Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]=[C:9]=[O:10])[CH2:3]1.Cl.Cl.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([N:21]2[C:25](=[O:26])[C:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][NH:22]2)[CH:16]=1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[C:25](=[O:26])[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][NH:22]3)[CH:16]=2)=[O:10])[CH2:3]1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: CC1CCCC(N=C=O)C1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(NC(=O)NCc2ccnc(-n3[nH]cc(-c4cccnc4)c3=O)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
13.9 mg (100 μmol) of 3-methylcyclohexyl isocyanate are initially charged, 34.0 mg (100 mol) of the compound from Example 4A, dissolved in 0.6 ml of 1,2-dichloroethane, and 25.8 mg (200 μmol) of diisopropylethylamine are added and the mixture is stirred at RT overnight. The mixture is then concentrated, the residue is taken up in DMSO, the precipitate is filtered off and the filtrate is purified by preparative HPLC (Method 3).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][OH:15]>>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[O:15][CH2:14][CH2:13][N:12]([CH3:16])[CH3:11]
Reactant: CN(C)CCO
Reactant: N#Cc1ccc(Cl)cc1F
Product: CN(C)CCOc1cc(Cl)ccc1CN

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 2-dimethylamino-ethanol analogously to the preparation of Intermediate 113.1. colorless oil; ES-MS: M+=229.2; HPLC: AtRet=1.18 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH:12]=[N:11][CH:10]=[N:9]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:2]1([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(-n2cncn2)cc1

Procedure:
Operating protocol A (82° C., 24 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 336 μl of iodobenzene (3 mmoles), 138 mg of 1,2,4-triazole (2 mmoles), 1.042 g of caesium carbonate (3.2 mmoles) and 1.2 ml of DMF.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[C:13]([C@@H:17]1[CH2:22][CH2:21][C@H:20](O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]3)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: Cc1ccc2cc(O)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-Methyl-quinolin-6-ol (4.13 g, 0.0259 mol), cis 4-tert-Butyl-cyclohexanol (4.86 g, 0.0311 mol) and triphenylphosphine (9.53 g, 0.0363 mol) in tetrahydrofuran (100 mL, 1 mol), cooled in an ice bath, was added diisopropyl azodicarboxylate (7.61 mL, 0.0363 mol) in Tetrahydrofuran (10 mL, 0.1 mol). The reaction mixture was stirred for 72 h at room temperature. The solvent was removed under reduced pressure and the residue was taken up in methylene chloride, adsorbed onto silica gel and purified by flash chromatography (0-30% ethyl acetate in hexanes) to give the title compound in 56% yield. ESI-MS (M+H+): 298.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:18]([Mg]Br)#[CH:19].O>O1CCCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[C:10]([CH:11]([OH:12])[C:18]#[CH:19])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Mg]Br
Reactant: O=Cc1c(-c2ccco2)nn2c(Cl)cccc12
Solvent: C1CCOC1
Solvent: O
Product: C#CC(O)c1c(-c2ccco2)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (3.36 g, 13.6 mmol) in tetrahydrofuran (100 mL) at −78° C. was added ethynylmagnesium bromide (32.7 mL, 0.5 M in tetrahydrofuran, 16.3 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added to the reaction and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated to a solid residue, 1-[(7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (3.63 g, 98%). 1H NMR (CDCl3): δ 7.98 (d, 1H), 7.59 (d, 1H), 7.16 (t, 1H), 7.03 (d, 1H), 6.95 (d, 1H), 6.55 (m, 1H), 6.16 (m, 1H), 2.76 (m, 1H), 2.63 (s, 1H). MS m/z 273 (M+1).
Reaction SMILES: OC[C:3]1[CH:4]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6](=[O:16])[N:7]2[C:12]=1[C:11]1[S:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8]2.[C:23]([O:26][C:27](=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:26][CH2:27][SH:13]1[C:11]2[C:12]3[N:7]([CH2:8][CH2:9][C:10]=2[CH:15]=[CH:14]1)[C:6](=[O:16])[C:5]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:4][CH:3]=3)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1CCc1ccsc1-2
Solvent: c1ccncc1
Product: CC(=O)OC[SH]1C=CC2=C1c1ccc(-c3ccccc3)c(=O)n1CC2

Procedure:
A suspension of 1.55 g of 4,5-dihydro-10-(hydroxymethyl)-8-phenyl-7H-thieno[2.3-a]quinolizin-7-one in 6.7 ml of pyridine was treated with 3.35 ml of acetic anhydride while stirring, whereby a clear solution was obtained after about 15 minutes. After stirring overnight, the precipitated yellow crystals were removed by filtration under suction and washed with ether. The filtrate was evaporated in vacuo and the residue together with the above yellow crystals were recrystallized from methanol. There was obtained pure (4,5-dihydro-7-oxo-8-phenyl-thieno[2,3-a]-quinolizin-1-yl)methyl acetate of m.p. 145°-146°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[C:3]1=[CH2:13].[N:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[CH:19]=[CH:18][C:17]=1[OH:27])=O>C(O)C>[CH3:1][N:2]1[C:3]2([O:27][C:17]3[CH:18]=[CH:19][C:20]4[C:25]([C:16]=3[N:14]=[CH:13]2)=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)[C:4]([CH3:11])([CH3:12])[C:5]2[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=Nc1c(O)ccc2ccc(O)cc12
Reactant: C=C1N(C)c2ccccc2C1(C)C
Solvent: CCO
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(ccc3ccc(O)cc13)O2
Yield: 24.7 %

Procedure:
In 100 ml of ethanol, 9.2 g (53 mmol) of 1,3,3-trimethyl-2-methyleneindoline and 10 g (53 mmol) of 1-nitroso-2,7-dihydroxynaphthalene were dissolved and the solution was heated to reflux for 3 hours. After removing the solvent, recrystallization was conducted using benzene to obtain 4.5 g of 1,3,3-trimethyl-9'-hydroxyspiro[indoline-2,3'-[3H]-naphtho[2,1-b] (1,4)oxazine] in the form of green-white solid. In 50 ml of methylene dichloride, 1.5 g (4.4 mmol) of the thus obtained spirooxazine compound was dissolved and 0.6 g (6 mmol) of the methacrylic acid chloride was added dropwise at room temperature and the mixture was allowed to react. After removal of the solvent, purification by column chromatography and recrystallization from methanol was conducted to obtain 1.2 g of 1,3,3-trimethyl-9'-methacryloxyspiro[indoline-2,3'-[3H]-naphtho-[2,1-b] (1,4)oxazine] as white solid.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:33])[NH:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[N:14]=2)[CH2:7]1)(=O)=O.[C:34]([O-:37])(=[S:36])[CH3:35].[K+]>CN(C)C=O>[C:34]([S:36][CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:33])[NH:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])[N:14]=2)[CH2:7]1)(=[O:37])[CH3:35]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)NCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)NCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Temperature: 80 °C
Reaction time: 7 h
Yield: 57.4 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-{4-[2-(p-nitrobenzyloxycarbonylamino)-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (607.3 mg, 1.22 mmol) (obtained as described in Reference Example 56(6)) in dimethylformamide (33 ml) was added potassium thioacetate (1.06 g, 7.35 mmol) at room temperature. The reaction mixture was stirred in an oil bath (80° C.) for 7 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed successively with 0.5M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (1:2) as the eluant to afford 3-acetylthio-1-{4-[2-(p-nitrobenzyloxycarbonylamino)-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (335.8 mg, yield 58%) as a pale brown solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>C(N(CC)CC)C>[C:9]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:10])[CH2:8][C:7]([CH3:6])=[O:11]
Reactant: C=C1CC(=O)O1
Reactant: OCCCCl
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCCCCl
Yield: 81.6 %

Procedure:
3-Chloropropanol (47.3 g, 0.500 mole) and a catalytic amount of triethylamine at 65° were treated dropwise with diketene (42 g, 0.50 mole). After the addition was complete, the reaction was stirred at 65° for an additional hour. Distillation of the residue furnished 72.9 g (82%) of 3-chloropropyl acetoacetate as a clear liquid, b.p. 78°-85° at 150 torr.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH2:34]1[C:37]2([CH2:40][NH:39][CH2:38]2)[CH2:36][O:35]1.C(=O)([O-])[O-].[K+].[K+].CC#N>C(Cl)Cl>[F:31][C:28]([F:29])([F:30])[C:27]([C:24]1[CH:23]=[CH:22][C:21]([N:8]2[CH2:9][CH2:10][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:12][C@@H:7]2[CH2:6][N:39]2[CH2:40][C:37]3([CH2:36][O:35][CH2:34]3)[CH2:38]2)=[CH:26][CH:25]=1)([OH:33])[CH3:32]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: C1NCC12COC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CC3(COC3)C2)cc1)C(F)(F)F
Temperature: 100 °C
Yield: 31.9 %

Procedure:
A 10-mL microwave vial was charged with ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (0.140 g, 0.265 mmol, Intermediate B), 2-oxa-6-azaspiro[3.3]heptane (0.026 g, 0.265 mmol. ASW MedChem, Inc. New Brunswick, N.J.), potassium carbonate (0.040 g, 0.291 mmol), and 3 mL of MeCN. The tube was sealed and heated in a microwave (Emrys Optimizer Automated Microwave Synthesizer, Uppsala, Sweden) at 100° C. for 1 h. The mixture was diluted with 5 mL of CH2Cl2, filtered, and the filtrate was concentrated. The resulting oil was purified by column chromatography on silica gel (20-100% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(4-((2S)-2-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.045 g) as a mixture of two isomers:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:10]([O:17][C:18]([NH:20][C:21](=[NH:24])SC)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[CH2:10]([O:17][C:18]([NH:20][C:21]([N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)=[NH:24])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CSC(=N)NC(=O)OCc1ccccc1
Reactant: OCCC1CCNCC1
Solvent: CC#N
Product: N=C(NC(=O)OCc1ccccc1)N1CCC(CCO)CC1
Yield: 40.9 %

Procedure:
A mixture of 6.2 g (0.028 mol) of 4-hydroxyethyl piperidine and 3.6 g (0.028 mol) of N-benzyloxycarbonyl-S-methyl isothiourea in 50 ml of acetonitrile was refluxed overnight. Evaporation and flash chromatography on silica gel with ethyl acetate gave 3.5 g (41%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CC(C)=O>[CH3:3][C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:19][CH2:20][CH2:21][Cl:22])=[CH:9][CH:10]=1)([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(OCCCCl)cc1
Temperature: 50 °C
Yield: 83.5 %

Procedure:
To a stirred solution of 4-tert-butylphenol (20.0 g, 0.16 mol) in acetone (500 mL) were added potassium carbonate (100 g, 0.72 mol) and 1-bromo-3-chloropropane (50.6 g, 0.33 mol). The reaction was heated to 50° C. for 18 hours. The reaction was filtered and the solvents evaporated to provide 30.3 g of 3-[4-(1,1-dimethylethyl)phenoxy]-1-chloropropane as a colorless oil; 200 MHz NMR δ 1.47 (s,9H), 2.36 (p, J=5.5Hz, 2H), 3.88 (t, J=5.5 Hz, 2H), 4.22 (t, J=5.5Hz, 2H), 7.0, 7.47 (ABq, J=9.6Hz, 4H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(C=P(CCCC)(CCCC)CCCC)#N.[CH3:44][C:45]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:48])[CH2:46]O>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:44][C:45]([CH3:48])([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH3:46])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(CO)c1ccccc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCCc1nc(C)n(CC(C)(C)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 9.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cyanomethylene tri-n-butylphosphorane (1 g), 2-methyl-2-phenylpropan-1-ol (0.63 g) and toluene (30 mL) was stirred at 100° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.13 g, 10%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8](Cl)(=[O:10])=[O:9])=[N:6][CH:7]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[N:12]1[C:17]2[C:16](=[CH:2][CH:3]=[CH:4][C:5]=2[NH:6][S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)(=[O:10])=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)nc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)nc1
Yield: 25 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoqunoline (40 mg, 0.27 mmol), 5-methyl-pyridine-2-sulfonyl chloride 440 (79 mg, 0.41 mmol), pyridine (1.5 ml) DMAP (cat.) and DCM (2 ml) gave the title compound (21 mg, 25%) after purification by column chromatography with n-hexane/EtOAc (93:7) as the eluent.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18])([O-:13])=[O:12]>N1C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:18])([O-:13])=[O:12]
Reactant: Oc1n[nH]c2ccccc12
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: O=C(c1cccc([N+](=O)[O-])c1)n1nc(O)c2ccccc21
Temperature: 95 °C
Yield: 27.9 %

Procedure:
To 16.0 (0.118 mol) of 1H-indazol-3-ol dissolved in 120 ml of dry pyridine was added 21.8 g (0.118 mol) of m-nitrobenzoyl chloride. The heterogeneous yellow mixture was heated at 95° C. for 21/2 hrs. then let cool to room temperature and poured onto 1 liter of ice/H2O. The light yellow precipitate was collected, washed well with H2O and air-dried. Recrystallization from aqueous EtOH afforded 12.7 g (27.9%) of 1-(m-nitrobenzoyl)-1H-indazol-3-ol as a colorless solid, mp 232°-234° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].CI.[CH2:20]1CCN2C(=NCCC2)CC1>O1CCCC1>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH3:20])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: COc1cc(O)c2ccccc2c1OC(C)=O
Reactant: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(OC)c2ccccc2c1OC(C)=O

Procedure:
A solution of 1-acetyloxy-2-methoxy-4-hydroxynaphthalene (23.2 g) and methyl iodide (6.4 mL) in tetrahydrofuran (250 mL) was treated dropwise with a solution of DBU (16.5 mL) in tetrahydrofuran (50 mL). The resulting precipitate of DBU.HI was removed by filtration, and the filtrate evaporated. Recrystallization from methanol gave 1-acetyloxy-2,4-dimethoxynaphthalene, m.p. 116°-117° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[N:17]12[CH2:22][CH2:21][CH:20]([CH2:19][CH2:18]1)[CH:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=1)[CH2:16]2
Reactant: Ic1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1
Reactant: Nc1ccccc1
Product: c1ccc(Nc2ccc(-c3ccc(OC4CN5CCC4CC5)cc3)cc2)cc1

Procedure:
The product of Example 8A (405 mg, 1 mmol) was treated with aniline (110 mg, 1.2 mmol) according to the procedure in Example 8B. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.25) as solid (200 mg, yield, 54%). 1H NMR (MeOH-d4, 300 MHz) δ 1.42-1.56 (m, 1H), 1.62-1.88 (m, 2H), 1.99-2.12 (m, 1H), 2.14-2.22 (m, 1H), 2.73-3.02 (m, 5H), 3.27-3.38 (m, 1H), 4.51-4.59 (m, 1H), 6.80-6.87 (m, 1H), 6.94 (d, J=8.8 Hz, 2H), 7.06-7.15 (m, 4H), 7.18-7.26 (m, 2H), 7.44 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H) ppm. MS (DCl/NH3) m/z 371 (M+H)+.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:18]([OH:19])=[C:16]([OH:17])[CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>N1C=CC=CC=1>[C:23]([O:17][C:16]1[CH:15]=[C:14]([CH:21]=[CH:20][C:18]=1[O:19][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1)[CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1
Reactant: O=C(NCCc1ccc(O)c(O)c1)OCc1ccccc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NCCc1ccc(OC(=O)c2cccnc2)c(OC(=O)c2cccnc2)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.6 %

Procedure:
19.0 g (66 mmol) of N-carbobenzoxydopamine obtained in Synthetic Example 1-(1) and 37.2 g (209 mmol) of hydrochloride of nicotinoyl chloride were added to 200 ml of pyridine. After stirring at room temperature for 12 hours, the mixture was allowed to react at 35°-40° C. for 2 hours. Then, the reaction mixture was poured into ice and a sodium carbonate solution followed by extraction with chloroform. The resulting extract was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain crude crystals. The thus-obtained crystals were recrystallized from ethyl acetate/diethyl ether (1:5 by volume) to obtain 23.5 g (yield: 71.6%) of the desired compound in the form of white crystals (m.p. 77°-78° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[O:15][CH2:16][CH3:17])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:16]([O:15]/[C:9](=[CH:8]\[C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][CH3:24])[CH:27]=2)=[CH:3][CH:4]=1)/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:17]
Reactant: CCOC(=O)/C(=C/c1ccc(Br)cc1)OCC
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)cc1)OCC
Yield: 89.4 %

Procedure:
To a solution of 10.8 g (36.1 mmol) of ethyl (Z)-3-(4-bromophenyl)-2-ethoxyacrylate, 108 mL (217 mmol) in 120 mL of toluene, aqueous 2 M sodium carbonate solution and 1.5 g (1.8 mmol) of dichloro[11′-bis(diphenylphosphino)ferrocene]palladium are added. The reaction medium is stirred and 9.25 g (39.7 mmol) of methyl[3-(4,4,5,5-tetramethyl[1.3.2]dioxaborolan-2-yl)phenyl]amine are then added. After stirring at 80° C. for 2 hours, the reaction medium is hydrolyzed and diluted with ethyl acetate. After separation of the phases by settling, the ethyl acetate phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 90/10 and then 80/20 heptane/ethyl acetate mixture. 10.5 g (94%) of ethyl (Z)-2-ethoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate are obtained in the form of a yellow oil. After taking up the product in pentane, 9.5 g (85%) of ethyl (Z)-2-ethoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate are obtained in the form of a pale yellow solid with a melting point of 52° C.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([OH:17])[C@H:12]1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][C:21](OC=C)=[O:22]>COCCOC>[C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([O:17][C:21](=[O:22])[CH2:20][Cl:19])[C@H:12]1[OH:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=COC(=O)CCl
Reactant: O=C(OC[C@H]1OC=C[C@@H](O)[C@H]1O)c1ccccc1
Solvent: COCCOC
Product: O=C(CCl)O[C@@H]1C=CO[C@H](COC(=O)c2ccccc2)[C@@H]1O
Reaction time: 6 h
Yield: 80 %

Procedure:
1.0 g (4 mmol) of 6-O-benzoylgalactal is taken up in about 20-25 ml of DME and 10-15 ml of vinyl chloroacetate and stirred with 1 g of lipase from Pseudomonas spec. (lipase P, Amano) at room temperature for about 5-7 h. Filtering off the reusable enzyme, concentration of the solution in vacuo and chromatography on silica gel (ether/hexane 1:1) or crystallization result in 6-O-benzoyl-3-O-chloroacetyl-galactal in 80% yield (1050 mg).