Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH2:25][CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[CH2:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3](=[O:27])[NH:31][CH2:30][CH2:28][OH:29])=[CH:5][N:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:26]
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)OC)cn2)CC1
Reactant: NCCO
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCO)cn2)CC1
Yield: 73 %

Procedure:
By the same procedure as described in the example 2, synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using ethanolamine. And then, the product was recrystallized with ethanol and hexane to give a desired compound.
Reaction SMILES: [CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]([O:12]C(=O)C)[C@H:10]1[NH:28][C:29]([C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41]([NH:43][C@@H:44]3[C@@H:50]([O:51]C(=O)C)[C@H:49]([O:55]C(=O)C)[C@@H:48]([CH2:59][O:60]C(=O)C)[O:47][C@:45]3([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[OH:46])=[O:42])[CH:37]=2)[CH:32]=1)=[O:30])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO.O1CCOCC1>[CH2:64]([C@@:45]1([O:47][C@H:48]([CH2:59][OH:60])[C@@H:49]([OH:55])[C@H:50]([OH:51])[C@H:44]1[NH:43][C:41]([C:36]1[CH:35]=[CH:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([C:29]([NH:28][C@@H:10]3[C@@H:11]([OH:12])[C@H:16]([OH:17])[C@@H:21]([CH2:23][OH:24])[O:22][C@:8]3([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[OH:9])=[O:30])[CH:32]=2)[CH:37]=1)=[O:42])[OH:46])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: CC(=O)OC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](NC(=O)c2ccc3cc(C(=O)N[C@@H]4[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@]4(O)Cc4ccccc4)ccc3c2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@]1(O)Cc1ccccc1)c1ccc2cc(C(=O)N[C@@H]3[C@@H](O)[C@H](O)[C@@H](CO)O[C@@]3(O)Cc3ccccc3)ccc2c1

Procedure:
A solution of 1.0 g of (naphthalene-2,6-dicarboxylic acid bis- [(benzyl 3,4,6-tri-O-acetyl-2-desoxy-α-D-glucopyranosid-2-yl)-amide] in 20 ml of methanol and 20 ml of dioxan was stirred at room temperature for 18 hours with ml of a 0.3M sodium methanolate solution. The resulting precipitate was washed with methanol, dioxan and ether, dried and gave naphthalene-2,6-dicarboxylic acid bis-[(benzyl 2-desoxy-α-D-glucopyranosid-2-yl)-amide], MS: m/z 717.2 ([M-H]-).
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][O:3]1.[NH:17]1[CH:21]=[CH:20][CH:19]=[N:18]1>CC#N>[CH2:9]([O:8][C:7]([NH:6][C@@H:5]([CH2:4][N:17]1[CH:21]=[CH:20][CH:19]=[N:18]1)[C:2]([OH:3])=[O:1])=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1cn[nH]c1
Reactant: O=C(N[C@H]1COC1=O)OCc1ccccc1
Solvent: CC#N
Product: O=C(N[C@@H](Cn1cccn1)C(=O)O)OCc1ccccc1
Temperature: 50 °C
Yield: 37.7 %

Procedure:
A suspension of (S)-benzyl 2-oxooxetan-3-ylcarbamate (0.67 g, 3.03 mmol), and pyrazole (0.22 g, 3.29 mmol) in CH3CN (12 mL) was heated at 50° C. for 24 h. The mixture was cooled to rt overnight and the solid filtered to afford (S)-2-(benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (330.1 mg). The filtrate was concentrated in vacuo and then triturated with a small amount of CH3CN (ca. 4 mL) to afford a second crop (43.5 mg). Total yield 370.4 mg (44%). m.p. 165.5-168° C. lit m.p. 168.5-169.5 [Vederas et al., J. Am. Chem. Soc., 107:7105 (1985)]. 1H NMR (400 MHz, CD3OD) δ 7.51 (d, J=2.0, 1H), 7.48 (s, J=1.5 Hz, 1H), 7.24-7.34 (m, 5H), 6.23 m, 1H), 5.05 (d, 12.7H, 1H), 5.03 (d, J=12.7 Hz, 1H), 4.59-4.66 (m, 2H), 4.42-4.49 (m, 1H). LCMS: Anal. Calcd. for C14H15N3O4: 289; found: 290 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]2[CH:6](Cl)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2]1([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH:1]1[CH:5]2[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2]1([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=12
Reactant: CN(C)CCOC12NC(c3ccccc31)C(Cl)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCOC12NC(Cc3ccccc31)c1ccccc12

Procedure:
The compound of Example 8 was dissolved in tetrahydrofuran and added to a suspension of lithium aluminum hydride in tetrahydrofuran and refluxed for 3 hrs. After washing with water, and extraction with ether, the subject compound was obtained; nmr (CDCl3): τ 2.25-3.15 (m, 8H, arom), 5.21 (br d, 1H, J = 5Hz, ##STR17## 5.90-6.90 (m, 5H, PhCH2 --, --OCH2 --, and --NH--), 7.25 (br t, 2H, --CH2N(CH3)2), and 7.63 (s, 6H, --N(CH3)2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@@:10]([CH2:47][CH:48]=O)([CH2:34][CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:28][CH2:29]3)(=[O:25])=[O:26])[C:11](=[O:33])[C@@:10]([CH2:47][CH2:48][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)([CH2:34][CH2:35][O:36][Si:37]([CH:38]([CH3:40])[CH3:39])([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](CC=O)(CCO[Si](C(C)C)(C(C)C)C(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C1COCCN1
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@](CCO[Si](C(C)C)(C(C)C)C(C)C)(CCN2CCOCC2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
N-((S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-(2-oxoethyl)-3-(2-((triisopropylsilyl)oxy)ethyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (Example 408, Step F) and morpholine were combined according to a procedure similar to the one described in Example 91, Step F. Purification by chromatography on silica gel (eluent: 50 to 100% EtOAc/DCM, gradient elution over 15 min) provided the title compound as a clear, colorless glass.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[Cl:19][C:20]1[C:21]([C:30]([F:33])([F:32])[F:31])=[N:22][N:23]([CH2:26][C:27](O)=[O:28])[C:24]=1[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[CH3:2][O:3][C:4]([C:6]1([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:7][CH2:8][N:9]([C:27](=[O:28])[CH2:26][N:23]2[C:24]([CH3:25])=[C:20]([Cl:19])[C:21]([C:30]([F:33])([F:32])[F:31])=[N:22]2)[CH2:10][CH2:11]1)=[O:5]
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: COC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 25 mL flask was added 4-(4-chloro-phenyl)-piperidine-4-carboxylic acid methyl ester hydrochloride (1.87 mmol, 1.0 equiv), 453 mg of (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (1.87 mmol, 1.00 equiv), 990 mg BOP (2.24 mmol, 1.2 equiv), 1.04 mL TEA (7.46 mmol, 4.00 equiv) and 10 mL NMP. A stir bar was placed in the flask and the reaction mixture was stirred overnight at room temperature under N2 atmosphere. The crude product was purified by normal phase HPLC (EtOAc-hexane as the eluent) to yield 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid methyl ester: MS (ES) M+H expected=478.1, found=478.3.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[F:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[CH2:1][CH:2]1[CH2:3][O:21]1
Reactant: C=CCc1ccc(OC)c(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(CC2CO2)cc1F
Temperature: 25 °C
Reaction time: 63 h
Yield: 37.3 %

Procedure:
4-Allyl-2-fluoro-1-methoxy benzene (1.2 g, 7.22 mmol) was dissolved in CH2Cl2 (35 ml) and treated successively with buffer pH=7.95 (35 ml, NaH2PO4 --Na2HPO4) and m-chloroperbenzoic acid 70% (2.2 g, 9 mmol). Reaction mixture was stirred at room temperature for 63 hours. The aqueous phase was extracted with CH2Cl2 (4×30 ml), combined organic phases were washed with sat. NaHCO3 (50 ml), dried over Na2SO4 and concentrated. The residue was chromatographed over siliga gel (hexan-ethyl acetate 9:1) to provide (RS)-2-(3-Fluoro-4-methoxy-benzyl)-oxirane (0.49 g, 37%) as a yellow oil MS: m/e=182 (M+).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]([NH2:13])([NH2:12])(=[O:11])=[O:10]>C(O)C>[NH2:12][S:9]([N:13]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])=[O:10]
Reactant: NS(N)(=O)=O
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: NS(=O)(=O)N=Cc1ccccc1
Temperature: 25 °C

Procedure:
Benzaldehyde (5 g, 4 mmol) and sulfamide (9.06 g, 94 mmol) were dissolved in anhydrous ethanol (100 mL). The reaction mixture was heated to reflux for 2 hours then cooled to room temperature. The resulting solid was filtered and dried to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH:5][N:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:5]2[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[CH:7][C:3]([C:2]([F:1])([F:17])[F:18])=[N:4]2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.8 %

Procedure:
To a mixture of tert-butyl (3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (501 mg, 1.89 mmol, 1 equiv.), 4-fluorophenylboronic acid (529 mg, 3.78 mmol, 2 equiv.) and copper acetate (517 mg, 2.83 mmol, 1.5 equiv.) in dichloromethane (28 mL) was added pyridine (301 mg, 0.301 mL, 3.78 mmol, 2 equiv) and the mixture was stirred in the presence of air for 2 d at room temperature. The reaction mixture was filtered over silica gel, the filter cake was washed with 250 mL of dichloromethane and the solvent of the filtrate was evaporated to give tert-butyl (1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (501 mg, 74%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:26])[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][NH:18]3)=[CH:13][CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][F:36]>CN(C)C=O.C(OCC)(=O)C>[F:36][CH2:35][CH2:34][N:18]1[C:19]2[C:14](=[CH:13][CH:12]=[C:11](/[CH:10]=[CH:9]/[C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)[CH:20]=2)[C:15](=[O:26])[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17]1
Reactant: FCCBr
Reactant: CCOC(=O)c1c[nH]c2cc(/C=C/c3nc(C(C)C)cs3)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCF)c2cc(/C=C/c3nc(C(C)C)cs3)ccc2c1=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
Ethyl 7-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate (368 mg, 1.00 mmol) was dissolved in dimethylformamide (6 ml), added with potassium carbonate (276 mg, 2.00 mmol) and 1-bromo-2-fluoroethane (0.223 ml, 3.00 mmol), and then the mixture was stirred overnight at 65° C. The reaction mixture was left stand for cooling and then diluted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=100:1) to obtain the title compound (254 mg, 61%) as colorless transparent oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:30]2[N:29]=[C:26]([NH:27][CH3:28])[NH:25][C:23](=[O:24])[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].[C:31]1([N:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:30]2[N:29]=[C:26]([NH:27][CH3:28])[N:25]=[C:23]([O:24][C:38](=[O:39])[N:37]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2]
Reactant: CNc1nc2c(ncn2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)[nH]1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 2′,3′,5′-tri-O-acetyl-2-N-methylguanosine 3 (3.0 g, 7.1 mmol, 1.0 eq) in dry pyridine (50 mL) were added diphenylcarbamoyl chloride (3.45 g, 15 mmol, 2.1 eq) and diisopropylethylamine (1.9 mL, 11.4 mmol, 1.6 eq). The dark brown reaction mixture was then stirred at room temperature for 1 h to obtain 2′,3′,5′-tri-O-acetyl-6-O-(diphenylcarbamoyl)-2-N-methylguanosine 4. TLC showed complete conversion at this stage of the reaction. The reaction mixture was then diluted with pyridine (15 mL) and EtOH (30 mL). To this solution cooled at 0° C. was added 2 M NaOH (25 mL), which was precooled at 0° C. The reaction mixture was stirred for 10 min at 0° C. Acetic acid (c.a. 5 mL) was then added to neutralize the solution. Extraction with CH2Cl2 followed by chromatography on silica gel afforded 5 in 55% yield (1.92 g). TLC (CH2Cl2:MeOH, 9:1 v/v): Rf=0.5; 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 2.81 (d, 3H), 3.51-3.56 (m, 1H), 3.61-3.66 (m, 1H), 3.90 (m, 1H), 4.02 (q, 1H), 4.15 (br.d, 1H), 4.62 (br.s, 1H), 4.99 (br.s, 1H), 5.21 (d, J=4.8 Hz, 1H), 5.48 (d, J=5.6 Hz, 1H), 5.82 (d, J=5.6 Hz, 1H), 7.28-7.32 (m, 4H), 7.4-7.44 (m, 6H), 8.19 (s, 1H); 13C NMR (DMSO-d6, 400 MHz) δ (ppm): 28.3, 61.5, 70.5, 73.1, 85.5, 116.4, 127.1, 129.4, 140.9, 141.8, 150.4, 155.6, 155.9, 159.6; ESI-MS (ES+) calculated for C24H24N6O6 492.1757, found 493.2 (M+H+), 515.2 (2M+Na+), 1007.4 (2M+Na+).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[OH-].[Na+].C(O)(=O)C>C(O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:19][CH2:20]3)[O:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCCCN1CCC2(CC1)CC(c1ccc(C=NN)cc1)=NO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: NN=Cc1ccc(C2=NOC3(CCN(CCCCC(=O)O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.4 g (0.946 mmol) of the ester from Example 18 in 6 ml ethanol were added 1.2 ml 2 N aqueous sodium hydroxide solution. The mixture was stirred at room temperature over night, and stirring was continued for another 30 min after addition of another 0.2 ml sodium hydroxide. It was brought to pH 5 with diluted acetic acid, and the precipitate of the title compound was filtered with suction. After stirring with a small amount of water for 30 min, it was filtered again, washed with water and with ethanol, and dried in vacuo at 60° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20].O>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:27]=3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1
Temperature: 100 °C
Yield: 97.3 %

Procedure:
A mixture of 4-(5-chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 (400 mg, 1 mmol), 3-methylsulfonylphenylboronic acid (230 mg, 1.1 mmol), bis (triphenylphosphine)palladium(II) dichloride (37 mg, 0.052 mmol) in 4 ml of acetonitrile and 4 mL of 1.0 M of sodium carbonate aqueous solution was heated to 100° C. in the microwave for 10 min. Water (5 mL) was added and the resulting solid was filtered and washed with water and ethyl acetate to yield crude 5-chloro-2-(3-methanesulfonyl-phenyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (400 mg).
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:23][C:24]1[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:26][N:25]=1.Cl>N1C=CC=CC=1>[CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:23][C:24]2[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:26][N:25]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)c1nnc(N)s1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(C(=O)OCC)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 34 %

Procedure:
To a solution of p-dodecylbenzenesulfonyl chloride (260 mg, 0.75 mmol) in pyridine (3 mL) was added ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (100 mg, 0.58 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl was added to quench the reaction. The mixture was extracted with ethyl acetate (3×40 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with CH2Cl2:methanol 49:1 to give the product as a solid, mp 96-97° C., in 34% yield (95 mg, 0.20 mmol); 1H NMR (300 MHz, CDCl3) δ 0.85 (t, 3H, J=6.6 Hz), 1.20-1.35 (m, 21H), 1.57 (m, 2H), 2.60 (t, 2H, J=7.0 Hz), 4.43 (q, 2H, J=7.2 Hz), 7.26 (d, 2H, J=8.0 Hz), 7.77 (d, 2H, J=7.7 Hz); 13C NMR (300 MHz, CDCl3) δ 14.1, 22.7, 29.3, 29.4, 29.6, 29.6, 31.1, 31.9, 35.9, 63.4, 126.6, 128.9, 136.9, 145.8, 159.9, 163.7, 167.9; MS (LCQ, ESI+) Calcd for C23H36N3O4S2 482.2, found 482.1 (M+H)+; HRMS (ESI+, m/z) Calcd for C23H36N3O4S2 482.2140, found 482.2134 (M+H)+.
Reaction SMILES: COC1C=C2C(=CC=1OC)C=CC(C([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:36])[C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[CH2:19][CH2:18]1)=O)C2.[H][H]>CO.[C].[Pd]>[CH3:31][O:30][C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([O:34][CH3:35])[C:27]=1[O:32][CH3:33])[C:23]([N:20]1[CH2:21][CH2:22][NH:17][CH2:18][CH2:19]1)=[O:36]
Reactant: COc1cc2c(cc1OC)CC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)C=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Yield: 147.6 %

Procedure:
In methanol (20 ml) is dissolved 1-(6,7-dimethoxy-3,4-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (0.6 g). The solution is subjected to catalytic reduction in a stream of hydrogen in the presence of a 10% palladium-carbon (0.3 g). The reaction mixture is filtered off. The filtrate is concentrated under reduced pressure. To the concentrate is added ether, and the mixture is stirred. The resulting colorless powder is collected by filtration to afford 6,7-dimethoxy-1,2,3,4-tetrahydro-2-naphthoyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (0.5 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:18]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:18][C:5]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[NH:3][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)[nH]c(-c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
To a solution (20 mL) of ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (1.0 g) in N,N-dimethylformamide was added N-chlorosuccinimide (874 mg) at 0° C. The reaction mixture was stirred at room temperature for 4 hr, 6% aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as colorless crystals (yield 509 mg, 44%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]/[N:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[N+]([C:22]([CH2:49][CH2:50][CH2:51][CH3:52])=[CH:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][C:25]=1[C:37]([N:39]1[CH2:48][CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40]1)=[O:38])([O-])=O>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:22]([CH2:49][CH2:50][CH2:51][CH3:52])=[C:23]([C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[CH:26][C:25]=3[C:37]([N:39]3[CH2:48][CH2:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40]3)=[O:38])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12]2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(N/N=C/C(=O)OCC)cc1
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Product: C=CCOc1ccc(-n2nc(C(=O)OCC)c(-c3ccc(C(=O)OC(C)(C)C)cc3C(=O)N3CCc4ccccc4C3)c2CCCC)cc1
Yield: 66.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-(allyloxy)phenyl)hydrazono)acetate (64 mg, 0.26 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (120 mg, 0.26 mmol) were converted to the title compound (114 mg, 67%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.10 (dd, J=8, 2 Hz, 1H), 8.04-8.03 (m, 1H), 7.43-6.81 (m, 9H), 6.11-6.04 (m, 1H), 5.45-5.40 (m, 1H), 5.34-5.30 (m, 1H), 5.02-4.98 (m, 1H), 4.59-4.57 (m, 2H), 4.48-4.38 (m, 1H), 4.32-4.26 (m, 2H), 4.15-3.98 (m, 1H), 3.58-3.32 (m, 1H), 2.86-2.45 (m, 4H), 1.61 (s, 9H), 1.27 (t, J=8 Hz, 1.5H), 1.20 (t, J=8 Hz, 1.5H), 1.11-0.92 (m, 4H), 0.62-0.57 (m, 3H); MS(ESI+) m/z 664.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH2:13](O)[CH3:14]>Cl>[CH2:13]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:14]
Reactant: CCO
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: Cl
Product: CCOC(=O)CCc1ccc(O)cc1
Temperature: 145 °C

Procedure:
4 drops of concentrated HCl are added, under stirring, to a solution of commercial 3-(4 Hydroxy-phenyl)-propionic acid (13.08 g; 78.79 mmol) in 100 mL of ethanol. The reaction medium is heated to reflux in a bath at 145° C. overnight. The ethanol is evaporated off and ethyl acetate is added. The organic phase is washed with a saturated NaHCO3 solution and with a NaCl solution. After drying over MgSO4 and evaporation, an oil is obtained. This latter is distilled by Kugelrohr (150-175° C.; 1.2 mmbar). A transparent oil which crystallizes is obtained in order to produce the expected compound 4′-1 (13.8 g; 71.1 mmol; 90%) in the form of a white solid.