Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[O:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1Oc1ccccc1
Solvent: ClCCl
Product: ClCc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Thionyl chloride (1.92 ml) was added in one portion to a solution of 2-phenoxybenzyl alcohol (4.80 g) in dry dichloromethane (50 ml). The resulting mixture was stirred at room temperature for 2 hours, then washed with water (×2), aqueous sodium bicarbonate (×2) and aqueous sodium chloride, dried and concentrated under reduced pressure to give 2-phenoxybenzyl chloride (4.87 g, 93%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[N:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:21]([C:18]1[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=1)[C:6]2=[CH2:7]
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: O=Cc1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C1c2cc(OC)c(OC)cc2C(=O)C1c1ccncc1
Yield: 95.7 %

Procedure:
5,6 Dimethoxy indanone (100 grams), Pyridine-4-carboxaldehyde (78.0 grams) and p-toluene sulfonic acid (138.4 grams) were suspended in toluene (1250 ml) and heated to reflux using water separator for 6 hours. The resulting mass was cooled to 25–40° C. and the solid was filtered off under suction. Further the wet solid was suspended in aqueous 10% sodium carbonate solution (1200 ml) and stirred for 30–60 minutes. The resulting pale yellow precipitate solid was filtered off under suction, washed with water (1000 ml) and dried at a temperature of 80° C. to afford 5,6 Dimethoxy-2-(pyridin-4yl)-methylene-indan-1one (Weight: 140 grams, 95.8%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]([OH:26])=O)=[CH:22][N:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1.Cl.C([N:41]=C=NCCCN(C)C)C.CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]([NH2:41])=[O:26])=[CH:22][N:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.4 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carboxylic acid (0.17 g), 1-hydroxybenzotriazole ammonia complex (0.08 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carboxamide as colorless crystals (0.15 g, yield 88%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 175-176° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[NH:34][C:33]2=[O:41])[CH2:28][CH2:27]1>CN(C)C=O>[O:41]=[C:33]1[N:32]([CH:29]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:31][CH2:30]2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCN2c3cccc4cccc(c34)S2(=O)=O)CC1
Temperature: 20 °C
Yield: 13.5 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7.2 g), triethylamine (3.6 cc) and 1-(4-piperidinyl)-2-benzimidazolinone (5.6 g) in dimethylformamide (100 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethanol (95-5 vol) as eluant, and recrystallization from boiling acetonitrile (200 cc), 2-{3-[4-(2-oxo-1-benzimidazolinyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.6 g) is obtained, m.p. 253° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2.Cl.[NH2:36][OH:37].[OH-].[Na+].O>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](/[C:12](=[N:36]/[OH:37])/[NH2:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH3:15])=[CH:7]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C#N)n4)ncnc32)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(/C(N)=N/O)n4)ncnc32)cc1
Temperature: 25 °C

Procedure:
A mixture of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl) isoquinoline-1-carbonitrile 29 (600 mg, 1.28 mmol, 1.0 eq), hydroxylamine hydrochloride (269 mg, 3.84 mmol, 3 eq) and NaOH (154 mg, 3.84 mmol, 3 eq) in EtOH (15 mL) was stirred at reflux 4 h. The mixture was cooled to RT, poured into water (100 mL) and then extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product (S,Z)-8-chloro-N′-hydroxy-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carboximidamide 30.
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]=2[OH:18])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1>FC(F)(F)C(O)=O>[Cl:17][C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2[O:18][C@@H:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]3[C:7]=2[CH:16]=1
Reactant: COC(=O)c1cc(Cl)cc(C2CC=CCC2)c1O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)cc2c1O[C@@H]1CCCC[C@@H]21
Temperature: 70 °C

Procedure:
A mixture of 9 g of methyl 3-(3-cyclohexenyl)-5chlorosalicylate and 20 ml trifluoroacetic acid is heated at 70° C. overnight. The cooled reaction mixture is diluted with hexanes, washed three times with water, dried and evaporated to dryness. The residue is purified with flash chromatography using 10% ethyl acetate/hexane to give four fractions
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[NH2:19][C:20]1[N:25]=[C:24](Cl)[N:23]=[C:22]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[Cl:34])[N:21]=1>O>[NH2:19][C:20]1[N:25]=[C:24]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])[N:23]=[C:22]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[Cl:34])[N:21]=1
Reactant: OCCNCCO
Reactant: Nc1nc(Cl)nc(-c2cc(Cl)ccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2cc(Cl)ccc2Cl)nc(N(CCO)CCO)n1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a mixture of 9.2 g of diethanolamine, 200 ml of N,N-dimethylformamide, and 15 g of anhydrous potassium carbonate was added 20 g of 2-amino-4-chloro-6-(2,5-dichlorophenyl)-1,3,5-triazine with stirring at room temperature and the mixture was further stirred at room temperature for 7 hours. This reaction mixture was diluted with 2 L (liters) of water with stirring and then stirred for 1 hour. The resulting crystals were collected by filtration, rinsed with water, and dried to obtain 24 g of white crystals. Those crystals were recrystallized from methanol, collected by filtration, and dried to give 21 g of the title compound as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)C(O)=COC=1CO.COC1C(OC(C(O)C2C=CC(O)=C(OC)C=2)CO)=CC=CC=1.[NH3:51]>C(O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[NH:51][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Reactant: N
Agent: COc1cc(C(O)C(CO)Oc2ccccc2OC)ccc1O
Agent: O=c1cc(CO)occ1O
Solvent: CCO
Product: O=c1cc(CO)[nH]cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5-benzyloxy-2-hydroxymethyl-4-pyrone (prepared from Kojic acid by the method of D. Erol, J. Med. Chem., 1994, 29, 893) (9.7 g, 40 mmol), concentrated aqueous (880) ammonia (100 mL), and ethanol (20 mL) was heated to reflux overnight. The mixture was allowed to cool to room temperature then filtered. The resultant solid was washed with ether and dried in vacuo (5.9 g); MS (APCI+) m/z 232 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH:31]([O:43][Si](C(C)(C)C)(C)C)[CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH:24]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C1(C)C=CC=CC=1>[C:14]1([NH:13][C:11]([C:10]2[CH:9]=[C:8]([C:37]3[CH:36]=[CH:35][C:34]([O:33][CH2:32][CH:31]([OH:43])[CH2:30][CH2:29][C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)=[CH:39][CH:38]=3)[CH:22]=[CH:21][CH:20]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccccc1)c1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)OC(CCc1cccnc1)COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1cccc(-c2ccc(OCC(O)CCc3cccnc3)cc2)c1
Temperature: 120 °C
Yield: 11.8 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (3 ml), aqueous sodium carbonate (2 M, 0.9 ml), ethanol (1.0 ml), 3-bromo-N-phenylbenzamide (0.48 g), (±)-4-[4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butoxy]benzeneboronic acid (0.7 g) and tetrakis(triphenylphosphine)palladium(0) (50 mg) with heating at 120° C. for 5 hours. The residue obtained after work up was purified by column chromatography over silica eluting with ethyl acetate:hexane (1:1) to give a colourless oil which was desilylated by treatment with tetrabutylammonium fluoride (0.7 ml; 1 M in tetrahydrofuran) in tetrahydrofuran at 0° C. After stirring at this temperature for 5 minutes a saturated solution of brine (5 ml) was added and the organic phase separated. The aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethanol:dichloromethane (1:19) to give the title compound as a colourless solid (0.09 g).
Reaction SMILES: I[C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[N+:8]([C:6]1[CH:7]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]([OH:11])=[N:4][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(O)c(-c2ccccc2)c1

Procedure:
In a schlenck tube, a mixture of 3-iodo-5-nitropyridin-2-ol (7.52 mmol, 2 g), phenylboronic acid (8.28 mmol, 1.01 g), PdCl2dppf.DCM (0.75 mmol, 0.6 g), Cs2CO3 (22.56 mmol, 7.4 g) in a dioxane/water 4:1 mixture (26 ml) was heated at 100° C. for 4 hours, under argon atmosphere. The solvent was evaporated and the crude mixture was extracted between water and ethyl acetate. The organic phase was evaporated and the crude was suspended in methanol affording a solid that was filtered off and dried under vacuum overnight affording 1.2 g (74% of yield) of the expected product.
Reaction SMILES: CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([C:47]([OH:49])=O)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1)([CH3:27])[CH3:26].[CH2:50]([N:52](CC)[CH2:53]C)[CH3:51].C(NC)C>CN(C)C=O>[CH2:50]([N:52]([CH3:53])[C:47]([C:41]1([C:38]2[CH:39]=[CH:40][C:35]([O:34][CH:31]3[CH2:32][CH2:33][N:28]([CH:25]([CH3:26])[CH3:27])[CH2:29][CH2:30]3)=[CH:36][CH:37]=2)[CH2:42][CH2:43][O:44][CH2:45][CH2:46]1)=[O:49])[CH3:51]
Reactant: CCN(CC)CC
Reactant: CC(C)N1CCC(Oc2ccc(C3(C(=O)O)CCOCC3)cc2)CC1
Agent: CCNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCN(C)C(=O)C1(c2ccc(OC3CCN(C(C)C)CC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (286 mg, 0.75 mmol) was added to a solution of 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxylic acid (200 mg, 0.58 mmol) in N,N-dimethylformamide (6 mL). Then triethylamine (243 μL, 1.74 mmol) was added. The mixture was stirred at room temperature for 15 minutes. Ethylmethylamine (500 μL, 5.8 mmol) was added and the reaction mixture stirred at room temperature for 18 hours. The reaction was concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate solution (30 mL) and ethyl acetate (2×75 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.5, by volume) to provide the title compound (80 mg, 35%). 1H NMR (400 MHz, CD3OD) δ 1.06-1.25 (m, 9H), 1.90-2.02 (m, 4H), 2.08-2.12 (m, 2H), 2.25-2.28 (m, 2H), 2.58 (m, 2H), 2.87 (m, 3H), 2.95 (m, 2H), 3.09-3.12 (m, 3H), 3.71-3.76 (m, 2H), 3.82-3.86 (m, 2H), 4.53 (m, 1H), 6.98 (d, 2H), 7.20 (d, 2H).
Reaction SMILES: C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O[C:13]1([C:24]#[C:25][CH:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:18]([CH3:20])([CH3:19])[CH2:17][CH:16]([OH:21])[CH2:15][C:14]1([OH:23])[CH3:22].[OH-].[Na+]>O>[OH:23][C:14]1([CH3:22])[CH2:15][CH:16]([OH:21])[CH2:17][C:18]([CH3:19])([CH3:20])[C:13]1=[C:24]=[CH:25][CH:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCC(O)C#CC1(O)C(C)(C)CC(O)CC1(C)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(O)C=C=C1C(C)(C)CC(O)CC1(C)O
Reaction time: 15 h
Yield: 63 %

Procedure:
To 10 ml of an anhydrous THF suspension containing 383 mg of lithium aluminum hydride was slowly added 10 ml of an anhydrous THF solution containing 1.0 g of 1-(1,2,4-trihydroxy-2,6,6-trimethylcyclohexyl)-oct-1-yn-3-ol over 10 minutes under ice-cooling in a nitrogen atmosphere. After the addition, the mixture was placed under refluxing conditions and stirred for 15 hours. After completion of the reaction, the reaction mixture was cooled, and 0.4 ml of water, 0.4 ml of a 15% sodium hydroxide aqueous solution, and 1.2 ml of water were carefully added thereto in this order, followed by vigorously stirring for 20 minutes. Any insoluble matter was removed by filtration with suction, and the filtrate was concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography to obtain 596 mg (yield: 63%) of 1-(2,4-dihydroxy-2,6,6-trimethylcyclohexylidene)oct-1-en-3-ol.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[C:1]([C:9](=[CH:14][N:15]([CH3:17])[CH3:16])[C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)c1ccccc1
Product: CN(C)C=C(C#N)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
Following the method of Toche et al. (Org. Prep. Proc. Intl. 1998, 39, 367), a mixture of 5.0 g (34.4 mmol) benzoylacetonitrile and 9.2 ml (69.0 mmol) N,N-dimethylformamide dimethyl acetal was stirred for 1 hour at room temperature. The reaction mixture was then concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was dried with sodium sulfate. Concentration in vacuo afforded 6.9 g (100%) 2-benzoyl-3-dimethylaminoacrylonitrile as a yellow oil which was used in the next step without further purification. ES-MS m/e (%):223 (M+Na+, 40), 201 (M+H+, 100).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:10]1[CH2:15][CH2:14][C@@H:13]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)[C@H:12]([C:25](OCC)=[O:26])[CH2:11]1)(=O)[CH3:8].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:7]([N:10]1[CH2:15][CH2:14][C@@H:13]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)[C@H:12]([CH2:25][OH:26])[CH2:11]1)[CH3:8]
Reactant: CCOC(=O)[C@@H]1CN(C(C)=O)CC[C@H]1N1CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1CC[C@@H](N2CCc3ccccc32)[C@H](CO)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
In a stream of nitrogen, lithium aluminum hydride (133 mg) was carefully added to dry tetrahydrofuran (5 ml) under ice cooling. To the resultant mixture was gradually added a solution of trans-1-(1-acetyl-3-ethoxycarbonylpiperidin-4-yl)indoline (850 mg) in dry tetrahydrofuran (5 ml) and the resulting mixture was stirred at 0° C. overnight. Under ice cooling and vigorous stirring, water (0.13 ml), a 5 N aqueous solution (0.13 ml) of sodium hydroxide and further water (0.4 ml) were successively added thereto. After allowing to warm the resultant mixture to room temperature, ethyl acetate (30 ml) was added thereto followed by drying over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system) to give the title compound (340 mg) as a pale yellow powder (yield: 49%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=O)[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].[C:26]([N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)([N:28]1C=CN=C1)=O.N1C=CN=CC=1N.N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C.ClCCl>[CH3:24][C:9]1([CH3:25])[CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[NH:11][CH:10]1[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:20])[NH:28][C:26]2[CH:34]=[N:35][CH:36]=[CH:37][N:33]=2)[CH:16]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Nc1cnccn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)Nc3cnccn3)c1)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
A solution of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (330 mg, 0.88 mmol) and 1,1′-carbonyldiimidazole (500 mg, 3.08 mmol) in tetrahydrofuran (6 mL) was heated to 60° C. for 2 h, then was cooled to room temperature and treated with pyrazin-2-amine (92.2 mg, 0.97 mmol,). After stirring for 20 min, the reaction mixture was treated with dropwise addition of a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (670 mg, 4.4 mmol) in tetrahydrofuran (2 mL). Upon completion of addition, the resultant mixture was stirred overnight. Thin layer chromatography (dichloromethane:ethyl acetate=5:1) showed the reaction was nearly complete. The reaction mixture was quenched with brine and acidified with 1N hydrochloric acid solution to pH=6, extracted with ethyl acetate (twice). The combined organic layers were washed with brine for 3 times, dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave crude product, which was purified by column chromatography (dichloromethane:ethyl acetate=5:1) to afford 175 mg of methyl 3,3-dimethyl-2-(3-(pyrazin-2-ylcarbamoyl)-phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid. Yield: 47.5%. MS (ESI+APCI) M+1=417.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[CH:6]=[C:5]([O:13][CH2:14][O:15][CH3:16])[CH:4]=1.[Li][CH2:18]CCC.CI>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([CH3:18])=[C:5]([O:13][CH2:14][O:15][CH3:16])[CH:4]=1
Reactant: COCOc1cc(OC)cc(OCOC)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COCOc1cc(OC)cc(OCOC)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
A solution of 8 (441 mg, 1.93 mmol) in anhydrous THF (1.55 mL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 1.16 mL, 2.90 mmol) in anhydrous THF (1.26 mL) at room temperature. After one hour, the solution was cooled to −78° C. and methyl iodide (480 μL, 7.73 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1→4:1; Hexane:EtOAc) to afford 9 as a yellow oil (314 mg, 67%): 1H NMR (CDCl3, 500 MHz) δ 6.38 (d, J=2.2 Hz, 1H), 6.24 (d, J=2.1 Hz, 1H), 5.08 (d, J=3.6 Hz, 2H), 5.06 (d, J=2.6 Hz, 2H), 3.72 (s, 3H), 3.40 (s, 6H), 1.97 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 160.3, 157.8, 155.4, 108.2, 93.9, 93.8, 93.7, 92.9, 55.0, 55.0, 54.6, 7.0; IR (film) νmax 2953, 2934, 2905, 1597, 1497, 1396, 1215, 1144, 1126, 1074, 1059, 1028, 922, 822 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C12H18O5, 243.1233. found, 243.1223.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc(S(=O)(=O)NCCCCCO)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 2-methoxyphenyl boronic acid were reacted to give the title compound as a clear oil. δC (DMSO, 62.9 MHz): 22.7, 29.0, 32.0, 42.7, 55.6, 60.6, 115.5, 121.4, 125.3, 126.1, 128.2, 129.8, 130.2, 138.8, 142.1 and 156.1.