Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:16]([O:15][C:13](=[O:14])[C:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:19])[CH3:18])[CH3:17]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1
Temperature: 35 °C
Yield: 40.7 %

Procedure:
To a solution of 4-chlorophenol (3 g, 23.3 mmol) in ethanol (100 mL) at room temperature is added potassium hydroxide (1.3 g, 23.3 mmol). The suspension is warmed at ˜35° C. for 15 min to complete dissolution before ethyl α-bromoisobutyrate (3.46 mL, 23.3 mmol) is introduced. The reaction is then heated to reflux where it is maintained for 16 h. After this time, the mixture is cooled to room temperature and filtered. The collected solids are washed with additional ethanol (10 mL) and the combined filtrates are concentrated under reduced pressure. The residue is dissolved in DCM (60 mL) and washed with water (×2). The organic phase is dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a clear colourless liquid (2.30 g, 40%). 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.25 (3H, t, J=7.1 Hz), 1.58 (6H, s), 4.23 (2H, q, J=7.1 Hz), 6.78 (2H, d, J=9.0 Hz), 7.19 (2H, d, J=9.1 Hz); m/z: 243/245 [M+H+].
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:64][CH3:65])[N:32]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]1[CH2:53][CH2:52][N:51](C(OCC2C=CC=CC=2)=O)[CH2:50][CH2:49]1>>[CH2:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:64][CH3:65])[N:32]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]2[CH2:49][CH2:50][NH:51][CH2:52][CH2:53]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCC3CCNCC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 4-{6-[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]hexyl}-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[NH:12][C:11](=O)[N:10]=[CH:9]2.C(Cl)(Cl)[Cl:23].C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:23][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: COCCOc1cc2cnc(=O)[nH]c2cc1OCCOC
Reactant: ClC(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Temperature: 27.5 °C

Procedure:
6,7-Bis(2-methoxy-ethoxy)-quinazolone (68 gm), chloroform (1360 ml) and dimethylformamide (7.5 ml) are taken in a reaction flask at 25-30° C. and stirring begun. To the contents is added oxalyl chloride (120 ml) at 25-30° C. slowly for 30 minutes, which is then heated to reflux for 1 hour 30 minutes. The solvent is distilled at 55-60° C. under vacuum, diisopropyl ether (560 ml) is added, cooled to 25-30° C. and then stirred for 30 minutes. The compound is filtered and washed with diisopropyl ether (100 ml). The compound is added to chloroform (1000 ml), the chloroform is washed two times with 8% NaHCO3 solution (each time 680 ml) and the resulting organic layer is washed with water (500 ml), the organic layer is dried over sodium sulfate and the solvent is distilled under a vacuum at 55-60° C. To the residue is added n-heptane and stirred for 1 hour at 25-30° C. The material, is filtered washed with n-heptane (100 ml) and then the material is dried at 50° C. under vacuum to obtain 65 gm of 4-Chloro-6,7-bis-(2-methoxyethoxy)-quinazoline.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][NH:10][CH2:9]1.S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25]>C(OCC)(=O)C>[N+:24]([C:16]1[CH:17]=[CH:18][C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:14]=2[CH:15]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCNCC2
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a cooled (0° C.) solution of trifluoroacetic acid (67.2 ml, =869.38 mmol), 2,3,4,5-Tetrahydro-1H-benzo[d]azepine (18 g, 122.44 mmol) was added drop-wise over a period of 20 min. To this, concentrated sulphuric acid (23.4 ml, 440.78 mmol) was added over a period of 45 min at 0° C., and the mixture was stirred for an additional 30 minutes. To this reaction mixture, concentrated nitric acid (8.1 ml, 192.23 mmol) was added drop-wise at 0° C. over a period of 1 h, followed by stirring at room temperature for 2 h. To the reaction mixture, ethyl acetate (250 ml) was added drop-wise at 0° C. The resulting precipitate was filtered and washed with ethyl acetate (100 ml). The crude solid product was added to chloroform (250 ml), washed with 10% sodium hydroxide solution (150 ml), dried over Na2SO4, and concentrated to give the sub-title compound as a light yellow solid (17.4 g). 1H NMR (300 MHz, DMSO-d6) δ 7.99-7.93 (m, 2H); 7.38 (d, J=8.1 Hz, 1H); 2.98-2.94 (m, 4H); 2.79-2.76 (m, 4H); MS: ESI (positive): 193 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10](Cl)[C:11]([F:14])([F:13])[F:12].[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:18][N:17]=[N:16]1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1N=C(Cl)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccccc1-n1nnnc1C(F)(F)F
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Four grams (16.8 mmol) of N-(2-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 9, 1.98 g (30.2 mmol) of sodium azide, 1.16 g (8.42 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 14 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×2). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 4.01 g of 1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 97.6%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.C(OC(=O)C)C>[F:15][C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc2c(Cl)nccc2c1F
Reactant: [F-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc2c(F)nccc2c1F
Temperature: 140 °C
Yield: 73.7 %

Procedure:
To a solution of 1-chloro-5-fluoro-6-methoxyisoquinoline (0.5 g, 2.363 mmol) in DMSO (5 mL), was added CsF (0.718 g, 4.73 mmol). The mixture was heated to 140° C. for 2 h. The reaction was diluted with ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using a gradient of 30-50% DCM in hexanes. The product fractions were collected and the solvent was removed under vacuum to give 1,5-difluoro-6-methoxyisoquinoline (340 mg, 74% yield). MS m/z 196.2 (M++1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[N:17]=[C:16]2[CH2:18][O:19][C:20](=O)[C:15]2=[CH:14][CH:13]=1.Cl>C1COCC1>[CH3:11][C:12]1[N:17]=[C:16]2[CH2:18][O:19][C:20](=[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])[C:15]2=[CH:14][CH:13]=1
Reactant: Cc1ccc2c(n1)COC2=O
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccccc21
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 29.5 %

Procedure:
A solution of 1,3-dihydro-indol-2-one (200 mg, 1.5 mmol.) in THF (2 mL) is placed under an argon atmosphere and cooled in an ice bath. A solution of Li bis(trimethylsilyl)amide (4.0 mL of a 1M solution in THF, 4.0 mmol) is added slowly at 0° C. and the resulting solution is stirred for 10 min. The ice-bath is then removed and a solution of 2-methyl-7H-furo[3,4-b]pyridin-5-one (150 mg, 1.00 mmol) in THF (6 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h and then poured into 10% aqueous HCl solution (50 mL). After 10 min at room temperature, the reaction is heated to ˜90° C. for 45 min followed by stirring at room temperature for 36 h. The solid which precipitated from solution is collected by filtration and washed sequentially with small volumes of MeOH, EtOAc, Et2O and dried under vacuum to give the title compound as a yellow solid (78 mg, 30%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11].NC1C=CC(O)=CC=1F>>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: Nc1ccc(O)cc1F
Product: Nc1ccc(O)c(F)c1
Yield: 97.9 %

Procedure:
This compound was prepared from 2-fluoro-4-nitrophenol (2.0 g, 12.7 mmol) in is the manner described for 4-amino-3-fluorophenol, affording 1.58 g (98%) of 4-amino-2-fluorophenol as a tan solid. 1H-NMR (DMSO-d6) □ 8.53 (s, 1H), 6.59 (dd, J=10.2, 8.5 Hz, 1H), 6.31 (dd, J=13.1, 2.8, Hz, 1H), 6.20 to 6.14 (m, 1H), 4.66 (s, 2H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[CH:21]=[N:22][N:23]([C:26]5[C:31]([F:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=5)[C:24]=4[CH3:25])=[O:19])=[CH:13][C:12]=3[CH3:37])[CH2:7][CH2:6]2)[O:4]CC1.C(C1(C2N=CC(NC(C3C=C(C)N(C4C=CC(C(F)(F)F)=CN=4)N=3)=O)=CC=2)CCC2(OCCO2)CC1)#N>>[F:32][C:31]1[C:26]([N:23]2[C:24]([CH3:25])=[C:20]([C:18]([NH:17][C:14]3[CH:15]=[N:16][C:11]([CH:8]4[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]4)=[C:12]([CH3:37])[CH:13]=3)=[O:19])[CH:21]=[N:22]2)=[N:27][CH:28]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:30]=1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ncc(C(F)(F)F)cc3F)c2C)cnc1C1CCC2(CC1)OCCO2
Agent: Cc1cc(C(=O)Nc2ccc(C3(C#N)CCC4(CC3)OCCO4)nc2)nn1-c1ccc(C(F)(F)F)cn1
Product: Cc1cc(NC(=O)c2cnn(-c3ncc(C(F)(F)F)cc3F)c2C)cnc1C1CCC(=O)CC1
Yield: 94.5 %

Procedure:
N-[6-(1,4-Dioxaspiro[4.5]dec-8-yl)-5-methylpyridin-3-yl]-1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-5-methyl-1H-pyrazole-4-carboxamide (274 mg) described in Example D196 was used in place of N-[6-(8-cyano-1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazolecarboxamide in Example F2(1), and reacted and treated in a similar manner to give the titled compound (237 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]1[CH2:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[CH2:12]1.Cl[CH2:20][C:21](=O)[CH3:22]>CN(C)C=O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]1[CH2:12][C:13](=[O:18])[C:14]2[C:21]([CH3:22])=[CH:20][O:17][C:15]=2[CH2:16]1
Reactant: CC(=O)CCl
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2F)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccc(F)cc1F)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.6 %

Procedure:
In dimethylformamide (10 ml) was suspended 60% sodium hydride (0.39 g, washed with hexane thrice), and to the suspension was added 5-(2,4-difluorophenyl)cyclohexane-1,3-dione (2.0 g) and then was added chloroacetone (0.83 g). The mixture was stirred at room temperature for 1 hour and then at 150° C. for 12 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from hexane to give colorless crystals of 6-(2,4-difluorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.13 g).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C.CCOC(C)=O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH:15]([N:1]2[C:9]3[C:4](=[C:5]([CH:10]=[O:11])[CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C:16]([O:18][CH3:19])=[O:17])=[CH:25][CH:24]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(C=O)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1H-indole-4-carbaldehyde (2.0 g, 13.79 mmol) in DMF (50 mL) was added NaH (0.66 g, 16.55 mmol) at 0° C. After stirring for 30 min at 0° C., a solution of methyl 2-bromo-2-(4-chlorophenyl)-acetate (4.67 g, 17.92 mmol) in DMF (20 mL) was added dropwise. The reaction was allowed to warm to rt and stirred for an additional 1 hr. Then it was diluted with EtOAc (200 mL) and quenched with water. The organic layer was separated and washed with brine (50 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified via column chromatography (0-20% EtOAc/hexanes) to provide the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:18][C:19]([OH:21])=[O:20])[CH:16]=[CH:17][C:3]1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:33](O)[CH2:34][OH:35]>>[OH:35][CH2:34][CH2:33][O:20][C:19](=[O:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:3]2[N:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[C:5](=[O:13])[C:4]=2[CH:14]=1
Reactant: OCCO
Reactant: CN1Cc2ccccc2C(=O)c2cc(CC(=O)O)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN1Cc2ccccc2C(=O)c2cc(CC(=O)OCCO)ccc21

Procedure:
5,6-Dihydro-5-methyl-11oxodibenz[b,e]azepine-2-acetic acid (2g), ethylene glycol (150 ml), and p-toluene-sulfonic acid (0.05 g) were put into an esterification apparatus, and refluxed for 3 hours. After the reaction, excess ethylene glycol was distilled off under reduced pressure, and the residue was dissolved in chloroform. The solution was washed with a 5% aqueous solution of potassium carbonate, washed in water, and dried over MgSO4. Then, the solvent was distilled off to give 2.1 g of an oily material. The oily material was purified by column chromatography over 50 l g of Wakogel C-200 l and elution of the column with chloroform gave 1.3 g of an oily matter.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][CH:29]([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][CH:29]([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CC(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (84 mg, 81%), MS (ISP) m/z=415.4 [(M+H)+], mp 202.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 3-methyl-butyric acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:7])=O.C(O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH2:7])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C(N)=O)cc1Br
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(CN)cc1Br
Temperature: 50 °C
Reaction time: 120 h

Procedure:
To 3-bromo-4-methylbenzamide (2.14 g, 10 mmol) in THF (10 mL) was added borane dimethyl sulfide complex (2 mL, 20 mmol) at 0° C. The mixture was then heated to 50° C. for 16 h. Additional borane dimethyl sulfide complex (1 mL, 10 mmol) was added and heating continued at 60° C. for an additional 5 days. The reaction mixture was cooled to room temperature and ethanol was cautiously added. When bubbling ceased, 1N HCl was added until the pH was ˜2. This mixture was stirred at 50° C. for 4 h. The mixture was partitioned between EtOAc and water. The aqueous was washed 3× with EtOAc. The aqueous was then adjusted to pH 10 with 2N NaOH and extracted 3× with EtOAc. The combined organics phases were dried over anhydrous Na2SO4, filtered, and evaporated to afford the title compound. LC-MS m/z 199.8 (M+H)+, 1.01 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](C)=[C:4]([N+:9]([O-:11])=[O:10])C=1.C(N(C)C)(OC)OC.C([O:22][CH2:23][CH3:24])C.O>CN(C=O)C.C1COCC1>[N+:9]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:24]=1[CH:23]=[O:22])([O-:11])=[O:10]
Reactant: CCOCC
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Agent: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1c(F)cccc1[N+](=O)[O-]
Temperature: 140 °C

Procedure:
To a solution of 4-fluoro-2-nitrotoluene (3 g, 17.96 mmol) in DMF (25 ml) was added (MeO)2CHNMe2 (3.12 ml, 23.35 mmol) and the mixture warmed at 140° C. for 4 hours in argon atmosphere. Then the solution was allowed to reach room temperature and diethyl ether (100 ml) and water (100 ml) was added. The organic layer was washed with water (2×100 ml) and brine (1×100 ml), dried (MgSO4) and solvent concentrated at reduced pressure, affording an oil which was treated with NaIO4 (11.5 g, 53.6 mmol). The mixture was stirred in 50% aqueous THF (100 ml) at room temperature for 24 hours. The mixture was filtered in a celite pad and eluted with EtOAc. The organic layer was washed with NaHCO3 (saturated solution, 3×100 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (50% CH2Cl2 /Hexane) affording 2-nitro-6-fluorobenzaldehyde as a brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.CS(C)=O.[OH-].[K+].[CH2:24](OS(OCC)(=O)=O)[CH3:25]>C1(C)C=CC=CC=1>[CH2:24]([N:9]([CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH3:25]
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1ccc(NCCc2ccccn2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCN(CCc1ccccn1)c1ccc(OC)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
With stirring, 10.6 g (0.044 mole) of N-[2-(2-pyridyl)ethyl]-4-methoxyaniline, prepared in a manner similar to that described in Example 1, part A, was added to 25.0 ml of dimethylsulfoxide. After the solution was complete, 4.9 g of ground potassium hydroxide was added slowly to the solution maintaining a temperature under 40° C. After approximately one hour, 13.6 g (0.088 mole) of diethylsulfate was added dropwise to the reaction mixture while maintaining a temperature in the range of 25° to 40° C., and the resultant mixture was stirred for approximately eighteen hours at ambient temperature. To the reaction mixture, there was added 50.0 ml of toluene with stirring. The insoluble potassium sulfate was collected by filtration and discarded. The toluene solution was washed several times with saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate. The toluene was removed under reduced pressure to obtain 5.5 g of N-ethyl-N-[2-(2-pyridyl)ethyl]-4-methoxyaniline (Formula VI: R1 =C 2 H5 ; R2 =R9 =H; R11 =CH3O), a brown-colored oil. A significant infrared maximum appeared at 1592 cm-1 (C=C;s). The nuclear magnetic resonance spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:14]=1)[C:7](N(CC)CC)=[O:8].C([Li])CCC.CCCCCC.[N:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:34][C:35]3[CH2:41][CH2:40][CH2:39][C:38](=[O:42])[C:36]=3[CH:37]=2)=[CH:29][CH:28]=1>O1CCCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:38]3([O:42][C:7](=[O:8])[C:6]=2[CH:14]=1)[C:36]1[CH:37]=[C:33]([C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)[S:34][C:35]=1[CH2:41][CH2:40][CH2:39]3
Reactant: O=C1CCCc2sc(-c3ccncc3)cc21
Reactant: CCN(CC)C(=O)c1cc(Cl)ccc1I
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1OC2(CCCc3sc(-c4ccncc4)cc32)c2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 77.1 %

Procedure:
In a 100 mL round bottomed flask was placed 5-chloro-N,N-diethyl-2-iodobenzamide (840 mg, 2.5 mmol) and tetrahydrofuran (10 mL). The mixture was stirred for 5 min at −78° C. then n-butyllithium in hexane (1.6M, 1.8 mL, 2.9 mmol) was added and the mixture was stirred for an additional 30 min at the same temperature. To the mixture was added a solution of 2-pyridin-4-yl-6,7-dihydro-1-benzothiophen-4(5H)-one (445 mg, 1.94 mmol) in tetrahydrofuran (15 mL). The mixture was stirred for an additional 16 hr during which time the reaction temperature was allowed to slowly rise from −78° C. to rt. The reaction mixture was then refluxed for 4 hr, cooled to rt and then diluted with EtOAc (50 mL). The resulting solution was washed with water (50 mL). The aqueous phase was separated and neutralized by the addition of 1N HCl (ca 1.21 mL, pH ca 7.0) and then extracted with EtOAc (50 mL). Finally, the combined organic phases were washed with brine (30 mL) then dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (40 g) column chromatography, eluting with 30% to 100% EtOAc/hexane to yield the title compound (550 mg; 77%) as an off-white foam, which included a small amount of 2-pyridin-4-yl-1-benzothiophene-4-ol as an impurity. The crude material was used in the next step without further purification. LCMS: (FA) ES+ 368, 370; 1H NMR (400 MHz, d6-DMSO) δ ppm 8.46 (dd, 2H), 7.98 (dd, 1H), 7.82 (dd, 1H), 7.57 (d, 1H), 7.49 (dd, 2H), 7.11 (s, 1H), 3.03-3.09 (m, 1H), 2.89-2.97 (m, 1H), 2.29-2.37 (m, 1H), 2.00-2.16 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:9](=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Cc1ccc(Br)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C(Br)c1ccc(Br)cc1
Temperature: 80 °C
Yield: 27.4 %

Procedure:
A solution of 1-(4-bromophenyl)propan-2-one (1.173 mmol) in carbon tetrachloride (2.5 mL) was degassed with a stream of nitrogen for five minutes, at which point the solution was treated with N-bromosuccinimide (1.291 mmol) and azobisisobutyronitrile (0.059 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture was heated overnight at 80° C. with stirring. The resulting orange solution was concentrated to dryness in vacuo. Purification of the crude material by silica gel chromatography (0-35% ethyl acetate/hexanes) afforded the title compound (94 mg, 19%). 1H NMR (400 MHz, DMSO-d6) d ppm 2.27 (s, 3 H) 6.12 (s, 1 H) 7.39 (m, J=8.59 Hz, 2 H) 7.62 (d, J=8.59 Hz, 2 H).