Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[O:17])[CH:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]2=[O:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[C:39]([C:41]1[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][CH:42]=1)#[N:40].Cl>C1COCC1>[C:39]([C:41]1[CH:48]=[CH:47][C:44]([CH:45]([C:15]23[CH2:14][CH2:13][CH2:12][N:11]2[C:10](=[O:18])[N:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:16]3=[O:17])[OH:46])=[CH:43][CH:42]=1)#[N:40]
Reactant: O=C1C2CCCN2C(=O)N1c1cc(Cl)cc(Cl)c1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)C23CCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To a solution of 3-(3,5-dichlorophenyl)-1,3-diazabicyclo[3.3.0]octane-2,4-dione, (5.63 g) in anhydrous THF (20 mL) at −78° C. was added LDA prepared from n-BuLi (13.6 mL) and diisopropylamine (3.33 mL). The reaction mixture was stirred at −78° C. for 30 minutes then at 0° C. for 1 hour. To this mixture was added in one portion 4-cyanobenzaldehyde (3.64 g). The reaction mixture was allowed to warm to room temperature for 3 hours then poured onto 1 N HCl (50 mL). The mixture was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and the solvent evaporated. The residue was purified by chromatography (SiO2, hexanes to 1:1 hexanes/EtOAc gradient elution) and HPLC (18C-Waters 40×210 mm, 1% HOAc/CH3CN gradient) to provide the titled product (5.5 g). MS (m/z) 416 (MH+); mp. 184.4° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=1)=[N:1]2
Reactant: O=Cc1ccccn1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (0.15 g, 0.764 mmol) in N,N-dimethyl acetamide (5 mL) were added 2-pyridine carboxaldehyde (0.082 g, 0.764 mmol), sodium hydrogen sulphite (58.5%, 0.15 g, 0.84 mmol), and p-toluenesulfonic acid (15 mg, 0.0764 mmol). The reaction mixture was stirred at 150° C. overnight. The mixture was cooled to room temperature. Water (40 mL) was added and the reaction mixture was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water and dried over anhydrous Na2SO4. The solvent was removed and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 1% methanol in CH2Cl2 as eluent) to give 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one (0.077 g, 36%) as a white solid. 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one was converted to the corresponding hydrochloride. Selected data: MS (m/z): 284.0; MP 215-217° C. (hydrochloride).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH3:44])[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH3:44])[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 114 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:17]1([S:23]([C:26]2[CH:31]=[CH:30][C:29](F)=[C:28]([Cl:33])[CH:27]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:33][C:28]1[CH:27]=[C:26]([S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:24])=[O:25])[CH:31]=[CH:30][C:29]=1[O:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(Cl)c1
Reactant: CC(C(=O)O)c1cc(O)cc(C(F)(F)F)c1
Product: CC(C(=O)O)c1cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 50 step (iii) and the product from example 29 step (i).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][C:7]1[O:11][C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[CH:22]=[CH2:23])=[N:9][N:8]=1>CO.[Pd]>[CH2:22]([C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([NH:12][C:10]3[O:11][C:7]([CH2:6][C:5]4[CH:24]=[CH:25][CH:26]=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:8][N:9]=3)[CH:14]=2)[NH:18][N:17]=1)[CH3:23]
Reactant: C=Cc1n[nH]c2ccc(Nc3nnc(Cc4cccc(OC)c4)o3)cc12
Agent: [Pd]
Solvent: CO
Product: CCc1n[nH]c2ccc(Nc3nnc(Cc4cccc(OC)c4)o3)cc12
Yield: 33.1 %

Procedure:
150 mg of [5-(3-methoxybenzyl)-1,3,4-oxadiazol-2-yl]-(3-vinyl-1H-indazol-5-yl)amine (as trifluoroacetic acid salt, prepared from “A43”) are hydrogenated at room temperature in 10 ml of methanol in the presence of 150 mg of Pd/C. The reaction mixture is filtered and evaporated. Purification by column chromatography on silica gel (eluent: heptane/EA) gives 50 mg of (3-ethyl-1H-indazol-5-yl)-[5-(3-methoxybenzyl)-1,3,4-oxadiazol-2-yl]amine (44%); MS-FAB (M+H+)=350.39; Rf (polar method): 1.836 min.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:19])[CH2:9][C:10]2[NH:14][C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([C:9]1[CH:25]=[CH:24][C:23](=[O:26])[N:14]2[C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[NH:11][C:10]=12)=[O:19]
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1cccc(Cl)c1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: O=C(c1cccc(Cl)c1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 559.9 mg (2.03 mmol) of 1-(3-Chlorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XXXIX), 220.2 mg (4.08 mmol) of sodium methylate and 171.3 mg (2.03 mmol) methyl propiolate.
Reaction SMILES: [CH2:1]([C:8]1[NH:12][N:11]=[C:10]([C:13]2[S:17][C:16]([C:18]([O:20]CCCC)=[O:19])=[C:15]([CH3:25])[CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)C>C(O)C.O>[CH2:1]([C:8]1[NH:12][N:11]=[C:10]([C:13]2[S:17][C:16]([C:18]([OH:20])=[O:19])=[C:15]([CH3:25])[CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)c1sc(-c2n[nH]c(Cc3ccccc3)n2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2n[nH]c(Cc3ccccc3)n2)sc1C(=O)O
Temperature: 0 °C
Yield: 94 %

Procedure:
A mixture of butyl 5-(5-benzyl-1H-1,2,4-triazol-3-yl)-3-methylthiophene-2-carboxylate (0.23 g, 0.64 mmol) and 1 N aqueous sodium hydroxide (3.8 mL, 3.8 mmol) in ethanol (7.6 mL) was stirred at reflux for 1 h. The reaction mixture was cooled to 0° C. and acidified with glacial acetic acid to pH 5-6, and diluted with water (25 mL). The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a colorless solid (0.18 g, 96%): 1H NMR (300 MHz, DMSO-d6) δ 12.94 (br s, 1H), 7.45 (s, 1H), 7.37-7.20 (m, 6H), 4.12 (s, 2H), 2.47 (s, 3H); MS (ES+) m/z 300.21 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:19]O>>[CH3:19][O:13][C:12](=[O:14])[CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][N:3]=[CH:4]2
Reactant: CO
Reactant: O=C(O)Cc1ccc2ncncc2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc2ncncc2c1
Temperature: 25 °C

Procedure:
A solution of quinazolin-6-yl-acetic acid (0.025 g, 0.133 mmol), thionyl chloride (0.1 mL) and methanol (2 mL) was heated to 60° C. for 6 hours. The reaction was cooled to room temperature and evaporated several times with dichloromethane to give quinazolin-6-yl-acetic acid methyl ester. This was dissolved in a solution of methanol (2 mL) and hydrazine (0.061 mL) and stirred at room temperature for several hours. The reaction was evaporated in vacuo to give quinazolin-6-yl-acetic acid hydrazide. 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.33 (bs, 1H), 9.26 (s, 1H), 7.96 (m, 3H), 4.25 (bs, 2H), 3.84 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])/[C:4](/[NH:13][C:14](=[O:41])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][Si](C(C)(C)C)(C)C)[CH:27]=2)=[O:23])=[CH:17][C:16]=1[CH3:40])=[CH:5]/[C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:42])/[C:4](/[NH:13][C:14](=[O:41])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])=[CH:17][C:16]=1[CH3:40])=[CH:5]/[C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12]
Reactant: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 102.2 %

Procedure:
To a solution of (Z)-2-[[4-[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]amino]carbonyl]-2,6-dimethylbenzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester (47 mg, 0.0773 mmol) in THF (1 mL) was added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.085 mmol, 85 μL) and the reaction was stirred for 3 days at ambient temperature. The reaction was diluted with ethyl acetate and was then washed with in turn with water and brine. The organic layer was dried (MgSO4), filtered and evaporated in vacuo to yield 39 mg of (Z)-2-[[4-[[(3-hydroxybenzyl)amino]carbonyl]-2,6-dimethylbenzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester as a yellow solid (quantitative yield).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C@H:19]1[CH2:21][O:20]1>CO>[O:20]1[CH2:21][C@H:19]1[CH2:18][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: ClC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc2c(c1)CCN(C[C@@H]1CO1)C2
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 1,2,3,4-tetrahydroisoquinoline (1 g, 7.52 mmol) in MeOH (40 mL) was added K2CO3 (5.19 g, 37.6 mmol) under 0° C. After stirring for 30 minutes, (R)-2-(chloromethyl) oxirane (0.692 g, 7.52 mmol) was added the reaction. The mixture was then stirred at 0° C. overnight before filtration and washing of the solid by with MeOH. The solution was concentrated and the residue purified by column separation to give the title compound as a colorless oil (70% purity). This crude was used directly in the next step. LCMS (m/z): 190.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH2:11](I)[CH2:12][CH3:13].NC1C=CSC=1C(OC)=O.C(I)CCC>>[CH2:11]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH2:12][CH3:13]
Reactant: CCCI
Reactant: COC(=O)c1ccsc1N
Agent: COC(=O)c1sccc1N
Solvent: CCCCI
Product: CCCNc1sccc1C(=O)OC
Yield: 54 %

Procedure:
In the same manner as in Reference Example 1-1), methyl 2-aminothiophene-3-carboxylate [Chem. Bet. 98, 3571 (1965)]and n-propyl iodide were used in place of methyl 3-aminothiophene-2-carboxylate and n-butyl iodide to obtain 10.76 g (54.0%) of Compound (h-1).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([CH3:37])[CH:29]=1>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=4[CH3:37])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Product: Cc1cc(F)ccc1-c1ccc(C(=O)Nc2ccc3nc(N(C)CCN(C)C)sc3c2)cc1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.15 g, 0.31 mmol) and 4-fluoro-2-methyl-phenyl boronic acid (0.071 g, 0.38 mmol) to afford 0.084 g (59%). LC/MS, Retention time=4.79 min; (m/z): calcd for C26H27FN4OS (M+H)+: 463.6; found: 463.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[C:14]([CH2:23][O:24][CH2:25][CH3:26])=[N:13][C:7]=3[CH:8]=[N+:9]([O-:12])[C:10]=2[CH:11]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O>[CH2:25]([O:24][CH2:23][C:14]1[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:11][C:10]=3[N+:9]([O-:12])=[CH:8][C:7]=2[N:13]=1)[CH3:26]
Reactant: C1CCNCC1
Reactant: CCOCc1nc2c[n+]([O-])c3cc(Br)ccc3c2n1CCCOC(C)C
Solvent: O
Product: CCOCc1nc2c[n+]([O-])c3cc(N4CCCCC4)ccc3c2n1CCCOC(C)C
Temperature: 150 °C

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline-5-oxide (0.500 g), water (4.0 mL), and piperidine (1.0 mL) were added sequentially to a 20 mL steel pressure vessel. The vessel was sealed and then heated in an oven at 150° C. for 16 hours. The reaction mixture was allowed to cool and then was extracted with chloroform (×2). The combined extracts were washed sequentially with water and brine and then dried over sodium sulfate. This material was combined with that from another run on the same scale and then purified by column chromatography on a Biotage Horizon™ High-Performance Flash Chromatography instrument using a silica gel cartridge and eluting with a gradient of 2-22% CMA in chloroform to provide 0.137 g of 2-ethoxymethyl-1-(3-isopropoxypropyl)-7-(piperidin-1-yl)-1H-imidazo[4,5-c]quinoline-5-oxide as a brown oil.
Reaction SMILES: [Cl-].[C:2]([O-:5])(=[O:4])[CH3:3].[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:22])([CH3:21])[CH:16]=[C:17]([F:20])[CH2:18]O)=[CH:11][CH:10]=1)[CH3:7].C1C=CC=CC=1>N1C=CC=CC=1>[C:2]([O:5][CH2:18][C:17]([F:20])=[CH:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:6][CH3:7])=[CH:14][CH:13]=1)([CH3:21])[CH3:22])(=[O:4])[CH3:3]
Reactant: CCOc1ccc(C(C)(C)C=C(F)CO)cc1
Reactant: CC(=O)[O-]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOc1ccc(C(C)(C)C=C(F)COC(C)=O)cc1
Yield: 99 %

Procedure:
The method of Example 11 was repeated using acetate chloride (0.17 ml), 4-(4-ethoxyphenyl)-2-fluoro-4-methylpent-2-enol (Example 9) (86 mg), benzene (4 ml) and pyridine (0.04 ml) to yield the title compound (0.1 g, 99%).
Reaction SMILES: Br.C1[O:10][C:9]2[CH:8]=[CH:7][C:6]([N:11]3[C:19]([C:20]4[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=4)=[CH:18][C:17](=[O:29])[C:13]([C:14]([OH:16])=[O:15])=[CH:12]3)=[CH:5][C:4]=2[O:3]1.[OH-].[Na+]>O>[OH:3][C:4]1[CH:5]=[C:6]([N:11]2[C:19]([C:20]3[CH:21]=[CH:22][C:23]([N:26]([CH3:27])[CH3:28])=[CH:24][CH:25]=3)=[CH:18][C:17](=[O:29])[C:13]([C:14]([OH:16])=[O:15])=[CH:12]2)[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CN(C)c1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc3c(c2)OCO3)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(O)c(O)c2)cc1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
In 10 ml of 47% by weight hydrobromic acid was suspended 0.15 g of 1-(3,4-methylenedioxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinic acid, and they were refluxed for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and diluted with 10 ml of water. This solution was adjusted to a pH of 12 with a 20% weight aqueous sodium hydroxide solution, washed with 20 ml of chloroform, and again adjusted to a pH of 6.0 with acetic acid. This solution was extracted with 50 ml of chloroform, and the extract was washed with 30 ml of a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/methanol (15:1 by volume) mixture) to obtain 0.05 g of 1-(3,4-dihydroxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 223°-227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[C:26]([O:25][C:23]([CH:22]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:5]=2[N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:7]1=[O:9])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)C(Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Cl)ccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4.00 g (14.9 mmol) of tert-butyl 5-chloro-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (Via) were dissolved in dry DMF (60 ml) in a heat-dried flask under a nitrogen atmosphere. 625 mg (15.6 mmol) of sodium hydride (60% suspension in mineral oil) were added while stirring at 0° C., and the reaction solution was then stirred at room temperature for 30 min. After renewed cooling in an ice bath, 4.44 g (16.4 mmol) of tert-butyl bromo-phenylacetate were added, and the mixture was stirred while cooling in ice for 1 h and then at room temperature for 2 h. The reaction solution was diluted with ethyl acetate, mixed with 10% aqueous ammonium chloride solution and then extracted with ethyl acetate (3×). The combined organic phases were washed with water and saturated NaCl solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 15-35% ethyl acetate in cyclohexane). Yield: 6.91 g (100%) of yellow oil
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:30](Cl)=[O:31])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:33]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:30]([N:33]4[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34]4)=[O:31])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Reactant: OC1CCNC1
Product: O=C(N1CCC(O)C1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
100 mg (0.21 mmol) of the compound from Example 179A and 19 mg (0.21 mmol) of 3-pyrrolidinol were reacted according to the General Method 5. Yield: 43 mg (39% of theory)
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH:18]([C@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[C:27](=[O:36])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C.[C:46]([O:50][C:51]([N:53]1[CH2:57][C@H:56]([F:58])[CH2:55][C@@H:54]1[CH:59]=[O:60])=[O:52])([CH3:49])([CH3:48])[CH3:47].P([O-])([O-])([O-])=O>ClCCl>[C:46]([O:50][C:51]([N:53]1[CH2:57][C@H:56]([F:58])[CH2:55][C@@H:54]1[C@@H:59]([OH:60])[C@H:28]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:27]([N:22]1[C@@H:21]([CH:18]([CH3:20])[CH3:19])[CH2:25][O:24][C:23]1=[O:26])=[O:36])=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@@H]1C=O
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CCc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](Cc1ccccc1)[C@H](O)[C@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 52.3 %

Procedure:
Add dibutylboron triflate (1 M in dichloromethane, 11.8 mL, 11.8 mmol) to a solution of 4-(S)-isopropyl-3-(3-phenylpropionyl)-oxazolidin-2-one (2.8 g, 10.7 mmol) in dichloromethane (40 mL) at 0° C. Stir 5 min. Add N,N-diisopropylethylamine (2.25 mL, 12.87 mmol) and stir 90 min. Cool to −78° C. and add 4-(R)-fluoro-2-(R)-formylpyrrolidine-1-carboxylic acid tert-butyl ester (2.53 g, 11.6 mmol) in dichloromethane (15 mL) over 15 min. Stir 90 min and then warm to room temperature over 18 h. Cool in ice bath and add 0.05 M pH 7 phosphate buffer (15 mL). Extract with dichloromethane and concentrate. Dissolve in methanol (50 mL) and cool in ice bath. Add aqueous hydrogen peroxide (15 mL, 30% solution) and remove ice bath. Stir 5 min and concentrate. Extract with ethyl acetate and wash extract with 1 N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a foam (2.68 g, 52%).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:19][CH2:18][C:8]2[O:9][C:10]3[C:15]([Cl:16])=[CH:14][C:13](Br)=[CH:12][C:11]=3[C:7]=2[CH2:6]1)(=[O:3])[CH3:2].[C:20]1([S:26]([O-:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].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>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]1[CH2:19][CH2:18][C:8]2[O:9][C:10]3[C:15]([Cl:16])=[CH:14][C:13]([S:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:28])=[O:27])=[CH:12][C:11]=3[C:7]=2[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=S([O-])c1ccccc1
Reactant: CC(=O)OC1CCc2oc3c(Cl)cc(Br)cc3c2C1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(=O)OC1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Temperature: 110 °C
Yield: 56.1 %

Procedure:
A mixture of the product of step B (230 mg, 0.66 mmol), sodium benzenesulfinate (132 mg, 0.80 mmol), di-palladium-tris(dibenzylideneacetone) (60 mg, 0.07 mmol), cesium carbonate (322 mg, 0.99 mmol) and xantphos (76 mg, 0.13 mmol) was suspended in anhydrous toluene (4 mL). The reaction flask was purged with argon and heated at 110° C. for 5 h. After cooling, the reaction mixture was diluted with dichloromethane and filtered through a celite bed. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, 7:3 hexanes/ethyl acetate) to give a single enantiomer of 6-chloro-8-(phenylsulfonyl)-1,2,3,4-tetrahydrodibenzo[b,d]furan-2-yl acetate (150 mg, 56%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.01-7.92 (m, 3H), 7.83 (d, J=1.8 Hz, 1H), 7.61-7.48 (m, 3H), 5.36-5.28 (m, 1H), 3.06-2.73 (m, 4H), 2.28-2.09 (m, 2H), 2.05 (s, 3H).