Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 17 %

Procedure:
6-Amino-9-benzyl-2-butylthiopurine (163 mg, 0.52 mmol) and bromine (0.6 ml) were dissolved in 180 ml of methylene chloride and the solution was stirred at room temperature for 4.5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (35 mg, yield 17%).
Reaction SMILES: C([O:5][C:6](=[O:47])[C@@H:7]([NH:37][S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:41]1([S:38]([NH:37][C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:25])([CH3:26])[CH3:24])[S:16]3(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:10]=2)[C:6]([OH:47])=[O:5])(=[O:40])=[O:39])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2OCc2ccccc2)S1(=O)=O

Procedure:
A solution of (S)-2-benzenesulfonylamino-3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid tert-butyl ester (80 mg, 0.114 mmol) in 12 mL of TFA/CH2Cl2 (5:1) is stirred at RT for 1 h. The solution is concentrated, then four times redissolved in CH2Cl2 and reconcentrated to give the title compound: (M−1)−=644.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([CH2:13][S:14][CH3:15])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([CH2:13][S:14]([CH3:15])=[O:25])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CSCc1cn(C)c2cc(Cl)ccc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cc(CS(C)=O)c(=O)c2ccc(Cl)cc21

Procedure:
In a similar manner to that described in Example 4 7-chloro-1-methyl-3-methylthiomethyl-4-quinolone was oxidised with 3-chloroperbenzoic acid to give the novel 7-chloro-1-methyl-3-methylsulphinylmethyl-4-quinolone m.p. 180°-181° (from dichloromethane:petroleum ether (b.p. 60°-80°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccccc2Cl)cc1
Yield: 83.3 %

Procedure:
2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.060 g (82%) of 2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]2[C:20]([CH3:23])=[N:21][N:22]=[C:3]12.[CH3:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1.O>O1CCCC1>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]3[C:20]([CH3:23])=[N:21][N:22]=[C:3]3[C:2]([NH:1][C:37]([NH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[CH:31]=3)=[O:38])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:8]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1(N)N=C(c2ccc(Cl)cc2)c2ccccc2-n2c(C)nnc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(NC(=O)Nc2cccc(C)c2)N=C(c2ccc(Cl)cc2)c2ccccc2-n2c(C)nnc21

Procedure:
In a nitrogen atmosphere, 4-amino-6-(4-chlorophenyl)-4-ethoxycarbonyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine (373 mg) was dissolved in dry tetrahydrofuran (4 ml) and thereto was added 3-methylphenyl isocyanate (139 μl), followed by reaction at room temperature for 3.5 hours. After the completion of the reaction, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous solution of citric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (chroloform:methanol=45:1) and crystallized to give 219 mg of N-[6-(4-chlorophenyl)-4-ethoxycarbonyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N'-(3-methylphenyl)urea as pale yellow needle crystals, mp. 168°-172° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12]1[O:14][C@@H:13]1[CH2:15]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH2:15][C@H:13]1[O:14][CH2:12]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Nc1c(OC[C@@H]2CO2)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 2-amino-3-nitrophenol (5.95 g, 38.6 mmol) and (2S)-(+)-glycidyl 3-nitrobenzenesulfonate (10.0 g, 38.6 mmol) in 150 mL of acetone was treated with 1.1 equivalents of K2CO3 (5.86 g, 42.4 mmol) and stirred at reflux for 18 hours. The suspension was cooled to ambient temperature; the solids were filtered; and the filtrate concentrated in vacuo to dryness. The resulting solids were partitioned between chloroform and water, and the aqueous layer extracted once with chloroform. The organic layers were combined and dried over Na2 SO4 and concentrated in vacuo to 8.0 g (99%) of an orange solid. TLC (Rf =0.5, CHCl3) and NMR indicated >95% purity, so the material was used without further purification. NMR.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20]Br)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20][S:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCSc1ccc([N+](=O)[O-])cn1

Procedure:
A heterogeneous solution of 2-mercapto-5-nitropyridine (96 mg, 0.62 mmol), N-tert-butoxycarbonyl-amino-2-bromoethane (0.14 g, 0.63 mmol), and K2CO3 (0.42 g, 3.0 mmol) in acetone (10 mL) was heated at 60° C. for 15 h. The cooled reaction mixture was filtered through Celite®, concentrated, and then purified by silica gel chromatography to give N-tert-butoxycarbonyl-amino-2-(5-nitro-2-pyridinylthio)ethane (37), which was treated with trifluoroacetic acid (5 mL) in dichloromethane (5 mL) at room temperature for 30 min. The reaction mixture was concentrated and then residue was suspended in dichloromethane, washed with saturated NaHCO3 followed by brine, dried over anhydrous MgSO4 and concentrated to give 1-amino-2-[(5-nitro-2-pyridinyl)thio]ethane (38) as a tan solid which was used without further purification. 1H NMR (DMSO-d6): δ 9.21 (d, J=3.0 Hz, 1H), 8.41 (dd, J=2.4 and 8.7 Hz, 1H), 7.81 (bs, 2H), 7.65 (d, J=8.7 Hz, 1H), 3.44 (t, J=6.6 Hz, 2H), 3.12 (t, J=6.6 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[CH2:14]=O.[BH4-].[Na+].O>CO>[CH3:14][N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
In a dried reaction flask, (S)-tert-butyl pyrrolidin-3-ylcarbamate (5.774 g, 31.0 mmol) and formaldehyde solution (6.82 mL, 37%) were dissolved in methanol (124 mL) under a nitrogen atmosphere. The solution was stirred at room temperature for 1 hr. Sodium borohydride (3.518 g, 93.1 mmol) was added in portion under an ice bath. The solution was stirred at room temperature for 3 hr. Water was added to the reaction solution. After rotary-evaporation, ethyl acetate and saturated aqueous sodium bicarbonate solution were added. The reaction solution was extracted with ethyl acetate. The combined organic phase was washed with salt water, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to produce a pale yellow solid (4.037 g) in 65% yield.
Reaction SMILES: [C:1]([O:12][CH2:13]C)(=[O:11])/[CH:2]=[CH:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>CO>[C:1]([O:12][CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC/C=C\C=C\C(=O)OCC
Solvent: CO
Product: CCCCC/C=C\C=C\C(=O)OC

Procedure:
Mass spectra (MS) were obtained in the electron impact mode at 70 eV using a Finnigan 4510 GC-MS. The MS of the major male-specific compound detected in E. conspersus aeration samples gave a prominent molecular ion a m/z 182 (ca. 20%), but a matching spectrum was not found in the GC-MS computer library of spectra (>31,000 MS) (FIG. 2). The presence of an M-31 peak at m/z 151 suggested a methyl ester structure for this component, as did ions at m/z 59 ([O=C--O--CH3 ]+) and m/z 74 ([CH2 =C(OH)--OCH3 ]+). Thus, the molecular formula was deduced to be C11H18O2 and a di-unsaturated, unbranched acidic moiety was thought most likely. A 20 g sample of the related compound, ethyl (2E,4Z)-decadienoate (called the pear ester), was obtained from International Flavors & Fragrances Inc. (IFF, Union Beach, N.J.). The pear ester standard was saponified and re-esterified with methanol by normal procedures to give methyl (2E,4Z)-decadienoate and a small percentage of the corresponding (2Z,4E)- and (2E,4E)-isomers. This standard of methyl (2E,4Z)-decadienoate gave an identical MS to that of the E. conspersus male-specific compound and the standard coeluted with the unknown by GC.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[CH:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C=O)C>[CH2:24]([O:17][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)c2ccc(Br)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OCc2ccccc2)c2ccc(Br)cc2c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 986.4 %

Procedure:
A solution of 6 (8.04 g, 2.2 mmol) in anhydrous DMF (150 mL) under Ar was treated with K2CO3 (5.65 g, 40.9 mmol), benzyl bromide (5.59 g, 32.7 mmol, 1.2 equiv) and BU4NI (402 mg, 1.1 mmol, 0.04 equiv). After stirring for 11 h at 25° C., the reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with saturated aqueous NaCl, dried (MgSO4) and concentrated. The resulting solid was recrystallized from 5% EtOAc-hexane to afford 12 (8.36 g, 10.49 g theoretical, 80%) as white needles. An additional 2.13 g (20%) of 12 was obtained by chromatography (SiO2, 4×20 cm, 10% EtOAc-hexane) of the crystallization mother liquors: mp 105° C. (needles, hexane); 1H NMR (CDCl3, 250 MHz) δ8.19 (d, 1H, J=8.8 Hz), 8.10 (s, 1H), 8.05 (d, 1H, J=1.8 Hz), 7.61 (dd, 1H, J=1.9, 8.9 Hz), 7.50 (m, 6H), 5.28 (s, 2H), 4.45 (q, 2H, J=7.1 Hz), 1.46 (t, 3H, J=7.1 Hz); 13C NMR (CDCl3, 100 MHz) δ166.5, 154.7, 136.4, 134.7, 130.8, 130.7, 129.1, 128.7, 128.3, 127.6, 126.3, 124.2, 122.5, 121.5, 104.6, 70.4, 61.4, 14.4; IR (KBr) vmax 2986, 1716, 1589, 1578, 1406, 1369, 1331, 1279, 1238, 1098, 1025, 962, 892, 816, 767, 725, 691 cm-1 ; FABHRS (NBA) m/z 384.0370 (M+, C20H17BrO3 requires 384.0361).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C.C(OCC)(=O)C>[NH:31]([C:32]([N:21]1[CH2:20][CH2:19][N:18]([C@H:16]([CH3:17])[C@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:24])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:23][CH2:22]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H](N1CCN(C(=O)Nc2ccccc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a ice cooled solution of (2R,3R)-2-(2,4-diflurophenyl)-3-(piperazin-1-yl)-1-(1H-1,2,4-triazole-1-yl)butan-2-ol 2 (150 mg, 0.44 mmol) in acetonitrile (10 ml) was added phenylisocyanate (60 mg, 0.5 mmol) in acetonitrile (4 ml). The reaction mixture was stirred at 0° C. for 2 h, diluted with 20 ml of ethyl acetate and successively washed with water, brine and dried over sodium sulphate. This organic extract was concentrated and the residue was purified by passing through a column of silica gel (hexane/EtOAc) to give the title compound as a colorless solid (170 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH2:15])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][O:26][CH2:27][C:28](O)=[O:29])=[C:19]([C:32]([O:34]C)=[O:33])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][O:26][CH2:27][C:28]([NH:15][C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][C:11]=2[CH3:14])=[O:29])=[C:19]([CH:18]=1)[C:32]([OH:34])=[O:33]
Reactant: Cc1ccc(-c2ccc(F)cc2)cc1N
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: Cc1ccc(-c2ccc(F)cc2)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 1-(ii), 4′-fluoro-4-methylbiphenyl-3-amine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-[(4′-fluoro-4-methylbiphenyl-3-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 96%).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH2:14]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:21]([N:20]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:1](=[O:13])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: CCCCCCNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
Homovanillic acid (182 mg, 0.999 mmol) dissolved in DMF (3 ml) was cooled in an ice-bath. N-Hexylbenzylamine (201 mg, 1.049 mmol) was added and then TBTU (337 mg, 1.049 mmol) followed by DIPEA (407 mg, 3.147 mmol). The mixture was stirred at room temperature overnight and evaporated. Sodium hydrogencarbonate aqueous solution (sat.) was added into the residue. The mixture was then extracted with ethyl acetate (×2). The extracts were combined and washed with water and brine and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/15 ml) using DCM and then MeOH/DCM (1:99) as eluant gave 264 mg the desired product, yield 74%.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[C:10](I)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]1([C:37]#[C:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>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.C(#N)C>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:38]([Si:39]([CH3:42])([CH3:40])[CH3:41])[O:23][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1ccccc1
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)c1oc2c(c1-c1ccccc1)c(=O)ccn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A resealable tube was charged with 1-benzyl-4-benzyloxy-3-iodo-2-pyridone 3 (5.000 g, 11.98 mmol), acetonitrile (100 mL), and triethylamine (6.06 g, 8.35 mL, 59.9 mmol). Dichlorobis(triphenylphosphine)palladium (II) (0.841 g, 1.20 mmol) and 1-phenyl-2-(trimethylsilyl)acetylene were added and argon was bubbled through the solution. The tube was sealed and the mixture stirred at 100° C. for 4 h. The reaction mixture was concentrated to afford 7-benzyl-3-phenyl-2-(trimethylsilyl)furo[2,3-b]pyridin-4(7H)-one 4d as a brown oil. MS (MH+) 374.2; Calculated 373 for C23H23NO2Si.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[N:11][C:12]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:14]=2)[N:9]=1.C(O)C>O>[O:18]([C:12]1[N:11]=[C:10]2[C:15]([CH:16]=[CH:17][C:8]([NH:7][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])=[N:9]2)=[CH:14][CH:13]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)C1CC1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)C1CC1
Temperature: 4 °C
Yield: 49.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with cyclopropanecarboxylic acid (4.8 g), N,N'-carbonyldiimidazole (9.07 g) and 2-amino-7-phenoxy-1,8-naphthyridine (10 g). The product produced by precipitation in water (11.2 g; m.p. approximately 170° C.) is dissolved in boiling ethanol (200 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)cyclopropanecarboxamide (6.4 g) is produced, m.p. 190° C.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>O1CCCC1>[CH3:12][C:9]([C:13]1[CH:14]=[CH:15][C:16]([S:19][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=[O:8])=[CH:17][CH:18]=1)([CH3:10])[CH3:11]
Reactant: O=C1CCCCC1Cl
Reactant: CC(C)(C)c1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(SC2CCCCC2=O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-chlorocyclohexanone (6.1 g, 0.046 moles) in tetrahydrofuran (250 ml) cooled to +5° C. by an ice bath was added 4-t-butyl-thiophenol (6.6 g, 0.040 moles). After stirring for 15 minutes, triethylamine (13 ml) was added. The ice bath was removed and the mixture was stirred at room temperature for 60 hours. The mixture was filtered to remove a white solid. The filtrate was concentrated to an oil, and the product was purified by silica gel chromatography to give a white solid which was recrystallized from hexane (DSC 64.25° C.). The structure was supported by NMR and Ir.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18]>C1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: NCCOCCO
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCOCCO
Yield: 93.2 %

Procedure:
A suspension of 30.0 g (202.5 mmol) of phthalic anhydride, 20 mL (21.0 g, 199.4 mmol) of 2-(2-aminoethoxy)-ethanol in 400 mL of benzene was added 1.0×10-2 g (5.3×10-5 mmol) of TsOH.H2O. The reaction flask was connected to a Dean-Stark condenser and then heated to reflux for 14 h. The solvent was removed at reduced pressure and the residue was purified by SiO2 column chromatography (hexanes/AcOEt 1:1 then CHCl3 /MeOH 20:1) gave 43.7 g (93.1%) of 13 as a light yellow syrup. This syrup slowly crystallized on standing at room temperature overnight as needle-like crystals. mp 66°-66.5° C. Rf (hexanes/AcOEt 1:1) 0.17. 1H NMR (CDCl3) d 2.41 (t, 1H, J=6.2 Hz, OH), 3.57-3.93 (m, 8H), 7.69-7.87 (m, 4H). 13C NMR (CDCl3) d 37.52, 61.62, 68.24, 72.24, 123.36, 131.97, 134.00, 168.38 (C=O). Anal Calcd for C12H13NO4 : C, 61.28; H, 5.53; N, 5.96. Found: C, 61.34; H, 5.62; N, 5.94.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:23])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=2)[C:10](=O)[CH2:9]1.[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:23])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=2)[C:10](=[N:29][NH:28][C:25]([NH2:27])=[NH:26])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1c2c(nn1-c1ccccc1)CC(c1ccccc1Cl)CC2=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1c2c(nn1-c1ccccc1)CC(c1ccccc1Cl)CC2=NNC(=N)N
Yield: 190.9 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-2-phenyl-4,5,6,7-tetrahydroindazol-4-one (0.6 g), aminoguanidine hydrochloride (0.24 g), concentrated hydrochloric acid (0.45 ml), water (0.45 ml) and ethanol (20 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol-water to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-2-phenyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 150) (0.73 g) as colorless crystals.