Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][N:8]2C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.[Pd]>[CH:1]1([C@@H:7]2[CH2:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccccc2)CC1C1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: c1ccc([C@@H]2CCN[C@H](C3CCCCC3)C2)cc1

Procedure:
Benzyl 2-cyclohexyl-4-phenylpiperidine-1-carboxylate (1.05 g, 2.78 mmol) in EtOH (50 ml) was added Pd/C (0.5 g, 0.235 mmol) and hydrogenated with a balloon overnight. Filtered through celite and concentrated. The trans isomer was removed on the chiral OD column 20% IPA/Hexanes w/DEA affording the single cis diastereomer.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[C:24]1([CH2:30][CH:31]([NH2:37])[C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:30][CH:31]([NH:37][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])[C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC(Cc1ccccc1)c1cccs1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(Cc1ccccc1)c1cccs1
Yield: 45 %

Procedure:
The title compound was prepared in a yield of 45% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 2-phenyl-1-(2-thienyl)ethylamine.
Reaction SMILES: [Cl-:1].[Li+].[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:10]([Cl:14])[C:11]=2[Cl:13])[CH2:6][CH:5]1[CH2:21][CH3:22].CO>CN(C)C=O>[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:10]([Cl:14])[C:11]=2[Cl:13])[CH2:6][C:5]1([CH2:21][CH3:22])[Cl:1]
Reactant: [Cl-]
Reactant: CCC1Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCC1(Cl)Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O
Temperature: 90 °C
Yield: 53 %

Procedure:
A stirred solution of cupric chloride dihydrate (4.25 g. and lithium chloride (0.765 g.) in dimethylformamide (10 ml.) is heated to 90° C. and to the mixture is added a solution of methyl (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)-acetate (4.7 g., 0.015 mole) in dimethylformamide. The reaction mixture is heated at 90° C. for two hours and poured onto ice. The product is extracted into ether (100 ml.), washed with water, dried over anhydrous sodium sulfate and the ether distilled at reduced pressure. There is thus obtained 2.5 g. of methyl (1-oxo-2-ethyl-2,6,7-trichloro-5-indanyloxy)acetate (53% yield) which melts at 111° C. after recrystallization from methanol.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22]>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:25]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:26])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 1-Boc-4-(2-aminophenyl)-piperazine (270 mg, 1.0 mmol) in 10 mL of THF was added isopropyl isocyanate (90 uL, 1.46 mmol). After stirring for about 1 hour, another 90 microliter of isopropyl isocyanate was added. After stirring for about 3 days, another 290 microliter of isopropyl isocyanate was added. After stirring overnight, the solution was concentrated. Purification by silica gel chromatography (35 g SiO2, 20 to 50% EtOAc/hexanes, over 30 minutes at 35 mL/min) afforded about 240 mg (0.66 mmol, 66%) of the title compound as a white solid. LRMS: 363.2 (M+1)
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C.[H][H]>C(O)(=O)C.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[NH2:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Nc1cccc(CCCc2ccccc2)c1
Yield: 71.1 %

Procedure:
253 g of 1-phenyl-3-(3'-nitrophenyl)-prop-2-en-1-one are suspended in 2.5 liters of glacial acetic acid. 196 g of concentrated sulfuric acid and 10 g of 10% strength Pd on animal charcoal are added and the mixture is hydrogenated under 1.1 bar hydrogen pressure, at 65°-70° C., until hydrogen is no longer absorbed. When the mixture has cooled, part of the acetic acid is distilled off, the residue is rendered alkaline with sodium hydroxide solution and extracted with ether, the organic phase is dried with sodium sulfate and filtered, the solvent is distilled off and the residue is then distilled. 150 g of 3-(3-phenylpropyl)-aniline, of boiling point 148° C./0.2 mbar, are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH2:16][C:17]3[N:21]([CH2:22][CH2:23][O:24]COC)[C:20]4[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:19]=4[N:18]=3)[CH3:15])=[O:13])[C:6]=2[CH:34]=1.Cl.CCOC(C)=O>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH2:16][C:17]3[N:21]([CH2:22][CH2:23][OH:24])[C:20]4[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:19]=4[N:18]=3)[CH3:15])=[O:13])[C:6]=2[CH:34]=1
Reactant: COCOCCn1c(CN(C)C(=O)Cn2c(=O)oc3ccc(Cl)cc32)nc2cc(Cl)c(Cl)cc21
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(Cc1nc2cc(Cl)c(Cl)cc2n1CCO)C(=O)Cn1c(=O)oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 156.8 %

Procedure:
To a mixture of 2-(5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-({5,6-dichloro-1-[2-(methoxymethoxy)ethyl]-1H-benzimidazol-2-yl}methyl)-N-methylacetamide (110 mg) and MeOH (0.22 mL) was added 4 M hydrogen chloride/EtOAc (521 μL), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The obtained solid was washed with EtOAc to obtain 2-(5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-{[5,6-dichloro-1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]methyl}-N-methylacetamide hydrochloride (85 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:21]=1)[CH3:2].C([O-])(=O)C.[NH4+:30].C(OCC)C>C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH2:30])[C:8]=2[N:21]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)cc2n1CC(C)C
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOCc1nc2c(N)nc(C)cc2n1CC(C)C
Temperature: 150 °C
Reaction time: 36 h

Procedure:
A sealed glass tube containing 2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (2.51 g) from Part E and ammonium acetate (25.1 g) was heated to 150° C. After 36 hours, TLC monitoring indicated that the reaction was complete. The resulting reaction mixture was cooled and then dissolved in ethyl acetate. The ethyl acetate solution was washed with 25% aqueous sodium hydroxide. The resulting organic layer was dried with magnesium sulfate, and concentrated under reduced pressure to an orange oil. The oil was put through a column using 95/5 ethyl acetate/methanol, providing good separation. The oil recovered from the product fraction was dissolved in isopropyl alcohol, to which 1M HCl in diethyl ether was added. A white solid formed. More diethyl ether was added, and the white solid was filtered and dried under vacuum at 80° C. for 5 hours. The resulting solid was dissolved in water (50 ml), and the pH was adjusted to 11 using sodium carbonate. An oil separated and was extracted with dichloromethane. The resulting dichloromethane solution was dried with magnesium sulfate and concentrated under reduced pressure to a clear oil. The oil was triturated with methanol, and the resulting solid was dissolved in diethyl ether. The diethyl ether solution was subjected to high vacuum at room temperature to dry the product. The resulting partially solidified product was solidified by cooling with an isopropyl alcohol/dry ice bath to provide 2-(ethoxymethyl)-1-(2-methylpropyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 77.0-79.0° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:20]([O:23][CH2:24]C)(=[O:22])C.ClCCl.[C]=O>CO.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].C(N(CC)CC)C>[CH3:24][O:23][C:20]([C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[N:3]=1)=[O:22]
Reactant: CCOC(C)=O
Reactant: Clc1ccccc1-c1nc(Br)cnc1N1CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C]=O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCCC2)c(-c2ccccc2Cl)n1

Procedure:
To a solution of 5-bromo-3-(2-chloro-phenyl)-2-pyrrolidin-1-yl-pyrazine (0.25 g) in 7 ml methanol was added 2 ml ethyl acetate, 0.035 g [1,1′-bis(diphenylphosphino)-ferrocen]palladium(II)chloride 1:1 complex with dichloromethane and 0.25 ml triethylamine and the mixture was stirred at 110° C. under 70 bar carbon monoxide for 18 h. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel with heptane:ethyl acetate=2:1 to yield 0.15 g of the title compound as off-white foam, MS (ISP) 318.1 (M+H)+.
Reaction SMILES: [C:1]([S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH2:28])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:38]=1)[C:33](O)=[O:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:38]=1)[C:33]([NH:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:34]
Reactant: NCc1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc(F)cc(N2CCOCC2)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: O=C(NCc1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc(F)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 1-[2-(tritylsulfanyl)phenyl]methanamine (335 mg, 0.88 mmol), 3-fluoro-5-morpholin-4-yl-benzoic acid (WO2004/089929) (237 mg, 1.05 mmol) and DIPEA (0.38 mL, 2.19 mmol) in DMF (15 mL) was treated with HATU (400 mg, 1.05 mmol). The mixture was stirred at RT for 45 min, then partitioned between aqueous saturated NaHCO3 and EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to afford the title compound (quantitative) as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 7.35-7.29 (6H, m), 7.27-7.19 (10H, m), 7.17 (2H, m), 7.10 (1H, t, J 1.7), 6.98-6.92 (1H, m), 6.73-6.64 (2H, m), 5.98 (1H, br t, J 6), 4.21 (2H, d, J 6), 3.84 (4H, t, J 4.8), 3.19 (4H, t, J 4.8).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[O:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Br-]>O1CCOCC1.[Cu]I.CS(C)=O>[Cl:22][C:19]1[S:18][C:17]([C:15]([NH:14][CH2:13][CH:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]4=[O:23])=[CH:3][CH:4]=3)[CH2:12]2)=[O:16])=[CH:21][CH:20]=1
Reactant: Oc1ccccn1
Reactant: O=C(NCC1CC(c2ccc(Br)cc2)=NO1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: O=C(NCC1CC(c2ccc(-n3ccccc3=O)cc2)=NO1)c1ccc(Cl)s1

Procedure:
Aryl bromide (Example 1, 100 mg, 0.25 mmol) and 2-hydroxypyridine (95 mg, 1.0 mmol) were dissolved in 1.5 mL dry dioxane and 0.5 mL dry DMSO in a sealed tube. To it were added N,N′-dimethylethylenediamine (27 μL, 0.25 mmol), CuI (95 mg, 0.125 mmol) and K3PO4 (106 mg, 0.5 mmol) in order. The mixture was stirred and heated in 120° C. bath till all the bromide starting material had been consumed (3 hrs, monitored by analytical HPLC). The mixture was filtered and directly subjected to reverse phase preparative HPLC to isolate the title compound as a white powder after lyophilization. MS found for C20H16ClN3O3S as (M+H)+ 414.1, 416.1
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[NH4+:41].[NH4+].[ClH:43]>>[ClH:43].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:41])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.2 g (2.49 mMol) of 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were stirred in 100 ml of saturated ethanolic hydrochloric acid for 6 hours at room temperature. Then the mixture was evaporated to dryness in vacuo, the residue was dissolved in 100 ml of ethanol, mixed with 2.5 g (26 mMol) of ammonium carbonate and stirred overnight at room temperature. After distillation of the solvent the crude product thus obtained was purified by column chromatography (100 g silica gel; eluant: dichloromethane/ethanol=4:1). By concentrating the eluates the desired compound was obtained as a white, amorphous solid. Yield: 1.10 g (83% of theory), Rf value: 0.18 (silica gel; dichloromethane/ethanol=4:1) C28H30N6O3 ×HCl (498.6) ##EQU8##
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][N:16]1[C:21](=[O:22])[C:20]2[C:23]3[CH2:29][CH2:28][CH2:27][CH2:26][C:24]=3[S:25][C:19]=2[N:18]=[C:17]1[CH3:30]>>[C:1]12([CH2:11][C:12]([NH:15][N:16]3[C:21](=[O:22])[C:20]4[C:23]5[CH2:29][CH2:28][CH2:27][CH2:26][C:24]=5[S:25][C:19]=4[N:18]=[C:17]3[CH3:30])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc2sc3c(c2c(=O)n1N)CCCC3
Product: Cc1nc2sc3c(c2c(=O)n1NC(=O)CC12CC4CC(CC(C4)C1)C2)CCCC3

Procedure:
1-Adamantaneacetyl chloride (BBB-SCI) and 3-amino-2-methyl-5,6,7,8-tetrahydro-3 H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one (Matrix) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.57-1.72 (m, 13 H) 1.72-1.85 (m, 4 H) 1.89-1.99 (m, 3 H) 2.08 (m, 1 H) 2.15 (m, 1H) 2.35 (s, 3 H) 2.69-2.78 (m, 2 H) 2.79-2.88 (m, 2 H) 10.78 (s, 1 H); MS (ESI+) m/z 412 (M+H)+.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17]O)=[C:13]([I:19])[CH:12]=1.C(O)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:10][C:11]1[CH:12]=[C:13]([I:19])[C:14]([CH2:17][F:7])=[CH:15][N:16]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1cnc(F)cc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: FCc1cnc(F)cc1I
Reaction time: 3 h
Yield: 53 %

Procedure:
Add diethylaminosulfur trifluoride (892 mg, 4 mmol) drop-wise to a solution of (6-fluoro-4-iodo-pyridin-3-yl)-methanol in dichloromethane (25 mL) in a round bottom flask under nitrogen, and then add ethanol (0.3 mL) at 0-5° C. Stir the mixture for 3 hours. Pour the reaction mixture into saturated sodium bicarbonate solution. Abstract the product into chloroform, and wash with water and saturated aqueous sodium chloride. Separate the organic layer from the aqueous layer and dry over MgSO4. After filtration, evaporate the organic solvent in vacuo to give a crude product. Purify the crude with flash column chromatography (10% methanol in dichloromethane) to give the title compound (0.32 g, 53%). MS (ES) m/z 256 [M+1]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH3:28][O:29][CH:30]([C:34]([NH:36][CH2:37][C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])=[O:35])[C:31](O)=[O:32]>>[CH2:13]([O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:31](=[O:32])[CH:30]([O:29][CH3:28])[C:34]([NH:36][CH2:37][C:38]([F:43])([F:44])[C:39]([F:40])([F:42])[F:41])=[O:35])[C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=2[C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]1=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: COC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: COC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, the title compound was prepared in the same manner as example 1c (99%). White solid. MS: m/e=606(M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH2:6][O:7]2.[CH3:14][Mg]Br.O>C(OCC)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH3:14])([OH:13])[CH2:5][CH2:6][O:7]2
Reactant: C[Mg]Br
Reactant: O=C1CCOc2cc(F)cc(F)c21
Solvent: O
Solvent: CCOCC
Product: CC1(O)CCOc2cc(F)cc(F)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.00 g (10.86 mmol) of the compound from Example 170A were dissolved in 40 ml of diethyl ether at 0° C., and 5.4 ml (16.29 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, addition of water and diethyl ether to the reaction solution and separation of the phases. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane). 2.03 g (93% of theory) of the title compound were obtained.
Reaction SMILES: C(S([C:6]1[N:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1)(=O)=O)C.[OH-:16].[Na+].Cl>>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:8]=[N:7][C:6](=[O:16])[NH:11][CH:10]=1
Reactant: [OH-]
Reactant: CCS(=O)(=O)c1ncc(C(F)(F)F)cn1
Agent: Cl
Agent: [Na+]
Product: O=c1ncc(C(F)(F)F)c[nH]1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
2-Ethylsulfonyl-5-trifluoromethylpyrimidine (4.7 mmol) was added to 1M NaOH, the mixture stirred at 5° C. for 10 min, then at room temperature for 10 min and finally the pH was adjusted to 2 with HCl. After filtration the filtrate was evaporated, the residue dried and extracted with benzene, the benzene solution evaporated, the residue extracted with boiling ethyl acetate, (3×40 ml), and the ethyl acetate solution evaporated to yield the product; yield 0.50 g (67%). For final purification the product was sublimed at 110°-120° C./0,01 mmHg; m.p. 154° C., 1H NMR (DMSO-d6): δ 8.50 (H-4, H-6), MS [70 eV; m/z (% rel. int.)] 164 (99, M), 145 (21), 136 (100), 117 (25), 116 (16), 109 (11), 90 (28), 89 (40), 75 (35). IR (KBr): 1690 cm-1 (CO).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6]Cl)[CH3:3].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:15][CH:16]=1)[CH3:3]
Reactant: CCCC(=O)c1ccc(O)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCC(=O)c1ccc(OCCN(CC)CC)cc1
Yield: 98.8 %

Procedure:
2-(Diethylamino)ethyl chloride hydrochloride (624 mg, 3.65 mmol) was added to a stirred solution of p-hydroxybutyrophenone (200 mg, 1.21 mmol) in anhydrous acetone (6 mL) followed by the addition of potassium carbonate (668 mg, 4.84 mmol). The resulting mixture was heated at reflux for 48 hours. The mixture was diluted with ethyl acetate, washed with water (2×) and sat. brine, dried over sodium sulfate, and concentrated to an oil. Flash silica gel column chromatography, eluting with 1:1 hexanes/ethyl acetate, afforded 21 (315 mg, 98%) as a light yellow oil: MS (ES+) m/z 264.1 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7](=[O:35])[C@H:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33]C)=[CH:23][CH:22]=1)[NH:9][C:10](=[O:19])[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:35])[C@H:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])=[CH:23][CH:22]=1)[NH:9][C:10](=[O:19])[C:11]1[C:12]([Cl:18])=[CH:13][CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 50.4 %

Procedure:
BBr3 (1 mL, 1M in CH2Cl2) was added to a CH2Cl2 (10 mL) solution of N-(2,6-dichlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (0.215 g) at 0° C. with stirring and the solution was slowly warmed to room temperature. The mixture was stirred for 3 h and quenched with EtOH. The solvent was removed and the residue was taken up in EtOAc. The solution was washed with satd. NaHCO3 followed by brine, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: hexanes/EtOAc 2:1) to yield 0.105 g of N-(2,6-dichlorobenzoyl)-4-(2-hydroxyphenyl)-L-phenylalanine methyl ester. ESMS: m/z 444 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH:19]2[O:21][CH2:20]2)=[C:6]([CH:15]=1)[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8]
Reactant: COC(=O)CCC(=O)c1cc(C)ccc1O
Reactant: BrCC1CO1
Product: COC(=O)CCC(=O)c1cc(C)ccc1OCC1CO1

Procedure:
Methyl 3-(5-methyl-2-hydroxybenzoyl)propionate was reacted with epibromohydrin in a similar manner to the procedure described in Example 1(ii) to give methyl 3-[5-methyl-2-(2,3-epoxypropoxy)benzoyl]propionate as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH2:19][C:11]3([CH2:14][CH:13]([C:15](OC)=O)C3)C=2)[O:3]1.FC(F)(F)S(OC1CCC([C:33]([O:35][CH3:36])=[O:34])=CC=1)(=O)=O>>[CH3:20][C:2]1([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH2:19][CH2:11][C:14]([C:33]([O:35][CH3:36])=[O:34])=[CH:13][CH:15]=2)[O:3]1
Reactant: COC(=O)C1CC2(C=C(B3OC(C)(C)C(C)(C)O3)C2)C1
Reactant: COC(=O)C1=CC=C(OS(=O)(=O)C(F)(F)F)CC1
Product: COC(=O)C1=CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Yield: 46.6 %

Procedure:
The title compound was prepared following the method described in step 2 for the preparation of methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3.3]hept-5-ene-2-carboxylate, using methyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohexa-1,3-dienecarboxylate as the reactant. (46.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.00 (dt, J=5.3, 1.5 Hz, 1H), 6.75 (dt, J=5.3, 1.6 Hz, 1H), 3.74 (s, 3H), 2.42-2.35 (m, 2H), 2.34-2.27 (m, 2H), 1.26 (s, 12H).