Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O-:9])=[O:8])[CH2:2]1.B(O[O-])=O.[Na+].O.[OH-].[Na+].[C:18](O)(=O)C>>[S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O:9][CH3:18])=[O:8])[CH2:2]1
Reactant: O=C([O-])C1=CCCSC1
Reactant: CC(=O)O
Agent: O=BO[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C1=CCCSC1
Temperature: 55 °C
Reaction time: 19 h
Yield: 76 %

Procedure:
To a solution of 0.934 gm (5.75 mmol) of 5,6-dihydro-2H-thiopyran-3-carboxylate from part C in glacial acetic acid (40 mL) was added 1.98 gm (12.88 mmole) sodium perborate. The reaction mixture was stirred at 55° C. under N2 for 19 hrs. whereupon the solution was poured into H2O (50 mL) and neutralized with 50% NaOH to pH=7. The solution was extracted three times with methylene chloride. The combined organic layers were washed once with saturated sodium bicarbonate and once with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.832 gm (76%) of methyl 5,6-dihydro-2H-thiopyran-3-carboxylate, 1,1 dioxide as a white solid; mass spectrum m/e=190 (EI, M+) Part E: Preparation of Methyl-2H-thiopyran-3-carboxylate, 1,1-dioxide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[B-](F)(F)(F)[CH:13]=[CH2:14].[K+]>C(O)C>[CH3:11][C:3]1[C:2]([CH:13]=[CH2:14])=[CH:7][CH:6]=[CH:5][C:4]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Product: C=Cc1cccc([N+](=O)[O-])c1C

Procedure:
1-Bromo-2-methyl-3-nitrobenzene (5.00 g, 23.1 mmol), potassium trifluoro(vinyl)borate (5.00 g, 37.3 mmol)), TEA (6.45 mL, 46.3 mmol) and PdCl2(dppf)-CH2Cl2Adduct (0.945 g, 1.157 mmol) were added to ethanol (75 mL). The mixture was degassed and then reflux for 3 hrs. The reaction was poured into brine and extracted with ETOAc. The organic layer was separated, dried over Na2SO4, filtered then concentrated. The residue was purified by chromatography on a 330 g ISCO Redi-Sep column using ethyl acetate/hexane solvent system to yield 2-methyl-1-nitro-3-vinylbenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1Cl

Procedure:
2-Chloro-4-nitrobenzoic acid (50 g, 248 mmol) was subjected to methylation using methanol (500 mL) and H2SO4 (98%, 15 mL) according to the procedure described in the example 66 to obtain the title compound(83)
Reaction SMILES: [OH-].[Na+].Cl.Cl.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][S:12][C:13](=N)N.BrC[CH2:18][CH2:19][CH2:20][Cl:21]>O>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:13][S:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1
Reactant: N=C(N)SCc1ccccn1
Reactant: ClCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCCSCc1ccccn1
Temperature: 73 °C
Reaction time: 15 h
Yield: 76.7 %

Procedure:
A 10 N aqueous solution of sodium hydroxide (100 cc) is added dropwise, in the course of 20 minutes and whilst keeping the temperature below 15° C., to a solution of 2-(pyrid-2-ylmethyl)-isothiourea dihydrochloride (120 g) in distilled water (250 cc), cooled to 13° C. After heating for 20 minutes at 73° C. and then cooling to 13° C., a 10 N aqueous solution of sodium hydroxide (60 cc) and then 1-bromo-4-chlorobutane (85 g) are added, whilst stirring, and stirring is continued for 15 hours at a temperature of about 20° C. The reaction mixture is then extracted three times with methylene chloride (430 cc in total); the organic extracts are combined, washed with distilled water (300 cc); dried over anhydrous sodium sulphate and filtered. The solution is poured onto neutral silica gel (100 g) contained in a column of diameter 3 cm; the column is eluted with methylene chloride (3700 cc). The first fraction (700 cc) is discarded. The second (2000 cc) is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. Pyrid-2-ylmethyl 4-chlorobutyl sulphide (82 g) is thus obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:46]([C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH:56]([NH2:60])[C:57]([OH:59])=[O:58])=[CH:51][C:50]=1[NH2:61])(=[O:48])[CH3:47]>CN(C=O)C>[C:46]([C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH:56]([NH:60][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:57]([OH:59])=[O:58])=[CH:51][C:50]=1[NH2:61])(=[O:48])[CH3:47]
Reactant: CC(=O)c1ccc(CC(N)C(=O)O)cc1N
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(CC(NC(=O)c2ccc([N+](=O)[O-])cc2)C(=O)O)cc1N
Reaction time: 0.5 h

Procedure:
To 4-nitrobenzoic acid (50.1 mg), HATU (114 mg) and DIEA (105 μL) was added 1 mL DMF and the mixture was stirred for 30 minutes. Then the resulting solution was added to 3-(4-acetyl-3-aminophenyl)-2-aminopropanoic acid (66.7 mg, 1.0 equiv) in 1.0 mL DMF, and the reaction was stirred at room temperature, monitored by LC-MS. The title product was then isolated by preparative HPLC. 1H NMR (400 MHz, MeOD): δ 8.28 (d, J=8.8 Hz, 2H), 7.93 (d, J=8.8 Hz, 2H), 7.72 (d, J=8.4 Hz, 1H), 6.69 (d, J=1.6 Hz, 1H), 6.61 (dd, J′=8.4 Hz, J″=1.6 Hz, 1H), 3.28 (dd, J′=13.8 Hz, J″=10.0 Hz, 1H), 3.02 (dd, J′=13.8 Hz, J″=10.0 Hz, 1H), 2.51 (s, 3H); ESI-MS (m/z) 372.34 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[NH2:26])=[CH:20][C:19]=3[CH3:28])=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([N+:29]([O-])=O)=[CH:4][N:3]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:2]1[C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[NH2:26])=[CH:20][C:19]=3[CH3:28])=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([NH2:29])=[CH:4][N:3]=1
Reactant: Cc1cc(NC(N)=O)ccc1-c1ccccc1-c1c(C)sc2c([N+](=O)[O-])cnc(N)c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(NC(N)=O)ccc1-c1ccccc1-c1c(C)sc2c(N)cnc(N)c12
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A suspension of Example 66E (0.44 g, 1.01 mmol), NH4Cl (0.054 g, 1.01 mmol), and iron powder (0.45 g, 8.1 mmol) in ethanol (16 mL) and water (4 mL) was heated at 80° C. for 3 hours, cooled to room temperature, and filtered through diatomaceous earth (Celite®). The pad was washed with ethyl acetate and ethanol and the filtrate was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), flitered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 0.15 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 2.29 (s, 3H), 4.48 (s, 2H), 4.59 (s, 2H), 6.80 (d, J=7.46 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.25-7.29 (m, 3H), 7.30 (s, 1H), 7.31 (s, 1H), 7.60 (d, J=8.81 Hz, 2H), 8.67 (s, 1H), 8.86 (s, 1H); MS (ESI(+)) m/e 404 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].[OH:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>CN1CCCC1=O>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][O:11][CH2:10][CH2:9][O:20][N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Fc1ccccc1COCCBr
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCCOCc1ccccc1F
Temperature: 0 °C
Yield: 82 %

Procedure:
108 ml of triethylamine were added dropwise to a mixture of 165 g (0.71 mol) of 1-bromo-2-(2-fluorobenzyloxy)-ethane, 116 g (0.7 mol) of N-hydroxyphthalimide and 710 ml of N-methyl-2-pyrrolidone at from 20° to 25° C. in the course of 1 hour. After 5 hours at 60° C. the cold reaction mixture was poured into 200 ml of ice water and the precipitate was filtered off under suction, washed with water and isopropanol and dried under reduced pressure over phosphorus pentoxide. Yield: 82%; mp.: 62°-64° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28]Br)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CC(C)([O-])C.[K+]>CN(C)C=O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=3)[C:2]([CH3:14])([CH3:1])[CH2:3]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A process vial with a suspension of 1 g 3,3-dimethyl-6-nitro-2,3-dihydro-1H-indole, 1.59 g 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester and 1.17 g potassium tert-butoxide in 10 ml N,N-dimethylformamide was sealed with a teflon septum and placed in the microwave cavity. The reaction mixture was stirred for 15 minutes at 100° C. by microwave-assisted heating (Emrys Optimizer, Personal Chemistry). After removal of the solvent under reduced pressure the residue was purified by flash chromatography on silica gel with a n-heptane/ethylacetate gradient. The fractions containing the product were combined and evaporated to yield a white solid.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:27][CH2:28][CH:29]([CH2:31]O)[OH:30].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:31][CH:29]([OH:30])[CH2:28][OH:27])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: OCC(O)CO
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g of 4-(n-hexadecylamino)benzoic acid, 1.00 g of glycerol, and 5.35 ml of boron trifluoride etherate in 200 ml of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:23]([O:25][CH3:26])=[O:24])=[C:11]3[C:16]=2[O:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:12]3)=[C:5]([CH3:27])[O:4][N:3]=1.Cl.[N:29]([O-])=[O:30].[Na+]>C(OCC)(=O)C.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:23]([O:25][CH3:26])=[O:24])=[C:11]3[C:16]=2[O:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]3[N:29]=[O:30])=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(-c2c(C)noc2C)c2c1NC(c1ccccc1)CO2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2c(C)noc2C)c2c1N(N=O)C(c1ccccc1)CO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
A suspension of methyl 8-(3,5-dimethylisoxazol-4-yl)-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate (0.230 g, 0.631 mmol) in ethyl acetate (6.13 mL) was cooled to 0° C. and treated with 6.0 M hydrogen chloride in water (0.789 mL, 4.73 mmol) and water (0.460 mL) followed by sodium nitrite (0.0871 g, 1.26 mmol) in water (0.690 mL) dropwise. The reaction mixture was stirred at 0° C. for 15 min, the ice bath was removed, and stirred for 30 min which gave a biphasic solution. After another 30 min a suspension was present. The reaction mixture was diluted with EtOAc (40 mL) and water (20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude tan solid. Purification by flash column chromatography (100% hexanes to 50% EtOAc/hexanes) gave the desired product (0.228 g, 92%) as a yellow solid. LCMS calculated for C21H20N2O4 ([M−NO]+H)+: m/z=364.1. found: 364.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])Cl.[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].C(N(CC)CC)C>C(OCC)C>[CH2:13]([O:15][C:16]([C:17]1[C:4]([C:3]2[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:2]=2[F:1])=[N:6][O:7][C:18]=1[CH3:19])=[O:20])[CH3:14]
Reactant: CC#CC(=O)OCC
Reactant: ON=C(Cl)c1ccc(Br)cc1F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(Br)cc2F)noc1C
Yield: 83.1 %

Procedure:
In a fashion similar to that described for preparation 15, 2-fluoro-4-bromo-benzoyl chloride oxime (2.00 g, 7.92 mmol), ethyl-2-butynoate (1.33 g, 11.9 mmol), triethylamine (2.2 ml, 15.8 mmol) in diethyl ether (10 ml), and diethyl ether (20 ml) gave 4-ethoxycarbonyl-5-methyl-3-(2-fluoro-4-bromophenyl)isoxazole (2.16 g, 83%) after column chromatography (silica gel, hexanes/diethyl ether gradient). 1H NMR (400 MHz, CDCl3) δ 7.36-7.29 (m, 3H), 4.16 (q, 2H, J=6.8 Hz), 2.70 (s, 3H), 1.15 (t, 3H, J=6.9 Hz)ppm.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].[CH3:14][O:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:11]([C@@H:2]3[O:1][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3]3)=[O:12])[CH2:24]2)[CH:18]=1
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Reactant: COC(=O)c1cccc(C2CCCNC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc([C@H]2CCCN(C(=O)[C@H]3COc4ccccc4O3)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (240 mg, 1.21 mmol) in DCM (5 ml) was added to an ice-cold mixture of 3-(piperidin-3-yl)benzoic acid methyl ester (267 mg, 1.21 mmol), triethylamine (59 mg, 0.58 mmol) and DCM (10 ml). After stirring for 2 h at RT, the mixture was washed with 1 M HCl (10 ml) and 1 M Na2CO3. The organic phase was dried over Na2SO4 and evaporated to dryness and the residue was purified by flash chromatography using heptane/EtOAc as eluent. The first eluting diastereomer was collected to afford 98 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1>[CH3:24][O:23][C:21](=[O:22])[C:20]([N:12]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:11])[CH2:9][CH3:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:25]
Reactant: COC(=O)C(=O)Cl
Reactant: CCC(=O)c1ccc(F)cc1Nc1ccccc1
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(F)cc1N(C(=O)C(=O)OC)c1ccccc1
Temperature: 110 °C

Procedure:
To a solution of 1-(4-fluoro-2-phenylamino-phenyl)-propan-1-one (6.0 g, 24.7 mmol) in toluene (75 mL) was added methyl chlorooxoacetate (14.2 mL, 148 mmol) at room temperature under nitrogen. The reaction mixture was heated at reflux at 110° C. for 16 hr. The reaction mixture was concentrated under vacuum to afford N-(5-fluoro-2-propionyl-phenyl)-N-phenyl-oxalamic acid methyl ester. The crude product was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:4]=1[C:5](OC)=[O:6].[NH3:14]>C1COCC1.CO>[Br:13][C:10]1[CH:9]=[C:4]2[C:3]([CH2:2][NH:14][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: N
Reactant: COC(=O)c1cc(Br)ccc1CBr
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NCc2ccc(Br)cc21

Procedure:
Methyl 2-bromomethyl-5-bromobenzoate (0.1 mol) was dissolved in THF/methanol (200 ml) (1:1) and the solution obtained was saturated with dry ammonia gas. The solvent was removed and the residue was triturated with water, diethyl ether and hexane and then recrystallised from ethanol/dichloromethane to obtain 6-bromo-2,3-dihydro-isoindol-1-one (12.5 g). 1H NMR (400 MHz, d6 DMSO) δ 8.70 (1H, bs), 7.78 (1H,s), 7.77 (1H, d, J=7 Hz), 7.55 (1H, d, J=7 Hz), 4.35 (2H,s). m/z (ES+) 212 (M+). b) 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate Prepared in a similar manner to that of Example 1a using 6-bromo-2,3-dihydro-isoindol-1-one. 1H NMR (360 MHz, CDCl3) δ 12.5 (1H, brs), 8.05 (1H,d, J=1 Hz), 7.94 (1H, dd, J=7 and 1 Hz), 7.66 (1H, dd, J=7 and 1 Hz), 5.07 (2H, s), 4.60 (3H, s). m/z (ES+) 226 (M+). c) (6-Bromo-3H-isoindol-1-yl)hydrazine 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate (3.7 g) was dissolved in THF (35 ml) and triethylamine (2.8 ml) was added followed by hydrazine (1 M in THF, 35 ml). After an hour the solid which had precipitated was filter off and dried to give title compound (2.8 g) 1H NMR (360 MHz, CDCl3) δ 12.5 (1H, brs), 7.85 (1H,d, J=1 Hz), 7.51 (1H, dd, J=7 and 1 Hz), 7.25 (1H, dd, J=7 and 1 Hz), 4.49 (2H, s). m/z (ES+) 226 (M+). d) 8-Bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (6-Bromo-3H-isoindol-1-yl)hydrazine (2.8 g) was stirred in 10% trifluoroacetic acid in dichloromethane (40 ml) and 5-methyl-3-phenyl-4-isoxazole carboxaldehyde was added (2.33 g) and the reaction was stirred for 0.5 hours. The solvent was removed and the residue was partitioned between ethyl acetate and water and the organic layer was washed with saturated sodium hydrogen carbonate, dried, filtered and evaporated. The residue was taken up into methanol and dichloromethane, sodium acetate was added and the stirred suspension was treated dropwise with bromine (0.5 ml). The reaction was diluted with water and extracted into dichloromethane and dried, filtered and evaporated. The product was purified by silica chromatography using ethyl acetate as eluant to yield the title compound (1.46 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)#[N:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]3[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:24]=3[CH:23]=2)=[CH:18][CH:17]=1.[Al+3].[Cl-].[Cl-].[Cl-]>CN(C=O)C.O=S(Cl)Cl>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]3[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:24]=3[C:23]=2[C:6]([C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:8])=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: COc1ccc(C(=O)O)cc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC)c(C#N)c2)cc1
Yield: 107.5 %

Procedure:
1.8 g of the title compound was prepared from 3.9 g (3.9 mmol) of 3-cyano-4-methoxybenzoic acid (converted to the acid chloride with 30 mL of SOCl2 and three drops of DMF), 6 g (22 mmol) of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene, and 14.7 g (110 mmol) of AlCl3 in a manner similar to that in Preparation 4.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.BrCCBr.[Mg].[C:19](=[O:21])=[O:20].Cl>O1CCCC1>[CH3:10][C:6]1([CH3:11])[C:5]2[CH:12]=[CH:13][C:2]([C:19]([OH:21])=[O:20])=[CH:3][C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: CC1(C)CCOc2cc(Br)ccc21
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC1(C)CCOc2cc(C(=O)O)ccc21
Temperature: 0 °C

Procedure:
A solution of 14.2 g of 7-bromo-3,4-dihydro-4,4-dimethyl-2H-1-benzopyran and 1.1 g of 1,2-dibromoethane in 80 ml of tetrahydrofuran was added dropwise using a heatable ultrasonics bath, to a suspension, boiling under reflux, of 1.6 g of magnesium shavings in 20 ml of tetrahydrofuran. After heating under reflux for an additional 2 hours, the reaction mixture was cooled to 0° C. and a strong stream of carbon dioxide gas was conducted in (about 1 hour). Thereafter, the mixture was poured on to ice, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with water, dried and evaporated. After recrystallization from ethyl acetate/hexane, there were obtained 5.3 g of 3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-carboxylic acid, melting point 173°-174° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.[CH3:16][C:17]([CH3:22])([CH3:21])[CH2:18][CH2:19][NH2:20]>C1(C)C=CC=CC=1>[CH3:16][C:17]([CH3:22])([CH3:21])[CH2:18][CH2:19]/[N:20]=[CH:8]/[C:7]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:6]=1[NH:5][CH2:4][CH2:3][N:2]([CH3:15])[CH3:1]
Reactant: CC(C)(C)CCN
Reactant: CN(C)CCNc1c(F)cccc1C=O
Solvent: Cc1ccccc1
Product: CN(C)CCNc1c(F)cccc1/C=N/CCC(C)(C)C

Procedure:
2-(2-(Dimethylamino)ethylamino)-3-fluorobenzaldehyde (157 mg, 0.7467 mmol) and 3,3-dimethylbutan-1-amine (150 μL, 1.115 mmol) were stirred at RT in toluene (5 mL) with 4 Å MS overnight. The suspension was filtered and volatiles removed on a rotary evaporator at 40° C. 1H-NMR was consistent with 2-((E)-(3,3-dimethylbutylimino)methyl)-N-(2-(dimethylamino)ethyl)-6-fluorobenzenamine (175 mg). The crude product was carried on to next reaction.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Brc1ccccn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Product: O=C(c1ccccn1)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12l and 2-bromopyridine
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[O:13][CH3:14].[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:22][O:23][C:19]=2[CH:18]=1>C(O)(C)C>[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]4[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=4[O:13][CH3:14])[CH2:28][CH2:29]3)=[N:22][O:23][C:19]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C=O)ccc1OCC1CO1
Solvent: CC(C)O
Product: COc1cc(C=O)ccc1OCC(O)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 55 °C
Yield: 89.2 %

Procedure:
A stirred mixture of 4-(2,3-epoxypropoxy)-3-methoxyphenyl methanone (4.5 g, 22.5 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.36 g, 24.3 retool) in isopropyl alcohol (150 ml) was heated at 55° C. for 16 hours. The mixture was cooled and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography over a silica gel column (SiO2, 80 g; eluted with dichloromethane, DCM, and 1% CH3OH in DCM). The oil thus obtained solidified quickly, weight: 9.47 g. Recrystallization from ethanol and isopropyl ether, then toluene provided 8.6 g (86%) of white crystals, m.p.=107°-108° C.