Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([S:7][C:8]([F:11])([F:10])[F:9])[NH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.ClC1C=C(C=CC=1)C(OO)=[O:24].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:6]=[C:5]([S:7]([C:8]([F:11])([F:10])[F:9])=[O:24])[NH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: FC(F)(F)Sc1cc(Br)c(-c2ccc(Cl)cc2)[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=S(c1cc(Br)c(-c2ccc(Cl)cc2)[nH]1)C(F)(F)F
Reaction time: 2 h
Yield: 50.1 %

Procedure:
A solution of 3-bromo-2-(p-chlorophenyl)-5-[(trifluoromethyl)thio]pyrrole (0.65 g, 0.00182 mol) in chloroform is cooled with an ice-water bath, treated with a solution of 3-chloroperoxybenzoic acid (0.52 g, 60% pure, 0.00182 mol) in chloroform, stirred for two hours, treated with saturated sodium metabisulfite solution, diluted with methylene chloride, washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a white solid. Flash chromatography of the solid using silica gel and a 1:10 ethyl acetate/hexanes solution gives the title product as a white solid (0.34 g, mp 177°-179° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [AlH4-].[Li+].[CH:3]([N:6]1[C:10]([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=O)=[CH:23][C:18]=4[O:17][CH2:16][CH2:15][N:14]3[CH:27]=2)=[CH:9][CH:8]=[N:7]1)([CH3:5])[CH3:4]>O1CCCC1>[CH:3]([N:6]1[C:10]([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([CH2:24][NH2:26])=[CH:23][C:18]=4[O:17][CH2:16][CH2:15][N:14]3[CH:27]=2)=[CH:9][CH:8]=[N:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)n1nccc1-c1cn2c(n1)-c1ccc(C(N)=O)cc1OCC2
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1nccc1-c1cn2c(n1)-c1ccc(CN)cc1OCC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Lithium tetrahydroaluminate (0.047 g, 1.3 mmol) was suspended in tetrahydrofuran (8 mL) and cooled to 0° C. A solution of 2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide (0.3 g, 0.9 mmol) in tetrahydrofuran (2 mL) was added and the reaction mixture was stirred at cold temperature for 10 min. The flask was gradually brought to room temperature and stirred for 16 h. The reaction was quenched by pouring into a mixture of diethyl ether and saturated aqueous Rochelle's salt solution (1:1). The mixture containing significant emulsion was stirred very vigorously until the phases separated (ca. 2 h). The phases were partitioned and the aqueous layer was extracted numerous times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated to give (0.15 g, 0.46 mmol) (2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methanamine (MS (ESI+) m/z 323.1 (M+H+), calcd. 323.4) which was dissolved in glacial acetic acid (0.8 mL) and water (5 mL). A solution of potassium cyanate (0.114 g, 1.41 mmol) in water was added dropwise. N,N-dimethylformamide (3 mL) was added to help with dissolution. The resulting reaction mixture was stirred at room temperature for 12 h. Subsequently, the reaction was heated at 50° C. for 3 h. The mixture was cooled to room temperature and filtered to provide 0.02 g (10% yield) of 337. MS(ESI+) m/z 367.1 (M+H+), calcd. 367.4. 1H NMR (400 MHz, DMSO) δ 8.53 (s, 5H), 8.33 (d, J=8.2 Hz, 1H), 7.61 (d, J=3.7 Hz, 1H), 7.43 (s, 1H), 7.01 (d, J=8.7 Hz, 1H), 6.91 (s, 1H), 6.63 (s, 1H), 6.38 (s, 1H), 5.62 (s, 2H), 5.42 (s, 7H), 4.47 (s, 3H), 4.17 (d, J=5.8 Hz, 2H), 1.44 (d, J=6.4 Hz, 6H)
Reaction SMILES: [C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[S:8][CH:7](Cl)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(Cl)Cl>[C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[S:8][CH:7]([C:22]2[CH:23]=[CH:24][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: COc1ccccc1
Reactant: C=CC(=O)N1Cc2cc(OC)ccc2SC(Cl)C1
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N1Cc2cc(OC)ccc2SC(c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
The above-mentioned 4-acryloyl-2-chloro-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.3 g) and anisole (1.1 g) were dissolved in methylene chloride (50 ml) and stannic chloride (2.8 g) was added thereto and agitated at room temperature for 2 hours. To the reaction mixture water was added and extracted with chloroform. The chloroform phase was washed with a saturated saline solution and dried on sodium sulfate and thereafter the solvent was distilled out under reduced pressure. Residue was purified by silica gel column chromatography (Wako Gel C-200, 50 g) and eluted with a mixed solvent of n-hexane (70 parts)+ethyl acetate (30 parts) to give 4-acryloyl-2-[4-methoxyphenyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH3:13])=[CH:7][C:5]=2[CH:6]=1.[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:12][CH3:13])=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][Cl:15])=[CH:20][CH:21]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)c1ccc2oc(Cl)cc2c1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Yield: 72.3 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 1-(2-chlorobenzofuran-5-yl)propan-1-one (140 mg, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (371 mg, 2.0 eq) to give 220 mg desired product (72%, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.16 & 7.10 (d, J=8.6 Hz, 2H), 7.00 & 6.99 (d, J=8.4 Hz, 1H), 6.90 & 6.81 (d, J=8.6 Hz, 2H), 6.76 & 6.70 (d, J=8.8 Hz, 2H), 6.52 & 6.44 (d, J=9.0 Hz, 2H), 6.45 (s, 1H), 4.73 & 4.48 (s, 1H), 4.26 & 4.08 (t, J=6.0 Hz, 2H), 3.83 & 3.72 (t, J=6.0 Hz, 2H), 2.50 (q, J=7.2 Hz, 2H), 0.91 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([CH2:11][CH:12]=[CH2:13])[CH2:9][C@H:8]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:6]12[CH3:7])[C:22]1[CH:21]=[CH:20][C:19]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:18][C:17]=1[CH2:16][CH2:15]3)(=[O:3])[CH3:2].B.C1C[O:38]CC1.C[N+]([O-])(C)C.O>COCCOCCOC.C1COCC1>[C:1]([O:4][C@H:5]1[C@H:10]([CH2:11][CH2:12][CH2:13][OH:38])[CH2:9][C@H:8]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:6]12[CH3:7])[C:22]1[CH:21]=[CH:20][C:19]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:18][C:17]=1[CH2:16][CH2:15]3)(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: C=CC[C@@H]1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)[C@H]1OC(C)=O
Agent: B
Agent: C[N+](C)(C)[O-]
Solvent: COCCOCCOC
Solvent: O
Product: CC(=O)O[C@H]1[C@H](CCCO)C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A solution of 629 mg (1.41 mmol) of 29 in anhydrous diglyme (21 mL) was stirred at 0° C. as 1.49 mmol of borane-THF (1.49 mL of a 1 M solution in THF) was added. Reaction was stirred at 0° C. for ½ h the allowed to warm to rt and stir for 2 h. To this was added 660 mg (5.96 mmol) of trimethylamine oxide and reaction was stirred and heated at 150° C. for 2 h, cooled to rt, poured into H2O (150 mL) and extracted with CH2Cl2 (3×, 100 mL). Combined organic extracts were washed with 10% sodium metabisulfite (70 mL), H2O (70 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on a 3×22 cm column of silica gel using hexanes/EtOAc (1.5:1) as eluent gave 530 mg (81%) of 30 as a white solid. Data for 30: TLC, T-6, Rf0.34. 1H NMR (500 MHz, CDCl3) δ 0.83 (s, 3H, H-18), 2.09 (s, 3H, Oac), 2.85 (m, 2H, H-6), 3.85 (t, 2H, J=5.7 Hz, —CH2O—), 4.63 (d, 1H, J=7.8 Hz, H-17α), 5.04 (s, 2H, benzylic), 6.72 (d, 1H, J=2.6 Hz, H-4), 6.78 (dd, 1H, J=8.2, 2.6 Hz, H-2), 7.19 (d, 1H, J=2.6 Hz, H-1), 7.31-7.44 (m, 5H, Ar—H); HRMS (ES) calcd for C30H38O4Na (M+Na+) m/e 485.2668, found m/e 485.2679.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]=[O:16])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C1COCC1>[C:25]([O:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]=[O:16])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: O=Cc1ccc2c(c1)C(=O)c1cccc(O)c1-2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc2c1-c1ccc(C=O)cc1C2=O
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a stirred suspension of 1.53 g (6.83 mmol) of 4-hydroxy-7-formyl-fluoren-9-one, prepared in Step G of Example 43, in 25 mL THF at 0° C. was added 1.24 mL (8.88 mmol) of triethylamine and 0.58 mL (8.2 mmol) of acetyl chloride. The mixture was stirred further for 0.5 hour and then partitioned between EtOAc, ice, 1N HCl, and brine. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by chromatography on silica gel using methylene chloride as eluant gave 1.46 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].Cl.[NH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:6]
Reactant: CCOC(=O)CCCN
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: CCOC(=O)CCCNC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoic acid (0.080 g, 0.20 mmol) and ethyl 4-aminobutyrate hydrochloride, according to Reference S and the general procedure for amide formation afforded ethyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzamido)butanoate. MS (ESI) m/z: Calculated: 503.2; Observed: 504.1 (M++1).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36]>C(Cl)Cl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([N:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -35 °C
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
A solution of Boc-Phe-OH (5.48 g) and NMM (2.09 g) in methylene chloride (50 ml) was cooled to -20° C. To this solution was added dropwise isobutyl chloroformate (2.82 g) maintaining the temperature between -22° C. to -20° C. in 7 minutes. After stirring the mixture for 20 minutes at the same temperature, the solution was cooled to -35° C. and HNMeBzl (2.50 g) was added dropwise to the solution. The reaction mixture was stirred for 2 hours during which period the temperature was gradually raised to -2° C. The solution was washed successively with water (twice), diluted sodium hydrogencarbonate solution (twice), water 0.5N hydrochloric acid (twice), and sodium chloride solution, and dried over magnesium sulfate. After evaporation, the solidified residue was pulverized in hot diisopropyl ether (10 ml), and after cooling, n-hexane (30 ml) was added to the mixture. The crystalline solid was filtered, washed with n-hexane (5 ml×2), and dried to give Boc-Phe-NMeBzl (6.49 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[CH2:12]([OH:17])[C:13]([F:16])([F:15])[F:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:17][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ncc(Br)cn1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)COc1ncc(Br)cn1
Yield: 74 %

Procedure:
A mechanically stirred slurry of 5-bromo-2-(methanesulfonyl)pyrimidine (24 g, 0.10 mol), trifluoroethanol (15 g, 0.15 mol), and potassium carbonate (28 g, 0.20 mol) in acetonitrile (250 mL) was heated at 70° C. for 12 hours. HPLC analysis indicated complete conversion. The solids were removed by filtration, and rinsed well with acetonitrile. The solvent was removed in vacuo and the residue partitioned between ether (50 mL) and water (25 mL). The aqueous phase was extracted with ether (2×25 mL), the organic layers combined, and washed with brine. Dried (Na2SO4), filtered, and solvent removed in vacuo, affording product as a pale yellow liquid, 19 g, 74 percent yield.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:9]([C:17](=[O:20])[NH:18][N:19]=2)[C:10]=1[CH:11]([OH:16])[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:23]=1.O>CN1CCCC1=O>[C:1]([C:5]1[N:6]=[C:7]([NH:30][CH2:29][CH2:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[C:8]2[N:9]([C:17](=[O:20])[NH:18][N:19]=2)[C:10]=1[CH:11]([OH:16])[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1cccnc1
Reactant: CC(C)CC(O)c1c(C(C)(C)C)nc(Cl)c2n[nH]c(=O)n12
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)CC(O)c1c(C(C)(C)C)nc(NCCc2cccnc2)c2n[nH]c(=O)n12

Procedure:
A solution of 70 mg of the product of Step A, 34 mg of TEA and 33 mg of 2-pyridin-3-yl-ethylamine in 1-methyl-2-pyrrolidinone (1.5 mL) was heated to 80° C. After six h, the reaction mixture was cooled, poured into water and extracted with EtOAc and then 15% IPA/chloroform. The organic extracts were washed dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in EtOAc and washed with water and sat. sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, concentrated, and the residue was recrystallized from ether/hexanes to provide the title compound as a white solid. MS (M+H+)=397.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:27]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([C:15]=1[Cl:27])=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)c2cccnc2n(Cc2ccccc2)c1=O
Yield: 98 %

Procedure:
A solution of 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (3) (0.94 g, 2.9 mmol) was heated in neat POCl3 at 90° C. for 3 h. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in water, neutralized by solid NaHCO3, and extracted by dichloromethane. The organic layer was subsequently washed by saturated NaHCO3 solution, water and brine, dried over Na2SO4, and evaporated to yield 0.9 g (98%) of 1-benzyl-4-chloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (4) as white solids. MP: 109° C.; 1H-NMR (DMSO-d6): δ 1.31 (t, J=6.9 Hz, 3H), 4.37 (q, J=6.9 Hz, 2H), 5.62 (s, 2H), 7.27 (m, 5H), 7.51 (dd, J=4.7, 8.0 Hz, 1H), 8.46 (dd, J=1.5, 7.5 Hz, 1H), 8.80 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 343 (M+1), 365 (M+23).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]([CH2:19]O)[CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(C)(=O)=O.[CH2:27]([N:29](CC)CC)C.[C-]#N.[NH4+].[NH4+].[NH4+].[NH4+].[C-]#N.[C-]#N.[C-]#N>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([CH2:19][C:27]#[N:29])[CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CO)CCOCc1ccccc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CC#N)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3-Benzyloxy-1-hydroxymethyl-propyl)-carbamic acid tert-butyl ester (7.4 g, 25 mmole) was dissolved in 100 ml DCM. Mesyl chloride (4.3 g, 37.5 mmole) and triethylamine (5.0 g, 50 mmole) were added. The reaction was stirred at room temperature for 20 minutes. 100 ml DCM and 100 ml water were added. The organic layer was washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was dissolved in 200 ml toluene. Tetraammonium cyanide (10 g, 37.5 mmole) was added and the reaction was stirred at room temperature overnight. The organic layer was washed with water (2×100 ml), brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified by column (EtOAc/hexane from 100/0 to 30/70 in 45 minutes). Yield, 6.4 g, 84%. 1H NMR (CDCl3 400 MHz δ 7.29-7.38 (m, 5H), 5.20 (d, J=5.9 Hz, 1H), 4.50 (m, 2H), 3.91 (m, 1H), 3.54-3.66 (m, 2H), 2.60-2.77 (m, 2H), 1.89-1.99 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[C:35]([O:37][CH:38]2[CH2:43][CH2:42][CH2:41][O:40][CH2:39]2)[CH:34]=[C:33]([F:44])[C:32]=1[C:45]1[N:50]=[C:49]([C:51](O)=[O:52])[CH:48]=[CH:47][C:46]=1[F:54].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:51]([C:49]3[CH:48]=[CH:47][C:46]([F:54])=[C:45]([C:32]4[C:31]([F:30])=[CH:36][C:35]([O:37][CH:38]5[CH2:43][CH2:42][CH2:41][O:40][CH2:39]5)=[CH:34][C:33]=4[F:44])[N:50]=3)=[O:52])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(OC3CCCOC3)cc2F)n1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(OC4CCCOC4)cc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (30 mg, 0.074 mmol), 6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxylic acid (26 mg, 0.074 mmol) and HATU (56 mg, 0.15 mmol) in DMF (0.3 mL) and DIPEA (39 μL, 0.22 mmol) was stirred at room temperature for 2 h. The reaction mixture was quenched with water and the resulting mixture was extracted with EtOAc (2 times). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to afford an amide intermediate, 4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH2:10]([S:14]CCCC)[CH2:11][CH2:12][CH3:13]>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:14][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: COc1ccccc1I
Reactant: CCCCSCCCC
Product: CCCCSc1ccccc1OC

Procedure:
The general procedure was used to convert 2-iodoanisole and n-butyl sulfide to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a light yellow oil (329 mg, 84% yield). 1H NMR (300 MHz, CDCl3) δ 7.18–6.75 (m, 4H; Hb, Hc, Hd, He); 3.82 (s, 3H; Hj), 2.84–2.79 (t, J=7.3, 2H; Hf), 1.60–1.52 (m, 2H; Hg), 1.43–1.36 (m, 2H; Hh) 0.87–0.82 (t, J=7.3, 3H; Hi). 13C NMR (75 MHz, CDCl3) δ 156.98 (C6), 128.56 (C2), 126.54 (C4), 125.22 (C1), 120.98 (C3), 110.28 (C5), 55.73 (C11), 31.49 (C7), 30.94 (C8), 22.06 (C9), 13.66 (C10). Anal. Calcd. for C11H160S: C, 67.30; H, 8.22; S, 16.33; Found C, 67.43; H, 8.28; S, 16.10.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(C1C=CC=CC=1)C.C1COCC1.[CH3:22][Si:23]([CH3:40])([CH3:39])[CH2:24][CH2:25][O:26][CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[N:30]=[CH:29]1.[Cl:41][C:42]1[CH:59]=[CH:58][C:45]([CH2:46][N:47]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]([CH:56]=[O:57])=[CH:48]2)=[CH:44][CH:43]=1>C1COCC1>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:46][N:47]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]([CH:56]([C:29]3[N:28]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:40])([CH3:39])[CH3:22])[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[N:30]=3)[OH:57])=[CH:48]2)=[CH:58][CH:59]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccccn2)c1
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)c2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: C[Si](C)(C)CCOCn1cc(-c2ccccn2)nc1C(O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
Lithium diisopropylamide (2 M solution in petane/ethylbenzene/THF, 57 uL, 0.12 mmol) was added to a stirred solution of 2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-pyridine (10.5 mg, 0.038 mmol) in dry THF (3 mL) at −78° C. under N2. After 1 hour at this temperature, a solution of N-4-chlorobenzylindole-3-carboxaldehyde (31 mg, 0.12 mmol) in dry THF (1 mL) was then added through a cannula. The resultant clear solution was stirred at −78° C. for 2 hours. The temperature was then allowed to rise to room temperature and the reaction was quenched by the addition of saturated aqueous NH4Cl (5 mL), extracted with dichloromethane (3×10 mL). The organic layer was separated, dried (Na2SO4), and concentrated under reduced pressure. Flash silica gel chromatography (4:1 hexane/ethyl acetate then 2:1 ethyl acetate/hexane then 4:1 ethyl acetate/MeOH) provided the product [1-(4-Chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol as a light yellow syrup (18 mg, 87%). 1H NMR δ −0.05 (s, 9H), 0.81 (t, 2H, J=7), 3.38 (t, 2H, J=7), 5.05–5.35 (m, 5H), 6.30 (s, 1H), 6.95–7.30 (m, 9 H), 7.45 (d, 1H, J=6), 7.65 (s, 1H), 7.71 (t, 1H, J=6), 8.05 (d, 1H, J=6), 8.60 (d, 1H, J=4)ppm; ESMS calcd for (C30H33ClN4O2Si): 544.2; found: 545.2 (M+H)+.