Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][O:17][C:18]1[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].[Cl:31]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.C(OCC)(=O)C.O>[Cl:31][C:23]1[C:19]([C:20]([OH:22])=[O:21])=[C:18]([O:17][CH3:16])[N:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1nc(C(F)(F)F)ccc1C(=O)O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C(F)(F)F)cc(Cl)c1C(=O)O
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
A solution of LiTMP was formed by cooling a solution of 2,2,6,6-tetramethylpiperidine (862 mg, 6.1 mmol) in THF (5 mL) to −50° C. then adding a solution of n-butyllithium (2.4 mL of 2.5 M in hexanes, 6.1 mmol) dropwise and stirring the mixture for 10 minutes at −50° C. This solution was then cooled to −78° C. and a solution of 2-methoxy-6-(trifluoromethyl)nicotinic acid (300 mg, 1.35 mmol) in THF (5 mL) was added dropwise. This mixture was stirred at −78° C. for 2 hours then added via cannula to a pre-cooled solution of hexachloroethane (1.44 g, 6.1 mmol) in THF (5 mL) at −50° C. This mixture was allowed to warm to room temperature over 1 hour then poured into water (20 mL), ethyl acetate (100 mL) added, then washed with hydrochloric acid (2 N, aq, 100 mL). The organic phase was dried over magnesium sulphate, filtered and evaporated to give 4-chloro-2-methoxy-6-(trifluoromethyl)nicotinic acid (312 mg) as an orange solid: 1H NMR (360 MHz, CDCl3): δ 7.36 (1H, s), 4.08 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.C([O-])(O)=O.[Na+]>C(O)C.O>[NH2:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)ccc1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A mixture of compound 4-bromo-2-nitrophenol (1 g, 4.59 mmol) and 5 nCl2 (5.2 g, 22.9 mmol) in ethanol (10 mL) was stirred at 70° C. for 2 h. After cooled down, the mixture was diluted with water (100 mL), adjusted to pH 7 with saturated aqueous NaHCO3 and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, concentrated to give 2-amino-4-bromophenol (770 mg, 89%) as a grey solid. LCMS: 188 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 4.79 (s, 2H), 6.48 (dd, J1=2.4 Hz, J2=8.4 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 9.26 (s, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.[NH2:32][C:33]1[N:38]=[C:37]([NH:39][CH2:40][CH2:41][CH2:42][N:43]2[CH:47]=[C:46]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=3[Cl:55])[CH:45]=[C:44]2[C:56](O)=[O:57])[CH:36]=[CH:35][C:34]=1[N+:59]([O-:61])=[O:60]>CN(C=O)C>[NH2:32][C:33]1[N:38]=[C:37]([NH:39][CH2:40][CH2:41][CH2:42][N:43]2[CH:47]=[C:46]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=3[Cl:55])[CH:45]=[C:44]2[C:56]([NH:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:57])[CH:36]=[CH:35][C:34]=1[N+:59]([O-:61])=[O:60]
Reactant: NCCN1CCCC1
Reactant: Nc1nc(NCCCn2cc(-c3ccc(Cl)cc3Cl)cc2C(=O)O)ccc1[N+](=O)[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Nc1nc(NCCCn2cc(-c3ccc(Cl)cc3Cl)cc2C(=O)NCCN2CCCC2)ccc1[N+](=O)[O-]
Reaction time: 12 h
Yield: 13 %

Procedure:
Hünig's Base (2.5 eq), HOBT (1.2 eq), EDC (1.2 eq) and 1-(2-aminoethyl)pyrrolidine (1.5 eq) were added sequentially to a solution of 1-{3-[(6-amino-5-nitro(2-pyridyl))amino]propyl}-4-(2,4-dichlorophenyl)pyrrole-2-carboxylic acid (11) (1 eq) in DMF (2M) at room temperature with stirring. After 12 hours, the DMF was removed under high vacuum via a centrifugal evaporator. The residue is dissolved in EtOAc and washed with sat. aq. NaHCO3, dried (Na2SO4), filtered, and concentrated. The crude product was purified using a plug of silica eluting with 4% MeOH in CH2Cl2 to give (1-{3-[(6-amino-5-nitro(2-pyridyl))amino]propyl}-4-(2,4-dichlorophenyl)pyrrol-2-yl)-N-(2-pyrrolidinylethyl)carboxamide (12) as a yellow solid (13% yield, 96% pure).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[C:19]([O:23][C:24](=[O:27])[CH2:25][O:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=1[Cl:11])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2,6-dichloro-4-nitrophenol (2.5 g) and potassium carbonate (3.3 g) in dimethyl-formamide (50 mL) is added tert-butyl-bromoacetate (10 mL) and the mixture is stirred at room temperature for two days. The solution is then poured into 500 mL water, extracted three times with hexanes, and the pooled organic extracts are washed with saturated aqueous ammonium chloride and then dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure followed by trituration of the resulting oil with hexanes provides the desired product as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C1(C)C=CC=CC=1.O>[CH2:1]([C:5]1[N:6]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][CH:16]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
A mixture of 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (0.6 m=111.9 g), p-bromobenzylbromide (0.6 m=153.02 g), anhydrous potassium carbonate (0.75 m=103.5 g), and dry N,N-dimethylacetamide (900 mL) was stirred at room temperature for 4 hours. The mixture was diluted with 1.2L of toluene and 1.8L of water. After mixing for half an hour, the layers were separated. The organic layer was washed two more times with 900 mL portions of water, then dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated. The residual oil was pumped overnight to a weight of 191.71 g (89.9% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([OH:13])[CH:7]=1)=[O:4].[CH3:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C1(C)C=CC=CC=1>[Cl-:1].[OH:13][C:8]1[CH:7]=[C:6]([NH:5][C:3]([CH2:2][N+:17]2[CH:18]=[CH:19][N:15]([CH3:14])[CH:16]=2)=[O:4])[CH:11]=[CH:10][C:9]=1[CH3:12]
Reactant: Cn1ccnc1
Reactant: Cc1ccc(NC(=O)CCl)cc1O
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)C[n+]2ccn(C)c2)cc1O
Product: [Cl-]

Procedure:
36.6 g (0.183 mol) of 2-chloro-N—(3-hydroxy-4-methylphenyl)acetamide and 29.2 ml (0.366 mol) of 1-methyl-1H-imidazole in 180 ml of toluene were refluxed for one and a half hours.
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[F:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([Cl:13])=[C:2]3[Cl:1])=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo [2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 2 hours, after which a solution of 4-(4-fluorobenzoyl) benzyl bromide (645 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 16 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1) to provide the title compound as white powder (371 mg, yield 43%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=CC=1.[NH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].N1C=CC=CC=1.C(OC)(OC)(OC)CCCC.[NH2:35][CH:36]([CH2:39][CH3:40])[CH2:37][CH3:38]>C(#N)C>[NH2:15][C:14]1[N:35]([CH:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[C:4]([CH2:5][CH2:6][CH2:1][CH3:11])=[N:12][C:13]=1[C:16]#[N:17]
Reactant: CCC(N)CC
Reactant: N#CC(N)C#N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCCCC(OC)(OC)OC
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCc1nc(C#N)c(N)n1C(CC)CC
Temperature: 85 °C
Yield: 112.4 %

Procedure:
Aminomalononitrile p-toluenesulfonate (1.00 g, 3.95 mmol), pyridine (0.32 mL, 3.95 mmol), and trimethyl orthovalerate (1.36 mL, 7.90 mmol) were combined in acetonitrile (16 mL), and the solution was heated at 85° C. for 1 hour. 3-Aminopentane (0.7 mL, 6 mmol) was added, and the reaction was heated for 1 hour and ten minutes and then allowed to cool to room temperature overnight. The solvent was removed under reduced pressure, and the resulting oil was partitioned between aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate layer was separated and washed with aqueous sodium bicarbonate, water, and brine. The combined aqueous fractions were extracted with ethyl acetate, and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1.04 g of crude 5-amino-2-butyl-1-(1-ethylpropyl)-1H-imidazole-4-carbonitrile as a brown oil. 1H-NMR (300 MHz, CDCl3) δ 3.90-3.78 (m, 1H), 3.71 (br s, 2H), 2.55 (m, 2H), 0.95 (t, J=7.3, 3H), 0.86 (t, J=7.4, 6H); MS (ESI) m/z (M+1)+235.
Reaction SMILES: Cl[CH2:2][C:3]([CH2:5]Cl)=O.[NH2:7][C:8]1[S:9][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:12]=1.[CH3:20][CH2:21][OH:22]>>[CH2:21]([O:22][CH2:5][C:3]1[N:7]=[C:8]2[N:12]([CH:2]=1)[CH:11]=[C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:9]2)[CH3:20]
Reactant: CCO
Reactant: CCOC(=O)/C=C/c1cnc(N)s1
Reactant: O=C(CCl)CCl
Product: CCOCc1cn2cc(/C=C/C(=O)OCC)sc2n1
Temperature: 80 °C

Procedure:
1,3-Dichloroacetone (0.252 g, 2 mmol) was added to a solution of (E)-ethyl 3-(2-aminothiazol-5-yl)acrylate (0.199 g, 1 mmol) in EtOH (5 mL). The solution was heated at 80° C. overnight in a closed vial. The reaction mixture was then evaporated and the residue was treated with a saturated NaHCO3 solution (20 mL). It was extracted with EtOAc (30 mL). The organic layer was separated, dried over Na2SO4, filtered and evaporated. The crude was purified by silica gel column chromatography (50-100% gradient of EtOAc in Hexanes) to provide pure (E)-ethyl 3-(6-(ethoxymethyl)imidazo[2,1-b]thiazol-2-yl)acrylate (0.080 g) as a tan solid. ES+(M+H)+281.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=[O:21])[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([O:21][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@@H]3C)nc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Temperature: 0 °C

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (220 mg, 2.78 mmol), followed by dropwise addition of Tf2O (393 mg, 1.39 mmol) with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of ice-water (50 mL), extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (292 mg, crude).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].CC1C=C([OH:18])C=C(C)C=1.CC1C=CC(C)=C(O)C=1O>>[CH3:1][C:2]1[CH:7]=[C:6]([OH:18])[C:5]([CH3:8])=[CH:4][C:3]=1[OH:9]
Reactant: Cc1cc(C)cc(O)c1
Reactant: Cc1ccc(C)c(O)c1
Agent: Cc1ccc(C)c(O)c1O
Product: Cc1cc(O)c(C)cc1O

Procedure:
By following in the same manner as in Example 53, except that 100 g. (819 m. moles) of 2,5-dimethylphenol were used instead of 3,5-dimethylphenol, 1.45 g. (10.5 m. moles) of 3,6-dimethylcatechol and 1.85 g. (13.4 m. moles) of 2,5-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 46.9 percent.
Reaction SMILES: [OH-:1].[K+].C(O)C[OH:5].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]#N)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.Cl>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([OH:5])=[O:1])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: OCCO
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)C1(c2ccc(Br)cc2)CC1
Temperature: 137.5 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of KOH (6.06 g, 0.11 mol) in 10 mL of H2O was added 40 mL of ethylene glycol and 1-(4-bromophenyl)-cyclopropanecarbonitrile (Intermediate 113, 10.0 g, 0.45 mol). This solution was heated to 135-140° C. for 4 h, cooled to room temperature, and then poured into a mixture of 100 mL ice and 10% aqueous HCl. The resulting mixture was allowed to stand overnight at 5° C., the solid was collected by filtration and washed with H2O. The colorless solid was dried under reduced pressure to give 10.6 g (97%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1.C([Li])CCC.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:33]([Sn:28]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:29][CH2:30][CH2:31][CH3:32])[C:2]1[CH:3]=[CH:4][C:5]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)=[N:6][CH:7]=1)[CH2:34][CH2:35][CH3:36]
Reactant: Brc1ccc(I)nc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: O=C1CCC1
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C2(O)CCC2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold (−10° C.) solution of 5-bromo-2-iodopyridine (3.0 g, 10.57 mmol) in tetrahydrofuran (35 mL) was added isopropylmagnesium chloride (5.55 ml, 11.10 mmol, 2 M solution in tetrahydrofuran) dropwise over 10 minutes. The reaction was allowed to warm to 0° C. over 1 hour and then cooled to −10° C. Cyclobutanone (0.792 ml, 10.57 mmol) was added dropwise, and the reaction was warmed to 15° C. over 1 hour to give a homogenous solution. The reaction was cooled to −78° C. (precipitate formed). The reaction was warmed to ˜0° C. and diluted with an additional 50 mL tetrahydrofuran to dissolve the precipitate. The reaction was cooled to −78° C., and n-butyllithium (4.23 ml, 10.57 mmol, 2.5 M in hexane) was added dropwise. The reaction was stirred for 0.5 hours, and tributyltin chloride (2.87 mL, 10.57 mmol) was added dropwise. The reaction was stirred at −78° C. for 15 minutes, and was then quenched by the dropwise addition of saturated aqueous sodium bicarbonate solution. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water, brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a gradient of 0 to 10% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 440.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[N:6]1)[CH3:4].[C:19]([C:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:26]=[C:25]([C:27]([NH:1][CH2:2][C@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=3)=[N:6]2)[CH3:4])=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 56.3 %

Procedure:
(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.29 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (259 mg, 1.68 mmol) using the method of Example 34(d). Crude product was purified twice by CombiFlash (1st column: C-18, eluent: 0-100% MeCN in water; 2nd column: silica, eluent: 0-7% MeOH in DCM) to yield 288 mg (56%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.49 (d, 3H), 2.48 (s, 3H), 3.56-3.73 (m, 2H), 4.60-4.75 (m, 1H), 6.94 (d, 1H), 7.27 (bs, 1H), 7.87 (d, 1H), 7.91-8.01 (m, 2H), 8.08 (dd, 1H), 8.58 (bs, 1H), 14.2 (bs, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:11]([C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 99.5 %

Procedure:
Following procedure A, 2-chloro-5-nitropyridine (300 mg, 1.89 mmol, 1.00 eq) and 3-tert-butylphenol (358 mg, 2.38 mmol, 1.26 eq) were dissolved in DMSO (6 mL). Anhydrous K2CO3 (420 mg, 3.04 mmol, 1.60 eq) was added and the reaction mixture was stirred at room temperature for 70 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100) to afford the title compound as colourless solid (512 mg, 1.88 mmol, 99% yield). Rf=0.37 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C15H17N2O3+ [M+H]+ 273.1234. found: 273.1232. 1H NMR (400 MHz, CDCl3) δ 9.08-9.04 (m, 2H, aromatic H), 8.47 (dd, J=9.1, 2.8 Hz, 1H, aromatic H), 7.39 (t, J=7.9 Hz, 1H, aromatic H), 7.33 (ddd, J=7.9, 1.8, 1.2 Hz, 1H, aromatic H), 7.17 (t, J=2.1 Hz, 1H, aromatic H), 7.01 (dd, J=9.1, 0.5 Hz, 1H, aromatic H), 6.98 (ddd, J=7.9, 2.4, 1.2 Hz, 1H, aromatic H), 1.34 (s, 9H, C(CH3)3). 13C NMR (101 MHz, CDCl3) δ 167.21, 153.88, 152.76, 145.26, 140.31, 134.93, 129.50, 123.17, 118.62, 118.47, 111.28, 35.02, 31.36.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[O:13]CC(C)(C)CO2)=[CH:4][CH:3]=1.C(N(CCCC)CCCC)CCC.CN(C)[CH:43]=[O:44].CC[O:48]CC>C(O)CCC.[C]=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:23]([C:22]1[CH:21]=[C:20]([CH:27]=[CH:26][CH:25]=1)[O:19][CH2:18][CH2:17][CH2:16][C:8]([C:5]1[CH:4]=[CH:3][C:2]([C:43]([OH:44])=[O:48])=[CH:7][CH:6]=1)=[O:13])#[N:24]
Reactant: CCOCC
Reactant: CC1(C)COC(CCCOc2cccc(C#N)c2)(c2ccc(Br)cc2)OC1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: CCCCO
Product: N#Cc1cccc(OCCCC(=O)c2ccc(C(=O)O)cc2)c1

Procedure:
500 mg (1.16 mmol) of 3-[3-[2-(4-bromophenyl)-5,5-dimethyl-1,3-dioxane-2-yl]propoxy]benzonitrile, 260 mg (1.4 mmol) of tributylamine and 42 mg (0.06 mmol) of bis(triphenylphosphine)palladium (II) chloride were stirred in 3 ml of 1-butanol and 5 ml of dimethylformamide at 100° C. in carbon monoxide atmosphere overnight. Ether was added to the reaction liquid. After washing with water, 0.5 N hydrochloric acid, saturated sodium hydrogencarbonate solution and saturated aqueous common salt solution, the reaction mixture was dried over anhydrous magnesium sulfate. The solvent was evaporated. 9 ml of 6 N hydrochloric acid solution and 9 ml of acetic acid were added to the residue, and the resultant mixture was heated under reflux for 4 hours. The solvent was evaporated. Saturated aqueous sodium hydrogencarbonate solution was added to the residue. The resultant mixture was washed with ethyl acetate, and the aqueous layer was made acidic with hydrogen chloride. After the extraction with ethyl acetate, the organic layer was washed with saturated aqueous common salt solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][C:17]#[N:18])[C:4]=2[N:3]=1.N1CCOCC1.Cl.C(Cl)(Cl)Cl>C1COCC1.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[NH:10][C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][C:17]#[N:18])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: ClC(Cl)Cl
Product: N#CCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Reaction time: 2 h
Yield: 24.9 %

Procedure:
A solution of [8-chloro-2,6-dioxo-7-(2-propen-1-yl)-1,2,6,7-tetrahydro-3H-purin-3-yl]acetonitrile (0.084 g, 0.32 mmol) in THF (5 ml) was degassed by the successive application of vacuum and nitrogen pressure to the reaction mixture. The solution was subsequently treated with morpholine (0.3 ml, 3.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.03 mmol). After 2 hours, the mixture was treated with 2M aqueous hydrochloric acid (3 ml) and chloroform (5 ml). The mixture was separated and the organic phase evaporated. The product was purified from the residue using mass-directed HPLC, to afford the title compound as a white solid (0.018 g, 25%). NMR δH (400 MHz, d6-DMSO) 4.95 (s, 2H), 11.49 (s, 1H), 14.63 (br. s, 1H); m/z 226 [MH+].
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC(=O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C:26](=[O:25])[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: O=C1CCNC1
Product: CC(C)(C)c1nc(N2CCC(=O)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and pyrrolidin-3-one. MS (m/e): 385.3 (MH+).