Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.[Br:18][CH2:19][CH2:20][CH2:21]Br>CN(C=O)C.CCOC(C)=O>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:21][CH2:20][CH2:19][Br:18])[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: BrCCCBr
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: BrCCCn1c2ccc(Br)cc2c2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
Crushed KOH (0.0673 g, 1.20 mmol, 1.2 equiv) was added to 3,6-dibromocarbazole (0.3250 g, 1.00 mmol) in 2 mL DMF solution and the mixture was stirred for 30 min. 1,3-dibromopropane (0.5047 g, 2.50 mmol, 2.5 equiv) in 3 mL DMF solution was added dropwise into the mixture and it was stirred at room temperature overnight. The crude reaction mixture was diluted with 30 mL EtOAc and washed with 1M HCl 2×10 mL and water 3×10 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford 0.1275 g colorless oil as product, yield 28.6%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Sulfur trioxide pyridine complex (720 mg, 4.5 mmol) was added to a solution of 3-[3-(2,3-dichlorophenylsulfonyloxy)-5-methylphenoxy]propanol (580 mg, 1.5 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.3 mL, 4.2 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (545 mg, 93%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (s, 1 H), 7.92 (d, J=8.0 Hz, 1 H), 7.76 (d, J=8.0 Hz, 1 H), 7.34(t, J=8.0 Hz, 1 H), 6.61 (s, 1 H), 6.57 (s, 1 H), 6.50 (s, 1 H), 4.21 (t, J=6.0 Hz, 2 H), 2.87 (t, J=6.0 Hz, 2 H), 2.26 (s, 3 H).
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][C@@H:38]([CH3:42])[CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:61][CH3:62])[N:32]2[CH2:43][CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][N:47](C(OCC2C=CC=CC=2)=O)[CH2:46]1>>[CH3:42][C@H:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:61][CH3:62])[N:32]2[CH2:43][CH2:44][CH:45]2[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 3-{2-[6-amino-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-9-yl]ethyl}-1-piperidinecarboxylate.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([CH2:22][CH2:23][CH2:24][PH:25](=[O:27])[OH:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:28]([NH:31][CH2:32][CH2:33]O)(=[O:30])[CH3:29]>O1CCCC1.CN(C)C1C=CN=CC=1>[C:16]1([CH2:22][CH2:23][CH2:24][PH:25](=[O:26])[O:27][CH2:33][CH2:32][NH:31][C:28](=[O:30])[CH3:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)NCCO
Reactant: O=[PH](O)CCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NCCO[PH](=O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.7 %

Procedure:
To a solution of 0.31 g (1.5 mmol) of 1,3-dicyclohexylcarbodiimide in tetrahydrofuran (3 ml) is added 0.28 g (1.5 mmol) of 3-phenylpropylphosphinic acid in tetrahydrofuran (1 ml). The resulting suspension is stirred for 10 minutes at room temperature. N-acetyl ethanolamine (0.10 g, 1.0 mol) is then added, followed by 18 mg or 4-dimethylaminopyridine. The mixture is stirred for 2 hours. The solvent is evaporated under reduced pressure, and the residue is stirred with ethyl acetate (20 ml). The resulting suspension is filtered. The filtrate is washed with 5% potassium hydrogen sulfate (8 ml), saturated sodium bicarbonate (2×5 ml), and brine (5 ml), and evaporated to give 0.12 g of a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]#[N:32])[CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:3]2[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]#[N:32])[CH2:27][CH2:26]3)=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:10][CH2:11]1
Reactant: Brc1cccnc1OC1CCN(c2ccc3ccccc3n2)CC1
Reactant: N#CC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#CC1CCN(c2cccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Yield: 70 %

Procedure:
To a solution of 2-(4-((3-bromopyridin-2-yl)oxy)piperidin-1-yl)quinoline (see PREPARATION P2.2; 383 mg, 1.0 mmol) in toluene (10 mL) were added piperidine-4-carbonitrile (110 mg, 1.0 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (62 mg, 0.1 mmol) and sodium tert-butoxide (t-BuONa) (180 mg, 2.0 mmol). The mixture was stirred and heated at reflux overnight under N2 atmosphere. Then the reaction mixture was filtered, diluted with water (50 mL), and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water (60 mL) and brine (60 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 50% EtOAc in hexanes) to give the title product (290 mg, 0.7 mmol, 70% yield) as white solid. ESI-MS (M+1): 414 calc. for C25H27BrN5O 413.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:14][CH2:13]2)(=O)=O)=CC=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([CH:25]=1)[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[F:16][C:17]([F:27])([F:28])[C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:11][C@@H:12]2[O:14][CH2:13]2)=[C:22]([CH:25]=1)[CH:23]=[O:24]
Reactant: O=Cc1cc(C(F)(F)F)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(C(F)(F)F)ccc1OC[C@H]1CO1
Temperature: 60 °C
Yield: 72.2 %

Procedure:
A mixture of (R)-glycidyl 4-toluenesulphonate (24 g), 5-trifluoromethyl-2-hydroxybenzaldehyde (20 g) and potassium carbonate (16 g) in dimethylformamide (550 ml) was stirred and heated at 60° C. for 72 hours. After cooling, brine (1.5 L) was added and the resultant mixture extracted with ether (4×500 ml). The combined ether extracts were washed with brine (2×500 ml), then water (500 ml) and dried over magnesium sulphate. The residue was purified by flash column chromatography on silica eluting with a 3:1 mixture of petroleum ether (b.p. 40-60 ° C.) and ethyl acetate to give (R)-5-trifluoromethyl-2-(2,3-epoxypropoxy)benzaldehyde (18.7 g) as a yellow oil.
Reaction SMILES: N.[C:2]([C:4]1[C:5]([N:10]([CH3:12])[CH3:11])=[N:6][CH:7]=[CH:8][CH:9]=1)#[N:3]>[Ni].C(O)C>[NH2:3][CH2:2][C:4]1[C:5]([N:10]([CH3:12])[CH3:11])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)c1ncccc1C#N
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CN(C)c1ncccc1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
Saturated aqueous ammonia (17 ml) and Raney nickel (3.0 g) were added to a solution of 3-cyano-2-(dimethylamino)pyridine (2.45 g) in ethanol (50 ml) and the mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere of 1 atmospheric pressure. After absorption of 760 ml of hydrogen, the catalyst was removed by filtration. By concentrating the mother liquid, 3-(aminomethyl)-2-(dimethylamino)pyridine (2.61 g) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20][CH2:21][O:22][CH3:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.C(=O)=O.CC(C)=O.Cl[Si:40]([CH3:43])([CH3:42])[CH3:41].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH:16]=[C:15]([O:18][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20][CH2:21][O:22][CH3:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCC12CCC(=O)C(C)=C1c1ccc(OCOC)cc1C2
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCCC12CC=C(O[Si](C)(C)C)C(C)=C1c1ccc(OCOC)cc1C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (163 mg, 0.52 mmol) in anhydrous THF (2.5 mL) was cooled in an ice bath and stirred under a nitrogen atmosphere while 0.4M LDA in THF (1.9 mL, 0.78 mmol) was added by syringe. After stirring at 0° C. for 30 minutes, the solution was cooled to −78° C. (dry ice-acetone bath) and treated with chlorotrimethylsilane (0.100 mL, 0.78 mmol). The resulting mixture was allowed to slowly warm to room temperature, then stirred at room temperature overnight. The mixture was diluted with EtOAc (60 mL) and shaken with 5% aqueous NaHCO3 (30 mL). The aqueous phase was separated and extracted with more EtOAc (30 mL). The combined organics were washed with saturated brine, dried over MgSO4, filtered, and concentrated under vacuum to an oil (204 mg). The 1H NMR of this material showed a 9:1 mixture of 9a-butyl-7-methoxymethoxy-4-methyl-3-trimethylsilyloxy-9,9a-dihydro-1H-fluorene and starting material.
Reaction SMILES: [H-].[Na+].[C:3]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:7])[CH2:4][CH2:5][CH3:6].[Br:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>CN(C)C=O>[Br:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][CH2:6][CH2:5][CH2:4][C:3]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7]
Reactant: CCCC(=O)Nc1cc(C(=O)OCC)ccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(=O)CCCCc2ccccc2Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 136.4 %

Procedure:
One-hundred milligrams of sodium hydride (60% water-in-oil suspension) were added to a solution of 247 mg of ethyl 3-butyrylamino-4-nitrobenzoate in 10 ml of N,N-dimethylformamide in a nitrogen atmosphere at room temperature in some divided portions. The reaction suspension was stirred at the same temperature for 1 hour, and a solution of 244 mg of 2-bromobenzyl bromide in 2 ml of N,N-dimethylformamide was gradually added dropwise thereto over a period of 10 minutes. The reaction mixture was stirred at room temperature for 1 hour, and was poured in ice water. The oily substance precipitated was extracted with methylene chloride. The organic solvent layer was washed with water, dried, and then concentrated under reduced pressure. The residue was developed through silica-gel flash column chromatography, and was eluted with a mixture of 25% ethyl acetate and n-hexane to give 540 mg of yellow oil of ethyl 3-[N-(2-bromobenzyl)butyrylamino-4-nitrobenzoate.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][C@@H:17]([CH3:19])[C@H:16]([CH3:20])[C@@H:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1.CCCCCC.C(OCC)(=O)C>CCCCCC.C(O)C>[CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][CH:17]([CH3:19])[CH:16]([CH3:20])[CH:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@@H](C)[C@H](C)[C@H]3O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)OC(C)C(C)C3O

Procedure:
The synthetic (±)-1 was resolved into enantiomers, (±)-calanolide A and (-) calanolide A, by preparative HPLC. Thus, using a normal phase silica gel HPLC column (250 mm×4.6 mm I.D. Zorbasil, 5 μm particle size, MAC-MOD Analytical, Inc., PA, USA), the synthetic (±)-1 appeared as one peak with a retention time of 10.15 minutes when hexane/ethyl acetate (70:30) was used as the mobile phase at a flow rate of 1.5 mL/min and a wavelength of 290 nm was used as the uv detector setting. However, on a chiral HPLC column packed with amylose carbamate (250 mm×4.6 mm I.D. Chiralpak AD, 10 μm particle size, Chiral Technologies, Inc., PA, USA), two peaks with retention times of 6.39 and 7.15 minutes in a ratio of 1:1 were observed at a flow rate of 1.5 mL/min. The mobile phase was hexane/ethanol (95:5) and the uv detector was set at a wavelength of 254 nm. These two components were separated using a semi-preparative chiral HPLC column, providing the pure enantiomers of calanolide A. The chemical structures of the separated enantiomers, which were assigned based on their optical rotations and compared with the reported natural product, were characterized by spectroscopic data. HPLC chromatograms (±)-calanolide A and its optical forms are shown in FIG. 6.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:20][C:19]=2[CH2:27][CH3:28])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([CH2:23][CH:24]([CH3:25])[CH3:26])[S:20][C:19]=2[CH2:27][CH3:28])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(CC(C)C)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: CCc1sc(CC(C)C)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 51.2 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-{cyclohexyl[2-ethyl-5-(2-methylpropyl)thiophen-3-yl]methoxy}benzoic acid (256 mg) synthesized in Example 81 (4) and ethyl 3-(methylamino)propanoate (101 mg) to give the title compound (159 mg, 51%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>>[CH2:23]([N:25]([CH2:26][CH3:27])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20])[CH3:24]
Reactant: CCNCC
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CCN(CC)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and diethylamine to give 253. MS: (ESI+)=369.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(O)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(O)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.5 %

Procedure:
A solution of 4-amino-phenol (1.00 g, 9.2 mmol) and triethylamine (1.42 ml, 10.1 mmol) was cooled to 0° C. and 4-trifluoromethyl-benzoyl chloride (1.36 ml, 9.2 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The reaction mixture was poured in water (50 ml). A precipitate was collected by filtration and taken up in ethyl acetate (200 ml). The organic solution was washed with 1N HCl (100 ml), water (100 ml), brine (100 ml), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound as a pale yellow solid (1.98 g, 77% yield).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([NH2:25])=[N:22][C:21]=1[CH3:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:22][C:21]=1[CH3:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Benzoyl chloride (0.04 mL, 0.36 mmol) was added to a mixture of 2-amino-4-methylthiazole-5-carboxylic acid benzylamide (0.083 g, 0.033 mmol), 4-dimethylamino-pyridine (10 mg) and triethylamine (0.06 mL, 0.43 mmol) in tetrahydrofuran (10 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 8 h, then concentrated. The residue was purified by column chromatography to afford the title compound in 75% yield (87 mg); 1H NMR (CDCl3, 300 MHz) δ 7.90-7.24 (m, 11H), 5.97 (s, br, 1H), 4.59 (d, J=5.8 Hz, 2H), 2.45 (s, 3H); MS (ES+) m/z 352.0 (M+1).
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Si:11]([O:18][CH2:19][C:20]1[N:21]=[C:22]([Cl:30])[S:23][C:24]=1[C:25](OCC)=[O:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].Cl>C(Cl)Cl>[Si:11]([O:18][CH2:19][C:20]1[N:21]=[C:22]([Cl:30])[S:23][C:24]=1[C:25]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:26])([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1sc(Cl)nc1CO[Si](C)(C)C(C)(C)C
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1nc(Cl)sc1C(=O)N1CCOCC1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
A solution of 2N Me3Al in hexanes (0.91 ml, 1.82 mmol) was added slowly to a solution of 0.16 ml (1.8 mmol) of morpholine in 4 ml CH2Cl2. After stirring for 15 min, a solution of 0.5 g (1.5 mmol) of ethyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-1,3-thiazole-5-carboxylate (Intermediate 218) in 4 ml CH2Cl2 was added. The solution was heated at 80° C. in a microwave reactor for 1 hour before pouring into dilute aqueous HCl. The mixture was extracted 3 times with CH2Cl2, which was washed with brine, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (100% CH2Cl2 followed by gradient elution to 30% EtOAc in CH2Cl2 to give 315 mg of product. MS (ES) (MH+): 377 for C15H25ClN2O3SSi; NMR (d6-DMSO): 0.1 (s, 6H), 0.9 (s, 9H), 3.6 (m, 4H), 3.7 (m, 4H), 4.1 (q, 2H), 4.75 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][CH:3](CO)O.[OH:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11].C(OCC)(=O)CC(C)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[C:2]([O:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11])(=[O:1])[CH3:3]
Reactant: CC(=O)CCO
Reactant: OCC(O)CO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(=O)CC(C)=O
Solvent: O
Product: CC(=O)CCOC(C)=O
Yield: 61 %

Procedure:
The method described in Example 5 is followed starting with glycerol and 4-hydroxy-2-butanone, suitably protected at the hydroxy group with an acetyl radical. 4-acetoxy-2-butanone is prepared starting from ethyl acetoacetate, protected at the carbonyl group as diethylacetal, by reduction with lithium-aluminium hydride, followed by restoring the keto group by means of silica in the presence of water (A: Banerje 8 G. P. Kalena, Synth. Commun (1982) 12, 225). 1,3-dioxolane-2-methyl-2'-(2-hydroxyethyl-4-acetylthiomethylene distills at 164°-170° C. (10 mm Hg). Yield 61%.
Reaction SMILES: O[C:2]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20]([NH:22][CH3:23])=[O:21])[CH:14]=[CH:13]3)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1.C([OH:26])C>>[OH:26][C:8]1[N:7]=[CH:6][N:5]2[CH2:4][CH2:3][C@@H:2]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([C:20]([NH:22][CH3:23])=[O:21])[CH:14]=[CH:13]4)[C:9]=12
Reactant: CNC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Reactant: CCO
Product: CNC(=O)c1ccc2cc([C@@H]3CCn4cnc(O)c43)ccc2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
6-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide (5.20 kg, 16.9 mol), ethanol (130 L) and activated carbon (260 g) were stirred at room temperature, and the insoluble material was filtered off, and washed with ethanol (15.6 L). The above-mentioned operations were repeated three times. The filtrates and washings were combined, and (2S,3S)-tartranilic acid (15.95 kg, 70.8 mol) and ethanol (20.8 L) were added thereto. The mixture was heated to about 50° C., allowed to cool to room temperature, stirred for about 4 hr, cooled to about 0° C., and stirred for about 1 hr. The precipitated crystals were collected by filtration, and washed with ethanol (31.2 L). The obtained wet crystals (about 23 kg) in ethanol (156 L) were stirred at room temperature for about 2 hr, and the mixture was cooled to about 0° C., and stirred for about 1 hr. The precipitated crystals were collected by filtration, and washed with ethanol (31.2 L). The obtained wet crystals (about 20 kg) were added to 1 mol/L aqueous sodium hydroxide solution (104 L), and the mixture was stirred at room temperature for about 1 hr. The precipitated crystals were collected by filtration, washed with water (93.6 L), and dried under reduced pressure to a constant amount to give 6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide 1 hydrate (4.11 kg, 12.6 mol). yield 25%. containing 5.6 wt % water (by Karl-Fisher water measurement).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2([CH2:22][OH:23])[CH2:21][CH2:20][C:17]3([O:19][CH2:18]3)[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOC(C)=O>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:15][CH2:16][C:17]([CH2:18][OH:19])([CH2:20][CH2:21]2)[O:23][CH2:22]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1(c2cccc(Oc3ccccc3)c2)CCC2(CC1)CO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
To a solution of (6-(3-phenoxyphenyl)-1-oxaspiro[2.5]octan-6-yl)methanol (55.9 mg, 0.180 mmol) in CH2Cl2 (2 mL) at 0° C. was added p-toluenesulfonic acid monohydrate (3.43 mg, 0.018 mmol). The solution was warmed to rt and stirred for 1 h. The reaction was then diluted with EtOAc, washed successively with sat'd aq NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (0 to 100% EtOAc:hexanes) to afford the title compound (15 mg, 27% yield) as an oil. LCMS, [M+Na]+=333.0.