Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[C:4]([N:8]([CH2:20][O:21][CH3:22])[S:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=[N:31]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[S:9]([N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:34]2[N:30]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)[N:31]=[CH:32][CH:33]=2)[C:3]=1[F:23])[CH2:20][O:21][CH3:22])(=[O:11])=[O:10]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: COCN(c1cccc(Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COCN(c1cccc(-c2ccnn2C2CCCCO2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 127.8 %

Procedure:
N-(3-Bromo-2-fluoro-phenyl)-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (12 g, 29.25 mmol) was dissolved in 1,4-dioxane (156 mL) and argon was bubbled through the solution for 10 minutes. 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (prepared as described in WO2010/010154) (10.6 g, 38.03 mmol, 1.3 eq) was then added, followed by cesium carbonate (9.5 g, 29.25 mmol, 2 eq), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (Pd(dppf)Cl2.CH2Cl2) (1.2 g, 1.46 mmol, 0.05 eq) and water (0.9 mL) and the reaction mixture was heated to 100° C. and stirred at this temperature for 2 h. A further addition of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4 g, 0.5 eq) was made and heating was continued for 2 h. The mixture was then concentrated under reduced pressure, taken up with AcOEt (200 mL) and filtered over a Celite pad. The filtrate was washed with water and brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on silica gel (cyclohexane/AcOEt 7:3) to give 18 g of 2,5-difluoro-N-{2-fluoro-3-[2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenyl}-N-methoxymethyl-benzene-sulfonamide contaminated by N-tetrahydropyranylpyrazole.
Reaction SMILES: [CH2:1]1[O:13][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21]>C(O)C>[CH2:20]([NH:21][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCCCCCCN
Reactant: CCCCCCCCCCC1CO1
Solvent: CCO
Product: CCCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-dodecene oxide (50 g.) and hexamethylenediamine (15.8 g.) and recrystallization of the resulting product from ethanol gave N,N'-(1,6-hexylene)-bis[2-hydroxydodecylamine] (I: R = CH3 (CH2)9, R' = H, X = (CH2)6, Z = H) (35 g., m.p. 123.6°-128.0° C.).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH2:9][NH:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1O)([O-:22])=[O:21]>>[CH3:17][N:13]1[C:12](=[O:18])[C:11]([NH:10][CH2:9][C:8]([N:5]2[CH2:4][CH2:3][CH:2]([O:1][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6]2)=[O:19])=[CH:16][CH:15]=[N:14]1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: Cn1nccc(NCC(=O)N2CCC(O)CC2)c1=O
Product: Cn1nccc(NCC(=O)N2CCC(Oc3ccccc3[N+](=O)[O-])CC2)c1=O
Yield: 24 %

Procedure:
Compound 15 is prepared from intermediate 5b and from 2-nitro-phenol following synthesis method 3 (yield: 24%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[C:27](F)[CH:26]=2)=[N:4][C:5]([N:8]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:24])([CH3:23])[CH2:18]2)C(=O)OC(C)(C)C)=[CH:6][CH:7]=1.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([NH:33][C@H:34]3[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]3)[CH:26]=2)=[N:4][C:5]([NH:8][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:23])([CH3:24])[CH2:18]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CC1CCOC(C)(C)C1)c1ccc(Cl)c(-c2cc(F)ncc2Cl)n1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(CNc2ccc(Cl)c(-c3cc(N[C@H]4CC[C@H](O)CC4)ncc3Cl)n2)CCO1
Temperature: 135 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3,5′-dichloro-2′-fluoro-2,4′-bipyridin-6-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate (30 mg, 0.062 mmol) in DMSO (0.4 mL) was added trans-4-aminocyclohexanol (36 mg, 0.31 mmol) and DIEA (0.022 mL, 0.12 mmol). The mixture was stirred at 135° C. for 3 hr. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The resulting residue was re-dissolved in trifluoroacetic acid (1 mL), stirred for 15 min at ambient temperature, and then concentrated under reduced pressure. The crude resulting residue was purified by reverse phase HPLC and lyophilized to give 23 mg of trans-4-(3,5′-dichloro-6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexanol as its TFA salt. LCMS (m/z): 479.3 (MH+), retention time=0.72 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (d, J=12.91 Hz, 2H) 1.08 (s, 6 H) 1.15-1.35 (m, 4 H) 1.54 (d, J=12.91 Hz, 2 H) 1.71-2.10 (m, 5 H) 3.00 (d, J=6.65 Hz, 2 H) 3.31-3.63 (m, 5 H) 6.47 (s, 1 H) 6.58 (d, 1 H) 7.50 (d, J=9.00 Hz, 1 H) 8.05 (s, 1 H)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][N:7]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8]([CH3:9])=[O:20])=[N:6][N:7]=1
Reactant: CSc1nnc(N)c(=O)n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(S(C)=O)nnc(N)c1=O
Yield: 59.2 %

Procedure:
1.7 g of 6-amino-4-methyl-3-methylthio-1,2,4-triazin-5-one are dispersed in 200 ml of methylene chloride, and 1.8 g of 3-chloroperbenzoic acid are added in portions at 15°-20° C. A clear yellow solution is thereby formed and is evaporated at 40° C. in vacuo. The solid residue is treated with ethyl actetate, whereupon the 3-chlorobenzoic acid formed in the reaction dissolves completely. The undissolved pure product is filtered off to give 1.1 g of 6-amino-4-methyl-3-methylsulfinyl-1,2,4-triazin-5-one with a melting point of 189° C. (decomposition).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=1)#[N:2].[F:18][C:19]([F:29])([F:28])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:27][CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][C:19]([F:29])([F:18])[F:28])[CH2:22][CH2:23]2)=[O:15])=[CH:11][N:10]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)cn1
Reactant: NC1CCN(CC(F)(F)F)CC1
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1ccc(C(=O)NC2CCN(CC(F)(F)F)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a solution of 6-(2-cyanophenyl)nicotinic acid (50.2 mg, 0.224 mmol) in dimethylformamide (1 mL) was added 1,11-carbonylbis(1H-imidazole) (36.3 mg, 0.224 mmol) and the reaction mixture stirred at room temperature for 1 hour. A solution of 1-(2,2,2-trifluoroethyl)piperidin-4-amine (49 mg, 0.269 mmol) in dimethylformamide (0.5 mL) was then added and the reaction stirred overnight at room temperature. Further 1-(2,2,2-trifluoroethyl)piperidin-4-amine (25 mg, 0.134 mmol) in dimethylformamide (0.5 mL) was added and stirred for a further 48 hours. The dimethylformamide was evaporated off and the residue partitioned between ethyl acetate (10 mL) and water (3 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and evaporated to a buff coloured solid. This was triturated with a mixture of heptane and t-butyl methyl ether and the white solid was filtered off and dried to give 6-(2-cyanophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide (44 mg) 1H NMR (400 MHz, DMSO-d6) ppm 1.58-1.68 (m, 2H) 1.82-1.86 (m, 2H) 2.47-2.54 (m, 2H) 2.97 (m, 2H) 3.20 (q, J=10.25 Hz, 2H) 3.84 (m, 1H) 7.71 (td, J=6.2, 1.6 Hz, 1H) 7.87 (td, J=6.2, 1.6 Hz, 1H) 7.99 (m, 3H) 8.37 (dd, J=13.0, 2.4 Hz, 1H) 8.59 (d, J=7.4 Hz, 1H) 9.15 (dd, J=1.3, 0.8 Hz, 1H) LCMS 389 (M+1) ELSD 1.19 minutes.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([NH2:17])=[O:16])[CH:11]=[N:12][CH:13]=2)[CH2:4][CH2:3]1.C[O:19][C:20](=O)[C:21]([C:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=O.CC([O-])(C)C.[K+].[NH4+].[Cl-]>CN(C=O)C.C1COCC1.CCOC(C)=O>[CH3:32][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:26]=1[NH:25][CH:24]=[C:23]2[C:21]1[C:20](=[O:19])[NH:17][C:15](=[O:16])[C:14]=1[C:10]1[CH:11]=[N:12][CH:13]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:9]=1
Reactant: COC(=O)C(=O)c1c[nH]c2c(C)cccc12
Reactant: CN1CCN(c2cncc(CC(N)=O)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc2c(C3=C(c4cncc(N5CCN(C)CC5)c4)C(=O)NC3=O)c[nH]c12
Reaction time: 1 h

Procedure:
2-[5-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-acetamide (150 mg, 0.64 mmol) and (7-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (209 mg, 0.96 mmol) are dissolved under an atmosphere of argon in a mixture of dry DMF (2 ml) and dry THF (2 ml). A solution of 1.0 M KOtBu in THF (1.9 ml, 1.9 mmol) is then added at RT. After 1 h at 50° C., TLC analysis indicated complete conversion of starting materials. The reaction mixture is diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. The organic layer is separated, washed with brine, dried over Na2SO4, and the organic solvent is evaporated. The residue is purified by FCC (EtOAc/AcOH/H2O 600:115:150) to afford the title compound. 1H NMR (d6-DMSO 400 MHz): δ 2.15 (s, 3H), 2.28-2.32 (m, 2H), 2.92-3.00 (m, 2H), 3.15 (s, 3H), 6.21 (d, J=9 Hz, 1H), 6.64 (t, J=9 Hz, 1H), 6.88 (d, J=9 Hz, 1H), 7.22 (s, 1H), 7.98 (br s, 1H), 8.20-8.22 (m, 1H). ES+−MS: 402.6 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][C:32]=2[CH3:38])=[C:28]([CH:39]([CH3:41])[CH3:40])[NH:27][N:26]=1)(=[O:3])[CH3:2].[C:42]([OH:46])(=[O:45])[CH:43]=[CH2:44].C(O)(=O)CC=C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:44]=[CH:43]/[C:42]([OH:46])=[O:45])=[CH:33][C:32]=2[CH3:38])=[C:28]([CH:39]([CH3:41])[CH3:40])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: C=CC(=O)O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C=CCC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 4 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromo-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole and acrylic acid instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole and 3-butenoic acid, respectively.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[C:6]([CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=CC(OC(F)(F)F)=CC=2)=[O:19])[CH:5]=1)([O-:3])=[O:2].[C:32]([O:35][CH2:36][CH3:37])(=[O:34])C.CO>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[C:6]([CH2:16][NH:17][C:18]([NH:20][CH2:21][CH2:26][C:32]([O:35][CH2:36][CH3:37])=[O:34])=[O:19])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(C)=O
Reactant: O=C(NCc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12)Nc1ccc(OC(F)(F)F)cc1
Solvent: CO
Product: CCOC(=O)CCNC(=O)NCc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
1-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)-3-(4-trifluoromethyloxyphenyl)-urea, FAB-MS: M+ =439; TLC: ethyl acetate/methanol (3:1) Rf =0.50.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1.C(N(CC)CC)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([NH:16][CH2:15][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)n1
Reactant: NCC1CCOCC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Brc1cccc(NCC2CCOCC2)n1
Temperature: 110 °C

Procedure:
To a solution of 2-bromo-6-fluoropyridine (3 g, 17.05 mmol) in DMSO (8 mL) was added (tetrahydro-2H-pyran-4-yl)methanamine (3.10 g, 20.46 mmol) and triethylamine (5.68 mL, 40.9 mmol). The mixture was heated at 110° C. for 18 hr. The mixture was allowed to cool to ambient temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution (1×), water (1×), brine (1×), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography over silica gel providing 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a white solid. Yield: 4.24 g. LCMS (m/z): 270.9/273.0 [M+H]+; Retention time=0.78 min.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1)[CH3:2].[Cl:10]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:10][C:4]1[CH:5]=[C:6]([CH:8]=[O:9])[S:7][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1ccc(C=O)s1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1sc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of 5-ethyl-2-thiophenecarboxaldehyde (6.0 g) in N,N-dimethylformamide (60 ml) was added N-chlorosuccinimide (8.57 g), and the mixture was stirred at room temperature for 2 hours, and subsequently stirred under heating at 60° C. for 2 hours. N-chlorosuccinimide (4.00 g) was further added thereto, and the mixture was further stirred under heating at 60° C. for 2 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=33:1) to give 4-chloro-5-ethyl-2-thiophenecarboxaldehyde (3.1 g) as colorless oil. (2) The above 4-chloro-5-ethyl-2-thiophenecarboxaldehyde was treated in a manner similar to Reference Example 1 to give 3-bromo-1-(4-chloro-5-ethyl-2-thienylmethyl)benzene as yellow oil. APCI-Mass m/Z 347/349 (M+H+MeOH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:5]=1Br>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([C:9]2[C:4]([C:3]([O:2][CH3:1])=[O:15])=[CH:5][C:6]([O:12][CH3:13])=[CH:7][C:8]=2[O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)=[O:15]
Reactant: COC(=O)c1cc(OC)cc(OC)c1Br
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)cc(OC)c1-c1c(OC)cc(OC)cc1C(=O)OC
Temperature: 150 °C
Reaction time: 72 h
Yield: 67.8 %

Procedure:
2-Bromo-3,5-dimethoxy-benzoic acid methyl ester (5.2 g) was dissolved in DMF (16 mL), and Cu powder (2.4 g) was added. After stirring at 150° C. for 3 days, the mixture was filtered and evaporated under vacuum. The crude material was subjected to silica gel chromatography using effluent of 30-60% ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 4,6,4′,6′-tetramethoxy-biphenyl-2,2′-dicarboxylic acid dimethyl ester (2.5 g, 68%) as a clear oil.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]([CH2:18][OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[C:20]([N:24]=[C:25]=[S:26])([CH3:23])([CH3:22])[CH3:21]>C(O)C>[C:20]([NH:24][C:25]([NH:8][C@@H:9]([CH2:18][OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[S:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@@H](CO)Cc1ccc(O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccc(O)cc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
0.15 cm3 of triethylamine is added to a solution of 0.2 g of 4-[(2R)-2-amino-3-hydroxypropyl]phenol in 10 cm3 of absolute ethanol, followed by addition of 0.18 cm3 of tert-butyl isothiocyanate. The mixture is stirred at a temperature in the region of 20° C. for 18 hours and is then heated at a temperature in the region of 60° C. for 4 hours. After cooling, the reaction medium is evaporated under reduced pressure (1 kPa) at a temperature in the region of 40° C. and then chromatographed under an argon pressure of 60 kPa on a column of silica gel (particle size 40-63μ; diameter 2.5 cm; height 29 cm), eluting with a mixture of dichloromethane/methanol (98/2 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. 0.2 g of N-(tert-butyl)-N′-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]thiourea is obtained in the form of a colorless viscous oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.42 (s: 9H); 2.63 (dd, J=13.5 and 8 Hz: 1H); 2.72 (dd, J=13.5 and 5.5 Hz: 1H); from 3.25 to 3.40 (mt: 2H); 4.29 (unresolved complex: 1H); 4.83 (t, J=4.5 Hz: 1H); 6.67 (d, J=8 Hz: 2H); 7.05 (d, J=8 Hz: 2H); 7.15 (d, J=8 Hz: 1H); 7.26 (broad s: 1H); 9.16 (s: 1H)].
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CC(=O)CC.C(OC(=O)C)(=O)C.[O-2].[Mg+2]>C(O)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-acetoacetyl-L-aspartic acid, 21.7 parts, was mixed with 25 parts by volume of 2-butanone and 10.8 parts acetic anhydride. A solution of 0.056 parts magnesium oxide in 2.0 parts by volume of glacial acetic acid was added and the mixture was stirred at room temperature for 90 minutes. The solid was collected on a filter under nitrogen, rinsed with 2-butanone, and dried at 0.1 mm to afford 17.3 parts N-aceto-acetyl-L-aspartic anhydride.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:26])[N:13]([CH3:25])[CH2:14][CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH:23]=[O:24])[CH2:18][CH2:17]1)([CH3:10])([CH3:9])[CH3:8]>O1CCCC1.[Cl-].[Na+].O>[C:7]([O:11][C:12](=[O:26])[N:13]([CH2:14][CH2:15][C@H:16]1[CH2:17][CH2:18][C@H:19]([CH2:22][CH2:23][OH:24])[CH2:20][CH2:21]1)[CH3:25])([CH3:8])([CH3:10])[CH3:9]
Reactant: CN(CC[C@H]1CC[C@H](CC=O)CC1)C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CC[C@H]1CC[C@H](CCO)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
800 mg (21 mmol) of lithium aluminium hydride were added within 10 minutes to a solution of 4.5 g (15.87 mmol) crude trans-methyl-{2-[4-(2-oxo-ethyl)-cyclohexyl]-ethyl}-carbamic acid tert-butyl ester in 40 ml of tetrahydrofuran. After stirring for 3 hours at room temperature, 40 ml of brine was dropped carefully into the reaction mixture. The reaction mixture was stirred for another 20 minutes at room temperature and then partitioned between ether, 1N HCl and water. After drying of the ether phase over sodium sulfate and concentration under reduced pressure, 4.26 g of trans-{2-[4-(2-hydroxy-ethyl)-cyclohexyl]-ethyl}-methyl-carbamic acid tert-butyl ester was obtained, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20]([CH2:22][O:23][CH3:24])[C:19]([C:25]1[N:29]=[CH:28][NH:27][N:26]=1)=[CH:18]2)[S:5]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=[O:7])=[O:6].CI.[C:32](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][CH2:3][N:4]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20]([CH2:22][O:23][CH3:24])[C:19]([C:25]1[N:26]([CH3:32])[N:27]=[CH:28][N:29]=1)=[CH:18]2)[S:5]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=[O:7])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COCN(c1cccc2cc(-c3nc[nH]n3)n(COC)c12)S(=O)(=O)c1cccs1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COCN(c1cccc2cc(-c3ncnn3C)n(COC)c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
A mixture of N-(methoxymethyl)-N-[1-(methoxymethyl)-2-(1H-1,2,4-triazol-3-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (0.70 g), methyl iodide (0.20 mL), potassium carbonate (0.25 g) and N,N-dimethylformamide (8 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.14 g, yield 19%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4-1:0, volume ratio). melting point 110-111° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][C:3]1=2.Br[C:19]1[CH:20]=[C:21]([CH:24]=[O:25])[S:22][CH:23]=1>>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:19]3[CH:20]=[C:21]([CH:24]=[O:25])[S:22][CH:23]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=Cc1cc(Br)cs1
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C=O)c3)ccc21

Procedure:
In a similar manner to Example 3(b), by reaction of 4.3 g (18.7 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylboronic acid with 2.36 g (12.3 mmol) of 4-bromo-2-thiophenecarboxaldehyde, 2.3 g (63%) of the expected aldehyde derivative are obtained, with a melting point of 84-5° C.
Reaction SMILES: [I:1]Cl.C[Si](C)(C)[C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]4[CH:30]=[CH:29][C:28]5[C:27]6[C:22](=[CH:23][C:24]([C:31]7[CH:43]=[CH:42][C:41]8[C:40]9[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=9)[C:34]([CH2:47][CH2:48][CH3:49])([CH2:44][CH2:45][CH3:46])[C:33]=8[CH:32]=7)=[CH:25][CH:26]=6)[C:21]([CH2:53][CH2:54][CH3:55])([CH2:50][CH2:51][CH3:52])[C:20]=5[CH:19]=4)=[CH:12][CH:13]=3)[C:8]([CH2:61][CH:62]([CH3:65])[CH2:63][CH3:64])([CH2:56][CH:57]([CH3:60])[CH2:58][CH3:59])[C:7]=2[CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[I:1][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]4[CH:30]=[CH:29][C:28]5[C:27]6[C:22](=[CH:23][C:24]([C:31]7[CH:43]=[CH:42][C:41]8[C:40]9[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=9)[C:34]([CH2:47][CH2:48][CH3:49])([CH2:44][CH2:45][CH3:46])[C:33]=8[CH:32]=7)=[CH:25][CH:26]=6)[C:21]([CH2:53][CH2:54][CH3:55])([CH2:50][CH2:51][CH3:52])[C:20]=5[CH:19]=4)=[CH:12][CH:13]=3)[C:8]([CH2:61][CH:62]([CH3:65])[CH2:63][CH3:64])([CH2:56][CH:57]([CH3:60])[CH2:58][CH3:59])[C:7]=2[CH:6]=1
Reactant: ClI
Reactant: CCCC1(CCC)c2ccccc2-c2ccc(-c3ccc4c(c3)C(CCC)(CCC)c3cc(-c5ccc6c(c5)C(CC(C)CC)(CC(C)CC)c5cc([Si](C)(C)C)ccc5-6)ccc3-4)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC1(CCC)c2ccccc2-c2ccc(-c3ccc4c(c3)C(CCC)(CCC)c3cc(-c5ccc6c(c5)C(CC(C)CC)(CC(C)CC)c5cc(I)ccc5-6)ccc3-4)cc21
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
ICl (1.0 M in methylene chloride, 2.80 ml, 2.80 mmol) is added dropwise to a solution of 2-trimethylsilyl-9,9-bis(2-methylbutyl)-9′,9′,9″,9″-tetrakis(n-propyl)-7,2′;7′,2″-terfluorene (13a) (2.45 g, 2.80 mmol) in CCl4 (15 ml) at 0° C. After stirring for 30 min, the reaction mixture is poured into a Na2CO3 aqueous solution (5 wt %) with vigorous stirring until discoloration for extraction with methylene chloride. The organic extracts are washed with brine before dried over MgSO4. Upon evaporating off the solvent, the residue is washed with ethanol to yield 2-iodo-9,9-bis(2-methylbutyl)-9′,9′,9″,9″-tetrakis(n-propyl)-7,2′;7′,2″-terfluorene (14a) (2.36 g, 91%) as a light yellow solid.