Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C@H:9]([OH:17])[CH2:8][CH2:7]1)=[O:4].N1C=CN=C1.[Si:25](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[Si:25]([O:17][C@H:9]1[C:10]2[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH2:7][CH2:8]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(N[C@@H]1CC[C@@H](O)c2ccc(F)cc21)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](NC(=O)C(F)(F)F)c2cc(F)ccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2,2-Trifluoro-N-((1R,4R)-7-fluoro-4-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (2.71 g, 9.78 mmol, 1 equiv) and imidazole (1.33 g, 19.56 mmol, 2 equiv) were dissolved in anhydrous DMF (40 mL) and cooled in ice bath. Tert-Butyldiphenylsilyl chloride (3.25 mL, 12.71, 1.3 equiv) was added dropwise. The reaction solution was stirred at RT for 16 h. The DMF was removed by evaporation. The residue was dissolved in EtOAc (200 mL) and washed with water, brine and dried (Na2SO4). The organic phase was evaporated to dryness to give an oil residue, which was purified by ISCO (40 g column, EtOAc-hexane 10-50%) to give a white solid product (2.16 g, TLC: pure) and a mixture (3.0 g). 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.26-7.30 (q, 1H), 7.09 (m, 1H), 6.98 (dd, 1H), 5.07-5.14 (m, 1H), 4.77-4.80 (m, 1H), 2.06-2.15 (m, 1H), 1.74-1.92 (m, 2H), 1.56-1.669 m, 1H), 1.03 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[C:3](=[O:5])[CH3:4].[CH:8]([O:10][CH2:11][CH3:12])=[CH2:9]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>[CH2:8]([O:10][CH:11]([O:7][C:2]([CH3:6])([CH3:1])[C:3](=[O:5])[CH3:4])[CH3:12])[CH3:9]
Reactant: CC(=O)C(C)(C)O
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)OC(C)(C)C(C)=O
Yield: 66.7 %

Procedure:
In a 200 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 15 gm (147 mmol) of 3-methyl-3-hydroxy-2-butanone, 500 mg (2.0 mmol) of pyridinium p-toluenesulfonate and 100 ml of anhydrous methylenechloride were mixed with stirring under nitrogen stream, and 11.7 gm (162 mmol) of ethyl vinyl ether was added dropwise at room temperature for 3 hours while stirring. After the reaction, the reaction mixture was washed with 5% aqueous sodium hydrogen carbonate, and then the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Distillation of the crude product afforded 17.09 gm of 3-(1-ethoxyethoxy)-3-methyl-butane-2-one (b.p. 38-40/l mmHg, yield: 66%).
Reaction SMILES: C1(S(C2(SC)[CH2:15][C@H:14]3[C@:12]([C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][CH:17]=4)([CH2:13]3)[CH2:11]2)(=O)=O)C=CC=CC=1.[CH3:28][OH:29].Cl>C(OCC)(=O)C.CCCCCC>[C:16]1([C@:12]23[CH2:13][C@H:14]2[CH2:15][C:28](=[O:29])[CH2:11]3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CSC1(S(=O)(=O)c2ccccc2)C[C@@H]2C[C@]2(c2cccc3ccccc23)C1
Reactant: CO
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1C[C@@H]2C[C@]2(c2cccc3ccccc23)C1
Yield: 99 %

Procedure:
(1S,5S)-3-Benzenesulfonyl-1-(1-naphthyl)-3-methylsulfanyl-bicyclo[3.1.0]hexane (3 g, 7.6 mmol), methanol (18 mL) and concentrated hydrochloric acid (5.4 mL) were heated to reflux for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (20:80)).The reaction mixture was concentrated under reduced pressure to remove methanol. The pH of the reaction mass was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous layer was extracted with diethyl ether (300 mL). The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 3 g of crude oil, which was purified by preparative HPLC to give 1 g (62%) of 99% pure product. 1H NMR δ(300 MHz,CDCl3): 0.75-0.78 (1H,t, J=4 Hz), 1.37 (1H,m), 1.98-2.04 (1H,m), 2.49-2.55 (1H,d ,J=18 Hz), 2.77-2.79 (2H,d,J=6 Hz), 3.03-3.11 (2H,dd,J=18,6 Hz), 7.39-7.44 (1H,m), 7.48-7.57 (3H,m),7.76-7.78 (1H,d,J=6 Hz), 7.87-7.90 (1H,m), 8.12-8.15 (2H,d ,J=9 Hz).
Reaction SMILES: [C:1]([C:4]1([CH2:10][CH2:11][C:12]([OH:14])=O)[NH:8][C:7](=[O:9])[CH2:6][NH:5]1)([OH:3])=[O:2].C[Si](C)(C)N[Si](C)(C)C.C[Si](C)(C)Cl>C(#N)C>[O:9]=[C:7]1[CH2:6][N:5]2[C:12](=[O:14])[CH2:11][CH2:10][C:4]2([C:1]([OH:3])=[O:2])[NH:8]1
Reactant: O=C(O)CCC1(C(=O)O)NCC(=O)N1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: O=C1CN2C(=O)CCC2(C(=O)O)N1
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
A mixture of 2-carboxy-4-oxo-2-imidazolidine-propanoic acid (2 g, 9.89 mmol), hexamethyldisilazane (20 mol) and trimethylchlorosilane (10 ml) in dry acetonitrile (50 ml) was refluxed under nitrogen for 4 hours. After cooling, the precipitate was filtered off and the filtrate was evaporated under vacuum. The residue was dissolved in methanol (20 ml) containing some drops of concentrated hydrochloric acid and stirred for 10 minutes. The insoluble material was filtered off and the filtrate was evaporated to dryness. The residue was triturated with acetonitrile and crystallized with tetrahydrofuran (250 ml) to yield 0.9 g (50%) of the title compound, m.p. 207° C. (with decomposition). NMR (DMSO-d6): deltaH : 9.20 (b.s., 1H, NH); 3.82 and 3.46 (ABq, J=16.8 Hz, 2H, NCH2CO); 2.90-1.80 (c.a., 4H, CH2 -CH2). MS (E.I., 70 eV, 1.5 mA) m/z=184 (M+), 139 (M--COOH)+, 83 (C3H3N2O)30 .
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[Li+]>N1C=CC=CC=1.C1COCC1.CO>[CH3:15][O:14][C:12]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1)=[O:13]
Reactant: COC(=O)c1csc(N)n1
Reactant: COC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Nc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Methyl 2-aminothiazole-4-carboxylate (1.0 g, 6.32 mmol) was dissolved in dry pyridine and methyl chloroformate (0.733 ml, 9.48 mmol) was added slowly in RT. The reaction mixture was stirred at RT overnight and evaporated to dryness. The evaporation residue was dissolved in dry THF/methanol (9:1) mixture, 1M lithium hydroxide (3.50 ml, 3.50 mmol) was added and the reaction mixture was stirred for 4 h in RT. 1M litium hydroxide (2.33 ml, 2.33 mmol) was added and the mixture was stirred overnight and evaporated to dryness. DCM was added and pH was adjusted to 3. The product was filtered and dried in vacuum. Yield 76%. 1H-NMR (400 MHz; DMSO-d6): δ 3.75 (s, 3H), 7.95 (s, 1H), 12.05 (s, 1H), 12.76 (bs, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[Cl:17][S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19]>CCOCC>[Cl:17][S:18]([NH:21][C:22](=[O:23])[O:16][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=1[C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:20])=[O:19]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCOCC
Product: Cc1cc(C(C)(C)C)c(OC(=O)NS(=O)(=O)Cl)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A solution of 2,6-di-t-butyl-4-methylphenol (22.04 g, 0.1 moles) in 100 mL Et2O was added dropwise to a solution of chlorosulfonyl isocyanate (8.7 mL, 0.1 moles) in 100 mL Et2O at -15° C. under an atmosphere of N2. This was stirred for 2 hours, concentrated and trituration of the resulting gel with hexanes gave 26.82 g (74%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:24][CH:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[CH:31]1([CH2:36][C:37](Cl)=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]1.[OH-].[Na+]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]3[CH2:24][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:37](=[O:38])[CH2:36][CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reactant: O=C(Cl)CC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CC1CCCC1)NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
To a stirred cold (ice bath) solution of 4-amino-1-[2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine (339 mg, 1 mmol, described in Example 7b) and pyridine (158 mg, 2 mmol) in methylene chloride (6.7 mL) was added cyclopentylacetyl chloride (161 mg, 1.1 mmol). After 15 min, the reaction was allowed to warm to ambient temperature and stirred for 18 h. The reaction was added methylene chloride (75 mL) and 1N sodium hydroxide (50 mL). The aqueous layer was extracted with methylene chloride (50 mL). The organic layers were combined and washed with 1N sodium hydroxide (2×50 mL), brine (35 mL) and dried (sodium sulfate). The solution was filtered and concentrated to give a foam. This material was chromatographed over silica gel (eluting in sequence with 1) methylene chloride; 2) 3:97 methanol:methylene chloride) and crystallized with ether to give the title compound as a white solid (323 mg, 72%), mp 149.5°-150.5° C.; MS(CI): 449 (M+H); NMR (300 MHz,DMSO-d6): 1.02-1.17(m, 2H), 1.26-1.74(m, 10H), 2.01(d, 2H, 2H, J=6.0 Hz), 2.09(m, 1H), 2.18-2.32(m, 2H), 2.47(m, 2H), 2.86-3.00(m, 2H), 3.28(d, 1H, J=14 Hz), 3.37(d, 1H, J=14 Hz), 3.54(m, 1H), 4.33(s, 1H), 6.89-7.00(m, 3H), 7.15-7.31(m, 4H), 7.61(d, 1H, J=7.7 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[CH3:18])[CH3:9].[CH3:19][N:20]=[C:21]=[O:22]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C(OCC)(=O)C>[CH3:19][NH:20][C:21](=[O:22])[O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[CH3:9])=[C:12]([CH3:18])[CH:13]=1
Reactant: CN=C=O
Reactant: CC(=Nc1ccc(O)cc1C)c1ccccc1O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1ccc(N=C(C)c2ccccc2O)c(C)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 90 %

Procedure:
To a 350 milliliter glass pressure bottle equipped with a magnetic stirrer was added 4.83 grams (0.020 moles) of 4-[1-(2-hydroxyphenyl)ethylideneamino]-3-methylphenol prepared in Part A, 1.42 grams (0.025 moles) of methyl isocyanate, 100 milliliters of ethyl acetate and 5 drops of dibutyl tin diacetate. The resulting reaction mixture was stirred for 96 hours at room temperature, filtered and then washed twice with a 1% aqueous sodium bicarbonate solution followed by a single wash with saturated brine solution. After drying the reaction mixture over magnesium sulfate, it was concentrated under reduced pressure to give 5.36 grams (0.018 moles) of 4-[1-(2-hydroxyphenyl)ethylideneamino]-3-methylphenyl methylcarbamate in the form of an orange solid having a melting point of 133°-138° C. and the following structural formula: ##STR17##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[CH:6][C:5]=1[NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Cl)[CH:19]=1.C(N(CC)CC)C.[CH3:35][CH:36]([OH:43])[CH2:37][NH:38][CH2:39][CH:40]([OH:42])[CH3:41].COC1C=C(C=CC=1OC)C(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[CH:6][C:5]=1[NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:38]([CH2:39][CH:40]([OH:42])[CH3:41])[CH2:37][CH:36]([OH:43])[CH3:35])[CH:19]=1
Reactant: CC(O)CNCC(C)O
Reactant: COC(=O)c1cc(N2CCCC2=O)ccc1NC(=O)c1cccc(CCl)c1
Agent: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(N2CCCC2=O)ccc1NC(=O)c1cccc(CN(CC(C)O)CC(C)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
Subsequently, 2-(3-chloromethyl-benzoylamino)-5-(2-oxo-pyrrolidin-1-yl)benzoic acid methyl ester (14 mg) was dissolved in anhydrous methylene chloride (5 ml). Triethylamine (7 mg: dissolved in 2 ml of anhydrous methylene chloride) and diisopropanolamine (compound B′) (10 mg: dissolved in 2 ml of anhydrous methylene chloride) were added dropwise to the solution at 0° C., and the mixture was stirred at room temperature for 24 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-(3-{[bis-(2-hydroxy-propyl)-amino]-methyl}-benzoylamino)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (8.0 mg, yield 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Cl)ccc2s1
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Clc1ccc2sc(SCCN3CCOCC3)nc2c1
Temperature: 25 °C
Yield: 67 %

Procedure:
Dissolved in 5 ml of N,N-dimethylformamide was 1.00 g (5.0 mmol) of 5-chloro-2-mercaptobenzothiazole, and 0.26 g (10.8 mmol) of hydrogenated sodium were added to the solution, which was stirred at room temperature. One hour later, 0.93 g (5.0 mmol) of a hydrochloride of 2-chloroethylmorpholine were added to the suspension, which was then stirred for 2 hours at 80° C. The solution was diluted with 100 ml of chloroform, followed by addition of 100 ml of a 5% saline solution and washing. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residues were purified by silica gel chromatography to obtain 1.05 g of white crystalline powders (67% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.[C:10](=O)(O)[O-].[Na+].COS(OC)(=O)=O>CC(=O)CC>[OH:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc(O)cs1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(O)cs1

Procedure:
50.0 g (0.347 mol) of 4-hydroxy-2-thiophenecarboxylic acid and 58.3 g (0.694 mol) of sodium bicarbonate are heated at the boiling point in 900 ml of absolute 2-butanone under nitrogen, and 43.7 g (0.347 mol) of dimethylsulfate are added dropwise in the course of 20 minutes. The mixture is heated under reflux for a further 2.5 hours. It is then evaporated in vacuo and the residue is partitioned between saturated sodium bicarbonate solution and ether. The aqueous phase is extracted five more times with 80 ml of ether each time. The combined organic phases are dried over sodium sulfate/active charcoal, filtered and evaporated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[OH:12])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:24][O:25][CH3:26].O>ClCCl>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[O:12][CH2:24][O:25][CH3:26])[CH3:2]
Reactant: COCCl
Reactant: CCOC(=O)c1ccc(F)cc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(F)cc1OCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a solution of 4-fluoro-2-hydroxybenzoic acid ethyl ester (3.5 g) in dichloromethane (30 ml) were added N,N-diisopropylethylamine (5.0 g) and (chloromethyl)methyl ether (2.3 g) at 0° C., and this reaction mixture was stirred at room temperature overnight. This reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (2.8 g).
Reaction SMILES: C[O:2][C:3]1[CH:35]=[CH:34][C:6]2[C:7]3[CH:8]([C:19]4[CH:33]=[CH:32][C:22]([O:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:21][CH:20]=4)[O:9][CH2:10][C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[C:13]=3[S:14][C:5]=2[CH:4]=1>CN1C(=O)CCC1.C(Cl)Cl>[N:26]1([CH2:25][CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:19]([CH:8]3[C:7]4[C:6]5[CH:34]=[CH:35][C:3]([OH:2])=[CH:4][C:5]=5[S:14][C:13]=4[C:12]4[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=4[CH2:10][O:9]3)=[CH:33][CH:32]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc2c3c(sc2c1)-c1ccccc1COC3c1ccc(OCCN2CCCCC2)cc1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Oc1ccc2c3c(sc2c1)-c1ccccc1COC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 170 °C
Yield: 6.3 %

Procedure:
Add NaSEt (92 mg, 1.1 mmol) to a solution of 1-{2-[4-(10-methoxy-5H,7H-6-oxa-12-thia-dibenzo[a,e]azulen-7-yl)-phenoxy]-ethyl}-piperidine (266 mg, 0.55 mmol) in NMP (3 mL). Heat to 170° C. for 20 min. Add additional NaSEt (92 mg, 1.1 mmol) and continue heating for 1 h. Quench the reaction with water and dilute with CH2Cl2. Wash the organic phase with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0-10% (2M NH3 in MeOH)/CH2Cl2) followed by preparative HPLC to afford 7-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H,7H-6-oxa-12-thia-dibenzo[a,e]azulen-10-ol (16.3 mg, 6.3%)
Reaction SMILES: Br[CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH2:5][O:6][CH2:7][C@H:8]([NH2:12])[CH2:9][CH:10]=[CH2:11].C([O-])([O-])=O.[K+].[K+]>CCO>[CH2:9]([C@H:8]1[NH:12][CH2:2][C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[CH2:5][O:6][CH2:7]1)[CH:10]=[CH2:11]
Reactant: C=CC[C@@H](N)COCc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CC[C@@H]1COCc2ccccc2CN1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a solution of compound 18k (2.0 g, 7.0 mmol) in EtOH (20 mL) was added K2CO3 (4.8 g, 35.0 mmol) portionwise. The mixture was heated to reflux for 2 h to complete the reaction. The reaction mixture was cooled down to rt and concentrated under reduced pressure to give compound 18l (1.2 g, 84% yield), which was used without purification. LCMS (m/z): 204.1 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10](=[O:13])[CH2:11][CH3:12].[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([O:24][CH3:25])[CH:16]=1>CCCCCCC.CCOC(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH2:9][C:10](=[O:13])[CH2:11][CH3:12])=[C:17]([O:24][CH3:25])[CH:16]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CCC(=O)CNc1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCC(=O)CNc1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to Example 72, from 1-(4-iodo-pyridin-3-ylamino)-butan-2-one and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Yellow oil (43%). MS (ESI): m/z=289.134 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24]C(OCC2C=CC=CC=2)=O)[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH2:24])[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 86.9 %

Procedure:
Alternatively, N-benzyloxycarbonyl-L-glutamic acid y-t-butyl ester (34 g, 100 mmol) and EDCI (22 g, 110 mmol), HOBT (15 g, 110 mmol) were combined in 800 mL CH2Cl2 with triethylamine (24 mL, 172 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 minutes, then 1-ethoxycarbonylpiperazine (18 g, 120 mmol) was added. The resulting mixture was stirred at ambient temperature for 15 hours. The reaction mixture was then washed with water, 2N NaHSO4, and brine, then concentrated in vacuo to afford an oil, which was purified by flash column chromatography on silica gel (acetate/hexane=1/1) to afford 4-ethoxycarbonyl-1-(1-(benzyloxycarbonyl)amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (40 g). 4-ethoxycarbonyl-1-(1-(benzyloxycarbonyl)amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (40 g) was dissolved in 200 mL of MeOH, 2 g Pd/C(10%) was added and hydrogenated at 50 psi for 1 hour. Regular work up afforded 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (25 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[S:13])[NH2:12])=[CH:3]1.Br.[Br:15][CH2:16][C:17]([C:19]1[CH:20]=[NH+:21][CH:22]=[CH:23][CH:24]=1)=O>CN(C=O)C>[BrH:15].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[S:13][CH:16]=[C:17]([C:19]3[CH:20]=[NH+:21][CH:22]=[CH:23][CH:24]=3)[N:12]=2)=[CH:3]1
Reactant: Cn1cc(C(N)=S)c2ccccc21
Reactant: O=C(CBr)c1ccc[nH+]c1
Agent: Br
Solvent: CN(C)C=O
Product: Cn1cc(-c2nc(-c3ccc[nH+]c3)cs2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Methylindole-3-thiocarboxamide (0.5 g) was dissolved in anhydrous DMF (5 ml). This solution was added to a stirred suspension of 3-bromoacetyl-pyridinium hydrobromide (1.1 g) in anhydrous DMF (2 ml). This was stirred for 10 minutes at room temperature. The title compound was isolated by filtration and was washed thoroughly with ether, 0.5 g. δH (360 MHz, DMSO-d6) 3.91 (3 H, s, NCH3), 7.2-7.4 (2 H, m, H-5 and H-6), 7.58 (1 H, d, J=7.4 Hz, H-7) 8.03 (1 H, dd, J=5.5, 8.1 Hz, H-5" β pyr), 8.26 (1 H, s, H-5' thiazole), 8.36 (1H, d, partially buried, H-4), 8.38 (1 H, s, H-2), 8.83 (1 H, mc, H-4" γ pyr), 8.99 (1 H, d, J=8.2 Hz, H-6" α-pyr), 9.47 (1 H, mc, H-2" α-pyr); m/z 291 (M+, 100%), 135 (30).