Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[S:11][C:10]=1[C:18]([O:20]C)=[O:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1COCC1.CO.[OH-].[Na+]>O>[C:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[S:11][C:10]=1[C:18]([OH:20])=[O:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(C(C)(C)C)sc1C(=O)O
Temperature: 60 °C
Yield: 64.6 %

Procedure:
To a solution of methyl 3-(N-carbo-tert-butoxyamino)-5-tert-butylthiophene-2-carboxylate (10.7 g, 34.1 mmol) in a 2:1:1 mixture of THF, MeOH and H2O (340 mL) was added NaOH (4.09 g, 102.3 mmol, 3.0 equiv). The resulting solution was heated at 60° C. for 18 h, cooled to room temp. and concentrated under reduced pressure. The residue was separated between H2O (500 mL) and EtOAc (250 mL). The aqueous phase was adjusted to pH 2 with a 10% HCl solution, then extracted with EtOAc (2×400 mL). The organic phase was washed with a saturated NaCl solution (250 mL), dried (MgSO4), and concentrated under reduced pressure to afford 3-(N-carbo-tert-butoxyamino)-5-tert-butylthiophene-2-carboxylic acid as an orange solid (6.6 g, 65%). This material was used in the next step without further purification. An analytical sample of the carboxylic acid was further purified: mp 187-8° C., TLC (10% MeOH/CH2Cl2) Rf0.17; 1H NMR (CDCl3) δ1.40 (s, 9H), 1.54 (s, 9H), 7.73 (s, 1H), 9.19 (s, 1H); 13C NMR (CDCl3) δ28.2 (3C), 31.8 (3C), 35.4, 81.3, 104.6, 116.7, 146.7, 151.9, 166.6, 169.3; FAB-LRMS m/z (rel abundance) 300 (M+H, 30%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[CH:4][CH:3]=[N:2]1.[OH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17](OC)=O.[NH3:24]>>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH2:8][CH2:7][CH2:6][CH:11]([CH3:10])[O:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:16]3[C:15]=2[N:24]=[C:3]([NH2:2])[CH:4]=[CH:17]3)=[CH:4][CH:3]=[N:2]1
Reactant: N
Reactant: Oc1ccccc1-c1ccno1
Reactant: COC(=O)c1cccc(O)c1
Product: CC(CCCOc1ccccc1-c1ccno1)Oc1cccc2ccc(N)nc12

Procedure:
The title compound was prepared according to the procedure described in Example 92 substituting 2-isoxazol-5-ylphenol for methyl 3-hydroxybenzoate. 1H NMR (500 MHz, CDCl3) δ ppm 8.20 (d, 1H), 7.92 (d, 1H), 7.86 (dd, 1H), 7.34 (m, 1H), 7.23 (t, 1H), 7.16 (dd, 1H), 7.05 (d, 1H), 6.97 (m, 3H), 6.68 (d, 1H), 4.71 (m, 1H), 4.26 (m, 1H), 4.15 (m, 1H), 1.98–2.26 (m, 4H), 1.48 (d, 3H); MS (DCI/NH3) m/z 390 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([OH:11])[C:7]=1[C:8]([OH:10])=[O:9].Cl.[CH3:13][N:14]([CH3:16])O.C(N(CC)CC)C.O>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]([O:10][N:14]([CH3:16])[CH3:13])=[O:9])=[C:6]([OH:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)O
Reactant: O=C(O)c1c(O)cccc1Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)OC(=O)c1c(O)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.73 Grams of 6-chlorosalicylic acid was dissolved in 20 ml of tetrahydrofuran, and 1.95 g of N,N'-carbonyldiimidazole was added. After stirring at room temperature for 30 minutes, 1.47 g of N,N-dimethylhydroxylamine hydrochloride and 1.52 g of triethylamine were added, and the resulting mixed solution was stirred at room temperature for 7 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to column chromatography to obtain 1.1 g of 3-chloro-2-(N,N-dimethylaminooxycarbonyl)phenol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[C:3]=1[C:4](OC)=[O:5].C(O)(=O)C.[CH:20](N)=[NH:21]>COCCO>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:21][CH:20]=[N:1]2
Reactant: N=CN
Reactant: COC(=O)c1c(N)cc(OC)cc1OC
Solvent: COCCO
Solvent: CC(=O)O
Product: COc1cc(OC)c2c(=O)[nH]cnc2c1
Temperature: 130 °C
Yield: 76.2 %

Procedure:
A mixture of methyl 2-amino-4,6-dimethoxybenzoate (6.46 g, 30.6 mmol), formamidine acetate (15.92 g, 153 mmol) in 2-methoxyethanol (50 mL) was heated at 130° C. for 4 hours. After the solvent was removed under reduced pressure, the reaction was quenched with water, filtered, washed with water, and dried under vacuum with P2O5 to afford 5,7-dimethoxyquinazolin-4(3H)-one as a solid (4.805 g, 76%). 1H NMR (300 MHz, DMSO-d6) δ 11.7 (br, 1H), 7.98 (s, 1H), 6.72 (d, 1H), 6.60 (d, 1H), 3.92 (s, 3H), 3.88 (s, 3H); LC-MS (ESI) m/z 207 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].N1C=CC=CC=1.[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55]([NH:57][C:58]3([C:63](O)=[O:64])[CH2:62][CH2:61][CH2:60][CH2:59]3)=[O:56])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1>ClCCl.C(OCC)(=O)C>[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55]([NH:57][C:58]3([C:63]([N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH2:12]/[CH:13]=[CH:14]/[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:64])[CH2:59][CH2:60][CH2:61][CH2:62]3)=[O:56])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: O=C(NC1(C(=O)O)CCCC1)OCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
A solution of 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 3 ml of dichloromethane was treated under nitrogen at room temperature with 0.119 g of pyridine and a solution of the acid chloride prepared from 0.42 g of N-(9-fluorenylmethyloxycarbonyl)-cycloleucine in 3 ml of dichloromethane. The mixture was stirred at room temperature for 16 hours and diluted with ethyl acetate. The solution was washed with 5% aqueous sodium hydrogen carbonate solution, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulphate. The solvent was evaporated to give a foam, which was crystallized from diethyl ether/hexane to give 0.71 g of (E)-2′-[(1-(9-fluorenylmethyloxycarbonylamino)-1-cyclopentyl)carbonyl]-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoy]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide as a white solid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.[CH3:24][N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:31](=[O:32])[CH2:30][C:26]1[N:25]([CH3:24])[CH:29]=[CH:28][CH:27]=1
Reactant: Cn1cc(-c2ccc3c(c2F)CCN3)c2c(N)ncnc21
Reactant: Cn1cccc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cccc1CC(=O)N1CCc2c1ccc(-c1cn(C)c3ncnc(N)c13)c2F
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
A solution of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (100 mg, 0.281 mmol), (1-methyl-1H-pyrrol-2-yl)acetic acid (39.1 mg, 0.281 mmol), HATU (107 mg, 0.281 mmol), and DIEA (0.245 mL, 1.404 mmol) was stirred at room temperature for 3 days. The resulting suspension was poured into water (10 mL) and stirred for 30 min, and a precipitate formed. The precipitate was collected by filtration, and the residue was washed with water, then dried at the pump for an hour, then adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtOAc) to afford 5-{4-fluoro-1-[(1-methyl-1H-pyrrol-2-yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (70 mg, 61.7% yield) as an off-white solid. LC-MS (ES) m/z=405 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.25 (t, J=8.34 Hz, 2H), 3.54 (s, 3H), 3.69-3.79 (m, 3H), 3.87 (s, 2H), 4.33 (t, J=8.34 Hz, 2H), 5.82-5.95 (m, 2H), 5.95-6.19 (m, 2H), 6.69 (t, J=2.27 Hz, 1H), 7.16-7.24 (m, 1H), 7.26 (s, 1H), 7.93 (d, J=8.08 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].CO.O.O.[Sn](Cl)(Cl)(Cl)Cl.[N+](=[CH2:31])=[N-]>COCCOC>[CH3:31][O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[C:19]2[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=2[N:12]=[CH:11]1.[CH3:31][O:5][C@@H:4]1[C@@H:6]([CH2:7][OH:8])[O:9][C@@H:1]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[C@@H:2]1[OH:3]
Reactant: C=[N+]=[N-]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Product: CO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1CO

Procedure:
10 g of adenosine was suspended in 2 l of 1 mmole methanol solution of tin chloride dihydrate. 500 ml of 0.4-0.5M 1,2-dimethoxyethane solution of diazomethane was added to the solution with stirring. After stirring for 2 hours at room temperature, the solution was evaporated to dryness under reduced pressure. The residue was purified by ion exchange column chromatography and recrystallized from ethanol to give 2'-O-methyladenosine (Compound 1) and 3'-O-methyladenosine (Compound 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([N:16]([CH2:28][CH3:29])[C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][NH:23][CH:24]2[CH3:27])=[CH:19][CH:18]=1)[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:23]3[CH2:22][CH2:21][C:20]4[C:25](=[CH:26][C:17]([N:16]([CH2:28][CH3:29])[CH2:14][CH3:15])=[CH:18][CH:19]=4)[CH:24]3[CH3:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CCN(CC)c1ccc2c(c1)C(C)NCC2
Product: CCN(CC)c1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with Diethyl-(1-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amine to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5].[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:44][C:45]#[N:46])=[N:41][C:42]=1Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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:1][C:2]1[CH:26]=[CH:25][C:24]([C:42]2[C:37]([Cl:36])=[CH:38][CH:39]=[C:40]([CH2:44][C:45]#[N:46])[N:41]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5]
Reactant: N#CCc1ccc(Cl)c(Cl)n1
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2Cl)n(-c2ccccc2)n1
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: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3nc(CC#N)ccc3Cl)ccc2Cl)n(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
To a degassed solution of ethyl 5-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate (Preparation 5, 1.01 g, 1.34 mmol) and 2-(5,6-dichloropyridin-2-yl)acetonitrile (Preparation 59, 300 mg, 1.60 mmol) in dioxane (10 mL) was added Na2CO3 (213 mg, 2.01 mmol), water (1 drop) and Pd(PPh3)4 (144 mg, 0.134 mmol). The reaction was further degassed and heated to 80° C. for 1 hour. Further water (1 mL) was added and heating continued for 5 hours before cooling to room temperature. The reaction was filtered through Celite washing through with EtOAc, and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-100% MeCN in water with 0.1% formic acid to afford the title compound (360 mg, 49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:5]=[CH:4][C:3]=1[C@@H:11]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH3:12].[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[C@@H:11]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH3:12]
Reactant: [H][H]
Reactant: C=C(C)c1ccc([C@H](C)N[S@](=O)C(C)(C)C)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc([C@H](C)N[S@](=O)C(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
To a round bottom flask containing (R)—N—((S)-1-(2-fluoro-4-(prop-1-en-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (204 mg, 0.72 mmol) and a stir bar was added MeOH (7.2 mL). To this solution was added palladium on carbon (77 mg, 10%, 0.07 mmol) in MeOH (1 mL). A hydrogen atmosphere was inserted and the resulting reaction mixture stirred at room temperature for 18 hours, at which time more palladium on carbon was added (300 mg) in MeOH (5 mL). A hydrogen atmosphere was inserted again and the reaction mixture allowed to stir an additional 18 hours at room temperature. The reaction mixture was filtered through a syringe filter and concentrated to afford a light brown viscous oil of (R)—N—((S)-1-(2-fluoro-4-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide (149 mg, 0.52 mmol, 73% yield) which crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.20 (s, 9H) 1.24 (d, J=5.87 Hz, 6H) 1.58 (d, J=6.70 Hz, 3H) 2.89 (dt, J=13.79, 6.90 Hz, 1H) 3.35 (d, J=5.04 Hz, 1H) 4.76-4.85 (m, 1H) 6.90 (dd, J=12.03, 1.52 Hz, 1H) 6.98 (dd, J=7.90, 1.54 Hz, 1H) 7.24 (t, J=7.97 Hz, 1H). LCMS m/z 286.3 (M+H)+, Rt 1.01 min.
Reaction SMILES: [I:1][C:2]1[C:10]([I:11])=[C:9]([I:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH3:15])([CH3:14])[C:5]([CH3:13])=[N:6]2.I[CH3:17]>>[I-:1].[I:1][C:2]1[C:10]([I:11])=[C:9]([I:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH3:15])([CH3:14])[C:5]([CH3:13])=[N+:6]2[CH3:17]
Reactant: CC1=Nc2cc(I)c(I)c(I)c2C1(C)C
Reactant: CI
Product: CC1=[N+](C)c2cc(I)c(I)c(I)c2C1(C)C
Product: [I-]
Yield: 93.7 %

Procedure:
0.6 g (1.1 mmol) of 4,5,6-triiodo-2,3,3-trimethyl-3H-indole and 0.78 g (5.5 mmol) of iodomethane were heated at 30-40° C. for 20 hours in a sealed tube. The formed precipitate was filtered, and washed with small amounts of benzene and acetone to yield 350 mg of 4,5,6-triiodo-1,2,3,3-tetramethyl-3H-indolium iodide. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 8.53 (1H, s, arom.), 3.93 (3H, s, NCH3), 2.77 (3H, s, CH3), 1.60 (6H, s, C(CH3)2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:16]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:11][CH2:12][N:13]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]4[C:26](=[O:27])[C:25]5[C:24](=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:23]4=[O:32])[CH2:14][CH2:15]3)=[CH:8][S:7][C:6]=2[CH:16]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Fc1ccc2c(N3CCNCC3)csc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2csc3cc(F)ccc23)CC1
Yield: 69.7 %

Procedure:
A mixture of 1-(6-fluorobenzo[b]thien-3-yl)-piperazine (20.0 g, 84.6 mmol), N-(4-bromobutyl)phthalimide (26.3 g, 93.2 mmol), anhydrous potassium carbonate (17.5 g, 127 mmol), KI (1.40 g, 8.43 mmol), and anhydrous acetonitrile (500 mL) was stirred at reflux for 17 hours. The thick slurry was filtered, the insolubles washed with chloroform (2×100 mL), and the filtrate concentrated in vacuo. The residue was taken up in chloroform (400 mL), washed with water (200 mL), and dried (MgSO4). The solvent was removed in vacuo and the product chromatographed on silica gel, with 20% heptane/ethyl acetate as eluent, to afford 25.8 g of a yellow solid. Recrystallization from ether afforded 10.9 g (29%) of the title compound as a yellow powder: m.p.=94°-95° C.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.FC(F)(F)C(O)=O>ClCCl>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: Cn1ccc2cc(C(=O)O)ccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2cc(C(=O)O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
Dichloromethane (2 ml) and triethylsilane (1 ml) were added to 1-methyl-1H-indole-5-carboxylic acid (100 mg). The mixture was cooled to 0° C., trifluoroacetic acid (1 ml) was added dropwise thereto, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and precipitate was collected by filtration. The precipitate was washed with ether and dried under reduced pressure to give the title compound (66 mg, Y.:65%).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH2:7]([Li])CCCCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[C:21](=[O:27])[CH:20]=[CH:19]2>C1COCC1.CCCCCCC>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23]([N:22]([CH3:26])[C:21](=[O:27])[CH:20]3[CH2:7][CH:19]32)=[CH:24][CH:25]=1
Reactant: COc1ccc2c(ccc(=O)n2C)c1
Reactant: [Li]CCCCCC
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COc1ccc2c(c1)C1CC1C(=O)N2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 107.8 %

Procedure:
A suspension of 3.35 gm (15.1 mmol) trimethylsulfoxonium iodide in 10 ml of THF at 0° C. under nitrogen was treated portionwise with 5.8 ml (14.6 mmol) of 2.5 M n-hexyllithium in heptane over 30 minutes. The mixture was stirred for 30 minutes at 0° C. and then treated with 1.0 gm (5.02 mmol) 6-Methoxy-1-methyl-1H-quinolin-2-one followed by heating under reflux for 1.5 hours. The reaction mixture was allowed to cool to ambient temperature before quenching with 35 ml of water followed by extraction into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to afford 1.1 gm of desired product. Mass spectrum APCI m/e 204 (p+1).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2[N:18]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[O:1]([C:8]1[CH:9]=[C:10]([C:14]2[N:18]=[C:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3cccc(Oc4ccccc4)c3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2nc(-c3cccc(Oc4ccccc4)c3)no2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A mixture of methyl 4-[3-(3-phenoxyphenyl)-1,2,4-oxadiazol-5-yl]benzoate (1.69 g), 1 M aqueous sodium hydroxide solution (10 ml), methanol (15 ml) and tetrahydrofuran (15 ml) was stirred at 60° C. for 1 hr. After cooling, 1 M hydrochloric acid was added to acidify the reaction mixture. The crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give 4-[3-(3-phenoxyphenyl)-1,2,4-oxadiazol-5-yl]benzoic acid (1.35 g, yield 83%) as colorless crystals. melting point: 292–293° C.
Reaction SMILES: [CH2:1]([N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])[CH2:2][N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6].[CH2:21]([NH:28][NH:29][C:30]([NH:32][NH2:33])=[S:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:34]1(=[O:53])[N:38]([CH2:39][CH2:40][CH2:41][C:42](ON2C(=O)CCC2=O)=[O:43])[C:37](=[O:52])[CH:36]=[CH:35]1>CN(C)C=O>[CH2:2]([N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6])[CH2:1][N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15].[CH2:21]([N:28]([C:42](=[O:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:37](=[O:52])[CH:36]=[CH:35][C:34]1=[O:53])[NH:29][C:30]([NH:32][NH2:33])=[S:31])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NNC(=S)NNCc1ccccc1
Reactant: O=C(CCCN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CN(C)C=O
Product: NNC(=S)NN(Cc1ccccc1)C(=O)CCCN1C(=O)C=CC1=O

Procedure:
The EDTA-benzylthiocarbazide prepared in step 1 (20 mg; 34 μmol) and N-(gamma-maleimidobutyryloxy)succinimide (8 mg, 29 μmol=0.9 equiv.) were stirred in anhydrous dimethylformamide for 1 h. The mixture was then evaporated to dryness, and the residue was dried under high vacuum.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=1[OH:5])[CH3:2].[C:11]12([C:21](Cl)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.N1C=CC=CC=1>C(Cl)Cl>[C:11]12([C:21]([O:10][C:8]3[CH:7]=[CH:6][C:4]([OH:5])=[C:3]([CH2:1][CH3:2])[CH:9]=3)=[O:22])[CH2:18][CH:17]3[CH2:16][CH:15]([CH2:14][CH:13]([CH2:19]3)[CH2:12]1)[CH2:20]2
Reactant: CCc1cc(O)ccc1O
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cc(OC(=O)C23CC4CC(CC(C4)C2)C3)ccc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Ethylhydroquinone (1.85 mmol) and 1-adamantanecarbonyl chloride (1.4 eq.) were suspended in CH2Cl2 (3 mL/mmol), pyridine (1 mmol) was added, and the mixture stirred at r.t. for 48 h.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=[O:6].[O:19]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=2)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:19]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][CH2:11][CH2:10][CH2:9]3)=[O:6])[CH2:34][CH:33]=2)=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Reactant: O=C(CCCCl)NC1CCCOc2ccccc21
Product: O=C(CCCN1CC=C(c2ccc(Oc3ccccc3)cc2)CC1)NC1CCCOc2ccccc21

Procedure:
The compound (9) synthesized in Reference Example 9 and the compound (3) synthesized in Reference Example 3 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[CH:15][CH:14]=1.[CH3:26][S:27]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2)(=[O:29])=[O:28]>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:36]2[C:35]3[C:39](=[C:31]([CH2:30][S:27]([CH3:26])(=[O:29])=[O:28])[CH:32]=[CH:33][CH:34]=3)[NH:38][CH:37]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[CH:15][CH:14]=1
Reactant: N#CC1CC1C(O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3C#N)c[nH]c12

Procedure:
95.7 mg (0.43 mmol) of indium(III) chloride and 0.04 ml (0.49 mmol) of trifluoroacetic acid were added to 83.3 mg (0.40 mmol) of the compound from Example 167A and 100 mg (0.25 mmol) of the compound from Example 86A with a purity of 53% under argon in 5 ml of dichloromethane, and the mixture was heated under reflux for three days. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 41.0 mg (33% of theory) of the title compound as mixture of diastereomers.