Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[N:12][C:11]([CH2:14][OH:15])=[N:10]1.[H-].[Na+].[CH:18]1([N:21]2[C:25](S(C)(=O)=O)=[N:24][N:23]=[C:22]2[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:20][CH2:19]1>>[CH:18]1([N:21]2[C:25]([O:15][CH2:14][C:11]3[N:12]=[N:13][N:9]([C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[F:1])[N:10]=3)=[N:24][N:23]=[C:22]2[C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)[CH2:20][CH2:19]1
Reactant: CS(=O)(=O)c1nnc(-c2ccncc2)n1C1CC1
Reactant: Cc1ccc(F)c(-n2nnc(CO)n2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(F)c(-n2nnc(COc3nnc(-c4ccncc4)n3C3CC3)n2)c1

Procedure:
The title compound is prepared from [2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol), sodium hydride (1.5 mmol) and 4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][CH:16]=[C:17]([CH3:22])[CH2:18][N+:19]([O-:21])=[O:20]>O1CCCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:15][CH:16]=[C:17]([CH3:22])[CH2:18][N+:19]([O-:21])=[O:20])[CH3:11]
Reactant: CC(=CCBr)C[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC=C(C)C[N+](=O)[O-])C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 0.1 Mol of diethyl malonate and 0.25 Mol of sodium hydride in tetrahydrofuran was added a solution of 0.1 Mol 1-bromo-3-methyl-4-nitro-2-butene in tetrahydrofuran and stirred for 3 hours at room temperature. The reaction mixture was worked up via an acid extraction with ether. The excess of diethyl malonate was cautiously removed via distillation and the product purified by column chromatography over silica gel using ether/hexane 1:1 as eluent. A yellow oil was obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:33])[CH3:32].[CH3:34][CH2:35][O:36][C:37]([CH3:39])=[O:38]>N1C=CC=CC=1>[CH2:35]([O:36][C:37]([C@@H:39]1[CH2:32][C@H:3]([C:2]([O:1][C@H:2]2[CH2:19][CH2:18][C@@:17]3([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]4([CH3:31])[C@@H:16]3[CH2:15][CH2:14][C@H:13]3[C@@:8]4([CH3:30])[CH2:9][CH2:10][C@@:11]4([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]43)[C:3]2([CH3:33])[CH3:32])=[O:1])[C:4]1([CH3:17])[CH3:5])=[O:38])[C:34]1[CH:9]=[CH:8][CH:7]=[CH:16][CH:15]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)[C@H]6C[C@@H](C(=O)OCc7ccccc7)C6(C)C)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Yield: 15 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (1.3 g) in pyridine (10 ml) DMAP (0.57 g) was added followed by the crude reaction mixture (anhydride formation). The reaction mixture was stirred at reflux temperature for about 12 hours. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature, diluted with EtOAc, washed with dil HCl, water, followed by brine and dried over Na2SO4, and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography using hexane and ethyl acetate mixtures as an eluent to afford the title compound (300 mg, 15% yield). 1H NMR (300 MHz, CDCl3): δ 7.37-7.33 (5H, m), 5.16 (2H, m), 4.73 (1H, s), 4.61 (1H, s), 4.45-4.36 (1H, m), 3.65-3.6 (1H, m), 3.1-2.90 (1H, m), 2.85-2.6 (3H, m), 2.4 (1H, m), 2.3-1.9 (5H, m), 1.8-1.3 (17H, m), 1.26 (4H, m), 1.24 (3H, s), 1.22 (2H, m), 1.16 (3H, s), 1.14 (3H, s), 1.00 (2H, m), 0.8 (6H, s); Mass: [M+Na]+ 723 (15%); IR (KBr, cm−1): 3427, 2953, 17330, 1730, 1459, 1376, 1277, 1236, 1187, 1107, 1034, 940, 882.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][C@@H:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:4]([CH2:5][CH2:6]2)[CH:3]1[C:17]([O:19][CH3:20])=[O:18].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:21][S:22]([O:1][CH:2]1[CH2:8][C@@H:7]2[N:9]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@@H:4]([CH2:5][CH2:6]2)[CH:3]1[C:17]([O:19][CH3:20])=[O:18])(=[O:24])=[O:23]
Reactant: COC(=O)C1C(O)C[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1C(OS(C)(=O)=O)C[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
(1S,5R)-8-Tert-butyl 2-methyl 3-hydroxy-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (1.75 g, 6.14 mmol) was dissolved in dichloromethane (30 mL), methanesulfonyl chloride (0.95 mL, 123 mmol) was added, followed by dropwise addition of N,N-diisopropylethyl-amine (5.29 mL, 30.7 mmol). The reaction mixture was stirred at room temperature overnight. After quench with saturated NaHCO3, the reaction mixture was extracted with dichloro-methane. The combined organic layer was washed with water and brine. Dried and concentrated to give 2.23 g of crude product. The crude was carried over the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:48][S@@](C(C)(C)C)=O)([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH2:16][C:17]2[N:18]=[N:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)([NH2:48])[CH2:16][C:17]2[N:18]=[N:19][NH:20][N:21]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:11])[F:12])[CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N[C@](Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@](Cc1nn[nH]n1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)—N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide (60 mg, 0.079 mmol) in MeOH (3 mL) was added 4 N HCl in dioxane (1 mL). The reaction mixture was stirred at room temperature for 20 min, then concentrated to yield (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2H-tetrazol-5-yl)ethanamine. LCMS: RT=2.66 min [M+H] 418.55 (Phenomenex Luna C18 4.6×50 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 4 min gradient, flow rate 4 mL/min, wavelength 220 nm). To a solution of ((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2H-tetrazol-5-yl)ethanamine in THF (3 mL) and MeOH (0.5 mL) was added (diazomethyl)trimethylsilane (2.0 M in hexanes, 0.05 mL). After stirring at room temperate for 20 min, the reaction mixture was concentrated and purified by ISCO flash column chromatography (silica gel, EtOAc) to give ((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)ethanamine (10 mg, yield: 30%). LCMS: RT=2.83 min [M+H] 432.57 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:23][CH2:24][C@@H:25]([CH3:28])[CH2:26][CH3:27]>O1CCCC1>[CH3:21][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:23][CH2:24][C@@H:25]([CH3:28])[CH2:26][CH3:27])[C:18]([OH:20])=[O:19]
Reactant: CC[C@H](C)CCBr
Reactant: CC(C(=O)O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](C)CCC(C)(C(=O)O)c1ccccc1
Reaction time: 17 h
Yield: 90 %

Procedure:
Lithium bis(trimethylsilyl)amide (3.23 g, 19.3 mmol) was added to 8 mL of tetrahydrofuran and the resulting solution was cooled in an ice bath. Addition of a solution of 2-phenyl-propionic acid (1.16 g, 7.73 mmol) in 1 mL of tetrahydrofuran to the reaction solution was followed by addition of (S)-1-bromo-3-methyl-pentane (2.05 g, 12.4 mmol). The reaction vessel was removed from the cooling bath, placed in a 50° C. oil bath, and the reaction solution was stirred for 17 hours. After concentration, the resulting residue was dissolved in 25 mL of 1 N NaOH, washed with 25 mL of 2:1 hexane/iso-propyl acetate, acidified to pH 1 with 6 N HCl, and extracted with ethyl acetate (3× 30 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 1.63 g (90%) of a clear oil. 1H NMR (300 MHz, CDCl3): δ ppm 0.83 (m, 6H) 1.20 (m, 5H) 1.57 (s, 3H) 1.98 (m, 2H) 7.35 (m, 5H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH:18]([C:24](O)=[O:25])[CH2:17]2.C(N(CC)CC)C.ClC(OCC)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>O1CCCC1>[N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH:18]([C:24]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:25])[CH2:17]2
Reactant: C1COCCN1
Reactant: CCN1CC(C(=O)O)Cc2cccc(CSc3nc4ccccc4[nH]3)c21
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CC(C(=O)N2CCOCC2)Cc2cccc(CSc3nc4ccccc4[nH]3)c21
Yield: 45.3 %

Procedure:
To a solution of 8-(2-benzimidazolyl)thiomethyl-1-ethyl-1,2,3,4-tetrahydroquinoline-3-carboxylic acid (1.3 g) in tetrahydrofuran (50 ml) were added dropwise triethylamine (0.4 g) and ethyl chloroformate (0.4 g) with stirring under ice-cooling and the mixture was stirred for 30 minutes. Moreover morpholine (0.4 g) was added dropwise thereto and the mixture was stirred for 3 hours at room temperature. The solvent was distilled off and the resulting residue was dissolved in chloroform. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent:dichloromethane-methanol (200:1)], and recrystallized from ethyl acetate-ethanol to give 8-(2-benzimidazolyl)thiomethyl-3-morpholinocarbonyl-1-ethyl-1,2,3,4-tetrahydroquinoline (0.7 g).
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:10][C:11]([CH2:14]O)=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O.O>ClCCl>[CH2:1]([S:8][C:9]1[S:10][C:11]([CH2:14][Cl:18])=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cnc(SCc2ccccc2)s1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: ClCc1cnc(SCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1.18 g of 2-benzylsulfanyl-5-hydroxymethyl-thiazole dissolved in 5 ml of dichloromethane, 0.4 ml of thionyl chloride dissolved in 5 ml of dichloromethane are added dropwise at 0° C. to. The reaction mixture is then allowed to warm to room temperature and stirred for 0.5 hour. After the addition of 5 ml of water, the organic phase is washed twice with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. After removal of the solvent in vacuo, chromatography on silica gel (ether:hexane; 1:4) yields 2-benzylsulfanyl-5-chloromethyl-thiazole having a melting point of 57-61° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1)[CH3:2].C([Li])CCC.[CH:13]12[O:19][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]2>C1COCC1>[CH2:1]([N:3]1[C:7]([C@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]2[OH:19])=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cccn1
Reactant: C1CCC2OC2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1nccc1[C@H]1CCCC[C@@H]1O
Yield: 56.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 4a by using 1-ethylpyrazole (2.50 g, 26.0 mmol), butyl lithium (1.63 M solution in hexane; 18.1 mL, 29.5 mmol), cyclohexene oxide (2.97 g, 30.3 mmol) and THF (60 mL), to yield the title compound (2.86 g, 57%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:11][C:12]1[O:16][N:15]=[C:14]([CH3:17])[CH:13]=1>>[CH3:17][C:14]1[CH:13]=[C:12]([NH:11][S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])[O:16][N:15]=1
Reactant: Cc1cc(N)on1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Product: Cc1cc(NS(=O)(=O)c2ccc(Br)s2)on1

Procedure:
N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide was prepared in the same manner as described in Example 14 from 5-bromothiophene-2-sulfonyl chloride and 5-amino-3-methyl isoxazole. Purification was achieved by extraction of the crude sulfonamide into aqueous 2N NaOH, washing of the aqueous layer with ethyl acetate and acidification, using concentrated HCl, to pH˜2. Re-extraction into ethyl acetate was followed by washing of the organic material with water, brine and drying over magnesium sulfate. After evaporation of solvents, a brownish solid remained which was sufficiently pure to use in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:18][CH2:17][C:16]([C:24]([O:26]C)=[O:25])=[CH:15][C:14]=3[CH:28]=2)=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([S:20]([CH3:23])(=[O:21])=[O:22])[CH2:18][CH2:17][C:16]([C:24]([OH:26])=[O:25])=[CH:15][C:14]=3[CH:28]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-(4-ethoxyphenyl)-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.14 g). To the solution was added 1N sodium hydroxide solution (3 ml), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with evaporated to give 7-(4-ethoxyphenyl)-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.13 g) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:22])=[N:7]2.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:30][CH3:31]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:13]([O:15][CH2:30][CH3:31])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:22])=[N:7]2
Reactant: Cc1ccc2c(Br)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetic acid (17 g, 46.6 mmol) in DMF (200 mL) was added Cs2CO3 (30.4 g, 93.2 mmol), followed with the addition of iodoethane (11 g, 69.9 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours, diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product. LCMS-ESI+: calc'd for C19H24BrNO3: 394.1 (M+H+); Found: 394.0 (M+H+).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[N:7]=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:9]=1
Reactant: C#CCCn1cc(-c2ccccc2Cl)nn1
Reactant: Brc1ccccn1
Product: Clc1ccccc1-c1cn(CCC#Cc2ccccn2)nn1
Yield: 34.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 1-(but-3-ynyl)-4-(2-chlorophenyl)-1H-1,2,3-triazole (200 mg, 0.86 mmol, Example 259(B)) and 2-bromopyridine (150 mg, 0.95 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 93.4 mg (0.30 mmol, 35%) of 2-(4-(4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a yellow oil.
Reaction SMILES: [OH:1][C:2]1([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.I[CH2:18][C:19]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:12]([O:11][C:10]([NH:9][CH2:8][C:2]1([OH:1])[CH2:7][CH2:6][N:5]([CH2:18][C:19]2([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:4][CH2:3]1)=[O:16])([CH3:13])([CH3:15])[CH3:14]
Reactant: COC(=O)C1(CI)CCCCC1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCNCC1
Product: COC(=O)C1(CN2CCC(O)(CNC(=O)OC(C)(C)C)CC2)CCCCC1

Procedure:
The title compound was prepared by a method similar to that shown in the Step 2 of Example 3 by using tert-butyl [(4-hydroxypiperidin-4-yl)methyl]carbamate (Chem. Pharm. Bull., 2002, 50 (9) 1187-1194) and methyl 1-(iodomethyl)cyclohexanecarboxylate (Step 1 of Example 6).
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[N: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].C([O-])(=O)C.[Na+].[Br:25]Br>>[NH2:15][C:14]1[C:13]2[N:12]=[C:11]([Br:25])[N:10]([C@@H:1]3[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]3[OH:3])[C:19]=2[N:18]=[N:17][N:16]=1
Reactant: Nc1nnnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Nc1nnnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 20 °C
Reaction time: 72 h

Procedure:
The 2-azaadenosine [for preparation see Patent WO 01/16149, 2001] (70 mg, 0.26 mmol) was added to a solution of sodium acetate 0.5M (1.4 mL). The solution was heated until the 2-azaadenosine was solubilized. A solution of bromine (100 μL of Br2 in 10 mL of water) (6.3 mL, 1.22 mmol) was added and the mixture was stirred at 20° C. for 3 days. A second portion of the bromine's solution (6.3 mL, 1.22 mmol) was added and the mixture was stirred at 20° C. for 3 hours. The reaction mixture was evaporated to dryness. The crude product was purified on silica gel reverse-phase (C18) using water/acetonitrile (9/1) as eluant to give the title compound as a yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][C:10]=1[O:11][C:12]1[N:17]=[C:16]([NH:18][CH2:19][C:20]([O:22]CC)=O)[C:15]([N+:25]([O-])=O)=[C:14]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:30]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>[Zn].O1CCCC1>[CH2:1]([O:8][C:9]1[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][C:10]=1[O:11][C:12]1[NH:17][C:16]2[C:15](=[C:14]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:30]=3)[N:13]=1)[NH:25][C:20](=[O:22])[CH2:19][N:18]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNc1nc(Oc2cc(C#N)ccc2OCc2ccccc2)nc(Oc2cccc(C(=O)N(C)C)c2)c1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(OC2=C3NC(=O)CN=C3NC(Oc3cc(C#N)ccc3OCc3ccccc3)=N2)c1
Temperature: 70 °C
Yield: 139.8 %

Procedure:
2-(2-Benzyloxy-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxy)pyrimidine (1.1 g, 1.80 mmol), a compound of formula (H), and granular zinc (0.5 g)were mixed with tetrahydrofuran (50 mL)and 10% aqueous HCl (10 mL). The reaction mixture was heated for 30 minutes at 70° C. The volatiles were evaporated. Saturated aqueous NaHCO3 was added and the solution extracted with ethyl acetate (300 mL). The organic layer was dried (Na2SO4)and evaporated to afford 1.35 g of 2-(2-benzyloxy-5-cyanophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone, a compound of formula (J).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:33])[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>O1CCCC1>[NH2:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([O:20][C@H:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][N+:4]([O-:33])=[CH:5][C:6]=1[Cl:32])=[O:31]
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(N)c2)cc1OC
Temperature: 75 °C
Yield: 86.3 %

Procedure:
To a stirred solution of [(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]-3-nitrobenzoate (0.640 g, 1.30 mmol) in anhydrous tetrahydrofuran (30.0 mL) was added tin chloride dihydrate (1.18 g, 5.2 mmol). After heating at 75° C. for 16 hours, the reaction was allowed to cool to room temperature. The reaction was partitioned between ethyl acetate and sodium bicarbonate and extracted with ethyl acetate (×2). The combined organic extracts were dried on magnesium sulphate, filtered and the solvent was removed in vacuo to afford the title compound as a brown solid (0.520 g, 87% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:7]=[CH:6]2)#[N:2].Cl.[NH2:20][OH:21].C(=O)(O)[O-].[Na+]>C(O)C>[OH:21][NH:20][C:1](=[NH:2])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:7]=[CH:6]2
Reactant: NO
Reactant: CCOC(=O)CCn1ncc2cc(C#N)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCn1ncc2cc(C(=N)NO)ccc21
Temperature: 60 °C

Procedure:
Ethyl 3-(5-cyano-1H-indazol-1-yl)propanoate D47 (3.6 g, 14.80 mmol) was dissolved in ethanol (40 ml), hydroxylamine hydrochloride (2.057 g, 29.6 mmol) and sodium bicarbonate (6.22 g, 74.0 mmol) were added. The mixture was heated at 60° C. overnight. Cooled, filtered and the filtrate was evaporated, dissolved in EtOAc, washed with water (3×20 ml), dried over MgSO4 and evaporated again to give (1.75 g) of product. A further 0.290 g of white crystals were recovered from the rotary evaporater. MS (ES+): C13H16N4O3 requires 276; found (MH+) 277.
Reaction SMILES: [Br:1][C:2]1[C:8]([Br:9])=[C:7]([O:10][CH3:11])[C:6]([Br:12])=[CH:5][C:3]=1[NH2:4].[CH2:13]([O:15][C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH3:14]>CC(C)=O>[Br:1][C:2]1[C:8]([Br:9])=[C:7]([O:10][CH3:11])[C:6]([Br:12])=[CH:5][C:3]=1[NH:4][C:19]([NH:18][C:16](=[O:17])[O:15][CH2:13][CH3:14])=[S:20]
Reactant: CCOC(=O)N=C=S
Reactant: COc1c(Br)cc(N)c(Br)c1Br
Solvent: CC(C)=O
Product: CCOC(=O)NC(=S)Nc1cc(Br)c(OC)c(Br)c1Br
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2,3,5-Tribromo-4-methoxy-aniline (4.72 g, 13.1 mmol) was dissolved in acetone (150 mL) and ethoxycarbonyl isothiocyanate (1.63 mL, 14.4 mmol) was added. The solution was heated to 40° C. After 20 minutes a pale yellow precipitate had formed. The viscous mixture was cooled to rt and stirred at rt overnight. The solvent was removed under reduced pressure. Cyclohexane (˜150 mL) was added to the residue and the suspension sonicated. The solid was collected by filtration through a PTFE filter to give an off-white fluffy solid which was dried in the vacuum oven (40° C.) to afford the desired compound as an off-white solid, 6.00 g (93%). m/z: 488.78/490.80/492.75/494.80 [M+H]+.