Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:16](=O)[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH2:19][C:20]1[N:21]=[N:22][C:23](=[O:25])[CH:24]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[N:21]2[NH:22][C:23](=[O:25])[CH:24]=[C:20]2[NH:19][C:16]([CH3:17])=[C:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Reactant: NC1=CC(=O)N=N1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2cc(=O)[nH]n2C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A solution of 2-[(2,3-dichlorophenyl)methylene]-3-oxobutanoic acid, ethyl ester (2.8 g; 10.0 mmole) in dimethylformamide (7 ml) was treated with 3-amino-5-pyrazolone (990 mg) and the resulting mixture was heated at 65° C.±5° for 15 hours. The reaction mixture was allowed to cool to room temperature and then diluted with ethyl acetate. The solution was washed with water, brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent provided a foam which was purified by flash chromatography (7% methanol in dichloromethane). The product was crystallized from acetonitrile-isopropyl ether to provide the title compound as a solid (1.42 g; melting point 213°-218° C.; sinters above 155° C.).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)COc1ccc(F)cc1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
Into a 100 ml round bottom flask equipped with a magnetic stirrer, reflux condenser equipped with a connector to a 50% sodium hydroxide trap, 6.81 g (0.040 mole) para-fluorophenoxyacetic acid (the product of Example 2), 2.96 ml (0.044 mole) thionyl chloride, and about 40 ml toluene. The reaction mixture was stirred at reflux for two hours, allowed to cool to room temperature, and then concentrated to give 7.2 g of the product, a brwon liquid.
Reaction SMILES: C(#N)C.O.CN(C)C1C=CC(C=CC=O)=CC=1.OC(CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=O.[CH3:34][N:35]([CH2:52][CH2:53][CH2:54][NH:55][C:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH:62]1[S:66][CH2:65][C@@H:64]2[NH:67][C:68]([NH:70][C@H:63]12)=[O:69])=[O:57])[CH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]=[N+:47]=[N-:48])=[CH:42][C:41]=1[N+:49]([O-:51])=[O:50]>O>[N:46]([C:43]1[CH:44]=[CH:45][C:40]([NH:39][CH2:38][CH2:37][CH2:36][N:35]([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:57])[CH2:58][CH2:59][CH2:60][CH2:61][C@H:62]2[C@@H:63]3[C@@H:64]([NH:67][C:68]([NH:70]3)=[O:69])[CH2:65][S:66]2)[CH3:34])=[C:41]([N+:49]([O-:51])=[O:50])[CH:42]=1)=[N+:47]=[N-:48]
Reactant: CN(CCCNC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)CCCNc1ccc(N=[N+]=[N-])cc1[N+](=O)[O-]
Agent: CN(C)c1ccc(C=CC=O)cc1
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CC#N
Solvent: O
Product: CN(CCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)CCCNc1ccc(N=[N+]=[N-])cc1[N+](=O)[O-]

Procedure:
d-Biotinyl-N-hydroxysuccinimide ester (III) was synthesized from d-biotin (I) by the DCC method of Bayer and Wilchek (1980) "Methods of Biochemical Analysis" 26, 1-45 except that the ester was isolated by precipitation from ether and used without further purification. N-(3-Aminopropyl)-N'-(4-azido-2-nitrophenyl)-N-methyl-1,3-propanediamine (VI; approx. 5 mmol) was dissolved in a solution containing d-biotinyl-N-hydroxysuccinimide ester (1.7 g, 5.0 mmol) in pyridine-water (7:3 v/v, 50 ml), and the solution was incubated at 37° C. for 2 h. TLC on alumina with tetrahydrofuran-water (19:1; v/v) showed the reaction to be complete. The solvent was removed and the residue was dissolved in a mixture of 0.5M NaHCO3 (100 ml) and 2-butanol (100 ml). The large volume was necessary to visualize the interface between the phases. The 2-butanol layer was removed, washed successively with water (100 ml) and saturated NaCl (100 ml), and then slowly added to ether (900 ml). The suspension was stirred, the red precipitate was allowed to settle, and the supernatant was decanted. The precipitate was washed with ether (100 ml) and dried in vacuo to give the product (1.33 g, 50% yield from 4-fluoro-3-nitrophenyl azide), m.p. 114.5°-115° C. (corrected). % Elemental analysis calculated for C23H35N9O4S: C 51.8, H 6.6, N 23.6. % Found: C 50,6 H 6.8, N 23.4 (Australian Mineral Development Laboratories). TLC on alumina with methanol showed the product to be a single spot with RF 0.75 (the symmetrical disubstitution product formed from compounds IV and V has RF 0.6). TLC on silica with acetonitrile-water (19:1, v/v), using p-dimethylaminocinnamaldehyde spray to detect biotin derivatives (21), showed the product to be free of compounds I, II and III. Photobiotin is poorly soluble in water.
Reaction SMILES: [C:1]([O:4][C:5]12[O:21][N:13]([CH2:14][CH:15]3[CH:17]1[N:16]3[C:18](=[O:20])[CH3:19])[C:12]1[C:7](=[C:8]([OH:24])[CH:9]=[C:10]([CH:22]=[O:23])[CH:11]=1)[CH:6]2[CH2:25][O:26][C:27](=[O:29])[NH2:28])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:36](I)[CH2:37][CH2:38][CH3:39].C(Cl)(Cl)Cl>CC(C)=O.CO>[C:1]([O:4][C:5]12[O:21][N:13]([CH2:14][CH:15]3[CH:17]1[N:16]3[C:18](=[O:20])[CH3:19])[C:12]1[C:7](=[C:8]([O:24][CH2:36][CH2:37][CH2:38][CH3:39])[CH:9]=[C:10]([CH:22]=[O:23])[CH:11]=1)[CH:6]2[CH2:25][O:26][C:27](=[O:29])[NH2:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC12ON(CC3C1N3C(C)=O)c1cc(C=O)cc(O)c1C2COC(N)=O
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCOc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-hydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (80 mg) in acetone (1 ml) were added potassium carbonate (110 mg) and n-butyl iodide (90 μl), and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (20:1, v/v) to afford 11-acetyl-6-butoxy-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (61 mg).
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH2:8]([O:11][C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:9]=[CH2:10].C(N(CC)CC)C.Cl.[NH2:27][CH2:28][CH2:29][SH:30]>C(Cl)Cl.C(O)C>[CH2:8]([O:11][C:12]([NH:14][CH2:15][C:16]([NH:27][CH2:28][CH2:29][SH:30])=[O:18])=[O:13])[CH:9]=[CH2:10]
Reactant: NCCS
Reactant: C=CCOC(=O)NCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)NCC(=O)NCCS
Reaction time: 0.25 h

Procedure:
Add pivaloyl chloride (2.4 ml) in CH2Cl2 (10 ml) to a cooled (0°-5° C.) and stirred solution of N-allyloxycarbonylglycine (3.18 g) and triethylamine (2.8 ml) in dry CH2Cl2 (50 ml). Stir the mixture at 0°-5° C. for 15 mins. and then add a solution of 2-aminoethanethiol hydrochloride (2.4 g) and triethylamine (2.8 ml) in ethanol (15 ml) and CH2Cl2 (40 ml). Stir at room temperature for 1 hour, wash the mixture with aqueous 2 N-H2SO4 and aqueous NaHCO3, dry and evaporate. Triturate the resulting solid with ether, filter and dry to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=[O:18])[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC>CN(C=O)C>[CH3:16][C:15]1([CH3:17])[O:14][C:13](=[O:18])[NH:12][C:11]2[CH:19]=[CH:20][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)[CH:3]=3)=[CH:9][C:10]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Br)c3)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(-c4nccs4)c3)cc21
Temperature: 90 °C
Yield: 23.8 %

Procedure:
A mixture of 6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.25 g, 0.75 mmol), tri-n-butyl-thiazol-2-yl tin (0.5 g, 1.3 mmol) in DMF (5 mL) was degassed to remove oxygen and then heated under nitrogen at 90° C. for 3 hours. The reaction mixture was cooled to rt and treated with ice-water (70 mL). Ethyl acetate (100 mL) was added and organic layer was separated, washed with brine, and dried (MgSO4). After removal of solvent, the residue was purified by a silica gel column (hexane:ethyl acetate/1:1) to give the title compound as a white solid (60 mg, 23%): mp 223-224° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 9.13 (s, 1H), 8.45 (s, 1H), 7.94 (bs, 1H), 7.67-7.61 (m, 4H), 7.53 (t, 1H, J=7.68 Hz), 7.00 (d, 1H, J=8.81 Hz), 1.7 (s, 6H); MS (APCI) m/z 337([M+H]+, 100%); Anal. Calc. For C19H16N2O2S.0.25 H2O: C, 66.94; H, 4.88; N, 8.22. Found: C, 66.57; H, 4.65; N, 7.92.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br[C:22]([CH3:28])([CH3:27])[C:23](C#N)=[O:24]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[O:18][C:22]([CH3:28])([CH3:27])[C:23](=[O:24])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CSc1ccc(C(=O)Cc2ccccc2)c(Cl)c1
Reactant: CC(C)(Br)C(=O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.05 g of 1-{2-chloro-4-(methylthio)phenyl}-2-phenyl-ethanone in 60 ml dry THF was stirred at 0° C. for 20 minutes in the presence of 95% oil dispersion of sodium hydride (1.0 g), which was followed by dropwise addition of α-bromoisobutyryl cyanide (2.5 ml) diluted in 50 ml THF. The reaction solution was allowed to warm slowly to room temperature and was stirred overnight. Then the solvent was removed in vacuo, which was followed by extraction with 30 ml water and diethylether (50 ml×3). The organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=8:1) to yield 2.73 g of 5-{2-chloro-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone. NMR: δ1.56 (s, 6H), 2.48 (s, 3H), 7.10 (dd, J=8.4, 1.5 Hz, 1H), 7.24 (m, 3H), 7.26 (m, 3H), 7.37 (d, J=1.5 Hz, 1H). IR (cm−1): 1698, 1620, 1394, 1235, 1176, 1144.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:6][CH:7]=1.[CH:12]([NH:15][CH:16](C)C)(C)C.C(Cl)(=O)C(C)(C)C.CNC>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:15]([CH3:16])[CH3:12])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: CC(C)(C)C(=O)Cl
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)Cc1cncc(Br)c1
Reaction time: 0.42 h
Yield: 79.2 %

Procedure:
(5-Bromopyridin-3-yl)acetic acid (500 mg, 2.31 mmol) was dissolved in dichloromethane (5 mL), treated with di-iso-propylamine (402.4 μL, 2.31 mmol) and cooled in an ice water bath. Pivaloyl chloride (284.7 μL, 2.31 mmol) was added and the mixture was stirred for 25 minutes. 2 M dimethylamine (1.73 mL, 3.46 mmol) was added and the reaction was stirred 15 h. The mixture was washed with saturated ammonium chloride (1×), saturated sodium bicarbonate (1×), and dried over sodium sulfate to yield 2-(5-bromopyridin-3-yl)-N,N-dimethylacetamide as a brown oil (445 mg, 79%). MS: m/z 562 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O.[CH3:48][O:49][C:50](=[O:71])[C@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[NH:52][C:53](=[O:63])[C@H:54]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[NH2:55].C(N1CCOCC1)C>CN(C)C=O>[CH3:48][O:49][C:50](=[O:71])[C@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[NH:52][C:53](=[O:63])[C@H:54]([CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[NH:55][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, cooled (0° C.) solution of benzyloxycarbonylglycine (955mg, 4.5 mmole) and 1-hydroxybenzotriazole (1.2 g, 9 mmole) in dimethylformamide (15 ml) is added dicyclohexylcarbodiimide (1.03 g, 5 mmole). The mixture is stirred for 1 hour at 0° C. A cooled solution of phenylalanyl-phenylalanine methyl ester trifluoroacetate (2.0 g, 4.5 mmoles, described in U.S. Pat. No. 3,917,578, noted above) in dimethylformamide (20 ml) and N-ethyl morpholine (0.58 ml) is added and the mixture is stirred overnight at room temperature. The mixture is filtered and the filtrate is evaporated. The residue is dissolved in ethyl acetate (100 ml) and the solution is filtered. The filtrate is washed with 10% aqueous citric acid solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. The solution is dried over magnesium sulfate (anhydrous) and evaporated. The residue is crystalized from ethyl acetate-petroleum ether (30°-60°) to give the title compound as crystals, mp 122°-124° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([S:29]([C:32]4[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=4[C:34]([O:36][CH3:37])=[O:35])(=[O:31])=[O:30])[CH:25]=3)[N:20]=2)=[CH:15][CH:14]=1.[OH-].[Ca+2].[OH-]>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([S:29]([C:32]4[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=4[C:34]([O:36][CH3:37])=[O:35])(=[O:31])=[O:30])[CH:25]=3)[N+:20]=2[O-:6])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)c1ccc2nc(-c3ccc(F)cc3)ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)c1ccc2c(ccc(-c3ccc(F)cc3)[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.9 %

Procedure:
3-Chloroperoxybenzoic acid (77%; 82 mg, 0.37 mmol) was added to a solution of methyl 2-{[2-(4-fluorophenyl)quinolin-6-yl]sulfonyl}benzoate [Example 30] (103 mg, 0.24 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at room temperature under nitrogen for 2 days. Calcium hydroxide (308 mg, 4.16 mmol) was added and the resulting slurry stirred for 2 hours. The mixture was filtered and the filter cake washed thoroughly with dichloromethane. The filtrate was evaporated and the residue purified by flash chromatography, eluting with 10-25% diethyl ether/dichloromethane, followed by trituration with diethyl ether to give the title compound as a pale yellow solid (45 mg, 42%). 1H NMR (500 MHz, CDCl3) δ 8.94 (1H, d, J 9.2 Hz), 8.60 (1H, s), 8.28 (1H, m), 8.19 (1H, dd, J 1.6, 9.2 Hz), 8.02 (2H, dd, J 5.4, 8.7 Hz), 7.87 (1H, d, J 8.7 Hz), 7.71-7.61 (4H, m), 7.22 (2H, t, J 8.6 Hz), 3.95 (3H, s); m/z (ES+) 438 [MH+].
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:6]=1
Reactant: O=[N+]([O-])c1cnc(-c2ccccn2)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(-c2ccccn2)nc1Cl
Temperature: 0 °C
Yield: 79242.8 %

Procedure:
A solution of 5-nitro-2-(pyridin-2-yl)pyrimidin-4-ol (1.74 g, 0.008 mmol, 1 equiv.) in POCl3 (6.12 g, 0.04 mmol, 5 equiv.) was refluxed for 3 h. Then, the mixture was poured into ice (200 g), extracted with EA (200 mL×2). The combined organic phases were evaporated to afford 4-chloro-5-nitro-2-(pyridin-2-yl)pyrimidine (1.5 g, 80%). LCMS: 237 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH2:17])=[S:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20](=O)[C:21]([F:24])([F:23])[F:22]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[S:16][CH:19]=[C:20]([C:21]([F:24])([F:23])[F:22])[N:17]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(CBr)C(F)(F)F
Solvent: CCO
Product: FC(F)(F)c1csc(NC2CCN(Cc3ccccc3)CC2)n1
Yield: 89.3 %

Procedure:
To a stirred solution of (1-benzyl-piperidin-4-yl)-thiourea (0.5 g, 2.0 mmol) (prepared by a procedure similar to that described in WO 03/062215) in ethanol (15 ml) was added 3-bromo-1,1,1-trifluoroacetone (0.22 ml, 2.1 mmol) and the reaction mixture was heated at reflux for 1 h. After evaporation of the solvent, the crude product was crystallized from acetonitrile to yield D8 (0.61 g, 88%) as a white solid. C16H18F3N3S.HBr free base requires 341. Found 342 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]([OH:25])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][N:17]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2].C(N(CC)C(C)C)(C)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]([O:25][C:44](=[O:46])[CH3:45])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][N:17]([C:26]3[CH:27]=[CH:28][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cccc(CC)c1-c1cc2c(C(O)CC(C)C)cn(-c3ccc(C(C)C)cc3)c2cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CC)c1-c1cc2c(C(CC(C)C)OC(C)=O)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3-methyl-butan-1-ol (20 mg, 0.044 mmol) in DCM (2 mL), N,N-diisopropylethylamine (15 μL, 0.08 mmol), acetic anhydride (6.6 μL, 0.06 mmol), and DMAP (1 mg) were added. The mixture is stirred at room temperature for 4 h. All volatiles are removed under reduced pressure and the residue is purified by chromatography to afford acetic acid 1-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3-methyl-butyl ester as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([OH:7])=[C:5]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCOCC1>[CH3:1][C:2]1[C:6]([O:7][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:5]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1OC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A mixture of di-isopropyl 3-methyl-4-hydroxy-2,5-thiophene-dicarboxylate (656 g, 2.30 mol), triethylamine (297 g, 2.98 mol) and dioxane (2 l) was cooled with ice to about 10° C. The solution was added, while stirring, with benzoyl chloride (351 g, 2.5 mol) over about 10 minutes, followed by further stirring for 30 minutes at room temperature. After removing the precipitate of triethylamine hydrochloride salt by filtration, the solution was distilled in vacuo to remove dioxane. Toluene was then added to the remaining residue, and the solution was washed with 5% aqueous sodium bicarbonate and water, and then dried over MgSO4. The solvent was removed by distillation to give almost pure di-isopropyl 3-methyl-4-benzoyloxy-2,5-thiophene dicarboxylate (851 g, 95%). nD10 1.5499.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C1C(=O)N([I:30])C(=O)C1.FC(F)(F)C(O)=O.O>CN(C=O)C>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:30])=[CH:18][C:17]=1[F:22]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc2scnc2c(F)c1Nc1ccccc1F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate (8.64 g, 26.97 mmol) in DMF (100 mL) was added NIS (6.68 g, 29.67 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 5 h at ambient temperature, the reaction was treated by water (150 mL). The precipitate was filtered off and the filter cake was washed with water. The desired product was obtained as a yellow solid (10.34 g, 86.0% yield). 1H NMR (400 MHz, CDCl3): δ 9.14 (s, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 7.42 (d, J=10.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.63 (dd, J=15.0, 8.7 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].CN(C)C=O.[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:36]=3[NH:35][CH:34]=[CH:33]4)[N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:22])[CH3:21]>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:36]=3[NH:35][CH:34]=[C:33]4[CH:2]=[O:3])[N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:21])[CH3:22]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4cc[nH]c34)no2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)c[nH]c34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (1.1 mL) in dichloromethane (60 mL) at 0° C. was added a solution of N,N-dimethylformamide (1.16 mL) in dichloromethane (30 mL) dropwise during 30 mins. The reaction mixture was stirred at this temperature for 15 minutes. A solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D51) (3.5 g) in dichloromethane (60 mL) was added in one portion. The mixture was warmed to room temperature slowly. After stirred at room temperature for 5 hours, dichloromethane was evaporated off. Ethyl acetate (300 mL), water (100 mL) and concentrated HCl solution (5 mL) was added to the residue. The obtained mixture was stirred for 30 minutes. KOH was added to basify the solution to pH value about 8. The organic layer was separated, washed with water and brine, dried over MgSO4. Filtration and evaporation afforded the product 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D71) (4.0 g). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 4.87-4.93 (1H, m), 7.43-7.47 (2H, m), 8.07 (1H, dd), 8.21 (1H, dd), 8.37 (1H, d), 8.40-8.41 (2H, m), 10.06 (1H, s), 11.98 (1H, br s). MS (ES): C20H16ClN3O3 requires 381; found 382.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:12]1(C)[CH:17]=CC(S([O-])(=O)=O)=C[CH:13]=1.[NH+]1C=CC=CC=1>CC(C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][O:10][C:12]([CH3:17])([CH3:13])[O:11]2)=[CH:6][N:7]=1
Reactant: OCC(O)c1ccc(Br)nc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)OCC(c2ccc(Br)nc2)O1
Yield: 267.4 %

Procedure:
To a solution of 1-(6-bromopyridin-3-yl)ethane-1,2-diol (4.20 g) in acetone (80 mL) was added pyridinium p-toluenesulfonate (1.50 g), and the mixture was stirred with heating under reflux for 3 hr. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (4.12 g, yield 72%) as a pale-yellow solid. MS: 260 (MH+).