Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C@H:10]2[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45]
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Cl)c(OC)c2)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinylmethoxy]benzoate (142 mg, 0.46 mmol), 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (153 mg, 0.46 mmol) and N,N-dimethylaminopyridine (55.7 mg, 0.46 mmol) in DMF (10 ml) was added EDC.HCl (95.7 mg, 0.50 mmol) at it, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:5) as eluent to give methyl 4-[1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenyl acetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (260 mg, 90%) as a colorless amorphous solid. 1H-NMR (CDCl3) δ 2.00–2.19 (m, 3 H), 2.35–2.44 (m, 1 H), 3.35 (s, 2 H), 3.76 (s, 3 H), 3.89 (s, 3 H), 4.38–4.48 (m, 2 H), 4.63 (br s, 1 H), 4.94 (t, J=7.2 Hz, 1 H), 6.53 (d, J=8.4 Hz, 1 H), 6.66 (s, 1 H), 6.96–7.01 (m, 3 H), 7.12–7.42 (series of m, 8 H), 7.87 (d, J=8.0 Hz, 1 H), 7.98 (d, J=8.8 Hz, 2 H), 8.17–8.19 (m, 1 H); MS (ESI) m/z, 627(+), 628 (M++H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH2:20]([N:23]=[C:24]=[S:25])[CH:21]=[CH2:22].Cl>O>[CH2:20]([N:23]1[C:10](=[O:12])[CH:2]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:1][C:24]1=[S:25])[CH:21]=[CH2:22]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=CCN=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCN1C(=O)C(Cc2ccccc2)NC1=S
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A flask equipped with a magnetic stirrer was charged with phenylalanine (15.8 g, 0.100 mol), triethylamine (11.1 g, 0.11 mol) pyridine (100 mL), and water (50 mL). Allyl isothiocyanate (10.4 g, 0.11 mol) was added to the flask, and the mixture was kept at 40-450 for 4 hr. the mixture was cooled to room temperature and was then extracted with 3×200 mL of toluene. The aqueous phase was mixed with concentrated hydrochloric acid (16 mL, 0.19 mol) and boiled gently for 45 min. The reaction mixture was stirred rapidly as it cooled to room temperature. It was further cooled in an ice-water bath for 20 min, and the solid that had formed was collected and washed with water.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:25]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][NH:26]1>>[O:30]=[S:25]1(=[O:31])[CH2:29][CH2:28][CH2:27][N:26]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Reactant: O=S1(=O)CCCN1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)nc1C
Yield: 29.4 %

Procedure:
Using (4-iodophenyl) [4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (435 mg) described in Preparation Example 120 and isothiazolidine 1,1-dioxide (121 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (126 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=[CH:14][CH2:15][OH:16].O[C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=1>>[CH3:30][C:23]([O:22][C:21]1[CH:20]=[CH:19][C:18]([O:16][CH2:15][CH:14]=[CH:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:32][CH:31]=1)([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: Cc1oc(-c2ccccc2)nc1C=CCO
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCC=Cc2nc(-c3ccccc3)oc2C)cc1

Procedure:
Synthesized from 3-(5-methyl-2-phenyloxazol-4-yl)-prop-2-en-1-ol and ethyl 2-(4-hydroxyphenoxy)-2-methylpropanoate (American Home Products, U.S. Pat. No. 3,795,691) via an analogous procedure to that reported for Example 2, Step A:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[C:32]([O:31][C:29]([C@@H:6]1[CH2:7][C@H:8]([O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:10][C@H:5]1[C:3]([OH:4])=[O:2])=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@H]1C(=O)O
Yield: 63 %

Procedure:
A solution of compound 7 (4.2 mmol) and LiOH (16.8 mmol) in THF/H2O 1/1 (40 mL) was stirred at room temperature for 16 hrs. The reaction mixture was neutralized with 1N HCl to pH 2, and then extracted with DCM (100 mL). Organics were concentrated under reduced pressure and purified by chromatography on silica gel (Cyclohexane/EtOAc) to yield compound 8 as pale yellow oil in 63% yield.
Reaction SMILES: O[CH:2]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][N:5]=1)[CH3:3].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH:2]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][N:5]=1)[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1nccc2c1CCCC2
Solvent: ClCCl
Product: CC(Cl)c1nccc2c1CCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
1-(1-Hydroxyethyl)-5,6,7,8-tetrahydroisoquinoline (1.77 g, 10 mmole) is dissolved in 30 ml dichloromethane in a 100 ml one neck round bottom flask under nitrogen. The solution is cooled to 0° C., is treated dropwise with thionyl chloride (1.1 ml, 15 mmole) in 5 ml dichloromethane, and is stirred 2 h at 0° C. followed by 1 h at room temperature. The mixture is recooled to 0° C., is quenched with 50 ml saturated sodium bicarbonate, and the layers are separated. The aqueous layer is extracted with 3×25 ml dichloromethane and the combined organics are dried over potassium carbonate. The dried organics are concentrated in vacuo to a yellow oil. The crude material is chromatographed over 50 g silica gel (230-400 mesh), eluting with 10% acetone/hexane, while collecting 9 ml fractions. Fractions 10-24 are combined and concentrated to afford 1.96 g (100%) of 1-(1-chloroethyl)-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [C:1]([C:17](OC)=[O:18])([C:4]([C:7]([C:10]([C:13]([F:16])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[NH2:21][CH2:22][CH2:23][OH:24]>CO>[C:1]([C:17]([NH:21][CH2:22][CH2:23][OH:24])=[O:18])([C:4]([C:7]([C:10]([C:13]([F:14])([F:15])[F:16])([F:11])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: NCCO
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CO
Product: O=C(NCCO)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
1 mole each of C5F11COOCH3 (made by electrofluorination of hexanoyl chloride and subsequent reaction with methanol, 82 percent linear C5F11) and NH2C2H4OH was heated in methanol (about 200 mL) for 18 hours at 55-60° C. and stripped to provide 355.3 g C5F11CONHC2H4OH, 100 g of which was treated cautiously with 25 mL SOCl2 (obtained from Aldrich Chemical Company, Milwaukee, Wis.), heated for 18 hours at 55-60° C., and stripped to provide 102.1 g C5F11CONHC2H4Cl, 37.5 g of which was dissolved in 100 mL methanol and treated with 6.0 g powdered NaOH. After stirring the resulting mixture for 20 hours at 23° C., the mixture was quenched in water, extracted with dichloromethane, and dried over MgSO4. Distillation of the dried mixture yielded 15.0 g pure C5F11-oxazoline as a colorless liquid (boiling point 170° C.).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2].[Br:13]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH:1]=[O:2])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C=O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cc(C=O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of methyl 3-formylbenzoate (5.0 g, 30.5 mmol) in concentrated sulfuric acid (50 mL) was added N-bromosuccinimide (5.4 g, 30.5 mmol) in one portion at 0° C. After warming to room temperature, the reaction mixture was stirred for 2 days before being poured into 400 mL of ice/water. Once the ice had melted, the aqueous phase was extracted with DCM (2×400 mL). The combined organic phases were passed through a hydrophobic fit. The solvent was removed in vacuo and the residue was purified via silica gel chromatography, eluting with 0-10% EtOAc in isohexane, to give the title compound as an oil that solidified upon standing (4.6 g, 63%). 1H NMR (400 MHz, CDCl3): δ 10.02 (s, 1H), 8.45 (t, J=1.5 Hz, 1H), 8.41 (t, J=1.7 Hz, 1H), 8.20 (t, J=1.7 Hz, 1H), 3.98 (s, 3H).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[CH3:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31](O)=[O:32].CCCCCC>C(CC(C)(C)C)(C)C>[C:31]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])(=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Solvent: CC(C)CC(C)(C)C
Solvent: CCCCCC
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)OC/C=C(\C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 24 h

Procedure:
There were dissolved, in 1 g of isooctane, 100 mg of geraniol and 900 mg of ethyl ester of eicosapentaenoic acid, followed by the addition of lipase in an amount of 1% relative to the total amount of the resulting solution and then stirring the mixture at 60° C. for 24 hours. After confirming whether the reaction system reached its equilibrium state or not by the GC technique, the reaction solution was diluted by the addition of hexane to the solution in an amount of 10 times the volume thereof, followed by the removal of the lipase from the reaction solution through filtration and then the removal of the hexane through distillation to thus give a crude reaction product. The crude product was purified by silica gel column chromatography to give 122 mg of geranyl eicosapentaenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8]O[C:6]1=[O:10].[CH:16]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([N:23]2[CH2:8][CH2:9][CH:5]([CH2:4][C:3]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:2]=3[Cl:1])[C:6]2=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCCC1
Reactant: O=C1OCCC1Cc1ccc(Cl)cc1Cl
Product: O=C1C(Cc2ccc(Cl)cc2Cl)CCN1C1CCCCCC1
Temperature: 140 °C
Yield: 33.1 %

Procedure:
Charge vial with 3-(2,4-dichloro-benzyl)-dihydro-furan-2-one (300 mg, 1.2 mmol) and cycloheptylamine (139 mg, 1.2 mmol) and heat to 140° C. for 3 hours. Then heat to 195° C. overnight. Cool to room temperature and purify over silica gel which affords 135 mg (32%) of the title compound: Mass spectrum (apci) m/z=340.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]([O:21][CH3:22])(=[O:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].N1CCCCC1.C(O)(=O)C>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]([C:14]([O:21][CH3:22])=[O:20])[C:16]([O:18][CH3:19])=[O:17])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: COC(=O)CC(=O)OC
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(=Cc1ccc(OC)cc1[N+](=O)[O-])C(=O)OC
Yield: 72 %

Procedure:
A mixture of 4-methoxy-2-nitrobenzaldehyde (21.3 g, Org. Synth., Vol. V, p-139, 1973), dimethyl malonate (16.5 g), piperidine (2.5 ml), and acetic acid (0.25 ml) in methanol (125 ml) was heated under reflux for 24 hr. The reaction mixture was concentrated, diluted with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent:ethyl acetate:hexane=1:2) to obtain the titled compound (25 g).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.CO[C:48](=O)[C:49]1[CH:54]=[CH:53][C:52](Cl)=[CH:51][C:50]=1[NH:56][C:57]([CH:59]1[CH2:64][CH2:63][CH2:62][CH2:61][N:60]1[C:65](=[O:73])[C:66]1[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=1)=O>CN(C=O)C>[CH2:50]([N:56]1[C:3](=[O:12])[C:4]2[C:5](=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=2)[N:11]=[C:57]1[CH:59]1[CH2:64][CH2:63][CH2:62][CH2:61][N:60]1[C:65](=[O:73])[C:66]1[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:48]=1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)C1CCCCN1C(=O)c1ccc(C)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCCCC2c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Yield: 21 %

Procedure:
In an ice bath at −15° C., pure compound of Formula 202 (7.2 g, 29 mmol) was combined with 2-amino-4-chloro-benzoic acid methyl ester (4.5 g, 24 mmol), PyBroP (2.3 g, 4.9 mmol) and diisopropylethylamine (0.95 mL, 5.4 mmol) in DMF (30 mL). The resulting mixture was stirred ovemight, allowing the temperature to rise to room temperature with the bath. The solution was concentrated under vacuum and the residue partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with water (3×100 mL) and concentrated under vacuum. The resulting residue was purified by silica gel chromatography using 40% ethyl acetate/hexanes as eluent to give 2.66 g (21% yield) of the desired product of Formula 203, 4-chloro-2-{[1-(4-methyl-benzoyl)-piperidine-2-carbonyl]amino}-benzoic acid methyl ester, as a crystalline solid. LRMS (MH+) m/z 472.
Reaction SMILES: S1CCS[CH:2]1[C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[CH:14]3[CH2:15][C:16]([CH3:19])=[CH:17][CH2:18][CH:13]3[C:12]([CH3:21])([CH3:20])[O:11][C:10]=2[CH:22]=1.B(F)(F)F.[OH2:28]>O1CCCC1>[CH:2]([C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[CH:14]3[CH2:15][C:16]([CH3:19])=[CH:17][CH2:18][CH:13]3[C:12]([CH3:20])([CH3:21])[O:11][C:10]=2[CH:22]=1)=[O:28]
Reactant: CC1=CCC2C(C1)c1c(O)cc(C3SCCS3)cc1OC2(C)C
Reactant: O
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC1=CCC2C(C1)c1c(O)cc(C=O)cc1OC2(C)C

Procedure:
3-(1,3-dithiolan-2-yl)-6a,7,10,10 a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (VI) in the fourth step is then treated with mercuric oxide and boron trifluoride in an aqueous reaction medium containing an organic solvent which is water miscible, such as tetrahydrofuran. The oxidative cleavage is effected at room temperature to produce 3-formyl-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[ b,d]pyran-1-ol which can then be isolated by routine means.
Reaction SMILES: [CH3:1][C:2]1[C:22](C)=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH:16](O)[CH3:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:24])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH:16]=[CH2:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(CNc2cccn3c(C(C)O)c(C)nc23)c1C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=Cc1c(C)nc2c(NCc3c(C)cccc3C)cccn12
Yield: 141.8 %

Procedure:
A mixture of 1-[8-(2,3-dimethylbenzylamino)-2-methylimidazo[1,2-a]pyridine-3-yl]-1-ethanol (0.2 g, 0.65 mmol) and p-toluenesulfonic acid (0.029 g, 0.15 mmol) in benzene (40 ml) was refluxed for 20 h with Dean-Stark water separation. The solvent was evaporated under reduced pressure, the residue was solved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride: ethyl acetate (10:1) gave 0.062 g (33%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.CCN(CC)CC.[C:28]1([C:38](Cl)=O)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][C:4](=[O:20])[C:3]=1[CH2:38][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Cc1cccc2ccccc12

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N (0.160 mL, 1.15 mmol), 1-naphthoyl chloride (1.13 mmol), CH2Cl2 (6.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (6.0 mL), sodium cyanoborohydride (0.50 g, 7.9 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2 to 1.5% MeOH in CH2Cl2) to provide a solid (0.120 g, 203-205° C.(dec.)). 1H NMR (400 MHz, DMSO-d6) δ 11.223 (bs, 1 H), 8.057 (d, 1 H, J=7 Hz), 7.855-7.821 (m, 1 H), 7.603 (d, 1 H, J=8 Hz), 7.514-7.302 (m, 12 H), 6.866 (dd, 1 H, J=6.5 Hz, J=8 Hz), 5.975 (d, 1 H, J=7 Hz), 3.874 (s, 2 H), 3.621 (s, 2 H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([CH:18]=[N:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][NH:24]2)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]2[C:13]=1[CH:18]([NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=1[CH:22]=[N:23][NH:24]3)[C:3]([C:2]([F:29])([F:1])[F:30])([OH:17])[CH2:4][C:5]2([CH3:7])[CH3:6]
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]ncc12
Temperature: -30 °C
Yield: 21 %

Procedure:
100 mg (0.206 mmol) of 1,1,1-trifluoro-4-(5-bromo-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol is dissolved in one milliliter of dichloromethane, and the reaction mixture is cooled to −30° C. Four milliliters of a 1 M solution of BBr3 in dichloromethane is added in drops within 15 minutes, and the batch is then stirred for 45 more minutes at −30° C. At −30° C., about 10 ml of a saturated sodium bicarbonate solution is carefully added in drops. After dilution with ethyl acetate, it is stirred for ten minutes and then extracted twice with 50 ml each of ethyl acetate. The combined organic extracts are washed with water and brine. The residue that is obtained after the solvent is dried and spun off is chromatographed several times on silica gel (mobile solvent ethyl acetate/dichloromethane). 21 mg of the desired compound (together with the corresponding Desbrom compound) is isolated.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]([CH3:17])[CH3:16])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]([CH3:17])[CH3:16])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOC(C)C)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)ON=C(C(=O)O)c1csc(N)n1
Yield: 64.1 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-iso-propoxyiminoacetate (syn isomer, 26.8 g.), 1N aqueous solution of sodium hydroxide (156 ml.), methanol (156 ml.) and tetrahydrofuran (100 ml.) were treated in a similar manner to that of Example D-(4) to give 2-(2-aminothiazol-4-yl)-2-iso-propoxyiminoacetic acid (syn isomer, 15.3 g.), mp. 151° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[N:4]([CH3:15])[CH:3]=1.C1COCC1>>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[N:4]([CH3:15])[CH:3]=1
Reactant: COC(=O)c1cc2c(cn1)c(Br)cn2C
Solvent: C1CCOC1
Product: Cn1cc(Br)c2cnc(C(=O)O)cc21
Reaction time: 8 h
Yield: 89.4 %

Procedure:
In a 200 ml round bottom flask, methyl 3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (3E, 8.5 g, 32 mmol) was dissolved THF (50 ml) NaOH (32 ml, 63 mmol) solution was added to the mixture and the stirring continued at room temperature overnight. Another equivalent of base was added and the mixture was warmed with water bath to complete the reaction. Volatiles were removed in vacuo and the residue was cooled in an ice bath and neutralized with dilute HCl to pH 4.0-4.5. The precipitated product was collected by filtration to give the product 3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid (3F, 7.3 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].F[C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1ccccc1F
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccc(Cl)cc1Cl

Procedure:
AMR01045 A mixture of 2,4-dichlorophenol (2.00 g, 12.27 mmol), 2-fluorobenzonitrile (1.49 g, 12.27 mmol) and potassium carbonate (1.7 g, 12.27 mmol) in DMF (10 mL) was stirred under reflux for 1.5 h. After removal of DMF, the residue was dissolved in DCM and washed with NaOH (5%, 3×20 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated and 2-(2,4-dichlorophenoxy)benzonitrile was obtained as an oil (2.73 g, 84%), which was used in the next step without further purification. Rf: 0.64 (DCM) 1H NMR (300 MHz, CDCl3) δ 6.73 (1H, dd, J=8.4 Hz), 7.13 (1H, d, J=8.7 Hz), 7.22 (1H, td, J=8.7, 1.0 Hz), 7.35 (1H, dd, J=8.7, 2.4 Hz), 7.56 (1H, d, J=2.4 Hz) and 7.73 (1H, dd, J=7.5, 2.7 Hz).