Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[NH3:15]>COCCO>[NH2:15][C:2]1[C:3]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1sc2ccc(F)cc2c1Br
Reactant: N
Solvent: COCCO
Product: Nc1c([N+](=O)[O-])sc2ccc(F)cc12
Temperature: 90 °C

Procedure:
A solution of 3-bromo-5-fluoro-2-nitrobenzo[b]thiophene (1.51 g, 5.47 mmol) in 10 ml of 2-methoxyethanol was placed in a steel bomb. 2-Methoxyethanol (15 ml) was saturated with ammonia at 0° C. and the obtained solution was added to the steel bomb. The bomb was sealed, heated to 90° C. for 16 hours and cooled in an ice bath. After ammonia gas was sufficiently released, the reaction mixture was poured onto ice water (250 ml). The precipitate was filtered off, washed with water and dried. Yield 1.06 g (91%) of 3-amino-5-fluoro-2-nitrobenzo[b]thiophene.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=O)=O)=CC=1.[Br-:29].[Li+]>CC(C)=O.CCOCC>[Br:29][CH2:12][CH2:13][CH:14]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OCCC(c2ccc(F)cc2)c2ccc(F)cc2)cc1
Agent: [Li+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: Fc1ccc(C(CCBr)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3,3-bis(4-fluorophenyl)propyl 4-methylbenzenesulfonate, prepared in the previous step, in acetone (100 mL) was added lithium bromide (17.83 g, 205 mmol). The reaction mixture was stirred at room temperature for 17 h, and concentrated. The crude reaction mixture was diluted with Et2O, washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 0% to 20% EtOAc in hexanes) gave 3-bromo-1,1-bis(4-fluorophenyl)propane.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18].C(N(CC)CC)C.[C:26](O)(=[O:28])[CH3:27]>ClCCl>[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:26](=[O:28])[CH3:27])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18]
Reactant: NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Reactant: CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
4-Chloro-5-(3-aminopropoxy)-7-iodoisoindolinone hydrochloride (84.0 mg, 0.208 mmol) was suspended in dichloromethane, and the suspension was added with triethylamine (0.090 mL, 0.648 mmol) and anhydrous acetic acid (0.031 mL, 0.324 mmol), followed by stirring at room temperature for 12 hours. The solvent was evaported under reduced pressure and the residue was purified by slurry using water and acetonitrile to obtain 4-chloro-5-[3-(acetylamino)propoxy]-7-iodoisoindolinone (78.6 mg, yield 92%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:11][C:12]([F:16])([CH3:15])[CH2:13][OH:14]>>[F:11][C:12]([F:16])([CH3:15])[CH2:13][O:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CC(F)(F)CO
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CC(F)(F)COc1ccc(C(=O)O)cn1
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (1.79 g, orange oil) from 6-chloronicotinic acid (1.3 g, 8.25 mmol) and 2,2-difluoropropan-1-ol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([N:24]3[CH2:28][CH2:27][CH:26]([C:29](O)=[O:30])[C:25]3=[O:32])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:29]([CH:26]1[CH2:27][CH2:28][N:24]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH2:17]3)[C:25]1=[O:32])=[O:30]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2ccc3c(c2)CCC3)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc3c(c2)CCC3)C1=O
Yield: 43 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxylic acid (0.111 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.077 g (43%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:2]=1.[OH:13]O>ClCCl.C(O)C.CC(O)=CC(C)=O.CC(O)=CC(C)=O.[Cu]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][S@:8]2=[O:13])[CH:2]=1
Reactant: c1cncc([C@@H]2CCCCS2)c1
Reactant: OO
Agent: [Cu]
Agent: CC(=O)C=C(C)O
Solvent: ClCCl
Solvent: CCO
Product: O=[S@@]1CCCC[C@H]1c1cccnc1
Reaction time: 7 h

Procedure:
A solution of (S)-2-(3-pyridyl)tetrahydro-2H-thiopyran (1.5 g) in dichloromethane (15 ml) is treated with ethanol (15 ml), followed by copper acetylacetonate (0.22 g). The green-blue solution is treated with a solution of hydrogen peroxide (2 ml; 27.5%) in ethanol (2 ml). After 2 hours the solution is treated with a further quantity of solution of hydrogen peroxide (1 ml; 27.5%) in ethanol (1 ml), followed by a similar further quantity each hour for seven hours. Thus, a total of 10 ml of 27.5% hydrogen peroxide is used. After a further period of four hours, the mixture is treated with dichloromethane (10 ml) and extracted with water (4×25 ml). The combined aqueous extract is treated with sodium ethylenediaminetetraacetate (0.5 g), followed by sufficient solid sodium chloride to form a saturated solution. This is then extracted with dichloromethane (4×50 ml), and the combined organic extract is dried over magnesium sulphate and evaporated, to give (1R,2S)-2-(3-pyridyl)tetrahydro-2H-thiopyran 1-oxide (1.1 g), in the form of a yellow solid.
Reaction SMILES: [CH2:1]([C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20](=[O:26])[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(BC(C(C)C)C)(C(C)C)C.C1C[O:48]CC1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C@:4]2([CH2:1][CH2:2][CH2:3][OH:48])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[C:20](=[O:26])[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)[CH3:12])[CH2:6][CH2:5]2)=[CH:28][CH:29]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3cccn(C)c3=O)cc2)C(=O)O1
Agent: CC(C)C(C)BC(C)C(C)C
Product: C[C@@H](c1ccc(-c2cccn(C)c2=O)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (13.3 mg, 0.030 mmol) in dry THF (1.5 mL) was cooled to 0° C. Disiamyl borane (0.5M in THF, 5004, excess) was added. After 10 min, the mixture was warmed to rt and stirred for 1 h. The mixture was cooled to 0° C. again, quenched with water (1 mL) and NaBO3 (10 mg). The mixture was concentrated and purified by prep HPLC to afford (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (4.2 mg, 30% yield). LC-MS Method 1 tR=1.33 min, m/z=487(M+1); 1H NMR (CD3Cl) δ 7.47(dd, 1H), 7.38(m, 3H), 7.24(m, 2H), 7.07(t, 2H), 6.96(d, 2H), 6.39(t, 1H), 5.65(m, 1H), 4.26(t, 1H), 3.66(s, 3H), 2.91(m, 1H), 2.40-2.14(m, 3H), 1.54(d, 3H).
Reaction SMILES: [C:1]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:22][CH:23]1[CH:27]=[CH:26][CH:25]([CH3:28])[NH:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[C:1]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([N:24]1[CH:25]([CH3:28])[CH:26]=[CH:27][CH:23]1[CH3:22])=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C#N)cc1)C(=O)O
Reactant: CC1C=CC(C)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1C=CC(C)N1C(=O)C(Cc1ccc(C#N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
2.1 g of 2-[(N-Boc)amino]-3-(4-cyanophenyl)propionic acid are mixed with 0.715 g of 2,5-dimethyl-2,5-dihydropyrrole in 10 ml of DMF, 3.9 g of BOP are added and the pH is adjusted to 7 by addition of Et3N. After stirring for 18 hours at RT, the mixture is evaporated to dryness and is then taken up in EtOAc, washed with NaHCO3 solution, with KHSO4 /K2SO4 and with saturated NaCl solution. The resulting solution is dried over Na2SO4 and then evaporated. The residue is taken up in an ether/hexane mixture and then dried over Na2SO4. 1.4 g of the expected compound are obtained.
Reaction SMILES: CCO[C:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O)=[O:5].Cl.[C:16]([NH2:24])(=[NH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl>[C:17]1([C:16]2[N:24]=[C:4]([OH:5])[CH:6]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:23]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1cc(-c2ccccc2)nc(-c2ccccc2)n1

Procedure:
Ethyl benzoyl acetate (60 g, 312 mmol), benzamidine hydrochloride (65 g, 375 mmol) and potassium carbonate (172 g, 1250 mmol) were dissolved in 1,4-dioxane (1.2 liter) the reaction mixture was refluxed for 12 hours under nitrogen atmosphere. Reaction mixture was diluted with water, neutralized with cold 2N HCl, solid was filtered, washed with water and dried to yield the desired compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)(=[O:3])[CH3:2].[CH2:18]1COC[CH2:19]1>>[CH2:7]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH2:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:19][CH:18]=1.[C:1]([O:4][CH2:5][CH2:6][C:7]1([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH2:12]1)(=[O:3])[CH3:2]
Reactant: C1CCOC1
Agent: CC(=O)OCCC1(c2ccsc2)C=CC=CC1
Product: c1ccc(CCc2ccsc2)cc1
Reaction time: 0.5 h
Yield: 34 %

Procedure:
1-(3-thienyl)phenylethyl acetate dissolved in THF (20 ml) was added carefully to dry liquid ammonia (300 ml). Lithium metal was added in small portions until the blue color persisted. The resulting reaction mixture was stirred for 30 min and the reaction was quenched by addition of solid ammonium chloride. The residue, after the complete evaporation of liquid ammonia, was dissolved in water (100 ml) and was extracted with methylene chloride (4×50 ml). The combined organic layers was dried over MgSO4 and filtered. Removal of the solvent gave a crude product, which was purified by column chromatography using hexane followed by mixture of ethyl acetate in hexane as eluent to give 3-phenethylthiophene (3.2 g, 34% yield) and 1-(3-thienyl)phenethyl acetate (starting material, 7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].Cl[C:17]1[N:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:17]1[N:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1cccnc1Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccnc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under N2 in a 250 mL round-bottomed flask fitted with a reflux condenser and magnetic stirrer, 3,4-dichlorophenol (2.9 g, 17.8 mmol) was added to a suspension of K2CO3 (7.0 g, 51 mmol) in 70 mL of anhydrous DMF. After stirring the mixture for 15 min., 2-chloronicotinaldehyde (2.4 g, 17 mmol prepared according to the method in J. Heterocycl. Chem. 1995, 32, 1595) was added and the mixture was heated to 90–100° C. for 5 h. After allowing the reaction to cool to room temperature overnight, the mixture was diluted with water and extracted three times with EtOAc. The aqueous layer was then extracted with additional EtOAc and the organic layers were combined, washed with water and brine and dried over Na2SO4. Removal of the solvent in vacuo gave a brown solid which was further dried under vacuum overnight and then recrystallized from EtOAc to give the title product as tan crystals, 1.6 g; m.p. 97–99° C. A second crop of tan crystals weighing 0.716 g was later obtained, and concentration of the filtrate provided an additional 2.65 g of nearly pure title product; δH (CDCl3, 400 MHz) 7.08 (1H, dd), 7.17 (1H, m), 7.43 (1H, d), 7.49 (1H, d), 8.25 (1H, dd), 8.33 (1H, dd), 10.50 (1H, s).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=O.[CH2:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:21]>C(Cl)Cl>[CH2:20]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17](=[O:19])[CH2:16][CH2:15][O:14][CH3:13])[CH3:21]
Reactant: CCNCc1ccccc1
Reactant: COCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCN(Cc1ccccc1)C(=O)CCOC
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A suspension of 1,1′-carbonyldiimidazole (23.20 g, 0.14 mol) in dry DCM (240 mL) was added portion-wise over 15 min to a solution of 3-methoxypropionic acid (10.00 mL, 0.11 mol) in DCM (100 mL) under nitrogen at room temperature. The resulting solution was stirred under nitrogen for 1 h and then treated with a solution of N-ethylbenzylamine (32.70 mL, 0.22 mol) in dry DCM (140 mL) drop-wise over 50 min. The resultant pale brown solution was stirred under nitrogen at room temperature for 16 h and then reduced in vacuo. The orange residue was partitioned between EtOAc (500 mL) and saturated aqueous NaHCO3 (500 mL), the layers separated and the organic layer washed with aqueous HCl (2M, 500 mL) and brine (350 mL). Each of the aqueous washings was then re-extracted with EtOAC (250 mL) and the combined organic layer dried (MgSO4), filtered and reduced in vacuo to give a yellow oil. Purification by Biotage (silica, 5×90 g cartridges), eluting with cyclohexane:EtOAc 95:5 then 3:2 afforded the title compound as a pale yellow oil (20.39 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13].[CH:14](OC)=[O:15]>>[C:12]([CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][CH:14]=[O:15])[CH:3]=2)[NH:7][CH:6]=1)#[N:13]
Reactant: COC=O
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Product: N#CCc1c[nH]c2ccc(NC=O)cc12

Procedure:
A solution of 5-amino-1H-indole-3-acetonitrile (0.5 g) in methyl formate (20 ml) was stirred at room temperature for 24 h. The resulting solid precipitate was filtered off, washed with ether (2×20 ml) and dried in vacuo to give the title compound (0.41 g) as a white microcrystalline solid m.p. 196°-200° (softens 194°).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1I.C([Mg]Br)(C)C.[B:21](OC)([O:24]C)[O:22]C.Cl>O1CCCC1.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[B:21]([OH:24])[OH:22]
Reactant: Clc1ccc(-c2ccc(Br)c(I)c2)cc1
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: OB(O)c1cc(-c2ccc(Cl)cc2)ccc1Br
Temperature: -75 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution of 4-bromo-4′-chloro-3-iodobiphenyl (8.00 g, 20.40 mmol) in a mixed solvent system of anhydrous diethyl ether (80 ml) and anhydrous tetrahydrofuran (80 ml) at −75° C. is added isopropylmagnesium bromide (31.60 ml, 15% in tetrahydrofuran) dropwise, maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 2 hours, then allowed to warm to −25° C. at which point trimethyl borate (3.15 g, 30.60 mmol) is added dropwise. After the addition is complete the reaction is allowed to warm to room temperature and stir overnight, followed by cooling in an ice-bath and acidification with 2M aqueous hydrochloric acid. The crude product is extracted with ethyl acetate (×3), and the organic fractions are combined, washed with brine, then dried over anhydrous magnesium sulfate. The mixture is filtered and the filtrate is evaporated in vacuo to give a solid which is further triturated with hexanes to afford 4-bromo-4′-chlorobiphenyl-3-yl-boronic acid (5.20 g) as a white solid.
Reaction SMILES: C(OC(=O)C)(=[O:3])C.OO.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([CH3:31])[CH2:22][N:23]2[CH2:28][CH:27]([CH3:29])[O:26][CH:25]([CH3:30])[CH2:24]2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>[OH-].[K+]>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([CH3:31])[CH2:22][N+:23]2([O-:3])[CH2:24][CH:25]([CH3:30])[O:26][CH:27]([CH3:29])[CH2:28]2)=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(Cc1ccc(C(C)(C)C)cc1)CN1CC(C)OC(C)C1
Reactant: CC(=O)OC(C)=O
Agent: OO
Agent: [K+]
Agent: [OH-]
Product: CC(Cc1ccc(C(C)(C)C)cc1)C[N+]1([O-])CC(C)OC(C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 120 ml of acetic anhydride and 120 ml of 30% hydrogen peroxide is added dropwise to 40 g of 4-[3-(p-tert.-butyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine while cooling with an ice-bath so that the temperature does not exceed 45°-50° C. After stirring at room temperature for 16 hours, the mixture is cooled to -10° C. and treated with 280 ml of 40% potassium hydroxide solution, exhaustively extracted with chloroform and concentrated in vacuo at 30° C. (bath temperature). The residue is stirred at room temperature with 2-N sodium hydroxide solution for 16 hours and again extracted several times with chloroform. The combined chloroform extracts are washed neutral with sodium chloride solution, dried over sodium sulphate and evaporated. The highly viscous, syrupy residue is crystallised from ether/pentane. There is obtained pure 4-[3-(p-tert.butyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine-4-oxide in the form of the hydrate; melting point 115°-118° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[O:11][C:10]2[C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1)([OH:3])=O>S(Cl)(Cl)=O.C1(C)C=CC=CC=1>[N+:16]([C:12]1[C:10]2[O:11][C:7]3[CH2:6][CH2:5][CH2:4][C:1](=[O:3])[C:8]=3[C:9]=2[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: O=C(O)CCCc1cc2cccc([N+](=O)[O-])c2o1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1CCCc2oc3c([N+](=O)[O-])cccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A solution of 2-(3-carboxypropyl)-7-nitrobenzo[b]furan (500 mg) in thionyl chloride (5 ml) was refluxed for 1.5 hours. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was dissolved in dichloromethane (15 ml) and to the mixture was added aluminum chloride (435 mg) at 4° C. The mixture was stirred at ambient temperature for 2 hours and partitioned between 1N-hydrochloric acid and dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from a mixture of ethyl acetate and n-hexane to give 6-nitro-1-oxo-1,2,3,4-tetrahydrodibenzofuran (282 mg).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH3:45])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH3:45])[CH:42]=[CH:43][N:44]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (20 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (116 mg) in dichloromethane (20 ml) at −78° C. After finishing the dropping, an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (methanol:ethyl acetate=1:8), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methylimidazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (118 mg) (Compound 323) as yellow crystals, and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methylimidazol-2-yl)methyl]sulfonyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (33.5 mg) (Compound 324) as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:12][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[CH:4]2)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1ncc2cc(CO)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc2cc(COS(C)(=O)=O)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(1-methyl-1H-indazol-5-yl)methanol (0.15 g, 0.92 mmol) was dissolved in dichloromethane (3 mL), cooled to 0° C. and treated with triethylamine (0.14 mL, 1.0 mmol, 1.1 equiv) and methanesulfonyl chloride (0.079 mL, 1.0 mmol, 1.1 equiv). After stirring for 2 hours, the mixture was treated with additional triethylamine (0.14 mL, 1.0 mmol, 1.1 equiv) and methanesulfonyl chloride (0.079 mL, 1.0 mmol, 1.1 equiv). After an additional 1 hour, the mixture was diluted with dichloromethane (100 mL), washed with sodium bicarbonate (15 mL, aqueous saturated) and brine (15 mL), dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.