Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH2:29]([O:39][C:40]([NH:42][C:43]1[N:51]=[CH:50][N:49]=[C:48]2[C:44]=1[N:45]=[CH:46][N:47]2[CH2:52][C:53](O)=[O:54])=[O:41])[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:53](=[O:54])[CH2:52][N:47]1[CH:46]=[N:45][C:44]2[C:48]1=[N:49][CH:50]=[N:51][C:43]=2[NH:42][C:40]([O:39][CH2:29][C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1)=[O:41])[CH3:2]
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccc4c(c3)OCO4)ncnc21
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1cnc2c(NC(=O)OCc3ccc4c(c3)OCO4)ncnc21

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [6-N-(piperonyloxycarbonyl)-adenin-9-yl]-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 10.60 (s, 0.45H), 10.59 (s, 0.55H), 9.31 (brs, 0.55H), 9.11 (brs, 0.45H), 8.58 (s, 0.45H), 8.57 (s, 0.55H), 8.40 (d, 0.55H), 8.39 (d, 0.45H), 8.32 (s, 0.55H), 8.31 (s, 0.45H), 8.03–7.98 (m, 1H), 7.93 (d, 0.55H), 7.90 (d, 0.45H), 7.05 (s, 1H), 6.95 (d, 1H), 6.91 (d, 1H), 6.02 (s, 2H), 5.38 (s, 1.1H), 5.17 (s, 0.9H), 5.11 (s, 2H), 4.48 (s, 0.9H), 4.23 (q, 0.9H), 4.08 (s, 1.1H), 4.07 (q, 1.1H), 3.73 (t, 1.1H), 3.54 (t, 1.1H), 3.45 (t, 0.9H), 3.30 (t, 0.9H), 1.27 (t, 1.35H), 1.15 (t, 1.65H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14]([CH3:26])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)[CH3:9].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29].C(=O)(O)[O-].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:26])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[O:27])=[CH:19][C:20]=2[CH3:25])=[CH:35][CH:34]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1cc(-c2onc(C)c2NC(=O)O[C@H](C)c2ccccc2F)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3F)cc2C)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
[5-(4-Bromo-3-methyl-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester (0.350 g, 0.80 mmol), [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.292 g, 0.96 mmol), and sodium bicarbonate (0.235 g, 2.8 mmol) were combined in 2:1 DME:water (11 mL), and the solution was purged with N2 for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.030 g, 0.04 mmol) was added, and the reaction was stirred at 80° C. for 2 hour. After work-up, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: ClC1C=CC(C(C2C=C(C=CC=2)/C=C/[C:19]([OH:21])=[O:20])N2CCN(C)CC2)=CC=1.Br[C:28]1[CH:29]=[C:30]([CH:46]=[CH:47][CH:48]=1)[CH:31]([N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1>O1CCCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:31]([C:30]2[CH:29]=[C:28]([CH:48]=[CH:47][CH:46]=2)[C:19]([OH:21])=[O:20])[N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)=[CH:33][CH:34]=1
Reactant: CN1CCN(C(c2ccc(Cl)cc2)c2cccc(Br)c2)CC1
Reactant: CN1CCN(C(c2ccc(Cl)cc2)c2cccc(/C=C/C(=O)O)c2)CC1
Solvent: C1CCOC1
Product: CN1CCN(C(c2ccc(Cl)cc2)c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
The intermediate from Example 1, 1-(3-bromo-4'-chlorobenzhydryl)-4-methylpiperazine (1.10 g, 2.90 mmol), was dissolved in 10 mL of dry tetrahydrofuran and dried further over 4A molecular sieves for 24 hours. The solution was transferred to a dry flask under nitrogen and cooled to -78°. n-Butyllithium in hexane (1.1M, 2.6 ml) was added dropwise and the solution was stirred for 10 minutes at -78°. Carbon dioxide gas was bubbled into the reaction until the red solution turned yellow. The reaction was warmed to room temperature and the solvent was evaporated. The residue was dissolved in 20 mL of water and made basic with several drops of 1M sodium hydroxide. The aqueous solution was extracted with two 50 mL portion of ether and the pH was adjusted to 7-8 with 1M hydrochloric acid. After chilling in an ice bath, the precipitate was collected by filtration to give 341 mg (33%) of 3-(4-chloro-α-(4-methyl-1-piperazinyl)benzyl)benzoic acid as a white powder, m.p. 225°-230° (dec.). Calc. for C19H21ClN2O2. 0.75 H2O: C, 63.68; H, 6.33; N, 7.82; Cl, 9.89. Found: C, 63.68; H, 6.34; N, 7.82; Cl, 9.89.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[O:7]1)=[O:5])[CH3:2].[N:25]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].CCCC[Sn](OC(C)=O)(CCCC)CCCC>CC(O)(C)C.CCO.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12]([NH:13][CH2:14][C:15]2[N:27]=[N:26][N:25]([C:28]3[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=3)[CH:16]=2)=[O:17])[O:7]1)=[O:5])[CH3:2]
Reactant: C#CCNC(=O)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc(N)cc2)nn1
Yield: 85.8 %

Procedure:
The general click procedure was used substituting the following quantities using: 37 (29.5 mg, 0.084 mmol); 4-azidoaniline (11.3 mg, 0.084 mmol); CuSO4 (3.0 mg, 0.02 mmol); NaAsc (7.0 mg, 0.03 mmol); TBTA (5.0 mg, 0.009 mmol); in t-BuOH/EtOH/H2O (2:1:0.5); afforded 48 as a white solid (35 mg, 85.9%). 1H NMR (400 MHz, CDCl3): d=8.73 (s, 1H); 8.18 (bs, 1H); 7.86 (s, 1H); 7.85-7.83 (d, 1H, J=8.17 Hz); 7.46-7.35 (d, 2H, J=8.58 Hz); 7.06 (s, 1H); 6.80-6.78 (d, 2H, J=8.62 Hz), 4.78-4.77 (q, 1H): 4.48-4.47 (d, 2H, J=5.60 Hz); 4.29-4.23 (m, 2H); 3.65-3.64 (d, 1H, J=1.59 Hz): 3.51-3.51 (d, 1H, J=1.59 Hz); 3.41-3.24 (m, 2H): 1.33-1.30 (t, 3H). 13C NMR (100 MHz, CDCl3): 169.12, 166.74, 166.14, 153.09, 151.8, 147.32, 144.44, 127.90, 121.86, 120.73, 115.77, 115.0, 62.07, 53.39, 52.23, 34.51, 34.39, 32.70, 13.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2/[CH:26]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccc(Cl)cc23)cc(OC)c1OC
Yield: 79.2 %

Procedure:
Substantially the same procedure as in Example 12 was repeated using 3',4',5'-trimethoxyacetophenone (2.1 g) and 5-chloroindole-3-carboxaldehyde (1.8 g) to give Compound 30 (2.94 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:5][C:6]=1[CH:7]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].B1([C:40]2[NH:44][N:43]=[CH:42][CH:41]=2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC.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]>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[CH:7]([C:6]1[CH:5]=[C:4]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[S:3][C:2]=1[C:40]1[NH:44][N:43]=[CH:42][CH:41]=1)[N:8]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:9][CH2:10]2
Reactant: CC1(C)OB(c2ccn[nH]2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)ccc2C1c1cc(-c2ccncc2)sc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCc2cc(Cl)ccc2C1c1cc(-c2ccncc2)sc1-c1ccn[nH]1
Temperature: 95 °C

Procedure:
A mixture of tert-butyl 1-(2-bromo-5-pyridin-4-yl-3-thienyl)-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (72.0 mg, 0.142 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxabolone)-pyrrazole (27.6 mg, 0.142 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (11.7 mg, 0.0142 mmol) and sodium carbonate (29 mg, 0.27 mmol) in 1,2-dimethoxyethane (3.0 mL, 29 mmol) and water (1.0 mL, 56 mmol) was heated at 95° C. for 4.5 h. A LCMS showed the desired product together with unreacted starting material. Additional [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (11.7 mg, 0.0142 mmol) 3-(4,4,5,5-Tetramethyl-1,3,2-dioxabolone)-pyrrazole (56 mg, 0.29 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol), sodium carbonate (100 mg, 0.9 mmol) and 1,2-dimethoxyethane (3.0 mL, 29 mmol) were added. The mixture was heated at 100° C. for another 4 h. The mixture was dry-loaded onto silica gel and purified by chromatography to afford tert-butyl 6-chloro-1-[2-(1H-pyrazol-5-yl)-5-pyridin-4-yl-3-thienyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (41 mg, 58%). LCMS AA ES+ 493.2, 495.1.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:10][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1.[CH:21](O)=O.C=O.[OH-].[Na+]>O>[Br:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][N:16]([CH3:21])[CH2:15][CH2:14]3)[O:10][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c2cc(COC3CCNCC3)oc12
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Br)c2cc(COC3CCN(C)CC3)oc12
Temperature: 95 °C

Procedure:
4-(4-Bromo-7-methoxybenzofuran-2-ylmethoxy)-piperidine (0.98 g), formic acid (0.65 ml) and formaldehyde (0.56 g of a 37% w/w solution in water) were combined and heated to 95° C. overnight. After cooling to room temperature the mixture was diluted with water (70 ml) and a concentrated aqueous solution of sodium hydroxide added until the solution was basic (pH=14). It was extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a pale yellow oil (1.03 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([C:17]3[CH:21]=[CH:20][N:19]([Si](C(C)C)(C(C)C)C(C)C)[CH:18]=3)=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]1=[O:39])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCOCC1.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([C:17]3[CH:21]=[CH:20][NH:19][CH:18]=3)=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:9]1=[O:39])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cccc3c2n(C(=O)OC(C)(C)C)c(=O)n3Cc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)n1c(=O)n(Cc2ccccc2)c2cccc(-c3cc[nH]c3)c21
Reaction time: 0.75 h
Yield: 82 %

Procedure:
To a solution of 3-benzyl-2-oxo-7-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (0.768 g, 1.40 mmol) in 30 ml 1,4-dioxane was added tetrabutylammonium fluoride (1.548 mL of a 1M solution in tetrahydrofuran, 1.548 mmol) dropwise over 5 minutes. The reaction mixture was stirred for 45 minutes, and was then added to 200 mL of 1:1 water/ethyl acetate. The layers were separated and the aqueous layer was extracted twice with 100 mL ethyl acetate. The combined organic fractions were dried over sodium sulfate and concentrated in vacuo and purified by flash chromatography (20 to 40% gradient ethyl acetate in hexanes) to give 0.447 g of crude 3-benzyl-2-oxo-7-(1H-pyrrol-3-yl)-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester. This material was dissolved in 7 mL tetrahydrofuran and cooled to 0° C. under nitrogen. To this solution was added di-tert-butyldicarbonate (0.752 g, 3.45 mmol) and 4-dimethylaminopyridine (14 mg, 0.115 mmol) and stirring was continued for one hour as the reaction mixture was allowed to warm to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (1 to 10% gradient ethyl acetate in hexanes) to give 0.550 g of 3-benzyl-7-(1-tert-butoxycarbonyl-1H-pyrrol-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester, MS: 490 (M+H)+.
Reaction SMILES: [NH:1]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>COCCOC>[CH2:23]([N:1]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCCCCS(=O)(=O)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)CCCCCS(=O)(=O)N(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
To a cold solution (ice bath) of ethyl 6-(anilinosulfonyl)hexanoate (64b) (0.86 g, 2.88 mmol) in 1,2-dimethoxyethane (5 ml) a 60% suspension of sodium hydride in mineral oil (0.12 g, 3.0 mmol) and a solution of benzylbromide (0.49 g, 2.88 mmol) in 1,2-dimethoxyethane (3 ml) were added, and the resulting solution was stirred at ambient temperature for 24 hours. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel with petroleum ether-tert-butylmethyl ether (3:2, v/v) as eluent to give the title compound (0.56 g, 50%) as an oil. 1H NMR (DMSO-d6, HMDSO), δ: 1.16 (3H, t, J=7.0 Hz); 1.21-1.87 (6H, m); 2.27 (2H, t, J=6.6 Hz); 3.21 (2H, t, partially overlapped with a signal of H2O, J=7.6 Hz); 4.05 (2H, q, J=7.0 Hz); 4.89 (2H, s); 7.14-7.58 (10H, m).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[I-].[K+].Cl[CH2:26][CH2:27][CH2:28][C:29]#[CH:30]>CS(C)=O>[F:7][C:8]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:30][CH2:29][CH2:28][C:27]#[CH:26])=[CH:15][CH:16]=1
Reactant: C#CCCCCl
Reactant: Oc1ccc(Oc2ccc(F)cc2F)cc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCCCOc1ccc(Oc2ccc(F)cc2F)cc1
Temperature: 25 °C

Procedure:
With cooling, a solution of 4.2 g of potassium tert-butoxide in 20 ml of anhydrous dimethyl sulfoxide is added to a solution of a 8 g of 4-(2,4-difluorophenoxy)phenol in 20 ml of anhydrous dimethyl sulfoxide and 0.3 g of finely powdered potassium iodide. With stirring, a solution of 4,4 g of 1-chloro-4-pentine in 5 ml of dimethyl sulfoxide is added dropwise at 10°-15° C. to the above mixture. After 2 hours the reaction mixture is warmed to room temperature (20°-23° C.) and stirred for 24 hours at this temperature. The reaction mixture is then poured into ice-water and extracted repeatedly with a 1:2 mixture of diethyl ether/hexane. The combined organic phases are washed until neutral with cold 10% aqueous sodium hyroxide and then with water and dried over sodium sulfate. The solvent is removed by vacuum distillation and the residue is further purified by chromatography over silica gel 60 (eluant: 1:9 mixture of diethyl ether/n-hexane), affording the pure 1-[4-(2,4-difluorophenoxy)-phenoxy]-4-pentine with a refractive index nD22 =1.5392.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15](OC(=O)C)(=O)C>CS(C)=O.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[CH2:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: C=C(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a stirred solution of methyl 2-(4-nitrophenyl)acetate (8.0 g, 40.994 mmol, 1.0 eq) in DMSO (40 mL) was added tetramethyldiaminomethane (8.38 mL, 61.491 mmol, 1.5 eq) followed by acetic anhydride (12.78 mL, 135.17 mmol, 3.3 eq) at RT and the mixture was stirred for 2 h. The reaction mixture was diluted with water (40 mL), extracted with ether (80 mL×2) and the solvent evaporated. The crude product was purified by CC using EtOAc/PE (1:9) as eluent) to get methyl 2-(4-nitrophenyl)acrylate (4.0 g, 47%, solid; TLC system: EtOAc/PE (3:7), Rf: 0.60).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Li+].[BH4-]>C1COCC1>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (3.02 g, 11.8 mmole) in THF (100 mL), is added to LiBH4 (1.75 g, 80.24 mmole) in one portion at 0° C. The reaction is kept at 0° C. for 15 minutes and warmed up to room temperature for 1 hour. The reaction is quenched using 5N HCl (100 mL) at 0° C. The THF is removed on rota vapor, the aqueous solution is then extracted with ethyl acetate (2×100 mL). The combined organic solution is washed with brine (3×200 mL), dried over Na2SO4 and concentrated. The crude product is purified on a silica gel column, eluting with 20% ethyl acetate in hexane and concentrated to provide the titled compound as off-white solid.
Reaction SMILES: I.[I:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15].[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][C:27]([C:30]([O-])=[O:31])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH3:17].[Na+].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[I:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:30]([C:27]1[CH:28]=[N:29][C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH2:16][CH3:17])[CH2:23][CH2:22]2)=[CH:25][CH:26]=1)=[O:31]
Reactant: NCCCCCCCCCCCCI
Reactant: CCN1CCN(c2ccc(C(=O)[O-])cn2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: I
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCI)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
To 170 mg of 12-iodododecylamine hydroiodide were added 120 mg of sodium 6-(4-ethyl-1-piperazinyl)-pyridine-3-carboxylate, 10 ml of methylene chloride, 95 mg of 1,3-dicyclohexylcarbodiimide (DCC) and 12 mg of 1-hydroxybenzotriazole (HOBt) and the mixture was stirred at room temperature for 3 hours. Insolubles were filtered off and the filtrate was chromatographed over a silica gel column to afford 169.5 mg of the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:45])=[N:17][C:18]([CH3:44])=[C:19]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:30][CH:29]=2)[C:20]=1[N:21]1[CH2:24][CH:23]([CH:25]([CH3:27])[CH3:26])[CH2:22]1)[C:9]([O:11]C(C)C)=[O:10])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:45])=[N:17][C:18]([CH3:44])=[C:19]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:33]=2)[C:20]=1[N:21]1[CH2:24][CH:23]([CH:25]([CH3:27])[CH3:26])[CH2:22]1)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(C(C)C)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CC(C(C)C)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
The 0.98 mL of 1M sodium hydroxide (39.3 mg, 0.98 mmol) was added to a solution (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(3-isopropylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (145 mg, 0.245 mmol) in ethanol (3 mL) and stirred for 18 h at 90° C. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(4-fluoro-phenethoxy)phenyl)-4-(3-isopropylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid 99.4 mg (74%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.36 (t, J=8.1 Hz, 2H), 7.30 (br. s, 1H), 7.12 (t, J=8.8 Hz, 2H), 7.1 (d, J=8.1 Hz, 1H), 6.97 (d, J=8.1 Hz, 1H), 6.86 (br. s, 1H), 4.93 (s, 1H), 4.21 (t, J=6.6 Hz, 2H) 3.96 (br. s, 1H), 3.86 (br. s, 1H), 3.70 (br. s, 1H), 3.47 (br. s, 1H), 3.03 (t, J=6.2 Hz, 2H), 2.39 (s, 3H), 2.07 (s, 3H), 2.05-2.01 (m, 1H), 1.52-1.47 (m, 1H), 1.08 (s, 9H), 0.65 (d, J=6.2 Hz, 6H). UPLC (M+H)=549.5.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>>[CH3:13][N:14]([CH2:15][CH2:16][OH:17])[CH2:10][CH2:9][CH:8]([CH:5]1[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3][CH2:4]1)[CH3:12]
Reactant: CNCCO
Reactant: CC1=CCC(C(C)CC=O)CC1
Product: CC1=CCC(C(C)CCN(C)CCO)CC1

Procedure:
The procedure of Example 1 was followed using 50g (0.3 mole) of 3-(4-methyl-3-cyclohexenyl)butyraldehyde and 25g (0.33 mole) of 2-methylaminoethanol. Obtained following distillation was 27g of pure N-methyl-N-(2-hydroxyethyl)-N-[3 . . . butyl]amine as a clear, colorless liquid; bp 104°-106° (0.1mm); ir (τ max. film) 3.0 (m), 3.5 (s), 6.9 (s), 9.6 (s), 12.5 (m) microns; nmr (δ CDCl3) 5.38 (m, 1H), 3.8 (broad m, 1H) 3.6 (m, 2H), 2.5 (m, 4H), 2.2 (s, 3H), 2.1 to 0.8 (m, 16H) ppm; ms (molecular ion) 225.
Reaction SMILES: Br[C:2]1[C:3]([Cl:20])=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>O.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.CCO>[Cl:20][C:3]1[C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=2)=[CH:7][N:6]=[C:5]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(Br)cnc21
Reactant: OB(O)c1cccc(F)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(-c3cccc(F)c3)cnc21
Temperature: 80 °C
Yield: 73.8 %

Procedure:
5-Bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.660 g, 1.78 mmol), 3-fluorophenylboronic acid (0.298 g, 2.13 mmol), Pd(PPh3)4 (0.103 g, 0.0888 mmol) and 10% K2CO3 (aq., 3.70 mL, 2.66 mmol) were added to an argon degassed solution of 2:1 toluene:EtOH (6 mL). The reaction was then heated to 80° C. for 18 hours. The reaction was then diluted with water and extracted with DCM. The organic fractions were dried, filtered, concentrated, and purified by column chromatography (1:1 hexanes:DCM) to give 4-chloro-5-(3-fluorophenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.508 g, 73.9% yield).