Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[C:23]([Cl:29])[CH:22]=1)(=[O:20])=[O:19])[CH3:2].B(Cl)(Cl)Cl.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:29][C:23]1[CH:22]=[C:21]([S:18]([N:4]2[CH:3]([CH2:1][CH3:2])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=3)(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[OH:27]
Reactant: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(Cl)c1
Yield: 39.9 %

Procedure:
The title compound was prepared from 6-ethyl-8-fluoro-5-[(3-chloro-4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (0.41 g, 0.96 mmol), tetrabutylammonium iodide (0.85 g, 2.3 mmol), and 1 M boron trichloride in dichloromethane (6.7 mL, 6.7 mmol) according to the procedure and in the same manner as described in Example 35, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (20:80 to 35:65 gradient), followed by re-crystallization from a mixture of ethyl acetate-hexane, to yield 2-chloro-4-[(6-ethyl-8-fluorophenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.16 g, 41%), m.p. 174-177° C.;
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([C:24]#[N:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:24][NH2:25])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Yield: 100 %

Procedure:
The title compound (1.05 g, 100%) was prepared from 4-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}tetrahydro-2H-pyran-4-carbonitrile and lithium aluminium hydride similarly to the procedure used for intermediate 51. LRMS APCI+ m/z 345 [MH]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[NH:10]1[C:1]([C:3]2[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=2)=[N:2][N:12]=[N:11]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Br)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(-c2nnn[nH]2)nc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
10 g of 2-cyano-5-bromopyridine prepared in the Preparation example 5 was dissolved in 100 ml of dimethylformamide, 5.33 g of sodiumazide, and 4.4 g of ammoniumchloride were added to the solution at room temperature, and the solution was stirred at the temperature of 110° C. for 3 hours for reaction. The reaction mixture was added with water and then was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated and concentrated in vacuo thereby to obtain 10.5 g of the title compound. Yield 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25](O)=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1.Cl.[CH3:33][NH:34][CH3:35].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([N:34]([CH3:35])[CH3:33])=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1
Reactant: CNC
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: CN(C)C(=O)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
trans-4-{[(2-{[(5-Chloropyridin-2-yl)amino]-carbonyl}benzofuran-3-yl)amino]carbonyl}cyclohexane-carboxylic acid (176 mg) obtained in Example 8(2) is suspended in pyridine (8 ml), and thereto are added successively dimethylamine hydrochloride (65 mg), 1-hydroxybenzotriazole (108 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg) under ice-cooling, followed by stirring at room temperature for 19 hours. To the reaction solution is poured ice-water and the precipitates are collected by filtration. The resulting precipitates are dissolved in chloroform and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate) The resulting residue is suspended in n-hexane and the precipitates are collected by filtration to give the title compound (137 mg). APCI-MS M/Z:469/471[M+H]+
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:47]=[CH:46][C:18]2[C:19]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:20]([CH2:22][O:23][C:24]3[C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][N:26]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:25]=3)[O:21][C:17]=2[CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:47]=[CH:46][C:18]2[C:19]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[C:20]([CH2:22][O:23][C:24]3[C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:25]=3)[O:21][C:17]=2[CH:16]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1oc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2c(-c3ccccc3)c(COc3nn(-c4ccccc4)cc3C(=O)O)oc2c1
Yield: 91.6 %

Procedure:
To a mixture of ethyl 3-({6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-yl}methoxy)-1-phenyl-1H-pyrazole-4-carboxylate (0.40 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 1 hr. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-({6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-yl}methoxy)-1-phenyl-1H-pyrazole-4-carboxylic acid as colorless crystals (0.35 g, yield 92%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 200-201° C.
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].Br[C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][CH:17]=1>CN1C(=O)CCC1.O.[Cu]Cl>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7]
Reactant: COc1cccc(Br)c1
Reactant: OCc1cccc(O)c1
Agent: Cl[Cu]
Agent: [K]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cccc(Oc2cccc(CO)c2)c1
Temperature: 170 °C
Yield: 52.1 %

Procedure:
To a solution of the potassium salt of 3-hydroxybenzyl alcohol (8.1 g, 50 mmol) in N-methyl pyrolidinone (20 ml) were added 3-bromoanisole (11.22 g, 60 mmol), copper (I) chloride (0.1 g, 1 mmol) and p-hydroxyquinoline (0.1 g, 1 mmol) and the reaction was heated to 170° C. for fifty hours. The reaction was cooled to room temperature, diluted with water (150 ml) and extracted with ether (5×50 ml). The combined extracts were dried (MgSO4) and evaporated. The residue was purified by flash chromatography (eluting with 10% ethyl acetate/60°-80° petrol) to afford 3-(3-methoxyphenoxy)benzyl alcohol as a pale oil 6.0 g (52%); δH (CDCl3) 3.80 (3H, s, OCH3), 4.64 (2H, s, CH2OH), 6.54-6.70 (3H, m, ArH), 6.88-7.10 (3H, m, ArH), 7.18-7.36 (2H, m, ArH).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[NH2:12].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH3:24])(=[O:23])=[O:22].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[F:20][C:18]1[CH:19]=[CH:14][C:15]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([NH:12][CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][CH:2]2[CH3:1])[CH:17]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Reactant: CC1CCc2ccccc2C1N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCc2ccccc2C1Nc1cc(F)ccc1S(C)(=O)=O
Temperature: 25 °C
Yield: 50 %

Procedure:
3,4-Dihydro-2-methylnaphthalen-1(2H)-one (5.2 g, 33.0 mmol), titanium(IV) isopropoxide (19.3 mL, 66.0 mmol) and 2 M solution of ammonia in ethanol (82.0 mL, 165 mmol) were stirred at room temperature for 6 h. The reaction was cooled to 0° C. and sodium borohydride was added portionwise during 10 min. (1.87 g, 49.5 mmol); the resultant mixture was stirred at rt for an additional 3 h. The reaction was quenched by pouring it into ammonium hydroxide (2 M, 20 mL), the precipitate that formed was filtered off and washed with ethyl acetate (20 mL×3). The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with 1 M HCl (15 mL). The acidic aqueous extracts were washed with ethyl acetate (30 mL), then treated with aqueous sodium hydroxide (2 M) to pH 10-12, and extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with brine (15 mL), dried (Na2SO4), and concentrated in vacuo to afford the desired product (1.20 g, 22.6% yield). The compound was used without further purification for the following reaction. A solution of 1,2,3,4-tetrahydro-2-methylnaphthalen-1-amine (63.0 mg, 0.39 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (85.0 mg, 0.43 mmol) and diisopropylethylamine (200 mg, 1.56 mmol) in N,N-dimethylformamide (1 mL) was stirred at 110° C. for 16 h. The reaction was cooled to room temperature, poured over water and extracted with diethyl ether. The solvent was concentrated in vacuo and the residue was purified by silica chromatography (10% ethyl acetate in hexanes) to give 65.0 mg (50%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, 1H), 7.20 (m, 4H), 6.52 (m, 3H), 4.25 (t, 1H), 2.99 (s, 3H), 2.86 (t, 1H), 2.65-1.65 (m, 4H), 1.16 (d, 3H); MS (ESI) m/z: 333.6 (M++1).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[CH2:15][C:16](=[O:19])[NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.O1CCCC1.[H-].[Na+].Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[CH2:15][C:16](=[O:19])[N:17]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C1CN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2CN1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1CN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2CN1Cc1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a solution of the product from Example 201C (64 mg, 0.233 mmol) in 4:1 tetrahydrofuran:N,N-dimethylformamide (2 mL) was added sodium hydride (11.2 mg, 0.280 mmol). The resulting mixture was stirred at ambient temperate for 30 minutes, and 1-(bromomethyl)-3-(trifluoromethyl)benzene (42.8 μL, 0.280 mmol) was added. The mixture was stirred at ambient temperature for 1 hour and was then partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography on a 12 g silica gel column eluting with 5% ethyl acetate/hexanes for 3 minutes then a gradient to 100% ethyl acetate over 20 minutes. The title compound was obtained as a thick oil (13 mg, 13%). 1H NMR (300 MHz, methanol-d4) δ ppm 7.99 (dt, J=11.3, 5.7 Hz, 2H), 7.65-7.49 (m, 4H), 5.42 (dd, J=12.6, 5.1 Hz, 1H), 4.70 (d, J=3.7 Hz, 2H), 3.81-3.61 (m, 2H), 3.50-3.35 (m, 1H), 3.16 (dd, J=13.4, 8.3 Hz, 2H), 2.87 (qd, J=10.1, 4.9 Hz, 1H), 2.39 (dd, J=10.4, 5.0 Hz, 1H), 2.20-1.85 (m, 3H), 1.02-0.82 (m, 4H); MS (ESI) m/z 275 (M+H)+.
Reaction SMILES: [Se](=O)=O.[O:4]1CCOCC1.[S:10]([NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)([CH3:13])(=[O:12])=[O:11].C>O>[S:10]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[O:4])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)([CH3:13])(=[O:11])=[O:12]
Reactant: C1COCCO1
Reactant: CCOC(=O)Cc1csc(NS(C)(=O)=O)n1
Agent: CCOC(=O)Cc1csc(=NS(C)(=O)=O)[nH]1
Agent: O=[Se]=O
Solvent: O
Product: CCOC(=O)C(=O)c1csc(NS(C)(=O)=O)n1

Procedure:
To a solution prepared by stirring a mixture of selenium dioxide (0.22 g.), dioxane (10 ml.) and water (0.2 ml.) for 10 minutes at 110° C. was added ethyl 2(2-mesylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (0.53 g.), and the mixture was refluxed for 1 hour. After the reaction, the reaction mixture was treated with activated charcoal. The precipitated crystals in the filtrate were collected by filtration and dried to give white crystals of ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (0.22 g.), mp. 222° to 225° C. On the other hand, the remaining filtrate was concentrated and the residue was washed with water and diethyl ether in turn and then dried to give the same object compound (0.12 g.).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:8]([CH2:30][C:31](=[O:40])[NH:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=2)[N:7]=1)=[O:5])C.C(O)(=O)C>C1COCC1.[OH-].[K+]>[C:14]([SiH2:13][O:12][C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:9]1[N:8]([CH2:30][C:31](=[O:40])[NH:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)n(CC(=O)Nc2ccc(Cl)cn2)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1cc(C(=O)O)nn1CC(=O)Nc1ccc(Cl)cn1
Reaction time: 16 h

Procedure:
To a solution of 2 g 5-(tert-Butyl-diphenyl-silanyloxymethyl)-1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-pyrazole-3-carboxylic acid ethyl ester in 10 ml THF, 7 ml aqueous KOH solution (10%) were added at RT and the mixture was stirred for 16 h. Then the solution was acidified by addition of 10 ml half concentrated acetic acid and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Yield: 1.8 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:24][CH2:25][CH:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:15]=3)[CH2:21][CH2:22]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCC(c3cccc(C(F)(F)F)c3)CC2)nc1
Temperature: 80 °C

Procedure:
To a mixture of 2-chloro-5-nitropyridine (500 mg, 3.2 mmol) and 4-(3-trifluoromethyl-phenyl)-piperidine hydrochloride in DMF (15 mL) was added diisopropylethylamine (1.70 mL, 9.60 mmol). The mixture was heated in a sealed tube at 80° C. for 24 hours. The mixture was concentrated to dryness and triturated in methanol to give 5′-nitro-4-(3-triflouromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([OH:26])=[O:25].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].C([O-])(O)=O.[Na+]>C1COCC1>[C:28]([C:23]1[S:19][C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH:22]=1)([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)c1cccs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C(=O)O)s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.1 %

Procedure:
To a solution of diisopropylamine (3.6 mL, 25.75 mmol) in 10 mL of THF at -78° C. under argon was added a 1.6M solution of n-butyllithium in hexane (16.1 mL, 25.75 mmol). The mixture was stirred for 15 min, and a solution of 2-thiophenecarboxylic acid 34 (1.5 g, 11.705 mmol) (2-thiophenecarboxylic acid 34 is readily available from Aldrich) in 5 mL of THF was added slowly. The mixture was stirred for 15 min, and ethyl chloroformate (2.7 mL, 28.33 mmol) was added. The mixture was stirred for 30 min at -78° C., and warmed to 0° C. for another 30 min. The reaction mixture was poured into saturated aqueous NaHCO3, and washed with 80% ethyl acetate/hexane. The aqueous layer was acidified with acetic acid and extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to afford a yellow solid. Flash chromatography yielded the desired acid 35 (1.76 g, 75%) as a white solid: m.p. >300° C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([NH:28][C:29](=[O:31])[CH3:30])[S:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([NH:28][C:29](=[O:31])[CH3:30])[S:26][CH:27]=2)=[CH:19][CH:20]=1)=[O:11])[NH2:2]
Reactant: CC(=O)Nc1nc(COc2ccc(CCOC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc(COc2ccc(CCOC(=O)NN)cc2)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
To a solution of 2-(4{[2-(acetylamino)-1,3-thiazol-4-yl]methoxy}phenyl)ethyl tert-butyl hydrazine-1,2-dicarboxylate (0.855 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (3.18 ml, 42.8 mmol) at 0° C. After stirring at 0° C. for 30 min, the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 4 times with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (20 ml) was added to suspend the residue. The suspension was filtered and washed once with ethyl acetate and 5 times with diethyl ether, and dried under reduced pressure to give the title compound (105.9 mg, 0.302 mmol, yield 35.3%) as a white solid.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.CN1C(=O)N(C)CCC1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][CH:21]=1.CI>C1COCC1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([CH3:2])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][CH:21]=1
Reactant: COc1ccc(CC(C)C(=O)OC(C)(C)C)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(CC(C)(C)C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
An oven dried flask was charged with THF (40 mL) under nitrogen and cooled to −78° C. and 2M LDA in THF (7.19 mL, 14.38 mmol) was added dropwise followed by DMPU (8 mL, 5.75 mmol). Tert-butyl 3-(4-methoxyphenyl)-2-methylpropanoate (1.44 g, 5.75 mmol) was added by cannula in THF (4×5 mL), and the reaction was stirred at −78° C. for 1 hr. Methyl iodide (1.079 mL, 17.26 mmol) was added dropwise, and the reaction was stirred 30 minutes at −78° C. and then warmed to room temperature for 1 hr. The reaction was quenched with water (40 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with 1N HCl (2×30 mL) and brine (2×30 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 60% ethyl acetate/hexanes) afforded tert-butyl 3-(4-methoxyphenyl)-2,2-dimethylpropanoate. 1H NMR (CDCl3, 500 MHz) δ 7.07 (d, J=8.5 Hz, 2H), 6.79 (d, J=8.7 Hz, 2H), 3.78 (s, 3H), 2.76 (s, 2H), 1.43 (s, 9H), 1.11 (s, 6H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.[C:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:29]I)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:28][CH2:29][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C([O-])CCCOc1cccc2c1Cc1sc(S)nc1-2
Reactant: ICCC(c1ccccc1)c1ccccc1
Product: O=C(O)CCCOc1cccc2c1Cc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 27 %

Procedure:
Using 4-[(2-mercapto-8H-indeno(1,2-d]thiazol-7-yl]oxy]butyrate and 3,3-diphenylpropyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 27%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[O:16])=[C:11]([OH:31])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)[OH:16])=[C:11]([OH:31])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1cc(OCc2ccccc2)ccc1C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of (4-benzyloxy-2-hydroxy-phenyl)-(4-benzyloxy-phenyl)-methanone (T1) (1.6 g, 4 mmol) in 40 mL of THF:MeOH (1:1) was added sodium borohydride (0.160 g, 4 mmol) and solution stirred at 40° C. for 4 hours. After complete consumption of starting material (TLC) the solvents were evaporated, till about 5 mL remaining in the flask. The residue was carefully neutralized with 1 N H2SO4, till pH dropped to 6 and yellow solution turned colorless. This was extracted with 50 mL (4×EtOAc:water, 1:1). The organic layers were combined and dried over sodium sulfate and evaporated to give (1.12 g, 68%) of T2 as pinkish white solid. 1H NMR (400 MHz, DMSO-d6) δ, 9.42(s, 1H, OH-Ph), 7.30(m, 13H, Ar—H2′/6′, 2×C6H5), 6.89 (d, 2H, Ar—H3′/5′), 6.44 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H5), 6.38 (d, 1H, J=2.4 Hz, Ar—H3), 5.51 (d, 1H, CH—OH), 5.04 (s, 2H, PhCH2), 4.99 (s, 2H, PhCH2).