Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[NH:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=C2N=C(CCC3NC(=O)CCCC3)NC2=NC=1.[CH3:46][N:47]([CH3:66])[S:48](C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)(=[O:50])=[O:49]>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:46][N:47]([CH3:66])[S:48]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:25])[NH:24]4)[NH:13][C:10]3=[N:11][CH:12]=2)=[CH:6][CH:5]=1)(=[O:50])=[O:49]
Reactant: CN(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C1CCCCC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)N1
Agent: O=C([O-])[O-]
Agent: O=C1CCCCC(CCc2nc3cc(Br)cnc3[nH]2)N1
Agent: [Na+]
Product: CN(C)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=O)N4)nc3c2)cc1

Procedure:
The title compound is analogously synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound B1) from 100 mg of 7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound C1), 890 μl of aqueous sodium carbonate solution (strength 2.0 M), 138 mg N,N-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (compound C2), and 26 mg of trans-dichloro-bis(tricyclohexyl-phosphine)-palladium(II) at 160° C. for 30 min (microwave irradiation, power ≦300 W). Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-10 vol. % ethanol) yields 93 mg of the title compound as a waxy solid. ESI-MS: 442.4 (MH+). TLC: Rf=0.41 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[C:5]([CH3:18])=[N:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=2)[CH:9]=1.[CH3:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1>>[ClH:2].[CH3:17][C:12]1[CH:11]=[C:10]([C:8]2[CH:9]=[C:4]([CH2:3][N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[CH3:19])[C:5]([CH3:18])=[N:6][CH:7]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1ccc(-c2cnc(C)c(CCl)c2)cc1C
Reactant: Cc1ncc[nH]1
Agent: Cl
Product: Cc1ccc(-c2cnc(C)c(Cn3ccnc3C)c2)cc1C

Procedure:
The title compound, MS: m/e=292.2 (M+H+) was obtained as a beige solid (77% yield) by the reaction of 3-chloromethyl-5-(3,4-dimethyl-phenyl)-2-methyl-pyridine hydrochloride (1:1) with 2-methylimidazole (5 eq.), using sodium hydride (3 eq.) as base followed by formation of the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH:11]([CH2:17]Br)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:14][C:12]([CH:11]1[CH2:17][NH:1][C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=2[O:9]1)=[O:13])[CH3:16]
Reactant: Nc1cc(Br)ccc1O
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2cc(Br)ccc2O1
Yield: 78.2 %

Procedure:
A mixture of 2-amino-4-bromophenol (5.00 g, 26.6 mmol), ethyl 2,3-dibromopropionate (7.84 g, 29.2 mmol), and potassium carbonate (10.3 g, 81.8 mmol) in acetone (55 mL) was heated at reflux for 16 h. After evaporation of volatile material, the residue was partitioned between dichloromethane and water. The organic layer was washed with 1 M aq. sodium carbonate solution and brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient produced 6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl ester (5.95 g, 78%). Orange solid, MS (ISP)=286.0 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[CH:14][C:10]=2[C:11]([OH:13])=O)=[C:4]([CH3:21])[CH:3]=1.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].C(N(C(C)C)CC)(C)C.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.CCOCC>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[CH:14][C:10]=2[C:11]([NH:28][O:27][CH2:26][CH2:25][O:24][CH:22]=[CH2:23])=[O:13])=[C:4]([CH3:21])[CH:3]=1
Reactant: C=COCCON
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)O)cc(F)c(F)c1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=COCCONC(=O)c1cc(F)c(F)c(F)c1Nc1ccc(I)cc1C
Yield: 72.9 %

Procedure:
To a solution comprised of 2-(4-iodo-2-methyl-phenylamino)-3,4,5-trifluoro-benzoic acid (3.60 g, 8.84 mmol), O-(2-vinyloxyethyl)hydroxylamine (1.09 g, 10.5 mol) and diisopropylethylamine (2.80 mL, 16.0 mmol) in dichloromethane (50 mL) was added benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium-hexafluorophosphate (5.26 g, 10.1 mmol). The resultant solution was stirred 90 min at ambient temperature. The reaction mixture was diluted with ether (100 mL) and washed with water (3×50 mL) and saturated brine (50 mL). The organics were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography to afford 2-(4-iodo-2-methyl-phenylamino)-3,4,5-trifluoro-N-(2-vinyloxyethoxy)benzamide (3.17 g, 73%) as a pale-yellow foam.
Reaction SMILES: C([O:8][C:9]1[N:13]([CH3:14])[N:12]=[C:11]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][CH2:18]2)=[O:16])[CH:10]=1)C1C=CC=CC=1>CO.[C].[Pd]>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([C:15]([C:11]2[CH:10]=[C:9]([OH:8])[N:13]([CH3:14])[N:12]=2)=[O:16])[CH2:22][CH2:21]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: Cn1nc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cn1nc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1O
Yield: 46.9 %

Procedure:
A mixture of 1-{[5-(benzyloxy)-1-methyl-1H-pyrazol-3-yl]carbonyl}-4-(2-tert-butylphenyl)piperazine (1.75 g), and palladium-carbon (500 mg) in methanol (150 mL) was stirred under hydrogen atmosphere (5 atm). The mixture was filtered and concentrated under reduced pressure to purify the residue by silica gel column chromatography (ethyl acetate/methanol 100:0 to 90:10). Solvent was removed to obtain a solid (650 mg, 56%). LC/MS; ESI(+) m/z: 343 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].[CH3:19]N(C)C=O.C(Cl)(=O)C(Cl)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:19])=[O:13]
Reactant: O=C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 0 °C
Yield: 83.1 %

Procedure:
To a solution of 2-[(2,6-dichlorophenyl) amino]benzoic acid (25 g, 89 mmol) [J. S. Kaltenbronn et al, Arzneim-Forsch/Drug Res. 33(1),4a, 621-627 (1983)] and dimethylformamide (6.8 g, 93 mmol) in dry tetrahydrofuran (500 ml) is added oxalyl chloride (17 ml, 196 mmol) dropwise with stirring under an atmosphere of dry nitrogen at 0° C. The ice bath is removed and the reaction mixture is stirred without cooling for 15 minutes. The reaction mixture is poured into methanol (1500 ml). The solvent is evaporated and the residue is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is dried (MgSO4) and evaporated. Recrystallization of the residue from methanol provides pure 2-[(2,6-dichlorophenyl) amino]benzoic acid, methyl ester (21.9 g, 83%); mp 100°-103° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C(N(CC)CC)C>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])=[CH:3][N:4]=1
Reactant: C#CCCO
Reactant: Brc1cncc2ccccc12
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCC#Cc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
In an inert atmosphere, 0.268 g of bis(triphenylphosphine) palladium dichloride and 0.072 g of cuprous iodide was added with stirring to a deoxygenated solution of 5 g of 4-bromoisoquinoline, 3.02 g of 3-butyn-1-ol and 10 mL of triethylamine in 20 mL of dichloromethane. The reaction was stirred at room temperature for 1 hour and then at reflux for 18 hours. The cooled mixture was filtered and the filtrate was washed with water. The dried (Na2SO4) organic phase was concentrated in vacuo and the residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 3.4 g of 4-(4-isoquinolinyl)-3-butyn-1-ol as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CO
Product: CCOC(=O)CC1CC2CCC(C1)N2C(=O)OC(C)(C)C
Reaction time: 20 h

Procedure:
A reaction flask was charged with 3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester (0.254 g, 0.86 mmol) and PtO2 (0.028 g) in MeOH (4 mL). The reaction flask was evacuated and purged with hydrogen twice followed by stirring under a hydrogen atmosphere for 20 h. The reaction mixture was filtered through Celite, washed with MeOH, and concentrated to give the crude title compound as the major isomer (0.256 g, 100%, 1:3 a:β).
Reaction SMILES: [N+:1](C1NC2C=CC=CC=2N=1)([O-])=O.CCCCCC.CCOC(C)=O.[CH2:25]([N:28]1[C:32]2[CH:33]=[C:34](N)[CH:35]=[CH:36][C:31]=2[N:30]=[CH:29]1)[CH2:26][CH3:27]>CO.[Pd]>[CH2:25]([N:28]1[C:32]2[CH:33]=[CH:34][C:35]([NH2:1])=[CH:36][C:31]=2[N:30]=[CH:29]1)[CH2:26][CH3:27]
Reactant: CCCn1cnc2ccc(N)cc21
Reactant: O=[N+]([O-])c1nc2ccccc2[nH]1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCn1cnc2cc(N)ccc21

Procedure:
A solution of 5-nitrobenzimidazole (3.6 g, 23 mmol) in 100 ml of THF was stirred with NaH (1.5 g, 33 mmol) for 0.5 h at 25° C. To the solution was added allyl bromide (4.8 ml, 57 mmol) and resulting mixture was stirred for 12 h. The reaction mixture was concentrated in vacuo to provide an oil, which was subjected to column chromatography to yield 4.0 g (19.7 mmol, 89%) of a mixture of 1- and 3-allyl-5-nitrobenzimidazole. The nitrobenzimidazole mixture was stirred in 100 ml of MeOH for 12 under H2 in the presence of 10% Pd/C. The reaction mixture was filtered and concentrated in vacuo to provide oily residue which was subjected to column chromatography (50% Hexane/EtOAc) to provide 1.2 g (7.0 mmol) of 1-propyl-5-aminobenzimidazole and 1.1 9 (6.4 mmol) of 3-propyl-5-aminobenzimidazole.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][N:14]1[C:20](=[O:21])[C@@H:19]([NH:22][C:23](=[O:36])[C@@H:24]([N:27](C)[C:28](=O)OC(C)(C)C)[CH2:25][CH3:26])[CH2:18][O:17][C:16]3[CH:37]=[CH:38][CH:39]=[CH:40][C:15]1=3)=[C:8]([O:41][CH3:42])[CH:7]=[CH:6]2>CCOCC.CO>[ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][N:14]1[C:20](=[O:21])[C@@H:19]([NH:22][C:23](=[O:36])[C@@H:24]([NH:27][CH3:28])[CH2:25][CH3:26])[CH2:18][O:17][C:16]3[CH:37]=[CH:38][CH:39]=[CH:40][C:15]1=3)=[C:8]([O:41][CH3:42])[CH:7]=[CH:6]2
Reactant: CC[C@@H](C(=O)N[C@H]1COc2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC[C@H](NC)C(=O)N[C@H]1COc2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O
Yield: 95 %

Procedure:
2 M HCl in Et2O (419 μL) was added to a solution of tert-butyl (S)-1-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxobutan-2-yl(methyl)carbamate (65.7 mg, 105 μmol) in MeOH (105 μL). After 4 h the mixture was concentrated and the residue was dissolved in MeCN/H2O and the solution lyophilized to provide the title compound (55.9 mg, 95%) as a white solid. MS m/z 526/528 (MH)′
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:10]([CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=2[C@H:5]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@H:4]2[C:3]1=O.CC1C2NC(=O)[C@@H]3CN(C(OC(C)(C)C)=O)C[C@@H]3C=2C=CC=1>C1COCC1>[CH3:1][N:2]1[C:11]2[C:10]([CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=2[C@H:5]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@H:4]2[CH2:3]1
Reactant: Cc1cccc2c1N(C)C(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Agent: Cc1cccc2c1NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Solvent: C1CCOC1
Product: Cc1cccc2c1N(C)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of (±)-cis tert-butyl 5,6-dimethyl-4-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate, an intermediate from Example 18, Part B (0.40 g, 1.27 mmol) in 10 mL of THF at 0° C. was added borane THF complex (6.5 mL of a 1 M solution in THF, 6.5 mmol) dropwise. The reaction was allowed to warm to ambient temperature and was stirred for 2 h. The reaction was quenched carefully with water and extracted with ethyl acetate. The organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.37 g (97%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[C@:7]1([CH3:17])[CH2:8][CH2:9][CH2:10][C@@H:11]2[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[C@:7]1([CH3:17])[CH2:8][CH2:9][CH2:10][C@@H:11]2[O:16][C:18](=[O:20])[CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)O[C@H]1CCC[C@H]2[C@@H](O)CCC[C@]12C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CCC[C@]2(C)[C@@H](OC(C)(C)C)CCC[C@@H]12
Reaction time: 2 h
Yield: 91 %

Procedure:
A solution of 4.11 g (17.1 mMol) of (1S,4aS,5S,8aR)-5-tert-Butoxy-4a-methyl-decahydro-naphtalen-1-ol and 313.6 mg (2.6 mMol) of 4-dimethylaminopyridine in 26 ml of pyridine is treated with 13 ml of acetic anhydride under stirring and argon atmosphere for two hours. The reaction mixture is poured on ice-water and extracted three times with diethylether. The combined organic layer is washed twice with water, dried over sodium sulfate and evaporated in vacuo to yield 1.26 g of crude product which is chromatographed over 60 g of silicagel with hexane/ethylacetate 9/1 to give 4.64 g (91%) of Acetic acid (1S,4aS,5S,8aR)-5-tert-butoxy-4a-methyl-decahydronaphtalen -1-yl ester as an amorphous pure product.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][OH:19])[N:17]=1)[CH2:10][CH2:11][CH3:12].C(OCC)(=O)C>CN(C1C=CN=CC=1)C.O1CCOCC1.COCCO>[CH2:9]([C:13]1[NH:17][C:16]([CH2:18][OH:19])=[C:15]([I:1])[N:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1nc(CO)c[nH]1
Reactant: O=C1CCC(=O)N1I
Agent: CN(C)c1ccncc1
Solvent: COCCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCc1nc(I)c(CO)[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
4-DMAP (1.2 g; 10 mmol) and N-iodosuccinimide (25 g; 111 mmol) were added to a solution of 2-butyl-4-hydroxymethyl-imidazole (15.4 g; 100 mmol) in dioxane (210 ml) and 2-methoxyethanol (140 ml) and the mixture was stirred overnight at 50° C. Concentration gave 44.4 g of a brownish-yellow magma (theory; 28 g), which was further reacted without further purification. For characterisation, 2 g of the crude product were dissolved using ethyl acetate and washed with 5% NaHCO3 solution and saturated sodium chloride solution. Drying and concentration of the organic phases gave 1.2 g of a yellow solid [97% of theory; m.p.: 135°-40° C. (dec.); Rf : 0.24 (methylene chloride:methanol=10:1)].
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6](O)[CH2:5][C:4]1=[O:56])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]=[CH:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Temperature: 100 °C
Yield: 81.9 %

Procedure:
17-Ethyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclo hexyl)-1-methylvinyl)-23,25-dimethoxy-13,19,21,27-tetra methyl-11,28-dioxa-4-azatricyclo(22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (FR-900520) (100 mg) and p-toluenesulphonic acid (2 mg) were dissolved in dry toluene (20 ml) and were heated for 2 hours at 100° C. under an atmosphere of nitrogen. Removal of solvent in vacuo and chromatography on silica eluting with hexane/acetone [2:1] gave the sub-title compound as a foam (80 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)(=[O:31])=[O:30])=[CH:27][C:21]=2[S:20](=[O:44])(=[O:43])[N:19]=1.Cl>O1CCOCC1>[NH2:35][CH2:34][CH2:33][NH:32][S:29]([NH:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:18]([C:3]3[C:4](=[O:17])[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]4[C:11]([C:2]=3[OH:1])=[CH:10][CH:9]=[CH:8][N:7]=4)=[N:19][S:20](=[O:43])(=[O:44])[C:21]=2[CH:27]=1)(=[O:30])=[O:31]
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NCCNC(=O)OC(C)(C)C)ccc3N2)c(O)c2cccnc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NCCN)ccc3N2)c(O)c2cccnc21
Reaction time: 18 h

Procedure:
A solution of the product of Example 459A (0.0053 g, 0.0082 mmol) in a solution of hydrogen chloride in 1,4-dioxane (4 N, 3 mL) and stirred at 25° C. and stirred for 18 hours. The solvent was removed under reduced pressure to give the title compound as the hydrochloride salt (4 mg, 89%). 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.62 Hz, 6 H) 1.56 (m, 2 H) 1.68 (m, 1 H) 2.89 (m, 2 H) 3.10 (m, 2 H) 4.49 (m, 2 H) 7.51 (m, 2 H) 7.62 (d, J=2.21 Hz, 1 H) 7.74 (d, J=8.82 Hz, 1 H) 7.79 (s, 2 H) 8.03 (t, J=5.70 Hz, 1 H) 8.56 (dd, J=7.72, 1.84 Hz, 1 H) 8.89 (dd, J=4.41, 1.84 Hz, 1 H) 10.37 (s, 1 H) 14.16 (s, 1 H). MS (ESI−) m/z 548 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:15][CH2:14][N:13]2[C:30](O)=[O:31])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[NH2:45][OH:46].NO.Cl>C(Cl)Cl.O.C1COCC1>[OH:46][NH:45][C:30]([N:13]1[CH2:14][CH:15]=[C:16]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH:17]=[CH:18][N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])=[O:31]
Reactant: NO
Reactant: COc1ccc(S(=O)(=O)C2=CCN(C(=O)O)N(S(=O)(=O)c3ccc(OC)cc3)C=C2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C2=CCN(C(=O)NO)N(S(=O)(=O)c3ccc(OC)cc3)C=C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The 1,5-di-[(4-methoxyphenyl)sulfonyl]-diazepine-2-carboxylic acid (0.60 g, 1.24 mmol) is dissolved in methylene chloride (15 mL) at room temperature followed the addition of oxalyl chloride (0.32 mL, 2.54 mmol) and slow addition of DMF (0.09 g, 1.24 mmol). This solution is stirred for 30 minutes at room temperature. In a separate flask, hydroxylamine hydrochloride (0.34 g, 5.0 mmol) in water (5 mL) and THF (7 mL) is stirred at 0° C., and then triethylamnine (1.0 mL, 6 equiv) is added. This solution is stirred for 15 minutes. The acid chloride solution is added to the hydroxylamine solution at 0° C. and then warmed up to room temperature and stirred for 3 hours. The solution is acidified to pH˜1 with 1N HCl, poured into water and extracted with methylene chloride. The organic extracts are dried (Na2SO4) and concentrated down to an oil. The oil is purified by HPLC with a reverse phase column using 65% (95% water, 5% acetonitrile, 0.1% formic acid) and 35% (80% acetonitrile, 20% water) as the eluent. MS (ESI): 500 (M+H+), 517 (M+NH4+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:23][CH:24]([O:29][Si](C(C)(C)C)(C)C)[C:25]([F:28])([F:27])[F:26])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][C:45]=1[CH2:51][CH3:52].C1(C(O)=O)C2C(=CC=CC=2)C=CC=1.ClC1C=CC(OC2C=CC=CC=2CC(NCC2C=CC=C(OC(F)(F)C(F)F)C=2)(O)C(F)(F)F)=CC=1CC>CC(N(C)C)=O.C1(C)C=CC=CC=1>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:2]2[CH:3]=[C:4]([N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:22])([F:21])[CH:18]([F:19])[F:20])[CH:11]=3)[CH2:23][CH:24]([OH:29])[C:25]([F:27])([F:26])[F:28])[CH:5]=[CH:6][CH:7]=2)=[CH:46][C:45]=1[CH2:51][CH3:52]
Reactant: CCc1cc(O)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Br)c1)C(F)(F)F
Agent: CCc1cc(Oc2ccccc2CC(O)(NCc2cccc(OC(F)(F)C(F)F)c2)C(F)(F)F)ccc1Cl
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCc1cc(Oc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)ccc1Cl

Procedure:
A solution of N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine (75 mg, 0.124 mmol), cesium carbonate (81 mg, 0.248 mmol), 4-chloro-3-ethylphenol (44 mg, 0.358 mmol), copper triflate benzene complex (6.24 mg, 10 mol %), 1-naphthoic acid (43 mg, 0.248 mmol) in 2:1 toluene:dimethylacetamide (3.0 mL) was heated at 105° C. for 96 hours. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase chromatography eluting with 50-90% acetonitrile in water to afford 16.2 mg (23%) of the desired 3-[[-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C26H23ClF7NO3: 566.1332 [M+H]+, found: 566.1332. 1H NMR (CDCl3) δ 1.18 (t, 3H), 2.69 (q, 2H), 3.50-3.61 (m, 1H), 3.87 (dd, 1H), 4.28-4.39 (m, 1H), 4.63 (s, 2H), 5.88 (tt, 1H), 6.32-6.40 (m, 2H), 6.48 (dd, 1H), 6.69 (dd, 1H), 6.87 (d, 1H), 7.0-7.34 (m, 5H).
Reaction SMILES: [CH2:1]1[O:21][C:4]2([CH2:9][CH2:8][C:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:10](OC)=[O:11])[CH2:6][CH2:5]2)[O:3][CH2:2]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH2:2]1[O:3][C:4]2([CH2:9][CH2:8][C:7]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)([CH2:10][OH:11])[CH2:6][CH2:5]2)[O:21][CH2:1]1
Reactant: COC(=O)C1(Cc2ccccc2)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1(Cc2ccccc2)CCC2(CC1)OCCO2
Yield: 93 %

Procedure:
A solution of 22.3 g. (0.77 M) of 4-benzyl-4-carbomethoxy-1-cyclohexaneone ethylene ketal [5] (prepared as in Example 4B) in 220 ml. of tetrahydrofuran is added to 3 g. of lithium aluminum hydride in 30 ml. of tetrahydrofuran. The mixture is stirred at reflux temperature for about 5.5 hours and then cooled in ice. There is added successively 3 ml. of water, 3 ml. of aqueous 15% sodium hydroxide solution and 9 ml. of water. The inorganic gel is collected on a filter and the filtrate evaporated to dryness. The residue is recrystallized from methylene chloride: Skellysolve B to give 18.8 g. (93% yield) of 4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal (1), having a melting point of 76° to 78° C.