Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:22]1([CH2:28][CH2:29][CH2:30]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][CH2:29][CH2:30][O:20][C:19](=[O:21])[CH2:18][NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCCc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)OCCCc1ccccc1

Procedure:
Following General Procedure X and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester (from Example 73 below) using General Procedure O) and and 3-phenyl-1 -propanol (Aldrich), the title compound was prepared as a solid (mp=137° C.). The reaction was monitored by tlc (Rf=0.15 in 50% EtOAc/hexanes) and the product was purified by flash chromotography using 50% EtOAc/hexanes as the eluent.
Reaction SMILES: [F:1][C:2]1[S:43][C:5]2[C:6](=[O:42])[N:7](COCC[Si](C)(C)C)[C:8]3[C:9]([CH3:33])=[CH:10][C:11]([O:31][CH3:32])=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C@@H:20]([CH3:30])[CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:16][CH:15]=4)[C:13]=3[C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>>[NH2:22][CH2:21][C@@H:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:13]3[C:4]4[CH:3]=[C:2]([F:1])[S:43][C:5]=4[C:6](=[O:42])[NH:7][C:8]=3[C:9]([CH3:33])=[CH:10][C:11]=2[O:31][CH3:32])=[CH:15][CH:16]=1)[CH3:30]
Reactant: COc1cc(C)c2c(c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1)c1cc(F)sc1c(=O)n2COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c2[nH]c(=O)c3sc(F)cc3c2c1-c1ccc([C@@H](C)CN)cc1
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a solution (R)-tert-butyl 2-(4-(2-fluoro-8-methoxy-6-methyl-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (17 mg, 0.027 mmol) in CH2C2 (1 mL) at rt was added trifluoroacetic acid (1.0 mL) and the reaction was stirred at that temperature for 2 h. The mixture was concentrated and the residue was dissolved methanol (2 mL) and treated with NH4OH (2 mL). The resulting mixture was stirred at rt for 2 h and purified by preparatory HPLC (C18 silica, acetonitrile/water (with 0.05% TFA) gradient). The desired fractions were combined, concentrated and the residue was dissolved in aqueous HCl, concentrated and dried under high vacuum to afford the desired product (5 mg, 43%) as a hydrochloride salt: 1H NMR (500 MHz, CD3OD) δ 7.52 (dd, J=7.8, 1.5 Hz, 1H), 7.47 (dd, J=7.7, 1.5 Hz, 1H), 7.32 (s, 1H), 7.31-7.22 (m, 2H), 5.30 (d, J=2.7 Hz, 1H), 3.29-3.18 (m, 3H), 2.63 (s, 3H), 1.47 (d, J=6.1 Hz, 3H): ESI MS m/z 397 [C22H21FN2O2S+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[O:23])[C@H:19]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:20](=[O:23])[C@H:19]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:18][CH2:17]1
Reactant: Brc1ccncc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(c2ccncc2)C1=O
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
4-Bromopyridine (286 mg, 1.47 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (200 mg, 0.588 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.035 mmol), tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.024 mmol), and cesium carbonate (268 mg, 0.823 mmol) in dioxane (6 mL) and the mixture was heated at 150° C. in a Personal Chemistry Smith Creator™ microwave reactor. After 30 min, an additional amount of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.035 mmol) and tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.024 mmol) were added. After 30 min, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (55 mg). MS 418.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[O:9])=[CH:4][CH:3]=1.O.[NH2:22][NH2:23].N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH:22][NH2:23])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Cl)cc1
Reactant: NN
Agent: N
Solvent: O
Product: NNc1ccc(NC(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Dissolving 20 (6.5 g, 22 mmol) in hot alcohol (150 mL) and adding slowly a mixture of 100% hydrazine hydrate (1.6 mL), concentrated aqueous ammonia (1.7 mL) and alcohol (5 mL). The mixture was stirred at 75° C. for 2 h. The reaction mixture was filtered to give 21 (5.68 g, 84% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH3:9])[CH2:4][CH2:3]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]([CH3:9])[S:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[C:12]([N+:21]([O-:23])=[O:22])[CH:13]=2)(=[O:18])=[O:19])[CH2:4][CH2:3]1
Reactant: CNC1CCN(C)CC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: c1ccncc1
Product: CN1CCC(N(C)S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reaction time: 2 h

Procedure:
To a solution of 2.2 ml (15 mMol) of 1-methyl-4-methylamino-piperidine in 60 ml pyridine, 3.8 g (15 mMol) of 4-chloro-3-nitro-benzenesulphonic acid chloride were added, in batches, whilst cooling with ice. The mixture was then stirred for two hours with cooling, then evaporated to dryness, the residue was mixed with about 50 ml of water and made alkaline with concentrated ammonia whilst stirring vigorously. The crude product precipitated was suction filtered and purified by column chromatography (250 g silica gel, eluant: dichloromethane with 1.5% ethanol). Yield: 1.6 g (31% of theory), C13H18ClN3O4S (347.8) Rf value: 0.19 (silica gel; dichloromethane/ethanol=19:1)
Reaction SMILES: [N+:1]([C:4]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=1N)([O-:3])=[O:2].N([O-])=O.[Na+].[BrH:18]>C(O)(=O)C.S(=O)(=O)(O)O.O.[Cu](Br)Br>[Br:18][C:5]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: Br
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cccc(Br)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 2,3-dinitroaniline (2.27 g, 12.4 mmol) in 35 mL of glacial acetic acid was added dropwise to a stirred and cooled solution of sodium nitrite (0.95 g, 13.8 mmol) in concentrated sulfuric acid (7 mL) while the temperature of the reaction was held at 15-20° C. The resulting diazonium solution was then added over a five minute period to a stirred solution of copper bromide (1.85 g, 12.9 mmol) in a mixture of HBr (48%) (10 mL) and water (10 mL) heated at 75° C.-80° C. After the addition, the mixture was cooled to room temperature and added to water (500 mL). The light-green powder was filtered from the solution and dried in vacuum at room temperature to give the desired product 1-bromo-2,3-dinitrobenzene (3.0 g, 99%). This product was used in subsequent reaction without further purification. See, Donald L. Vivian J. Org. Chem. 1956, 21, 1188.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:9]1[N:8]=[C:7]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:6]2[C:11](=[C:2]([C:23]3[CH:22]=[N:21][C:20]([F:19])=[CH:25][CH:24]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Clc1nc(N2CCOCC2)c2cccc(Br)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cccc3c(N4CCOCC4)nc(Cl)nc23)cn1
Temperature: 95 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a 50 mL round bottom flask, 8-bromo-2-chloro-4-morpholin-4-yl-quinazoline (150 mg, 0.00046 mol), 2-fluoropyridine-5-boronic acid (58 mg, 0.00041 mol), sodium carbonate (72 mg, 0.00068 mol), DMF (10 mL) and water (3 mL) were added and the reaction vessel was degassed with nitrogen for 5-10 min. To the same reaction mixture, PdCl2(PPh3)2 (16 mg, 0.000023 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 60% ethyl acetate in hexane) to yield the desired product [90 mg, 60%]. 1H NMR (300 MHz, CDCl3): δ 8.44 (s, 1H), 8.17-8.24 (m, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.75 (dd, J′=2.7, J″=3.0 Hz, 1H), 3.89 (s, 8H). LC-MS (ESI): Calculated mass: 344.1; Observed mass: 345.0 [M+H]+ (RT: 1.63 min).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][N:15]1[C:19]([Cl:20])=[C:18]([C:21](Cl)=[O:22])[C:17]([Cl:24])=[N:16]1.CC(C)([O-])C.[K+].Cl>C1COCC1.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11](=[C:21]([C:18]2[C:17]([Cl:24])=[N:16][N:15]([CH3:14])[C:19]=2[Cl:20])[OH:22])[C:12]#[N:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(Cl)c(C(O)=C(C#N)c2ccc(C(C)(C)C)cc2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
1.00 g of 4-tert-butylphenylacetonitrile and 1.23 g of 1-methyl-3,5-dichloropyrazole-4-carbonyl chloride were dissolved in 20 ml of THF, and 1.01 g of potassium t-butoxide was added thereto with cooling with ice. After the resulting mixture was stirred overnight at room temperature, water was added thereto, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was dissolved in a mixed solvent of 10 ml of water and 10 ml of dioxane, and 0.38 g of potassium hydroxide was added thereto and heated under reflux for 4 hours. After having been left to be at room temperature, this was acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain 0.64 g of 2-(4-tert-butylphenyl)-3-(1-methyl-3,5-dichloropyrazol-4-yl)-3-hydroxyacrylonitrile from the fraction eluted with n-hexane:ethyl acetate=2:1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:20])[CH:11]=1.[OH:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:24][CH:23]=1.O>CN(C)C=O>[CH3:20][C:12]1[CH:11]=[C:10]([CH2:9][O:21][C:22]2[CH:37]=[CH:36][C:25]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[CH:24][CH:23]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(COc2ccc(C(=O)OCc3ccccc3)cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 42.9 %

Procedure:
3.6 g (26.3 mmol) of potassium carbonate, 5 g (21.9 mmol) of 4-chloromethyl-2-methylquinoline hydrochloride and 5.2 g (23 mmol) of benzyl 4-hydroxybenzoate are put into solution in 30 ml of dimethylformamide. The reaction medium is heated at 60° C. for 18 h then water is added. After extracting with ethyl acetate, the organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product is purified by chromatography over silica gel eluted with a 70/30 heptane/ethyl acetate mixture. 3.6 g (43%) of benzyl 4-(2-methylquinolin-4-ylmethoxy)benzoate are obtained in the form of a light-yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[O:23])[CH2:4][CH2:3]1.CN(C1C=CC=CN=1)C.[CH3:34][Si:35]([CH:38](O)[CH3:39])([CH3:37])[CH3:36].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:39][CH2:38][Si:35]([CH3:37])([CH3:36])[CH3:34])=[O:19])=[CH:21][CH:22]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[O:23])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Reactant: CC(O)[Si](C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)OCC[Si](C)(C)C)cc3)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 0.24 g (0.73 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7) in 10 ml of dry CH2Cl2 was added 0.09 g (0.74 mmol) of dimethylaminopyridine, 0.115 ml (0.80 mmol) of trimethylsilylethanol and 0.17 g (0.88 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride. The reaction mixture was stirred at 25° C. for 5 hours, washed with sat. aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo to an oil. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O[C:10](=O)[O:11][C:12]1[C:21]2[C:22](=[O:37])[N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=3[O:35][CH3:36])[C:24](=[O:25])[C:20]=2[C:19]([O:38][CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2)C.O.IC>O1CCCC1.C(OCC)(=O)C>[CH:39]([O:38][C:19]1[C:20]2[C:24](=[O:25])[N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=3[O:35][CH3:36])[C:22](=[O:37])[C:21]=2[C:12]([O:11][CH3:10])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)Oc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(OC)cc1OC)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc4c3OC)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Potassium carbonate (2.6 g, 19.0 mmol) and N,N-dimethyl-aminopyridine (DMAP, 0.464 g, 3.8 mmol) were added to carbonic acid 9-benzhydryloxy-7-(2,4-dimethoxy-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester ethyl ester 301 (1.2 g, 1.9 mmol) dissolved in tetrahydrofuran (40 ml) and water (20 ml) was added. After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo and diluted with ethyl acetate. It was washed twice with 5% citric Acid (aqueous), twice with water, once with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was dissolved in dimethylformamide (10 ml). To this reaction mixture was added potassium carbonate (1.24 g, 9.0 mmol) and iodomethane (methyl iodide, MeI, 2.55 g, 18.0 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate, washed twice with 5% citric acid, twice with water, once with brine, and concentrated in vacuo to afford 9-benzhydryloxy-7-(2,4-dimethoxy-benzyl)-5-methoxy-pyrrolo[3,4-g]quinoline-6,8-dione 302 (1.1 g, 1.9 mmol, 100%). 1H NMR (d-DMSO) δ 9.16 (dd, 1H), 8.60 (dd, 1H), 7.82 (s, 1H), 7.75 (m, 1H), 7.54 (d, 4H), 7.16 (m, 6H), 6.82 (d, 1H), 6.56 (d, 1H), 6.44 (dd, 1H), 4.66 (s, 2H), 4.10 (s, 3H), 3.76 (s, 3H), 3.70 (s, 3H). MS: 583.2 (M+23).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH:11]=[CH:10]1.[CH3:29][NH2:30]>>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:30][CH3:29])[C:12]=2[CH:11]=[CH:10]1
Reactant: CN
Reactant: Cc1cc(F)ccc1-n1ccc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Product: CNc1nc2c(OCC(F)(F)F)cccc2c2c1ccn2-c1ccc(F)cc1C
Temperature: 180 °C

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-β,β,β-trifluoroethoxypyrrolo[3,2-c]quinoline(970 mg, 2.4 mmol) was dissolved in aqueous solution of methylamine(40%, 10 ml) in the pressure tube, and the resultant was refluxed at 180° C. for 3 hours. After removing the solvent by distillation under reduced pressure, the residue was diluted in dichloromethane(20 ml), and washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 810 mg of desired compound as solid in 85% of yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][CH:9]=[C:8]([C:11](=O)[CH2:12]Br)[CH:7]=1)=[O:5])C.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:8]3[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[S:10][CH:9]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOC(=O)c1cc(C(=O)CBr)cs1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3csc(C(=O)O)c3)cs2)cc1OCC

Procedure:
5-Ethoxycarbonyl-3-(α-bromoacetyl)thiophene and 3,4-diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(5-carboxy-3-thienyl)thiazole.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[F:12])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[F:12][C:6]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15]
Reactant: O=C(CBr)c1cccc(F)c1F
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1cccc(F)c1F
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A solution of 2-bromo-1-(2,3-difluorophenyl)ethanone (7.20 g, 30.6 mmol) and potassium thiocyanate (3.01 g, 30.6 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (85 ml) was poured to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 5.67 g (86.8%) of the desired product as an oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[CH3:17][CH:18]([CH3:22])[CH2:19][CH:20]=[O:21].Cl>C(OCC)C.O1CCCC1>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH:20]([OH:21])[CH2:19][CH:18]([CH3:22])[CH3:17])[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)CC=O
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)CC(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
Sodium hydride, as a 60% mineral oil dispersion, (6.8 g, 169 mmol) was introduced into a dry round bottomed flask, and dry tetrahydrofuran (220 ml) was added thereto. The flask was stoppered with a serum cap, cooled in ice and flushed with nitrogen. Ethyl acetoacetate (20 g, 154 mmol) was added dropwise to the cooled and stirred slurry and the reaction was stirred for 10 minutes after the addition was complete. The solution was cooled at −78° C. and a solution of n-butyl lithium (85 ml of 2M solution in cyclohexane) was added dropwise to the reaction mixture and stirring was continued for a further 10 minutes. 3-Methylbutyraldehyde (154 mmol) was then added in one portion. After a further 10 minutes the reaction was poured in a HCl solution (50 ml of 37% HCl in 400 of water). Diethyl ether was added; the aqueous layer was removed and extracted again with 2×40 ml of diethyl ether. The ethereal extracts were combined, washed with a saturated brine solution, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The oily residue was purified by flash chromatography using hexane:ethyl acetate=8:2 as eluent obtaining 16.6 g of 5-hydroxy-7-methyl-3-oxo-octanoic acid ethyl ester. Yield 50%.
Reaction SMILES: [N:1]([C@H:4]1[C:7](=[O:8])[NH:6][C@H:5]1[C:9]([O:11][CH3:12])=[O:10])=[N+]=[N-].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.[Pd]>[NH2:1][C@H:4]1[C:7](=[O:8])[NH:6][C@H:5]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)[C@@H]1NC(=O)[C@@H]1N=[N+]=[N-]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: COC(=O)[C@@H]1NC(=O)[C@@H]1N

Procedure:
A solution of methyl cis-3-azido-4-oxoazetidine-2-carboxylate (8.5 g, 50 mmol) and an equivalent of p-toluenesulfonic acid in 200 ml of ethanol is hydrogenated for 3 hours over 1 g of 10% Pd on carbon at 40 psi. The solution is filtered and the filtrate is evaporated to title product or the tosylate salt which can be converted to the free base by standard methods.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(=O)O)cc1OCc1ccccc1
Yield: 85.7 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(3-benzyloxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (0.55 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 1 hr. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the precipitated crystals were collected by filtration to give 1-benzyl-3-[(3-benzyloxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylic acid as crystals (0.45 g, yield 85%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 184-185° C.