Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:21][C:20]=2[O:34][CH3:35])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O.CO.C(#N)C>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[O:1])=[CH:21][C:20]=2[O:34][CH3:35])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1cc(Sc2ccccc2C#N)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: COc1cc(S(=O)c2ccccc2C#N)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of OXONE™ (0.470 g, 0.7636 mmol) in water (5 mL) was added to a solution of 3-[4-(2-cyano-phenylsulfanyl)-2-methoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.209 g, 0.5091 mmol) in a mixture of MeOH (5 mL) and acetonitrile (5 mL). The reaction mixture was stirred at room temperature for 3 hours, then water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (hexane/EtOAc, 7/3) to give 0.215 g of 3-[4-(2-cyano-benzenesulfinyl)-2-methoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (not shown in Scheme O) as a clear oil.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:50]1[C:55](=[O:56])[N:54]([CH3:57])[CH:53]=[C:52]2[CH2:58][N:59]([CH2:62][CH2:63][C:64]3[N:72]=[C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][N:66]4[N:65]=3)[C:60](=[O:61])[C:51]=12.[NH:73]1[CH2:78][CH2:77][O:76][CH2:75][CH2:74]1>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:57][N:54]1[C:55](=[O:56])[C:50]([N:73]2[CH2:78][CH2:77][O:76][CH2:75][CH2:74]2)=[C:51]2[C:60](=[O:61])[N:59]([CH2:62][CH2:63][C:64]3[N:72]=[C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][N:66]4[N:65]=3)[CH2:58][C:52]2=[CH:53]1
Reactant: C1COCCN1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1nc3ccccn3n1)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1nc3ccccn3n1)C2
Temperature: 120 °C
Yield: 14.8 %

Procedure:
Palladium diacetate (65.3 mg, 0.291 mmol), Xantphos (168 mg, 0.291 mmol) and Cs2CO3 (284 mg, 0.873 mmol) were each rapidly added in sequence to a suspension of 7-chloro-5-methyl-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (100 mg, 0.291 mmol, see Example c6)) and morpholine (25.3 mg, 0.291 mmol) in dioxane (5 ml). The reaction mixture was heated in a microwave at about 120° C. for about 40 min. The solvent was removed and the resulting mixture was purified by preparative HPLC (system: Waters 2767 PHW003, eluent: MeCN/ammonium acetate buffer (gradient: 7:93 to 30:70 over 15 min), column: Boston Analytics, C-18, 10 μm, 10×250 mm) to afford the title compound (17 mg, 0.043 mmol, 14.82% yield).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:10]([CH3:12])([CH3:11])[O:9][C:8]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:7]=2[C@H:6]1[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][Si](C(C)(C)C)(C)C)=[CH:21][C:20]1=[O:34])(=[O:3])[CH3:2].Cl>CO.O1CCOCC1>[C:1]([O:4][C@@H:5]1[C:10]([CH3:12])([CH3:11])[O:9][C:8]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:7]=2[C@H:6]1[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][C:20]1=[O:34])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)c2cc(C#N)ccc2OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)O[C@H]1[C@H](n2ccc(CO)cc2=O)c2cc(C#N)ccc2OC1(C)C
Yield: 95.8 %

Procedure:
In 15.0 ml of methanol, is dissolved 1.45 g of trans-3-acetoxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxy-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 4. Then, 3.00 ml of 4N hydrochloric acid in dioxane is added thereto at 0° C. and reacted at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is mixed with water and ethyl acetate, and the product is extracted by ethyl acetate. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using ethyl acetate as a developing solvent to obtain 1.06 g of trans-3-acetoxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-hydroxymethyl-1-pyridinyl)-2H-benzo[b]pyran.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([C@@H:8]1[CH2:12][C@H:11]([C:13](=O)[CH3:14])[C@H:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[N:9]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:7].[C:37](O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OC)(C)(C)C>[CH3:3][CH2:4][O:5][C:6]([C@@H:8]1[CH2:12][C@H:11]([C:13]([CH3:37])=[CH2:14])[C@H:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[N:9]1[C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[O:7]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCOC(=O)[C@@H]1C[C@H](C(C)=O)[C@H](c2ccc(OC)c(OCCCOC)c2)N1C(=O)OC(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C=C(C)[C@H]1C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(OC)c(OCCCOC)c1
Temperature: 50 °C
Reaction time: 7 h

Procedure:
A suspension of 0.104 g (0.0026 mol) of a 60% suspension of sodium hydride in mineral oil in 20 mL of tetrahydrofuran is treated with 0.89 g (0.0025 mol) of methyltriphenylphosphonium bromide. The white suspension is heated to 50° C. and stirred for 7 hours at this temperature. The red suspension is cooled to 0° C. and a solution of (2S,4S,5R)-4-Acetyl-5-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (0.60 g, 0.00125 mol) dissolved in 5 mL of tetrahydrofuran is added. The mixture is stirred for 1.5 hours at 0° C. and diluted with 20 mL of tert-butylmethyl ether. A 10% aqueous solution of citric acid (25 mL) is added and the mixture extracted. The aqueous phase is re-extracted with a further 20 mL of tert-butyl methyl ether and the organic phases combined. The combined organic phases are washed with 20 mL of water containing 10 mL of saturated aqueous sodium hydrogen carbonate followed by 30 mL of water. The organic phase is dried and the solvent removed in vacuum at 30° C. to give the crude product as an oil. This oil is chromatographed over silica-gel, eluting with heptane/ethyl acetate (4/1) to give the desired product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C@H:14]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C@@H:17]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:16]([C@@H:34]([CH2:40][CH3:41])[C:35](OCC)=[O:36])[C:15]1=[O:42])[CH:12]=[CH2:13].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([C@H:14]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C@@H:17]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:16]([C@@H:34]([CH2:40][CH3:41])[CH:35]=[O:36])[C:15]1=[O:42])[CH:12]=[CH2:13]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OCC)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of oxalyl dichloride (166 μL, 1.87 mmol) in DCM (4.16 mL) at −60° C. was added a solution of DMSO (222 μL, 3.12 mmol) in DCM (4.16 mL) under N2. After about 20 min, a solution of 540 mg (1.25 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 9, Step B) in 4.2 mL of DCM was added, and the resulting solution was stirred for 15 min. Triethylamine (872 μL, 6.24 mmol) was then added. After being stirred at −60° C. for 5 min, the reaction was allowed to warm to rt, and 5 mL of water was added. The solution was extracted (2×DCM), washed (sat. aq. NaCl solution), dried (MgSO4) and concentrated under the reduced pressure to give the crude title compound containing 20% starting material (SM).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4([CH3:23])OCC[O:19]4)[CH:14]=3)[CH:9]=2)[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:19])[CH3:23])[CH:14]=3)[CH:9]=2)[CH:2]=1
Reactant: CC1(c2ccc3cc(Cc4cccnc4)ccc3c2)OCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)c1ccc2cc(Cc3cccnc3)ccc2c1
Reaction time: 3 h
Yield: 101.3 %

Procedure:
A solution of 150 mg of 2-(3-pyridylmethyl)-6-(2-methyl-1,3-dioxolan-2-yl)naphthalene in 15 ml of 1N hydrochloric acid was allowed to stand for 3 hours at room temperature. The solution was neutralized with sodium carbonate and extracted with methylene chloride. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure to give 130 mg of 2-(3-pyridylmethyl)-6-acetylnaphthalene as an oil.
Reaction SMILES: [F:1][C@H:2]1[C@@H:6]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[CH:24][C:25]([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)=[CH:26][C:21]4=[N:20][CH:19]=2)[CH:14]=[CH:13]3)[CH2:5][N:4](C(OCC2C=CC3C(=CC=CC=3)C=2)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:18]1[N:22]3[CH:23]=[CH:24][C:25]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:26][C:21]3=[N:20][CH:19]=1)[CH:14]=[CH:13]2
Reactant: O=C(OCc1ccc2ccccc2c1)N1C[C@@H](F)[C@@H](Oc2cccc3ccc(-c4cnc5cc(-c6cccnc6)ccn45)nc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: F[C@H]1CNC[C@H]1Oc1cccc2ccc(-c3cnc4cc(-c5cccnc5)ccn34)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
A solution of cis-naphthalen-2-ylmethyl 3-fluoro-4-(2-(7-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)pyrrolidine-1-carboxylate (2.0 mg, 0.003 mmol) in 1 ml DCM was cooled to 0° C. and 1 ml TFA was added. The mixture was stirred for 16 hours at ambient temperature and then concentrated. The residue was purified by preparative TLC, eluting with 15% MeOH/0.5% NE4OH in chloroform to give the title compound as a film (1.1 mg, 78% yield). MS APCI (+) m/z 426.2 (M+1) detected.
Reaction SMILES: [CH2:1]([CH2:8][NH:9][CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:21])[CH:17]=2)[C:12]1([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([CH2:8][NH:9][CH2:10][C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:21])[CH:17]=2)[C:12]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2ccccc2)c2ccc(F)cc2CCC1CNCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2c(c1)CCC(CNCCc1ccccc1)=C2c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
Trifluoroacetic acid (10 cm3) was added to 2-(N-benzylmethylamino)methyl-6-fluoro-1-phenyl-1,2,3,4-tetrahydronaphthalene-1-ol (1.5 g) and the resulting solution was stirred at room temperature for 2 h. The excess trifluoroacetic acid was removed under reduced pressure and the resultant brown oil was taken up into petroleum ether (b. p. 40-60° C.) and passed through a short column [basic alumina, eluting with petroleum ether (b. p. 40-60° C.)-ethyl acetate (20:1)]. The fractions containing the product were combined and the solvent removed under reduced pressure to afford the title compound (0.97 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:39])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[O:29][CH3:30])([C:20]#[N:21])[CH:18]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:17][CH:16]2[C:36]([OH:38])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:45][C@@H:44]([CH2:46][CH2:47][NH2:48])[CH2:43][O:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:45][C@H:44]([CH2:43][OH:42])[CH2:46][CH2:47][NH:48][C:36]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:39])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[O:29][CH3:30])([C:20]#[N:21])[CH:18]([CH2:31][C:32]([CH3:34])([CH3:33])[CH3:35])[NH:17]1)=[O:38]
Reactant: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)O)C1c1cccc(Cl)c1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)NCC[C@H](O)CO)C1c1cccc(Cl)c1F
Yield: 60.6 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 58c (0.4 g, 0.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.25 g, 1.7 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.6 g, 4.7 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.23 g, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:5]=[CH:6][CH:7]=O.[C:13]([CH2:15][C:16]([NH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])#[N:14]>>[CH2:22]([O:21][C:19](=[O:20])[NH:18][C:16](=[O:17])/[C:15](/[C:13]#[N:14])=[CH:7]/[CH:6]=[CH:5]/[C:4]1[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=1)[CH3:23]
Reactant: CCOC(=O)NC(=O)CC#N
Reactant: O=CC=Cc1ccc(O)c(O)c1
Product: CCOC(=O)NC(=O)/C(C#N)=C/C=C/c1ccc(O)c(O)c1

Procedure:
The compound was prepared as described in Example 3 by adding 3,4-dihydroxycinnamaldehyde (32 mg, 0.2 mmol) to N-cyanoacetylurethane (32 mg, 0.2 mmol). After refluxing for 1 h and recrystallization from ethanol-water an orange solid was obtained (54 mg, 90%). The product gave the following analytical data:
Reaction SMILES: C1N=CNC1=O.[CH2:7]([C:9]1[CH:10]=[N:11][C:12]([C:18]2[NH:19][C:20](=[O:27])[C:21]([CH:24]([CH3:26])[CH3:25])([CH3:23])[N:22]=2)=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])C.C(C1(CC(O)=O)C2C=CC=CC=2OCC1)(O)=O>>[CH:24]([C:21]1([CH3:23])[C:20](=[O:27])[NH:19][C:18]([C:12]2[N:11]=[CH:10][C:9]([CH3:7])=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=[N:22]1)([CH3:26])[CH3:25]
Reactant: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)O)c1
Agent: O=C(O)CC1(C(=O)O)CCOc2ccccc21
Agent: O=C1CN=CN1
Product: Cc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)O)c1

Procedure:
The composition according to claim 45 wherein the imidazolinone compound is 5-ethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid and the safener compound is selected from the group consisting of the diammonium salt of 4-carboxy-3,4-dihydro-2H-1-benzopyran-4-acetic acid and 4-carboxy-3,4-dihydro-2H-1-benzopyran-4-acetic acid.
Reaction SMILES: C[N:2]([C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)=[CH:10][C:9]=1[CH3:31])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].Cl>CO.O>[Cl:30][C:25]1[CH:24]=[C:23]([C:17]2([C:19]([F:21])([F:20])[F:22])[O:16][N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:2][CH2:3][C:4]([OH:6])=[O:5])=[O:32])=[C:9]([CH3:31])[CH:10]=3)[CH2:18]2)[CH:28]=[C:27]([Cl:29])[CH:26]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)CC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
In a solution of 2.6 g of methyl N-[4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylbenzoyl]glycine (Compound of the present invention No. 5-128) synthesized similarly to Synthetic Example 5 in 10 ml of methanol, a solution of 1.0 g of potassium hydroxide in 10 ml of water was added with stirring at room temperature, and stirred at the same temperature for further 1 hour. After the completion of the reaction, 10 ml of 12N hydrochloric acid was added and extracted with ethyl acetate (50 ml×1), the organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2.4 g of the aimed product as pale yellow resinous resinous substance.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CCC>[Cu].CO.O>[C:20]([CH2:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:2]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:14][CH:15]=1)([OH:22])=[O:21]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(Nc2ccc(Cl)cc2C(=O)O)cc1
Temperature: 10 °C
Yield: 35 %

Procedure:
To a 100 ml round bottomed flask was added 2,5-dichlorobenzoic acid (1.9 g, 10 mmol), 4-aminophenylacetic acid (1.5 g, 10 mmol), anhydrous sodium carbonate (3.2 g, 26 mmol), activated copper metal powder (0.25 g, 4 mmol) and 1-butanol (50 ml). The flask was fitted with a magnetic stirrer bar, water condenser, silica gel guard tube and heated under reflux for 48 hours. TLC (RPC18, Water, 20: methanol, 80) showed the formation of a slower moving component at Rf 0.55. The solvent was removed under reduced pressure with final drying under high vacuum. The residue was dissolved in 50 ml water and heated to boiling, then charcoal was added and the mixture filtered through celite, washing through with a further 25 ml of hot water. This solution was cooled to 10° C. in an ice bath and then acidified to pH≈2 with concentrated aqueous HCl. The oil that separated was extracted into chloroform, the solution dried with anhydrous magnesium sulphate, filtered and the solvent removed by rotary evaporation to leave a sticky solid. Recrystallization from water/acetic acid gave the title compound (1.07 g, 35%). δH (300 MHz, DMSO-d6) 3.54 (2H, s), 7.15-7.27 (5H, m), 7.39 (1H, dd) 7.81 (1H, d), 9.54 (1H, broad s) and 12.0-13.5 (2H, broad). Mass spectrum: (ES−) 304 (M−H). λmax (EtOH)=292, 364 nm.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:13]2[CH:24]=[CH:25][C:26]([C:28]([O:30]CC)=[O:29])=[CH:27][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(O)C>[CH2:3]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:13]2[CH:24]=[CH:25][C:26]([C:28]([OH:30])=[O:29])=[CH:27][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(Cc1ccccc1)n2Cc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(Cc1ccccc1)n2Cc1ccc(Cl)cc1Cl
Yield: 85.5 %

Procedure:
Ethanol (80 ml) and 10% sodium hydroxide aqueous solution (37 g) are added to 2-benzyl-1-(2,4-dichlorobenzyl)-5-ethoxycarbonylbenzimidazole (0.50 g) (example 13) and the solution is refluxed for 4 hours. After the reaction solution is cooled, its acidity is adjusted to pH 6 with 10% hydrochloric acid. The sediment is gathered, washed with water, dried under reduced pressure, and thus, 2-benzyl-5-carboxy- 1 -(2,4-dichlorobenzyl) benzimidazole (0.40 g) is obtained.
Reaction SMILES: [C:1]([CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])#[N:2]>C(O)C.Cl.[Pd]>[NH2:2][CH2:1][CH2:3][P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10]
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOP(=O)(CCN)OCC
Yield: 63 %

Procedure:
A mixture of diethyl cyanomethylphosphonate (17.7 g; 0.1 moles) in ethanol (70 ml) and aqueous HCl (40 ml of 10% HCl) over 10% Pd/C (1 g) is stirred in a pressure vessel at 60 psi. When the calculated amount of H2 had been absorbed (about 26 hours), the catalyst is filtered off over Celite, washed with ethanol, and the filtrate is neutralized with NaHCO3 and evaporated to dryness under vacuum. The residue is extracted with absolute ethanol (2×50 ml) and the clear extract is distilled at about 110° C. and 0.18 mbar to give a colorless liquid (11.4 g; yield 63%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[N:13]=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[C:20]([C:21]=1[C:22]#N)=[CH:19][CH:18]=[CH:17][CH:16]=2.C(O)(=[O:32])C.O>C1(C)C=CC=CC=1>[Cl:11][C:12]1[N:13]=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[C:20]([C:21]=1[CH:22]=[O:32])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CC(=O)O
Reactant: N#Cc1c(Cl)nc(-c2ccccc2)c2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1c(Cl)nc(-c2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In an atmosphere of argon and at -5° C. 10.7 ml of a 20% diisobutylaluminum hydride solution in toluene are slowly added dropwise to 2.64 g of 3-chloro-4-cyano-1-phenyl-isoquinoline in 150 ml of absolute toluene. The mixture is stirred for 10 minutes at 0° C. and then hydrolized with a small amount of glacial acetic acid until the reaction is weakly acid. Next, water is added and the toluene phase is separated. The organic phase is washed successively with saturated sodium bicarbonate solution and with water, dried and the solvent is removed under reduced pressure. The residue is rubbed with ether and recrystallized from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:28])([F:27])[F:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[C:15]([O:17]CC)=[O:16])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:28])([F:26])[F:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:20][CH:21]3[CH2:22][CH2:23]3)[C:15]([OH:17])=[O:16])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)C(CC1CC1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C(CC1CC1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
35 mg (purity 87%, 0.07 mmol) of ethyl 2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoate (racemate) were hydrolysed with lithium hydroxide according to General Method 6B. Yield: 60 mg (purity 88%, quant.)