Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:17])C(OCC)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][NH:19][CH2:20][CH2:21][NH2:22]>CO>[CH3:18][N:19]1[CH2:20][CH2:21][N:22]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[C:11]1=[O:17]
Reactant: CCOC(=O)C(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CNCCN
Solvent: CO
Product: CN1CCN=C(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with ethyl 4-nitrophenylpyruvate (5.00 g, 22.4 mmol) and anhydrous methanol (112 mL). The resulting solution was cooled to 0° C. with an ice bath, and N-methylethylenediamine (1.66 g, 22.4 mmol) was added dropwise. After addition was complete, the bath was removed and the reaction was stirred at room temperature for 18 h. After this time the reaction was concentrated under reduced pressure. The residue was purified by column chromatography to afford 1-methyl-3-(4-nitrophenyl)-5,6-dihydropyrazin-2(1H)-one (102h) in 20% yield (1.02 g) as a yellow solid: mp 191-192° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.26 (d, 2H, J=6.9 Hz), 8.05 (d, 2H, J=7.2 Hz), 3.94 (t, 2H, J=6.3 Hz), 3.55 (t, 2H, J=6.3 Hz), 3.02 (s, 3H); MS (ESI+) m/z 234.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1.C(O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH2:8][CH:7]([OH:15])[C:6]=2[CH:16]=1
Reactant: O=C1Cn2cccc2Sc2ccc(Cl)cc21
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: OC1Cn2cccc2Sc2ccc(Cl)cc21
Yield: 88 %

Procedure:
The titre compound was obtained starting from 9b (112 mg, 0.45 mmol) using the procedure described above: 88% yield; melting point 118-119° C. (ethanol); IR (CHCl3) 3300 cm−1; 1H NMR (CDCl3) δ7.48 (d, 1H, J=2.1 Hz); 7.32 (d, 1H, J=8.0 Hz), 7.15 (dd, 1H, J=8.1, 2.1 Hz), 6.88 (m, 1H), 6.34 (m, 1H), 6.11 (m, 1H), 5.02 (m, 1H), 4.85 (dd, 1H, J=13.9, 1.9 Hz), 4.29 (dd, 1H, J=13.9, 6.6 Hz), 2.10 (dd, 1H, J=9.6 Hz). Anal. (C12H10CINOS): C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].Br[C:13]#[N:14]>C(O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:13]([NH2:14])=[N:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: N#CBr
Solvent: CCO
Solvent: O
Product: Nc1nc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C

Procedure:
7.6 g (50 mmol) of 4-nitro-ortho-phenylenediamine was dissolved were dissolved in 100 mL of ethanol and 20 mL of H2O. 7.9 g (75 mmol) of BrCN was added in one portion to this stirring solution, and the resulting mixture was heated under reflux for 1.0 h. The reaction mixture was cooled to room temperature, concentrated to 20 mL then neutralized with saturated NaHCO3 solution to pH 8, and resulting solid 5-nitro-1H-benzoimidazol-2-ylamine collected via filtration was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]C(=O)[CH2:15][CH2:14]1)(=[O:12])=[O:11].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO[CH:44]([O:47][CH3:48])[O:45][CH3:46].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:44]([O:45][CH3:46])([O:47][CH3:48])[CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: COC(OC)OC
Reactant: CCOC(=O)C1=CC(=O)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: CCOC(=O)C1=CC(OC)(OC)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Yield: 87.8 %

Procedure:
6.1 g (16.2 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 was dissolved in 120 ml of methanol and 4.1 g (16.2 mmol) of pyridinium p-toluenesulfonate and 8.86 ml (81.0 mmol) of trimethoxymethane were sequentially added thereto with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 6.0 g of the title compound as a white powder (yield: 88%).
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH3:6])=[O:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=O)=[CH:10][CH:9]=1.CI>O1CCCC1.CO.CN(C)C=O.O>[CH3:18][O:17][CH:15]=[C:14]([C:11]1[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC=O
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: COC=C(C(=O)OC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Suspend sodium hydride (3.4 g, 142 mmol) in anhydrous tetrahydrofuran (100 mL). Cool in an ice/water bath. Add methyl formate (8.8 mL, 142 mmol), methanol (1 drop), and methyl 4-fluorophenylacetate. Warm slowly to ambient temperature. After 18 hours, concentrate in vacuo to give a residue. Dissolve the residue in dimethylformamide and cool in an ice/water bath. Add methyl iodide (8.0 mL, 130 mmol). Warm slowly to ambient temperature. After 3.5 hours, pour the reaction mixture into water and extract twice with ether. Dry the combined organic layers over MgSO4 filter, and concentrate in vacuo to give the title compound: Rf =0.52 (silica gel, 2/1 hexane/ethyl acetate).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[C:16]([OH:23])[C:15]=1[CH2:24][CH2:25][CH3:26].[C-:27]#[N:28].[Na+].[I-].[Na+]>CN(C)C=O>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][C:27]#[N:28])=[C:15]([CH2:24][CH2:25][CH3:26])[C:16]=1[OH:23])(=[O:22])[CH3:21]
Reactant: [C-]#N
Reactant: CCCc1c(OCCOCCOCCOCCBr)ccc(C(C)=O)c1O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOCCOCCC#N)ccc(C(C)=O)c1O
Yield: 98.8 %

Procedure:
A solution of 2.23 g of 1-[4-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-hydroxy-3-propylphenyl]ethanone, 0.34 g of sodium cyanide and 0.77 g of sodium iodide in 40 ml of dimethyl formamide was stirred and heated at 80° for 70 minutes. The solvent was removed in vacuo, water was added to the residue and the product was extracted with ether. The dried (over magnesium sulfate) extract was concentrated in vacuo to give 1.93 g of crude 3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]propanenitrile. The low resolution mass spectrum showed the molecular ion at m/e 379.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15][CH2:14]1.[CH3:21][N:22]1[C:26]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=2)=[N:25][N:24]=[N:23]1>C1COCC1.C(OCC)(=O)C.O>[CH3:21][N:22]1[C:26]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][C:13]3([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15][CH2:14]3)=[CH:29][CH:28]=2)=[N:25][N:24]=[N:23]1
Reactant: COC(=O)C1CCC1
Reactant: Cn1nnnc1-c1ccc(CCl)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccc(-c3nnnn3C)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
A solution of diisopropylamine (1.05 mL, 7.5 mmol) in THF (5 mL) was colled to −10° C. and a solution of n-butyl lithium (2.9 mL, 7.25 mmol) in hexanes was added dropwise while maintaining the temperature below 0° C. After addition, the solution was stirred for 30 min at 0° C. The solution was cooled to −70° C. and a solution of methyl cyclobutane carboxylate (0.57 g, 5 mmol) in THF (2 mL) was added dropwise maintaining the internal temperature between −60 to −70° C. After addition, the reaction mixture was stirred for 30 min at −50 to −60° C. Then, a solution of 4-(1-methyltetrazol-5-yl)benzyl chloride (0.94 g, 4.5 mmol) in THF (5 mL) was added dropwise and the reaction mixture was stirred for 1 h at −60 to −70° C. Then, it was allowed to warm to room temperature and stirred overnight at which point TLC analysis indicated the absence of 4-(1-methyltetrazol-5-yl)benzyl chloride (Note: the product and 4-(1-methyltetrazol-5-yl)benzyl chloride has the same Rf value, however they were differentiated by spraying with PMA). The mixture was poured into a mixture of water (70 mL) and ethyl acetate (70 mL). An emulsion formed and was filtered through celite. The resulting two layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solution was concentrated under vacuum and the residue was purified by silica gel chromatography eluting with 1:2 ethyl acetate:hexane to give methyl 1-[[4-(1-methyltetrazol-5-yl)phenyl]methyl]cyclobutane carboxylate (0.42 g, 32%) as a syrup. HR MS: obs. mass, 301.1668. Calcd mass, 301.1664.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1.CI>O>[CH3:3][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)C(O)c1ccc(-c2ccccc2OC)cc1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 0.01 moles of sodium hydride in 25 ml. of dry dimethylformamide which has been cooled to 0°C is added dropwise a solution of 0.01 moles of ethyl 2'-hydroxy-4-biphenylylglycolate in 10 ml. of dimethylformamide. The reaction mixture is stirred for 15 minutes and 0.015 moles of methyliodide is then added dropwise. The mixture is allowed to stir overnight at room temperature. 200 ml. of water is added and the resulting mixture is extracted well with ether. The ether extract is washed with water, dried over sodium sulfate, evaporated to dryness and distilled to obtain ethyl 2'-methoxy-4-biphenylylglycolate.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:8](=[O:15])[NH:9][C:10](SC)=[N:11][CH:12]=2)=[CH:4][CH:3]=1.S1C=CN=C1CSCCN.Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8](=[O:15])[NH:9][CH:10]=[N:11][CH:12]=2)=[CH:16][CH:17]=1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Agent: Cl
Agent: NCCSCc1nccs1
Product: O=c1[nH]cncc1Cc1ccc(Cl)cc1

Procedure:
An intimate mixture of 5-(4-chorobenzyl)-2-methylthio-4-pyrimidone (1.36 g) and 2-(2-thiazolylmethylthio)ethylamine (0.9 g) was heated at 130°-135° for 31/2 hours. After cooling the reaction mixture was treated with 2N hydrochloric acid. Evaporation to dryness followed by recrystallisation from isopropanol/methanol gave 2-[2-(2-thiazolyl-methylthio)ethylamino[-5-(4-chlorobenzyl)-4-pyrimidone monohydrochloride, m.p. 172.5°-174.5°.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.C(N(CC)CC)C.CS(C)=[O:39]>F[B-](F)(F)F.[Ag+]>[OH:39][C:3]1([CH3:2])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4][CH2:29]1
Reactant: CS(C)=O
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: CC1(O)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reaction time: 3 h
Yield: 58 %

Procedure:
2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) was dissolved in absolute dimethylsulfoxide (5 ml). To this solution was added silver fluoroborate (0.20 g) and then the mixture was stirred under shielding from light for 3 hours at room temperature. To the solution was added a solution of triethylamine (0.1 g) in dimethylsulfoxide (0.5 ml) and the solution was further stirred for 5 hours and then allowed to stand overnight at room temperature. Precipitates were filtered off and the filtrate was poured into ice-water and then extracted with ethyl acetate. The extract was washed with water and dried. The residue obtained by distilling off the solvent under reduced pressure was crystallized by a small amount of ether to give colorless crystals of 2,2,2-trichloroethyl 3-hydroxy-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (280 mg) (58%). This substance was recrystallized from a mixed solvent of benzene-n-hexane to give colorless needles melting at 169° to 171° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[C:18](Cl)=[N:19][CH:20]=1>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[C:18]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[N:19][CH:20]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a suspension of sodium hydride (5.08 g, 127 mmol) in dimethylformamide (75 mL) was added diethyl malonate (19.26 mL, 127 mmol) at 0° C. The solution was then stirred at ambient temperature for 30 minutes and a solution of 5-bromo-2-chloro-3-nitropyridine (30 g, 127 mmol) in dimethylformamide (75 mL) was added dropwise. The dark brown mixture was then stirred at 100° C. for 2 hours before being cooled to ambient temperature and quenched with a saturated solution of ammonium chloride (500 mL) at 0° C. The mixture was extracted with ethyl acetate (3×500 mL) and the combined organics were dried over magnesium sulfate. The solvent was removed in vacuo to give a dark brown oil which was purified by flash column chromatography (10% ethyl acetate/hexane) to afford diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate as a brown solid (31.8 g, 88 mmol, 69%). 1HNMR (400 MHz, CDCl3): δ ppm 8.86 (s, 1H), 8.61 (s, 1H), 5.44 (1H, s), 4.29 (q, 4H), 1.27 (t, 6H).
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](=[O:25])[NH:14][C@H:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:11][Si:10]([CH3:27])([CH3:26])[CH2:9]1)=O)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[CH3:26][Si:10]1([CH3:27])[CH2:11][C@@H:12]([C:13]([NH:14][C@H:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)=[O:25])[NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[Si](C)(C)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si]1(C)CN[C@H](C(=O)N[C@@H]2CCCc3ccccc32)C1
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of (R)-tert-butyl-3,3-dimethyl-5-((R)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)-1,3-azasilolidine-1-carboxylate (4.9 g, 12 mmol) in CH2Cl2 (50 mL) was added TFA (7 mL) at rt. After 4 h, the reaction mixture was concentrated in vacuo to obtain (R)-3,3-dimethyl-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-azasilolidine-5-carboxamide TFA salt (5.0 g, 12 mmol, 100% yield) as a white solid, which was used directly in the next step. 1H NMR (400 MHz, CD3OD) δ 7.14-7.25 (m, 4H), 5.12 (t, J=5.5 Hz, 1H), 4.0 (dd, J=11.9, 6.6 Hz, 1H), 2.79 (m, 2H), 2.76 (d, J=4.5 Hz, 1H), 2.45 (dd, J=15, 4.5 Hz, 1H), 1.85-2.06 (m, 4H), 1.53 (dd, J=15, 6.8 Hz, 1H), 1.08 (dd, J=15, 4.5 Hz, 1H), 0.41 (3H), 0.38 (s, 3H); MS(ESI+) m/z 289 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:9][CH:10]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]#[N:22]>CC(C)=O>[CH:7]([C:6]1[CH:9]=[CH:10][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][C:5]=1[O:11][CH2:20][C:21]#[N:22])=[O:8]
Reactant: N#CCCl
Reactant: CN(C)c1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)c1ccc(C=O)c(OCC#N)c1

Procedure:
82 parts of 4-dimethylaminosalicylaldehyde is dissolved in 500 parts by volume of acetone, then 96 parts of potassium carbonate and 45 parts of chloroacetonitrile are added and the whole is boiled under reflux for 10 hours. After the solution has been filtered it is concentrated and the crystals deposited are recrystallized from benzene with the addition of animal charcoal. 36 parts of colorless crystals of 2-formyl-5-dimethylaminophenoxyacetonitrile is obtained with a melting point of 124° to 125°C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:3].[NH3:11]>CC(C)=O>[CH3:1][C:2]1([CH3:3])[NH:11][C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4]1
Reactant: N
Reactant: CC(C)=CC(=O)C=C(C)C
Solvent: CC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1
Yield: 70 %

Procedure:
Heinz Annalen der Chemie 203 336 (1880) converts acetone to phorone in about 30% yield, and reacts phorone with ammonia to form triacetone amine in 70% yield.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:25]=[CH:26][C:27]2[C:28]3[S:36][C:35]([CH2:37][OH:38])=[N:34][C:29]=3[CH:30]=[N:31][C:32]=2[CH:33]=1>ClCCl>[Br:23][C:24]1[CH:25]=[CH:26][C:27]2[C:28]3[S:36][C:35]([CH:37]=[O:38])=[N:34][C:29]=3[CH:30]=[N:31][C:32]=2[CH:33]=1
Reactant: OCc1nc2cnc3cc(Br)ccc3c2s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1nc2cnc3cc(Br)ccc3c2s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
Dess-Martin periodinane (2.16 g, 5.08 mol, [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one]) was added to a suspension of (7-bromo[1,3]thiazolo[4,5-c]quinolin-2-yl)methanol (prepared in Part F of Example 2, 1.0 g, 3.4 mmol) in dichloromethane (30 mL), and the resulting suspension was stirred at room temperature for 1.5 hours. The reaction mixture was filtered to isolate solid, which was washed with dichloromethane and diethyl ether to provide 877 mg of 7-bromo[1,3]thiazolo[4,5-c]quinoline-2-carbaldehyde as a brown solid.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:10])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.[Fe](Cl)(Cl)Cl>[C:1]([NH:4][CH:5]([CH2:10][N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: CN1CCNCC1
Agent: Cl[Fe](Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(CN1CCN(C)CC1)NC(C)=O
Temperature: 20 °C
Reaction time: 66 h

Procedure:
To a solution of 8.57 g of methyl 2-acetamidoacrylate in 500 mL of dichloromethane stirred under inert atmosphere, about 6.65 mL of N-methylpiperazine are added, then 0.97 g of iron trichloride are added, and the mixture is stirred at a temperature of about 20° C. for 66 hours. Then, 300 mL of an aqueous solution of sodium sulfate are dropped to the reaction medium while stirring the reaction mixture and the mixture filtered through Celite. After separation of the phase by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated in a vacuum oven under reduced pressure (2 kPa) at a temperature of about 40° C. in order to obtain an orange-colored liquid. The aqueous phase is extracted with 3 times 150 mL of dichloromethane and all of the organic extracts are collected, dried over sodium sulfate, then concentrated under reduced pressure (2 kPa) at a temperature of about 20° C. in order to obtain an yellow oil. Both of the organic extracts as described above are combined and purified by chromatography under argon pressure (50 kPa), on a column of silica gel (particle size 40-63 μm; diameter 5 cm; height 25 cm), eluting with successive mixtures of 20% dichloromethane/methanol/aqueous ammonia (99/1/0, 97/3/0, 90/10/0.25, 80/20/0.25 by volume). The fractions containing the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 30° C. About 3.3 g of methyl 2-(acetylamino)-3-(4-methyl-piperazinyl)propanoate are obtained in the form of a yellow liquid. [Infrared spectrum CCl4 3437; 3318; 2941; 2798; 1749; 1685; 1499; 1458; 1374; 1286; 1204; 1168 and 1014 cm−1]
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH2:13][NH:12][CH2:11][CH2:10][C:9]=3[C:5]=2[C:4]([NH:14][C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)=[N:3][CH:2]=1.Cl.[CH3:23][N:24]([CH3:31])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[CH3:23][N:24]([CH3:31])[CH2:25]/[CH:26]=[CH:27]/[C:28]([N:12]1[CH2:11][CH2:10][C:9]2[C:5]3[C:4]([NH:14][C:15]4[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=4)=[N:3][CH:2]=[N:1][C:6]=3[S:7][C:8]=2[CH2:13]1)=[O:29]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Oc1cccc(Nc2ncnc3sc4c(c23)CCNC4)c1
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cccc(O)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from 3-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol from Example 16A (52 mg, 0.18 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (41 mg, 0.25 mmol) to yield 7 mg (9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:11]=[C:10]2[NH:35]C(=O)C(F)(F)F)=[O:6].C(O)(C)C.O1CCCC1>C(N(CC)CC)C>[NH2:35][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:5]([C:4]3[CH:42]=[C:43]([F:45])[CH:44]=[C:2]([F:1])[CH:3]=3)=[O:6])[CH:8]=2)[N:12]([C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:11]=1
Reactant: O=C(c1cc(F)cc(F)c1)c1ccc2c(c1)c(NC(=O)C(F)(F)F)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C(=O)c3cc(F)cc(F)c3)cc12
Yield: 98.9 %

Procedure:
N-[5-(3,5-Difluoro-benzoyl)-1-trityl-1H-indazol-3-yl]-2,2,2-trifluoro-acetamide (6.12 g, 10 mmol) was heated at 100° C. in a mixture isopropanol/tetrahydrofuran 8:2 (100 mL) and triethylamine (12.2 mL) for 48 hours. The volatiles were partially evaporated and the resulting mixture cooled and filtered. The solid was washed with diethyl ether. After drying under vacum at 70° C. the title compound was obtained as a white solid (5.1 g, 99% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24](I)[CH:25]=2)[N:20]=[CH:19][N:18]=1.C(NC(C)C)(C)C>C1COCC1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[Cl:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ncnc2ccc(I)cc12
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ccc3ncnc(Cl)c3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (1.12 g, 5.35 mmol), 4-chloro-6-iodoquinazoline (1.35 g, 4.65 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.16 g, 0.23 mmol), copper(I) iodide (0.044 g, 0.23 mmol), and diisopropylamine (0.47 g, 4.65 mmol) in anhydrous THF (20 mL) was stirred at room temperature under nitrogen for 2 hours. After concentration, the residue was dissolved in CH2Cl2 (100 mL), washed with aqueous NH4Cl and brine, dried over sodium sulfate, and concentrated to give the crude product as brown oil. Purification by silica gel column using 20% EtOAc in hexane afforded 1.63 g (94%) of the title compound as a sticky, yellow oil: 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.67-1.75 (m, 2H), 1.87-1.92 (m, 2H), 2.84 (m, 1H), 3.20-3.26 (m, 2H), 3.78 (br d, 2H), 7.88 (dd, 1H), 7.97 (d, 1H), 8.26 (d, 1H), 9.00 (s, 1H).