Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)=[CH:5][CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.C1C[O:29]CC1>>[CH3:16][C:12]1[N:11]=[C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH2:2][OH:29])=[CH:8][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: C1CCOC1
Reactant: C=Cc1ccc(Oc2cccc(C)n2)cc1
Agent: B1C2CCCC1CCC2
Product: Cc1cccc(Oc2ccc(CCO)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128 %

Procedure:
To the solution of 2-[(4-ethenylphenyl)oxy]-6-methylpyridine (1.23 g, 5.82 mmol) in dry THF (20 mL), was added 9-BBN (17 mL, 8.50 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (3M, 7 mL), and 30% H2O2 (7.2 mL). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with DCM. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (1.71 g, 7.46 mmol, 128% yield) as a colorless oil. LCMS: rt=2.07 min, [M+H+]=230
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: Clc1ccc(SSc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 1.4 g. of p-chlorobenzenethiol in 5 ml. pyridine, 960 mg. of methyl xanthide was added in one portion. Evaporation of excess pyridine and volatile byproduct gave the known bis(p-chlorophenyl) disulfide in quantitative yield (1.4 g.). No free thiol could be detected by titration with iodine. The product was easily recrystallized from ethanol. Similar results were obtained using ethyl instead of methyl xanthide.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[CH3:10])=[CH:5][CH:4]=1)=[CH2:2].O1CCCC1.[Li].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C@H:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[CH3:10])=[CH:7][CH:8]=1)=[CH2:2]
Reactant: C=Cc1ccc([C@@H](C)N=Cc2cccc(C)n2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc([C@@H](C)NCc2cccc(C)n2)cc1
Reaction time: 4 h

Procedure:
A solution of 1 g of N-(6-methyl-pyridine-2-carbaldehyde)-(R)-1-(4-vinylphenyl)-ethylimine (Example 1) and 5 ml of dry tetrahydrofuran is added dropwise to a mixture of 5 ml of dry tetrahydrofuran and 0.42 g of lithium alanate at 0° C. and in the absence of moisture. The mixture is then stirred for 4 hours without cooling, after which it is hydrolysed at 0° C. with 1 ml of concentrated sodium sulfate solution. The precipitate is filtered off and washed with ethyl acetate. The aqueous phase of the filtrate is separated off and rinsed with ethyl acetate, and the combined organic phases are dried over sodium sulfate. After the solvent has been evaporated off at room temperature and under about 1.5 Pa, the residue is distilled in a bulb tube furnace at a furnace temperature of 250° C. and under 0.01 Pa. 0.63 g (63% of theory) of a yellow oil is obtained. [α]D20 =+52.9 (0.926, chloroform). 250 MHz-1HFT-NMR (CDCl3): δ=1.41 (d; 3H), 2.26 (broad; 1H), 2.53 (s; 3H), 3.70 (s; 2H), 3.82 (q; 1H), 5.21 (m; 1H), 5.72 (m; 1H), 6.71 (m; 1H), 6.97-7.50 (m; 7H)ppm.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1)C.Cl[CH2:14][C:15]([N:17]=[C:18]=[O:19])=[O:16].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:19]=[C:18]1[NH:17][C:15](=[O:16])[CH2:14][N:11]1[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:12]
Reactant: O=C=NC(=O)CCl
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CN(c2cccc(C(=O)O)c2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12 mmol of ethyl-3-aminobenzoate were dissolved in 120 ml Dioxan. 1 eq of chloroacetyl isocyanate were added. The reaction mixture was stirred at rt for 1 h and then heated to 120° C. for an additional 2 h. The reaction was cooled to rt, 2 eq of DBU added and again stirred at rt overnight. The solvent was evaporated and the crude extracted from DCM. The crude material was dissolved in 20 ml MeOH and 4 ml of 4N NaOH were added. The reaction mixture was stirred at rt for 20 h. After evaporation of the organic layer the aqueous phase was acidified to pH=1 and the resulting white solid was filtered off and dried under vacuum. MS(ISO): 219.2 (M−H+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10](I)[C:3]=12.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)[C:3]=12
Reactant: OB(O)c1cccnc1
Reactant: Nc1ncnc2c1c(I)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: Nc1ncnc2c1c(-c1cccnc1)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 13.4 %

Procedure:
To a solution of Example 57a (0.250 g, 0.50 mmoles) in DMF (5 ml), ethanol (2.5 ml) and water (2.5 ml), 3-pyridinylboronic acid (0.080 g, 0.65 mmoles) and sodium carbonate (0.264 g, 2.5 mmoles) were added and the system is degassed for 30 min. Tetrakis triphenylphosphine Palladium (0.109 g, 0.095 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.030 g, 13% yield). MP: 253-255° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.78 (d, J=1.7 Hz, 1H), 8.65 (dd, J=4.7, 1.3 Hz, 1H), 8.24 (s, 1H), 8.05 (dd, J=7.9, 1.6 Hz, 1H), 8.00 (td, J=7.9, 1.9 Hz, 1H), 7.77 (d, J=7.2, 1.7 Hz, 1H), 7.54-7.43 (m, 3H), 7.37-7.30 (m, 5H), 7.12 (br s, 2H), 5.54 (s, 2H). Mass: 447.19 (M++1).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:17]=[C:16]([CH3:37])[CH:15]=2)=[CH:9][C:8]=1[CH3:38])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:38][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=3[C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:17]=[C:16]([CH3:37])[CH:15]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3-c3cccnc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2-c2cccnc2)c1
Yield: 110.4 %

Procedure:
A solution of 3-{2-methyl-4-[3-methyl-5-(2-pyridin-3-yl-4-trifluoromethyl-phenoxy)-phenoxy]-phenyl}-propionic acid ethyl ester (0.089, 0.166 mmol) in ethanol (7 mL) is treated with 5 N NaOH (2 mL) and heated to until saponification is completed. The mixture is cooled, and the solvent is removed in vacuo to afford a residue that is neutralized with 1 N HCl. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 0.093 g (100%) of the title compound. 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C29H24O4F3N 508.1736, found 508.1724.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:22]([O:23]C)=[CH:21][C:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BrH:25]>>[BrH:25].[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[C:22]([OH:23])=[CH:21][C:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1S(=O)(=O)c1ccc(F)cc1)CCN(C)CC2
Agent: Br
Product: CN1CCc2cc(O)c(S(=O)(=O)c3ccc(F)cc3)cc2CC1
Temperature: 25 °C

Procedure:
A solution of D5 (300 mg, 0.86 mmol) in aqueous 48% HBr (10 mL) was heated at 120° C. overnight. The mixture was cooled to room temperature and the solvent removed, azeotroping with toluene. Diethyl ether was added to the residue to yield the title compound D6 as the hydrobromide salt (340 mg). MH+ 336. 1H NMR δ (DMSO-d6) 2.75 (3H, d), 2.88-3.25 (6H, m), 3.50-3.66 (2H, m), 7.35-7.50 (2H, t), 7.76 (1H, s), 7.90-8.03 (2H, m), 9.85 (1H, br.s), 10.80 (1H, br.s).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33][C:34]2=O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1COCC1>[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33]/[C:34]/2=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[CH:30][CH:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCc2ccc(OCc3ccccc3)cc21
Reactant: COC(=O)C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/C=C1\CCc2ccc(OCc3ccccc3)cc21
Temperature: -78 °C
Yield: 38 %

Procedure:
At −78° C., lithium bis(trimethylsilyl)amide (1.0 M in hexanes) (4 mL, 26 mmol) was added slowly to a solution of methyl 2-(trimethylsilyl)acetate (4 g, 26 mmol) in THF (20 mL). The reaction mixture was maintained at −78° C. for 22 minutes. 1.2 (3.5 g, 15 mmol) in THF (20 mL) was then added slowly to the mixture. The mixture was stirred at −78° C. and allowed to warm to room temperature overnight. The reaction mixture was then poured into water (30 mL) and extracted with EtOAc (300 mL). The organic layers were washed with brine and dried over anhydrous sodium sulfate. After removing solvent by rotary evaporation, the residue was purified by column chromatography (1:4 EtOAc/hexane). The Product 1.3 was obtained in 38% yield as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21](SC)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[NH2:25][NH2:26]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([NH:25][NH2:26])[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CSc1nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Reactant: NN
Product: NNc1nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1

Procedure:
A solution of 6-(3-fluoropyridin-4-yl)-2-(methylthio)-5-pyridin-3-yl-3H-imidazo[4,5-b]pyridine (Example 47, 0.05 g, 0.15 mmol) in hydrazine (0.5 mL) was heated in a sealed tube at 100° C. for 30 hours. The solvent was evaporated and the residue (0.05 g) was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C@@H:14]1[C@@H:21]2[C@@H:17]([CH2:18][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:20]2)[CH2:16][CH2:15]1)(=[O:12])=[O:11])([O-:3])=[O:2].S(OC)(O[CH3:39])(=O)=O.N12CCCN=C1CCCCC2.O>CN(C)C=O>[CH3:39][N:13]([C@@H:14]1[C@@H:21]2[C@@H:17]([CH2:18][N:19]([S:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)(=[O:24])=[O:23])[CH2:20]2)[CH2:16][CH2:15]1)[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: COS(=O)(=O)OC
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CN([C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
2-Nitro-N-((3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-yl)benzenesulfonamide (250 mg, 0.481 mmol) from Example 299 and dimethyl sulfate (0.138 mL, 1.444 mmol) were combined in N,N-dimethylformamide (3 mL) at 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.145 mL, 0.962 mmol) was added dropwise. The reaction mixture was stirred for 0.5 hours, water was added, and the precipitate was collected by filtration. The resultant crude material was purified using a 12 g silica gel cartridge eluting with a gradient of 0-60% ethyl acetate/hexane over 20 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.15 (dd, J=12.1, 4.7, 3H), 7.94 (d, J=8.3, 2H), 7.88 (dd, J=7.7, 1.3, 1H), 7.68 (dtd, J=19.1, 7.5, 1.3, 2H), 4.29 (dt, J=10.8, 7.0, 1H), 3.63 (dd, J=9.9, 1.5, 1H), 3.21 (dd, J=9.7, 2.3, 1H), 2.90 (s, 3H), 2.89-2.81 (m, 2H), 2.58-2.39 (m, 2H), 1.83-1.72 (m, 1H), 1.68-1.58 (m, 1H), 1.50 (qd, J=11.8, 7.3, 1H), 1.21 (ddd, J=19.4, 12.4, 7.1, 1H); MS (ESI+) m/z 551 (M+NH4)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:12]=[N:11][C:10]=1[C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])(=O)=O.[H-].[Na+]>CN(C=O)C.O>[CH:28]1([N:27]2[CH2:6][CH2:7][CH2:8][C:9]3[N:13]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=4)[N:12]=[N:11][C:10]=3[C:25]2=[O:26])[CH2:29][CH2:30]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOS(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc3c2CCCN(C2CC2)C3=O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)propyl methanesulfonate (218 mg, 0.5 mmol) obtained in Example 1201a) and 60% sodium hydride (24 mg, 0.6 mmol, 1.2 eq.) were dissolved in DMF (5 ml) and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was diluted with water (10 ml), and the precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (85 mg, 50.1%).
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][O:4][C:5]1[C:6]([CH3:16])=[CH:7][C:8]([C:11](OCC)=[O:12])=[N:9][CH:10]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].CCOC(C)=O>C1COCC1.CCO>[F:17][CH:2]([F:1])[CH2:3][O:4][C:5]1[C:6]([CH3:16])=[CH:7][C:8]([CH2:11][OH:12])=[N:9][CH:10]=1
Reactant: CCOC(=O)c1cc(C)c(OCC(F)F)cn1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(CO)ncc1OCC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
A mixture of ethyl 5-(2,2-difluoroethoxy)-4-methylpicolinate (2.0 g, 8.2 mmol, Step-2) and calcium chloride (3.62 g, 32.6 mmol) in THF-EtOH (1:1, 60 mL) is stirred at rt for 30 minutes. Then, the mixture is cooled to 0° C., and sodium borohydride (771 mg, 20.4 mmol) is added portionwise. After stirring 1 day, the reaction is quenched with saturated aqueous ammonium chloride solution (200 mL), and the aqueous layer is extracted with DCM (200 mL×2). The combined organic layer is dried over sodium sulfate, and after filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (10:1 then EtOAc only) to give 1.61 g (97% yield) of the title compound as white solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=2)=[C:7]([O:19]C)[CH:6]=1)[OH:4].B(Br)(Br)Br>>[F:18][C:14]1[N:13]=[C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[C:2]([F:21])([F:22])[F:1])=[CH:6][C:7]=2[OH:19])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(C(O)C(F)(F)F)ccc1Oc1cccc(F)n1
Agent: BrB(Br)Br
Product: Oc1cc(C(O)C(F)(F)F)ccc1Oc1cccc(F)n1
Yield: 84 %

Procedure:
According to the procedure of example 5(b) except substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine by 2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3 methoxyphenyl}ethanol (0.15 mmol; 50 mg) and adding 3.5 equivalents (0.47 mmol; 470 μl) of boron tribromide, the title compound was prepared in 84% yield (0.13 mmol; 38 mg) after purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—40/60).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccs1

Procedure:
A mixture of 12.8 g of 2-(2-thienyl)ethanol and 20.2 g of triethylamine in 500 ml of dichloromethane is reacted with 12.6 g of methanesulfonyl chloride as described in Example 2 to give the product as an oil.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Li+]>O1CCCC1>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:4]([OH:23])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)CC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 95.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid ethyl ester (2.50 g, 7.39 mmol) in tetrahydrofuran (30 mL) was treated with a 0.8M aqueous lithium hydroxide solution (11.1 mL, 8.86 mmol). The reaction mixture was stirred at 25° C. for 23 h. The resulting reaction mixture was partitioned between water (75 mL) and ethyl acetate (75 mL) and then treated with a 1N aqueous hydrochloric acid solution (15 mL). The layers were shaken and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid (2.20 g, 96%) as a white solid which was used without further purification: mp 137-138° C.; FAB-HRMS m/e calcd for C16H22O4S (M+H)+311.1317, found 311.1321.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[C:4]([C:6]1[C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=[CH:8][C:7]=1[OH:16])=[O:5].[OH-].[Na+].Cl>O.CO>[F:1][C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[C:4]([C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=[CH:8][C:7]=1[OH:16])=[O:5]
Reactant: COC(=O)c1cncc(O)c1C(=O)c1cc(Cl)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cncc(O)c1C(=O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Methyl 4-(2'-fluoro-5'-chlorobenzoyl)-5-hydroxynicotinate of Preparative Example 25 (1.2 g) is added to a solution of sodium hydroxide (0.67 g) in water (4 mL) and methanol (12 mL). A yellow solution is obtained after 5 min. The mixture is stirred at room temperature for 1.25 h. The resulting solution is acidified with 1N hydrochloric acid (14 mL) to pH=2 and the mixture is allowed to stand overnight. The white solid is collected by filtration and washed with water (3×5 mL) and dried to yield 4-(2'-fluoro-5'-chlorobenzoyl)-5-hydroxynicotinic acid (1.04 g).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]1([N:21]2[C:29](=[O:30])[C:28]3[C@@H:27]4[C:31]([CH3:33])([CH3:32])[C@@:24]([CH3:34])([CH2:25][CH2:26]4)[C:23]=3[NH:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O.CO>[CH2:1]([N:22]1[C:23]2[C@@:24]3([CH3:34])[C:31]([CH3:33])([CH3:32])[C@H:27]([CH2:26][CH2:25]3)[C:28]=2[C:29](=[O:30])[N:21]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2)n1Cc1ccccc1
Temperature: 25 °C
Yield: 4 %

Procedure:
A mixture of benzyl bromide (1.54 mL, 13.0 mmol), potassium carbonate (3.58 g, 25.9 mmol), and (4S,7R)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 1.74 g, 6.5 mmol) in acetone (20 mL) and methanol (3 mL) was heated at reflux overnight, then a further portion of benzyl bromide (0.75 mL, 6.3 mmol) was added and the reaction mixture was allowed to stir at room temperature over the weekend. The solvent was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was evaporated and the residue was chromatographed (0-50% ethyl acetate/hexanes), and recrystallized from ethyl acetate/hexanes to give (4S,7R)-1-benzyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (94 mg, 3%) as a white solid. APCI-MS (M+H) 359.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:30][CH3:31])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])[C:11](=[O:32])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.I[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[N:41]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C1CCCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:30][CH3:31])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])[C:11](=[O:32])[C@H:10]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[N:41]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(CI)n1
Reactant: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)[C@H](Cc2cccc(OC)n2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
To a solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)piperidin-2-one (Example 420, Step A, 0.7 g, 1.413 mmol) in THF (5.65 ml) at −78° C. was added dropwise sec-butyllithium, (1.4 M in cyclohexane, 1.06 ml, 1.483 mmol). The reaction was warmed to −10° C. After about 5 minutes, the reaction was returned to a −78° C. bath. A solution of 2-(iodomethyl)-6-methoxypyridine (Example 420, Step B, 0.387 g, 1.554 mmol) in THF (1 mL) was added dropwise to the cooled reaction mixture. The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction contents were poured into saturated sodium bicarbonate and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (step gradient elution 5 to 50% diethyl ether in dichloromethane) afforded the title compound as the more polar diastereomer.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH:21]2C(O)=O)=O)=[CH:16][CH:15]=1.C(OC(C)C)(C)C>C(OC(=O)C)(=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]2[N:20]3[C:21]([CH2:22][CH2:23][CH2:24]3)=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)C#Cc1ccccc1
Reactant: O=C(O)C1CCCN1C(=O)c1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)OC(C)C
Product: COC(=O)c1c(-c2ccccc2)c(-c2ccc(F)cc2)n2c1CCC2
Temperature: 28 °C
Reaction time: 4 h

Procedure:
Methyl phenylpropiolate (methyl dehydrocinnamate (0.96 g, 6 mmol)) is dissolved in acetic anhydride (14 ml) and brought to the boiling temperature of acetic anhydride in a hot oil bath (140° C.). The total amount of 1-(4-fluorobenzoyl)pyrrolidine-2-carboxylic acid (1.42 g, 6 mmol) is added, and the thoroughly mixed solution is refluxed (1 28° C.) for 20 h with stirring. After standing for 4 hours and cooling to RT, a pure crystalline solid deposits (TLC: Al2O3, diisopropyl ether, Rf 0.7). The crystals are filtered off with suction, washed with water (20 ml) and finally with isopropyl ether (10 ml). The dried crystals weigh 650 mg (32.5% of theory)