Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:21])[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 16 %

Procedure:
6-Amino-9-benzyl-2-ethylthiopurine (214 mg, 0.75 mmol) and bromine (0.5 ml) were dissolved in 100 ml of methylene chloride and the solution was stirred at room temperature for 7 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 (43 mg, yield 16%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([O:18]CC2C=CC=CC=2)=[CH:16][CH:15]=[CH:14][N:13]=1.[ClH:26].C(OCC)(=O)C>CO>[ClH:26].[ClH:26].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Cc1[nH]cnc1CSCCNc1ncccc1OCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1[nH]cnc1CSCCNc1ncccc1O
Reaction time: 48 h

Procedure:
2-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]amino-3-benzyloxypyridine (1.3 g; 0.0036 moles) was treated with conc. hydrochloric acid (10 ml) and heated to 60° for 4 hours. The reaction mixture was stripped in vacuo to a green oil, dissolved in methanol, treated with ethyl acetate and left to stand for 2 days. The red crystals obtained were filtered off and recrystallised from methanol/ethyl acetate to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-hydroxypyridine dihydrochloride as dark red crystals (0.17 g, mp 210°-212°).
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].[Cl:11][CH2:12][CH2:13][CH2:14][CH:15](I)CCCC.O>CN(C)C=O>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10]
Reactant: CCCCC(I)CCCCl
Reactant: O=C1NC(=O)C2CC12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C2CC2C(=O)N1CCCCCl
Reaction time: 48 h

Procedure:
Sodium hydride (0.11 g, 60% dispersion in oil) was added to a stirred solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.5 g) and 1-chloro-4-iodooctane (0.98 g) in dry dimethylformamide (50 ml) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred for 48 hours and water (50 ml) was then added dropwise. The aqueous mixture was extracted with dichloromethane (2×200 ml) and the combined organic extracts were then washed with water (2×400 ml), dried (MgSO4) and evaporated in vacuo to give an oil. The oil was purified by chromatography on silica (80 g) using 1:1 ethyl acetate/hexane as eluant to give the title compound as a colourless oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([C:43]1[C:44]([Cl:49])=[N:45][CH:46]=[CH:47][CH:48]=1)[S:33]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])(C(C)(C)C)(C)C>O1CCCC1>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([S:33]([CH:32]([C:43]2[C:44]([Cl:49])=[N:45][CH:46]=[CH:47][CH:48]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])(=[O:35])=[O:34])=[CH:37][CH:38]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC(c1cccnc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCO)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under ice cooling, tetrabutylammonium fluoride (a 1 mol/l tetrahydrofuran solution; 0.70 ml) was added to a tetrahydrofuran (10 ml) solution of 3-[6-(tert-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]hexyl]-2-chloropyridine (294 mg, 0.585 mmol). The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column. The fraction obtained from the hexane:ethyl acetate (=1:1) eluate was concentrated under reduced pressure, whereby the title compound (212 mg, 93%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[N:19]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:29]=O.[CH3:31][NH:32][CH3:33].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([NH:14][C:15]2[S:16][C:17]([CH2:31][N:32]([CH3:29])[CH3:33])=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[N:19]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1OC
Reactant: CNC
Reactant: C=O
Solvent: O
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)c(CN(C)C)s2)cc1OC
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a stirred solution of 3,4-dimethoxy-N-(4-(3-nitrophenyl)thiazol-2-yl)benzenesulfonamide (0.267 g, 0.68 mmol) in ethanol (10 mL, warming required) was added an aqueous solution of formaldehyde (37%, 0.5 mL, about 0.194 g, 6.5 mmol) followed by the dropwise addition of a solution of dimethylamine in water (60 wt %, 55 mL, about 0.274 g, 6.1 mmol). The addition was slightly exothermic, and the pale yellow solution became yellow-orange in color. After 0.5 h, a pale yellow solid separated from solution. After 19 h, the solid was collected by filtration, it was washed with ethanol, and dried in vacuo to give a pale yellow solid (0.277 g, 86.3% yield), mp 203° C.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:22])(=O)=O>C(OCC)C>[Cl:22][CH:3]([C:2](=[O:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:16])([F:17])[F:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccccc1C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1C(F)(F)F
Yield: 64.3 %

Procedure:
Using ethyl 3-oxo-3-[2-(trifluoromethyl)phenyl]propanoate (1.0 g, 3.8 mmol), sulfuryl chloride (620 mg, 4.9 mmol) and diethyl ether (50 mL) as starting materials and in the same manner as in Example 20-B(i), the title compound (720 mg, 64%) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:12]([Si](C(C)C)(C(C)C)C(C)C)[CH:13]=[CH:14][C:3]=12.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C>O>[CH:25]1([NH:31][C:2]2[C:3]3[CH:14]=[CH:13][NH:12][C:4]=3[N:5]=[CH:6][C:7]=2[S:8]([CH3:11])(=[O:9])=[O:10])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(S(C)(=O)=O)cnc21
Reactant: NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CS(=O)(=O)c1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 25 °C
Yield: 14.9 %

Procedure:
4-Chloro-5-(methylsulfonyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (61 mg, 0.16 mmol) in cyclohexylamine (200 μL, 1.74 mmol) was stirred with N,N-diisopropylethylamine (40 μL, 0.23 mmol) at 120° C. for 30 minutes The reaction mixture was allowed to cool to room temperature and, after addition of water, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1→5/1 (v/v)) to give the title compound as a colorless solid (7.0 mg, yield 15%).
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.[F:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:23][C:15]([F:14])=[CH:16][C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2sc(F)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(F)sc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2-fluoro-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [Se](=O)=[O:2].[CH:4]1[C:9]([C:10]([CH2:12]Br)=[O:11])=[CH:8][CH:7]=[C:6]([Cl:14])[CH:5]=1.CC[O:17][CH2:18]C>CO>[Cl:14][C:6]1[CH:7]=[CH:8][C:9]([C:10](=[O:11])[C:12]([O:17][CH3:18])=[O:2])=[CH:4][CH:5]=1
Reactant: O=[Se]=O
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOCC
Solvent: CO
Product: COC(=O)C(=O)c1ccc(Cl)cc1
Yield: 35 %

Procedure:
Selenium dioxide (35.5 g; 320 mmol) was dissolved in 250 mL of MeOH (warm to reflux with stirring), and 19.6 g (315 mmol) of α-bromo-4-chloroacetophenone was added. The reaction mixture was warmed to reflux for 24 hours, cooled, filtered and concentrated leaving an orange oil. The oil was diluted with 1500 mL of Et2O and washed three times with 200 mL of H2O and once with 200 mL of brine, dried (Na2SO4) and concentrated. The crude oil was crystallized from Et2O and hexanes at -20° C. The white needles were filtered while cold and washed with small portions of cold hexanes to yield 22 g (35%) of methyl p-chlorophenyl-α-oxoacetate, m.p. 56°-57° C., 1H-NMR (CDCl3)δ8.0-7.9 (m, 2H), 7.5-7.4 (m, 2H), 3.9 (s, 3H); 13C-NMR (CDCl3)δ184.4, 163.5, 141.6, 131.4, 131.0, 129.3, 52.7.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12]O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][CH2:12][CH2:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1cccc(CCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(CCCBr)c1
Reaction time: 12 h
Yield: 94.5 %

Procedure:
Compound 95-1 (220 mg) was dissolved in methylene chloride (10 ml), triphenylphosphine (350 mg) and N-bromosuccinimide (238 mg) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (30 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (280 mg) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[C:9]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]5([NH:25]C(=O)OC(C)(C)C)[CH2:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)=[N:11][C:12]=3[CH2:13][CH2:14][C:5]=2[CH:4]=[N:3]1>C(O)(C(F)(F)F)=O>[CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[C:9]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]5([NH2:25])[CH2:22][CH2:23][CH2:24]5)=[CH:17][CH:16]=4)=[N:11][C:12]=3[CH2:13][CH2:14][C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1CC2
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc2c1-c1cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc1CC2
Reaction time: 0.01 h
Yield: 26.6 %

Procedure:
Tert-butyl (1-(4-(1-methyl-8-phenyl-4,5-dihydro-1H-pyrazolo[3,4-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (3 mg, 0.006 mmol) was dissolved in TFA (0.5 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜1 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (1 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (0.65 mg, 22% yield). 1H NMR (500 MHz, CH3OD) 8.06 (s, 1H), 7.50 (d, 2H), 7.43 (d, 3H), 7.27-7.36 (br m, 5H), 4.19 (s, 1H), 3.22 (t, 2H), 2.93 (t, 2H), 2.73-2.83 (br m, 2H), 2.54-2.66 (br m, 2H), 2.18-2.33 (br m, 1H), 1.92-2.03 (br m, 1H). LCMS (Method A): RT=4.21 min, M+H+=407
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](O)=[O:19])([CH3:14])([CH3:13])[CH3:12].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>>[C:25]([C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:23]=1[OH:24])[C:18]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:19])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)c1cc(C(=O)Oc2ccccc2[N+](=O)[O-])cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
A mixture of o-nitrophenol (1.39 g), 3,5-di-t-butyl-4-hydroxybenzoic acid (2.50 g) and trifluoroacetic anhydride (8.5 ml) was stirred at room temperature overnight. The mixture was poured into ice water, neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, washed with water, saturated saline, and dried over anhydrous MgSO4. The solvent was distilled off and crystallization of the residue from diisopropyl ether afforded 2-nitrophenyl 3,5-di-t-butyl-4-hydroxybenzoate (2.60 g, 70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])C(F)(F)F)=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:41])([F:40])[F:39])[CH:30]=2)[C:3]1=[O:42].CC1(C)N(CCCCCCCCCSCCCC(F)(F)[F:64])C(=O)N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O>>[CH3:43][C:2]1([CH3:1])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:64])[F:26])=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:40])([F:41])[F:39])[CH:30]=2)[C:3]1=[O:42]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)F
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)F
Yield: 73 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, the compound of Example 12 replacing the compound of Example 1. A pale yellow oil is obtained with a yield of 73% (140 mg).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2cccc(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, light grey solid (67 mg, 88%), MS (ISN) m/z=306.5 [(M+H)+], mp 248.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[S:7].Br[C:9]1[CH:10]=[C:11]([O:17][C:18]2[C:19]([CH3:25])=[N:20][CH:21]=[CH:22][C:23]=2[CH3:24])[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.CN(C=O)C.[H-].[Na+]>O>[CH3:25][C:19]1[C:18]([O:17][C:11]2[C:12]([C:15]#[N:16])=[N:13][CH:14]=[C:9]([S:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:10]=2)=[C:23]([CH3:24])[CH:22]=[CH:21][N:20]=1
Reactant: S=c1cccc[nH]1
Reactant: Cc1ccnc(C)c1Oc1cc(Br)cnc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
Pyridine-2(1H)-thione (0.768 g, 6.90 mmol) and 5-bromo-3-(2,4-dimethylpyridin-3-yloxy)picolinonitrile (2.00 g, 6.58 mmol) were added to DMF (12 mL) and cooled to 0° C. 95% Sodium hydride (0.174 g, 6.90 mmol) was slowly added and the reaction was warmed to ambient temperature and stirred overnight. The reaction mixture was poured into water (100 mL) and stirred for 30 minutes. A cloudy milky solution that was not filterable resulted. The reaction was extracted twice with ethyl acetate. The combined organic layers were washed twice with water and brine, dried, and concentrated. The residue was purified over silica gel (2:3 to 0:1 hexane:ethyl acetate) to afford 3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (2.03 g, 6.07 mmol, 92.3% yield) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].Cl.CN(C)CCCN=C=NCC.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>ClCCl>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:13]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)=[O:15])[CH2:31][CH2:30]1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cc3cc([N+](=O)[O-])ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-nitroindole-2-carboxylic acid (4.38 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 4.89 g) in dichloromethane (150 mL) was treated with N-methylpiperazine (2.83 mL) and stirred at ambient temperature for 16 h. The reaction mixture was poured into dichloromethane (200 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% 2 M ammonia in methanol/dichloromethane) to give the title compound (1.8 g). 1H NMR (400 MHz, CDCl3): δ 10.97 (br s, 1H), 8.58 (d, J=2.15 Hz, 1H), 8.11 (dd, J=2.15, 7.04 Hz, 1H), 7.44 (d, J=9.00 Hz, 1H), 6.89 (s, 1H), 3.95 (br m, 4H), 2.52 (t, J=4.89 Hz, 4H), 2.34 (s, 3H). MS (electrospray): exact mass calculated for C14H16N4O3, 288.12; m/z found, 289.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH2:7][C:8]1[CH:9]=[N:10][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:13]=1)=[CH2:6])[CH3:2].C(N(CC)CC)C.[C:30]([OH:33])(=[S:32])[CH3:31]>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:6][S:32][C:30](=[O:33])[CH3:31])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CC(O)=S
Reactant: C=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)Cc1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.49 g, 1.60 mmol) and triethylamine (0.17 g, 1.64 mmol) were added to thioacetic acid (3 mL) at 0° C. The mixture was stirred at room temperature for 6 h. The mixture was poured onto ice-water and extracted with CH2Cl2. The organic phase was washed with saturated NaHCO3 and dried. The crude product was purified by flash chromatography (MeOH/CH2Cl2, 2.5:100) to give 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-propionic acid ethyl ester (0.36 g, 61%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[O:23]=[C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH2:15][CH:16]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24]([O:32][CH2:33][CH3:34])=[O:31])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(C=Cc1ccccc1)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(Oc2ccccc2)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-phenoxyphenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-oxo-3-(4-phenoxyphenyl)-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: Cl.C[N:3](C)[CH2:4][CH2:5][CH2:6]N=C=NCC.[CH3:13][C:14]1[NH:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:28]=[C:29]([C:33]4([C:39]([OH:41])=O)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:30]=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)[N:15]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C(N)C#C>ClCCl.CN(C)C=O>[CH3:13][C:14]1[NH:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:28]=[C:29]([C:33]4([C:39]([NH:3][CH2:4][C:5]#[CH:6])=[O:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:30]=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)[N:15]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1nn(-c2ccc(Sc3cccc(C4(C(=O)O)CCOCC4)c3)cc2)c(=O)[nH]1
Agent: C#CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C#CCNC(=O)C1(c2cccc(Sc3ccc(-n4nc(C)[nH]c4=O)cc3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCL HCl) (1.0 mmol) is added to a mixture of 4-(3-{[4-(3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl]thio}phenyl)tetrahydro-2H-pyran-4-carboxylic acid (1.0 mmol) (example 15), 1-hydroxybenzotriazole (1.0 mmol), N-methylmorpholine (1.65 mmol) and propargylamine (1.0 mmol) in dichloromethane-dimethylformamide (1:1) at 0° C. The solution is stirred overnight at room temperature, washed with water and the aqueous layer is extracted with dichloromethane. The combined organic extracts are dried with sodium sulphate, filtered and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography over silica gel to yield the title product.