice in the warm state with ethyl acetate. The combined extracts are filtered through Hyflo, dried over magnesium sulphate and purified with active charcoal. The solvent is evaporated off to leave 12.3 parts (70% of theory) of 2-amino-3-hydroxy-5-chloropyridine, m.p. 198°-201° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](Br)=[C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]2=[C:8]([CH:16]=1)[CH2:9][O:10][CH2:11]3)([O-:3])=[O:2].[Cu][C:19]#[N:20]>CN(C=O)C>[N+:1]([C:4]1[C:5]([C:19]#[N:20])=[C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]2=[C:8]([CH:16]=1)[CH2:9][O:10][CH2:11]3)([O-:3])=[O:2]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc2c3c(cccc3c1Br)COC2
Solvent: CN(C)C=O
Product: N#Cc1c([N+](=O)[O-])cc2c3c(cccc13)COC2
Temperature: 140 °C
Reaction time: 3 h

Procedure:
5-Nitro-6-bromo-1H,3H-benzo[de]isochromene (23.0 g, 78.2 mmol) was dissolved in anhydrous DMF (500 mL). Then, copper (I) cyanide (10.5 g, 117 mmol) was added to the mixture at room temperature. The mixture was stirred at the internal temperature of 140° C. for 3 hours, and then cooled to 70° C. The resulting insoluble material was separated by filtration. The filtrate was poured into water (1500 mL), and stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration, washed with acetonitrile, and air-dried. The title compound was obtained as yellow solid (15.9 g, 85%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH:18]([O:17][CH:11]([CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][O:1][C:30]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:28][CH:27]=2)=[O:31])[CH:5]=1)[C:12]([OH:14])=[O:13])([CH3:19])[CH3:20]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OC(C)C
Product: CC(C)OC(Cc1cccc(CCOC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)O

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:46][CH3:47])[C:32]([C@H:34]3[CH2:39][CH2:38][C@H:37]([CH2:40][C:41]([O:43]CC)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+]>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:46][CH3:47])[C:32]([C@H:34]3[CH2:39][CH2:38][C@H:37]([CH2:40][C:41]([OH:43])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@H:14]2[CH3:48])[CH:4]=[C:3]([C:2]([F:1])([F:50])[F:49])[CH:8]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](C(=O)N(CC)c2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Agent: [K+]
Agent: [OH-]
Product: CCN(c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)C(=O)[C@H]1CC[C@H](CC(=O)O)CC1

Procedure:
Ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](ethyl)amino]carbonyl}cyclohexyl)acetate (100 mg; 0.138 mmol) was treated with 4 M KOH (1 mL) as in EXAMPLE 87 to afford (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](ethyl)amino]carbonyl}cyclohexyl)acetic acid as a white solid. LCMS=699.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.92 (s, 1 H), 7.80 (s, 1 H), 7.75 (s, 1H), 7.29-7.22 (m, 1 H), 7.19-7.17 (m, 1 H), 7.15-7.11 (m, 1 H), 5.67 (d, J=8.3 Hz, 1 H), 4.93 (d, J=14.9 Hz, 1 H), 4.25-4.10 (m, 2 H), 3.91 (d, J=14.9 Hz, 1 H), 3.54-3.46 (m, 1 H), 3.09-3.01 (m, 1 H), 2.68-2.61 (m, 1 H), 2.27-2.24 (m, 1 H), 2.15-2.11 (m, 1 H), 1.96-1.51 (m, 6 H), 1.26-1.21 (m, 1 H), 1.17-1.12 (m, 3 H), 0.83-0.67 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([N:8]=[C:9]=[O:10])[CH:7]=1.Cl.[NH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([NH:8][C:9]([NH:14][CH2:15][C:16](=[O:17])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:10])[CH:7]=1
Reactant: NCC(=O)c1ccccc1
Reactant: COc1ccc(Cl)cc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1NC(=O)NCC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
5-Chloro-2-methoxyphenylisocyanate (5.3 g, 29 mmol) was dissolved in THF (250 ml) under N2 and heated to 60° C. To this solution was added 2-aminoacetophenone-HCl (5 g, 29 mmol) followed by triethylamine (3.8 g, 30 mmol). After being stirred 1.5 h, the reaction mixture was diluted with ethyl acetate (2 vol) and washed with 1N HCl solution, saturated NaCO3 solution, and brine before being dried, MgSO4. Concentration gave a solid which was washed with diethylether 6 g (65%). mp 171-173° C.; IR(KBr, υ=cm−1) 3336, 1706, 1644, 1600, 1560, 1482, 1262, 1220, 1182, 1126; 1H NMR (300 MHz, CDCl3) δ 3.79 (3H, s), 4.84 (2H, d, J=4.3 Hz), 5.97 (1H, br.s), 6.71 (1H, d, J=8.7 Hz), 6.88 (1H, dd, J=8.7 Hz, 2.5 Hz), 7.97-8.00 (2H, m), 8.18 (1H, d, J=2.5 Hz); MS(DCl)m/z: 319(MH+); Anal. calcd. for C16H15ClN2O3: C, 60.29; H, 4.74; N, 8.79. Found: C, 60.17; H, 4.64; N, 8.70.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][C:11]([F:18])([F:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[S:29]>O1CCCC1>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:28](=[S:29])[NH:27][C:21]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=2[Cl:19])[C:3]=1[NH:9][CH2:10][C:11]([F:17])([F:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(F)(F)CNc1c(N)cccc1N
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNc1c(N)cccc1NC(=S)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-[(2,6-diaminophenyl)amino]-2,2-difluoropropanoate (998.3 mg, 3.851 mmol) in tetrahydrofuran (20 mL) was added a solution of 2,4-dichlorophenyl isothiocyanate (785.9 mg, 3.851 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 1 hr and warmed to room temperature and stirred for 2 hrs. After removal of solvent, the residue was purified by silica gel column chromatography eluting with a 0-60% ethyl acetate/n-hexane gradient mixture to give the title compound as an amorphous (1.61 g, 3.486 mmol, 91%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:33]1([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)#[CH:32]>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][C:33]3([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:27])[CH3:29]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC1(O)CCOCC1
Solvent: O
Solvent: CC#N
Product: Cc1cc2ccc(C#CC3(O)CCOCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (80) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 4-ethynyltetrahydro-2H-pyran-4-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.76 (d, J=8 Hz, 7.68 (s, 1H), 7.57 (m, 3H), 7.42 (d, J=9 Hz, 1H), 7.30 (m, 2H), 5.16 (s, 1H), 3.85 (br m, 2H), 3.65 (br m, 2H), 2.60 (s, 3H), 1.92 (br m, 2H), 1.77 (br m, 2H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 3.5 min run): tR (min)=2.41.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[CH3:16][O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Product: COc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-methoxy-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as white solid. MS: 330.0 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.Cl.[NH2:14][CH:15]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]1=[O:17].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:8])[N:14]([CH:15]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]1=[O:17])[C:9]2=[O:10]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: NC1CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3ccc(Br)cc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of 4-bromophthalic anhydride (10.0 g, 44.1 mmol), rac-α-aminoglutarimide hydrochloride (7.25 g, 44.0 mmol) and sodium acetate (3.61 g, 44.0 mmol) in acetic acid (150 mL) was heated to reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under vacuum. The residue was stirred in water (170 mL) for 3 hours, and the resulting solid was filtered, washed with additional water (80 mL), and dried under vacuum, to afford 13.8 g of 5-bromo-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione, in 93% yield; 1H NMR (DMSO-d6) δ 2.03-2.10 (m, 1H), 2.43-2.63 (m, 2H), 2.82-2.97 (m, 1H), 5.17 (dd, J=12.8 Hz, J=5.3 Hz, 1H), 7.85-7.88 (d, J=7.9 Hz, 1H), 8.10 (dd, J=7.9 Hz, J=1.7 Hz, 1H), 8.16 (d, J=1.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.9, 30.9, 49.2, 125.3, 126.4, 128.5, 130.1, 133.2, 137.6, 165.9, 166.4, 169.7, 172.7; Anal. Calcd for C13H9N2O4Br: C, 46.32; H, 2.69; N, 8.31. Found: C, 46.23; H, 2.47; N, 8.41.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>C(#N)C>[CH2:29]([N:18]1[CH2:19][CH2:20][CH:15]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:10])[C:2]=2[F:1])[CH2:16][CH2:17]1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: O=S(=O)(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(c2cccc(S(=O)(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-{2-fluoro-3-[(trifluoromethyl)sulfonyl]phenyl}-piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and allylbromide (0.01 g). MS m/z (rel. intensity, 70 eV) 351 (M+, 47), 350 (61), 324 (bp), 322 (29), 133 (36).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O-:9])=[O:8].[Na+].ClN1C(=O)CCC1=O.S(Cl)(Cl)(=O)=O.[NH2:24][C:25]1[C:26]([F:47])=[C:27]([C:31]2[N:32]=[C:33]([C:43]([CH3:46])([CH3:45])[CH3:44])[S:34][C:35]=2[C:36]2[CH:41]=[CH:40][N:39]=[C:38]([NH2:42])[N:37]=2)[CH:28]=[CH:29][CH:30]=1.N1C=CC=CC=1>ClCCl>[NH2:42][C:38]1[N:37]=[C:36]([C:35]2[S:34][C:33]([C:43]([CH3:45])([CH3:46])[CH3:44])=[N:32][C:31]=2[C:27]2[C:26]([F:47])=[C:25]([NH:24][S:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)(=[O:9])=[O:8])[CH:30]=[CH:29][CH:28]=2)[CH:41]=[CH:40][N:39]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S([O-])c1ccccn1
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccccn3)c2F)c(-c2ccnc(N)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a suspension of sodium 2-pyridinesulfinate (48.4 mg, 0.291 mmol) in dichloromethane (3 ml) was added N-chlorosuccinimide (38.9 mg, 0.291 mmol). After 1 hour, the reaction mixture was filtered through a short Celite plug. To the crude sulfonyl chloride solution was added the 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (50 mg, 0.146 mmol) and pyridine (0.035 ml, 0.437 mmol), and the mixture was stirred for 3 hours at ambient temperature. After 3 hours, the reaction was quenched with methanol, and the crude reaction mixture was concentrated, redissolved in methanol, and purified via reversed-phase HPLC chromatography, eluting with 30-60% acetonitrile/0.1% aqueous trifluoroacetic acid. The desired fractions were combined, neutralized with aqueous saturated sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (8.8 mg, 12%) as tan solid. MS (ESI): 485 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl-].Cl>C1COCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]([OH:18])[CH2:5][CH2:1][CH2:2][CH3:3])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(C(O)CCCC)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 152.9 %

Procedure:
To a cold (−78° C.) solution of 4-[(4-butylphenyl)ethynyl]benzaldehyde (2.6 g, 10.0 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) in anhydrous THF (40 mL) was added dropwise a solution of butylmagnesim chloride in THF (7.5 mL, 15.00 mmol, 2N). The resulting solution was stirred at −78° C. for 1 hr, then allowed to reach rt and stirred at rt for 5 hrs. An aqueous solution of HCl (10 mL, 1N) was added and the resulting mixture was extracted with Et2O (3×). The combined organic layers were washed with water and brine, dried over MgSO4 and the solvents were removed under reduced pressure to give 2.45 g (76%) of the title compound as a white solid. HPLC, Rt: 5.4 min (purity: 100%). 1H NMR (CDCl3) δ: 7.51 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.3 Hz, 2H), 4.68 (t, J=7.2 Hz, 1H), 2.62 (t, J=7.9 Hz, 2H), 1.88-1.19 (m, 10H), 0.98-0.83 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:6][C:3]=1[C:4]#[N:5].[Cl:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[N:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[C:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:31][C:27]2[CH:28]=[N:29][CH:30]=[C:25]([Cl:24])[CH:26]=2)[N:9]=1
Reactant: Oc1cncc(Cl)c1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Oc1cncc(Cl)c1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
To the product of Example 131 (100 mg, 0.2793 mmol) was added 5-chloro-3-pyridinol (181 mg, 1.397 mmol), Cs2CO3 (228 mg, 0.6983 mmol) and toluene (1.5 mL) before heating to 100° C. After stirring 14 hours the reaction solution was filtered and concentrated. The residue was purified by flash chromatography (silica gel) eluting with a gradient of 1 to 3% ethyl acetate/dichloromethane affording the product. MS (electrospray) m/e 453.9 MH+ (Rt=4.1 min LC/MS).