Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:13][CH:14]1OC(C)OC(C)O1.[I-].[PH4+].[OH-].[NH4+]>I.C(OC(=O)C)(=O)C.[PH2](O)=O>[CH3:1][C:2]1[NH:3][C:4]([CH2:13][CH3:14])=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c(C)c[nH]c1C
Reactant: CC1OC(C)OC(C)O1
Agent: I
Agent: O=[PH2]O
Agent: [I-]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(C)[nH]c(CC)c1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
2,4-Dimethyl-3-carbethoxy-pyrrole (0.668 g) was dissolved in a mixture of hydriodic acid (10 ml), acetic anhydride (10 ml) and hypophosphorous acid (2 ml). Paraldehyde (0.75 ml) was added. The solution was stirred 5 min., decolorized with phosphonium iodide, and poured into ice water. The cooled mixture was brought to pH 8 with ammonium hydroxide. The product was filtered off and distilled (90°-100°, 5 × 10-4 mm), giving colourless crystals (53%), m.p. 108°-109° after changing to prisms at 105°. For analysis, it was recrystallized from hexane as prismatic rods, m.p. 107°-109° (lit17) 106°-107°).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=3[O:28][CH3:29])(=[O:18])=[O:17])[C:7](=[O:15])[N:8]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:4]=2[CH:3]=1>[Ni].CCO>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=3[O:28][CH3:29])(=[O:18])=[O:17])[C:7](=[O:15])[N:8]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]3)[C:4]=2[CH:3]=1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)n1c(=O)n(C2CCCCC2)c2cc(Cl)ccc21
Agent: [Ni]
Solvent: CCO
Product: COc1cc(N)ccc1S(=O)(=O)n1c(=O)n(C2CCCCC2)c2cc(Cl)ccc21

Procedure:
1.8 g (4.10- 3 mol) of the compound obtained in Example 3 in 95° EtOH were hydrogenated under 50 bar in the presence of Raney® nickel. The catalyst was filtered off on C elite® and rinsed with hot 95° EtOH and the filtrate was evaporated under vacuum to give 1.22 g of the expected product in the form of a white solid. The product crystallized from absolute ethanol. M.p.=211° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].B1C2CCCC1CCC2.P(=O)(O)(O)O.[K].FC(F)(F)S(O[C:30]1[C:31]([CH3:59])([CH3:58])[C@H:32]2[C@:45]([CH3:48])([CH2:46][CH:47]=1)[C@@H:44]1[C@:35]([CH3:57])([C@@:36]3([CH3:56])[C@H:41]([CH2:42][CH2:43]1)[C@H:40]1[C@H:49]([C:52]([CH3:54])=[CH2:53])[CH2:50][CH2:51][C@:39]1([NH2:55])[CH2:38][CH2:37]3)[CH2:34][CH2:33]2)(=O)=O.C1(C)C=CC=CC=1>C1COCC1.O1CCOCC1.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]>[NH2:55][C@:39]12[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:40]1[C@@H:41]1[C@@:36]([CH3:56])([CH2:37][CH2:38]2)[C@@:35]2([CH3:57])[C@@H:44]([C@:45]3([CH3:48])[C@@H:32]([CH2:33][CH2:34]2)[C:31]([CH3:58])([CH3:59])[C:30]([CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:7][CH3:8])=[O:6])=[CH:47][CH2:46]3)[CH2:43][CH2:42]1
Reactant: C=CCCC(=O)OC
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCCCC(=O)OC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
A solution of methyl 4-pentenoate (0.031 g, 0.269 mmol) in THF (1.5 mL) was cooled to 0° C. and 9-BBN (0.5M in THF) (0.574 mL, 0.287 mmol) was added dropwise. The mixture was removed from the ice bath and was stirred at rt for 2 h. To the solution was added a solution of phosphoric acid, potassium salt (1M) (0.448 mL, 0.448 mmol) followed by a solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (0.1 g, 0.179 mmol) in 1,4-dioxane (1.5 mL) and finally 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, Toluene (7.38 mg, 8.96 μmol). The mixture was heated to 85° C. for 16 h, cooled to rt, diluted with water (15 mL), and extracted with ethyl acetate (3×15 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 5-50% EtOAc in hexanes gradient and a 12 g silica gel column to give the title compound (0.072 g, 77% yield) as an off-white foam. LCMS: m/e: 524.5 (M+H)+, 2.04 min (method 1). 1H NMR (400 MHz, chloroform-d) δ=5.23 (d, J=5.3 Hz, 1H), 4.73 (d, J=2.0 Hz, 1H), 4.62-4.59 (m, 1H), 3.67 (s, 3H), 2.55 (td, J=10.9, 5.3 Hz, 1H), 2.33 (t, J=7.5 Hz, 2H), 2.09-1.92 (m, 4H), 1.70 (s, 3H), 1.07 (s, 3H), 0.97 (s, 6H), 0.89 (s, 3H), 0.83 (s, 3H), 1.78-0.80 (m, 26H).
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[CH2:11]([NH:18][S:19]([CH2:22][C:23]#[N:24])(=[O:21])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][S:19](/[C:22](=[CH:9]/[C:6]1[S:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:8][CH:7]=1)/[C:23]#[N:24])(=[O:21])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#CCS(=O)(=O)NCc1ccccc1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)NCc1ccccc1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and benzylaminosulfonylacetonitrile as in Example 1 gave (E)-2-(benzylaminosulfonyl)-3-(2-nitrothien-5-yl)acrylonitrile
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.O1CCCC1.C(OCC)(=O)C>C(OCC)C.CC(O)C>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: c1ccc(CSc2ccccc2)cc1
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: BrCCCCCCC(Sc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 20.02 g of benzylphenylthioether in 300 ml of diethyl ether is cooled, under nitrogen, in a dry ice bath (the starting thioether precipitates out of solution). Sixty-two ml of 1.7M t-butyllithium , in pentane, is added and after 30 minutes most of the precipitate is re-dissolved. The reaction mixture is warmed to 0° C. for 10 minutes, but it appears that more precipitate is being formed, therefore the reaction is recooled to -78° C. for 30 minutes. The resulting yellow solution is transferred, under nitrogen via canula to a cooled, -78° C., second flask charged with 38.5 ml of 1,6-dibromohexane in 400 ml of diethyl ether (200 ml of tetrahydrofuran needed to maintain a homogenous solution). After the addition, the reaction mixture is allowed to warm to room temperature over 4 hours. Ten ml of ethyl acetate and 10 ml of 2-propanol is added and the reaction is concentrated in Vacuo. The white oily residue is dissolved in chloroform, washed with dilute hydrobromic acid and saturated sodium chloride, dried and concentrated in vacuo to give 74.6 g of crude product. The crude product was purified 3× by chromatography (hexane to chloroform to methyl alcohol) to give 29.26 g of pure product.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:7]1[CH:22]=[CH:21][C:10]2[O:11][C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=1)[CH3:6])C.[OH-].[K+]>C(O)C.O>[O:16]=[C:15]1[CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][C:10]2[CH:21]=[CH:22][C:7]([CH:5]([CH3:6])[C:4]([OH:23])=[O:3])=[CH:8][C:9]1=2
Reactant: CCOC(=O)C(C)c1ccc2c(c1)C(=O)Cc1ccccc1O2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1ccccc1O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To 151 mg of ethyl2-(10,11-dihydro-11-oxo dibenzo[b,f]-oxepin-2-yl)-propionate in 2ml of ethanol was added 400 mg of potassium hydroxide in 2 ml of water and the mixture was stirred at room temperature for 0.5 hour. After the completion of the reaction, to this was added water and the mixture was extracted with benezene. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain pale brown oil, which was chromatographed over silica gel, eluted with chloroform and there was obtained 112 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]oxepin-2-yl)-propionic acid as pale yellow oil. This was crystallized from the mixed solvent of ethyl acetate-n-hexane to give pale yellow crystals having a melting point of 156°-157° C.
Reaction SMILES: Cl.C([Si](C)(C)[O:7][CH2:8][C@@H:9]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[CH:19][C:14]=2[C:13]([C:20]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:41])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[N:26][CH:27]=2)=[O:21])=[CH:12]1)[CH3:10])(C)(C)C>O1CCOCC1.C1COCC1>[OH:7][CH2:8][C@@H:9]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[CH:19][C:14]=2[C:13]([C:20]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:41])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=3)[CH:25]=[N:26][CH:27]=2)=[O:21])=[CH:12]1)[CH3:10]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)c2cncnc21
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[C@@H](CO)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
10% Hydrochloric acid in 1,4-dioxane (0.2 mL) was added to N-(5-{7-[(S)-2-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl}-pyridin-3-yl)-2-(3-trifluoromethyl-phenyl)-acetamide (Preparation 105, 59 mg, 0.098 mmol) in THF (2 mL) and the mixture was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and triturated with ether-pentane to afford the title compound as an off white solid in 86% yield, 41 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][C@H:16]([CH2:18][O:19][CH3:20])[CH2:15][N:14]3[C:21](=[O:31])[C@@H:22]([NH:26][C:27](=[O:30])[O:28][CH3:29])[CH:23]([CH3:25])[CH3:24])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:32][C@@H:33]1[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:35]([C:45]2[NH:46][C:47]([C:50]3[CH:55]=[CH:54][C:53](B4OC(C)(C)C(C)(C)O4)=[CH:52][CH:51]=3)=[CH:48][N:49]=2)[CH2:34]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][O:28][C:27]([NH:26][C@@H:22]([CH:23]([CH3:25])[CH3:24])[C:21]([N:14]1[CH2:15][C@@H:16]([CH2:18][O:19][CH3:20])[CH2:17][C@H:13]1[C:11]1[NH:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:53]3[CH:52]=[CH:51][C:50]([C:47]4[NH:46][C:45]([C@@H:35]5[CH2:34][C@H:33]([CH3:32])[CH2:37][N:36]5[C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])=[N:49][CH:48]=4)=[CH:55][CH:54]=3)=[CH:3][CH:4]=2)=[CH:9][N:10]=1)=[O:31])=[O:30]
Reactant: C[C@H]1C[C@@H](c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(Br)cc3)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)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: COCCOC
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 85 °C
Yield: 36.7 %

Procedure:
Methyl (S)-1-((2S,4S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (621 mg, 1.26 mmol), (2S,4S)-tert-butyl 4-methyl-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (628 mg, 1.39 mmol), Pd(PPh3)4 (145 mg, 0.13 mmol), and K2CO3 (2M in H2O, 2.0 mL, 4.16 mmoL) were combined in DME (13 mL). The mixture was degassed with bubbling N2 for 10 min the heated to 85° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford (2S,4S)-tert-butyl 2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (342 mg, 37%).
Reaction SMILES: [Na].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[C:13]([CH:16]([CH2:28][CH2:29][CH2:30][CH:31]1[O:33][CH2:32]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:15])[CH3:14].O>C(O)C.CCOCC>[C:13]([CH:16]([CH2:28][CH2:29][CH2:30][CH:31]([OH:33])[CH2:32][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:11])([F:12])[F:2])[CH:5]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:15])[CH3:14]
Reactant: CCOC(=O)CCCCCCC(CCCC1CO1)C(C)=O
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCCC(CCCC(O)COc1cccc(C(F)(F)F)c1)C(C)=O

Procedure:
Sodium (1.15 g., 0.05 mole) is dissolved in ethanol (60 ml.). 3-Trifluoromethylphenol (14.6 g., 0.09 mole) is added and then ethyl 8-acetyl-12,13-epoxytridecanoate (13.0 g., 0.0435 mole). The resulting solution is heated under reflux for 1.5 hour. It is then cooled and poured into 300 ml. of water. The oily product is taken up in ether, washed with 100 ml. of 5% sodium hydroxide solution, water and brine and dried over sodium sulfate. The ether is evaporated in vacuo leaving 17.4 g. of the title compound as a yellow oil. It is used in the next step without purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[NH3:24]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH2:24])=[O:2])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Product: NC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (40 mg, 0.13 mmol) and ammonia (10 mL, 7 M in MeOH) was stirred at r.t. for 16 h. The solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-60% EtOAc/hexanes+2% AcOH) to give 18 mg of the title compound as a light yellow solid. MS: (+) m/z 296.06 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:17]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[F:26][C:19]1[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=1[C@H:17]1[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CNCC[C@@H]1c1cc(F)c(F)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Step D was dissolved into 40 ml of 1:1 dichloromethane/trifluoroacetic acid and stirred at ambient temperature for 60 min. The solution was then concentrated and taken up in 250 mL of 3:1 chloroform/isopropyl alcohol then washed with saturated aqueous sodium bicarbonate solution, and saturated aqueous brine (100 mL each). The organic phase was then dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the title compound as a colorless crystalline solid which was used without further purification. LC/MS 365.4 (M+1).
Reaction SMILES: C([O:8][CH:9]1[CH2:12][N:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:10]1)C1C=CC=CC=1>[Ni].C(O)C>[C:13]([N:11]1[CH2:12][CH:9]([OH:8])[CH2:10]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N1CC(OCc2ccccc2)C1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)N1CC(O)C1
Temperature: 40 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
A solution of 4.4 parts of 3-benzyloxy-1-(tert.-butyl)azetidine in 30 parts of ethanol was added to an autoclave together with 2 parts of Raney nickel as catalyst. Under a hydrogen gas pressure of 100 atmospheres, the mixture was stirred at 40° C. for 15 hours to perform the reduction. The catalyst was separated by filtration, and the remaining ethanol solution was concentrated to dryness. The resulting oily substance was dissolved in n-hexane and cooled. As a result 2.0 parts of 1-(tert.butyl)-3-azetidinol melting at 42°-43° C. The yield was 76%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([N:1]=[CH:22][C:20]2[O:21][C:17]([C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=3)=[CH:18][CH:19]=2)[CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Product: Oc1ccc(Cl)cc1N=Cc1ccc(-c2ccc(Cl)cc2)o1

Procedure:
Using 2-amino-4-chlorophenol and 5-(4-chlorophenyl)furan-2-carbaldehyde, 3.18 g of 4-chloro-2-{[5-(4-chlorophenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 95%).
Reaction SMILES: CCN(CC)CC.Br[C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:24])[CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH:12]=[CH:13][CH:14]=1.[CH2:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=[CH2:27].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:18]([CH:17]([CH2:21][CH2:22][CH3:23])[C:16]([NH:15][C:11]1[CH:10]=[C:9](/[CH:27]=[CH:26]/[CH2:25][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:14]=[CH:13][CH:12]=1)=[O:24])[CH2:19][CH3:20]
Reactant: CCCC(CCC)C(=O)Nc1cccc(Br)c1
Reactant: C=CCNC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(CCC)C(=O)Nc1cccc(/C=C/CNC(=O)OC(C)(C)C)c1
Temperature: 90 °C

Procedure:
Et3N (1.2 mL) was added to a solution of N-(3-bromophenyl)-2-propylpentanamide (0.6 g, 2.01 mmol), tert-butyl allylcarbamate (1.026 g, 6.55 mmol) and P(o-tol)3 (0.06 g, 0.201 mmol) in DMF (10 mL). The reaction mixture was degassed for 30 min and then added Pd(OAc)2 (0.09 g, 0.409 mmol) was added. The reaction mixture was again degassed for 15 min and then refluxed at 90° C. for 8 h. The reaction mixture was diluted with EtOAc, washed with H2O, brine. The organic layer was concentrated under reduced pressure. Purification by column chromatography(100-200 mesh silica, elution 10% to 15% EtOAc in hexane) gave (E)-tert-butyl 3-(3-(2-propylpentanamido)phenyl)allylcarbamate as a yellow oil. Yield (0.7 g, 37%). 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.24 (s, 1H), 7.08 (dd, J=1.2, 7.2 Hz, 2H), 6.48 (d, J=16.0 Hz, 1H), 6.26-6.16 (m, 1H), 4.67 (bs, 1H), 3.89 (bs, 2H), 2.17-2.04 (m, 1H), 1.73-1.64 (m, 4H), 1.48 (s, 9H), 1.45-1.14 (m, 4H), 0.91 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:38][C:39]([NH2:41])=[O:40].[Br-]>C1COCC1>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[CH2:38][C:39]([NH2:41])=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CBr
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CC(N)=O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 21.7 %

Procedure:
A solution of the bishydrochloride salt of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (110 mg, 0.25 mmol) in THF (2 mL) at room temperature was treated with diisopropylethylamine (165 μL, 1.0 mmol) followed by 2-bromoacetamide (42 mg, 0.3 mmol). The reaction mixture was heated at 50° C. for 8 h and an additional amount of bromide (42 mg, 0.3 mmol) then added. The reaction mixture was then stirred for an additional 16 h at room temperature and evaporated. The crude reaction was then partitioned between EtOAc (3 mL) and a saturated aqueous NaHCO3 solution (3 mL). The organic phase was isolated and further washed with an additional portion of a saturated aqueous NaHCO3 solution (3 mL) and brine (2×3 mL). The organic component was dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 80% EtOAc/hexane then 5% MeOH/EtOAc as eluant to afford the title compound as an oil (23 mg, 22%). LC/MS (Method A) 5.09 min, [M+1]+ 424.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[CH:28]=[CH:27]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:35]([C:32]2[CH:33]=[C:34]3[C:29]([CH:28]=[CH:27][NH:26]3)=[CH:30][CH:31]=2)=[O:36])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccc2Cl)CC1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3cc[nH]c3c2)c2ccccc2Cl)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-chlorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.4 mmol) and indole-6-carboxylic acid (219 mg, 1.4 mmol) afforded, after purification (SiO2: 33% to 50% EtOAc in hexane), 579 mg (83%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][C:41]([NH:43][CH:44]1[CH2:46][CH2:45]1)=[O:42].O>CN(C)C=O>[CH:44]1([NH:43][C:41](=[O:42])[CH2:40][O:22][C:18]2[CH:17]=[C:16]([S:13]([N:12]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[CH:9][C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:11]3)(=[O:14])=[O:15])[CH:21]=[CH:20][CH:19]=2)[CH2:46][CH2:45]1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Reactant: O=C(CBr)NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)NC3CC3)c2)c1)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1h (100 mg, 0.22 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of cesium carbonate (215 mg, 0.66 mmol) and 2-bromo-N-cyclopropyl-acetamide (61 mg, 0.34 mmol, prepared by a known method disclosed in “Journal of Medicinal Chemistry, 1987, 30(1), 20-24”) and then the reaction solution was stirred for 16 h. 50 mL of water were added, and the reaction solution was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product tert-butyl ((1-((3-(2-(cyclopropylamino)-2-oxoethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 3a (100 mg, a yellow oil), which was used directly in the next step.