Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].Cl>CN(C=O)C.[Cl-].[Na+].O>[F:15][C:13]1[CH:12]=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 22 %

Procedure:
Methylsulfonamide (2.421 g, 25.4 mmol) was dissolved in DMF (100 mL) and NaH (60% in oil, 1.00 g, 25 mmol) was added. The reaction stirred for 1 h and added to a stirred solution of 2,4-difluoronitrobenzene (4.372 g, 27.5 mmol) in DMF (20 mL). The reaction mixture was stirred for 2 h, poured into a mixture (1:1) of brine and 1 M HCl, and extracted with toluene. The organic phase was dried (MgSO4), and concentrated to give a solid that was crystallized from toluene/petroleum ether. The flask tipped over and some material was lost, to give 1.32 g, 5.64 mmol in 22% yield. MS (posES-FIA) m/z=found: 234; Calcd: 234.01; Anal (C7H7F N2O4S), C, H, N, S.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][NH2:4].OC1C=CC=CN=1.[C:14]([O:18][C:19](=[O:48])[NH:20][C@H:21]([C@@H:39]1[CH2:43][C@@H:42]([CH:44]([CH3:46])[CH3:45])[C:41](=[O:47])[O:40]1)[CH2:22][N:23]1[CH2:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH2:25][C:24]1([CH3:38])[CH3:37])([CH3:17])([CH3:16])[CH3:15]>O>[C:14]([O:18][C:19](=[O:48])[NH:20][C@@H:21]([CH2:22][N:23]1[CH2:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH2:25][C:24]1([CH3:38])[CH3:37])[C@@H:39]([OH:40])[CH2:43][C@H:42]([C:41](=[O:47])[NH:4][CH2:3][C@@H:2]([CH3:1])[CH2:5][CH3:6])[CH:44]([CH3:46])[CH3:45])([CH3:15])([CH3:17])[CH3:16]
Reactant: CC[C@H](C)CN
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Agent: Oc1ccccn1
Solvent: O
Product: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
0.24 ml of (S)-2-methylbutylamine (2.0 mmol) and 37 mg of 2-hydroxypyridine (0.39 mmol) were added to 200 mg of {(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (1m) (0.39 mmol), and the mixture was stirred at 80° C. for four hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/acetone=3/1) to obtain 184 mg of the title compound (yield: 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: ClCCOCCCl
Reactant: N#CCc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(Cl)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.1 %

Procedure:
To a stirred suspension of 2-(4-chlorophenyl)acetonitrile (3.06 g, 20.3 mmol) at 0° C. in DMSO (200 mL) was added NaH (1.79 g, 60% in mineral oil, 44.6 mmol). The reaction was stirred at 0° C. for 15 min then at room temperature for 30 min, resulting in a dark purple solution. To this solution was added 1-chloro-2-(2-chloroethoxy)ethane (3.18 g, 22.33 mmol) dropwise. The resulting mixture was stirred at room temperature overnight before diluting with 50 mL water and neutralizing to pH˜7.0 with 1.0 M aq. HCl. The reaction was extracted with Et2O (3×200 mL) and the combined organics were washed with brine (200 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (10-30% EtOAc/hexane eluent) to provide 4-(4-chlorophenyl)tetrahydro-2H-pyran-4-carbonitrile as a yellow crystalline solid (4.01 g, 89% yield) (Note: This compound does not ionize well on LC/MS. It does not have intense UV absorption at 220 nM. The TLC Rf is 0.6 in 30% EA/Hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][NH:21][CH2:22]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNC4)no2)cc1Cl
Reaction time: 16 h
Yield: 200.7 %

Procedure:
1,1-dimethylethyl 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 3) (2.57 g, 5.47 mmol) was stirred in 4M HCl in 1,4-Dioxane (100 mL). After 1 hour reaction became cloudy and stirring continued for a further 16 hours. Evaporation yielded 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.23 g). 1H NMR (400 MHz, d6-DMSO) δ 9.43 (2H, s), 8.19 (1H, s), 8.11 (1H dd), 8.03-8.00 (1H, m), 7.51-7.45 (3H, m), 4.89 (1H, sept.), 4.38 (2H, s), 3.43 (2H, t), 3.35-3.32 (2H, m), 1.37 (6H, d); m/z (API-ES) 370, 372 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[H-].[Na+].[CH3:14]I.O>C1COCC1>[I:1][C:2]1[C:3](=[O:11])[N:4]([CH3:14])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CI
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc([N+](=O)[O-])cc(I)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-iodo-5-nitropyridin-2-ol (2.66 g, 10.0 mmol) in THF (30 mL) was cooled to −20° C. NaH (60% dispersion in mineral oil, 0.600 g, 15.0 mmol) was added cautiously in three portions. After being stirred for 30 min at this temperature, methyl iodide (6.23 mL, 100.0 mmol) was added dropwise through a syringe. The resulting mixture was allowed to warm to rt during a 30 min period. Stirring was continued for 18 h at rt. Water (15 mL) was added with caution to quench the reaction. THF was removed under reduced pressure and methylene chloride (80 mL) was added to the aqueous phase. Layers were separated and the aqueous phase was extracted with methylene chloride (2×50 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated to afford the desired product as a yellow crystalline solid. 1H-NMR (CDCl3, 400 MHz): δ=3.73 (s, 3H), 8.65 (d, J=2.8 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H). MS (ES+): m/z 280.96 [MH+]. HPLC: tR=2.55 min (ZQ2000, polar—5 min).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][O:14][C:15]=2[CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].O.ClCCl>O1CCOCC1>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:13][O:14][C:15]=2[CH:16]([CH3:22])[C:17]([OH:19])=[O:18])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)C(C)c1onc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C(=O)O)c1onc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
Ethyl [4-[4-(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]propanoate from Step 2 (198 mg, 0.495 mmol) and aqueous sodium hydroxide (10%, 0.30 mL) were dissolved in dioxane (15 mL). The solution was heated to reflux and held for 16 hours. Upon cooling to room temperature, water (20 mL) was added, and the solution was extracted with ether (2×30 mL). The combined ethereal solution was extracted with dilute sodium hydroxide (5%, 2×30 mL). All of the aqueous phases were combined and acidified with hydrochloric acid (conc.) to pH<2. The acidic aqueous phase was extracted with ether (2×30 mL). The final ether solution was dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield a crude solid. Trituration with dichloromethane yielded crystals. The suspension was cooled to 0° C., filtered, washed with hexane and dried to yield [4-[4-(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]propanoic acid as a white crystalline solid (135 mg, 73%): mp 207° C. Mass spectrum: MH+=373. Anal. Calc'd. for C18H16N2O5S: C, 58.06; H, 4.33; N, 7.52; S, 8.61. Found: C, 57.87; H, 4.35; N, 7.49; S, 8.54.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (36 mg, 0.2 mmol) to give 5-{-4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:15][CH2:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[C:7](=[O:16])[C:6]=2[CH:17]=1.[BH4-].[Na+].O>C(O)C>[OH:16][CH:7]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:14][CH2:15][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:17][C:6]1=2
Reactant: Cc1ccc2c(c1)C(=O)c1cccnc1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)C(O)c1cccnc1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
4.46 g of 7-methyl-10,11-dihydro-5H-benzo-[4,5]cyclohepta[1,2-b]pyridin-5-one was dissolved in 22 ml of ethanol. To the solution was added 0.39 g of sodium borohydride with water-cooling. The resulting mixture was stirred for 1 hour at room temperature. To the reaction mixture was added 44 ml of water. The resulting crystals were collected by filtration and dried to obtain 4.19 g of 5-hydroxy-7-methyl-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine. They were recrystallized from ethanol to obtain 3.90 g of colorless crystals having a melting point of 202°-203° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([NH:5][C@@H:6]([CH3:32])[C@H:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]O)[CH:25]=1)[N:19]=[CH:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(N(CC)CC)C.CS(Cl)(=O)=O.OS([O-])(=O)=O.[K+].[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>[Cl-].[Na+].O.ClCCl>[F:33][C:2]([F:1])([F:34])[C:3]([NH:5][C@@H:6]([CH3:32])[C@H:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[CH:25]=1)[N:19]=[CH:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: C[C@H](NC(=O)C(F)(F)F)[C@H](Oc1ccc2c(cnn2-c2cccc(CO)c2)c1)c1ccccc1
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](Oc1ccc2c(cnn2-c2cccc(CN3CCOCC3)c2)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.92 h

Procedure:
To a stirred, ice-cooled solution of 2,2,2-trifluoro-N-((1R,2S)-1-(1-(3-(hydroxymethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide (144, 119 mg, 0.35 mmol) and triethylamine (0.35 mL, 2.5 mmol) was added methanesulfonyl chloride (140 μL, 1.8 mmol). The mixture was stirred for 55 min at 0° C. and brine was then added followed by dichloromethane (10 mL) and aqueous KHSO4 (1M). The phases were separated and the organic phase washed with sat aqueous NaHCO3. To the organic phase was the added morpholine (1 mL, 11.5 mmol). The mixture was stirred at ambient temperature for 16 h and was then evaporated. The residue was subjected to preparative HPLC (Kromasil C-18, 2.5×20 cm) using a gradient (holding 0.1% TfA) of 30-90% acetonitrile in water/60 min. Fractions containing the title compound were combined and evaporated. The residue, comprising the TfA-salt of the title compound was dissolved in MeOH and absorbed on a plug of acidic ion exchange resin (SCX, 5 g, pre-washed with MeOH). Eluting with MeOH and methanolic ammonia (2M) subsequently afforded after evaporation, re-dissolving in water and lyophilization 2,2,2-trifluoro-N-((1R,2S)-1-(1-(3-(morpholinomethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide (105 mg, 77%).
Reaction SMILES: [Br:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)([CH3:4])[CH3:3].[Mg].C1O[C:16]2([CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[O:15]C1>O1CCCC1>[Br:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)([CH3:4])[CH3:3].[Cl:11][C:7]1[CH:6]=[C:5]([C:2]([C:19]2[CH2:20][CH2:21][C:16](=[O:15])[CH2:17][CH:18]=2)([CH3:4])[CH3:3])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(C)(Br)c1cccc(Cl)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C1=CCC(=O)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The Grignard reagent of 2-bromo-2-(3-chlorophenyl)propane is prepared by adding dropwise a solution of 9.3 grams (0.040 mole) of 2-bromo-2-(3-chlorophenyl)propane in 45 mL of dry tetrahydrofuran to 1.1 grams (0.044 mole) of magnesium turnings in 25 mL of refluxing tetrahydrofuran. Upon completion of addition, the Grignard reagent is stirred at reflux for one hour. The reaction mixture is then cooled in an ice-water bath, and a solution of 6.2 grams (0.040 mole) of 1,4-cyclohexanedione mono-ethylene ketal in about 25 mL of tetrahydrofuran is added dropwise. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 18 hours. After this time the reaction is quenched by the addition of 100 mL of aqueous 10% hydrochloric acid. The reaction mixture is stirred for 10 minutes and then is extracted with two 50 mL portions of diethyl ether. The combined extracts are washed with 10 mL of water and then are dried with magnesium sulfate. The mixture is filtered and concentrated under reduced pressure, yielding 1-[2-(3-chlorophenyl)propan-2-yl]-1-cyclohexen-4-one.
Reaction SMILES: [Na].N#N.C(O[C:7]([C:9]1[C:10]([N:17]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[CH2:23][CH2:22][CH2:21]3)=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=1)=[O:8])C.CC(C)([O-])C.[Na+].Cl>C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH2:32]([O:31][C:29]([CH:28]1[CH2:27][N:17]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[CH2:23][CH2:22][CH2:21]3)[C:10]2[N:11]=[C:12]([S:15][CH3:16])[N:13]=[CH:14][C:9]=2[C:7]1=[O:8])=[O:30])[CH3:33]
Reactant: CCOC(=O)CCN(c1ccc2c(c1)CCC2)c1nc(SC)ncc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCOC(=O)C1CN(c2ccc3c(c2)CCC3)c2nc(SC)ncc2C1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To sodium (25 wt % dispersion in paraffin wax, 1.6 g, 16.9 mmol) was added t-butanol (30 mL) under stirring and N2. After 10 minutes, a solution of 4-[(2-ethoxycarbonyl-ethyl)-indan-5-yl-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (6.6 g, 15.4 mmol) in 40 mL of toluene was added to the sodium t-butoxide solution. The mixture was then heated at 90° C. for 30 minutes. The solution was cooled and poured into crushed ice. The solution was adjusted to pH 7 using HCl solution. The precipitates were extracted into EtOAc twice. The solvent was evaporated under vacuum and the product (bright yellow solid, 4 g, 62%) was recrystallized from isopropanol. 1H NMR (300 MHz, CDCl3) indicated that the presence of both enol and keto forms in a 4:1 ratio.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19]([Cl:23])(=O)(=[O:21])[OH:20]>C(Cl)(Cl)Cl>[O:18]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:19]([Cl:23])(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound (330 mg) obtained in Example 24-1 was dissolved in chloroform and then added with chlorosulfuric acid (manufactured by Kishida Chemical Co., Ltd.) (0.177 ml) under ice-cooling. The solution was stirred at room temperature for 2 days, and then concentrated and dried. The resultant was gradually added with phosphorus pentachloride (300 mg) and then heated to 80° C., followed by stirring for 4 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].N1C=CC=CC=1.Cl[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20]>C1(C)C=CC=CC=1.C(Cl)Cl.O>[C:19](=[O:20])([O:21][CH:22]([CH3:24])[CH3:23])[O:10][C:8]1[CH:9]=[C:2]([Cl:1])[C:3]([CH:4]=[O:5])=[C:6]([Cl:11])[CH:7]=1
Reactant: CC(C)OC(=O)Cl
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)Oc1cc(Cl)c(C=O)c(Cl)c1
Yield: 81 %

Procedure:
To a 250 mL dry round bottom flask were added 2,6-dichloro-4-hydroxybenzaldehyde (5.73 g, 30.0 mmol), anhydrous CH2Cl2 (30 mL) and pyridine (3.0 mL, 36.5 mmol). The mixture was stirred in an ice-water bath, then a solution of isopropyl chloroformate in toluene (1.0 M, 33.4 mL) was added. After stirring at 0° C. for 2 hours, water (100 mL) and CH2Cl2 (50 mL) were added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (40 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 3,5-dichloro-4-formylphenyl isopropyl carbonate (6.72 g) as a colorless oil. Yield: 81%. 1H NMR (CDCl3, 300 MHz): δ=10.53 (s, 1H), 7.41 (s, 2H), 5.09 (seventet, J=6.3 Hz, 1H), 1.48 (d, J=6.3 Hz, 6H). 13C NMR (CDCl3, 75.5 MHz): δ=187.8, 153.8, 151.5, 138.0, 127.8, 122.8, 74.6, 21.8.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1>C(O)(=O)C.[Pt]=O>[OH:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]([OH:12])[CH2:2][CH2:3]1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: O=[Pt]
Solvent: CC(=O)O
Product: OC1CCC(O)c2ccccc21
Reaction time: 24 h
Yield: 58.3 %

Procedure:
To a solution of 1,4-naphthoquinone (10 g, 63.3 mM) in glacial acetic acid were added platinum oxide (0.75 g, 3.3 mM) and the mixture was hydrogenated in a Parr apparatus under a pressure of 30-40 psi for about 24 h at room temperature. The catalyst was filtered off, the acetic acid was evaporated under vacuum, the residue was dissolved in hot water (200 ml) and the solution cooled to give crystalline 1,4-dihydroxytetralin in 58.3% yield (4.0 g).
Reaction SMILES: Cl.C([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)C1C=CC=CC=1.[C:17]1([CH2:27][C:28]([OH:30])=O)[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=O)=[CH:19][CH:18]=1>CCOC(C)=O>[C:10]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:28](=[O:30])[CH2:27][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:11]2[C:10]([OH:9])=[O:16])=[O:26])=[CH:21][CH:22]=1)([OH:16])=[O:9]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H]1CCCN1C(=O)Cc1ccc(CC(=O)N2CCC[C@H]2C(=O)O)cc1
Yield: 134.4 %

Procedure:
Using General Procedure A with 1.0 g (4.1 mmol) L-Proline benzyl ester hydrochloride and 400 mg (2.1 mmol) 1,4-phenylenediacetic acid afforded, after flash chromatography (EtOAc), 1.07 g (91%) of the title compound as a colorless oil.
Reaction SMILES: C(O[C:4](=[C:7]([C:10]#[N:11])[C:8]#[N:9])[CH2:5][CH3:6])C.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:13][SH:14].C([O-])(=O)C.[K+].O>C(O)C>[CH2:17]([O:16][C:12]([C:13]1[S:14][C:4]([CH2:5][CH3:6])=[C:7]([C:8]#[N:9])[C:10]=1[NH2:11])=[O:15])[CH3:18]
Reactant: CCOC(CC)=C(C#N)C#N
Reactant: CCOC(=O)CS
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(CC)c(C#N)c1N
Temperature: 60 °C

Procedure:
Add 2-(1-ethoxy-propylidene)-malononitrile, prepared in preparation 38, (230.0 g, 1531 mmol) in ethanol (1.3 L) stir with overhead stirring under nitrogen at rt and add ethyl thioglycolate (168.8 mL, 1531 mmol) and potassium acetate (225.4 g, 2297 mmol). Heat the resulting red mixture at 60° C. for 2 h. Add water (300 mL) and cool the mixture to 5° C. for 1 h. Collect the precipitate that forms by filtration, wash with 20-25% water/ethanol, and dry at rt for 3 d affording the title compound as light orange needles: 1H NMR (DMSO-d6) δ 6.76 (bs, 2H), 4.18 (q, J=7.1, 2H), 2.86 (q, J=7.5, 2H), 1.223 (t, J=7.1, 3H), 1.220 (t, J=7.5, 3H); 13C NMR (DMSO-d6) 163.8, 163.7, 153.7, 112.9, 100.0, 96.3, 60.0, 23.2, 14.3, 14.2.
Reaction SMILES: [CH:1](OC(=O)C)=[O:2].[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>>[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH:24][CH:1]=[O:2])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: Nc1ccc(OC2CCN(c3ccncc3)CC2)cc1
Reactant: CC(=O)OC=O
Product: O=CNc1ccc(OC2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
Acetic formic anhydride (1.5 g; pre-formed by heating acetic anhydride and 98% formic acid at 60° C. for 2 hours) was cooled to 5° C. and 4-[1-(4-pyridyl)piperidin-4-yloxy]aniline (1.0 g) was added. The mixture was stirred at ambient temperature for 16 hours and then evaporated. The residue was dissolved in water (50 ml) and the mixture was basified to pH10 by the addition of a 2M aqueous sodium hydroxide solution. The resultant mixture was extracted with methylene chloride, washed with water and with brine, dried (MgSO4) and evaporated to give N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}formamide as a foam (0.72 g);
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:5][CH:6]=[CH2:7])[CH2:3][OH:4].[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:16][O:4][CH2:3][C:2]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:1])[CH2:5][CH:6]=[CH2:7]
Reactant: CI
Reactant: C=CCC(C)(CO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(C)(COC)c1ccccc1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 2-methyl-2-phenylpent-4-en-1-ol (3.2 g, 18.15 mmol) in 17 mL of DMF was added sodium hydride (1.25 g, 31.25 mmol, 60% in mineral oil). The mixture was stirred until foaming ceased and then methyl iodide (6 mL, 96 mmol) was added. After 2 hours, the mixture was quenched with 50 mL of saturated aqueous ammonium chloride solution and extracted with three 50 mL portions of ethyl acetate. The combined organic layers were washed with 30 mL of saturated aqueous ammonium chloride solution, five 25 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3.4 g (98.4% yield) of (1-methoxymethyl-1-methylbut-3-enyl)benzene which was used without further purification.