Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:4][C@@H:2]1[CH3:3].[SH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1>>[OH:4][C@H:2]([CH3:3])[CH2:1][S:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: C[C@@H]1CO1
Reactant: COC(=O)c1ccc(S)cc1
Product: COC(=O)c1ccc(SC[C@@H](C)O)cc1

Procedure:
100 mg of (R)-propylene oxide was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (R)-methyl 4-(2-hydroxypropylthio)benzoate. 169 mg of (R)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 179 mg of (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (R)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.2 (M)+.
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(N(CC)CC)C.[Cl:18][C:19]([Cl:26])([Cl:25])[CH2:20][O:21][C:22](Cl)=[O:23]>ClCCl>[Cl:18][C:19]([Cl:26])([Cl:25])[CH2:20][O:21][C:22]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:23]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCC(Cl)(Cl)Cl)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Tetrahydroisoquinoline [Aldrich] (39.9 g, 300 mmol) was dissolved in dichloromethane (400 ml) and treated with triethylamine (32 g, 315 mmol). The mixture was cooled in an ice bath and a solution of 2,2,2-trichloroethylchloroformate (65.0 g, 306 mmol) in dichloromethane (100 ml) introduced dropwise over 15 minutes. After addition, the mixture was allowed to warm to room temperature and stirred for a further 30 minutes. The solution was washed with 1M aqueous hydrochloric acid (2×100 ml), then washed successively with water (100 ml), sodium bicarbonate (100 ml) and brine (50 ml), then dried (MgSO4), filtered and evaporated to give the title compound (D6) as a pale orange oil 92.5 g; δH (CDCl3 rotomers observed) ppm 2.90 (2H, app.t), 3.74-3.81 (2H, m), 4.67, 4.72 (2H, 2s), 4.80 (2H, s), 7.12-7.21 (4H, m).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Na+:5].[Na+].[B:7]([O-:10])([O-])[O-:8].[Na+].[Na+].[Na+].[OH:14][OH:15]>>[C:1]([O-:4])([O-:3])=[O:2].[C:1]([O-:4])([O-:3])=[O:2].[OH:14][OH:15].[OH:14][OH:15].[OH:14][OH:15].[Na+:5].[Na+:5].[Na+:5].[Na+:5].[B:7]([O:10][O-:14])=[O:8].[Na+:5]
Reactant: [O-]B([O-])[O-]
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Product: O=BO[O-]

Procedure:
The anionic surface active agent can be added to either an aqueous solution of sodium carbonate or sodium borate, or to the aqueous hydrogen peroxide. Further, the order of mixing or addition is optional in this invention. More specifically, high specific volume sodium percarbonate or sodium perborate can be obtained in similar fashion (1) by adding the surface active agent to an aqueous solution of sodium carbonate or sodium borate and either (a) adding the resulting solution to aqueous hydrogen peroxide, or (b) adding aqueous hydrogen peroxide to the above-mentioned solution, or (2) by adding the surface active agent to aqueous hydrogen peroxide and either (a) adding the resulting solution to an aqueous solution of sodium carbonate or sodium borate, or (b) by adding an aqueous solution of sodium carbonate or sodium borate to the above-mentioned hydrogen peroxide solution. In this invention, 15 to 70 percent by weight aqueous solution of sodium carbonate and 10 to 100 percent by weight aqueous hydrogen peroxide are used. Alternatively, 1 to 70 percent by weight aqueous solution of sodium borate and 5 to 100 percent by weight aqueous hydrogen peroxide are used. When sodium carbonate or sodium borate is not entirely dissolved, the slurry liquid may be used. Furthermore, according to this invention, solid sodium carbonate or sodium borate itself can be added to aqueous hydrogen peroxide containing a surface active agent.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH2:12][CH2:11]3)[CH2:5][C:4](=[O:17])[CH:3]=1.O.[C:19](O)(=[O:22])[CH2:20][CH3:21]>C(OC(=O)CC)(=O)CC.FC(S(O)(=O)=O)(F)F>[OH:17][C:4]1[CH2:5][CH:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH2:12][CH2:11]3)[CH2:7][C:2](=[O:1])[C:3]=1[C:19](=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)O
Reactant: O=C1C=C(O)CC(c2ccc3c(c2)CCC3)C1
Agent: CCC(=O)OC(=O)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: CCC(=O)C1=C(O)CC(c2ccc3c(c2)CCC3)CC1=O
Temperature: 130 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
3-Hydroxy-5-(5-indanyl)cyclohex-2-en-1-one (4.0 g; 18 mmole) was dissolved in a mixture of propionic acid (4 ml) and propionic anhydride (4 ml) at 130° C. under nitrogen. To the resulting clear solution was added 8 drops of trifluoromethyl sulphonic acid and the mixture was allowed to stir at 130° C. under nitrogen for a further 11/2 hours. The mixture was poured into water (500 ml) and stirred until all the anhydride had reacted (approx 30 min). The resulting solid was filtered off, pressed dry at the pump and then dissolved in dichloromethane and purified by column chromatography over silica gel (eluant dichloromethane) to give 3-hydroxy-5-(5-indanyl)-2-propionylcyclohex-2-en-1-one (1.88 g; 37%), mp 98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[N:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5].Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:17][C:12]1[C:11]2[C:16](=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([Cl:1])=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:41])[CH:8]=[CH:9][CH:10]=2)[N:15]=[CH:14][CH:13]=1
Reactant: O=C(Nc1cccc2c(N=P(c3ccccc3)(c3ccccc3)c3ccccc3)ccnc12)c1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 130 °C
Yield: 100.1 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-4-[(triphenylphosphoranylidene)amino]quinoline (310 mg), 6N hydrochloric acid (5 ml) and acetic acid (5 ml) was heated for 3 hours at 130° C. After cooling, the mixture was neutralized with 6N sodium hydroxide solution, and the insoluble material was collected by filtration. The residue was recrystallized from ethyl acetate to give 4-amino-8-(2,6-dichlorobenzoylamino)quinoline (174 mg).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][N:7]1[CH:12]=[C:11]([C:13]#[N:14])[C:10](=[O:15])[NH:9][C:8]1=[O:16])C>O1CCOCC1>[O:16]=[C:8]1[NH:9][C:10](=[O:15])[C:11]([C:13]#[N:14])=[CH:12][N:7]1[CH2:6][CH2:5][CH:4]=[O:3]
Reactant: CCOC(CCn1cc(C#N)c(=O)[nH]c1=O)OCC
Solvent: C1COCCO1
Product: N#Cc1cn(CCC=O)c(=O)[nH]c1=O
Temperature: 60 °C
Yield: 130.7 %

Procedure:
1-(3,3-diethoxy-propyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (Prep 34, 50 mg, 0.21 mmol) was dissolved in dioxane (5 mL) and 1N HClaq (500 μl) was added. The mixture was warmed at 60° C. for 15 minutes. The solvents were evaporated and the residue submitted to liophilization to give 53 mg of the title compound (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[N:59]1[CH:64]=[CH:63][C:62]([CH2:65][CH2:66][NH2:67])=[CH:61][CH:60]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:67][CH2:66][CH2:65][C:62]3[CH:63]=[CH:64][N:59]=[CH:60][CH:61]=3)=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: NCCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ccncc1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (390 mg, 0.982 mmol), 1-hydroxybenzotriazole (221 mg, 1.637 mmol) and EDCI (314 mg, 1.637 mmol) were dissolved in DCM (Volume: 4.0 ml). The suspension was stirred at room temperature for 10 minutes where it turned clear. Hunig's Base (0.286 ml, 1.637 mmol) and 2-(pyridin-4-yl)ethanamine (0.098 ml, 0.819 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was concentrated and triturated with ethyl acetate to afford the product as a white solid. Yield: 328 mg (White solid) 1H-NMR (500 MHz, DMSO-d6) 8.46, 7.91, 7.63, 7.55, 7.34, 7.25-7.18, 7.14-7.06, 6.72, 5.49, 4.54-3.80, 3.32, 3.07-2.77, 2.73, 2.37-2.28, 1.77-1.18.
Reaction SMILES: C(OC[O:10][C@@H:11]1[C@@:27]2([CH3:28])[C@@H:23]([CH2:24][CH2:25][C@@H:26]2[CH:29]([CH3:45])[CH2:30][CH:31]=[C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:22]2[C@@H:13]([C@:14]3([CH3:62])[C@H:19]([CH2:20][C@H:21]2[O:46][Si](C(C)(C)C)(C)C)[CH2:18][C@H:17]([O:54][Si](C(C)(C)C)(C)C)[CH2:16][CH2:15]3)[CH2:12]1)C1C=CC=CC=1>CCOCC.C(S)C.[Cl-].[Zn+2].[Cl-]>[OH:54][C@@H:17]1[CH2:16][CH2:15][C@@:14]2([CH3:62])[C@H:19]([CH2:20][C@@H:21]([OH:46])[C@@H:22]3[C@@H:13]2[CH2:12][C@H:11]([OH:10])[C@@:27]2([CH3:28])[C@H:23]3[CH2:24][CH2:25][C@@H:26]2[CH:29]([CH3:45])[CH2:30][CH:31]=[C:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:18]1
Reactant: CC(CC=C(c1ccccc1)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]4C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3C[C@H](OCOCc3ccccc3)[C@]12C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCS
Product: CC(CC=C(c1ccccc1)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 12α-benzyloxymethoxy-3α,7α-di-tert-butyldimethylsilyloxy-17β-[(1,1-diphenyl)-1-penten-4-yl]-5β-androstane (4.63 g), 1M zinc chloride in ether (10.5 ml) and ethanethiol (2.0 ml) in ether (10 ml) is stirred at room temperature for about 30 minutes. The mixture is concentrated in vacuo and the residue taken up in ether. The ether solution is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:38][CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)=[O:14])=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:21][CH:22]=1
Reactant: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccc(F)cc1
Reactant: NCCc1ccncc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1cc(C(=O)NCCc2ccncc2)ccc1OCc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
4-(4-fluorobenzyloxy)-3-isobutylbenzoic acid(1.51 g) was dissolved in chloroform(50 ml) and triethylamine(1.38 ml), and then diphenylphosphinic chloride(0.95 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(2-aminoethyl)pyridine(0.61 g) added thereto, was stirred for 2 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.74 g of the aimed compound as white crystals.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH3:16]>>[Br:6][C:7]1[C:8]([CH3:16])=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:14][C:15]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: O=S(=O)(O)Cl
Product: Cc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1Br
Temperature: 0 °C

Procedure:
Chlorosulfonic acid (150 mL, 2.18 mol) was added slowly to compound of Example 1b (74 g, 0.344 mol) at 0° C. The reaction mixture was refluxed for 4.5 h and then was poured into ice-cold water (1500 mL) with stirring. The solid was filtered, washed with water till filtrate was neutral and dried to obtain the title compound. Yield: 72.40 g (66.8%); 1H NMR (DMSO-d6, 300 MHz): δ 2.40 (s, 3H, CH3), 7.80 (s, 1H, Ar), 8.30 (s, 1H, Ar); MS: m/e (ES−) 315 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH3:17])[C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25].Cl>C1C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH3:17])[C:3]=1[C:4]([OH:6])=[O:5])(=[O:26])[CH3:25]
Reactant: CCOC(=O)c1c(C)cc(N)c(C(=O)O)c1C
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)c1c(C)cc(NC(C)=O)c(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.6 %

Procedure:
To a mixture consisting of 1 g of 2-amino-5-ethoxycarbonyl-4,6-dimethylbenzoic acid, 20 ml of benzene, and 0.7 ml of pyridine in a flask cooled with ice water was added dropwise with stirring a solution of 600 mg of acetyl chloride in 5 ml of benzene. The mixture was further stirred for 5 hours at room temperature, and then heated to reflux for one hour. After cooling, the mixture was shaken with dilute hydrochloric acid and the layers were separated. The acidic aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with water, and dried over sodium sulfate. The solvent was removed by distillation. The resulting residue was recrystallized from ethanol/water to yield 1.02 g of 2-acetylamino-5-ethoxycarbonyl-4,6-dimethylbenzoic acid melting at 170°-171° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:50]([C:52]1[CH:60]=[C:59]([CH3:61])[C:55]([C:56](O)=[O:57])=[C:54]([CH3:62])[CH:53]=1)#[N:51].CCN(C(C)C)C(C)C>CN(C=O)C>[C:50]([C:52]1[CH:60]=[C:59]([CH3:61])[C:55]([C:56]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:7][CH2:8][CH:9]([N:12]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH2:10][CH2:11]2)[CH3:5])=[O:57])=[C:54]([CH3:62])[CH:53]=1)#[N:51]
Reactant: Cc1cc(C#N)cc(C)c1C(=O)O
Reactant: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(C#N)cc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine (1.00 g, 2.62 mmol), EDCI (0.55 g, 2.88 mmol) and HOBT (0.39 g, 2.88 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 4-cyano-2,6-dimethyl-benzoic acid (0.50 g, 2.88 mmol) followed by DIPEA (1.14 mL, 6.55 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 96:3:1, v/v/v) afforded 4-cyano-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (0.77 g, 54%) as a white foam. 1H NMR (CDCl3) δ 0.98-1.04 (d+m, 4H), 1.22 (m, 1H), 1.54 (m, 1H), 1.73-1.82 (m, 3H), 2.16 (t, 1H), 2.33 (s, 3H), 2.36 (s, 3H), 2.40 (m, 1H), 2.52 (m, 1H), 2.69-2.88 (m, 3H), 3.21 (m, 1H), 3.33 (m, 1H), 3.73 (s, 3H), 3.77 (m, 1H), 3.96 (s, 2H), 6.63 (d, 2H, J=9.0 Hz), 6.73 (d, 2H, J=9.0 Hz), 7.05 (d, 1H, J=6.0 Hz), 7.27 (s, 2H), 7.84 (br s, 1H), 8.25 (s, 1H), 8.31 (d, 1H, J=6.0 Hz).
Reaction SMILES: [F:1][C:2]1([F:35])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:32][CH3:33])=[C:27]([N+:29]([O-])=O)[CH:28]=5)[C:20]([CH3:34])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[H][H]>CO.[Pd]>[NH2:29][C:27]1[CH:28]=[C:23]([C:21]2[C:20]([CH3:34])=[CH:19][CH:18]=[C:17]([NH:16][C:14]([C:11]3([C:9]4[CH:8]=[CH:7][C:5]5[O:6][C:2]([F:1])([F:35])[O:3][C:4]=5[CH:10]=4)[CH2:12][CH2:13]3)=[O:15])[N:22]=2)[CH:24]=[N:25][C:26]=1[O:32][CH3:33]
Reactant: [H][H]
Reactant: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1N
Yield: 77.8 %

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-5′-nitro-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (71 mg, 0.15 mmol) in methanol (10 mL) was added Pd/C (15 mg, 0.015 mmol) The reaction was stirred at room temperature under a balloon of hydrogen for one hour before being filtered and evaporated to yield the product (53 mg, 77%). ESI-MS m/z calc. 454.15. found 455.1 (M+1)+. Retention time 1.75 minutes.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].F[C:11](F)(F)[C:12](O)=O.C1(=O)OC(=O)C[C@@H]1O>C(O)C>[CH2:11]([O:8][C:1](=[O:9])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3])[CH3:12]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: O=C1C[C@H](O)C(=O)O1
Solvent: CCO
Product: CCOC(=O)[C@@H](O)CC(=O)O
Yield: 98.7 %

Procedure:
By using the reagents, procedures and conditions described by Example 3A L-malic acid was converted to L-malic anhydride trifluoroacetate and the latter was allowed to react with ethyl alcohol to provide in 98.7% yield L-malic acid monoethyl ester melting at about 48° to about 49.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][C:8]1=[CH2:9]>ClCCl>[CH2:9]=[C:8]([CH2:10][C:11]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:12])[C:7]([OH:14])=[O:13]
Reactant: C1COCCN1
Reactant: C=C1CC(=O)OC1=O
Solvent: ClCCl
Product: C=C(CC(=O)N1CCOCC1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
Morpholine (23.6 g, 271 mmol) was slowly added to a stirred solution of itaconic anhydride (30.36 g, 271 mmol) suspended in dichloromethane (200 mL) below −5° C. and stirred at that temperature for 1 hr. The reaction mixture was allowed to slowly warm up to room temperature and evaporated under reduced pressure below 30° C. to give a viscous oil. This was triturated with ethyl acetate to give 2-Methylene-4-morpholin-4-yl-4-oxo-butyric acid as white solid (36.8 g, 68%). The product was used without further purification in the next step.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:15][CH3:16])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].[CH:17]1([C:22](=[O:36])[CH2:23][CH2:24][C:25]#[C:26][C:27]2[CH:32]=[C:31]([CH3:33])[C:30]([OH:34])=[CH:29][C:28]=2[CH3:35])[CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1>[CH3:16][O:15][C:9](=[O:14])[CH2:10][C:11](=[O:12])[CH2:13][C:22]([CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)([OH:36])[CH2:23][CH2:24][C:25]#[C:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([OH:34])=[CH:29][C:28]=1[CH3:35]
Reactant: Cc1cc(C#CCCC(=O)C2CCCC2)c(C)cc1O
Reactant: COC(=O)CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)(CCC#Cc1cc(C)c(O)cc1C)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To a freshly prepared solution of LDA (1 M, 2.2 mL, 2.2 mmol) cooled to 0° C. was added methyl acetoacetate (0.12 mL, 1.1 mmol) dissolved in THF (1 mL). After stirring for 30 minutes, 1-cyclopentyl-5-(4-hydroxy-2,5-dimethyl-phenyl)-pent-4-yn-1-one (0.10 g, 0.37 mmol) from Step 1 above dissolved in THF (1 mL) was added. The reaction was stirred for 1 hour, and then warmed to room temperature. After quenching with 10 mL saturated ammonium chloride, the layers were separated. The aqueous layer was extracted with 2×15 mL CH2Cl2, and the organic layers were combined. After drying over Na2SO4, and filtering to remove the solids, the mother liquor was concentrated to an oil. Flash chromatography of the oil gave the desired product (69 mg, 48% yield).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:12]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:39])=[O:4])[CH:8]=[N:9][CH:10]=2)=[CH:18][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)cc2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)O)c3)cc2)cc1C)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.279 mL, 0.279 mmol) was added to a solution of (E)-[5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 123-(1); 46.5 mg, 0.093 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (29.7 mg, 66%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]2[C:6]([CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1.S(=O)(=O)(O)[OH:18].OO.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH3:1][S:2]([C:3]1[N:12]2[C:6]([CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1)=[O:18]
Reactant: O=S(=O)(O)O
Reactant: CSc1nnc2n1C=Cc1ccccc1C2
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)c1nnc2n1C=Cc1ccccc1C2
Reaction time: 7 h

Procedure:
To 0.230 g of 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine in 3 ml of acetic acid was added 0.2 ml of concentrated sulfuric acid and, under ice-cooling, 0.3 ml of a 30% aqueous solution of hydrogen peroxide was added dropwise. The mixture was allowed to stand at 3°-5° C. for 7 hours, at the end of which time an aqueous solution of sodium sulfite was added to the mixture to decompose the excess hydrogen peroxide. The solvent was evaporated off and the residue was diluted with water. The crystals were collected by filtration. By the above procedure was obtained 3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from methanol yielded colorless needles, m.p. 176°-177° C. Based on infrared absorption spectrum and other data, this compound was identified with the compound obtained in Example 17.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]>>[CH3:1][N:2]([CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]=[C:28]3[S:24][C:25](=[O:30])[NH:26][C:27]3=[O:29])=[CH:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)c1ccccn1
Reactant: O=C1CSC(=O)N1
Product: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)c1ccccn1
Yield: 86.2 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 610 mg (1.85 mmol) of 3′-[(methylpyrid-2-ylamino)methyl]biphenyl-4-carbaldehyde with 216 mg (1.85 mmol) of 2,4-thiazolidine dione, 640 mg (81%) of expected product are obtained.