Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)=[CH:17][C:16]=2[N+:31]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.C(OCC)(=O)C.[Fe]>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)=[CH:17][C:16]=2[NH2:31])=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Cl)cn3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Cl)cn3)cc2N)cc1
Temperature: 80 °C
Yield: 94.5 %

Procedure:
A suspension of the product of Example 199B (282 mg, 0.5816 mmol), iron powder (200 mg, 3.577 mmol), and ammonium chloride (204 mg, 3.809 mmol) in ethanol (8 mL) and water (4 mL) was heated at 80° C. for 45 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound as a beige solid (250 mg, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[S:18]([O:10][CH2:9][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[OH:11])([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc([C@H](O)CO)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2cccc(C)c2)cc1
Reaction time: 17 h
Yield: 84.2 %

Procedure:
To a stirred solutioll of (S)-1-(3-methylphenyl)-1,2-ethanediol (1.78 g, 11.7 mmol) in pyridine (35 ml) was added p-toluenesulfonyl chloride (2.46 g, 12.9 mmol), and 4-dimethylaminopyridine (1.58 g, 12.9mmol) at 0° C. and the reaction mixture was stirred at 0° C. to rt for 17 h. The reaction mixture was acidified with 6 N HCl aqueous solution and extracted with CH2Cl2. The extract was washed with water and brine, dried (Na2SO4), and concentrated to give 3.02 g of yellow oil, which was purified by column chromatography (silica gel: 100 g, ethyl acetatelhexane:1/9 to 1/3) to afford 2.63 g (73%) of desired product as light yellow oil. Its optical purity was 97% ee by HPLC employing a chiral stationary phase (chiral pak AS, Daicel Chemical Industries, eluted with n-hexane/EtOH:98/2; detection time:: 55 min for (R)-isomer 59 min for (S)-isomer).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1(=[O:15])[O:10][C:8](=O)[CH:7]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:6]12.O.[C:17](O)(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.COC1C=CC(O)=CC=1>C1(C)C=CC=CC=1>[C:17]([O:2][CH2:1][CH2:3][N:4]1[C:5](=[O:15])[CH:6]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:7]2[C:8]1=[O:10])(=[O:20])[CH:18]=[CH2:19]
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: NCCO
Reactant: C=CC(=O)O
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCN1C(=O)C2CCCCC2C1=O
Temperature: 25 °C

Procedure:
A one liter three necked flask was equipped with a mechanical stirrer, condenser and Dean-Stark trap. The flask was charged with 61 g of ethanolamine (1.0 mol.), 300 milliliters toluene, and 151 g of hexahydrophthalic anhydride (1.0 mol.). The reaction was refluxed for 4 hours at which time one mole of water had been collected from the azeotrope. The reaction flask was cooled to room temperature (about 25° C.). Next, the flask was charged with 72 g acrylic acid (1.0 mol.), 16 g p-toluenesulfonic acid (0.08 mol.), and 2 g of p-methoxyphenol (0.01 mol.). The reaction was refluxed for 16 hours at which time one mole of water had been collected from the azeotrope. Next, the reaction flask was placed under vacuum (15 mmHg, 2 kPa) and heated to 120° C. to insure removal of the toluene. The remaining liquid was collected to yield 254 g of 6HPIA (94%). The structure was confirmed by IR and 13C NMR.
Reaction SMILES: [CH3:1][C:2]1([NH:5][C:6]2[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]([NH2:16])=[O:15])=[CH:8][N:7]=2)[CH2:4][CH2:3]1.C1(C2[O:25]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1([NH:5][C:6]2[N:11]=[C:10]([S:12]([CH3:13])=[O:25])[C:9]([C:14]([NH2:16])=[O:15])=[CH:8][N:7]=2)[CH2:4][CH2:3]1
Reactant: CSc1nc(NC2(C)CC2)ncc1C(N)=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(NC2(C)CC2)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a stirring solution of 2-(1-methylcyclopropylamino)-4-(methylthio)-pyrimidine-5-carboxamide (305 mg, 1.280 mmol) in chloroform (25.6 mL) was added portionwise 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (502 mg, 1.920 mmol). The resulting pale yellow solution was stirred at ambient temperature overnight. The reaction solution was concentrated under reduced pressure to give crude product as a white solid. Ethyl acetate (10 mL) was added and the slurry was stirred at room temperature for 1 h, filtered, washed with ethyl acetate, and dried in a vacuum oven for a few hours to afford 2-(1-methylcyclopropylamino)-4-(methylsulfinyl)pyrimidine-5-carboxamide (242 mg, 0.952 mmol, 74.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35-8.90 (m, 2H), 7.88-8.14 (m, 1H), 7.28-7.59 (m, 1H), 2.74 (s, 3H), 1.32-1.46 (m, 3H), 0.68-0.84 (m, 2H), 0.50-0.70 (m, 2H). MS (ESI) m/z 255.0 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:20]=[C:19]([S:21][C:22]3[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=3)[NH:18][C:17]=2[CH:29]=1.[C:30]1(=O)[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH2:31]1>C(O)C>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:27]([C:25]3[O:26][C:22]([S:21][C:19]4[NH:20][C:16]5[CH:15]=[CH:14][C:13]([Cl:12])=[CH:29][C:17]=5[N:18]=4)=[CH:23][CH:24]=3)[C:31]3[C:32](=[O:36])[CH2:33][CH2:34][CH2:35][C:30]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: O=Cc1ccc(Sc2nc3ccc(Cl)cc3[nH]2)o1
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)c1[nH]ccc1N
Solvent: CCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(Cl)ccc3[nH]2)o1
Yield: 12.6 %

Procedure:
A mixture of 3-amino-2-ethoxycarbonyl-pyrrole (0.276 g 1.79 mmol), 5-(6-chloro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (0.5 g, 1.79 mmol) and 1,3-cyclohexanedione (0.201 g, 1.79 mmol) in 5 ml of ethanol is heated at reflux temperature for 2 hours. The reaction mixture is then concentrated under reduced pressure and purified on a silica gel column (120 g) eluted with a mixture of dichloromethane and methanol (99/1, v/v). The fractions containing the expected products are concentrated under reduced pressure and then purified using preparative LC/MS method B on a Xbridge C18 column (Waters, 30*100 mm) eluted with a 0 to 50% gradient of acetonitrile in aqueous 10 mM ammonium formate pH=9.0 at a 30 ml/min. flow rate in 12 min. The fraction containing the expected product are concentrated under reduced pressure. The residue is resuspended in 2 ml of acetonitrile, heated at reflux temperature and cold to room temperature. The insoluble material is collected by filtration, washed with diisopropyl ether (2×2 ml) and dried under vacuum to yield 115 mg of 9-[5-(5-chloro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester as a white powder. Yield=12%. Analytical LC/MS (method B): m/z=509 (positive ion mode, [M+H]+, 1 Cl present), m/z=507 (negative ion mode, [M−H]−, 1 Cl present)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[Cl:12]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([Cl:12])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1Cl
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)ccc1Cl
Temperature: 25 °C
Reaction time: 18.75 h

Procedure:
A 2 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was charged with 2-chloro-5-iodobenzoic acid (199.41 g, 0.706 mol), dichloromethane (1.2 L, KF=0.003 wt % water) and the suspension was set stirring at ambient temperature. Then N,N-dimethylformamide (0.6 mL, 1.1 mol %) was added followed by oxalyl chloride (63 mL, 0.722 mol, 1.02 equiv) which was added over 11 min. The reaction was allowed to stir at ambient overnight and became a solution. After 18.75 hours, additional oxalyl chloride (6 mL, 0.069 mol, 0.10 equiv) was added to consume unreacted starting material. After 2 hours, the reaction mixture was concentrated in vacuo to afford crude 2-chloro-5-iodobenzoyl chloride as a pale yellow foam which will be carried forward to the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Cl[C:10]1[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CS(C)=O>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2
Reactant: COC[C@@H]1CCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COC[C@@H]1CCCN1c1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL pressure tank reactor, was placed (S)-2-(methoxymethyl)pyrrolidine (96.45 mg, 0.85 mmol, 5.00 equiv), methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (50 mg, 0.17 mmol, 1.00 equiv), potassium carbonate (46.7 mg, 0.34 mmol, 2.00 equiv), toluene/DMSO (2/0.4 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 17 mg (27%) of (S)-methyl 3-(2-(methoxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[C:22]([CH3:30])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:30][C:22]1[CH:21]=[C:20]([NH:19][CH:2]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][C:8]=2[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:29]=[CH:28][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1ccc(N)cc1C
Reactant: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(NC(CC(C)C)c2cc(-c3ccccc3)oc2C)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-methyl-5-phenylfuran (1.1 g), methyl 4-amino-2-methylbenzoate (1.1 g), sodium carbonate (0.6 g) and sodium iodide (2.4 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.5 g, 33%) as an oil.
Reaction SMILES: O1CCOCC1.[Cl:7][C:8]1[N:9]=[N:10][CH:11]=[C:12](Cl)[N:13]=1.Cl.[CH3:16][CH:17]1[NH:22][CH2:21][CH2:20][N:19]2[C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=[C:18]12.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:7][C:8]1[N:9]=[N:10][CH:11]=[C:12]([N:22]2[CH2:21][CH2:20][N:19]3[C:23]([C:26]([F:29])([F:27])[F:28])=[N:24][CH:25]=[C:18]3[CH:17]2[CH3:16])[N:13]=1
Reactant: CC1NCCn2c1cnc2C(F)(F)F
Reactant: Clc1cnnc(Cl)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1c2cnc(C(F)(F)F)n2CCN1c1cnnc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a Dioxane (12.0 ml) solution of 3,5 dichloro-1,2,4-triazine (780 mg, 5.20 mmol) was added 8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine hydrochloride (CA, 1257 mg, 5.20 mmol) followed by diisopropylethylamine (2.73 ml, 15.60 mmol). Dichloromethane (2 mL) was added to solubilize the reaction. The reaction was stirred for 2 hrs at RT and then diluted with DCM. The reaction was washed with saturated sodium bicarbonate then brine, dried with sodium sulfate and concentrated to anoil. Purification of the oil on Biotage Normal Phase system (DCM:MeOH, 0-9% B) to afford the product as a solid, 1-17, (1.2 g, 71.7%). LRMS (ESI) m/z 319.1 [(M+H)+; calcd for C11H10ClF3N6: 319.1].
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:36])[CH2:12][C:13]1[CH:22]=[C:21]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:35])[CH:19]=2)[CH:14]=1.CI>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:9][O:10][C:11](=[O:36])[CH:12]([C:13]1[CH:22]=[C:21]([C:23](=[O:34])[C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:35])[CH:19]=2)[CH:14]=1)[CH3:1]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(S(C)(=O)=O)cc2)c2cc(F)ccc2c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1cc(C(=O)c2ccc(S(C)(=O)=O)cc2)c2cc(F)ccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To in situ generated lithium diisopropylamide (LDA) (0.33 mmol) [from diisopropylamine (0.33 mmol) and n-butyllithium (0.36 mmol)] in tetrahydrofuran (1.5 mL) at −78° C. under nitrogen was added a solution of [6-fluoro-4-(4-methanesulfonyl-benzoyl)-naphthalen-2-yl]-acetic acid methyl ester (0.120 g, 0.30 mmol, prepared in an analogous manner to the precursor of example 2-1 according to Scheme 2) in tetrahydrofuran (1.0 mL) drop-wise. The reaction mixture was stirred for 30 minutes at −78° C. Methyl iodide (0.051 g, 0.36 mmol) in hexamethylphosphoramide (HMPA) (2.4 mL) was then added drop-wise. The resulting mixture was stirred at −78° C. for 20 minutes, then warmed to −30° C. and stirred for an additional 2 hours. The reaction was quenched with an aqueous solution of saturated ammonium chloride (2 mL), and the resulting mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (silica gel, 100-200 mesh, 20% ethyl acetate in hexane) gave 2-[6-fluoro-4-(4-methanesulfonyl-benzoyl)-naphthalen-2-yl]-propionic acid methyl ester (0.070 g, 56.4%) as an off-white solid. MS cald. for C22H19FO5S [(M+H)+] 415, obsd. 415.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.[CH2:32]([N:34](CC)[CH2:35][CH3:36])[CH3:33].N1CCCC1>C1(C)C=CC=CC=1>[CH3:8][N:9]([C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[CH2:10][CH2:11][N:34]1[CH2:35][CH2:36][CH2:33][CH2:32]1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CN(CCN1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-[methyl-(4-nitro-phenyl)-amino]-ethyl ester TFA salt (74 mg, 0.21 mmol) in toluene (1 mL) is added triethylamine (50 μL) and pyrrolidine (53 μL, 0.63 mmol). The mixture is shaken in 70° C. block shaker overnight. The reaction mixture is concentrated and purified by reverse phase high performance liquid chromatography to give methyl-(4-nitro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine as a di-TFA salt (85 mg).
Reaction SMILES: [Br:1]([O-])(=O)=O.[Na+].[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:16]([F:19])([F:18])[F:17].S(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.CCOCC>[Br:1][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:16]([F:17])([F:18])[F:19]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of sodium bromate (1109 mg, 7.35 mmol) in H2O (3.3 mL) was added 4-methyl-3-trifluoromethyl-benzoic acid (500 mg, 2.449 mmol) in ethyl acetate (5 mL), followed by a solution of sodium bisulfite (765 mg, 7.35 mmol) in H2O (9 mL) over a period of about 15 min. The mixture was stirred overnight at room temperature and overnight at 50° C. The mixture was poured in ether (50 mL). The aqueous layer was extracted twice with ether and the combined organic layer was washed with anhydrous Na2S2O3 solution, dried, filtered and concentrated in vacuo to give the crude 4-(bromomethyl)-3-(trifluoromethyl)benzoic acid 35 (563 mg, 81%) which was used without further purification. (m/z)=282 and 284 (M+H)+.
Reaction SMILES: [Br:1]C1C=C(OC)C2CCN(C)CCC=2C=1.Cl.C[O:18][C:19]1[C:29]2[CH:28]=[CH:27][N:26]([CH3:30])[CH2:25][CH2:24][C:23]=2[CH:22]=[C:21]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:20]=1.Br>>[BrH:1].[OH:18][C:19]1[C:29]2[CH:28]=[CH:27][N:26]([CH3:30])[CH2:25][CH2:24][C:23]=2[CH:22]=[C:21]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:20]=1
Reactant: COc1cc(Br)cc2c1CCN(C)CC2
Reactant: COc1cc(S(C)(=O)=O)cc2c1C=CN(C)CC2
Agent: Br
Agent: Cl
Product: CN1C=Cc2c(O)cc(S(C)(=O)=O)cc2CC1

Procedure:
By the same procedure, 8-bromo-6-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is converted to 6-methoxy-3-methyl-8-methylsulfonyl-1H-3-benzazepine hydrochloride which is treated with 48% hydrobromic acid to give 6-hydroxy-3-methyl-8-methylsulfonyl-1H-3-benzazepine hydrobromide.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:13][CH:12]=1.O.[NH2:25][NH2:26]>CCO>[N:17]1([C:14]2[CH:15]=[CH:16][C:11]([C:10]3[C:5]4[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:3](=[O:2])[NH:26][N:25]=3)=[CH:12][CH:13]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(-n2ccnc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccc(-n3ccnc3)cc2)c2ccccc12

Procedure:
A solution of methyl-2-[4-(1H-imidazol-1-yl)benzoyl]benzoate (1.3 g, 4.25 mmol) in 15 mL of EtOH is treated with hydrazine monohydrate (0.26 g, 5.20 mmol) and heated to reflux for 1 day. The white solid which precipitates is filtered and recrystallized from EtOH to give 4[4-(1H-imidazol-1-yl)phenyl]-1-oxo-1,2-dihydrophthalazine. M.P. 309.5°-311° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[Cl:9][C:10]1[CH:15]=[C:14]([CH2:16]Cl)[CH:13]=[C:12]([F:18])[CH:11]=1.O>CN(C)C=O>[Cl:9][C:10]1[CH:15]=[C:14]([CH2:16][O:8][CH2:3][C:4]([F:7])([F:6])[F:5])[CH:13]=[C:12]([F:18])[CH:11]=1
Reactant: OCC(F)(F)F
Reactant: Fc1cc(Cl)cc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(Cl)cc(COCC(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
Under argon stream, to a suspension of sodium hydride (601 mg, 60 wt. % oil dispersion) in dimethylformamide (13 ml) was added dropwise trifluoroethanol (1.08 ml) at 0° C., and the mixture was stirred for 15 minutes. To this reaction solution was added dropwise a solution of 1-chloro-3-fluoro-5-chloromethylbenzene (2.23 g) in dimethylformamide (9 ml), and then the mixture was stirred at room temperature for 1 hour. To this reaction mixture was added water, and the mixture was extracted with a mixed solvent of n-hexane/ethyl acetate=1/1. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 9/1) to give the titled compound (2.85 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]1[O:11][C:12]([CH3:27])=[C:13]([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][C:18]=2[O:25][CH3:26])[N:14]=1>O1CCCC1>[Cl:3][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:15][C:13]2[N:14]=[C:10]([C:6]3[O:5][CH:9]=[CH:8][CH:7]=3)[O:11][C:12]=2[CH3:27])=[C:18]([O:25][CH3:26])[CH:19]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Solvent: C1CCOC1
Product: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Thionyl chloride (2.59 g) was added dropwise to a stirred suspension of 4-[2-(2-furyl)-5-methyl-4oxazolylmethoxy]-3-methoxybenzyl alcohol (6.30 g) in tetrahydrofuran (100 ml) at 0° C. After stirring at room temperature for 1 hours, the reaction mixture was poured onto ice to give 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole as crystals (5.67 g, yield 85%).
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[CH3:16][O:17][CH:18]1[CH:22]([CH:23]=O)[CH2:21][CH:20]([O:25][CH3:26])[O:19]1.[NH4+].[Cl-]>C1COCC1>[CH3:16][O:17][CH:18]1[CH:22]([CH:23]=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH2:21][CH:20]([O:25][CH3:26])[O:19]1
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: COC1CC(C=O)C(OC)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1CC(C=C2SCCCS2)C(OC)O1
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
According to a procedure described in Boger, D. L.; Brotherton, C. E. J. Org. Chem. 1984, 49, 4050-4055, to a solution of 2-trimethylsilyl-1,3-dithiane (1.2 mL, 6.3 mmol) in dry THF (40 mL) at 0° C. was added n-butyllithium (4 mL of 1.6 M in hexanes). After 15 minutes at 0°C. and 20 minutes at 4 mL of 1.6 M ambient temperature, a solution of 2,5-dimethoxytetrahydrofuran-3-carboxaldehyde (1.00 g, 6.00 mmol) in dry THF (10 mL) was added dropwise. After 17 hours at ambient temperature, the resultant mixture was treated with saturated aqueous NH4Cl (10 mL) and partitioned between EtOAc and H2O. The layers were separated and the aqueousueous phase extracted with EtOAc:hex (1:1) two times. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to afford a residue which was purified via flash column chromatography with 10% EtOAc/hex as eluant to yield 1.06 g (70%) of a mixture of diastereomeric 2-(2,5-dimethoxy-tetrahydrofuran-3-yl-methylidene)-1,3-dithiane as a yellow oil, which was used without any further purification. 1H NMR: δ 6.00 (d, 1H, J=9.6 Hz), 5.93 (d, 1H, J=9.6 Hz), 5.77 (d, 1H, J=9.6 Hz). Anal. Calculated for C11H18O3S2 : C, 50.35; H, 6.92; S, 24.44. Found: C, 50.07; H, 7.00; S, 24.33.