Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Br)cc(C)c1O
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1c(C)cc(Br)cc1OC
Temperature: 85 °C
Reaction time: 19 h
Yield: 4.8 %

Procedure:
A solution of 5.89 g (27 mmol) of 1-bromo-4-hydroxy-3-methoxy-5-methylbenzene (Syn. Lett. 1997, 1351-1352) in 100 mL of acetonitrile was treated with 5.33 g (38.5 mmol) of powdered K2CO3 and 5.75 mL (31.8 mmol) of 1-iodooctane. After stirring at 85° C. for 19 h, the reaction was cooled and concentrated. The residue was dissolved in 100 mL of H2O and extracted with 100 mL of Et2O. After separating phases, the organic layer was washed with 100 mL of 10% Na2S2O3, dried over MgSO4 and concentrated. The residue was purified on a Biotage 40L column using a gradient of hexane, 99/1 v/v hexane/EtOAc and 98/2 v/v hexane/EtOAc to afford 0.43 g of the title compound as a colorless oil. Several mixed column fractions were rechromatographed to yield an additional 703 mg of the title compound. RF: 0.63 (19/1 v/v hexane/EtOAc); 1H-NMR (500 MHz) δ 0.93 (t, J=6.8, 3H), 1.33-1.39 (m, 8H), 1.46-1.52 (m, 2H), 1.75-1.81 (m, 2H), 2.27 (s, 3H), 3.85 (s, 3H), 3.91 (t, J=6.6, 2H), 6.90 (d, J=2.3, 11H), 6.95 (d, J=2.3, 11H).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>O1CCCC1.CN(C1C=CN=CC=1)C>[Br:1][CH2:2][C:3]([NH:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: NC1CCCCC1
Reactant: O=C(Cl)CBr
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(CBr)NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To a solution of bromoacetyl chloride (5.50 mL, 66.9 mmol) in tetrahydrofuran (120 mL) at 0° C. was added a mixture of 4-dimethylaminepyridine (2.80 g, 22.9 mmol) and cyclohexylamine (5.00 mL, 43.7 mmol) in tetrahydrofuran (60 mL). The mixture was warmed to room temperature and stirred an additional 18 hours. The reaction was quenched with water and extracted with dichloromethane. The organic phase was dried (sodium sulfate), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with 10% ethyl acetate:hexanes) to provide of the title compound (25% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.18 (m, 5H), 1.64 (m, 5H), 3.52 (m, 1H), 3.99 (s, 2H), 8.04 (br d, 1H, J=7.1 Hz); MS (DCI/NH3) m/e 237/239 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.[C-:14]#[N:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:14]#[N:15])=[CH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: [C-]#N
Product: COc1ccc2c(c1)CCC=C2C#N

Procedure:
The process of claim 1 wherein (1) 6-methoxytetralone is reacted with cyanide ion and a Lewis acid so as to form 6-methoxy-1-cyano-3,4-dihydronaphthalene, (2) the 6-methoxy-1-cyano3,4-dihydronaphthalene is dehydrogenated to 6-methoxy-1-cyanonaphthalene, (3) the 6-methoxy-1-cyanonaphthalene is halogenated so as to form a 6-methoxy-5-halo-1-cyanonaphthalene and then trifluoromethylated to replace the halo substituent with a trifluoromethyl group, and (4) the resultant 6-methoxy-5-trifluoromethyl-1-cyanonaphthalene is hydrolyzed to 6-methoxy-5-trifluoromethyl-1-naphthoic acid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:10][CH:9]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:8]1=[O:33])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:10][CH:9]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:8]1=[O:33]
Reactant: CC(=O)OCCN1C(=O)C(NC(=O)OC(C)(C)C)N=C(c2ccccc2F)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2N(CCO)C1=O
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of (3RS)-1-(2-acetoxyethyl)-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (0.83 g) in 85 % aqueous ethanol (20 ml) was added potassium carbonate (0.19 g). The mixture was warmed at 65°-70° C. under stirring for 3 hours. Ethanol was removed in vacuo from the reaction mixture and to the aqueous residue was added water (50 ml). The resultant precipitate was collected by filtration, washed with water and dried under reduced pressure to afford (3RS)-1-(2-hydroxylethyl)-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-2, 3-dihydro-1H-1,4-benzodiazepin-2-one (0.75 g) as a white crystalline powder, which was used in a following reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH:12]([N:15]1[C:19]2[N:20]=[CH:21][N:22]=[CH:23][C:18]=2[C:17]([C:24]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([NH:32][CH3:33])[CH:31]=2)=[O:25])=[CH:16]1)([CH3:14])[CH3:13].F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:32]([C:30]2[CH:29]=[N:28][CH:27]=[C:26]([C:24]([C:17]3[C:18]4[CH:23]=[N:22][CH:21]=[N:20][C:19]=4[N:15]([CH:12]([CH3:14])[CH3:13])[CH:16]=3)=[O:25])[CH:31]=2)[CH3:33])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CNc1cncc(C(=O)c2cn(C(C)C)c3ncncc23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: CC(C)n1cc(C(=O)c2cncc(N(C)C(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 50 °C
Yield: 42.4 %

Procedure:
(4-chlorophenyl)acetic acid (22 mg, 0.13 mmol) was added to a stirring mixture of (7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)[5-(methylamino)pyridin-3-yl]methanone (30 mg, 0.10 mmol) (Preparation 149) and N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (57 mg, 0.15 mmol) in pyridine (1.0 mL). The mixture was heated to 50° C. for 16 hours, evaporated in vacuo and partitioned between saturated aqueous sodium bicarbonate (10 mL) and EtOAc (10 mL). The aqueous layer was washed with further EtOAc (2×10 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo and purified by preparative HPLC to afford the title compound 43% yield, 19 mg, 1H NMR (400 MHz, DMSO) δ: 1.52 (d, 6H), 3.40 (br. s, 3H), 3.59 (s, 2H), 5.00-5.18 (m, 1H), 7.00-7.42 (m, 4H), 8.21 (s, 1H), 8.50 (s, 1H), 8.86 (s, 1H), 8.90-9.12 (m, 2H), 9.48 (s, 1H);
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH:30]([OH:33])([CH3:32])[CH3:31]>O1CCOCC1.CN(C=O)C>[CH:30]([O:33][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])([CH3:32])[CH3:31]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OC(C)C)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and isopropanol in dioxane and DMF. ES-MS m/e (%): 429 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[S:20]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)(=[O:21])=[O:22]
Reactant: O=C(O)C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: O=C(O)C1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.9 %

Procedure:
26.0 g (0.2 mol) of piperidine-4-carboxylic acid were dissolved in 250 ml of pyridine and the solution was treated with 47.6 g (0.2 mol) of 2-naphthylsulfonyl chloride in portions at room temperature. The whole was stirred at room temperature for about 5 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and 2 M hydrochloric acid. The organic phase was dried and concentrated under reduced pressure. 48.5 g (75%) of the product were obtained.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1N)=[O:12])[CH3:9].[ClH:23]>C(#N)C>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[Cl:23])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1N
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)c1cnn(C(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a mixture of t-butyl nitrite (7.2 mL, 60.5 mmol), cuprous chloride (4.8 g, 48.5 mmol), and anhydrous acetonitrile (120 mL) was added 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylic acid ethyl ester (8.4 g, 39.8 mmol) in portions over 30 minutes at 0° C. The reaction mixture was stirred at room temperature for 1 h, then at 65° C. for 1 h. The mixture was then poured into 6N HCl (120 mL) and extracted with dichloromethane. The aqueous phase was extracted three times with dichloromethane. After the combined organic phases were concentrated in vacuo, the crude residue was purified by flash chromatography eluting with a gradient of 0-20% ethyl acetate/hexanes, then 20% ethyl acetate/hexanes to give 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid ethyl ester (5.5 g, 39%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1.[I-:33].[Na+].I>CC(C)=O>[I:33][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1
Reactant: [I-]
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: I
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccccc1-c1cc(I)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
To N-(6-chloro-4-o-tolylpyridin-3-yl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (460 mg, 0.97 mmol, example 12) in acetone (3 mL) was added sodium iodide (1.17 g, 7.8 mmol) and hydriodic acid (170 μL, 1.07 mmol). The reaction mixture was heated to reflux for 4 hours. Acetone was evaporated and acetonitrile (3 mL) was added and the reaction mixture heated again to reflux. After 16 hours, the reaction mixture was carefully neutralized with saturated aqueous NaHCO3 solution and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. Filtration and removal of volatiles under reduced pressure afforded a brown solid. The desired compound was isolated by flash chromatography on silica gel (50% EtOAc in n-hexane) as an amber oil (324 mg, 59%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)C[C:2]1=O.Cl.C1([NH:18]N)C=CC=CC=1>C(O)(=O)C>[NH:18]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[CH:2]1
Reactant: NNc1ccccc1
Reactant: O=C1Cc2ccccc2C1
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc2[nH]ccc2c1
Temperature: 0 °C

Procedure:
2-Indanone (5.25 g, 39.7 mmol) and phenylhydrazine hydrochloride (5.74 g, 39.7 mmol), were heated to reflux in glacial acetic acid (60 cm3) for 1 hour, and then cooled. The solution was poured into ice/water, and the solid precipitate collected by filtration. After partial purification by column chromatography, and crystallization (charcoal) from ethyl acetate to yielded colourless needles of the title compound. Yield 0.64 g (80%). M.p. 205° C. 1H NMR (DMSO-d6) δ: 3.65 (2H, s,), 7.0-7.2 (8H,), 10.40 (1H, br,).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:34][C:35]([N:37]([CH3:45])[C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][C:35]([N:37]([C:38]2[CH:39]=[CH:40][C:41]([NH:44]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:42][CH:43]=2)[CH3:45])=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C(=O)CN1CCCCC1)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(piperidin-1-yl-methylcarbonyl)-N-methyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C31H32N4O4
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:43]=[CH:42][C:10]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)=[O:12])=[CH:9][CH:8]=1.[OH-].[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:43]=[CH:42][C:10]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([O:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=3)[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccc(OC(F)(F)F)cc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 84.6 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]-2-(4-trifluoromethoxyphenoxy)propionate (1.65 g), which is the product of Example 126, was reacted with aqueous sodium hydroxide solution (1N, 5.54 ml) and the reaction mixture was treated to give the title compound (1.33 g) as colorless crystals.
Reaction SMILES: [CH3:1][CH:2]([CH:7]([CH3:9])[CH3:8])[CH2:3][CH:4]([OH:6])[CH3:5].[C:10](O)(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:5][CH:4]([O:6][C:10](=[O:14])[CH:11]=[CH:12][CH3:13])[CH2:3][CH:2]([CH3:1])[CH:7]([CH3:9])[CH3:8]
Reactant: C/C=C/C(=O)O
Reactant: CC(O)CC(C)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OC(C)CC(C)C(C)C
Temperature: 125 °C
Yield: 53.5 %

Procedure:
The obtained 4,5-dimethyl-hexan-2-ol (296 g), crotonic acid (391 g,), PTSA (3 g), and toluene (300 mL) were charged into a 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a Dean-Stark trap, and a condenser. The reaction mixture was heated to reflux at about 120-130° C. Water was removed azeotropically. The reaction was aged at reflux for about 4-5 hours until no more water evolved. The reaction was cooled to room temperature and quenched with water (400 mL). The organic layer was separated and subsequently washed with sodium carbonate (5%, 300 mL), and further fractional distilled to provide but-2-enoic acid 1,3,4-trimethyl-pentyl ester (241 g) with a boiling point of 108° C. at 13 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]3[S:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[C:17](=[O:25])[N:16]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1S
Reactant: COc1ccc(-c2cccc(C#N)n2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cccc(-c3nc(=O)c4ccccc4s3)n2)cc1
Yield: 66.1 %

Procedure:
6-(4-Methoxyphenyl)-2-pyridinecarbonitrile (0.81 g, 3.8 mmol) and methyl thiosalicylate (1.07 g, 6.3 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. After cooling, the precipitates were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.87 g, 65%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccccc1CCl
Solvent: Cc1ccccc1
Product: Cc1ccccc1Cc1ccccc1C
Yield: 81 %

Procedure:
A German patent, Ger.Offen 2,547,030 (1977), disclosed the preparation of o-benzyl toluenes by the reaction of o-methylbenzyl halides with substituted benzenes in the presence of Al-silicate. The 2-CH3C6H4CH2Cl was stirred with toluene and Al-silicate (25% Al2O3) at 110° C. to give 81% 2-methylbenzyltoluene. According to a Japanese patent, JP 59,186,937 (1984), o-benzylphenol was prepared by the liquid phase reaction of benzyl alcohol with phenol in the presence of γ-Al2O3. For example 7.5 g γ-Al2O3 was added to a mixture of 32.5 g benzyl alcohol and 47 g phenol at 190° C. under stirring to give a product-containing 49.9% o-benzylphenol. A German Patent, Ger. Offen DE 3,700,917 (1988), disclosed the preparation of p-substituted o-benzylphenols by alkylation of p-substituted phenols with benzylalcohol in the presence of Na-Y type zeolite. A mixture of 0.5 mole 4-ClC6H4OH, 0.1 mole C6H5CH2OH and 0.6 g of Na-Y type zeolite was heated at 200° C. for 3 hrs to give 25.4% 2-benzyl-4-chlorophenol.
Reaction SMILES: [CH3:1][C:2]1[C:12]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:19][C:20]([F:44])([F:43])[CH2:21][NH:22][C:23]([C:25]1([CH2:39][CH2:40][CH2:41]Br)[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]>>[CH3:1][C:2]1[C:12]([N:13]2[CH2:14][CH2:15][N:16]([CH2:41][CH2:40][CH2:39][C:25]3([C:23](=[O:24])[NH:22][CH2:21][C:20]([F:44])([F:19])[F:43])[C:38]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[O:32][C:31]4[C:26]3=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:17][CH2:18]2)=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)c1cccc(N2CCNCC2)c1C
Product: CCOC(=O)c1cccc(N2CCN(CCCC3(C(=O)NCC(F)(F)F)c4ccccc4Oc4ccccc43)CC2)c1C

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 53 and the compound prepared in step (b) of Example 114 were used as the starting compounds. Thus, ethyl 2-methyl-3-[4-[3-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-xanthen-9-yl]propyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH:13]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH:13]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1cn(CCCN2C(=O)c3ccccc3C2=O)c2ccccc12
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)c1cn(CCCN2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
2-(N-tert-butoxycarbonylamino)-1-{1-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-propyl]-3-indolyl}-1-ethanone (0.30 g, 0.65 mmol) was dissolved in dry THF (7.5 ml) and cooled to −10° C., sodium bis(trimethylsilyl)amide (0.65 ml, 1 M in THF, 0.65 mmol) was added and the resulting yellow solution stirred for 15 minutes. Benzylbromide (0.16 ml, 1.30 mmol) was added and the stirring continued for 15 minutes at −10° C., the cooling bath was removed and stirring continued for 4 hours. Saturated NH4Cl(aq) was added followed by removal of the aqueous phase. The organic solvent was evaporated in vacuum and the residue chromatographed furnishing the sub-title product (0.28 g, 79%).
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:19])[CH2:15][CH:16](O)[CH3:17]>>[C:1]([O:12][CH:16]([CH3:17])[CH2:15][N:14]([CH3:19])[CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CC(O)CN(C)C
Product: CCCCCCC/C=C/C(=O)OC(C)CN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1-dimethylamino-2-propanol as starting materials to give the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:31]([O:33]C)=[O:32])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:35]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:31]([OH:33])=[O:32])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:35]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(Cl)ccc4o3)c(N3CCCc4cc(F)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3cc4cc(Cl)ccc4o3)c(N3CCCc4cc(F)ccc43)nc2c1
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of methyl 2-(5-chloro-1-benzofuran-2-yl)-3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (53 mg, 0.11 mmol) in methanol (25 mL) and water (1 mL) was added sodium hydroxide (12.0 mg, 0.30 mmol) with stifling overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (10 mL), adjusted pH to 5 with hydrogen chloride (3 N) to give the precipitation, which was collected by filtration to afford 2-(5-chloro-1-benzofuran-2-yl)-3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylic acid (37.5 mg, 73%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>CCOC(C)=O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[N:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([I:12])=[CH:8][CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1nnc2ccc(I)cc2c1O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(I)cc2c1O

Procedure:
A solution of ethyl 4-hydroxy-6-iodo-3-cinnolinecarboxylate (Prep. 3, 0.27 g) and 4-chlorobenzylamine (3.50 mL) is heated at 90° C. for 30 minutes. The reaction is cooled slightly and poured into 25 mL EtOAc. Hexanes are added to precipitate the product and the resulting solid is filtered and dried. The product is further purified by trituration with CH2Cl2/hexanes (0.29 g, 85%). Physical characteristics are as follows: m.p. 307-308° C.; 1H NMR (300 MHz, DMSO-d6) δ9.99, 8.47, 8.15, 7.57, 7.40, 4.55; IR (drift) 2972, 2958, 2901, 2846, 1645, 1601, 1557, 1488, 1458, 1356, 933, 922, 822, 806, 722 cm−1; MS (ESI) m/z 439.8 (M+H)+, 437.8 (M−H)−; Anal. Calcd for C16H11ClIN3O2: C, 43.71; H, 2.52; N, 9.56; Found: C, 43.94; H, 2.50; N, 9.43.