Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[O:2]=[C:3]1[N:8]2[CH:9]=[CH:10][S:11][C:7]2=[N:6][C:5]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4]1.[H-].[Na+].[CH:34]1([CH2:37][O:38][C:39]2[C:46](OC)=[CH:45][CH:44]=[CH:43][C:40]=2[CH:41]=O)[CH2:36][CH2:35]1.[C:49](OCC)(=O)[CH3:50]>CS(C)=O>[CH:34]1([CH2:37][O:38][C:39]2[C:46]([CH2:49][CH3:50])=[CH:45][CH:44]=[CH:43][C:40]=2/[CH:41]=[CH:12]/[C:5]2[N:6]=[C:7]3[S:11][CH:10]=[CH:9][N:8]3[C:3](=[O:2])[CH:4]=2)[CH2:36][CH2:35]1
Reactant: CCOC(C)=O
Reactant: O=c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2sccn12
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC1CC1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of Step 2 intermediate (13.0 g, 28.08) was added NaH (1.2 g, 30.88) in dry DMSO (75 ml) and stirred for 0.5 h. A solution of 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (6.3 g, 30.88 mmol) in DMSO was added dropwise to this solution at room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4 to yield a crude solid which was purified by column chromatography using 10% ethyl acetate in DCM to afford 7.5 g of the desired compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 0.30-0.33 (m, 2H), 0.52-057 (m, 2H), 1.10-1.20 (br m, 1H), 3.72-3.90 (m, 5H), 6.29 (s, 1H), 7.00-7.11 (m, 3H), 7.34 (d, J=6.3 Hz, 1H), 7.44-7.50 (m, 1H), 7.90-8.00 (m, 1H), 8.14 (d, J=6.2 Hz, 1H); ESI-MS (m/z) 355.17 (M+H)+.
Reaction SMILES: Cl[C:2]1C=C(C=C(OC(C)C)C=1OC)C(O)=O.[CH2:17]([O:24][C:25]1[C:43]([O:44][CH:45]2[CH2:50]CCC[CH2:46]2)=[CH:42][C:28]([C:29]([NH:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)=[O:30])=[CH:27][C:26]=1[Cl:51])C1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O.C(Cl)Cl>[Cl:51][C:26]1[CH:27]=[C:28]([CH:42]=[C:43]([O:44][CH:45]([CH3:46])[CH3:50])[C:25]=1[O:24][CH3:17])[C:29]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:40]([CH3:2])[CH:41]=1)=[O:30]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OCc3ccccc3)c(OC3CCCCC3)c2)cc1
Reactant: COc1c(Cl)cc(C(=O)O)cc1OC(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OC)c(OC(C)C)c2)cc1C
Temperature: 60 °C
Yield: 41.8 %

Procedure:
A mixture of 3-chloro-5-isopropoxy-4-methoxybenzoic acid (5) (250 mg, 1.02 mmol), methyl 4-amino-2-methylbenzoate (6) (177 mg, 1.07 mmol) and TEA (150 μL, 1.07 mmol) in EtOAc (2.5 mL) was treated with T3P (50% in EtOAc) (1.63 mL, 2.55 mmol) and the mixture was heated at 60° C. for 5 h. The mixture was diluted with DCM (5 mL) and washed with 1M HCl (5 mL) followed by satd. NaHCO3 solution (5 mL). The organic solvents were removed in vacuo and the residue purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane to yield methyl 4-(3-chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoate (7) (167 mg, 40%): m/z 392 [M+H]+ (ES+), 390 [M−H]− (ES−). 1H NMR (400 MHz, CDCl3) δ:7.98 (1H, d), 7.78 (1H, s), 7.59-7.50 (2H, m), 7.40 (2H, dd), 4.67 (1H, sep), 3.94 (3H, s), 3.89 (3H, s), 2.62 (3H, s), 1.40 (6H, d).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11](Cl)(=[O:14])[CH2:12][CH3:13].C1CCCCC1>C1(C)C=CC=CC=1>[C:11]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)(=[O:14])[CH2:12][CH3:13]
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: CCC(=O)Cl
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Product: CCC(=O)Nc1nc(C(Cl)(Cl)Cl)ns1
Temperature: -15 °C
Yield: 91 %

Procedure:
A solution of 21.8 grams (0.1 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 18.5 grams (0.2 mole) propionyl chloride in 300 milliliters toluene was refluxed at about 110° C. for 14 hours. The product precipitated (18.4 grams, 91% yield) upon cooling to -15° C. and was isolated by filtration. A pure product of m.p. 150.0° C. was obtained by recrystallization from cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(I)c(Br)c1
Reactant: Sc1ccc(Cl)cc1
Product: Cc1ccc(Sc2ccc(Cl)cc2)c(Br)c1

Procedure:
Prepared from 4-chloro-benzenethiol and 2-bromo-1-iodo-4-methyl-benzene.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]([CH2:14]O)[CH:10]=[CH:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)(Cl)Cl.C(#N)C>[C:1]1([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]([CH2:14][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:10]=[CH:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(CO)c(-c2ccccc2)c1-c1ccccc1
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(CN2CCCCC2)c(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Compound 24 described above (0.17 g, 0.620 mmol) was dissolved in chloroform (4 mL) (Wako Pure Chemical Industries, Ltd.), and thionyl chloride (0.5 mL) (Wako Pure Chemical Industries, Ltd.) was added dropwise while cooling with ice. The mixture was returned to room temperature and stirred for 2 hours, and then the solvent was distilled off under reduced pressure, to thereby obtain a residue. The residue was dissolved in acetonitrile (4 mL) (Wako Pure Chemical Industries, Ltd.), and piperidine (0.19 g, 2.23 mmol) (Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was refluxed for 1 hour and allowed to cool to room temperature. The solvent was distilled off under reduced pressure, and then a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the concentrated residue, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was washed with water and brine. After that, the organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to alumina column chromatography (n-hexane (Wako Pure Chemical Industries, Ltd.) as an eluent), to thereby obtain the title compound (0.18 g, 85% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[CH:7][CH:6]=1)=[O:4].F[B-](F)(F)F.[O:22]=[N+:23]=[O:24]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[C:9]([N+:23]([O-:24])=[O:22])[CH:10]=1)=[O:4]
Reactant: O=[N+]=O
Reactant: COC(=O)c1ccc(N2CCCC2=O)cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCCC2=O)c([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
An ice-cold mixture of the above ester (2.0 g, 9.1 mmol) in 30 mL of dichloromethane was treated with nitronium tetrafluoroborate (2.5 g, 18.8 mmol). The resulting mixture was stirred at 10° C. for 2 h and then at ambient temperature for 4 h. The reaction mixture was quenched with water (20 mL) and the organic layer was evaporated under vacuum. The white solid precipitate was collected by filtration, washed with water and dried to give 2.2 g (92%) of 1-(4-methoxycarbonyl-2-nitrophenyl)pyrrolidin-2-one, mp 159-161° C. (chloroforn/ether).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:34])([CH3:33])N1CCOC1=O.NS(O)(=O)=O.[Br:40]N1C(=O)CCC1=O>ClCCl>[Br:40][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:34])([CH3:33])[CH3:25])=[O:9]
Reactant: C[Si](C)(C)N1CCOC1=O
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Reactant: O=C1CCC(=O)N1Br
Agent: NS(=O)(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 46 %

Procedure:
The clear solution obtained after refluxing a mixture consisting of 40 ml of dichloromethane, 608.7 mg (1.75 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide and 450 mg (2.83 mmoles) of N-trimethylsilyl-2-oxazolidinone for two hours was cooled in an ice-bath and 0.1 g of amidosulfonic acid (1 mmole) was added thereto. Bromination was carried out in half an hour using 469 mg (2.63 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 46% yield of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]([NH2:11])=[S:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Br[CH2:13][C:14](=O)[C:15]([OH:17])=[O:16].[CH3:19][CH2:20]O>>[C:1]([O:7][CH2:8][C:9]1[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:19][CH3:20])=[O:16])[N:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCC(N)=S
Reactant: CCO
Reactant: O=C(O)C(=O)CBr
Product: CCOC(=O)c1csc(COC(=O)C(C)(C)C)n1
Temperature: 25 °C

Procedure:
2-Amino-2-thioxoethyl pivalate (3.0 g, 17.12 mmol) and 3-bromo-2-oxopropanoic acid (3.14 g, 18.83 mmol) were dissolved in EtOH (20 mL), 4 Å molecular sieves added and the reaction mixture heated at reflux for 20 h then cooled to RT, filtered, washed with EtOH and evaporated in vacuo. The residual semi solid was treated with 50% EtOAc/DCM and the resulting light brown solid filtered off. The filtrate was evaporated in vacuo and the residue purified by chromatography on silica with 20% EtOAc/isohexane as eluent to afford the sub-title compound as a pale yellow oil. Yield: 2.47 g
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[NH2:20])[CH:8]([O:21][CH3:22])[CH2:7]1)=O)C.C(OC(O[CH2:32][CH3:33])(OCC)C)C.[C:34](O)(=O)C>>[CH2:32]([C:33]1[N:12]([CH:9]2[CH2:10][CH2:11][NH:6][CH2:7][CH:8]2[O:21][CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[N:20]=1)[CH3:34]
Reactant: CCOC(=O)N1CCC(Nc2ccc(C)cc2N)C(OC)C1
Reactant: CC(=O)O
Reactant: CCOC(C)(OCC)OCC
Product: CCc1nc2cc(C)ccc2n1C1CCNCC1OC
Temperature: 60 °C

Procedure:
To a solution of 4-(2-amino-4-methyl-phenylamino)-3-methoxy-piperidine-1-carboxylic acid ethyl ester (800 mg, 2.60 mmol) in acetic acid (5 mL) was added 1,1,1-triethoxy ethane (550 mg, 3.12 mmol). After heating at 60° C. for 30 minutes, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (15/1 CH2Cl2/CH3OH) to 4-(2-ethyl-5-methyl-benzoimidazol-1-yl)-3-methoxy-piperidine-1-carboxylic acid ethyl ester (940 mg, 89%) as a white solid.
Reaction SMILES: C(=O)=O.CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:14]([O:18][C:19](=[O:30])[N:20]([C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24][CH2:23]1)[CH3:21])([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC>C(Cl)Cl>[C:14]([O:18][C:19](=[O:30])[N:20]([CH:22]1[CH2:23][CH2:24][CH:25]([CH:28]=[O:29])[CH2:26][CH2:27]1)[CH3:21])([CH3:15])([CH3:17])[CH3:16]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CO)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCC(C=O)CC1
Reaction time: 0.08 h
Yield: 100.4 %

Procedure:
To a dry-ice cooled solution of 8.94 ml (125.9 mmol) DMSO in 150 ml CH2Cl2 was added 5.95 ml (69.24 mmol) oxalylchloride. After 5 min at −78° C., a solution of 16.2 g (66.5 mmol) trans-(4-Hydroxymethyl-cyclohexyl)-methyl-carbamic acid tert-butyl ester in 50 ml of CH2Cl2, was added slowly. 10 min later, 43.8 ml (314.75 mmol) of Et3N was added, and the mixture was allowed to attain RT. The mixture was partitioned between Et2O/1N HCl and water. The solvent was evaporated under reduced pressure yielding 16.12 g of clean (4-Formyl-cyclohexyl)-methyl-carbamic acid tert-butyl ester, MS: 241 (m).
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][O:4][NH:3]1.[CH2:13](Br)[CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[CH2:13]([N:3]1[O:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:2]1[CH3:1])[CH2:14][CH2:15][CH3:16]
Reactant: CC1NOCCc2ccccc21
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCN1OCCc2ccccc2C1C
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 3.27 g. (0.02 mole) of 1-methyl-1,2,4,5-tetrahydro-3,2-benzoxazepine, 5.5 g. (0.04 mole) of butyl bromide and 3.18 g. (0.03 mole) of sodium carbonate was heated under stirring for 3 hours at 90° C. and for an additional four hours at 120° C. After cooling the reaction mixture was taken up with diethyl ether, and the inorganic residue filtered off. The filtrate was then evaporated in vacuo and the residue rectified by collecting the fraction boiling at 90° C./0.1 mm Hg. Yield 2.3 g. of 2-butyl-1-methyl-1,2,4,5-tetrahydro-3,2-benzoxazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1(CO)[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:18][CH:17]=1
Reactant: OCC1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCC4CCCC4)cc3)c2cc1OC
Yield: 89.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclopentylmethanol (26 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (64 mg, yield 75%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[OH:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]=[C:19](O)[CH:18]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[OH:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]=[C:19]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:18]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1c2ccccc2[nH]c2cc(O)cc(O)c12
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=c1c2ccccc2[nH]c2cc(OS(=O)(=O)C(F)(F)F)cc(O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
Trifluoromethanesulfonic anhydride (3.1 mL, 18.4 mmol) was slowly added to a solution of 1,3-dihydroxy-10H-acridin-9-one (4.0 g, 17.6 mmol), and 2,6-lutidine (65 mL) in CH2Cl2 (180 mL) at 0° C. See J. Reisch et al., Liebigs Ann. Chem., pp. 685-689 (1991). The reaction then was allowed to slowly warm to room temperature. After 16 h, the reaction was concentrated, redissolved in EtOAc (250 mL), and washed with 10% citric acid (5×50 mL) water (2×25 mL), and brine (2×25 mL). The organics then were dried (Na2SO4), filtered, and concentrated. The crude material then was purified via Biotage chromatography using 5% EtOAc/hexanes as eluent to yield 1.77 g (28%) of trifluoromethanesulfonic acid 1-hydroxy-9-oxo-9,10-dihydro-acridin-3-yl ester as an orange solid. Rf=0.50 (50% EtOAc/hexanes). 1H NMR (DMSO-d6, 400 MHz) δ: 12.45 (s, 1H), 8.25 (d, 1H), 7.87 (dd, 1H), 7.59 (d, 1H), 7.40 (dd, 1H), 6.99 (s, 1H), 6.67 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]#N)=[CH:6][CH:5]=2.O.[PH2]([O-])=[O:15].[Na+].N1C=CC=CC=1>C(O)(=O)C.[Ni]>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH:11]=[O:15])=[CH:6][CH:5]=2
Reactant: O=[PH2][O-]
Reactant: Cc1cc2cc(C#N)ccc2[nH]1
Agent: [Ni]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2cc(C=O)ccc2[nH]1
Temperature: 45 °C
Reaction time: 1.25 h
Yield: 80.3 %

Procedure:
A mixture of 3.9 g 2-methyl-1H-indole-5-carbonitrile [Journal of Organic Chemistry (1994), 9(21), 6372-7], 7.22 g sodium hypophosphite monohydrate and 2.60 g Raney-Nickel in 110 ml acetic acid (50%)/pyridine 1:1 was stirred at 45° C. for 75 min. After cooling down to room temperature, the reaction mixture was filtered (dicalite), then the filtrate poured into ice-water and extracted 3 times with EtOAc. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated. The residue was crystallized from n-heptane to give 3.19 g of 2-methyl-1H-indole-5-carbaldehyde as light red solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]=1.O>[N+]([O-])(O)=O>[CH:2]([C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]=1)=[O:1]
Reactant: O=c1c(CO)coc2ccccc12
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=Cc1coc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A quantity of 35.2 g. (0.2 mole) of 3-(hydroxymethyl)-chromone is dissolved in 250 ml of concentrated nitric acid with stirring at 25° C. There is no initial heat of reaction. The temperature gradually rises to 30° C over the next several minutes and is kept there for about 5 minutes with ice-acetone bath cooling. Water, 600 ml, is added to the reaction solution. The separated, pale yellow solid is filtered, washed well with water and dried to give 25 g. of crude aldehyde melting at 145°-148°.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:3]=1.C(OCC)(=[O:21])C>[OH-].[Na+]>[F:16][C:15]([F:18])([F:17])[CH2:14][O:13][CH2:12][C:4]1[NH:3][C:2](=[O:21])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1
Reactant: Nc1nc(COCC(F)(F)F)nc2nccnc12
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(COCC(F)(F)F)nc2nccnc12

Procedure:
Obtained using the procedure described in section d of Example 2, starting with 5.0 g (0.0193 mole) of 4-amino-2-[(2,2,2-trifluoroethoxy)methyl]pteridine in 105 ml of 5% aqueous sodium hydroxide. Heating time: 1 hour 30 minutes at 80° C. Yld: 2.5 g (50%), m.p. 165°-167° C. (ethyl acetate).
Reaction SMILES: [O:1]=[C:2]([CH2:20][CH2:21][C:22]1C=CC=[CH:24][CH:23]=1)/[CH:3]=[CH:4]/[CH:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][S:6]1.O=C(CCCCC)/C=C/C1N(CCCCCCC(O)=O)C(=O)CS1>>[OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:3]=[CH:4]/[CH:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][S:6]1
Reactant: O=C(O)CCCCCCN1C(=O)CSC1/C=C/C(=O)CCc1ccccc1
Agent: CCCCCC(=O)/C=C/C1SCC(=O)N1CCCCCCC(=O)O
Product: CCCCCC(O)/C=C/C1SCC(=O)N1CCCCCCC(=O)O

Procedure:
This compound is prepared essentially by the method as described in Example 13, Step D, except that the 7-[2-(3-oxo-5-phenyl-1-trans-pentenyl)-4-oxo-3-thiazolidinyl]-heptanoic acid is replaced with 7-[2-(3-oxo-1-trans-octenyl)-4-oxo-3-thiazolidinyl]heptanoic acid. Chromatographic purification of the product resulting this method on silica gel affords the title compound as a pale yellow, viscous oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:15]/[C:16](=[CH:19]\[CH2:20][C:21]1[C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]=1[CH3:29])/[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:14][O:13][CH:3]([O:2][CH3:1])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:15]/[C:16](/[CH3:17])=[CH:19]/[CH2:20][C:21]2[C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]=2[CH3:29])=[CH:8][CH:7]=1
Reactant: CC1=C(C/C=C(\C)CO)C(C)(C)CCC1
Reactant: COC(CSc1ccc(O)cc1)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(CSc1ccc(OC/C(C)=C/CC2=C(C)CCCC2(C)C)cc1)OC
Yield: 85 %

Procedure:
By the method of example 13, 4-((2,2-dimethoxyethyl)thio)phenol (example 64) and (E)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenol (Chem. Abstr., 94, 65904 h) are coupled in the presence of triphenylphosphine and diethyl azodicarboxylate to provide (E)-1-((2,2-dimethoxyethyl)thio)-4-(2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenyloxy)benzene as a colorless oil after chromatography (85% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1.[CH2:22]([NH2:25])[CH:23]=[CH2:24]>C(O)CCC>[CH2:22]([NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1)[CH:23]=[CH2:24]
Reactant: C=CCN
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Solvent: CCCCO
Product: C=CCNc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12

Procedure:
To a suspension of 104 mg of 1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile in nBuOH was added 252 uL of allylamine. The reaction was heated at 210 C in a microwave reactor for 1 h, then partitioned between EA and saturated aqueous sodium bicarbonate. The organic solution was washed with brine once, then dried (Na2SO4) and concentrated. Flash chromatography (540% EA/hex, Gilson, 40 g silica) gave a pink solid.
Reaction SMILES: C([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]2[O:24][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:26][N:27]=2)[CH:9]=1)(=O)C(C)(C)C.[OH-].[Na+].O.Cl>CO.C1COCC1>[C:28]([C:25]1[O:24][C:23]([C:10]2[CH:9]=[C:8]([OH:7])[CH:13]=[CH:12][C:11]=2[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[N:27][N:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1ccc(F)c(-c2ccc(OC(=O)C(C)(C)C)cc2-c2nnc(C(C)(C)C)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(C)(C)C)o2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.1 %

Procedure:
To a solution of 2-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl pivalate (405 mg) in methanol (3.0 mL) and THF (3.0 mL) was added 1N aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at room temperature for 4 hr. Water and hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (114 mg) as a white amorphous solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:18][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: COCCCCOc1ccnc(CO)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COCCCCOc1ccnc(CCl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
5.6 g of crude 2-hydroxymethyl-4-(4-methoxybutoxy)pyridine was dissolved in 80 ml of chloroform to obtain a solution. A solution of 3.8 g of thionyl chloride in 10 ml of chloroform was dropwise added to this solution at 0° C. The obtained mixture was stirred at 0° C. for one hour. After the completion of the reaction, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with 200 ml of chloroform twice. The extract was dried over magnesium sulfate and filtered, The filtrate was distilled to remove the solvent. The obtained residue was dried in a vacuum to obtain 5.09 g of the title compound as a crude oil.