Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]2[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]3[C:20]4[C:25]([CH:26]=[CH:27][C:12]2=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:8]=[CH:9][CH:10]=1)=[NH:4].C1CCN2C(=NCCC2)CC1.[C:39](N1C=CN=C1)(N1C=CN=C1)=[S:40].Cl>C(#N)C>[S:40]=[C:39]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[C:7]([N:11]3[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]4[C:20]5[C:25]([CH:26]=[CH:27][C:12]3=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:8]=[CH:9][CH:10]=2)[NH:4]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: N=C(NO)c1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CC(=O)N(c2cccc(-c3noc(=S)[nH]3)c2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.6 %

Procedure:
To an ice-cold solution of 5-[3-(N-hydroxyamidino)phenyl]-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione (310 mg, 0.94 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (561 □L, 3.75 mmol) in acetonitrile (5.7 mL) was added dropwise, a solution of thiocarbonyldiimidazole (251 mg, 1.41 mmol) in acetonitrile (6 mL). The mixture was stirred at room temperature for 1.5 hours, to which was added 1M hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-0/1), to give the titled compound (161 mg, yield 41%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)[CH2:9]1)=O)(C)(C)C.Cl.CCOC(C)=O.C(Cl)[Cl:33].CO>CCOC(C)=O>[ClH:33].[CH:20]1[C:21]2[C:16](=[C:15]([NH:14][CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:18][N:19]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cccc3cnccc23)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: c1cc(NC2CCCNC2)c2ccncc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a solution of 3-(isoquinolin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (80 g, 0.244 mol) in EtOAc (1000 mL) was added HCl-EtOAc (1000 mL) at room temperature. The mixture was stirred at room temperature for 2.5 hours. TLC (DCM:MeOH=10:1) showed complete conversion. The solid was collected by filtration and dried under vacuum to give the title compound (66 g, 100%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][CH2:15][O:16][CH3:17].[I-].[K+]>C(O)C.O>[CH3:17][O:16][CH2:15][CH2:14][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCCOc1ccc(C(=O)O)cc1

Procedure:
4-Hydroxybenzoic acid (3.00 g, 2.17×10−2 mol) was dissolved in a mixture of ethanol (15 cm3) and potassium hydroxide (3.22 g, 5.64×10−2 mol) in water (5 cm3). The solution was then heated gently and stirred before 1-bromo-2-methoxyethane (3.32 g, 2.39×10−2mol) and potassium iodide (0.01 g, 6.02×10−5 mol) was added slowly. The resulting reaction mixture was then refluxed (15 hrs) and the solvent evaporated and the resulting solid residue dissolved in water (50 cm3). The solution was washed with ether and then made strongly acidic with hydrochloric acid. The resulting precipitate was isolated and recrystallised from ethanol. Yield 1.36 g (32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([CH:21]=O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10][CH2:11]1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1cccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)c1

Procedure:
124 mg of the target compound (0.35 mmol, 42.7%) was obtained using 1-(3-methoxyphenyl)piperazine (315 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[NH2:24].NC1C=C(C=CC=1N)C(N)=O>>[O:6]([C:7]1[CH:14]=[CH:13][C:10]([C:11]2[NH:24][C:23]3[CH:22]=[CH:21][C:20]([S:25]([NH2:28])(=[O:26])=[O:27])=[CH:19][C:18]=3[N:17]=2)=[CH:9][CH:8]=1)[C:5]1[CH:15]=[CH:16][CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1N
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Agent: NC(=O)c1ccc(N)c(N)c1
Product: NS(=O)(=O)c1ccc2[nH]c(-c3ccc(Oc4ccccc4)cc3)nc2c1

Procedure:
This compound was prepared according to the methods described in Example 22 and Scheme 3, substituting 4-phenoxybenzaldehyde for 4-(4-fluoro-phenoxy)-benzaldehyde, and 3,4-diaminobenzene sulfonamide for 3,4-diaminobenzoic acid amide.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][C:70]([CH3:73])=[CH:69][N:68]=2)[C:56]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.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:38]1([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[CH:71][C:70]([CH3:73])=[CH:69][N:68]=4)[C:56]=3[CH3:74])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:39][CH2:40][O:35][CH2:36][CH2:37]1
Reactant: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)nc1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)nc1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.025 g, 0.053 mmol), 2,5-dimorpholinopyridin-3-amine (0.104 g, 0.39 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(5-methylpyridin-2-yl)quinoline (0.10 g, 0.33 mmol) and Pd2dba3 (0.012 g, 0.013 mmol) in toluene (3.28 mL) was added sodium t-butoxide (0.079 g, 0.820 mmol). The reaction mixture was heated to 120° C. and stirring continued for 7 h. The reaction was then cooled to rt and diluted with water (15 mL). The mixture was extracted with EtOAc (2×15 mL) and DCM (1×15 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-di(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(5-methyl-2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (1H, d, J=4.9 Hz), 7.70 (2H, m), 7.63 (2H, m), 7.22 (1H, br. s.), 7.02 (1H, m), 6.46 (1H, br. s.), 3.92 (4H, br. s.), 3.78-3.87 (4H, m), 3.22 (4H, m), 3.09 (4H, m), 2.50 (3H, s), 2.20 (3H, s). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([N:12]([C:20]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](=[O:37])[NH:29][O:30]C4CCCCO4)=[CH:22][N:21]=3)C(=O)OC(C)(C)C)[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[ClH:40]>CO>[ClH:40].[ClH:40].[CH:1]1([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:20]3[N:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([NH:29][OH:30])=[O:37])=[CH:24][CH:25]=3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(CC2CCCC2)C1
Agent: Cl
Solvent: CO
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(CC3CCCC3)C2)nc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of tert-butyl [(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate (179 mg, 0.35 mmol) in MeOH (1 mL) was added hydrogen chloride methanol reagent 10 (3 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 1 hr. The solvent was removed in vacuo and the residue was dissolved in dioxane (1 mL). To the reaction mixture was added 4N HCl in dioxane (4 mL) and stirred for 1 hr at ambient temperature. To the reaction mixture was added MeCN and the solvent was removed in vacuo. Obtained colorless solid was triturated with MeCN to give (2E)-3-(6-{[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide dihydrochloride (115 mg, 85%) as colorless powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:37](Cl)(Cl)=[O:38]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:26][C:37](=[O:38])[NH:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4n[nH]c(=O)o4)cc32)cc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.040 g, 0.0771 mmol) in DCM (0.2 mL) at −78° C. was added phosgene (0.081 mL of a ˜20% solution in toluene) dropwise. After stirring at −20° C. overnight, the reaction was quenched with saturated aqueous NaHCO3, and the product was extracted with EtOAc and DCM. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified via SiO2 column chromatography, eluting with mixtures of EtOAc and hexane, to afford the title compound. LC/MS: m/e 546.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.96 (1H, d, J=6.4 Hz), 7.62 (11-1, d, J=8.4 Hz), 7.54 (1H, d, J=7.8 Hz), 7.29 (1H, d, J=5.5 Hz), 7.03-7.04 (3H, m), 6.86-6.89 (3H, m), 4.50-4.90 (2H, br), 1.14 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](Cl)=[O:8].[CH2:13]([NH2:15])[CH3:14]>C1C=CC=CC=1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([NH:15][CH2:13][CH3:14])=[O:8]
Reactant: CCN
Reactant: O=C(Cl)/C=C/c1cccc(Cl)c1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCNC(=O)/C=C/c1cccc(Cl)c1

Procedure:
Trans 3-chlorocinnamoyl chloride (4.4 g) in dry benzene (75 ml) was allowed to react with an excess of ethylamine in dry ether (75 ml) according to the procedure of Example 2. Trans 3-chloro-N-ethylcinnamamide, m.p. 87°-88° C., was obtained which had NMR, IR, and elemental analysis consistent with this structure.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH3:20])=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:17]([CH3:29])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[C:17]([CH3:29])=[N:16][N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:19]=2[CH3:20])=[CH:26][CH:25]=1
Reactant: COc1ccc(-c2c(C)nn(-c3ccc(OCc4ccccc4)cc3)c2C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2c(C)nn(-c3ccc(O)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of 1-(4-benzyloxyphenyl)-4-(4-methoxyphenyl)-3,5-dimethyl-1H-pyrazole (57 mg, 0.15 mmol) in methanol (2 mL) and tetrahydrofuran (3 mL) was flushed with nitrogen. A catalytic amount of palladium on carbon (10% wet) was added, and the reaction was again flushed with nitrogen followed by hydrogen. After the reaction was allowed to stir at room temperature for 1 hour, it was filtered through a pad of Celite and concentrated to give 37 mg of the desired phenol. LC-MS (C18H18N2O2 calculated 294) m/z 295 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:22]1([CH3:26])[CH:23]=[CH:24][CH:25]=[C:20]([C:19]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[CH:17][N:18]=2)[CH:21]=1
Reactant: Cc1cccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(-c2nccnc2N2CCNCC2)c1
Reaction time: 2 h

Procedure:
Dissolve 3′-m-tolyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (3.3 g, 9.32 mmol) in DCM (10 mL). Add cold (from refrigerator) trifluoroacetic acid (42.6 g, 28.8 mL). Stir for 2 hr. at room temperature. Partition reaction mixture between methylene chloride and 5N NaOH (pH aqueous=14). Separate layers. Extract aqueous layer with methylene chloride (2×20 mL). Combine organic layers, dry over anh. sodium sulfate, filter and concentrate to give the title preparation (2.35 g, 99%). MS (ES): m/z=255 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[CH3:12][C:11]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:13]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 89.4 %

Procedure:
To 10 g (72 mmol) of 3-nitroaniline, 10 ml (106 mmol) of acetic anhydride were added, followed by stirring. White crystals were precipitated with exotherm. After stirring for 10 minutes, ice water was poured into the reaction mixture. The crystals were dissolved in chloroform, followed by washing successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was distilled out under reduced pressure. The residue was washed with ethyl ether, whereby 11.6 g of white powder were obtained (yield: 89%).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6](=[O:28])[C:7](=[O:27])[CH:8]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.[OH-].[Li+]>O1CCOCC1.O>[O:28]=[C:6]([C:7](=[O:27])[CH:8]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)CC(=O)C(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC(=O)C(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 3,4-dioxo-5-[((phenylmethoxy)carbonyl)amino]-6-phenylhexanoic acid ethyl ester (400 mg, 1.0 mmol) in dioxane/H2O (10:1), lithium hydroxide (72 mg, 3.0 mmol) is added. The mixture is stirred for 3 h, the solvents are removed in vacuo and the crude product is used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:38])[CH:34]=[C:35]([Br:37])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.CC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:38][C:33]2[CH:32]=[C:31]([Br:30])[CH:36]=[C:35]([Br:37])[CH:34]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: Oc1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(Br)c2)c1CCC(=O)OCC
Temperature: 25 °C
Yield: 99 %

Procedure:
To a mixture of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (14.54 g, 30.84 mmol), 3,5-dibromophenol (8.55 g, 33.92 mmol), and potassium carbonate (8.53 g, 61.68 mmol) were added N,N-dimethylformamide (210 mL) and acetone (420 mL) at room temperature. The resulting suspension was heated to reflux for 2 days. Then, the reaction mixture was cooled to room temperature and diluted with water (200 mL). The organic compound was extracted into ethyl acetate (2×200 mL) and the combined organic extracts were washed with brine solution (200 mL). The organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the crude product which was purified by using a Biotage column chromatography (FLASH 40L, Silica), eluting with 10% ethyl acetate/hexanes to obtain 4-{3-[6-(3,5-dibromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (19.61 g, 99%) as a colorless oil: ES(+)-HRMS m/e calculated for C29H38O6Br2 (M+H)+ 641.1108, found 641.1101.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([CH3:18])=[N:9][C:8]=1[C:19]([O:21]C)=[O:20].O.[OH-].[Li+]>CO.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]([CH3:18])=[N:9][C:8]=1[C:19]([OH:21])=[O:20]
Reactant: COCCCCc1c(C(=O)OC)nc(C)n1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCCCc1c(C(=O)O)nc(C)n1-c1ccccc1
Temperature: 25 °C
Yield: 29.4 %

Procedure:
Methyl 5-(4-methoxybutyl)-2-methyl-1-phenyl-1H-imidazole-4-carboxylate (3.85 g) was dissolved in methanol (26 ml)-water (24 ml), lithium hydroxide monohydrate (800 mg) was added and the mixture was heated under reflux for 2 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH=7 with 1M hydrochloric acid, subjected to DIAION HP-20 (manufactured by Mitsubishi Chemical), washed with water and a fraction eluted with acetone was concentrated under reduced pressure to give the object product (1.08 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.[Li+].[OH-]>CC(O)C.C(Cl)Cl.O>[CH3:27][S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:17])(=[O:25])=[O:26]
Reactant: CCOC(=O)C1(NC(=O)c2ccccc2S(C)(=O)=O)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 69 h
Yield: 100.8 %

Procedure:
A 50 mL flask containing 2-[(2-methylsulfonylbenzene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (186, 0.50 g, 1.27 mmol) is charged with 1,4-dioxane (5 mL) and MeOH (5 mL). A stirring bar is added and stirring is initiated. After dissolution, water (2.5 mL) is added followed by the LiOH (133 mg, 3.17 mmol). After 69 h, tlc analysis (silica, 5% i-PrOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜12 mL). The contents of the flask are poured into a separatory funnel containing EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated. Pumping to constant weight gives 0.46 g of white solid.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][C:16]([C:26]([F:29])([F:28])[F:27])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[O:19]([C:18]1[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=[C:16]([C:26]([F:29])([F:27])[F:28])[CH:17]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(NC(=S)Nc1ncc(C(F)(F)F)cc1Oc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=S)Nc1ncc(C(F)(F)F)cc1Oc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
1-Benzoyl-3-(3-phenoxy-5-(trifluoromethyl)pyridin-2-yl)thiourea (0.230 g, 0.551 mmol) was dissolved in methanol (7 mL) and a 1M solution of sodium hydroxide (3.00 mL, 3.00 mmol) was added. The resulting mixture was heated to 50° C. and agitated for one hour. Methanol was then evaporated and the resulting slurry was filtered and solids were washed with water and dried to give 1-(3-phenoxy-5-(trifluoromethyl)pyridin-2-yl)thiourea (0.147 g, 85.2% yield) as white solid.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.O>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[F:17][C:14]([F:15])([F:16])[C:4]1([OH:3])[CH2:5][CH2:6][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:12][CH2:13]1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)CCC2(CC1)OCCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(C(F)(F)F)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 0° C., 12.20 g (40.89 mmol) of trimethyl {[8-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-8-yl]oxy}silane (Example 5A) were dissolved in 164 ml of 1 molar tetrabutylammonium fluoride solution in tetrahydrofuran, and the mixture was stirred at room temperature for 3 hours. For work-up, about 600 ml of water were added to the reaction, and the target molecule was extracted with dichloromethane. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. Drying gave 9.33 g (100% of theory) of the title compound as a brownish oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]2[NH:15][C:14](=[O:18])[C:13]3[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C>O1CCCC1>[CH2:10]1[CH2:9][NH:8][CH2:17][C:16]2[NH:15][C:14](=[O:18])[C:13]3[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=3[C:11]1=2
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c(=O)c3ccccc23)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]c2c(c3ccccc13)CCNC2
Temperature: 60 °C
Yield: 117.3 %

Procedure:
6-Oxo-1,4,5,6-tetrahydrobenzo[c]-1,7-naphthyridine-3(2H)-carboxylic acid tert-butyl ester (1.13 g) was added to tetrahydrofuran (30 ml) and dissolved by stirring the mixture at 60° C. 4N Hydrochloric acid-ethyl acetate (20 ml) was added, and the mixture was stirred with heating at 60° C. for 1 hr. The reaction mixture was ice-cooled, and the precipitated solid was collected by filtration, washed with ethyl acetate and dried to give 1,3,4,5-tetrahydrobenzo[c]-1,7-naphthyridin-6(2H)-one (884 mg, yield 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=O)[N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:7]=[N:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[S:33])[N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:7]=[N:8]2
Reactant: COc1ccc(-n2cnc3cc(OC)cc(OC)c3c2=O)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-n2cnc3cc(OC)cc(OC)c3c2=S)cc1
Yield: 72.1 %

Procedure:
The mixture of 5,7-dimethoxy-3-(4-methoxyphenyl)-quinazoline-4-one (240 mg, 0.76 mmol), as prepared in Example 18 or 19, and Lawesson's reagent (310 mg, 0.76 mmol) in toluene (4 mL) was refluxed overnight. The mixture was evaporated to dryness. EtOAc was added and the mixture was washed with water, brine and dried over MgSO4. Evaporation gave a crude solid. Purification was performed by flash chromatography on silica gel, loaded with dichloromethane and eluted with 45% ethyl acetate in hexane. The pure fraction was combined and evaporated to give a yellow foam (180 mg, 72%).