Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][C:12](=[O:28])[C:11]=1[C:29]1[NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[N:30]=1)[CH2:2]2.[OH-].[Na+]>Br.CC(O)=O>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@H:3]([NH:9][C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][C:12](=[O:28])[C:11]=1[C:29]1[NH:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=1)[CH2:2]2
Reactant: COc1ccc(-c2ccc3[nH]c(=O)c(-c4nc5ccccc5[nH]4)c(N[C@@H]4CN5CCC4CC5)c3c2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(-c3ccc(O)cc3)cc2c(N[C@@H]2CN3CCC2CC3)c1-c1nc2ccccc2[nH]1
Temperature: 60 °C

Procedure:
4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-yl)-6-(4methoxyphenyl)quinolin-2(1H)-one (Example 70) was dissolved in 30% HBr/AcOH and heated at 60° C. until the reaction was complete. The resulting mixture was allowed to cool, and it was then neutralized with 2 M NaOH. The resulting mixture was extracted with EtOAc, and the organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by reverse phase HPLC to give the desired product. MS m/z 478.6 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:25])[NH:10][C@@H:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:12]([O:14]C)=[O:13])[N:3]=[CH:2]1.[OH-].[Li+].O1CCCC1>O>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:25])[NH:10][CH:11]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:12]([OH:14])=[O:13])[N:3]=[CH:2]1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)NCCc1c[nH]cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 570.4 %

Procedure:
To 500 mg (1.44 mmol) of methyl(S)-2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propanoate are added 500 mg of lithium hydroxide, 7 mL of tetrahydrofuran and 2 mL of water. The reaction medium is placed in a microwave reactor with stirring, at 100° C. for 10 minutes. Seven other identical tests are performed. The various tests are combined and concentrated to dryness. The crude product obtained is purified by filtration on a pad of silica (eluent: 1/1 dichloromethane/methanol). 2.73 g of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propanoic acid in the form of a pale yellow powder are obtained in a yield of 70%.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5](=[O:8])[O:4]1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([F:23])([F:22])[C:17]([F:21])=[C:18]([F:20])[F:19]>C(#N)C>[F:19][C:18]([F:20])([O:1][CH2:2][CH:3]1[CH2:7][O:6][C:5](=[O:8])[O:4]1)[CH:17]([F:21])[C:16]([F:23])([F:22])[F:15]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: O=C1OCC(CO)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1OCC(COC(F)(F)C(F)C(F)(F)F)O1
Temperature: 45 °C

Procedure:
Example 2 was prepared by combining 4-(hydroxymethyl)-1,3-dioxolan-2-one (100 g, 0.84 moles) (Huntsman, Salt Lake City, Utah) with potassium carbonate (23 g, 0.166 moles) and acetonitrile (200 mL) in a 600 mL Parr reactor. The reactor was warmed to 45° C. and hexafluoropropene (139 g, 0.92 moles) was added at a constant rate. The reactor was stirred until the decrease in pressure stopped. Volatile material was removed from the reaction mixture by rotary evaporation. The olefin of the desired product was present and was saturated by reaction with anhydrous HF at room temperature. Vacuum distillation was done to purify the product. The fraction that boiled at 145-150° C. at 3 T (0.4 kPa) was collected. The fraction was 97.5% pure. The product was analyzed by GC/MS and F-19 NMR. MCMB/LiFePO4 coin cells (2325) made and cycled as per Test Method E with Example 2 as the only electrolyte solvent had high impedance, and the capacity fade rate could not be calculated.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2].Cl.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[CH:28]C=N2)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:29][CH2:28][N:7]([CH2:10][CH2:2][C:1]([C:4]3[CH:5]=[N:6][N:7]([C:10]4[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=4)[C:8]=3[CH3:9])=[O:3])[CH2:8][CH2:4]2)[CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1cnn(-c2ncccc2Cl)c1C
Reactant: Clc1cccc(-n2cccn2)c1
Agent: Cl
Product: Cc1c(C(=O)CCN2CCN(c3cccc(Cl)c3)CC2)cnn1-c1ncccc1Cl
Yield: 71.9 %

Procedure:
4-Acetyl-1-(3-chloro-2-pyridyl)-5-methylpyrazole (648 mg), 1-(3-chlorophenyl)pyrazole hydrochloride (641 mg), and p-formaldehyde (1.65 g) were reacted, and the product was worked up in the same manner as in Example 5-(4) to yield 439 mg of the title compound.
Reaction SMILES: [C:1]12([CH2:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.C(Cl)[Cl:20]>CO.O=[Pt]=O>[ClH:20].[C:1]12([CH2:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: ClCCl
Reactant: c1cc(CC23CC4CC(CC(C4)C2)C3)ccn1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: C1CC(CC23CC4CC(CC(C4)C2)C3)CCN1
Reaction time: 24 h
Yield: 62 %

Procedure:
A mixture of 4-(1-adamantylmethyl)pyridine (500 mg, 2.20 mmol) and PtO2 (15 mg) in MeOH (20 mL) containing concd HCl (1 mL) was allowed to shake under H2 (25-30 psi) for 24 h. NMR analysis showed only about 45% reaction. An additional portion of catalyst was added and the reaction was allowed to proceed as above for an additional 24 h. The analysis now showed about 70% reaction. The reaction was allowed to proceed at 50 psi for a final 24 h (72 h total). A crystalline solid was observed in the reaction mixture. The addition of CH2Cl2 and warming dissolved this material. The analysis now showed ˜95% reaction. The catalyst was removed by filtration (Celite) and the solvent was removed to give a yellow solid. The solid was dissolved in boiling MeOH (12 mL) and the solution was hot filtered. The filtrate was concd to 8 mL and was cooled in an ice bath to give a suspension. The solid was collected, was washed with ice cold MeOH (3×1 mL) and was dried in vacuo (100° C., 0.005 Torr) to give the title compound as a pale yellow crystalline solid (365 mg, 62%): mp >300° C.; 1H NMR (DMSO-d6) 0.95 (d, J =4.5, 2H), 1.22-1.78 (m, 17H), 1.90 (s, 3H), 2.81 (dd, J=22 and 11, 2H), 3.13 (d, J=12, 2H), 8.68 (bs, 1H), 8.89 (bs, 1H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].C(N(CC)C(C)C)(C)C.[Cl-].[Mg+2].[Cl-].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C(Cl)=O)=[CH:26][CH:25]=1>C(#N)C>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:26][CH:25]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a suspension of potassium ethyl malonate (17.12 g, 100.6 mmol) in acetonitrile (150 mL) were added N,N-diisopropylethylamine (28 mL, 160 mmol) and magnesium chloride (12.11 g, 127.2 mmol). The resulting mixture was stirred for 1 hour. A solution of 4-chlorophenylacetyl chloride (10.12 g, 53.53 mmol) in acetonitrile (100 mL) was then added and the mixture was heated to 60° C. and stirred for 20 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in 1N aqueous HCl (250 mL) and was extracted with EtOAc (100 mL×2). The combined organic phases were dried over anhydrous MgSO4 and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica, elution with a 0%-80% mixture of EtOAc in hexane (linear gradient, 45 min) to obtain ethyl 4-(4-chlorophenyl)-3-oxobutanoate (5.0 g, 39%) as a yellow oil. LC/MS (FA) ES− 239. 1H NMR (d6-DMSO, 400 MHz): δ: 7.37 (2H, d, J=13.8 Hz), 7.20 (2H, d, J=13.8 Hz), 4.07 (2H, q, J=7.2 Hz), 3.89 (2H, s), 3.66 (2H, s), 1.17 (3H, t, J=7.2 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:7]=2[CH2:6]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH:4]=[C:5]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[O:9][C:8]4[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:7]=4[CH2:6]3)[CH2:32][CH2:33]2)=[CH:24][CH:23]=1
Reactant: Oc1cccc2c1CC(=CCCBr)c1cccnc1O2
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(F)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 23 h
Yield: 38.6 %

Procedure:
To a solution of 5-(3-bromopropylidene)-5,11-dihydro-7-hydroxy-[1]benzoxepino[2,3-b]pyridine (2.59 g) in DMF (10 ml) was added 4-(4-Fluorophenyl)-4-hydroxypiperidine (1.02 g) and triethylamine (835 μM). The solution was stirred at room temperature for 23 hours. The reaction was quenched with water, extracted with ethyl acetate, and evaporated in vacuo. The residue was purified by silica gel chromatography (87:10:3 ethyl acetate:methanol:triethylamine) to yield 0.9 g (39%) of the title compound. 1H-NMR (DMSO) d: 1.64-1.69 (2H, m), 1.74-1.85 (2H, m), 2.27-2.52 (8H, m), 4.81 (1H, s), 5.16 (2H, brs), 6.08 (1H, t), 6.62-6.71 (3H, m), 7.12 (2H, t), 7.40-7.51 (3H, m), 7.72 (1H, dd), 8.48 (1H, dd), 9.09 (1H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[CH:5][CH:4]=1)#[N:2].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:26])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1ccc(CSc2cccc[n+]2[O-])cc1
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(CS(=O)c2cccc[n+]2[O-])cc1

Procedure:
The procedure employed is identical to that of Example 68 using 3.6 gm (0.015 mol) 2-(4-cyanophenylmethylthio)pyridine N-oxide in 50 ml of chloroform with 3 gm (0.015 mol) MCPBA in 50 ml chloroform.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=3[F:30])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br.CO.[OH-].[Na+]>ClCCl>[F:30][C:22]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=1[O:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:12]=[C:11]([C:5]3[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=3)[S:19][C:18]=12
Reactant: COc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1OC
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(O)c(O)c4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a stirred solution of 331 (172 mg, 0.40 mmol) in anhydrous dichloromethane (20 ml) at −78° C. was slowly added BBr3 (˜4 mL, 1.0 M in CH2Cl2). The temperature was allowed to warm to room temperature over 1.5 hrs, and the reaction mixture was stirred overnight. After cooling to 0° C., MeOH and 1 N NaOH (few mL) were added, respectively. The reaction mixture was stirred for 1 h, concentrated, diluted with MeOH and water, shaken for 30 min, isolated by filtration, and rinsed with MeOH. The mother liquid was concentrated, dissolved in a minimum of MeOH, and diluted with a small amount of water. The pH of the solution was adjusted to 4 with 1N NaOH in order to get a pale brown suspension. After shaking for 15 min, the suspension was filtered off, rinsed with water, air-dried, and dried under high vacuum to afford the title compound 332 (154 mg, 96% yield) as a yellow-green solid. MS (m/z): 399.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][N:14]([CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: O=CCc1ccccc1
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCN(CCc1ccccc1)CC2

Procedure:
The title compound (104 mg) was prepared from 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 190) and phenylacetaldehyde as in Example 35. MS (ESI): exact mass calculated for C24H28FN3, 377.23. found, m/z 378.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.41-7.27 (m, 9H), 4.39 (m, 1H), 3.88-3.84 (m, 1H), 3.73-3.71 (m, 1H), 3.56-3.52 (m, 3H), 3.45-3.20 (m, 3H), 3.17-3.14 (m, 2H), 2.89-2.84 (m, 2H), 1.41 (t, J=6.6 Hz, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][SH:8].C(O)C.Br[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[C:14]=1[O:24][CH3:25]>O>[CH3:7][S:8][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[C:14]=1[O:24][CH3:25]
Reactant: CS
Reactant: COc1ccc([N+](=O)[O-])c(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(SC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A reaction mixture containing 21 g. of potassium carbonate, 25 g. of methanethiol and 30 ml. of ethanol was cooled in an ice-water bath. 33.5 g. of 3-bromo-4-nitro-veratrole were added thereto. The reaction mixture was stirred for 1 hour under cooling and was then allowed to warm up to ambient temperature, at which temperature it was stirred for an additional 24 hours. 3 l. of water were then added and the resulting precipitate of 3-methylthio-4-nitroveratrole formed in the above reaction was separated by filtration. The filter cake was recrystallized from a benzene-ethanol solvent mixture to yield yellow crystals melting at 137°-140° C. (weight = 22.8 g)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH3:19][O:20][CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>>[CH3:19][O:20][CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=1)=[O:16]
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: COC[C@@H]1CCCN1
Product: COC[C@@H]1CCCN1C(=O)c1cnoc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and (S)-2-methoxymethyl-pyrrolidine (6.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (12.8 mg). Calcd for C17H17F3N2O3: 354.1191, found 354.1189.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>O(C1C=CC=CC=1)C1C=CC=CC=1>[OH:12][C:13]1[C:8]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:9]=2)[N:7]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Temperature: 120 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
A mixture of 4-methoxyaniline (12.3 g, 100 mmol) and diethyl 2-(ethoxymethylene)malonate (21.6 g, 100 mmol) was stirred at 120° C. under nitrogen for 4 hrs. The solution was cooled to room temperature and Ph2O (100 mL) was added. The reaction mixture was refluxed at 260° C. under nitrogen for 8 hrs. The solution was cooled to room temperature and diluted with hexanes. The resultant precipitate was collected by filtration, washed with 25% ethyl acetate in hexanes, and dried under vacuum to give ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate as a pale-yellow solid (4.21 g, 17%). 1H NMR (400 MHz, DMSO-d6) δ 1.26 (t, J=7.0 Hz, 3H), 3.83 (s, 3H), 4.19 (q, J=7.0 Hz, 2H), 7.32 (dd, J=3.2, 9.6 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.56 (d, J=9.6 Hz, 1H), 8.47 (s, 1H), 12.27 (s, 1H). MS 248 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[CH2:21]1[O:23][CH:22]1[CH2:24][OH:25]>CO>[OH:23][CH:22]([CH2:24][OH:25])[CH2:21][O:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CO1
Reactant: Cc1c(-c2cccc(O)c2)oc2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(-c2cccc(OCC(O)CO)c2)oc2ccccc12
Temperature: 200 °C

Procedure:
The ester which results from the condensation of 2'-hydroxyacetophenone and m-anisic acid is converted to 2-(3-methoxyphenyl)-3-methylbenzofuran by reductive cyclization in dioxane with a titanium tetrachloride/zinc metal catalyst according to the method of Banerji and Nayak, J Chem. Soc., Chem. Comm., (1990), 150. The 2-(3-methoxyphenyl)-3-methylbenzofuran (47.6 gm, 0.198 mol) is treated with several volumes of pyridine hydrochloride at 200° C. for about 6 hours to cleave the methyl ether moiety to the free hydroxyl group. Three volumes of water are added to the cooled reaction mixture and the system is extracted twice with ether. The ether extracts are combined, washed once with water and then dried over sodium sulfate. Removal of solvent by rotary evaporation affords the desired product, 2-(3-hydroxyphenyl)-3-methylbenzofuran. 2-(3-hydroxyphenyl)-3-methyl-benzofuran (22.4 gm 0.1 mol) is dissolved in 100 mL of methanol in a 250 ml round bottom flask under an atmosphere of argon. To this well stirred solution is added sodium methoxide (0.54 gm, 0.01 mol). Glycidol (Aldrich, 8.14 gm, 0.11 mol) is added and the system is gradually heated and held at reflux for 18 hours. The solution is neutralized with methancsulfonic acid. The solvent is removed by rotary evaporation. The resulting product is heated on a Kugelrohr apparatus at 200° C. under a vacuum of 1 mm Hg, to remove any 3-methoxy-1,2-propanediol by-product, affording 2-[3-(2,3-dihydroxypropoxy)phenyl]-3-methylbenzofuran having the structure: ##STR61##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14]>>[N:1]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCCCCCl
Reactant: C1CCNCC1
Product: N#CCCCCCN1CCCCC1

Procedure:
Using piperidine and 6-chloro-hexanenitrile as substrates. MS (ion spray) m/z 181 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:8][C:7]([CH3:9])=[CH:6][C:4](=[O:5])[CH:3]=1>CCO>[CH3:9][CH:7]1[CH2:6][C:4](=[O:5])[CH2:3][CH:2]([CH3:1])[O:8]1
Reactant: Cc1cc(=O)cc(C)o1
Solvent: CCO
Product: CC1CC(=O)CC(C)O1
Reaction time: 3 h

Procedure:
A solution of 2,6-dimethyl-γ-pyrone (17 g, Aldrich) in EtOH 95% (300 mL) was hydrogenated for 3 days under 70 psi. After filtration over celite, the solvent was evaporated and replaced by CH2Cl2. The solution was then treated with celite (30 g) and PCC (48.5 g). The suspension was stirred for 3 hr. and the reaction was diluted with Et2O (300 mL) and then filtered over a pad of celite. The filtrate was evaporated to dryness and the residual solution was then chromatographed using hexane/Et2O (1:1) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH2:16][C:17]([O:19]CC)=O)[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:26]([OH:28])[CH3:27]>>[C:26]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:17]([CH2:16][N:8]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:23][CH:22]=2)=[O:19])=[CH:10][CH:11]=1)(=[O:28])[CH3:27]
Reactant: CCO
Reactant: CCOC(=O)CN(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1ccc(NC(=O)CN(C(=O)c2ccc(F)cc2)c2ccc(F)cc2)cc1

Procedure:
An ethanol solution of ethyl [(4-fluorobenzoyl)-(4-fluorophenyl)amino]acetate was mixed with 3 M sodium hydroxide aqueous solution and heated under reflux. The reaction solution was concentrated, the residue was mixed with 1 M hydrochloric acid and chloroform, the organic layer was separated, washed and dried and then the solvent was evaporated under a reduced pressure. A dichloromethane solution of the thus obtained carboxylic acid crude product was mixed with 4-aminoacetophenone and WSC.HCl in that order and then stirred. The reaction solution was mixed with 1 M hydrochloric acid, the organic layer was separated, washed and dried and then the solvent was evaporated under a reduced pressure. By purifying the thus obtained crude product by SCG, N-[(4-acetyl-phenylcarbamoyl)methyl]-4-fluoro-N-(4-fluorophenyl)benzamide (white foam) was obtained.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH:1]1([N:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:22]([CH3:21])(=[O:24])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: c1cncc(CNC2CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.85 g. portion of 3-cyclohexylaminomethylpyridine was dissolved in 15 ml. of dichloromethane, and 2.8 g. of potassium carbonate and 1.6 ml. of methanesulfonyl chloride were added. The mixture boiled vigorously for a short time, and was then stirred at ambient temperature overnight. The mixture was diluted with 25 ml. of additional dichloromethane, and was extracted with 20 ml. of water and dried over magnesium sulfate. The organic solution was reduced in volume and chromatographed over silica gel, eluting first with dichloromethane and then with 9:1 dichloromethane:ethyl acetate. The product-containing fractions were evaporated under vacuum, and the residue was triturated with petroleum ether and diethyl ether to obtain 0.8 g. of the desired product.
Reaction SMILES: C(O[N:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:16]=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]2)=[O:22])[CH:18]=[CH:19][CH:20]=1)C.[NH2:32][NH:33][C:34](=O)[CH2:35][N:36]([CH3:38])[CH3:37].C[O-].[Na+]>CO>[CH3:37][N:36]([CH2:35][C:34]1[N:4]=[C:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[NH:32][N:33]=1)[CH3:38]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)NCCC4CCCCN4)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)NCCC5CCCCN5)c4)c3c2)n1
Temperature: 105 °C

Procedure:
To a suspension of (3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)-N-(2-piperidylethyl)carboxamide.3HCl (412 mg, 0.78 mmol) and N-amino-2-(dimethylamino)acetamide (275 mg, 2.35 mmol) in anhydrous methanol (5.0 mL) in a screw-top pressure tube was added sodium methoxide (626 mL of a 25% w/w in methanol). The tube was sealed, heated in a 105° C. oil bath for 48 h and then concentrated to dryness. Purification of the residue by preparatory TLC using 40% ethyl acetate in methanol gave the desired product after precipitation from methanol/ethyl acetate with ethyl ether (12 mg, 3% yield) 1H NMR (DMSO-d6) δ 13.7 (br s, 1H), 8.7 (br s, 2H), 8.4 (s, 1H), 8.1–8.0 (m, 2H), 7.85 (br d, 1H), 7.7–7.6 (m, 2H), 3.6 (s, 2H), 3.5–3.3 (m, 2H), 2.5–2.2 (m, 6H), 2.2 (s, 6H), 1.6–1.3 (m, 6H); ES-MS (m/z) 473 [M+H]+.