Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:19](O)[CH2:20][OH:21].CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:21][CH2:20][CH2:19][O:18]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OCCO
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)N1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Reaction time: 108 h
Yield: 56.8 %

Procedure:
A mixture of 74.7 parts of 1-acetyl-4-(4-fluorobenzoyl)piperidine, 46.5 parts of 1,2-ethanediol, 3 parts of 4-methylbenzenesulfonic acid and 810 parts of benzene was stirred for 108 hours at reflux temperature using a water separator. After cooling, the reaction mixture was washed successively with 250 parts of water, 22.5 parts of ammonium hydroxide and 250 parts of water. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3COCH3 50:50). The eluent of the desired fraction was evaporated, yielding 50 parts (56.8%) of 1-acetyl-4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]piperidine (interm. 45).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5](=[O:8])([OH:7])[OH:6].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:27]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]I)=[CH:38][CH:37]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].CCN(C(C)C)C(C)C.Cl>CO>[CH2:27]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:1][CH2:2][CH2:3][CH2:4][P:5](=[O:7])([OH:6])[OH:8])=[CH:38][CH:37]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: NCCCP(=O)(O)O
Reactant: CCCCCCCCCc1ccc(CI)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCCCCCCCCc1ccc(CNCCCP(=O)(O)O)cc1
Reaction time: 12 h
Yield: 19.3 %

Procedure:
3-Aminopropylphosphonic acid (0.060 g, 0.436 mmol) and tetrabutylammonium hydroxide (1.0M in methanol, 0.44 mL, 0.43 mmol) in methanol (3 mL) were heated at 50° C. for 15 min until all of the solids had dissolved. 4-(Nonyl)benzyliodide (0.100 g, 0.291 mmol) and DIEA (0.112 g, 0.872 mmol) were added and stirring was continued for 12 h at 50° C. The reaction was made acidic (pH˜5) by the addition of concentrated hydrochloric acid then directly purified using LC-3 to give the title compound (0.020 g): 1H NMR (500 MHz, CD3OD) δ 7.39 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 4.15 (s, 2H), 3.14 (t, J=7.6 Hz, 2H), 2.64 (t, J=7.7 Hz, 2H), 2.00 (m, 2H), 1.79 (td, J=5.3, 18.5 Hz, 2H), 1.61 (m, 2H), 1.24-1.36 (m, 14H), 0.89 (t, J=7.0 Hz, 3H); ESI-MS 356.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:20][CH2:21][CH2:22][CH2:23]Cl)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].[CH2:33]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]2[CH2:41][NH:42][CH2:43][CH:36]12)[CH3:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:42]4[CH2:41][CH:37]5[CH:36]([N:35]([CH2:33][CH3:34])[CH2:40][CH2:39][CH2:38]5)[CH2:43]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN1CCCC2CNCC21
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCCC2CN(CCCOc3cc4c(Nc5ccc(F)c(Cl)c5)ncnc4cc3OC)CC21
Temperature: 80 °C
Reaction time: 7 h
Yield: 38.5 %

Procedure:
A mixture of N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (1.50 g), K2CO3 (5.00 g) and 1-ethyloctahydro-1H-pyrrolo[3,4-b]pyridine (0.90 g) in 25 mL of DMF was stirred for 7 h at 80° C., and then cooled down. The resulted mixture was poured into 50 mL of ice-water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (0.75 g, 38.60%), HPLC: 98.30%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 514.1 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.03 (t, J=4.6 Hz, 3H), 1.52-1.62 (m, 2H), 1.97-2.00 (m, 3H), 2.07-2.09 (m, 2H), 2.08-2.11 (m, 4H), 2.40 (q, J=4.6 Hz, 2H), 2.51-2.56 (m, 1H), 2.57-2.61 (m, 2H), 2.88-2.92 (m, 2H), 3.94 (s, 3H), 4.18 (t, J=8.6 Hz, 2H), 7.19 (s, 1H), 7.44 (t, J=10.4 Hz, 1H), 7.82 (s, 2H), 8.13 (t, J=6.8 Hz, 1H), 8.50 (s, 1H) ppm.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.Cl.NO.CC([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[F:21])=O>C(O)C>[F:20][C:16]1[C:15]([F:21])=[CH:14][CH:19]=[CH:18][C:17]=1[CH:6]([NH2:3])[CH3:7]
Reactant: CC(=O)c1cccc(F)c1F
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CCO
Product: CC(N)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (2.66 mL) and hydroxylamine hydrochloride (712 mg) were added to a solution of 2,3-difluoroacetophenone (1 g) in ethanol (35 mL), and the reaction solution was heated to reflux for 3 hours. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. Zinc (2.29 g) was added to a solution of the resulting residue in trifluoroacetic acid (30 mL), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was made basic with a 5 N aqueous solution of sodium hydroxide, and then extracted with chloroform. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.4 g of a crude purified product containing the title compound (purity: 72 wt %). The physical properties of the compound are as follows.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[I-:14].[K+].[N:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>CC(=O)CC>[I-:14].[CH2:2]([N+:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC#CCCCCCCCl
Reactant: Cc1ccncc1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC#CCCCCCC[n+]1ccc(C)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol) and 4-picoline (3 mmol) in butanone. The mixture was refluxed for 3 days and cooled to room temperature, filtrated. The butanone was removed in a vacuum, and the resulting residue was partitioned between water and ethyl ether. The aqueous layer was washed extensively with ether until no 4-picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (87%). 1HNMR (300 MHz, CDCl3, ppm), 9.28 (d, 2H), 7.92 (d, 2H), 4.92 (t, 2H), 2.68 (s, 3H), 1.96-2.18 (m, 6H), 1.32-1.50 (br, 10H), 0.88 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:10](=S)=[S:11].[OH-].[Na+]>C(O)C>[SH:11][C:10]1[NH:1][C:2]2[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: S=C=S
Reactant: Cc1ccc(N)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2nc(S)[nH]c2c1

Procedure:
A mixture of 12.2 g (0.1 mole) of 3,4-diaminotoluene, 35 ml of carbon disulfide, and 4.0 g (0.1 mole) of sodium hydroxide was heated at reflux in 350 ml of ethanol. After 2.5 hours the mixture was concentrated in vacuo. The residue was suspended in 200 ml of 4% aqueous hydrochloric acid, collected by filtration, washed sequentially with water and diethyl ether, and air dried to yield 12.2 g of 2-mercapto-5-methylbenzimidazole, as confirmed by the nmr and infrared spectra. The title compound (796 mg) was prepared by the method of Example 6 using 8-hydroxymethylimidazo[1,2-a]pyridine as the hydrochloride salt and using 569 mg (3.5 mmole) of 2-mercapto-5-methylbenzimidazole instead of 2-mercapto-5-methoxybenzimidazole. Structure assignment was supported by elemental analysis.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:17]3[N:18]([CH3:22])[N:19]=[CH:20][CH:21]=3)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[CH3:22][N:18]1[C:17]([C:15]2[CH:14]=[CH:13][C:9]3[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=3[CH:16]=2)=[CH:21][CH:20]=[N:19]1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3ccnn3C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CNCCc2cc(-c3ccnn3C)ccc21
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of N-trifluoroacetyl-7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (48 mg, 0.14 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and the solution stirred overnight at 20 C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and the solvent evaporated. Flash chromatography (0-15% MeOH in CH2Cl2, silica) resulted in 30 mg of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.48 (s, 1H), 7.21 (m, 2H), 7.13 (s, 1H), 6.27 (s, 1H), 3.89 (s, 3H), 3.3-2.9 (m, 9H), 2.79 (dd, J=7, 14 Hz, 1H), 1.40 (d, J=8 Hz, 3H). MS calculated for C15H19N3+H: 242, observed: 242.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].I[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20])[C:7]2=[O:12]
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2c(Cl)cccc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2c(Cl)cccc2C1=O
Yield: 18.6 %

Procedure:
Using analogous reaction conditions as described in example 1, 5-chloro-3,4-dihydro-2H-isoquinolin-1-one (I-12d: 100 mg, 0.552 mmol) was reacted with 3-iodo-4-methyl-pyridine (121 mg, 0.552 mmol), 1,4-dioxane (6 mL), copper iodide (10.5 mg, 0.0552 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (23.51 mg, 0.165 mmol) and potassium phosphate (190.44 mg, 1.38 mmol) to afford the crude product. Purification by column chromatography on silica gel (35% ethylacetate in hexane) afforded 28 mg of the product (18% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[CH3:15].[H-].[Na+].[CH3:18]I>CN(C=O)C>[CH3:18][O:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[CH3:15]
Reactant: CI
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of racemic (cis)-tert-butyl 4-hydroxy-3-methylpiperidine-1-carboxylate (310 mg, 1.44 mmol) (CAS#955028-93-0; prepared as described in US 20070249589)] in DMF (5 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 75 mg, 1.87 mmol). The reaction mixture was stirred at 0° C. for 10 minutes and MeI (0.13 mL, 2.02 mmol) was added. After 2 h the reaction was quenched with saturated aqueous NH4Cl. The aqueous phase was washed three times with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (0-100% EtOAc/heptanes) to provide racemic (cis)-tert-butyl 4-methoxy-3-methylpiperidine-1-carboxylate. 1H NMR (400 MHz, CDCl3) δ ppm 3.36-3.50 (m, 6 H), 3.34 (dt, J=6.6, 3.3 Hz, 1 H), 3.22-3.29 (m, 1 H), 1.78-1.96 (m, 2 H), 1.49 (s, 9 H), 0.95 (d, J=6.8 Hz, 3 H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH3:16][O:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][O:23][CH3:24].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][O:23][CH3:24])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COCCNCCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCN(CCOC)C(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 76.6 %

Procedure:
To a slurry of 212.0 g of 2,4-dinitrobenzoic acid in 900 ml of toluene were added with stirring 101.0 g of triethylamine, followed by 159.6 g of bis(2- methoxyethyl)amine. Next 75.7 g of phosphorus oxychloride was added dropwise at such a rate to maintain the reaction temperature below 90° C. The mixture was refluxed for 5 hrs, cooled to 80° C., and poured slowly into 1000 ml of aqueous 5% NaHCO3 solution with stirring. The precipitate was filtered, washed with water and recrystallized from hot methanol to yield 250.7 g of N,N-bis(2-methoxyethyl)-2,4-dinitrobenzamide, mp 89° C. An additional 19.0 g of material was recovered from the toluene filtrate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:11](C(OC)=O)=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)=[O:4].[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:22](O)=[O:23].S(Cl)(Cl)=O.ClCC1C=CC(C(Cl)=O)=CC=1>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([F:18])[CH:20]=1)=[CH:8][NH:9]2)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)OC)c2[nH]ccc12
Reactant: Cc1ccc(C(=O)O)cc1F
Agent: O=C(Cl)c1ccc(CCl)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2[nH]cc(C(=O)c3ccc(C)c(F)c3)c12

Procedure:
The desired compound was prepared according to the method of Example 90, step 2, except substituting 4-methoxycarbonylindole for 4,7-dimethoxycarbonylindole, and substituting 3-fluoro-4-methylbenzoyl chloride, prepared by reaction of 3-fluoro-4-methylbenzoic acid with thionyl chloride, for 4-chloromethylbenzoyl chloride.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]([O:32][Si:33]([CH2:38][CH3:39])([CH2:36][CH3:37])[CH2:34][CH3:35])([C:28]([F:31])([F:30])[F:29])/[CH:4]=[CH:5]\[CH2:6][C:7]([CH3:27])([CH3:26])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[CH2:13]S(C1SC2C=CC=CC=2N=1)(=O)=O.[Li]N([Si](C)(C)C)[Si](C)(C)C.[C:52]([O:55][C@@H:56]1[CH2:61][CH:60](O)[CH2:59][C@@H:58]([O:63][C:64](=[O:66])[CH3:65])[CH2:57]1)(=[O:54])[CH3:53]>C1COCC1>[C:52]([O:55][C@@H:56]1[CH2:61][C:60](=[CH:13]/[CH:12]=[CH:11]/[CH2:10][CH2:9][CH2:8][C:7]([CH3:27])([CH3:26])[CH2:6]/[CH:5]=[CH:4]\[C:3]([O:32][Si:33]([CH2:38][CH3:39])([CH2:34][CH3:35])[CH2:36][CH3:37])([C:2]([F:1])([F:40])[F:41])[C:28]([F:31])([F:30])[F:29])[CH2:59][C@@H:58]([O:63][C:64](=[O:66])[CH3:65])[CH2:57]1)(=[O:54])[CH3:53]
Reactant: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCC/C=C/CS(=O)(=O)c1nc2ccccc2s1)(C(F)(F)F)C(F)(F)F
Reactant: CC(=O)O[C@@H]1CC(O)C[C@@H](OC(C)=O)C1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCC/C=C/C=C1C[C@@H](OC(C)=O)C[C@H](OC(C)=O)C1)(C(F)(F)F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of 322 mg of (2E,9Z)-2-(12,12,12-Trifluoro-7,7-dimethyl-11-triethylsilanyloxy-11-trifluoromethyl-dodeca-2,9-diene-1-sulfonyl)-benzothiazole in 2 ml of THF was added at −78° 0.5 ml of LiN(SiMe3)2 (1.0 M in THF) and stirring of the red solution was continued for 30 min. To this solution was added at −78° a solution of 107 mg of (1R,3R)-1,3-diacetoxy-5-hydroxy-cyclohexane in 1 ml of THF over 10 min and stirring was continued for 5 h after which time t.l.c. indicated almost completion of the reaction. The mixture was warmed to 22°, washed with sat. aqueous NH4Cl-solution, the organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on a Lobar CN-column (Merck) with CH2Cl2/CH3CN/hexane 15:5:200 to give 230 mg of the pure (t.l.c.) title compound as a colorless oil. IR (neat): 1735 m (CO); MS (El): 613/1 (M−C2H5).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(Br)cc1F
Product: O=C(O)Cc1ccccc1Nc1ccc(Br)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-fluoro-4-bromoaniline to yield 2-[(2-fluoro-4-bromophenyl)amino]phenylacetic acid.
Reaction SMILES: [C:1]1([S:7]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][OH:20]>>[C:1]1([S:7]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14](=[N:19][OH:20])[CH2:13][CH2:12]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCN(CCS(=O)c2ccccc2)CC1
Reactant: NO
Agent: Cl
Product: O=S(CCN1CCC(=NO)CC1)c1ccccc1

Procedure:
1-(2-Phenylsulfinylethyl)-4-piperidone oxime is prepared from 1-(2-phenylsulfinylethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[O:13][CH2:14]C)#[N:2].COC1C=C([N+]([O-])=O)C=CC=1C#N>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[O:13][CH3:14])#[N:2]
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Agent: COc1cc([N+](=O)[O-])ccc1C#N
Product: COc1cc(S(=O)(=O)Cl)ccc1C#N

Procedure:
The titled compound was prepared analogously to 4-cyano-3-ethoxy-benzenesulfonyl chloride (Intermediate 127c) by replacing 2-ethoxy-4-nitro-benzonitrile with 2-methoxy-4-nitro-benzonitrile.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][N:12]1[C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=O)C1C=CC=CC=1>CO>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]([N:12]2[CH2:13][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:15][NH:11]2)=[O:32])=[CH:26][CH:27]=1
Reactant: CC(C)(C)C(=O)OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Solvent: CO
Product: CC(C)(C)C(=O)OC1CNN(C(=O)Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
2-[2-(4-Fluorophenyl)acetyl]-4-(2,2-dimethylpropionyloxy)-pyrazolidine-1-carboxylic acid 1-benzyl ester, 31, (1.71 g, 3.86 mmol) is dissolved in methanol (40 mL). The flask is flushed with nitrogen and charged with 10% palladium on carbon (300 mg). The reaction flask is stirred vigorously at room temperature under 1 atmosphere of hydrogen gas for 6 hours. The flask is flushed with nitrogen and the reaction mixture filtered through a pad of Celite, rinsing with ethyl acetate (100 mL). The filtrate is concentrated in vacuo to afford 1.18 g (98% yield) of the desired product as a tan solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[N:14]=[CH:13][N:12]([CH3:16])[C:11]=2[C:10](=[O:17])[NH:9][C:8]1=[O:18].[H-].[Na+].[C:21]([O:24][C@H:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29]I)(=[O:23])[CH3:22]>CS(C)=O>[C:21]([O:24][C@H:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][N:9]1[C:10](=[O:17])[C:11]2[N:12]([CH3:16])[CH:13]=[N:14][C:15]=2[N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:8]1=[O:18])(=[O:23])[CH3:22]
Reactant: CC(=O)O[C@H](C)CCCCI
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2Cc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(Cc2ccco2)c1=O
Reaction time: 0.42 h
Yield: 77.9 %

Procedure:
To a stirring suspension 3-(2-furylmethyl)-7-methylxanthine (0.40 g, 1.62 mmol) in dimethylsulfoxide (20 ml) was added sodium hydride (41 mg, 1.71 mmol) in one portion. After stirring for 25 minutes, (R)-5-acetoxy-1-iodohexane (0.46 g, 1.71 mol) was added neat. After stirring at room temperature for 72 hours, the reaction was quenched by the addition of water (75 ml) and extracted with ethyl acetate (3x 35 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (2x 35 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to give (R)-1-(5-acetoxyhexyl)-3-(2-furylmethyl)-7-methylxanthine (0.49 g, 78% yield) as a colorless oil.
Reaction SMILES: [OH:1]O.S(=O)(=O)(O)O.[Cl:8][C:9]1[CH:30]=[CH:29][C:12]2[C:13]3[C:14](=[CH:25][NH:26][C:27]=3[CH3:28])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1>C(O)(=O)C.C(Cl)Cl.[OH-].[NH4+]>[Cl:8][C:9]1[CH:30]=[CH:29][C:12]2[C:13]3[CH:27]([CH3:28])[NH:26][C:25](=[O:1])[C:14]=3[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1
Reactant: OO
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1NC(=O)C2=C1c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 1 h

Procedure:
In one portion, 1 ml of 30% hydrogen peroxide was added to 40 ml of a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 2.0 g (5.8 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with methylene chloride and neutralized with concentrated ammonium hydroxide solution. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to a dark residue. Crystallization from ethyl acetate gave 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one as pale yellow prisms, mp 239°-241° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:23]O>N1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]3[C:13]([C:14]4[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=4)=[N:23][O:12][C:11]3=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1ncc2c(O)c(C(=O)c3cccc(C)c3)cnc21
Agent: Cl
Solvent: c1ccncc1
Product: CCn1ncc2c3onc(-c4cccc(C)c4)c3cnc21

Procedure:
1-Ethyl-4-hydroxy-5-(3-methylbenzoyl)-1H-pyrazolo[3,4-b]pyridine (4.25 g) was refluxed overnight in 75 ml of pyridine containing 4.5 g of hydroxylamine hydrochloride. The pyridine was then removed under reduced pressure and the residue triturated with 5% hydrochloric acid. The product was then filtered off and recrystallized from methanol to give 2.63 g of analytically pure product, mp 122°-123° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([C:13]2[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C>C(O)C.[C].[Pd]>[F:19][C:14]1[C:13]([C:4]2[NH:3][CH:2]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]=2[CH3:12])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)c1c(Cl)[nH]c(-c2cccnc2F)c1C
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c[nH]c(-c2cccnc2F)c1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a solution of ethyl 2-chloro-5-(2-fluoropyridin-3-yl)-4-methyl-1H-pyrrole-3-carboxylate (10.0 g) and triethylamine (5.5 mL) in ethanol (250 mL) was added 10% palladium carbon (50% containing water, 1.43 g), and the mixture was stirred under a hydrogen atmosphere at 60° C. for 3 hr. After cooling, the reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound as colorless crystals (yield 7.93 g, 90%).