Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:13]=[C:12]([C:15]5[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]6[O:22][C:21]([C:23]7[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=7)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=6[CH:34]=5)[CH:11]=[CH:10][C:9]=4[CH2:8][CH:7]([CH2:41]O)[N:6]3[C:43]=2[CH:44]=[CH:45][CH:46]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(N(CC)C(C)C)(C)C.Cl.[F:72][CH:73]1[CH2:76][NH:75][CH2:74]1>C(Cl)Cl.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:13]=[C:12]([C:15]5[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:17][C:18]6[O:22][C:21]([C:23]7[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=7)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=6[CH:34]=5)[CH:11]=[CH:10][C:9]=4[CH2:8][CH:7]([CH2:41][N:75]4[CH2:76][CH:73]([F:72])[CH2:74]4)[N:6]3[C:43]=2[CH:44]=[CH:45][CH:46]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CO)C4)cc12
Reactant: FC1CNC1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN3CC(F)C3)C4)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
To a solution of 5-(11-fluoro-6-(hydroxymethyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (180 mg, 0.280 mmol) in DCM (8 mL) at 0° C. was added trifluoromethanesulfonic anhydride in DCM (0.560 mL, 0.560 mmol). The mixture was stirred at 0° C. for 2 h, then at RT for 1 h. The mixture was evaporated in vacuo to remove the volatiles, redissolved in DMF (8 mL), followed by addition of N,N-diisopropyl ethylamine (362 mg, 2.80 mmol) and 3-fluoroazetidine hydrochloride (125 mg, 1.120 mmol). The mixture was heated to 60° C. and stirred for 3 h. 20 ml H2O was added and the mixture stirred for 10 min. Filtration collected the yellow solid. After washing with additional H2O, the yellow solid was purified by chromatography, and eluted with 0-70% ethyl acetate in hexane to gave 5-(11-fluoro-6-((3-fluoroazetidin-1-yl)methyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (42 mg, yield: 21%). MS (M+H)+: 700.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.N1C=CC=CC=1>O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COc1ccc(C2=CCCCC2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(C2=CCCCC2)cc1
Temperature: 180 °C

Procedure:
56.5 Grams of p-(1-cyclohexenyl)-anisol and 125 g of pyridine-hydrochloride are thoroughly mixed and heated for 3 hours in an atmosphere of nitrogen to 180° C. The reaction mixture is cooled to room temperature, treated with water and extracted with 3 × 400 ml of benzene. The benzene extracts are washes with 3 × 300 ml of water, dried over sodium sulphate and evaporated in vacuo. The solid residue yields the crude p-(1-cyclohexenyl)-phenol (m.p. 115-119° C), which can be purified by recrystallisation from benzene and then melts at 120°-122° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([NH:13]C(=O)OC(C)(C)C)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].[ClH:21]>ClCCl.O1CCOCC1>[ClH:21].[NH2:13][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[CH2:3][CH2:2][OH:1]
Reactant: COc1ccccc1C(CCO)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccccc1C(N)CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 172A, 100 mg (0.36 mmol) were dissolved in 2 ml of dichloromethane, and 1.63 ml (6.52 mmol) of a 4M solution of hydrogen chloride in dioxane were added. The yellow solution was subsequently stirred at RT for 1 h. The reaction mixture was evaporated to dryness on a rotary evaporator and dried in an HV. This gave 88 mg (100% of theory) of the title compound.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:5]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[CH2:31][O:32][Si](C(C)C)(C(C)C)C(C)C)[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:5]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[CH2:31][OH:32])[CH:2]=[CH2:3]
Reactant: C=CCn1c(-c2ccc(OC)cc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCn1c(-c2ccc(OC)cc2CO)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Methyl 1-allyl-3-cyclohexyl-2-(4-methoxy-2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate (1 eq) was dissolved in THF (0.28M solution) and a 1M solution of tetrabutylammonium fluoride in THF (1 eq) was added. The mixture was stirred at RT for 2 h, then all volatiles were evaporated in vacuo and the residual material was dissolved in Et2O. The solution was washed with 1N HCl, saturated aq. NaHCO3 solution and with brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was purified by FC (PE:EtOAc, 8:2). After evaporation of the solvents the product was obtained as colourless foam (88%). (ES+): m/z 434.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[F:20][C:21]1[CH:22]=[C:23]([N:35]2[CH2:39][C@H:38]([CH2:40][NH:41][C:42](=[O:44])[CH3:43])[O:37][C:36]2=[O:45])[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30]1.C(N(CC)CC)C.C[Si](C)(C)Cl>CN1CCCC1=O>[C:42]([NH:41][CH2:40][C@@H:38]1[O:37][C:36](=[O:45])[N:35]([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]3([OH:34])[CH2:33][CH2:32][N:31]([C:2]4[N:11]=[C:10]5[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]5[CH:12]5[CH2:14][CH2:13]5)=[CH:4][C:3]=4[F:19])[CH2:30]3)=[C:21]([F:20])[CH:22]=2)[CH2:39]1)(=[O:44])[CH3:43]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCNC3)c(F)c2)C(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)C3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 1, step 7 with 39 mg 7-chloro-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (MW: 282.66, 0.24 mmol), 99 mg N-{(5S)-3-[3-fluoro-4-(3-hydroxy-pyrrolidin-3-ylmethoxy)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide. (MW: 367.38, 0.24 mmol) 101 mg triethylamine (MW: 101.19, 1.0 mmol) and 80 mg trimethylchlorsilan (MW: 108.64, 0.75 mmol) in 2 ml N-methyl-pyrrolidin-2-one. Yield: 70 mg, 46%. MS: 614.7 (M+H)+, 612.7 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:13])[CH:4]=1)=[O:2].CC(CC)=C.O.P([O-])(O)(O)=[O:21].[Na+].Cl([O-])=O.[Na+].Cl>CC(O)(C)C.O.CCOC(C)=O>[CH2:11]([O:10][C:8]([C:6]1[NH:7][C:3]([C:1]([OH:21])=[O:2])=[CH:4][C:5]=1[CH3:13])=[O:9])[CH3:12]
Reactant: O=P([O-])(O)O
Reactant: CCOC(=O)c1[nH]c(C=O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C=C(C)CC
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1[nH]c(C(=O)O)cc1C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of ethyl 5-formyl-3-methyl-1H-pyrrole-2-carboxylate (0.25 g, 1.38 mmol) in t-BuOH (50 mL) was added 2-methylbutene as a 2M solution (24 mL, 48.3 mmol). In a separate flask sodium dihydrogen phosphate monohydrate (1.3 g, 9.42 mmol) and sodium chlorite (1.1 g, 12.2 mmol) were dissolved in water (30 mL). The aqueous solution was added to the alcoholic reaction mixture dropwise and stirred for 3 h. The solution was acidified with aqueous 1N HCl to a pH ˜4 and EtOAc (100 mL) added. The layers were separated, the aqueous layer extracted with EtOAc (5×25 mL), the organic layers combined, dried over sodium sulfate, filtered and the volume reduced (˜50 mL). Ethyl acetate (100 mL) was added and the solution extracted with sat. sodium bicarbonate (5×25 mL), the aqueous layers combined, acidified with 1N HCl to pH˜4-5, saturated with NaCl and extracted with EtOAc (5×25 mL). The organic layers were combined, dried over sodium sulfate, filtered and evaporated to afford 5-[(ethyloxy)carbonyl]-4-methyl-1H-pyrrole-2-carboxylic acid (0.196 g, 72%) as a white solid along with 3-chloro-5-[(ethyloxy)carbonyl]-4-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:4][N:3]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1cnc(-c2ccc(O)cc2)cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-5-bromopyrazine (366 mg) in dimethoxyethane (20 mL) was added 4-hydroxyphenylboronic acid (320 mL), 1.5N sodium carbonate aqueous solution (2.5 mL) and tetrakis(triphenylphosphine)palladium (0) (54 mg). The mixture was stirred at 80° C. for 3 hours. To the reaction mixture was added water (20 mL) and the whole was extracted with ethyl acetate (50 mL×3). The extract was washed with saturated saline solution, then dried over anhydrous Na2SO4. The removal of the solvent provided crystal residue, which was washed with diethyl ether (10 mL) to give the subject compound (305 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12]>C(#N)C>[NH2:12][CH2:11][CH2:10][NH:13][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:9])=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CC#N
Product: N#Cc1ccc(NCCN)nc1
Temperature: 77.5 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
A mixture of 2-chloro-5-cyanopyridine (0.60 M) in acetonitrile (120 ml) and ethylene diamine (85 ml) were stirred overnight (ca. 16 h) at 75-80° C. under argon. The ethylene diamine was removed under reduced pressure and then dried in vacuo for 2-3 h. The residual solution was basified with 1M sodium hydroxide solution (˜100 ml). The aqueous solution was saturated with sodium chloride and extracted with a solution of 95% ethyl acetate and 5% methanol (3×150 ml) and with a solution of 95% acetonitrile and 5% methanol (3×150 ml). The organic extracts were combined and extracted with a saturated sodium chloride solution (2×70 ml). The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude white to tan solid was triturated with ether (2×50 ml) and dried overnight in vacuo resulting in 78% yield of 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: [NH2:1][C:2](=[O:25])[CH2:3][O:4][NH:5][C:6]([C@@H:8]1[CH2:14][CH2:13][C@@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[O:16]CC1C=CC=CC=1)=[O:7]>CO.[Pd]>[NH2:1][C:2](=[O:25])[CH2:3][O:4][NH:5][C:6]([C@@H:8]1[CH2:14][CH2:13][C@@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[OH:16])=[O:7]
Reactant: NC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A mixture of (2S,5R)-N-(2-amino-2-oxoethoxy)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 54 (0.11 g, 0.40 mmol) and Pd/C (0.040 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 55 (0.10 g, 98%) as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([CH2:15][OH:16])[CH2:13][S:14][C@H:9]12)=[O:6].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.O>CN(C)C=O.CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH:27][C:28](=[O:33])[C:29]([F:31])([F:32])[F:30])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([CH:15]=[O:16])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) (1.0 g.) was dissolved in a mixture of dimethylformamide (6 ml.) and acetone (30 ml.). Jones reagent (1.25 ml.), which was prepaed from conc. sulfuric acid (0.28 ml.), chromium trioxide (0.33 g.) and water (0.9 ml.), was dropwise added thereto over 2 minutes with stirring and cooling at 0° to 2° C. After stirring for 20 minutes at the same temperature, the reaction mixture was poured into ice-water (50 ml.). After acetone was distilled off, the residue was twice extracted with ethyl acetate (50 ml.). The extracts were washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with diisopropyl ether to give 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}-acetamido]-3-formyl-3-cephem-4-carboxylic acid (syn isomer) [or this compound can be represented as 3-hydroxy-6-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)dione (syn isomer)] (0.56 g.).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:4].[CH2:23]([CH2:25][NH2:26])O>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[N:26]3[CH2:25][CH2:23][O:9][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Reactant: NCCO
Solvent: CCO
Product: O=C1Nc2ccc(Cl)cc2C2(c3ccccc3)OCCN12
Yield: 74.8 %

Procedure:
To a solution of 3.77 g of 2-trichloroacetamido-5-chlorobenzophenone in 100 ml of ethanol was added 3.05 g of monoethanolamine, and the resulting mixture was refluxed for 2 hours. Then, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using chloroform as an eluent to give 2.25 g of 9-chloro-2,3,6,10b-tetrahydro-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one, having a melting point of 216° - 217°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20]COC)=[CH:15][CH:14]=2)=[N:3]1.Cl.C(=O)([O-])O.[Na+].C(=O)([O-])[O-]>CO>[CH3:1][C:2]1([CH3:24])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)=[N:3]1
Reactant: COCOCc1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CO
Product: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Temperature: 40 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
2.62 g (8.05 mmol) of 4,4-dimethyl-2-(4'-methoxymethoxymethylbiphenyl-2-yl)oxazoline was dissolved in methanol (20 ml). 6N hydrochloric acid (10 ml) was added thereto, followed by stirring at 40° C. for 2 hours. The reaction liquid was poured into a saturated aqueous solution of sodium hydrogen-carbonate, carbonate, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 2.20 g of the title compound as a crystal (yield 97%).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([CH2:26][C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=3)[C:30]([O:32]C)=[O:31])[C:15](=[O:25])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[NH:1]([C:8]1[N:13]=[C:12]2[N:14]([CH2:26][C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=3)[C:30]([OH:32])=[O:31])[C:15](=[O:25])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(CN2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(CN2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Temperature: 60 °C
Yield: 33.3 %

Procedure:
A solution of 90 mg (0.17 mmol) of methyl 3-[[7-anilino-3-(2-bromophenyl)-1,2,3,4-tetrahydro-2-oxopyrimido[4,5-d]pyrimidin-1-yl]methyl]benzoate in tetrahydrofuran/methanol/water (6 ml:6 ml:1.5 ml) was treated with 27 mg (1.125 mmol) of lithium hydroxide monohydrate then heated at 60° C. for 3 hours under a nitrogen atmosphere. The solvent was evaporated and the residue partitioned between ethyl acetate (10 ml) and 2M hydrochloric acid (10 ml). The ethyl acetate layer was separated, washed with saturated aqueous sodium bicarbonate (10 ml), dried over magnesium sulfate, filtered and evaporated to give 30 mg (35%) of 3-[[7-anilino-3-(2-bromophenyl)-1,2,3,4-tetrahydro-2-oxopyrimido[4,5-d]pyrimidin-1-yl]methyl]benzoic acid as a pale yellow solid of melting point 180-183° C. [Mass spectrum (ESI) MH+ =530].
Reaction SMILES: C([O:3][C:4](=[O:47])[CH:5]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CCO>[C:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[NH:32][CH:5]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:23][C:24]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:47])=[O:3])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccccc12)Nc1ccccc1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(Nc2ccccc2C(=O)c2ccccc2)C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
0.213 g (0.341 mmol) of 2-(2-Benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid ethyl ester was dissolved in 1.6 ml of THF/EtOH=1/1 and treated with 0.568 ml of 3N NaOH(5 eq). The reaction flask was stirred for 20 h at ambient temperature. The mixture was then poured onto crashed ice/NH4Cl, extracted twice with AcOEt, washed with brine, dried over sodium sulfate, and evaporated to dryness. Twofold crystallization from hexane/AcOEt yielded 0.199 g of the title product as yellow crystals of mp. 125° (dec.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[CH3:15][C:16]([CH3:19])([O-:18])[CH3:17].[K+]>C1COCC1.C(OCC)C>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:12])[O:18][C:16]([CH3:19])([CH3:17])[CH3:15])=[CH:8][CH:9]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1
Reaction time: 8 h

Procedure:
A mechanically stirred solution of 4-(trifluoromethoxy)phenyl isocyanate (10.54 g, 51.9 mmol) in THF (200 mL) at 0° C. was treated with the dropwise addition of 1.0 M potassium tert-butoxide solution in THF (55 mL, 55 mmol). The solution was allowed to come to room temperature, and stirred overnight. The mixture was diluted with diethyl ether (300 mL), washed successively with saturated ammonium chloride solution (2×100 mL), water (100 mL), and brine (100 mL), dried over sodium sulfate, and concentrated in-vacuo. The residue was combined with material from a previous reaction (5.4 g scale), and purified over silica gel, eluting with 10%-20%-50% ethyl acetate/hexanes to yield 20.0 g of an off-white solid as product. 1H NMR (400 MHz, DMSO) δ ppm 1.48 (s, 9 H) 7.26 (d, J=8.35 Hz, 2 H) 7.54 (d, J=8.79 Hz, 2 H) 9.56 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:21]=[CH:20][C:12]3[C:13]([CH3:19])([CH3:18])[CH:14]=[C:15]([CH3:17])[O:16][C:11]=3[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[OH-:25].[Na+]>C(OCC)(=O)C.O.CC(C)=O>[OH:25][C:15]1([CH3:17])[CH2:14][C:13]([CH3:19])([CH3:18])[C:12]2[CH:20]=[CH:21][C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=3)=[CH:10][C:11]=2[O:16]1
Reactant: [OH-]
Reactant: CC1=CC(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CC1(O)CC(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Yield: 70 %

Procedure:
A mixture of 6.5 g of the 7-(4-nitrophenoxy)-2,4,4-trimethyl-4H-1-benzopyran, 26 ml of water, 13 ml of conc. hydrochloric acid and 65 ml of acetone was refluxed for 2 hours. An 10% aqueous solution of sodium hydroxide was added to the reaction mixture to neutralize it, and then 100 ml of water and 200 ml of ethyl acetate were added, and the mixture was subjected to oil-water separation. The oil layer was washed with 50 ml of brine, dried over magnesium sulfate and concentrated. Toluene (5 ml) and 45 ml of hexane was added to the residue, and the precipitated crystals were collected by filtration, washed with 50 ml of hexane and dried to give 5.1 g (yield 70%) of a pale brown powder (mp. 159°-160° C., recrystallized from ethanol).
Reaction SMILES: C[Si]([CH:5]([Si](C)(C)C)[C:6]([NH2:8])=[O:7])(C)C.C([Li])CCC.[CH:18]([S:21]([N:24]1[C:28]2[CH:29]=[C:30]([C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[NH2:41])(=[O:23])=[O:22])([CH3:20])[CH3:19].C(C1NC2C=CC=CC=2N=1)(=O)C1C=CC=CC=1.Cl>O.O1CCCC1>[CH:18]([S:21]([N:24]1[C:28]2[CH:29]=[C:30]([C:33]([OH:40])([CH2:5][C:6]([NH2:8])=[O:7])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[NH2:41])(=[O:22])=[O:23])([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Agent: Cl
Agent: O=C(c1ccccc1)c1nc2ccccc2[nH]1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(O)(CC(N)=O)c3ccccc3)cc21
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A solution of 50 ml. of tetrahydrofuran containing 7.33 ml. of bistrimethylsilylacetamide (30 millimoles) and 18.75 ml. of a 1.6 Molar solution of n-butyl lithium (30 millimoles) was stirred at -78° C. for ten minutes. A solution of 1.03 g. (3 millimoles) of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole in 100 ml. of tetrahydrofuran was then added to the cold reaction mixture dropwise over one hour. The temperature of the reaction mixture was maintained at -78° C. throughout the addition, and the reaction mixture was stirred for four hours at -78° C. following complete addition of the benzoylbenzimidazole. The reaction mixture next was diluted with 75 ml. of water and 33 ml. of 1 N hydrochloric acid. The organic layer was separated and the aqueous acid layer was extracted several times with ethyl acetate. The organic layer and extracts were combined, washed with fresh water and dried. Removal of the solvent by evaporation under reduced pressure afforded a white solid product. Purification of the product by chromatography over silica gel afforded 1-isopropylsulfonyl-2-amino-6-(α-hydroxy-α-aminocarbonylmethylbenzyl)benzimidazole.