Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:27][CH3:28])[CH:4]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[CH2:27]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:23])=[CH:20][CH:19]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:28]
Reactant: CCOC(=O)CCN
Reactant: CCC(CC)C(Nc1ccc(C(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2C)C(CC)CC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
To a mixture of 4-{[2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl]amino}benzoic acid (250 mg) synthesized above, β-alanine ethyl ester hydrochloride (151 mg), 1-hydroxybenzotriazole monohydrate (151 mg), triethylamine (275 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (188 mg), and the mixture was stirred at room temperature for 1 day. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (55% ethyl acetate/hexane) to give the title object compound (85.0 mg, 27%) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=2)=[O:10])[CH:3]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)c1cc(Br)ccn1
Product: CC(C)c1ccc(NC(=O)c2cc(Br)ccn2)cc1

Procedure:
In a manner similar to that describe in Preparation 34, 4-bromo-pyridine-2-carboxylic acid and 4-isopropylaniline were converted to the title compound.
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][C:27]([C:48]#[N:49])=[N:28][C:29]=3[NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:12][C@@H:11]1[C:50]([NH:52][CH2:53][CH3:54])=[O:51])(=O)C1C=CC=CC=1.[CH3:55]N>[Pd].C(O)C>[NH3:24].[C:36]1([CH:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:34][NH:33][C:29]2[N:28]=[C:27]([CH2:48][NH:49][CH3:55])[N:26]=[C:25]3[C:30]=2[N:31]=[CH:32][N:24]3[C@@H:13]2[O:12][C@H:11]([C:50]([NH:52][CH2:53][CH3:54])=[O:51])[C@@H:10]([OH:9])[C@H:14]2[OH:15])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: CN
Agent: [Pd]
Solvent: CCO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC)nc32)[C@H](O)[C@@H]1O
Product: N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10% Palladium on carbon (0.2 g) was added to a solution of (2S,3R,4R,5R)-4-(benzoyloxy)-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (1.0 g, 1.4 mmol) (Preparation 7) in 33% w/w methylamine in ethanol (75 ml). The reaction mixture was stirred under an atmosphere of hydrogen gas (4414 kPa, 60 psi) for 16 hours at room temperature. The solid was filtered off and the solvent was removed from the filtrate under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume) increasing in polarity to dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume) to give the title compound (0.52 g) as a solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][C:12]([F:15])([F:14])[F:13])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)C(C)C)(C)C.C([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(OC(C)(C)C)=O>Cl.O1CCOCC1>[N:32]1([C:2]2[C:3]3[CH:10]=[C:9]([CH2:11][C:12]([F:15])([F:14])[F:13])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)Cc1cc2c(Cl)ncnc2s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Cc1cc2c(N3CCNCC3)ncnc2s1
Yield: 66.2 %

Procedure:
190 mg of 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (0.75 mmol) was added to a stirred solution of 290 mg of N,N-diisopropylethylamine (2.25 mmol) and 168 mg of 1-Boc-piperazine (0.9 mmol) in 20 mL and was heated at reflux overnight. Solvent was removed under reduced pressure and the residue was loaded on silica gel column. Elution with DCM:MeOH produced 215 mg of Boc-intermediate as a pale yellow solid. Later it was dissolved in 20 mL of 4M HCl in dioxane and stirred for 2 hs. Solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and saturated sodium carbonate solution. Organic layer was washed with brine, dried over MgSO4 and evaporated to afford 150 mg of 4-(piperazin-1-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine, which was used in the next step without purification.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][O:25][CH:26]1[CH2:29][NH:28][CH2:27]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:28]1[CH2:29][CH:26]([O:25][CH2:24][C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)[CH2:27]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: c1csc(COC2CNC2)c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-(2-thienylmethoxy)azetidine hydrochloride (29 mg, 0.14 mmol; which may be prepared as described in Step 3), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a brown solid. This solid was triturated in acetone and diethyl ether, filtered, washed with diethyl ether then dried to give the title compound (8 mg, 18%) as a pale brown solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[F-:10].[K+].CN1C(=O)CCC1>CCOC(C)=O>[F:10][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: [F-]
Reactant: N#Cc1ccc(Cl)cn1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(F)cn1
Yield: 56.6 %

Procedure:
Add 5-chloro-pyridine-2-carbonitrile (3.0 g, 21.7 mmol) and potassium fluoride (3.9 g, 67.1 mmol) to a flask containing NMP (75 mL). Heat the mixture to reflux for 16 h. Add additional potassium fluoride (1.0 g, 17.2 mmol) and NMP (10 mL), then continue heating at reflux for 3 h. Cool the mixture, dilute with EtOAc, then wash with saturated NaCl (3×50 mL). Collect the organic layer, concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (20:1) to obtain the desired intermediate (1.5 g, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]1[CH2:14][CH2:13][CH2:12]1.[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: BrCC1CCC1
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CCC2)cc1
Yield: 37.2 %

Procedure:
4-Bromophenol (2.5 g, 14.5 mmol), (bromomethyl)cyclobutane (1.6 mL, 15 mmol), sodium hydroxide (0.8 g, 20 mmol) and DMF (3 mL) were allowed to react to yield the sub-title compound (1.3 g, 36%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:37])[CH2:28][NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:45](Cl)(Cl)=[O:46].CCOC(C)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[O:37][C:45](=[O:46])[N:29]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:28]4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CNCc4ccccc4)cc3)cc2)CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CN(Cc5ccccc5)C(=O)O4)cc3)cc2)CC1
Temperature: 0 °C

Procedure:
1-{4′-[4-(2-Benzylamino-1-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.190 g, 0.38 mmol) was dissolved in toluene (4 mL) then placed under N2 atmosphere at 0° C. Triethylamine (0.159 mL, 1.14 mmol) and phosgene (1.9M in toluene, 0.201 mL, 0.38 mmol) were added and the reaction stirred at 0° C. After two hours an additional portion of each of triethylamine (0.160 mL) and phosgene (0.200 mL) were added and the reaction stirred an additional 20 minutes. The reaction was submitted to standard workup procedures and silica gel chromatography (0-40% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH3:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-bromo-N-(3-methoxyphenyl)benzenesulphonamide (0.5 g 1.46 mmol) and K2CO3 (0.5 g) in anhydrous DMF (7 ml) MeI (1 ml) was added and this was stirred at 50° C. for 0.5 h. The mixture was diluted to 50 ml with H2O and extracted in EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4, filtered and the filtrate was passed through silica gel bead. The filtrate was evaporated to dryness to give the product (0.5 g; 96%), as a pale solid. 1H-NMR (CDCl3) 3.14 (5, 3H); 3.75 (s, 3H); 6.58 (broad d, 1H), 6.69 (t, 1H, J=2.20 Hz); 6.80 (dd, 1H, J=2.5, 8.34, Hz); 7.18 (tr, 1H, J=8.15 Hz); 7.40 (d, 2H, J=8.67 Hz); 7.58 (d, 2H, J=8.64 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[O:24]>C(Cl)Cl>[CH3:29][O:28][CH2:27][CH2:26][O:25][C:23]([N:11]1[CH2:10][CH:9]2[CH2:14][CH:13]([N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1C2CNCC1C2
Reactant: COCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)N1CC2CC(C1)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (2) (50 mg, 0.25 mmol) in 5 mL of methylene chloride was added triethylamine (67 μL, 0.5 mmol) and the solution was cooled to 0° C. Methoxyethyl chloroformate (32 μL, 27.5 mmol) was added and the solution was stirred for 1 h. The solvent was removed in vacuo and the residue was washed with 50 mM sodium acetate in methylene chloride solution. The solution was stirred 10 min and passed through a phase separator. The solvent was removed in vacuo to give crude 3-(methoxyethoxycarbonyl)-6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH2:17]1[O:19][CH2:18]1.[ClH:20]>C(O)C.CCOCC>[ClH:20].[OH:19][CH2:18][CH2:17][N:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[CH2:12]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCCC2
Reactant: C1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)CN(CCO)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 8-nitro-2,3,4,5-tetrahydro-1H-2-benzazapine (5.08 g, 22.2 mmol) in ethanol (200 ml) at 0° C. was added 2.5M sodium hydroxide solution (10.0 ml). To this solution, in a pressure bottle, was added ethylene oxide (4.2 ml) and the bottle was capped and stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the residue was partitioned between dichloromethane and dilute sodium hydroxide. The organic phase was dried (magnesium sulfate) and concentrated to give a yellow solid. This solid was taken up in ethanol and acidified with hydrochloric acid in ethanol. Addition of ether effected precipitation of the title salt as an orange solid (2.69 g, 44%). m.p. 193.5-4.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:14][CH3:15])[N:4]=[CH:3]1.S(=O)(=O)(O)[OH:18].[OH-:22].[Na+]>O>[CH3:1][C:2]([CH3:16])([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:14][CH3:15])[NH2:4])[C:3]([OH:18])=[O:22]
Reactant: O=S(=O)(O)O
Reactant: [OH-]
Reactant: CCC1CCCCCCCCC(C)(C)C=N1
Agent: [Na+]
Solvent: O
Product: CCC(N)CCCCCCCCC(C)(C)C(=O)O
Yield: 73 %

Procedure:
With stirring, 975 g (4.37 moles) of 3,3-dimethyl-12-ethyl-1-azacyclododecene (prepared in accordance with Example β) are added dropwise in the course of about 35 minutes to a solution of 450 g (4.6 moles) of sulfuric acid in 600 g of water. The clear, slightly yellowish solution is then treated with steam for 20 minutes in order to remove any aldehyde impurities. The aqueous solution is subsequently stirred in an autoclave for 3 hours at 50° C. under an oxygen pressure of 20 bar. The acid reaction mixture is neutralised with sodium hydroxide solution, affording 820 g (3.2 moles) of 2,2-dimethyl-11-ethyl-11-aminoundecanoic acid, corresponding to a yield of 73% of theory. Melting point: 164°-165° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([N:6]([CH3:8])[CH3:7])=O.CO.Cl>C1COCC1>[CH3:8][N:6]([CH3:7])[CH2:4][CH2:3][C@@H:2]([NH2:1])[CH2:9][S:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)C(=O)C[C@@H](N)CSc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CC[C@@H](N)CSc1ccccc1
Reaction time: 8 h

Procedure:
A solution of Example 1C (8.68 g) in THF (200 mL) was treated with BH3-dimethylsulfide (18.2 mL) at room temperature, stirred overnight, treated slowly with methanol (20 mL), followed by 2N HCl (50 mL), stirred overnight, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 5% 7N NH3/CH3OH in dichloromethane to give the desired product.
Reaction SMILES: ClC1C=[C:4]([C:11](C)([CH3:28])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=CC=C(OC3C=CC=CC=3)[CH:16]=2)C=CC=1OCC.[OH-].[K+].CN1CCN(C)C1=O.Cl>O>[CH3:4][CH:11]([CH3:28])[CH2:12][O:13][CH2:14][CH:15]([CH3:20])[CH3:16]
Reactant: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CC(C)COCC(C)C
Temperature: 150 °C
Reaction time: 18 h

Procedure:
100 g of 3-phenoxybenzyl 2-(3-chloro-4-ethoxyphenyl)-2-methylpropyl ether and 25 g of 97% potassium hydroxide were added to 300 ml of 1,3-dimethyl-2-imidazolidinone (hereinafter referred to as DMI) and the mixture was stirred at 150° C. for 18 h. After cooling to room temperature, the mixture was poured into water and made acidic with a concentrated aqueous hydrochloric acid solution. After extraction with benzene, the benzene solution was washed with water and dried. Benzene was distilled off under reduced pressure and the obtained oily residue was purified according to a column chromatography (silica gel, developer: benzene) to obtain 45.6 g of 3-phenoxybenzyl 2- 3-chloro-4-hydroxyphenyl)-2-methylpropyl ether (m.p. 68° to 69° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:26](O)=[O:27])[CH:20]=[CH:19]2)=[O:15]>C(Cl)Cl.N1C=CC=CC=1>[OH:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:26]([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:17]=2)[CH:22]=1)=[O:27]
Reactant: COC(=O)c1ccc2cc(C(=O)O)ccc2c1
Reactant: Nc1cc(C(=O)O)ccc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2cc(C(=O)Nc3cc(C(=O)O)ccc3O)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.8 %

Procedure:
A solution of 3-amino-4-hydroxybenzoic acid (0.142 g, 0.927 mmol) and the acyl chloride prepared from acid 74 (in 84% yield) (0.259 g, 1.019 mmol) in DCM (5 ml) and pyridine (6 ml) was stirred at room temperature for under at for 24 h. The solvent was removed under reduced pressure. HCl (aq, 4 M, 6 ml) was added and the precipitate was filtered, washed with water (10 ml) and dried under vacuum. Trituration with methanol (15 ml) and acetone (10 ml) afforded 75 as an off-white solid (0.084 g, 0.230 mml, 25%). 1H NMR (400 MHz, DMSO-d6) δ 3.92 (3H, s), 7.00 (1H, d, J 8.4 Hz), 7.67 (1H, d, J 8.8 Hz), 8.04-8.10 (2H, m), 8.16-8.27 (2H, m), 8.33 (1H, s), 8.70-8.66 (2H, m), 9.80 (1H, s), 10.55 (1H, bs). 13C NMR (100 MHz, DMSO-d6) δ 53.09, 116.18, 122.59, 125.94, 126.45, 126.26, 126.80, 128.45, 128.48, 129.19, 130.35, 130.40, 130.93, 134.13, 134.66, 134.94, 154.61, 165.85, 166.84, 167.73. νmax (solid)/(cm−1) 3059, 1716, 1666, 1592, 1541, 1283, 1247, 1132, 759.
Reaction SMILES: C[O:2][C:3]1[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:6]2[CH2:7][CH2:8][O:9][C:5]=2[C:4]=1[C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.B(Cl)(Cl)Cl.O>ClCCl>[OH:2][C:3]1[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:6]2[CH2:7][CH2:8][O:9][C:5]=2[C:4]=1[C:18](=[O:27])[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cc1cc2c(c(C(=O)c3ccc(OC)cc3)c1OC)OCC2
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cc1cc2c(c(C(=O)c3ccc(OC)cc3)c1O)OCC2
Temperature: 0 °C

Procedure:
Ethyl 6-methoxy-7-(4-methoxybenzoyl)-2,3-dihydrobenzofuran-5-ylacetate (3.6 g) was dissolved in dichloromethane (40 ml) and cooled to 0° C. To this was added boron trichloride (30 ml 1M). The reaction was allowed to warm to room temperature and, after 2 hours, added to water. The dichloromethane solution was washed 2 times with water, dried, and evaporated. The residue was run on a silica gel column, being eluted with ethyl acetate/hexane to give ethyl 6-hydroxy-7-(4-methoxybenzoyl)-2,3-dihydrobenzofuran-5-ylacetate. Saponification as per Example 3 gave 6-hydroxy-7-(4-methoxybenzoyl)-2,3-dihydrobenzofuran-5-ylacetic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[Cl:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1>>[Cl:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:30][CH2:29]5)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:46])=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(Cl)cc3)CN2C1=O
Yield: 54.9 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-chlorobenzoyl chloride (45 μL, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 68 mg (55%) of 18-(4-chlorobenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.5% pure (HPLC), MS m/z 705 (M−H)−, HRMS: calcd. 707.2518 and found 707.2499 (M+H)+, mp 143-145° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].C(N(CC)CC)C.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33](O)=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reaction time: 8 h
Yield: 7.2 %

Procedure:
A mixture of the product of Example 11B (40.3 mg, 0.18 mmol), triethylamine (0.037 mL, 0.26 mmol), 2-(3,5-difluorophenyl)acetic acid (36.4 mg, 0.21 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (61.8 mg, 0.19 mmol) in DMF (0.75 mL) was stirred overnight, diluted with EtOAc, washed with 1 N NaOH and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (3% EtOAc/CH2Cl2) to give the title compound as a white solid (4.8 mg, 0.013 mmol). 1H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.44 (d, 1H), 8.23-7.90 (m, 3H), 7.26-7.00 (m, 3H), 3.80 (s, 2H); MS (DCI) M/Z 401.2 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[NH:8][CH:7]=N[C:5]=1[NH:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=2)[N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=1)=[O:3].C(N=[C:37]=[S:38])(=O)C1C=CC=CC=1.[CH2:39](Cl)Cl>>[F:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH:12]=[C:11]2[CH2:10][N:9]1[C:5]2[CH:39]=[CH:7][NH:8][C:4]=2[C:2](=[O:3])[NH:1][C:37]1=[S:38]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)n1cc(CNc2nc[nH]c2C(N)=O)c2cc(F)ccc21
Reactant: O=C(N=C=S)c1ccccc1
Product: CC(C)(C)OC(=O)n1cc(Cn2c(=S)[nH]c(=O)c3[nH]ccc32)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 7 h

Procedure:
tert-Butyl 3-({[5-(aminocarbonyl)-1H-imidazol-4-yl]amino}methyl)-5-fluoro-1H-indole-1-carboxylate (0.15 g, 0.32 mmol, obtained from Example 6(b)) was dissolved in CH2Cl2. Benzoylisothiocyanate (0.06 g, 0.35 mmol) was added and the mixture was stirred at r.t. for 7 h. The mixture was concentrated in vacuo. Ammonia (7 N in methanol, 3 mL) was added and the mixture was heated at 80° C. for 1 h. The mixture was concentrated and the residue was dissolved in ethyl acetate and washed with water. The organic layer were dried (MgSO4) and concentrated in vacuo. The crude product-mixture was used in the next step without further purification. MS (ESI) m/z 414 (M−1).