Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)C#N.C[Mg]Br.CC[O:15][CH2:16][CH3:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:16](=[O:15])[CH3:17])[CH:7]=[CH:8][N:9]=1
Reactant: CCOCC
Reactant: N#Cc1ccnc(Cl)c1
Agent: C[Mg]Br
Product: CC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 34.6 g. (0.25 mole) of 2-chloroisonicotinonitrile in 500 ml. of dry ether under a nitrogen atmosphere was added dropwise over 15 minutes 166 ml. of 3.0 M (0.5 mole) solution of methyl magnesium bromide. After stirring at room temperature for 24 hours the precipitate was filtered and added immediately to a mixture of 600 g. of ice and 300 ml. of water to which had been added 150 ml. of 6 N hydrochloric acid. The aqueous phase was extracted (4×100 ml.) with ether and the combined ether extracts dried and concentrated to an oil. The residual oil was extracted with warm petroleum ether (4×50 ml.) and the extracts combined and cooled in a dry ice/acetone bath. The resulting precipitate was filtered and dried to give 21.3 g. (55%) of the desired intermediate, m.p. 36°-38° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([C:27]#[N:28])([CH2:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]=1[N+:24]([O-:26])=[O:25])[CH2:6][CH2:7][CH:8]=[CH2:9])C.[Li+].[OH-].Cl>CO.O>[C:27]([C:5]([CH2:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]=1[N+:24]([O-:26])=[O:25])([CH2:6][CH2:7][CH:8]=[CH2:9])[C:4]([OH:29])=[O:3])#[N:28]
Reactant: C=CCCC(C#N)(Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCCC(C#N)(Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-cyano-2-(2-nitro-5-phenoxy-benzyl)-hex-5-enoic acid ethyl ester (2.84 g, 7.20 mmol) was dissolved in methanol (42 mL). In a separate flask LiOH (1.5 g, 36.0 mmol) was dissolved in water (21 mL). The LiOH solution was added to the methanolic solution containing 2-cyano-2-(2-nitro-5-phenoxy-benzyl)-hex-5-enoic acid ethyl ester and the reaction was allowed to stir at room temperature for 2 hours. Next, 12N HCl (3 mL) was added to the reaction mixture followed by removal of the methanol under reduced pressure. The reaction mixture was poured into a separatory funnel, ethyl acetate was added and the organic layer washed 2 times with 1N HCl and one time with saturated brine solution. The organic layer was separated, dried with sodium sulfate, filtered and the solvent was removed to yield a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH2:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=[O:18])[CH:12]=[CH2:13].[F-].[K+].[OH-].[Na+]>CN(C=O)C>[CH2:11]([C:14]1[CH:15]=[C:16]([CH:17]=[O:18])[CH:19]=[CH:20][C:21]=1[O:22][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH:12]=[CH2:13]
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: C=CCc1cc(C=O)ccc1O
Agent: [F-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCc1cc(C=O)ccc1Oc1cc(Cl)ccc1C#N
Yield: 14.4 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.34 g, 2.2 mmol), 3-allyl-4-hydroxybenzaldehyde (0.34 g, 2.1 mmol) and potassium fluoride (0.37 g, 6.3 mmol) were heated with stirring in dry DMF (4 mL) at 120° C. for 4 h. The reaction mixture was cooled, poured into 0.1N sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 0.1N sodium hydroxide solution (3×), water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo and the residue purified by chromatography to give 2-(2-allyl-4-formyl-phenoxy)-4-chlorobenzonitrile (0.09 g, 15%) as a colourless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)[O:21][C:19](=O)[CH2:18][C:16](=O)O1>CCO>[C:1]1([C:7]2[NH:8][N:9]=[C:10]3[C:11]=2[CH:16]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:18][C:19](=[O:21])[NH:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCO
Product: O=C1CC(c2ccccc2)c2c(n[nH]c2-c2ccccc2)N1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 142.6 %

Procedure:
To 3-phenyl-1H-pyrazol-5-amine (0.20 g, 1.26 mmol) in EtOH (8 mL) was benzaldehdye (0.14 mL, 1.39 mmol) followed by Meldrum's Acid (0.318 g, 1.39 mmol) and then the reaction was heated to 75° C. After 1.5 hr, the reaction mixture was cooled to room temperature and placed in an ice bath. The product was filtered off and dried under reduced pressure to give the title compound (0.26 g, 71% yield) as a white solid. LRMS m/z (APCI+) 290 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:27].[Li+]>C(Cl)Cl.CC(C)=O>[Br:27][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCCCCc1cccs1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: ClCCl
Product: BrCCCCCCCCc1cccs1
Reaction time: 2 h

Procedure:
To a stirring mixture of 8-(thiophen-2-yl)-octan-1-ol (0.132 g, 0.622 mmol) and triethylamine (0.126 g, 1.245 mmol) in methylene chloride (5 ml) at 0° under argon was added methanesulfonyl chloride (0.107 g, 0.933 mmol). After stirring for 2 hours at 0° the reaction was quenched with water and the organic layer was washed with 10% hydrochloric acid, saturated sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a pale oil. To this oil in acetone (2 ml) was added lithium bromide (0.216 g, 2.49 mmol) and the mixture was refluxed for 15 hours. The acetone was evaporated and the residue was taken up in ethyl ether, washed with 10% hydrochloric acid, saturated sodium bicarbonate, water, saturated sodium chloride, dried over magnesium sulfate, filtered through silica and concentrated to give the title compound which was carried on without further purification.
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH3:8][O:9][CH:10]([O:30][CH3:31])[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=2)=[CH:13][CH:12]=1>CO>[CH3:31][O:30][CH:10]([O:9][CH3:8])[C:11]1[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C(OC)OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(OC)c1ccc(C#Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
A 2.0 mol/L sodium hydroxide aqueous solution (0.10 L) was added to a THF (0.25 L)-methanol (0.25 L) solution of ethyl 4-{[4-(dimethoxymethyl)phenyl]ethynyl}benzoate (21 g) as obtained in Example 10-(2), and the mixture was stirred for 3 hours at room temperature. The solvent was distilled off, and then water and acetic acid were added to the residue to adjust it to pH 4. The precipitate was filtered off and dried. Hexane/ethyl acetate (3:1 (v/v)) was added, and the mixture was stirred for a while. The precipitate was filtered off and dried to obtain 4-{[4-(dimethoxymethyl)phenyl]ethynyl}benzoic acid (white solid) (15 g, 75%).
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:30]2[C@@H:39]3[C@@H:34]([CH2:35][CH:36]=[CH:37][CH2:38]3)[C:33](=[O:40])[N:32]([CH:41]3[CH2:46][CH2:45][N:44](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:43][CH2:42]3)[N:31]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28]C)C>>[CH3:18][O:20][C:21]1[CH:22]=[C:23]([C:30]2[C@@H:39]3[C@@H:34]([CH2:35][CH:36]=[CH:37][CH2:38]3)[C:33](=[O:40])[N:32]([CH:41]3[CH2:46][CH2:45][N:44]([S:1]([C:4]4[C:16]5[C:8](=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[CH:14][CH:15]=5)[CH:7]=[CH:6][CH:5]=4)(=[O:3])=[O:2])[CH2:43][CH2:42]3)[N:31]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc5c(N(C)C)cccc45)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from dansylchloride and starting compound A1 as described for compound 1. Crystallisation from methanol. M.p. 198-200° C.
Reaction SMILES: [OH:1][CH:2]([CH2:36][C:37]1[CH:42]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:40]([OH:47])=[C:39]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:38]=1)[CH2:3][N:4]1[C:11](=[O:12])[C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:8](=[O:9])[N:7]([CH2:17][CH:18]([OH:35])[CH2:19][C:20]2[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=2)[C:5]1=[O:6].[C:52](Cl)(=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69].Cl>>[C:52]([O:35][CH:18]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:32])([CH3:33])[CH3:34])[CH:21]=1)[CH2:17][N:7]1[C:8](=[O:9])[C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:11](=[O:12])[N:4]([CH2:3][CH:2]([O:1][C:52](=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:36][C:37]2[CH:42]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:40]([OH:47])=[C:39]([C:48]([CH3:49])([CH3:50])[CH3:51])[CH:38]=2)[C:5]1=[O:6])(=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69]
Reactant: CCC1(CC)C(=O)N(CC(O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)N(CC(O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Product: CCCCCCCCCCCCCCCCCC(=O)OC(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CN1C(=O)N(CC(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC(=O)CCCCCCCCCCCCCCCCC)C(=O)C(CC)(CC)C1=O
Yield: 52.3 %

Procedure:
7.0 g (0.01 mol) of 1,3-bis-[2-hydroxy-3-(3,5-di-tert.-butyl-4hydroxyphenyl)-propyl]-5,5-diethylbarbiturate and 6 g (0.02 mol) of stearic acid chloride in 50 ml of ligroin are brought to the reflux temperature and the resulting clear solution is kept at this temperature until the evolution of hydrochloric acid has ceased. After evaporating the solvent in vacuo, a syrupy residue is obtained which when chromatographed on a silica gel column gives 6.5 g (53% of theory) of 1,3-bis-[2-stearoyloxy-3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propyl]-5,5-diethylbarbiturate as an almost colourless oil.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([O:19][CH3:20])[CH:9]=[C:10]([O:17][CH3:18])[C:11]=2[CH2:15][CH3:16])[S:4]1(=[O:6])=[O:5].[Na].[C:22]1([N:28]2[C:32]([SH:33])=[N:31][N:30]=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[C:22]1([N:28]2[C:32]([S:33][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[C:8]([O:19][CH3:20])[CH:9]=[C:10]([O:17][CH3:18])[C:11]=4[CH2:15][CH3:16])[S:4]3(=[O:6])=[O:5])=[N:31][N:30]=[N:29]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCc1c(OC)cc(OC)c2c1C(=O)N(CCl)S2(=O)=O
Reactant: Sc1nnnn1-c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(OC)cc(OC)c2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Yield: 74 %

Procedure:
A solution of 2-chloromethyl-4-ethyl-5,7-dimethoxysaccharin (Example 22L, 0.4 g) and 1-phenyltetrazol-5-thiol sodium salt (0.28 g) in dimethylformamide (3 mL) was heated at 110° C. for two hours, then poured into water. Recrystallization of the resulting solid from ethanol-water afforded 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethyl-5,7-dimethoxysaccharin, 0.44 g, 74% yield, mp 162°-164° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.CCN=C=NCCCN(C)C.[C:35]([O:39][C:40]([N:42]1[CH2:47][C@H:46]2[CH2:48][CH2:49][C@@H:43]1[C@H:44]([C:50](O)=[O:51])[CH2:45]2)=[O:41])([CH3:38])([CH3:37])[CH3:36]>N1C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:50]([C@H:44]2[C@H:43]3[CH2:49][CH2:48][C@H:46]([CH2:47][N:42]3[C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:45]2)=[O:51])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC[C@@H]1[C@H](C(=O)O)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2N(C(=O)OC(C)(C)C)C3)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-Isopropoxyaniline (1.49 g, 9.87 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter, “WSC”; 1.89 g, 9.87 mmol) were added to a pyridine (20 mL) solution of the compound (1.68 g, 6.58 mmol) synthesized in (2), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and, after addition of ethyl acetate, washed once with distilled water, once with 1 N-hydrochloric acid aqueous solution, and once with 1N-sodium hydroxide aqueous solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the target (1.26 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:14][N:15]3[C:21](=[O:22])[C@@H:20]([NH:23][C:24](=[O:36])[C@@H:25]([N:27](C)[C:28](=O)OC(C)(C)C)[CH3:26])[C@H:19]([CH3:37])[N:18]([C:38](=[O:44])[CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])[C:17]4[CH:45]=[CH:46][CH:47]=[CH:48][C:16]3=4)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>C(Cl)Cl>[F:52][C:51]([F:54])([F:53])[C:49]([OH:55])=[O:50].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:14][N:15]3[C:21](=[O:22])[C@@H:20]([NH:23][C:24](=[O:36])[C@@H:25]([NH:27][CH3:28])[CH3:26])[C@H:19]([CH3:37])[N:18]([C:38](=[O:44])[CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])[C:17]4[CH:45]=[CH:46][CH:47]=[CH:48][C:16]3=4)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c4ccccc43)cc(=O)oc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2cc(=O)oc3cc(OC)ccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a rt solution of tert-butyl(S)-1-((3S,4S)-1-((7-methoxy-2-oxo-2H-chromen-4-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (42.7 mg, 62.4 μmol) in CH2Cl2 (249 μl) was added TFA (62.4 μl). The reaction was stirred at rt for 1.5 h, then concentrated, taken up in H2O, and lyophilized to provide (S)-N-((3S,4S)-1-((7-methoxy-2-oxo-2H-chromen-4-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino) propanamide 2,2,2-trifluoroacetate (41.2 mg, 95%) as a white solid. MS m/z 585 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:57])[C:30]([CH3:56])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH3:55])[CH:49]=3)=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:57])[C:30]([CH3:56])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH3:55])[CH:49]=3)=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccc(OC)c3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.9 %

Procedure:
p-Methoxyaniline (0.056 g, 0.457 mmol), triethylamine (0.046 g, 0.457 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.077 g, 0.457 mmol) were added to a methylene chloride solution (10 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-methoxyphenoxy)benzoic acid (0.100 g, 0.228 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=2:3) to obtain the titled compound (0.058 g, 0.107 mmol, 47%).
Reaction SMILES: C[O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:8])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Temperature: 0 °C

Procedure:
3-(4-Methoxybenzoyl)-2-phenylbenzofuran (16.4 g., 0.05 mol.) is combined with 50 g. of freshly distilled pyridine hydrochloride and the mixture is refluxed 1 hour. The hot mixture is poured with stirring onto an ice-dilute hydrochloric acid mixture and the precipitate is collected to give 3-(4-hydroxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20](C)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:12][C:11]([C:24]([F:27])([F:26])[F:25])=[N:10]2)=[CH:5][CH:4]=1.C([Mg]Cl)CCC.C(B(CC)CC)C.[NH2:41]OS(O)(=O)=O.C([O-])(=O)C.[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH2:41])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:12][C:11]([C:24]([F:27])([F:26])[F:25])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)cc1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: CCCC[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2nc(C(F)(F)F)nc2-c2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
To an ice cooled solution of 1-(4-methoxy-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole (10 g, 25.19 mmol) in THF (100 ml) was added dropwise a 2 M solution of n-butylmagnesium chloride in THF (21 ml, 42 mmol). Then the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0° C., a 1 M solution of triethylborane in THF (70 ml, 70 mmol) was added dropwise and the reaction mixture was refluxed for 18 h. After cooling, a solution of hydroxylamine-O-sulfonic acid (12 g, 106 mmol) and sodium acetate (17.38 g, 210 mmol) in H2O (140 ml) was added dropwise while maintaining the temperature below 15° C. Then the reaction mixture was stirred at room temperature for 2 h, the residue was extracted with ethyl acetate (2×100 ml), the organic layer was washed with saturated brine, dried over sodium sulfate and evaporated under vacuum. The resulting residue was chromatographed on silica gel using a 99/1 then 98/2 mixture of methylene chloride/methanol as the eluent, then recrystallized from ethanol to give a beige solid (2.5 g, 25%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[N:24][CH:25]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[N:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: COC(=O)Cc1ccc(N)cn1
Agent: Cl
Product: COC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cn1
Yield: 71 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.110 g, 0.36 mmol) was reacted with methyl 2-(5-aminopyridin-2-yl)acetate (0.067 g, 0.40 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.110 g, 74%) as a white solid. MW=466.79. 1H NMR (DMSO-d6, 500 MHz) δ 14.31 (s, 1H), 10.00 (s, 1H), 8.63 (d, J=2.5 Hz, 1H), 7.97-7.93 (m, 2H), 7.78-7.75 (m, 1H), 7.69-7.66 (m, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.12 (s, 1H), 3.95 (s, 2H), 3.65 (s, 3H), 3.19 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.26 (quin, J=7.5 Hz, 2H); APCI MS m/z 394 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][CH3:20]>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](=[O:10])[N:19]([CH3:20])[CH3:18])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)c1ccc(C(C)(C)C)c([N+](=O)[O-])c1

Procedure:
Following a similar procedure to that described in Preparation 4, but using 4-t-butyl-3-nitrobenzoic acid and dimethylamine hydrochloride instead of methanol, the title compound was obtained as an oily substance.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)[C:4]=1[C:19]([O:21][CH3:22])=[O:20])=[CH2:2].[C:23]([OH:26])(=[S:25])[CH3:24].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[C:23]([S:25][CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)[C:4]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:26])[CH3:24]
Reactant: CC(O)=S
Reactant: C=Cc1cccc(-c2cccc(C(=O)OC)c2)c1C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)c1cccc(-c2cccc(CCSC(C)=O)c2C(=O)OC)c1
Yield: 47.2 %

Procedure:
To a solution of 3-ethenyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (0.85 g, 2.9 mmol) in benzene (10 mL) was added thioacetic acid (2.1 mL, 29.4 mmol) followed by AIBN (0.053 g, 0.32 mmol). The solution was deoxygenated for 30 minutes by bubbling nitrogen through the solution and then heated at reflux for 4 hours. Saturated aqueous NaHCO3 (20 mL) was added to the solution and the mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (1:12 EtOAc/hexanes) to give 3-[2-(acetylthio)ethyl]-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (0.51 g, 48%) as an off white solid: 1H NMR (CDCl3) δ2.35 (s, 3H), 2.93 (m, 2H), 3.14 (m, 2H), 3.62 (s, 3H), 3.93 (s, 3H), 7.29 (dd, J=7.6, 0.9 Hz, 1H), 7.35 (dd, J=7.5, 0.8 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.55 (dt, J=8.0, 1.5 Hz, 1H), 8.03 (dt, J=7.9, 1.5 Hz, 1H), 8.07 (t, J=1.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N+:13]([O-])=[C:12]([CH3:18])[C:11]=2[CH3:19])[CH2:4][O:3]1.C(OC(=O)C)(=[O:23])C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:18][OH:23])[C:11]=2[CH3:19])[CH2:4][O:3]1
Reactant: Cc1c[n+]([O-])c(C)c(C)c1OCC1COC(C)(C)OC1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cnc(CO)c(C)c1OCC1COC(C)(C)OC1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 59.6 %

Procedure:
The 4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-2,3,5-trimethylpyridine 1-oxide (5.06 g, 18 mmol) obtained in the step (11e) was mixed with acetic anhydride (50 ml, 529 mmol) and the mixture was stirred at 85° C. for 1.5 hours. After cooled to room temperature, the reaction mixture was concentrated. Methanol (50 ml) and a 5N aqueous sodium hydroxide solution (50 ml, 250 mmol) were added to the residue and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was separated between water and ethyl acetate. The organic layer was washed with a 1N aqueous sodium hydroxide solution twice and dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the title compound (3.02 g, yield: 59.6%) as a brown oil.