Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](C)[CH:7]=[C:6]2[C:13]1[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][CH:23]=O)[N:20]=[C:15]2[CH:14]=1.[CH3:34]OC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1([CH3:34])[CH:11]=[CH:10][C:9]2[C:5]([C:6]([C:13]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[C:16]4[N:17]=[CH:18][C:19]5[N:20]([CH:23]=[N:22][CH:21]=5)[C:15]=4[CH:14]=3)=[CH:7][N:8]=2)=[CH:4]1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC=O)cnc3n1COCC[Si](C)(C)C)cn2C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC1(C)C=CC2=NC=C(c3cc4c(ncc5cncn54)n3COCC[Si](C)(C)C)C2=C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)formamide (0.10 g, 0.22 mmol) in 1,4-dioxane (4 mL) was treated with Lawesson's Reagent (0.053 g, 0.13 mmol) and heated to about 80° C. in an oil bath for about 15 min. The mixture was cooled and mercuric acetate (0.073 g, 0.23 mmol, Fluka) was added. The mixture was stirred for about 30 min at ambient temperature and another portion of mercuric acetate (0.073 g, 0.228 mmol, Fluka) was added and stirring was continued for about 2 h at ambient temperature. The mixture was diluted with EtOAc (20 mL) and filtered. The solvent was evaporated under reduced pressure then the material was purified by silica gel chromatography eluting with DCM/MeOH (95:5). The material obtained after concentration of the product-containing fractions was further purified by silica gel chromatography eluting with EtOAc to give 7-(5-methoxy-5-methyl-5H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.048 g, 49%): LC/MS (Table 2, Method a) Rt=3.16 min; MS m/z: 448 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:14])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]([CH:12]=[CH2:13])([NH2:11])[CH2:4]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1.C(OCC)C>[CH3:2][C:3]1([CH3:14])[CH2:8][C:7]([CH3:9])([CH3:10])[CH2:6][C:5]([NH:11][C:22](=[O:23])[O:24][CH3:25])([CH:12]=[CH2:13])[CH2:4]1
Reactant: COC(=O)Cl
Reactant: C=CC1(N)CC(C)(C)CC(C)(C)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC1(NC(=O)OC)CC(C)(C)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A mixture of amine hydrochloride 5 (0.25 g, 1.2 mmol) and Na2CO3 (0.73 g, 6.9 mmol) in THF (6 ml) was stirred at room temperature for 1 h. Methyl chloroformate (0.27 ml, 3.45 mmol) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was diluted with diethyl ether (20 ml), filtered and evaporated to the dryness. The crude product was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 10:1) to give 6 (0.24 g, 87%) as a colorless solid with m.p. 61-63° C. 1H-NMR (CDCl3, TMS): 0.92 and 1.15 (total 12H, both s, 3,5-CH3); 1.00-1.40 (4H, m, 4-CH2 and 2,6-CH); 2.00 (2H, d, 14 Hz, 2,6-CH); 3.62 (3H, s, CH3N); 4.72 (1H, br s, NH); 5.00 and 5.06 (total 2H, both d, 10.5 and 17 Hz, ═CH2) and 5.83 ppm (1H, dd, 10.5 and 17 Hz, ═CH).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:23][CH3:24])[C:13]1[N:18]=[C:17]([C:19](=[O:21])[CH3:20])[CH:16]=[C:15]([CH3:22])[N:14]=1>CO>[Br:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:23][CH3:24])[C:13]1[N:18]=[C:17]([C:19](=[O:21])[CH:20]=[CH:4][N:12]([CH3:23])[CH3:13])[CH:16]=[C:15]([CH3:22])[N:14]=1
Reactant: CCN(c1nc(C)cc(C(C)=O)n1)c1ccc(C(C)C)cc1Br
Agent: [Na]
Solvent: CO
Product: CCN(c1nc(C)cc(C(=O)C=CN(C)C)n1)c1ccc(C(C)C)cc1Br
Reaction time: 19 h
Yield: 121.6 %

Procedure:
Sodium (0.08 g, 3.5 mmol) was added to methanol (20 mL) with stirring. After the sodium reacted, a solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6-methyl-pyrimidinamine (1.0 g, 2.67 mmol) in methanol (5 mL) was added and the reaction mixture was stirred for 5 min. Gold's reagent ((dimethylaminomethyleneaminomethylene))dimethyl-ammonium chloride (0.66 g, 4 mmol) was added and stirring was continued for 19 h. The reaction mixture was concentrated in vacuo; the residue was dissolved in chloroform and the solution was washed with a saturated NaHCO3 solution, dried over MgSO4 and filtered solvent removal in vacuo gave a brown solid, which upon trituration with hexanes afforded N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-dimethylaminopropenoyl)-6-methylpyrimidinamine as a yellow solid (700 mg): NMR (CDCl3, 300 MHz): 7.9-7.65 (br s, 1H), 7.5 (s, 1H), 7.25-7.2 (m, 2H), 7.15 (s, 1H), 6.1-5.8 (br s, 1H), 4.3-4.15 (m, 1H), 3.9-3.75 (m, 1H), 3.2-3.0 (br s, 3H), 3.0-2.85 (m, 1H), 2.8-2.6 (br s, 3H), 2.5-2.3 (br s, 3H), 1.35-1.2 (m, 9H); CI-MS: 431, 433 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[CH2:6][OH:7].[H][H]>[Pd].CO>[NH2:11][C:10]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(CO)ccc1N
Yield: 108.8 %

Procedure:
A mixture of 3-methoxy-4-nitrobenzyl alcohol (1.0 g) and 10% palladium on carbon (100 mg) in methanol was stirred for 2 hours under 3 atmospheric pressure of hydrogen. After filtration, the filtrate was concentrated in vacuo to give 4-amino-3-methoxybenzyl alcohol (910 mg) as an oil.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH:5]([CH3:7])[CH3:6].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:11]1([CH2:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH:5]([CH3:7])[CH3:6])[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: c1nc[nH]n1
Reactant: CC(C)C(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)C(C)(C)C(=O)Cn1cncn1
Temperature: 40 °C
Reaction time: 15 h
Yield: 79.2 %

Procedure:
162.5 g (1 mol) of 1-chloro-3,3,4-trimethylpentan-2-one are added dropwise to a suspension of 84 g (1.2 mols) of 1,2,4-triazole and 165.6 g (1.2 mols) of potassium carbonate in 1 liter of ethanol. The mixture is stirred for 15 hours at 40° C., the inorganic precipitate is filtered off under suction, the solvent is distilled off, the precipitate is taken up in 500 ml of methylene chloride, the organic phase is extracted with 1 liter of water, the aqueous phase is extracted with 500 ml of methylene chloride, the methylene chloride phases are combined, and the combined phases are extracted with twice 1 liter of water. The solvent is distilled off from the organic phase. 154.6 g (79.3% of theory) of 1-(1,2,4-triazol-1-yl)-3,3,4-trimethylpentan-2-one are obtained as a colorless oil of refractive index nD20 =1.4827. ##STR16##
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17](=[O:41])[CH2:18][C:19]1[CH:20]=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[CH2:37][NH:38][CH2:39][CH3:40])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:15][O:16][C:17](=[O:41])[CH2:18][C:19]1[CH:20]=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:29][C:28]=2[CH2:37][N:38]([C:8](=[O:9])[C:7]([O:6][C:5]2[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:12])[CH3:11])[CH2:39][CH3:40])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)C(C)(C)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-chloro-phenoxy)-2-methyl-propionyl chloride (0.58 mmol) in CH2Cl2 was added (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.200 g, 0.52 mmol) in triethylamine (0.17 mL, 1.23 mmol), and the reaction was stirred at room temperature for 30 minutes. The mixture was concentrated and purified by silica gel chromatography (10-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[N:13]=[C:12]2[CH3:19])[CH:5]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH3:21])[CH:24]=3)[N:13]=[C:12]2[CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(O)cc2=O)c1
Reactant: COc1cccc(CBr)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(OC)c3)cc2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a solution of Intermediate 2 (460 mg, 1.68 mmol) in N,N-dimethylformamide (2 mL) was added 3-methoxybenzyl bromide (0.23 mL, 1.68 mmol), potassium carbonate (350 mg, 2.53 mmol) and 18-crown-6 (40 mg). The slurry was stirred at ambient temperature for one hour. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a white semi-solid (226 mg, 34% yield). MS (M+H): 395
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:7])[C:4](Cl)=[O:5].[NH:8]([C:10]1[C:18]2[O:17][CH:16]([CH3:19])[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)[NH2:9].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:19][CH:16]1[CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:8][NH:9][C:4]([N:3]([O:2][CH3:1])[CH3:7])=[O:5])[C:18]=2[O:17]1
Reactant: CON(C)C(=O)Cl
Reactant: CC1Cc2cccc(NN)c2O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)NNc1cccc2c1OC(C)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.9 g of N-methoxy-N-methylcarbamic chloride was added, drop-by-drop (over 5 minutes) to a mixture of 6.6 g of 1D, 125 ml of THF and 5.2 g of N,N-diisopropyl-N-ethylamine, at -10° C. The mixture was stirred for 1 hour at 0° C., and then mixed with ice water. The resulting mixture was extracted with ether, and extract was dried (MgSO4), filtered and the solvent was evaporated, to give 1-(2,3-dihydro-2-methylbenzofuran-7-yl)-4-methoxy-4-methylsemicarbazide (1E), as an amber syrup.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[N:10]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N+:11]=[N-:12].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].Cl.[Na+].[Cl-]>CC(O)(C)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH2:13]([N:10]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9])[N:12]=[N:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#CCCCCCCO
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Product: OCCCCCCc1cn(Cc2ccccc2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oct-7-yn-1-ol (0.948 g, 7.51 mmol) was dissolved in tBuOH (100 mL) and water (100 mL) to give a colourless solution. (Azidomethyl)benzene (1 g, 7.51 mmol), copper (II) acetate (0.136 g, 0.751 mmol) and sodium L-ascorbate (0.298 g, 1.502 mmol) were added. The reaction was left to stir overnight at room temperature, then was acidified to pH1 using 6M HCl. The mixture was saturated with solid NaCl and concentrated under pressure to give a green slurry. This was extracted with EtOAc, and the organics were separated, dried over MgSO4, and concentrated under reduced pressure. The resulting oil was dissolved in methanol and stirred with celite/charcoal. The mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28]([NH2:31])(=[O:30])=[O:29]>C(N(C(C)C)C(C)C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28]([NH2:31])(=[O:30])=[O:29])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Reactant: NS(=O)(=O)CCCCCCCl
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1
Yield: 95.6 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (500 mg, 1.74 mmol) and 6-chlorohexanesulfonamide (383 mg, 1.92 mmol) synthesized referring to a process described in J. Org. Chem. 52, 2162 (1987) were refluxed in N-ethyldiisopropylamine (5 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (100:3), to give 6-[4-[(3-chlorophenyl)phenylmethyl]1-piperazinyl]hexanesulfonamide (749 mg) as a colorless oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 95.4%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:24]([CH2:31][CH3:32])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[CH:43][C:44]([CH:47]=[O:48])=[N:45][CH:46]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH2:31]([N:24]([CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:4]1[C:5]([CH3:23])=[C:6]([CH:22]=[C:2]([C:41]2[CH:46]=[N:45][C:44]([CH:47]=[O:48])=[CH:43][CH:42]=2)[CH:3]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:32]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: CC1(C)OB(c2ccc(C=O)nc2)OC1(C)C
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
Product: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 66.5 %

Procedure:
A solution of 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.4 g, 0.793 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinaldehyde (0.28 g, 1.19 mmol) and tetrakis (0.091 g, 0.079 mmol) in dioxane (5 mL) was purged with argon for 10 min. To this, aq. Na2CO3 (0.301 g, 2.83 mmol) was added and again degassed for 10 min. Reaction mixture was heated at 100° C. for 16 h. On completion, it was concentrated to obtain crude material which was column purified to afford the title compound (0.28 g, 66.50%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14]>O1CCOCC1>[CH3:11][C:4]1[N:3]=[C:2]([NH:15][CH2:12][CH2:13][CH3:14])[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=1
Reactant: Cc1cc(C(=O)O)nc(Cl)n1
Reactant: CCCN
Solvent: C1COCCO1
Product: CCCNc1nc(C)cc(C(=O)O)n1

Procedure:
A solution of 2-chloro-6-methylpyrimidine-4-carboxylic acid (100 mg, 0.58 mmol) and propylamine (0.48 mL) in dioxane (1 mL) is stirred at 70° C. for 18 h. The reaction mixture is concentrated and purified by prep. HPLC (X-Bridge) to give 6-methyl-2-propylamino-pyrimidine-4-carboxylic acid (81 mg) as a yellow crystalline solid; LC-MS: tR=0.56 min, [M+H]+=196.08; 1H NMR (D6-DMSO): δ 0.89 (t, J=7.3 Hz, 3H), 1.53 (m, 2H), 2.32 (s, 3H), 3.25 (m, 2H), 6.92 (s, 1H), 7.36 (s br, 1H), 13.2 (s br, 1H).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:16][C:17]1[N:18]=[C:19]([CH:22](O)[CH2:23][CH2:24][CH2:25][N:26]2[C:34]([C:35]3[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=3)[C:38]#[N:39])=[C:33]3[C:28]([N:29]([CH3:46])[C:30](=[O:45])[N:31]([CH3:44])[C:32]3=[O:43])=[CH:27]2)[S:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:16][C:17]1[N:18]=[C:19]([CH:22]2[C:27]3[N:26]([C:34]([C:35]4[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=4)[C:38]#[N:39])=[C:33]4[C:32](=[O:43])[N:31]([CH3:44])[C:30](=[O:45])[N:29]([CH3:46])[C:28]4=3)[CH2:25][CH2:24][CH2:23]2)[S:20][CH:21]=1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCCC(O)c3nc(Cl)cs3)cc2n(C)c1=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)CCC3
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
Trifluoromethanesulfonic anhydride (3.95 ml, 23.41 mmol) was added dropwise to a solution of 3-(6-(4-(4-chlorothiazol-2-yl)-4-hydroxybutyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (5 g, 10.64 mmol) and triethylamine (3.56 ml, 25.5 mmol) in DCM (213 mL) at −78° C. The mixture was stirred for 1 min at −78° C. The reaction was quenched with saturated aqueous NaHCO3(aq) (100 mL) and extracted with DCM (3×100 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to afford crude racemic 3-(10-(4-chlorothiazol-2-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 16.2 %

Procedure:
Example 15 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (3,4-dichlorophenyl)acetic acid (0.041 g) to give the title compound (0.015 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(Br)cc1OC
Solvent: CC(=O)O
Product: COc1cc(Br)c([N+](=O)[O-])cc1OC
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Bromoveratrole (50 g, 0.23 mol) was added dropwise at 6°-9° to a stirred solution of 175 ml of concentrated nitric acid and glacial acetic acid (525 ml). After stirring at 6°-11° for 1.5 hours, the mixture was poured into 2.5 liters of ice-water. The light yellow solid was filtered after 0.5 hour, washed with water, and air-dried (62.5 g); m.p. 120°-122° (s. 118°). Following crystallization from 400 ml of ethanol, the title A compound as a light yellow product weighed 50.0 g; m.p. 121°-123°. Lit. m.p. 120°-122°, 122°-124° (J. Org. Chem., 25, 724 (1960).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:14][CH2:15][CH2:16][CH3:17])[NH:11][C:12]=1[Cl:13])=[O:7])[CH3:4].[Br:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH:24](Cl)[CH2:23][CH2:22]2>O1CCOCC1>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:14][CH2:15][CH2:16][CH3:17])[N:11]([CH:24]2[C:25]3[C:21](=[CH:20][C:19]([Br:18])=[CH:27][CH:26]=3)[CH2:22][CH2:23]2)[C:12]=1[Cl:13])=[O:7])[CH3:4]
Reactant: ClC1CCc2cc(Br)ccc21
Reactant: CCCCc1nc(C(=O)OCC)c(Cl)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCc1nc(C(=O)OCC)c(Cl)n1C1CCc2cc(Br)ccc21
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
Sodium hydride (64 mg, 2.8 mmol) was added to 2-butyl-5-chloro-1H-imidazole-4-carboxylic acid ethyl ester (647 mg, 2.8 mmol) in anhydrous 1,4-dioxane (3 mL). After 0.25 hour, a solution of 5-bromo-1-chloro-indane (696 mg, 3.0 mmol)in dioxane (2.0 mL) was added. The reaction mixture was heated at 110° C. for 20 hours, cooled to room temperature and concentrated in vacuo. The crude residue was chromatographed on SiO2 -gel using 50% ethyl acetate/hexanes to give 486 mg of a colorless oil. 1H NMR (250 MHz, d6 -DMSO): d 7.55 (s, 1 H), 7.36 (d, 1 H), 6.86 (d, 1 H), 6.10 (t, 1 H), 4.20 (q, 2 H), 3.25-2.65 (m), 1.65 (m, 2 H), 1.35 (m, 2 H), 122 (t,3H), 0.90 (t, 3 H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][OH:9])([O-])=O.O.[H][H]>[Pt].C(O)(C)C>[NH2:1][C:4]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][OH:9]
Reactant: O=[N+]([O-])c1ccc(OCCO)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(C)O
Solvent: O
Product: Nc1ccc(OCCO)c(N)c1
Temperature: 20 °C
Yield: 127.9 %

Procedure:
A 1 l autoclave reactor was filled with 120 g of 2-(2′,4′-dinitrophenoxy)ethanol, 3 g of a 1% platinum/carbon catalyst which included 50% water, and 400 ml of isopropanol. At a hydrogen pressure of 1 MPa and a temperature of 100° C., hydrogenation was carried out for 10 h. The system was then cooled to 20° C., and the reaction mixture was added dropwise under a nitrogen atmosphere through a filter into an initial charge of 240 g of 37% strength hydrochloric acid which had been previously flushed repeatedly with nitrogen. The resulting suspension was heated at reflux temperature for about 30 min and then cooled to 10° C. The product obtained after filtration was washed once with isopropanol to give 113.1 g of 2-(2′,4′-diamino-phenoxy)ethanol (89.1% yield) in 98% purity. Measuring the degrees of transmission of a 0.1% strength solution of the product in water in accordance with DIN 55945 gave, as results, Tx=99.4, Ty=98.9 and Tz=98.2.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][NH:28][CH3:29])=[CH:19]1.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:28]([CH3:29])[CH2:27][C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]([CH3:17])[CH:19]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: CNCc1cn(C)c2ccccc12
Reactant: Nc1ccc(C=CC(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1ccc(N)nc1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
EDC (0.35 g, 1.89 mmole) was added to a solution of 3-(6-aminopyridin-3-yl)acrylic acid (0.31 g, 1.89 mmole). 1-methyl-3-(methylaminomethyl)-1H-indole (0.30 g, 1.72 mmole), HOBt.H2O (0.24 g, 1.89 mmole) and diisopropylethylamino (0.60 mL, 3.44 mmole) in DMF (20 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (5% MeOH/CHCl3) gave the title compound (0.30 g, 55%) as a light yellow solid: MS (ES) m/e 321 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[CH:12][C:13]([N:16]3[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[NH:18][C:17]3=[O:24])=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:25]I>>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[CH:12][C:13]([N:16]3[CH2:21][CH2:20][C:19]([CH3:22])([CH3:23])[N:18]([CH3:25])[C:17]3=[O:24])=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1(C)CCN(c2cnc(C#Cc3cccc(F)c3)cn2)C(=O)N1
Product: CN1C(=O)N(c2cnc(C#Cc3cccc(F)c3)cn2)CCC1(C)C

Procedure:
The title compound, a light yellow solid, MS: m/e=339.1 (M+H+), was prepared in accordance with the general method of Example 165, by alkylation of 1-(5-((3-fluorophenyl)ethynyl)pyrazin-2-yl)-4,4-dimethyltetrahydropyrimidin-2(1H)-one (Example 166) with methyl iodide.