Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[C:4]([C:7]([NH2:9])=[O:8])[NH:5][CH:6]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:29]([NH:28][C:19]3[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=3[F:17])=[O:30])=[CH:12][CH:11]=2)=[C:4]([C:7]([NH2:9])=[O:8])[NH:5][CH:6]=1
Reactant: NC(=O)c1[nH]cc(Cl)c1-c1ccc(N)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: NC(=O)c1[nH]cc(Cl)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
To 0.03 g (0.127 mmol) of 4-chloro-3-(4-aminophenyl)-1H-pyrrole-2-carboxamide dissolved in 2.7 cm3 of tetrahydrofuran is added, at a temperature in the region of 20° C. under an argon atmosphere, 0.019 cm3 (0.134 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate. After stirring for 2 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue, which is recrystallized from 4 cm3 of acetonitrile. After filtering through a No. 3 sinter funnel, the solid is washed with 2 cm3 of acetonitrile and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 45° C. for 2 hours to give 0.037 g of 4-chloro-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrole-2-carboxamide in the form of a white solid; 1H NMR (400 MHz, DMSO d6, δ in ppm): 5.83 (broad m, 1H); 7.08 (s, 1H); 7.18 (broad m, 1H); 7.28 (d, J=8.5 Hz, 2H); 7.38 (m, 1H); 7.50 (partially masked m, 1H); 7.55 (d, J=8.5 Hz, 2H); 8.62 (dd, J=2.0 and 7.5 Hz, 1H); 9.04 (broad s, 1H); 9.39 (broad s, 1H); 11.8 (broad s, 1H); ES+: m/z=441: [M+H]+; ES−: m/z=439: [M−H]−.
Reaction SMILES: NC1C=C(N)C=C(N)C=1C1C=CC(C)=CC=1.[C:17]([O:20][CH:21]1[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:22]1[NH2:23])(=[O:19])[CH3:18].[I:41][C:42]1[C:47]([CH2:48][CH3:49])=[C:46]([I:50])[CH:45]=[C:44]([I:51])[C:43]=1[C:52]1[CH:57]=[CH:56][C:55]([C:58](Cl)=[O:59])=[C:54]([N+:61]([O-:63])=[O:62])[CH:53]=1>>[N+:61]([C:54]1[CH:53]=[C:52]([C:43]2[C:44]([I:51])=[CH:45][C:46]([I:50])=[C:47]([CH2:48][CH3:49])[C:42]=2[I:41])[CH:57]=[CH:56][C:55]=1[C:58]([C:21]1([O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:22]1[NH2:23])[O:20][C:17](=[O:19])[CH3:18])=[O:59])([O-:63])=[O:62]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1c(I)cc(I)c(-c2ccc(C(=O)Cl)c([N+](=O)[O-])c2)c1I
Agent: Cc1ccc(-c2c(N)cc(N)cc2N)cc1
Product: CCc1c(I)cc(I)c(-c2ccc(C(=O)C3(OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3N)c([N+](=O)[O-])c2)c1I

Procedure:
Freidel-Crafts acylation is performed on 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6) in the presence of AlCl3 and CH3COCl to yield 2′,4′,6′-triiodo-3′-acetyl-3-nitrobiphenyl-4-carboxylic acid (12). C 13 ⁢ H 6 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 ⁢ → C ⁢   ⁢ H 3 ⁢   ⁢ C ⁢   ⁢ O ⁢   ⁢ Cl Al ⁢   ⁢ Cl 3 ⁢ C 15 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 5 2′,4′,6′-triiodo-3′-acetyl-3-nitrobiphenyl-4-carboxylic acid (12) is then reacted with a zinc mercury amalgam and hydrochloric acid and heated to yield 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13). C 15 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 5 ⁢ → Δ Zn ( Hg ) ,   ⁢ H ⁢   ⁢ Cl ⁢ C 15 ⁢ H 10 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carbonyl chloride (14). C 15 ⁢   ⁢ H 10 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 ⁢ → S ⁢   ⁢ O ⁢   ⁢ Cl 2 ⁢ C 15 ⁢   ⁢ H 9 ⁢ Cl ⁢ I 3 ⁢ N ⁢   ⁢ O 3 1,3,4,6-tetra-O-acetyl-D-glucosamine (9) is reacted with 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carbonyl chloride (14) to yield 2-nitro-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (15). C14H21NO9+C15H9ClI3NO3→C29H29I3N2O12 2-nitro-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (15) is treated with stannous chloride and hydrochloric acid to yield 2-amino-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-D-glucosamine (16). C 29 ⁢   ⁢ H 29 ⁢ I 3 ⁢ N 2 ⁢ O 12 ⁢ → Sn ⁢   ⁢ Cl 2 ,   ⁢ H ⁢   ⁢ Cl ⁢ C 21 ⁢   ⁢ H 23 ⁢ I 3 ⁢ N 2 ⁢   ⁢ O 6 Example 2 is similar in general structure to Example 1, with the additional presence of a short alkyl chain attached to the radio-opaque tri-iodophenyl moiety at the C-3′ position to further increase lipophilicity of the molecule and enhance cell membrane permeability. The computed logP of Example 2 is 5.31.
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[C:3]1[O:4][CH:5]=[C:6](/[CH:8]=[C:9](/[C:21]([O:23][CH3:24])=[O:22])\[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=1>C(OCC)(=O)C.[Rh]>[C:21]([CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][C:6]1[CH:7]=[C:3]([Si:2]([CH3:26])([CH3:1])[CH3:25])[O:4][CH:5]=1)([O:23][CH3:24])=[O:22]
Reactant: CCCCCCCCCCC/C(=C\c1coc([Si](C)(C)C)c1)C(=O)OC
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCC(Cc1coc([Si](C)(C)C)c1)C(=O)OC

Procedure:
A solution of (E)-1-(2-trimethylsilyl-4-furyl)-2-carbomethoxytridec-1-ene (133 mg, 0.35 mmole) in ethyl acetate (20 ml) was hydrogenated over 5% rhodium on alumina (ca 10 mg) at room temperature for 3 days. The mixture was filtered through celite and the filtrate on evaporation gave an oil which was purified by preparative TLC (20×20 cm, 1000μ silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].O.CO>[NH2:1][C:4]1[C:5]([NH:10][CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCC1CC(=O)N(CNc2ncccc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCCC1CC(=O)N(CNc2ncccc2N)C1
Reaction time: 16 h
Yield: 113.1 %

Procedure:
Palladium on charcoal (10% wt, 0.478 g) is added to a solution of 1-{[(3-nitropyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x77 (1 eq, 2.5 g, 8.983 mmol) and NH4CO2H (5 eq, 44.9 mmol, 2.832 g) in water and methanol (1/1 (v/v), 35 ml). The resulting slurry is kept under agitation during 16 hours at room temperature, then filtration over celite and evaporation of the crude mixture afford 2.524 g of 1-{[(3-aminopyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x78.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([CH3:30])=[CH:24]3)[CH:12]=1)=[O:10].[C:31](Cl)(=[O:33])[CH3:32]>>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:31](=[O:33])[CH3:32])[C:25]([CH3:30])=[CH:24]3)[CH:12]=1)=[O:10]
Reactant: COC[C@H]1CCCN1C(=O)c1cc2nccc(Nc3ccc4[nH]c(C)cc4c3)c2s1
Reactant: CC(=O)Cl
Product: COC[C@H]1CCCN1C(=O)c1cc2nccc(Nc3ccc4c(c3)cc(C)n4C(C)=O)c2s1

Procedure:
The title compound was prepared by method analogous to Example 70A using (2R)-(2-methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-methanone and acetyl chloride as starting materials. MS: 463 (MH+); HPLC Rf: 4.88 min; HPLC purity: 94%.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>CCO.C(Cl)(Cl)Cl>[Cl:18][C:15]1[N:16]=[CH:17][C:12]([NH:11][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:13][CH:14]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CSC(=C[N+](=O)[O-])N(C)C
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN(C)C(=C[N+](=O)[O-])Nc1ccc(Cl)nc1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
A mixture of 1.5 g (0.0093 mole) of 1-dimethylamino-1-methylthio-2-nitroethylene and 1.1 g of 5-amino-2-chloropyridine was heated at 110-120° C. with stirring for 1 hour. After cooling, the reaction mixture was subjected to silica gel column chromatography using EtOH-CHCl3 (1:40) as the eluent to recover 0.38 g of the title compound as pale brown crystals. The NMR spectrum of this product showed that it was a 1:1 mixture of the title compound and N2 -(6-chloro-3-pyridyl)-N'-dimethyl-2-nitroacetamidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:9]([CH2:15][CH:16]([F:22])/[CH:17]=[CH:18]/[N+:19]([O-:21])=[O:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.OP([O-])(O)=O.[K+]>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C@H:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:15][CH:16]([F:22])[CH2:17][CH2:18][N+:19]([O-:21])=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H](CC(F)/C=C/[N+](=O)[O-])N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC(F)CC[N+](=O)[O-])N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl(2S,5E)-2-[bis(tert-butoxycarbonyl)amino]-4-fluoro-6-nitrohex-5-enoate, from Example 8, Step 4 (2.38 g, 5.66 mmol) in THF (56.6 mL) at 6° C. was added sodium borohydride (1.071 g, 283 mmol) followed by a slow addition of water (11.32 mL). The reaction mixture was stirred at room temperature for 4 hours, poured into 10% KH2PO4, and extracted with EtOAc (2×). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford 2.391 g of the title compound (colorless oil) that was used without further purification.
Reaction SMILES: C([NH:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])C1C=CC=CC=1>C(O)C.C(O)(=O)C.[C].[Pd]>[NH2:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOP(=O)(CNCc1ccccc1)OCC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOP(=O)(CN)OCC
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A 250-mL pressure tank reactor was purged, flushed and maintained with a hydrogen atmosphere, then, was added a solution of diethyl (benzylamino)methylphosphonate (3.5 g, 13.62 mmol, 1.00 equiv) in ethanol (180 mL), acetic acid (10 mL) and Palladium carbon (0.2 g, 0.10 equiv). The resulting solution was stirred for 24 h at 50° C. under 20 atm pressure. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 2.0 g (crude) of the title compound as brown oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:16])([CH3:15])[C:5](=[O:14])[NH:6]2.[CH:17]1(O)[CH2:20][CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH:17]1([N:6]2[C:7]3[C:3](=[C:2]([F:1])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=3)[C:4]([CH3:16])([CH3:15])[C:5]2=[O:14])[CH2:20][CH2:19][CH2:18]1
Reactant: OC1CCC1
Reactant: CC1(C)C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(=O)N(C2CCC2)c2ccc([N+](=O)[O-])c(F)c21
Reaction time: 5 h

Procedure:
To a solution of 4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (300 mg), cyclobutanol (0.136 mL) and triphenylphosphine (702 mg) in THF (15 mL) was added dropwise diethyl azocarboxylate (40% toluene solution, 1.48 mL) at 0° C., and the mixture was stirred for 5 hr under a nitrogen atmosphere. To the reaction mixture was added water at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=1[CH3:38]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=2[CH3:38])[N:8]=1)=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])cc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9) (1.80 g, 8.07 mmol) in THF (30 ml) at ambient temperature under nitrogen was added 1.0 M lithium bis(trimethylsilyl)amide in THF (8 mL, 8.00 mmol) and stirred for 20 min. To the solution was added a solution of 2-(bromomethyl)-1-methyl-4-nitrobenzene (1.81 g, 7.87 mmol) in THF (20 ml) and stirred overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (150 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The phases were separated and the aqueous phase washed with ethyl acetate (25 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave a yellow oil (3.5 g). The residue was loaded in dichloromethane and purified on silica 100 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (2.1 g); LCMS (System 4) MH+=373, tRET=2.60 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12]CC2C=CC=CC=2)[CH:6]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: COC(=O)Cc1cc(Cl)cc(OCc2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1cc(O)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (3-benzyloxy-5-chloro-phenyl)-acetic acid methyl ester (8 g, 28 mmol) in CH2Cl2 (100 mL) at 0° C. was added boron tribromide (1M in CH2Cl2; 56 mL, 56 mmol). The reaction mixture was warmed to room temperature over 30 minutes and stirred for 2 hours. Once no starting material was seen by analytical LCMS and tlc, the mixture was cooled to 0° C. and quenched with H2O (50 mL). The volume was reduced, and the residue was diluted with EtOAc (500 mL). The solid material was filtered, and the organic layer was separated and concentrated. The crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[CH3:11][NH2:12]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:12][CH3:11])=[O:6]
Reactant: CN
Reactant: O=C(O)c1cccc(O)c1
Product: CNC(=O)c1cccc(O)c1
Yield: 91.5 %

Procedure:
A mixture of 3-hydroxybenzoic acid (1.3 g, 9.4 mmol) and a ethanolic methylamine solution (33%, 1.5 ml, 12.1 mmol) were stirred at 60° C. for 48 h, then the solvent was evaporated in vacuo, and the residue redissolved in a small volume of ethanol. The product precipitated from the solution by the addition of ethyl acetate. The precipitate was collected by filtration and dried to give the subtitled compound (1.3 g, 91%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17](Cl)(=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20]>N1C=CC=CC=1>[CH3:20][CH:19]([CH3:21])[CH2:18][C:17]([NH:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:22]
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)CC(=O)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 58.1 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (1.1 g, 5.0 mmol) and isovaleryl chloride (0.68 mL, 5.5 mmol) in pyridine (10 mL) provided 3-methyl-N-[6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]-furan-2-yl]butyramide (0.87 g). Mp 154-155° C.;MS (FAB) m/z 300 ([M+H]+); Anal. Calcd. for C19H25NO2: C, 76.22; H, 8.42; N, 4.68; Found: C, 76.07; H, 8.52; N, 4.89.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].CB(O)O.ClCCl.[CH:14]([O:17][C:18]([N:20]1[C:26]2[C:27]3[CH2:28][CH2:29][CH2:30][C:31]=3[C:32](Br)=[CH:33][C:25]=2[C@@H:24]([NH:35][CH2:36][C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)[CH2:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15]>O1CCOCC1>[CH:14]([O:17][C:18]([N:20]1[C:26]2[C:27]3[CH2:28][CH2:29][CH2:30][C:31]=3[C:32]([CH3:1])=[CH:33][C:25]=2[C@@H:24]([NH:35][CH2:36][C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)[CH2:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CC(C)OC(=O)N1CCC[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(Br)c3c(c21)CCC3
Agent: CB(O)O
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc2c(c3c1CCC3)N(C(=O)OC(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Add cesium carbonate (383 mg, 2.52 mmol), methyl boronic acid (76 mg, 1.26 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (69 mg, 0.084 mmol) to a solution of (S)-6-(3,5-bis-trifluoromethyl-benzylamino)-4-bromo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (500 mg, 0.84 mmol) in dioxane (7 mL). Stir the mixture under nitrogen at 110° C. for 2 h. Cool down the mixture to room temperature and filter over Celite® washing with dichloromethane. Evaporate the solvent and purify the crude by chromatography, eluting with hexane/ethyl acetate (90/10) to afford the title compound (355 mg, 0.67 mmol, 80%). MS (ES+): 529 (M+H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[ClH:13].[NH2:14][CH2:15][C:16](=[O:22])[CH2:17][CH2:18][C:19](O)=[O:20]>>[ClH:13].[NH2:14][CH2:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1)=[O:20]
Reactant: NCC(=O)CCC(=O)O
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
From 4-(trifluoromethyl)benzyl alcohol (4.9 g; 28 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 2 h. The yield was 1.24 g (64%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18](=O)[C:17]([CH3:23])([CH3:22])[CH:16]2[C:24]([O-:26])=[O:25])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:27](OC(=O)C)(=O)C>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH:20]=[CH:19][S:18][C:17]([CH3:23])([CH3:22])[C@@H:16]2[C:24]([O:26][CH3:27])=[O:25])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCS(=O)C(C)(C)C2C(=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)N2C=CSC(C)(C)[C@@H]2C(=O)OC)cc1

Procedure:
A solution of 1.50 g (3.632 mmol) of methyl (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylate-1-oxide in 20 mL of acetic anhydride was heated to reflux for 4 h and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.985 g of methyl(3S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-3,4-dihydro-2H-1,4-thiazine-3-carboxylate as a colorless oil. Electrospray Mass Spec 396.1 (M+H)+.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(F)cc1OC
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccccc2)cc1OC
Temperature: 80 °C
Reaction time: 12 h
Yield: 81.3 %

Procedure:
To a solution of methyl 4-fluoro-2-methoxybenzoate (1.84 g, 10 mmol) in N,N-dimethylformamide (100 mL) were added phenol (0.94 g, 10 mmol) and potassium carbonate (2.67 g, 20 mmol). The mixture was heated to 80° C. and stirred for 12 hours. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=7:1) to give methyl 2-methoxy-4-phenoxybenzoate (2.1 g, 81%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.N1C=CC=CC=1.O[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl.O>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(O)C1CCOCC1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1ccc(OC(=O)C2CCOCC2)cc1
Temperature: 0 °C
Yield: 87.4 %

Procedure:
To a 100 mL dry round bottom flask were added tetrahydro-pyran-4-carboxylic acid (2.8 g, 21.5 mmol), thionyl chloride (2.8 mL, 34.4 mmol). The mixture was refluxed for 45 minutes, then all the volatile materials were rotary-evaporated. To the residue, anhydrous CH2Cl2 (10 mL) was added. The resulting solution was cooled to 0° C., and pyridine (2.63 g, 21.5 mmol) was added, followed by a solution of 4-hydroxybenzaldehyde (2.04 g, 25.8 mmol) in anhydrous CH2Cl2 (30 mL). The reaction mixture was stirred and warmed from 0° C. to room temperature slowly, then at room temperature overnight. To the reaction mixture, water (60 mL) was added and the CH2Cl2 layer was separated. The aqueous layer was extracted continually with CH2Cl2 (50 mL×3). The combined CH2Cl2 solution was washed with a cold aqueous solution of saturated NaHCO3 (80 mL). After drying and removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 4-formylphenyl tetrahydro-2H-pyran-4-carboxylate (4.40 g) as colorless oil. Yield: 87%. 1H NMR (CDCl3, 300 MHz): δ=9.97 (s, 1H), 7.91 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 4.06-4.00 (m, 2H), 3.55-3.47 (m, 2H), 2.88-2.81 (m, 1H), 2.03-1.88 (m, 4H). 13C NMR (CDCl3, 75.5 MHz): δ=190.9, 172.2, 155.3, 133.9, 131.1, 122.2, 115.9, 66.8, 40.1, 28.4.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>C(C(C)=O)C>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:10][CH:9]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccccc1NCc1ccc(F)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A suspension of 77 g of potassium carbonate in a mixture of 100 mL of methyl ethyl ketone, 50 g of 4-fluorobenzyl bromide and 26 mL of the methyl 2-aminobenzoate was refluxed for 8 h, cooled to room temperature, filtered and concentrated. Filtration on 600 mL of silica gel and washing with 10% ethyl acetate in hexane afforded the desired material as a yellow oil (41 g, 85% purity). This material was used as such for the next step.