Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:27]=[CH:26][C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([C:19]3[N:20]=[C:21]([NH2:24])[S:22][CH:23]=3)=[C:14]([CH3:25])[CH:13]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:27]=[CH:26][C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([C:19]3[N:20]=[C:21]([NH:24][C:36](=[O:43])[C:37]4[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=4)[S:22][CH:23]=3)=[C:14]([CH3:25])[CH:13]=2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COCCCOc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.3 %

Procedure:
To a solution of 4-{4-(4-(3-methoxypropoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-amine (21-5, 0.28 g, 0.74 mmol) in CH2Cl2 (5.0 mL) was added triethylamine (0.5 mL, 3.59 mmol) followed by isonicotinoyl chloride hydrochloride (0.22 g, 1.22 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered and recrystallized in toluene to give N-{4-(4-(4-(3-methoxypropoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (21, 0.99 mg) as light yellow solids in 27% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.00 (s, 1 H), 8.81 (s, 2 H), 7.99 (d, J=5.7 Hz, 2 H), 7.15 (s, 1 H), 6.98 (m, 4 H), 6.68 (s, 2 H), 4.00 (t, J=6.3 Hz, 2 H), 3.47 (t, J=6.3 Hz, 1 H), 2.05 (s, 6 H), 1.94 (t, J=6.3 Hz, 2 H). ESI-MS: m/z 489.7 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([CH3:17])[C:5](=[O:18])[CH2:4][N:3]=1.[C:19]1(B(O)O)C=CC=C[CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([CH2:17][CH2:19][CH3:20])[C:5](=[O:18])[CH2:4][N:3]=1
Reactant: COc1cc2c(cc1OC)N(C)C(=O)CN=C2Cl
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1C(=O)CN=C(Cl)c2cc(OC)c(OC)cc21
Temperature: 115 °C
Yield: 55.6 %

Procedure:
Heat at 115° C. for 12 hours under an inert atmosphere a mixture of 200 mg (0.74 mmol) of 5-chloro-7,8-dimethoxy-1-methyl-1,3-dihydro-1,4-benzodiazepin-2-one XVIIIaa, 109 mg (0.89 mmol) of benzene boronic acid, 182 mg (0.86 mmol) of K3PO4, 23 mg (0.020 mmol) of tetrakis(triphenylphosphine)Pd(0) in 5 ml of DMF. Allow to cool to room temperature. Add 80 ml of H2O and extract three times with 50 ml of Et2O. Dry the organic fractions on Na2SO4. Purify by chromatography (AcOEt). Recrystallize in EtOH. One obtains 122 mg of the abovenamed product in the form of colorless crystals.
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[CH3:18][NH2:19].[BH4-].[Na+].CO>C1COCC1>[CH3:18][NH:19][C@H:4]1[CH2:5][CH2:6][C@H:1]([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reaction time: 1.5 h

Procedure:
To a suspension of ketone 5 (10.4 g, 0.045 mol) in 2-PrOH (520 mL) was added methylamine (33.7 mL of a 2.0 M solution in THF, 0.067 mol). A clear, amber solution formed after ca 15 minutes, and a precipitate gradually formed a few minutes later. After 1.5 hours, the reaction mixture was cooled in an ice/water bath, NaBH4 (2.6 g, 0.067 mol) was added, and stirring was continued at 0° C. for 35 minutes. The reaction mixture was stirred at room temperature for 15 hours. MeOH (ca 2 mL) was added to quench any excess NaBH4 (no gas evolution was observed), and the solvents were removed under reduced pressure. The residue was partitioned between 1N HCl (500 mL) and EtOAc (250 mL). The aqueous layer was separated, adjusted to pH 7-8 with solid NaHCO3, and washed with EtOAc (200 mL). A precipitate formed during the wash, which was collected by vacuum filtration and dried to give 6-[trans-4-(methylamino)cyclohexyl]-3H-benzoxazol-2-one 15 (5.0 g, 46%). The organic layer was separated, and TLC analysis (89:10:1 CH2Cl2:MeOH:NH4OH) showed it contained compound 15. Compound 15 was also shown by TLC analysis to be present in the initial EtOAc extraction. The organic extracts were combined, concentrated under reduced pressure, dissolved in a minimal amount of MeOH, and a solid was precipitated out with diethyl ether. The solid was collected by vacuum filtration and dried to give 15 (1.6 g, 13%) as the HCl salt. To the aqueous layer (ca 1L), which also showed the presence of additional 15 by TLC, was added solid NaCl (ca 80 g), and the solution was concentrated under reduced pressure to approximately half its original volume. A solid formed and was collected by vacuum filtration and dried to give 15 (1.3 g, 12%). The solids were combined to give 6-[trans-4-(methylamino)cyclohexyl]-3H-benzoxazol-2-one 15 (7.9 g, 73%): 1H NMR (500 MHz, CD3OD): δ 7.10 (d, J=1.5 Hz, 1H), 7.03 (dd, J=8, 1.5 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 2.67-2.52 (m, 2H), 2.49 (s, 3H), 2.15-2.12 (m, 2H), 1.97-1.94 (m, 2H), 1.61-1.52 (mi, 2H), 1.38-1.30 (m, 2H).
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([O:28]CC)=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:31][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: CCOC(=O)c1cccc(N2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(N2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 6-(4-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperazin-1-yl)pyridine-2-carboxylate (1.3 g) in tetrahydrofuran (20 ml) and water (5 ml) is added, at room temperature, lithium hydroxide monohydrate (185 mg). The mixture is stirred at room temperature for 5 hours, and then ice-cold 1N HCl solution is added. The aqueous phase is extracted with ethyl acetate and then the combined organic phases are dried over sodium sulphate. The solids are filtered off and the solvent is distilled off. This gives 6-(4-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-1-yl)pyridine-2-carboxylic acid (700 mg).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:15]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1N
Reactant: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccccc1NCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
3.24 g of ortho-phenylenediamine was dissolved in 30 ml of dimithylformaide, to the solution were added 2.07 g of potassium carbonate and 1.52 g of cinnamyl chloride, and the mixture was stirred overnight at a room temperature. After adding 100 ml of water, the reaction mixture was extracted twice with 100 ml and 50 ml of chloroform, and the extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform, to obtain 2.0 g of the title compound as light brown crystals.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)([O-:5])=[O:4].[CH2:15]([O:17][C:18](=[O:21])[CH2:19]Br)[CH3:16].O>CN(C)C=O>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][N:10]1[C:11]2[C:7](=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1)[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1ccc2c([N+](=O)[O-])cccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
Sodium hydride (60%/mineral oil: 81 mg) was dissolved in dimethylformamide (5 mL), and the solution was cooled to 0° C. After addition of 4-nitroindole (300 mg), the mixture was stirred for one hour, and bromoacetic acid ethyl ester (340 mg) was added thereto, followed by stirring at 0° C. for 4 hours. Water was added thereto and the mixture was concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate, then concentrated to give the title compound (367 mg)
Reaction SMILES: [C:1](/[CH:3]=[C:4]1/[N:5]([CH3:24])/[C:6](=[N:22]/[CH3:23])/[S:7][CH:8]/1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)#[N:2].C(=O)([O-])[O-:26].[K+].[K+].OO>CS(C)=O.C(OCC)(=O)C>[C:1]([CH2:3][C:4]1[N:5]([CH3:24])/[C:6](=[N:22]/[CH3:23])/[S:7][C:8]=1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]1)(=[O:26])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: C/N=C1\SC(C2CCN(C(=O)OC(C)(C)C)CC2)/C(=C\C#N)N1C
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C/N=c1\sc(C2CCN(C(=O)OC(C)(C)C)CC2)c(CC(N)=O)n1C
Yield: 120 %

Procedure:
To a solution of tert-butyl 4-((2Z,4E)-4-(cyanomethylene)-3-methyl-2-(methylimino)-1,3-thiazolidin-5-yl)piperidine-1-carboxylate (0.30 g) obtained in Example 74a) in DMSO (6.0 mL) were added potassium carbonate (0.1 g) and a 30% aqueous hydrogen peroxide solution (1 mL) at 0° C. and mixed for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was crystallized from hexane to give the title compound (0.32 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[CH:9]=1.[I:17]N1C(=O)CCC1=O>CC(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[C:9]=1[I:17]
Reactant: Fc1ccccc1-c1cc2ncncc2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Fc1ccccc1-c1[nH]c2cncnc2c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a slurry of 6-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine (1.0 g) in acetone (25 mL) was added N-iodosuccinimide (1.4 g). The reaction was stirred at rt for 3 h, until complete conversion was observed by LC-MS. The reaction mixture was diluted with EtOAc (150 mL) and the solid was collected via filtration and washed with EtOAc yielding 1.23 g of desired (77% yield). LC-MS calculated for C12H7FIN3: 339.1, found 339.96 [M+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=3[O:21][CH3:22])[C:6]=2[CH:23]=1.N1C(C)=CC=CC=1C.Cl[C:33]([O:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:34]>ClCCl>[CH:36]1([O:35][C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[CH:8][N:7]([CH2:10][C:11]4[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=4[O:21][CH3:22])[C:6]=3[CH:23]=2)=[O:34])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: COC(=O)c1ccc(Cn2cnc3ccc(N)cc32)c(OC)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1ccc(Cn2cnc3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Reaction time: 24 h
Yield: 66.5 %

Procedure:
A solution of methyl 4-(6-aminobenzimidazol-1-ylmethyl)-3-methoxybenzoate (J) (0.63 g.) and 2,6-lutidine (0.36 ml.) in dichloromethane (10 ml.) was treated with cyclopentyl chloroformate (0.33 g.). After stirring for 24 hours the solution was diluted with dichloromethane. The mixture was washed successively with 20% w/v sodium hydroxide, water, and brine, then dried (MgSO4) and evaporated. The resultant residue was purified by flash chromatography on a 6×20 cm. silica gel column using 1:3 v/v hexane:ethyl acetate as the eluent to give the title compound (0.57 g., 93%); NMR: 1.7[m,8H, (CH2)4 ], 3.8(s,3H, OCH3), 3.9(s,3H, OCH3) 5.2(m,1H, CHO), 6.17-7.0(br m,3H), 7.5-7.8(br m,4H).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]=[CH:6][CH:5]1[CH3:12])=[O:3]>O.O.O.[Rh](Cl)(Cl)Cl.C(O)C>[CH3:1][C:2]([C@@H:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]=[CH:6][C@H:5]1[CH3:12])=[O:3]
Reactant: CC(=O)C1C(C)C=CCC1(C)C
Agent: Cl[Rh](Cl)Cl
Solvent: O
Solvent: CCO
Product: CC(=O)[C@H]1[C@H](C)C=CCC1(C)C

Procedure:
In a 200-ml four-necked flask equipped with a thermometer, condenser and a stirrer, placed were 2,6,6-trimethyl-3-cyclohexenyl methyl ketone (10 g) synthesized in Referential Example 1, ethyl alcohol (40 ml) and rhodium trichloride trihydrate (0.9 g). Under stirring, they were reacted at 90° C. for 24 hours. The reaction mixture at this time was sampled and analyzed by gas chromatography, resulting in that the content of trans-2,6,6-trimethyl-3-cyclohexenyl methyl ketone was 11%, while those of 2,6,6-trimethyl-2-cyclohexenyl methyl ketone and 2,6,6-trimethyl-1-cyclohexenyl methyl ketone produced by the above reaction were 87% and 2%, respectively.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH2:21][C:22]#[N:23])[C:13]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:14])[C:8](=[O:24])[C:7]3=[CH:25][N:26]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:5]([C:6]=23)=[N:4][CH:3]=1.[OH-:37].[Na+]>CO>[Cl:1][C:2]1[C:11]([CH2:10][NH:9][C@H:12]([CH2:21][C:22]#[N:23])[C:13]([NH:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])=[C:6]2[C:7]([C:8]([OH:24])=[O:37])=[CH:25][N:26]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:4][CH:3]=1
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@H](CC#N)C(=O)NC2CCCC2)C3=O)cc1
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@H](CC#N)C(=O)NC4CCCC4)c(Cl)cnc32)cc1
Reaction time: 0.33 h
Yield: 2.1 %

Procedure:
To a solution of (R)-2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-cyano-N-cyclopentylpropanamide in MeOH (2 mL) was added aqueous NaOH (1N, 0.5 mL). The reaction mixture was stirred for 20 min and the product was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (0.5 mg, 2.1% from Step A starting material). 1H NMR (400 MHz, CD3OD) δ 1.37-1.72 (m, 4 H) 1.83-1.95 (m, 4 H) 3.22-3.26 (m, 2 H) 3.69-3.76 (m, 1 H) 5.11 (s, 1 H) 5.14-5.17 (m, 1 H) 5.18 (s, 1 H) 7.88 (s, 1 H) 8.27 (s, 1 H). [M+H] calc'd for C18H18ClN5O2, 372; found, 372.4.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH3:18])[C:6]([O:16][CH3:17])=[C:7]([CH:9]([OH:15])[C:10](=[NH:14])[O:11]CC)[CH:8]=1.[C:19](Cl)(Cl)=[O:20].C(N(CC)CC)C>O1CCCC1>[Cl:2][C:3]1[CH:4]=[C:5]([CH3:18])[C:6]([O:16][CH3:17])=[C:7]([CH:9]2[O:15][C:19](=[O:20])[NH:11][C:10]2=[O:14])[CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=N)C(O)c1cc(Cl)cc(C)c1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(C)cc(Cl)cc1C1OC(=O)NC1=O
Temperature: 0 °C

Procedure:
By the procedure of Example 9, except that methylene chloride was used in place of chloroform for product extraction following the quench, ethyl 1-(5-chloro-2-methoxy-3-methylphenyl)-1-hydroxymethanecarboximidate hydrochloride (2.5 g., 8.5 mmoles) in 250 ml. of tetrahydrofuran was reacted with phosgene in the presence of triethylamine (2.7 g., 27 mmoles). The product was isolated by pouring the reaction mixture slowly over 1 liter of crushed ice. The aqueous phase was separated and extracted with three portions of methylene chloride. The combined organic phase/extracts was evaporated to solids. The crude product was taken up in 1 N sodium hydroxide, extracted with ether, and acidifed with 3 N hydrochloric acid to precipitate the desired product (1.81 g., 83%, m.p. 184°-186° C.). Recrystallization from toluene gave purified 5-(5-chloro-2-methoxy-3-methylphenyl)oxazolidine-2,4-dione (1.57 g., 72% overall; m.p. 187°-189° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C1C(=O)N([Br:22])C(=O)C1.O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:22][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH2:1][N:2]([CH3:3])[CH2:14][CH2:13][C:5]=12
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN1CCc2c(Br)c3ccccc3n2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3.7 g) in 40 mL of CHCl3 cooled at 0° C. was added 4 g of NBS in two portions. After stirring for 2 h at r.t., the reaction mixture was treated with 30 mL of water and 20 mL of saturated aqueous solution of NaHCO3, and then extracted with 200 mL of CH2Cl2. The extract was dried over Na2SO4 for 2 days, and then filtered through a pad of silica gel, concentrated to give 4 g of the title compound as a light brown solid.
Reaction SMILES: [CH:1]([C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=1[CH3:13])=[O:2].[CH3:14][C:15]([CH3:21])([CH3:20])[CH:16](O)[CH2:17][OH:18]>C1(C)C=CC=CC=1>[C:15]([CH:16]1[CH2:17][O:18][CH:1]([C:3]2[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=2[CH3:13])[O:2]1)([CH3:21])([CH3:20])[CH3:14]
Reactant: CCOC(=O)c1noc(C=O)c1C
Reactant: CC(C)(C)C(O)CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1noc(C2OCC(C(C)(C)C)O2)c1C
Temperature: 110 °C

Procedure:
To a solution of ethyl 5-formyl-4-methylisoxazole-3-carboxylate (Intermediate C) (50 mg, 0.273 mmol) in toluene (0.5 mL) was added 3,3-dimethylbutane-1,2-diol (32.3 mg, 0.273 mmol) and the mixture was heated at 110° C. for 4.5 hours. The resulting mixture was partitioned between EtOAc and water and the organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:33]=[CH:32][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:18])=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1>>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:21]=2)=[O:18])=[CH:32][C:33]=1[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1noc2cc(Br)ccc12
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1-c1ccc2c(C)noc2c1
Yield: 45.2 %

Procedure:
Example 7 was prepared in a similar manner to Example 4 using 6-bromo-3-methyl-1,2-benzisoxazole (11 mg) and 4-methyl-N-(3-morpholin-4-yl-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 9, 21 mg) to give the title compound as an oil (9.6 mg).
Reaction SMILES: [O:1]1CCCC1.[C:6]1([Si:12]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:17][Si:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:15][Si:14]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N)CCCCC.Cl>O>[C:24]1([Si:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:1])[O:17][Si:12]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:13][Si:14]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[OH:15])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc([Si]2(c3ccccc3)O[Si](c3ccccc3)(c3ccccc3)O[Si](c3ccccc3)(c3ccccc3)O2)cc1
Reactant: C1CCOC1
Agent: Cl
Solvent: CCCCCCN
Solvent: O
Product: O[Si](O[Si](O[Si](O)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
400 parts tetrahydrofuran and 55 parts hexaphenylcyclotrisiloxane were added to an Erlenmeyer flask, and dissolution was brought about. 3 parts hexylamine and 40 parts water were then added, and stirring was carried out for 30 minutes at room temperature. Conversion to the diol was confirmed by thin-layer chromatography, and the reaction solution was poured into 500 parts water and neutralized with dilute hydrochloric acid. The organic substance was precipitated with 600 parts of toluene, and this precipitate was repeatedly washed with water. Dehydration was then carried out with anhydrous sodium sulfate, and after filtration, the filtrate was condensed to 150 parts with a rotary evaporator. Hexane was then added to obtain crystals of hexaphenyltrisiloxane-1,5-diol in a yield of 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:20])[F:19])=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12]C(C)(C)C)=[O:11])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:19])[F:20])=[C:6](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(Cl)ccc1OC(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1cc(Cl)ccc1OC(F)F
Reaction time: 1 h

Procedure:
To a solution of (E)-tert-butyl 3-(5-chloro-2-(difluoromethoxy)phenyl)acrylate (458 mg, 1.503 mmol) in DCM (4 mL) was added TFA (2.0 mL, 26.0 mmol). After 1 h, the solvent was removed to give Intermediate 15 as a white solid. MS (ESI) m/z: 249.0 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH2:22]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:29]([N:28]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:16](=[O:18])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCNCCCCCC
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Product: CCCCCCN(CCCCCC)C(=O)C(C)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and di-n-hexylamine were used to obtain N,N-Di-n-hexyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1, as an oily product.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:20]4[CH2:23][CH:22]([OH:24])[CH2:21]4)[C:17]=3[F:19])[C:12](=[O:26])[C:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10]2)[CH2:8][CH2:7]1.O>N1C=CC=CC=1>[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:20]4[CH2:21][CH:22]([O:24][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:23]4)[C:17]=3[F:19])[C:12](=[O:26])[C:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(O)C3)c(F)cc2c1=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(OS(C)(=O)=O)C3)c(F)cc2c1=O
Temperature: 0 °C
Yield: 74 %

Procedure:
6.3 g (55.0 mmoles) of mesyl chloride are slowly added to a solution of 1.0 g (2.75 mmoles) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 50 ml of pyridine cooled to 0° C., and the reaction is maintained at 0° C. for 3 hours. The solution is added to a mixture of ice and water giving a precipitate which is filtered and washed with water. The solid is dried under vacuum yielding 0.9 g (73%) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-mesyloxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate melting at 191°-193° C.