Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.O.[Cu]I>[N:12]1[N:13]([C:2]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[N:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(I)c(C(=O)O)c1
Reactant: c1c[nH]nn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Temperature: 120 °C

Procedure:
A solution of 2-iodo-5-methylbenzoic acid (4.0 g, 15.3 mmol) in DMF (10 mL) was treated with 1,2,3-triazole (2.1 g, 30.5 mmol), Cs2CO3 (9.95 g, 30.5 mmol), CuI (0.145 g, 0.76 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.43 g, 3.05 mmol). The mixture was heated at 120° C. for 10 min in a microwave reactor. The reaction was cooled to room temperature, diluted with water, and washed with EtOAc. The aqueous phase was acidified with 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the faster eluting 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid A-5, followed by the undesired regioisomer isomer, 1-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid. Data for A-5: 1HNMR (500 MHz, DMSO-d6) d 12.98 (br s, 1H), 8.04 (s, 2H), 7.72-7.45 (m, 3H), 2.41 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[C:6](=[O:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: CCOC(=O)c1c(OCC)cc[nH]c1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(OCC)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A mixture of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (60 g, 0.284 mol), 4-fluoro phenylboronic acid (120 g, 0.853 mol), Cu(OAc)2 (113 g, 0.568 mol) and pyridine (88 g, 1.137 mol) in DCM (500 mL) was stirred at RT for 4 h open to air. The reaction mixture was filtered and the solids were washed with water. The filtrate was extracted with DCM (2×250 mL). The combined organics were dried over Na2SO4 and concentrated to afford ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate. The product was carried forward without further purification. (77 g, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[N:20]=2)=[CH:4][CH:3]=1.Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34]([C:37]([F:40])([F:39])[F:38])=[N:35][N:36]=2)[N:33]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:13]3[CH2:18][CH2:17][N:16]([C:28]4[CH:29]=[CH:30][C:31]5[N:32]([C:34]([C:37]([F:38])([F:40])[F:39])=[N:35][N:36]=5)[N:33]=4)[CH2:15][CH2:14]3)[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[N:20]=2)=[CH:6][CH:7]=1
Reactant: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNCC2)n1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)n1

Procedure:
A mixture of 4-[5-(4-fluorophenyl)-3-piperidin-4-ylimidazol-4-yl]-2-methoxypyrimidine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazol-1-yl]piperidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=2)[CH:3]=1.[NH2:24][C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[C:4]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[CH:3]=[C:2]([NH:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1cc(-c2cnn(C)c2)cc(Cl)n1)c1ccc(F)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cc(-c2cnn(C)c2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
1.34 g of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine synthesized by the same method as in Steps 1 and 2 of Example 4, 423 mg of 2-aminopyrazine, 154 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 544 mg of sodium t-butoxide and 74 mg of tris(dibenzylideneacetone)dipalladium were added in turn to 13 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 1.26 g of (S)—N2-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow powder. Subsequently, 1.0 g of the obtained (S)—N2-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine was dissolved in 1 ml of methanol, and 300 mg of maleic acid was added. The reaction solution was added with 6 ml of ethyl acetate, and stirred at room temperature for 2 hours. The precipitated solid was filtered to obtain 1.1 g of the objective compound as white powder.
Reaction SMILES: Cl[C:2](Cl)([C:12]([CH3:14])=[O:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[H][H]>O.C1(C)C=CC=CC=1.[H][H]>[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])[CH2:2][C:12]([CH3:14])=[O:13]
Reactant: CC(=O)C(Cl)(Cl)C(=O)Nc1ccccc1
Reactant: [H][H]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(=O)Nc1ccccc1

Procedure:
2.46 g (0.01 mole) of α,α-dichloroacetoacetanilide was dissolved in 20 ml of water and 30 ml of toluene, and dehalogenated with hydrogen using 5% Pd/C as catalyst. Hydrogen was allowed to react until no more would be absorbed. The first equivalent (251 ml at 739 mm pressure and 25° C.) was absorbed in 50 minutes (a rate of about 5 ml/min) whereas the 274 ml (second equivalent) was absorbed at the much slower rate of about 0.9 ml/min. On the basis of the hydrogen absorbed, it was concluded that the dehalogenation had proceeded to remove both chlorines and hence to give acetoacetanilide. This was confirmed by filtering off the catalyst, separating off the water phase and finally isolating the product from the toluene. Obtained were 1.57 g or 89% of acetoacetanilide, mp 79°-84° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-])=O)[CH:10]=1)=O)([O-])=O.[H][H].N>[Pd].C(O)C>[CH:13]1[CH:12]=[C:11]([NH2:16])[CH:10]=[C:9]([CH2:7][C:6]2[CH:19]=[CH:20][CH:21]=[C:4]([NH2:1])[CH:5]=2)[CH:14]=1
Reactant: [H][H]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: N
Solvent: CCO
Product: Nc1cccc(Cc2cccc(N)c2)c1
Yield: 85 %

Procedure:
34.1 g (0.1 mol) of 3,3'-dinitro-4,4'-dichlorbenzophenone, 1.5 g of 5% Pd/C, and 100 ml of ethanol were charged in a closed glass vessel equipped with a thermometer and a stirrer. While stirring the mixture at a temperature of 50° to 60° C., hydrogen was introduced thereinto and 22.9 l (1.02 mol) of hydrogen was absorbed in 7.5 hours. Since no more absorption of hydrogen was observed, the reaction was terminated at this point. The reaction solution was neutralized with 13.4 g (0.22 mol) of 28% aqueous ammonia and filtered to remove the catalyst. The filtrate was concentrated to give 3,3'-diaminodiphenylmethane as a brown oil. A high performance liquid chromatography revealed that the purity was 93.8%.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]#[C:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:9])([CH3:6])[CH3:5].O.O[Li].O>CO>[C:22]1([C:21]#[C:20][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:28])=[O:2])=[O:9])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1C#Cc1ccccc1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(NC(=O)c1ccc2ccccc2c1C#Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.3 %

Procedure:
8 mg 2-{[1-(phenylethynyl)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester were dissolved in 3 ml of MeOH and 1 ml of water was added. After addition of 1.95 mg of LiOH.H2O the reaction was stirred at room temperature for 14 h. Filtration of the crude mixture, RP-HPLC and freeze-drying gave 6.8 mg of 2-{[1-(phenylethynyl)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid (89%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH2:14])[CH:6]=1)=[O:4].[N:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21](O)=[O:22].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:21]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][N:15]=2)=[O:22])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(=O)n(CCN)c1
Reactant: O=C(O)c1cnccn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(=O)n(CCNC(=O)c2cnccn2)c1
Reaction time: 18 h

Procedure:
1-(2-aminoethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid methyl ester (0.396 g, 2.02 mmol) was coupled with 2-pyrazinecarboxylic acid (0.251 g, 2.02 mmol) in a mixture of dichloromethane (34 ml) and dimethylformamide (35 ml) with triethylamine (1.41 ml, 10.1 mmol)and propylphosphonic acid anhydride (0.7 ml, added as a 0.7 ml ethyl acetate solution). After 18 hours, the mixture was concentrated and the residue slurried in dichloromethane and aqueous sodium bicarbonate. The layers were separated and the aqueous layer extracted with dichloromethane (2X) and the combined organic layers dried (Na2SO4). Filtration, concentration, and purification via medium pressure liquid chromotography (silica gel, 5% methanol/dichloromethane) gave the desired product, MP: 195°-197° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH3:13])=[CH:9][C:8]([F:14])=[CH:7][CH:6]=2.[CH:16](O)=O>>[CH3:13][N:12]1[C:11]2[C:10]3[CH:9]=[C:8]([F:14])[CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([CH3:15])[C:2]=2[N:1]=[CH:16]1
Reactant: CNc1c(N)c(C)nc2ccc(F)cc12
Reactant: O=CO
Product: Cc1nc2ccc(F)cc2c2c1ncn2C

Procedure:
Using the method of Example 137, 3-amino-6-fluoro-2-methyl-4-methylaminoquinoline (from example 44) was reacted with formic acid to provide 1,4-dimethyl-8-fluoro-1H-imidazo[4,5-c]quinoline, m.p. 184°-186° C. Analysis: Calculated for C12H10FN3 : %C, 67.0; %H, 4.7; %N, 19.5; Found: %C, 66.6; %H, 4.4; %N, 19.7.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=3)[CH:12]=2)[C@@H:9]([O:28]C(=O)C)[C@H:8]([CH2:32][O:33]C(=O)C)[C@@H:7]([O:37]C(=O)C)[C@@H:6]1[O:41]C(=O)C)(=O)C.[BH4-].[Na+]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:10]2[C@@H:9]([OH:28])[C@H:8]([CH2:32][OH:33])[C@@H:7]([OH:37])[C@H:6]([OH:41])[C@H:5]2[OH:4])=[CH:12][C:13]=1[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]([OH:27])[CH3:26])=[CH:23][CH:24]=1
Reactant: CC(=O)OC[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](c2ccc(Cl)c(Cc3ccc(C(C)=O)cc3)c2)[C@H]1OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)[C@@H]3O)ccc2Cl)cc1

Procedure:
Compound 40 was prepared by reduction of (1S,2R,3R,4S,5R,6R)-4-(acetoxymethyl)-6-(3-(4-acetylbenzyl)-4-chlorophenyl)cyclohexane-1,2,3,5-tetrayl tetraacetate (38) with excess sodium borohydride and purification by preparative HPLC to give 0.6 mg of a clear film. MS (ESI+): 445 [M+Na]+, (ESI−): 467 [M+HCOO]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:13]O.S(=O)(=O)(O)O>O>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1ccc(O)c(F)c1

Procedure:
A mixture of 2.0 g of 3-fluoro-4-hydroxybenzeneacetic acid, 10 ml of methyl alcohol and 1 ml of concentrated sulfuric acid is heated at reflux temperature for 23.5 hours. The cooled solution is diluted with water and extracted with methylene chloride. The organic layer is washed with water, saturated sodium bicarbonate, water and saturated sodium chloride; dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:25% ethyl acetate/hexane) to give 1.9 g of the desired product.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1.[NH2:25][C@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:27]([NH2:29])=[O:28].CCN(CC)CC.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:29][C:27](=[O:28])[C@H:26]([NH:25][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1)[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C[C@@H](N)C(N)=O
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(S(C)(=O)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C#N)cc(N[C@H](CC(C)C)C(N)=O)nc1Nc1cccc(S(C)(=O)=O)c1
Temperature: 60 °C
Reaction time: 14 h
Yield: 50.1 %

Procedure:
A mixture of methyl 6-chloro-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (120.7 mg, 0.330 mmol), (R)-2-amino-4-methylpentanamide (67.1 mg, 0.515 mmol), and Et3N (0.1 mL, 0.717 mmol) in DMF (4 mL) was stirred at 60° C. for 14 h. Saturated aq NaHCO3 (20 mL) was added to the mixture, which was subsequently extracted with EtOAc (2×30 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and filtered (DM1020). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes/EtOAc=1/2) and then triturated with IPE to give the title compound (76 mg, 50%).
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]([O:7][Si](C)(C)C)=[CH2:6].[O:12]([CH2:19]C=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[O:12]([CH2:19][CH:1]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3][O:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=CCOc1ccccc1
Reactant: C=C(C=COC)O[Si](C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1C=COC(COc2ccccc2)C1
Temperature: -5 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
1-Methoxy-3-(trimethylsilyloxy)-1,3-butadiene (4.95 ml; 26 mmol) was added to a solution of phenoxyacetaldehyde (3.56 g, 26 mmol) in DCM (40 ml). The solution was cooled to −5° C. A 2.3 M solution of zinc chloride in DCM (5.6 ml, 13 mmol) was added. The reaction mixture was stirred for 16 hours, while it was warming up to room temperature. It was diluted with ethyl acetate (150 ml) and washed with a 10% aqueous solution of sodium hydrogensulphate (100 ml). The aqueous phase was extracted with ethyl acetate (100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (200 g), using ethyl acetate/heptane (1:1) as eluent, to give 2.36 g of 2-phenoxymethyl-2,3-dihydropyran-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH3:11].O=P(Cl)(Cl)Cl.CN(C1C=CC=CC=1)[CH:19]=[O:20]>>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([CH3:11])=[CH:5][C:6]=1[CH:19]=[O:20]
Reactant: CN(C=O)c1ccccc1
Reactant: COc1ccc(C)c(OC)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(OC)c(C=O)cc1C

Procedure:
To a solution of 2,4-dimethoxytoluene (5.50 g, 36.1 mmol) in 55 mL of N-methyl-N-phenyl-formamide was added at 0° C. POCl3 (10.9 mL, 3 eq.), and the mixture was heated for 60 Min. to 80° C. After cooling, the reaction mixture was poured onto crashed ice, the precipitate filtered and washed twice with water/MeOH=8/2 to leave after drying 5.40 g of the title product as light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10])=[O:24]
Reactant: O=C(Cl)CCCCBr
Reactant: Nc1ccccc1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCBr)Nc1ccccc1CCO
Yield: 100 %

Procedure:
A solution of 2-(2-aminophenyl)ethanol a2-0 (450 g, 3.28 mol, 1 eq) and triethylamine (332 g, 3.28 mol, 1 eq) in dichloromethane (2 l) is cooled at −5° C. and bromovalerylchloride (654 g, 3.28 mol, 1 eq) in dichloromethane (2 l) is added dropwise without exceeding 0° C. The organic phase is washed with HCl 1N (4×2 l) and brine (1×2 l). The aqueous layer is extracted with dichloromethane (1×2 l). The combined organic layers are dried over MgSO4, filtered and evaporated under vacuum to afford 1008 g of 5-bromo-N-[2-(2-hydroxyethyl)phenyl]pentanamide a2-1.
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([NH:24][C@H:25]([C:35]([O-:37])=[O:36])[CH2:26][CH:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O-:30])=[O:29])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C1([NH2+]C2CCCCC2)CCCCC1.C(Cl)(Cl)Cl.[CH3:55][N:56]([CH2:58][CH2:59]Cl)[CH3:57]>O1CCOCC1>[CH3:55][N:56]([CH3:57])[CH:58]([O:36][C:35](=[O:37])[C@H:25]([CH2:26][CH:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[NH:24][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:59]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(OC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1)N(C)C
Temperature: 70 °C
Yield: 88.4 %

Procedure:
To 1.10 g N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl ammonium salt, 1.8 ml chloroform and 1.9 ml solution of dimethylaminoethylchloride in the amount of 0.46 g, which stoichiometrically corresponds to two times molar volume, in dioxane were added to be subjected to reflux in oil bath at 70° C. for 30 hrs. After cooling down to a room temperature, said reaction mixture was similarly treated as in Step Example 1 to obtain N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-α-dimethylaminoethyl ester in the amount of 766 mg (yield; 88.4%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:10][C:11]#[N:12])[CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15]>C(#N)C.CS(C)=O.[F-].[K+].C(OCC)(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Ni]Cl>[CH2:15]([C:2]1[CH:3]=[C:4]([CH2:10][C:11]#[N:12])[CH:5]=[N:6][C:7]=1[CH2:8][CH3:9])[CH:14]=[CH2:13]
Reactant: CCc1ncc(CC#N)cc1Cl
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Ni]Cl
Agent: [Fe+2]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CS(C)=O
Product: C=CCc1cc(CC#N)cnc1CC
Temperature: 85 °C
Yield: 78.6 %

Procedure:
A solution of 5-chloro-6-ethyl-pyridin-3-yl-acetonitrile (3.00 g, 16.6 mmol) and allyl-tri-n-butyltin (5.4 mL, 17.4 mmol) in acetonitrile (30 mL, 0.5 M) and dimethylsulfoxide (2 mL), is degassed and treated with 1,1′-bis(diphenylphosphino)ferrocene-dicloronickel(II) (Ni(dppf)Cl2) (0.38 g, 0.55 mmol). The mixture is warmed to 85° C. for 2 h. After cooling to room temperature the solution is diluted with 10% aq potassium fluoride (30 mL) and ethyl acetate (30 mL). The solids are filtered and rinsed with ethyl acetate (30 mL). The organic layer is washed with saturated aq NaCl (80 mL) and dried over Na2SO4. The product is purified by MPLC (25-90% ethyl acetate in n-heptane) to provide 5-allyl-6-ethyl-pyridin-3-yl-acetonitrile as a yellow oil (2.43 g, 79%): Rf 0.28 (50% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.36 (s, 1 H), 7.44 (s, 1 H), 6.00-5.84 (m, 1 H), 5.15 (d, J=10.3 Hz, 1 H), 5.03 (d, J=17.2 Hz, 1 H), 3.71 (s, 2 H), 3.42 (d, J=6.0 Hz, 2 H), 2.83 (q, J=7.6 Hz, 2 H), 1.28 (t, J=7.6 Hz, 3 H). ESI-LCMS m/z calcd for C12H14N2: 186.1; found 187.0 (M+1)+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>COCCOC>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: COCCOC
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
Cyanuric chloride (7.30 g, 39.6 mmol) was dissolved in ethylene glycol dimethyl ether (100 ml), cooled to -15° C. and gradually added dropwise with morpholine (7.00 ml, 80.3 mmol) dissolved in ethylene glycol dimethyl ether (50 ml). This reaction mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The residue was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography, using n-hexane and ethyl acetate (6:4) as eluant, to obtain 6.32 g (yield: 68.0%) of 2,4-dichloro-6-morpholino-1,3,5-triazine as colorless crystals having melting point of 160.5° C.-161° C.