Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][O:9][C:10]([CH3:21])([CH2:18][CH:19]=[CH2:20])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1>C(OCC)(=O)C.[Pd]>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][O:9][C:10]([CH3:21])([CH2:18][CH2:19][CH3:20])[C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:3]1
Reactant: C=CCC(C)(OC[C@@H]1CCC[C@H](O)C1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(C)(OC[C@@H]1CCC[C@H](O)C1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.4 g of tert-butyl 2-((1R,3S)-3-hydroxycyclohexylmethoxy)-2-methylpent-4-enoate are issolved in 15 ml of ethyl acetate and, under an argon atmosphere in an autoclave, a patula tip of Pd/C (10%) is added. The autoclave is then flushed with H2, and the solution is stirred with an H2 pressure of 3 bar at RT overnight. The catalyst is then iltered off through Celite, and the filtrate is concentrated, resulting in 2.3 g of tert-butyl 2-((1R,3S)-3-hydroxycyclohexylmethoxy)-2-methylpentanoate as a mixture of two iastereomers as pale yellow oil.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.CON(C)[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([CH3:23])[CH:17]=1>C1COCC1>[CH3:23][C:18]1[CH:17]=[C:16]([C:15]([C:11]2[N:7]([CH3:6])[N:8]=[N:9][CH:10]=2)=[O:24])[CH:21]=[C:20]([CH3:22])[N:19]=1
Reactant: Cn1ccnn1
Reactant: CON(C)C(=O)c1cc(C)nc(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cnnn2C)cc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of n-BuLi (3.8 mL, 9.5 mmol, 2.5 M solution in hexane) was added slowly to a solution of 1-methyl-1H-1,2,3-triazole (0.83 g, 10 mmol) in THF (48 mL) at −50° C. After addition, stirring was continued for an additional 30 minutes and N-methoxy-N,2,6-trimethylisonicotinamide (0.97 g, 5.0 mmol, Intermediate 29: step a) dissolved in THF (12 mL) was slowly added. An additional 2 mL of THF was used to complete the quantitative addition. The mixture was stirred at −50° C. for 5 minutes then warmed to room temperature and stirred overnight. The solution was quenched with saturated aqueous NH4Cl. H2O was added and layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified using flash column chromatography (0 to 100% EtOAc/DCM) to provide the title compound.
Reaction SMILES: [C:1](Cl)(=O)C.[C:5]([C@H:8]1[CH2:11][C@@H:10]([C:12]([OH:14])=[O:13])[C:9]1([CH3:16])[CH3:15])(=[O:7])[CH3:6]>CO>[C:5]([C@H:8]1[CH2:11][C@@H:10]([C:12]([O:14][CH3:1])=[O:13])[C:9]1([CH3:16])[CH3:15])(=[O:7])[CH3:6]
Reactant: CC(=O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](C(C)=O)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (1.02 ml, 14.32 mmol) was added dropwise to MeOH (10 mL) at 0° C. and the resulting mixture was stirred at 0° C. for 30 mins. (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid from Step 1 (696 mg, 4.09 mmol) was added as a solution in MeOH (2 mL) and the reaction mixture was stirred overnight while warming up to room temperature. The volatiles were then removed under reduced pressure and the residue was purified by flash chromatography on silica gel (gradient elution, 2% to 20% EtOAc in Hexanes) to give methyl (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylate as a colorless oil. MS ESI calc'd. for C10H17O3 [M+H]+ 185. found 185. 1H NMR (500 MHz, CDCl3) δ 3.66 (s, 3H), 2.88 (dd, J=10.5, 7.6 Hz, 1H), 2.78 (dd, J=10.8, 8.1 Hz, 1H), 2.64 (app q, J=10.8 Hz, 1H), 2.06 (s, 3H), 1.92-1.87 (m, 1H), 1.43 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:28][CH2:29][CH3:30])=[N:11][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:19][C:16]([F:17])([F:18])[C:15]([C:12]1[N:11]=[C:10]([CH2:28][CH2:29][CH3:30])[C:9]([OH:8])=[CH:14][CH:13]=1)([O:24][CH2:25][O:26][CH3:27])[C:20]([F:23])([F:22])[F:21]
Reactant: CCCc1nc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCc1nc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Yield: 94 %

Procedure:
3-(Benzyloxy)-6-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylpyridine (407 mg, 0.931 mmol) was dissolved in ethanol (2.0 mL) and added with palladium carbon (40 mg). The resultant mixture was stirred under hydrogen atmosphere for 2 hours. After completion of the reaction, the reaction solution was filtered using celite and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 6-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylpyridin-3-ol (304 mg, yield 94%) was obtained as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[C:9]2[C:10]([NH:15]C(=O)C(C)(C)C)=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[NH2:15][C:10]1[C:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[OH:22])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)C(=O)Nc1ncccc1C(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ncccc1C(O)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
To a solution of N-{3-[(4-fluoro-phenyl)-hydroxy-methyl]-pyridin-2-yl}pivalamide (890 mg, 2.94 mmol) in ethanol (44 mL) was added 2 N aqueous sodium hydroxide solution (7.36 mL, 14.7 mmol). The reaction was heated to 100° C. for 5 hours. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield the title compound as a as a light yellow solid (548 mg, 85%) without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)n(Cc2cc(Cl)ccc2O)n1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C)n(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2)n1
Temperature: 100 °C
Yield: 66.8 %

Procedure:
To a solution of 1-(5-Chloro-2-hydroxy-benzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester 2 (0.6 g, 2.0 mmol) in DMF (5 mL) were added potassium carbonate (0.84 g, 6.1 mmol), potassium iodide (0.34 g, 2.0 mmol) and 4-chlorobenzylbromide (0.38 g, 2.2 mmol). The resulting mixture was heated at 100° C. overnight. The mixture was poured into water (20 mL) and extracted with Et2O (3×15 mL). The organic layers were combined, washed with brine (30 mL), dried (Na2SO4) and the volatiles were removed in vacuo to give 0.56 g (71%) of 1-(2-Benzyloxy-5-chloro-benzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester 3 as a white solid.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([C:21]#[C:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][CH2:23][O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: Nc1ccc(C#CCOC2CCCCO2)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)c(F)c1Nc1ccc(C#CCOC2CCCCO2)cc1F

Procedure:
2,3,4-Trifluorobenzoic acid and 2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]aniline were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B. After workup, followed by purification by chromatography on silica gel (50% EtOAc/PE as eluant), 3,4-difluoro-2-{2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]anilino}benzoic acid was isolated as a cream-yellow solid (68%); m.p. (Et2O/hexane) 164–166° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.60 (v br s, 1 H), 9.27 (br s, 1 H), 7.83 (ddd, J=8.2, 6.1, 1.9 Hz, 1 H), 7.36 (dd, J=12.0, 1.7 Hz, 1 H), 7.21–7.11 (m, 2 H), 6.96 (td, J=8.8, 5.5 Hz, 1 H), 4.80 (br s, 1 H), 4.47 (d, J=16.0 Hz, 1 H), 4.38 (d, J=16.0 Hz, 1 H), 3.79–3.71 (m, 2H), 3.51–3.45 (m, 2 H), 1.77–1.61 (m, 2 H), 1.56–1.44 (m, 4 H). Anal. calcd. for C21H18F3NO4: C, 62.2; H, 4.5; N, 3.5. Found C, 62.5; H, 4.4; N, 3.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17].C(N(CC)CC)C>C(#N)C>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][N:13]1[CH2:14][CH2:15][CH:10]([C:8](=[O:9])[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11][CH2:12]1)[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 85 °C
Reaction time: 15 h
Yield: 81.6 %

Procedure:
To a suspension of (4-chloro-phenyl)-piperidin-4-yl-methanone (1.0 g, 3.8 mmol) and bromo-acetic acid ethyl ester (0.71 g, 4.2 mmol) in acetonitrile (10 mL) was added triethylamine (0.78 g, 7.7 mmol), the reaction mixture was stirred at 85° C. for 15 h. The reaction mixture was cooled to ambient temperature, the solvent was removed, the residue was redissolved in DCM (20 mL), washed with water (20 mL), the organic layers were then washed with brine (20 mL) and dried over Na2SO4. Purification by flash chromatography gave the title compound as a white solid (1.01 g, 3.10 mmol, 81% yield). MS (ESI) m/z 310.3 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.45 min.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:40][CH3:41])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[O:21][C:20]2=[O:39])[CH:7]=1.N#N.[CH3:44][S:45]SC.N(OC(C)(C)C)=O>C(Cl)(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:27]1[CH:26]=[C:25]([C@H:22]2[O:21][C:20](=[O:39])[N:19]([CH2:18][C:9]3[CH:10]=[C:11]([C:14]([F:15])([F:17])[F:16])[CH:12]=[CH:13][C:8]=3[C:6]3[CH:7]=[C:2]([S:45][CH3:44])[CH:3]=[CH:4][C:5]=3[O:40][CH3:41])[C@H:23]2[CH3:24])[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=1
Reactant: COc1ccc(N)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: CSSC
Agent: CC(C)(C)ON=O
Agent: N#N
Solvent: ClC(Cl)Cl
Product: COc1ccc(SC)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4S,5R)-3-{[5′-amino-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Example 123) (40 mg, 0.0676 mmol) in CHCl3 (1 mL) that had been degassed with N2 was added methyl disulfide (10 μL, 0.101 mmol) and t-butyl nitrite (16 μL, 0.135 mmol). The reaction was stirred at room temperature for 30 minutes and then heated to reflux for 2 hours. The reaction was then cooled to room temperature and diluted with hexanes (3 mL). The solution was loaded directly onto a silica gel column and eluted with 25% EtOAc/hexanes. Fractions containing the desired product were combined and repurified by silica gel chromatography with 5 to 25% EtOAc/hexanes to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylthio)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.52 (40% EtOAc/hexanes). LCMS=624.1 (M+1)+. 1H NMR (CDCl3, 600 MHz, rotamers present) δ 6.94-7.85 (m, 9H), 5.58 (d, J=8.1 Hz) 5.25 (d, J=7.8 Hz), 4.94 (d, J=15.8 Hz), 4.85 (d, J=15.7 Hz), 3.65-4.12 (m, 5H), 2.47 (s), 2.44 (s), 0.54 (d, J=6.6 Hz), 0.40 (d, J=6.6 Hz).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([NH:22][CH:23]3[CH2:25][CH2:24]3)=[CH:20][C:19]([F:26])=[CH:18][N:17]=2)[CH2:12]1.C(N(CC)C(C)C)(C)C.Cl[C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([N:15]2[C:16]3=[N:17][CH:18]=[C:19]([F:26])[CH:20]=[C:21]3[N:22]([CH:23]3[CH2:24][CH2:25]3)[C:37]2=[O:39])[CH2:12]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Fc1cnc(N[C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c(NC2CC2)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=c1n(C2CC2)c2cc(F)cnc2n1[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 25 °C

Procedure:
N2-(Trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-N3-cyclopropyl-5-fluoropyridine-2,3-diamine (0.051 g, 0.138 mmol) was dissolved in a mixture of dichloromethane (10 mL) and N,N-diisopropylethylamine (0.100 ml, 0.575 mmol) and cooled in an ice bath under nitrogen. Triphosgene (0.041 g, 0.138 mmol) was added in one portion. The reaction allowed to stir in the ice bath and warm to room temperature over 14 hours. Water (5 mL) and dichloromethane (10 mL) were added and the reaction stirred vigorously. The phases were separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (first column 0-10% methanol in dichloromethane gradient, repurify using hexane to ethyl acetate gradient) gave 3-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-1-cyclopropyl-6-fluoro-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.017 g, 0.043 mmol, 31.1% yield). M+1: 396. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97-1.04 (m, 2 H) 1.10-1.17 (m, 2 H) 2.47-2.58 (m, 2 H) 2.88 (tt, J=6.92, 3.55 Hz, 1 H) 3.45-3.58 (m, 2 H) 4.55-4.65 (m, 1 H) 5.33 (quin, J=8.46 Hz, 1 H) 6.16 (br. s., 1 H) 7.05-7.12 (m, 1 H) 7.17 (dd, J=8.22, 2.35 Hz, 1 H) 7.25-7.35 (m, 1 H) 7.57 (d, J=8.02 Hz, 1 H) 7.60 (d, J=7.82 Hz, 1 H) 7.93 (t, J=2.15 Hz, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N+:14]([O-:16])=[O:15])[C:7]2[O:11][CH:10]([CH3:12])[CH2:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[NH3:17].COCCO>O>[NH2:17][C:7]1[C:6]([N+:14]([O-:16])=[O:15])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=1[CH2:9][CH:10]([OH:11])[CH3:12]
Reactant: N
Reactant: CC1Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2O1
Solvent: O
Solvent: COCCO
Product: CC(O)Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N
Temperature: 70 °C

Procedure:
0.39 Mole (88 g) of 2,3-dihydro-5,7-dinitro-2-methylbenzofuran, prepared according to J.A.C.S. 80, p. 4711-4714 (1958), is suspended in 1.1 l of 20% strength ammonia solution and 600 ml of Methyl Cellosolve. After 18 hours' heating at 70° C., the reaction mixture is cooled. The precipitate formed is drained and, after being made into a paste in water until neutral and then dried under vacuum, is recrystallized from 170 ml of dioxane. After being dried under vacuum, 0.30 mole (72 g) of the expected product is obtained; it melts at 177° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH2:5].O([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])S(C(F)(F)F)(=O)=O>ClCCl>[CH:15]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:1][CH2:2][CH2:3][CH2:4][NH2:5])([CH3:17])[CH3:16]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: NCCCO
Solvent: ClCCl
Product: CC(C)[Si](OCCCN)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Hydroxylpropylamine (100 μL, 1.31 mmol) was dissolved in dichloromethane (4.4 mL), and triisopropylsilyl triflate (371 μL, 1.38 mmol) was added dropwise at room temperature. After stirring at room temperature for 15 minutes, the mixture was worked up according to a conventional method to give the title compound as a crude product.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:10][C:9]2[N:8]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:7]3=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:17]([O:20][CH2:21][C:22]1[C:27]([Br:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=1Br)(=[O:19])[CH3:18].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:13]2[CH2:12][CH2:11][N:8]3[C:9]4[CH2:10][C:2]([F:1])([F:16])[CH2:3][CH2:4][C:5]=4[CH:6]=[C:7]3[C:14]2=[O:15])=[CH:24][C:25]([F:29])=[CH:26][C:27]=1[Br:28])(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(Br)cc(F)cc1Br
Reactant: O=C1NCCn2c1cc1c2CC(F)(F)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CC(F)(F)CC3)C1=O
Temperature: 100 °C
Yield: 59.2 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 1,4-dioxane (40 mL), 113o (890 mg, 3.94 mmol), 2,6-dibromo-4-fluorobenzyl acetate 101c (3847 mg, 11.8 mmol), Pd2(dba)3 (180 mg, 0.197 mmol), XantPhos (227 mg, 0.394 mmol), and cesium carbonate (2.57 g, 7.88 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 16 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 petroleum ether/ethyl acetate to afford 113p (1100 mg, 62%) as a white solid. MS-ESI: [M+H]+ 471.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2].[CH3:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>O.C(OCC)(=O)C.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]>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:47]=[CH:48][C:43]([S:40]([CH3:39])(=[O:42])=[O:41])=[CH:44][CH:45]=3)[CH:25]=[C:26]([CH2:28][OH:29])[CH:27]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CO)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(CO)cc(-c3ccc(S(C)(=O)=O)cc3)c2)c1CCC(=O)OCC
Temperature: 96 °C
Reaction time: 15 h
Yield: 55.1 %

Procedure:
To a mixture of 4-[3-[6-(3-bromo-5-hydroxymethyl-phenoxy)-hexyl]-2-(2-ethyoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.0 g, 3.34 mmol), 4-methanesulfonylphenylboronic acid (1.35 g, 6.74 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (369.8 mg, 0.51 mmol), and cesium carbonate (2.22 g, 6.74 mmol) was added dimethoxyethane (100 mL) at room temperature under nitrogen atmosphere. The resulting brown reaction mixture was heated to 96° C. and stirred for 15 h at which time the TLC analysis of the reaction mixture indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The two layers were separated and the aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with water and brine solution. The organic layer was dried over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent under vacuum gave the colored residue which was purified by using an ISCO 120 g column to obtain 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-hydroxymethyl-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (1.23 g, 55%) as a light brown oil: ES(+)-HRMS m/e calcd for C37H48O9S (M+Na)+ 691.2911. found 691.2913.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]#[N:20])=[C:13]1[C:12]1[C:7](=[C:8]([Cl:23])[C:9]([O:21]C)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl.N1C=CC=CC=1>>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]#[N:20])=[C:13]1[C:12]1[C:7](=[C:8]([Cl:23])[C:9]([OH:21])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(C#N)=C1c1ccc(OC)c(Cl)c1C2
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC12CCC(=O)C(C#N)=C1c1ccc(O)c(Cl)c1C2
Temperature: 200 °C

Procedure:
A mixture of 9a-butyl-8-chloro-4-cyano-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (65 mg) and pyridine hydrochloride (4.2 g) was heated in an oil bath at 200° C. for 85 minutes. After cooling to room temperature, the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by preparative layer chromatography on two 0.1×20×20 cm silica gel GF plates, developing with 5% MeOH in CH2Cl2. The product bands were eluted with 10% MeOH in CH2Cl2, the eluant evaporated under vacuum, and the residue lyophilized from benzene (3 mL) plus EtOH (0.1 mL) to afford 9a-butyl-8-chloro-4-cyano-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous yellow solid.
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].[CH3:9][O:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=O)[CH:32]=1.[Cl-].[NH4+]>CCOCC>[CH3:9][O:10][CH:11]=[CH:37][C:33]1[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1cccnc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Agent: [NH4+]
Solvent: CCOCC
Product: COC=Cc1cccnc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
Phenyllithium (111 ml of 1.8M solution in ether) was added dropwise to a stirred suspension of (methoxymethyl) triphenylphosphonium chloride (68.6 g) in dry ether (600 ml) at -50° C. The mixture was stirred at -50° C. for 2 hours and then allowed to reach 0° C. over 30 minutes. 3-Pyridinecarboxaldehyde (10.70 g) was added dropwise with stirring, and the mixture was stirred at room temperature for 18 hours. Anexcess of ammonium chloride solution was then added and the layers were separated. The aqueous layer was separated and washed with ether, and the organic layers were combined and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel initially using ethyl acetate/hexane (1:4) as eluant. The polarity was gradually increased to ethyl acetate/hexane (1:1) to give the pure product as an oil(8.82 g) which was used directly in the next stage.