Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](O)=[O:16])=[CH:14][C:9]=2[N:8]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]1=[O:23])[CH2:2][CH:3]([CH3:5])[CH3:4].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:34]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47]([O:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53])=[O:48])[CH2:35][CH:36]([CH3:38])[CH3:37]>C(Cl)Cl.CN(C)C=O>[CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([C:43]3[CH:44]=[CH:45][C:40]([O:39][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[C:41]([CH2:46][C:47]([O:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53])=[O:48])[CH:42]=3)=[O:16])=[CH:14][C:9]=2[N:8]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]1=[O:23])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCOC(=O)Cc1ccccc1OCCC(C)C
Reactant: CC(C)CCn1c(=O)n(CCC(C)C)c2cc(C(=O)O)ccc21
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CCOC(=O)Cc1cc(C(=O)c2ccc3c(c2)n(CCC(C)C)c(=O)n3CCC(C)C)ccc1OCCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 0.17 g of 1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid in 9 ml of methylene chloride are added 60 μl of oxalyl chloride and 20 μl of N,N-dimethylformamide successively. The mixture thus obtained is stirred at ambient temperature for 2 hours. Then, 0.42 g of aluminum chloride and 0.38 g of isopentyl 2-(2-isopentyloxyphenyl)acetate are successively added at ambient temperature, and the mixture thus obtained is stirred at the same temperature as above for 30 minutes. The reaction mixture is added to a mixture of methylene chloride and ice water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 0.29 g of isopentyl 2-[5-[(1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)carbonyl]-2-(isopentyloxy)phenyl]acetate as a light yellow oily product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)(=[O:8])=[O:7].[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20].S([O-])([O-])(=O)=O.[Mg+2]>S(=O)(=O)(O)O.C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[N:21][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:8])=[O:7]
Reactant: O=Cc1ccccc1S(=O)(=O)CCCCCl
Reactant: CCCCN
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CCCCN=Cc1ccccc1S(=O)(=O)CCCCCl

Procedure:
2.45 g of 2-[(4-chlorobutyl)sulfonyl]benzaldehyde was treated with 1.1 ml of n-butylamine, 3.4 g of magnesium sulfate, and 2 drops of concentrated sulfuric acid in 20 ml of diethyl ether in the same manner as described for Example 1, Part C to give 2.76 g of product. 1H-NMR (CDCl3) δ 0.96(t,3H,J=7 Hz); 1.32-1.50(m,2H); 1.65-1.79(m,2H); 1.84-1.93(m,4H); 3.11-3.20(m,2H); 3.46-3.53(m,2H); 3.67-3.74(m,2H); 7.55-7.73(m,2H); 8.00-8.13(m,2H); 9.12(s,1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH3:13][CH:14]([NH2:17])[CH2:15][CH3:16]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH:14]([CH3:13])[CH2:15][CH3:16])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: CCC(C)N
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: CCC(C)Nc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 1.07 g (7.5 mmol) of 1-methylpropylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 676 mg (yield: 82.7%) of the title compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([C:23]([OH:25])=[O:24])[C:12]2[C:7](=[CH:8][C:9]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1.[CH3:26]O>>[CH3:26][O:24][C:23]([C:4]1([CH3:3])[C:12]2[C:7](=[CH:8][C:9]([C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1)=[O:25]
Reactant: COc1cc2c(cc1C(=O)c1ccccc1)CCC2(C)C(=O)O
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1(C)CCc2cc(C(=O)c3ccccc3)c(OC)cc21

Procedure:
Analogously to the description in Example 2, 0.4 g of 1-methyl-5-benzoyl-6-methoxy-indane-1-carboxylic acid methyl ester and 5 ml of 2 N sodium hydroxide solution in 15 ml of methanol give 1-methyl-5-benzoyl-6-methoxy-indane-1-carboxylic acid of melting point 135°-137° C. (from ether-petroleum ether). The starting material can be obtained as follows:
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[C@@H:7]([NH:37]C(OC(C)(C)C)=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:45])[C@@H:7]([NH2:37])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:27])=[O:28])=[C:11]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (S)-3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-2-tert-butoxycarbonylaminopropionic acid tert-butyl ester (760 mg, 1.15 mmol) in methylene chloride (10 mL) is added TFA (3 mL) and the mixture is stirred at RT for 45 min. The solution is carefully poured into 8% NaHCO3 solution (50 mL) and the mixture is extracted with methylene chloride. The solvent is removed under reduced pressure to give the title compound which is used immediately in the next step.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:14]2[C:10]([O:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])=O.Cl.[N:24]12[CH2:31][CH2:30][CH:27]([CH2:28][CH2:29]1)[C@@H:26]([NH:32][C:33]([NH2:35])=[NH:34])[CH2:25]2.[O-]CC.[Na+]>C(O)C>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:8]1[N:9]=[C:10]2[N:14]([C:7]=1[C:5]1[CH:4]=[CH:3][N:35]=[C:33]([NH:32][C@@H:26]3[CH:27]4[CH2:28][CH2:29][N:24]([CH2:31][CH2:30]4)[CH2:25]3)[N:34]=1)[CH:13]=[CH:12][O:11]2
Reactant: N=C(N)N[C@H]1CN2CCC1CC2
Reactant: CN(C)C=CC(=O)c1c(-c2ccccc2Cl)nc2occn12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Clc1ccccc1-c1nc2occn2c1-c1ccnc(N[C@H]2CN3CCC2CC3)n1
Yield: 78.2 %

Procedure:
A mixture of 3-(dimethylamino)-1-[6-(2-chlorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]prop-2-en-1-one (316 mg, 1.0 mmol) and (R)—N-1-azabicyclo[2.2.2]oct-3-ylguanidine hydrochloride (427 mg, 2.0 mmol) is diluted with 5 ml of absolute ethanol and treated with 1.8 eq. of a 21% w/w solution of sodium ethoxide in ethanol (0.6 ml) to form a reaction mixture. The reaction mixture is heated to reflux for 24 hours. Volatiles are removed in vacuo and the residue is taken up in 12 ml of a 5:1 mixture of ethyl acetate and methanol, washed twice with 5 ml each of water, and then with a saturated sodium chloride solution (5 ml). The organic phase is dried with magnesium sulfate, filtered and concentrated in vacuo, to give a brown oil. The product is purified by flash chromatography on silica gel (ethyl acetate/methanol/ammonium hydroxide solution, 20:4:1) to yield 329 mg of a pale yellow solid (78%). M.p.=132-134° C.; 300 MHz 1H NMR (DMSO-d6) δ: 8.91 (s, 1H), 8.25 (s, 1H), 8.03 (d, J=5.1 Hz, 1H), 7.63-7.45 (m, 4H), 7.38 (d, J=6.9 Hz, 1H), 5.80 (br. s, 1H), 3.87 (m, 1H), 3.16 (br. s, 1H), 2.86 (m, 1H), 2.8-2.4 (m, 4H), 1.92 (br. s, 1H), 1.83 (br. s, 1H), 1.59 (m, 2H), 1.32 (br. s, 1H). LCMS: 421 [M+H]; calc. for C22H21ClN6O 0.1 EtOAc 0.75 H2O: C, 60.70; H, 5.30; N, 18.98; found. C, 61.17; H, 5.21; N, 18.68.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1>>[C:1]([N:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1CSCCN1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCSCC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and thiomorpholine as starting raw materials, to produce an intended compound.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[N:10]=[C:9]([N+:11]([O-])=O)[C:8]([OH:14])=[CH:7][CH:6]=1)[CH2:3][CH3:4]>[Pd].CO>[NH2:11][C:9]1[C:8]([OH:14])=[CH:7][CH:6]=[C:5]([CH:2]([CH3:1])[CH2:3][CH3:4])[N:10]=1
Reactant: CCC(C)c1ccc(O)c([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CO
Product: CCC(C)c1ccc(O)c(N)n1

Procedure:
6-(1-methylpropyl)-3-hydroxy-2-nitropyridine (23 g.) in 450 ml. of methanol is hydrogenated over 1 gm. of 5% palladium on carbon catalyst for 3 hours. The catalyst is removed on a filter and the filtrate is concentrated to dryness to give 2-amino-3-hydroxy-6-(1-methylpropyl)pyridine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:31]([Cl:34])=[CH:32][N:33]=1)[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]2[CH2:12][CH2:13][C:14]3[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:18]=3[C:10]=2[CH:9]=1)=[O:6].[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>>[Cl:34][C:31]1[C:4]([C:5]([NH:7][C:8]2[CH:30]=[CH:29][C:11]3[CH2:12][CH2:13][C:14]4[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)[C:18]=4[C:10]=3[CH:9]=2)=[O:6])=[CH:3][C:2]([N:39]([CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH3:40])=[N:33][CH:32]=1
Reactant: CNCCN(C)C
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Product: CN(C)CCN(C)c1cc(C(=O)Nc2ccc3c(c2)-c2c(c(C(N)=O)nn2-c2ccc(F)cc2)CC3)c(Cl)cn1
Reaction time: 24 h
Yield: 47.1 %

Procedure:
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 248 (0.8 g, 0.0016 mol) and N,N,N′-trimethylethylene diamine (3.3 g, 0.032 mol). The reaction was run at 100° C. for 24 h. After removal of the volatiles under vacuum, the residue was partitioned between water and CH2Cl2. The organic layer was washed an additional time with water and dried over MgSO4. The crude product mixture was purified by preparative HPLC to give 0.424 g of the title product, yield: 47%. 1H NMR (400 MHz, d6-DMSO): 2.13 (s, 6H), 2.34 (t, 2H, J=6.7 Hz), 2.87–2.95 (m, 4H), 2.96 (s, 3H), 3.59 (t, 2H, J=6.7 Hz), 6.58 (s, 1H), 7.2 (d, 1H, J=2 Hz), 7.27 (s, 1H), 7.29–7.37 (m, 3H), 7.41–7.44 (dd, 1H, J=8 Hz, 2 Hz), 7.53–7.58 (m, 3H), 8.13 (s, 1H), 10.36 (s, 1H). M+1=563.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:4][CH:3]=1.[S:18]([O:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH:33]=[CH:32][O:31]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>O=P(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:17][C@@H:32]2[O:31][C@@H:30]([CH2:29][O:28][S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[CH2:35][CH2:34][CH2:33]2)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OC(c3ccc(Cl)cc3)c3ccc(Cl)cc3Cl)O2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2.10 g of α-(4-chlorophenyl)-2,4-dichlorobenzyl alcohol and 1.78 of 2-tosyloxymethyl-3,4-dihydro-2H-pyran were dissolved in 40 ml of diethyl ester, and a catalytic amount (2 drops) of phosphorus oxytrichloride was added to the solution. The mixture was then stirred at room temperature for 4 days, after which 3 drops of triethylamine were added. The mixture was then concentrated by evaporation under reduced pressure and the residue was purified by column chromatography through silica gel eluted with a 15:5:1 by volume mixture of hexane, benzene and ethyl acetate, to give 3.41 g of the title compound in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22]
Reactant: C=C(C)c1cc(F)c(-c2nc(C(=O)OC)ccc2F)c(F)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)C)cc2F)n1
Temperature: 25 °C

Procedure:
To a degassed solution of methyl 6-(2,6-difluoro-4-(prop-1-en-2-yl)phenyl)-5-fluoropicolinate (1.0 equiv.) in MeOH (0.09 M) was added Pd/C (0.1 equiv.) and the reaction was stirred at rt under an atmosphere of hydrogen. After overnight stirring, filtered through a pad of Celite and washed with Methanol. The filtrate was concentrated and dried under vacuo to give methyl 6-(2,6-difluoro-4-isopropylphenyl)-5-fluoropicolinate. LC/MS=310.0 (M+H), Rt=1.00 min.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([O:20][CH3:21])[C:15](OCC)=[O:16])=[C:4]([CH3:24])[CH:3]=1.CO.O.[NH2:28][NH2:29]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([O:20][CH3:21])[C:15]([NH:28][NH2:29])=[O:16])=[C:4]([CH3:24])[CH:3]=1
Reactant: CCOC(=O)C(OC)c1ccccc1COc1ccc(Cl)cc1C
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(C(=O)NN)c1ccccc1COc1ccc(Cl)cc1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To 1.05 g (3 mmol) of ethyl 2-(4-chloro-2-methylphenoxymethyl)phenyl-2-methoxyacetate was added 6 ml of methanol and 0.75 g (15 mmol) of hydrazine monohydrate and stirred at 60° C. for 16 hours. After completion of the reaction, 100 ml of brine was added and extracted twice with 70 ml of dichloromethane. The extract was dried over anhydrous magnesium and concentrated under reduced pressure to give 2-(4-chloro-2-methylphenoxymethyl)phenyl-2-methoxyacetic acid hydrazide (0.93 g, 92.6%) as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([S:12][CH3:13])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:13][S:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:3][CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: OCCCN1CCOCC1
Reactant: CSc1ncnc2cc(O)ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ncnc2cc(OCCCN3CCOCC3)ccc12
Reaction time: 1 h
Yield: 48.9 %

Procedure:
7-Hydroxy-4-methylsulphanylquinazoline (2.5 g, 13 mmol) was suspended in methylene chloride (65 ml), triphenylphosphine (4.45 g, 17 mmol) was added followed by 4-(3-hydroxypropyl)morpholine (2.47 g, 17 mmol), (Bull Soc. Chim. Fr. 1962, 1117), and diethyl azodicarboxylate (2.92 g, 17 mmol) dropwise. After stirring for 1 hour the volatiles were removed by evaporation and the residue was partitioned between ethyl acetate/ether (20 ml/20 ml) and 1M hydrogen chloride (20 ml). The aqueous layer was separated and adjusted to pH9 with solid sodium hydrogen carbonate. The aqueous layer was extracted with methylene chloride. The organic layer was separated, washed with water, brine and dried (MgSO4). The volatiles were removed by evaporation and the residue was purified by chromatography eluting with methylene chloride/ethyl acetate/methanol (6/3/1 followed by 5/3/2 and 75/0/25) to give 4-methylsulphanyl-7-(3-morpholinopropoxy)quinazoline (2.03 g 49%).
Reaction SMILES: [CH3:1][C:2]1C=C(C)[N:5]=[C:4]([SH:9])[N:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH2:5])[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1
Reactant: CSc1nccc(C)n1
Reactant: Cc1cc(C)nc(S)n1
Product: CSc1nccc(-c2sc(N)nc2C)n1

Procedure:
This material is prepared by the procedure outlined for intermediate AC, replacing 4,6-dimethyl-pyrimidine-2-thiol in the first step (AC1) with 4-methyl-2-methylsulfanyl-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([F:42])[CH:40]=3)[N:35]([CH3:43])[CH:34]=2)[CH2:29]1>>[F:42][C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:43])[CH:34]=[C:33]2[CH2:32][CH:30]1[CH2:31][N:28]([CH2:16][CH:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH2:29]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Cn1cc(CC2CNC2)c2cc(F)ccc21
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(Cc2cn(C)c4ccc(F)cc24)C1)O3

Procedure:
This compound was prepared as described for Example 2, using (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.24 g, 0.53 mmol), 3-azetidin-3-ylmethyl-5-fluoro-1-methyl-1H-indole (0.12 g, 0.53 mmol), to afford 0.65 g of the (S)-enantiomer of the title compound as a light brown oil. The oxalate was prepared in methanol and collected as 0.047 g of a yellow solid, m.p. 193-195° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]3)=[N:9][C:10]=2[C:11]2[CH:26]=[CH:25][C:14]([C:15]([NH:17][C:18]3[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>>[C:33]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32][C@H:27]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:26]=[CH:25][C:14]([C:15]([NH:17][C:18]3[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[N:9]=1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: Cc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCCN4)n4ccnc(N)c34)cc2)n1
Product: C=CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3nccc(C)n3)cc2)c2c(N)nccn12
Yield: 27.4 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-methylpyrimidin-2-yl)benzamide (intermediate 29) and acryloylchloride, to afford the title compound (4.5 mg, 27.4%). Data: UPLC(C) Rt: 1.79 min; m/z 483.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:69]=[C:68]([O:70][CH3:71])[CH:67]=[C:66]([O:72][CH3:73])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:28]([CH:31](/[CH:52]=[CH:53]/[C:54]1[C:59]([O:60][CH3:61])=[CH:58][C:57]([O:62][CH3:63])=[CH:56][C:55]=1[O:64][CH3:65])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([NH:40][C:41](=[O:51])[C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-])=O)=[CH:44][CH:43]=2)[CH:33]=1)(=[O:30])=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH:9]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>O.CC(C)=O>[CH3:73][O:72][C:66]1[CH:67]=[C:68]([O:70][CH3:71])[CH:69]=[C:3]([O:2][CH3:1])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:28]([CH:31](/[CH:52]=[CH:53]/[C:54]1[C:59]([O:60][CH3:61])=[CH:58][C:57]([O:62][CH3:63])=[CH:56][C:55]=1[O:64][CH3:65])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([NH:40][C:41](=[O:51])[C:42]2[CH:43]=[CH:44][C:45]([NH2:48])=[CH:46][CH:47]=2)[CH:33]=1)(=[O:29])=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)[CH:9]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3ccc([N+](=O)[O-])cc3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3ccc([N+](=O)[O-])cc3)c2)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3ccc(N)cc3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3ccc(N)cc3)c2)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4,6-trimethoxystyryl-3-(4-nitrobenzamido)-4-methoxybenzyl-sulfone (example 10) (1.3 mmol) in acetone water (10:5) was heated to 50° C. After 30 min, sodiumhydrosulfite (Na2S2O4) (26.3 mmol) was added slowly, and the mixture was heated at reflux (50° C., 1 h.), cooled to room temperature and water was added. The product was rinsed with NaHCO3, and then isolated by extraction with ethyl acetate. The organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was recrystallized from 2-propanol to give pure (E)-2,4,6-Trimethoxystyryl-3-(4-aminobenzamido)-4-methoxy-benzylsulfone. m.p. 137-140° C. NMR (DMSO-d6) δ 3.82 (s, 3H), 3.83 (s, 6H), 3.86 (s, 3H), 4.22 (s, 2H), 6.14 (s, 2H), 6.80-8.16 (m, aromatic), 8.60 (s, 1H).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][N:22]3[C:23](=[O:27])[C:24]=2[CH2:25][CH3:26])[CH:14]=[CH:15][CH:16]=1>CN(C)C=O>[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[CH:31]=[CH:30][C:29]4([CH2:2][CH:28]4[N:22]3[C:23](=[O:27])[C:24]=2[CH2:25][CH3:26])[C:32]([O:34][CH3:35])=[O:33])[CH:14]=[CH:15][CH:16]=1
Reactant: CCc1c(/C=C/c2cccc(OC)c2)nc2ccc(C(=O)OC)cn2c1=O
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(/C=C/c2cccc(OC)c2)nc2n(c1=O)C1CC1(C(=O)OC)C=C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trimethyl-sulphoxonium iodide (1 g) was reacted with 50% sodium hydride (0.22 g) in dimethylformamide (30 ml) under stirring at room temperature for 30 minutes, then a solution of 2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, methyl ester, m.p. 177°-179° C., (1.27 g) in dimethylformamide (20 ml) was added. The mixture was allowed to react under stirring at room temperature for 2 hours, then it was diluted with ice water and the precipitate was filtered, so obtaining 1.19 g of 2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, methyl ester (m.p. 184°-188° C.), which was treated with 0.5% KOH in 95% ethanol solution (40 ml) at reflux temperature for 15 minutes. After cooling the reaction mixture was diluted with water and acidified with acetic acid and the precipitate was filtered: crystallization from CH 2 Cl2 /methanol gave 2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (0.65 g), m.p. 184°-188° C., NMR (CF3COOD) δ: 1.22(d.d) (one of 6,7-methylen protons), 1.36(t) (--CH2 --CH3), 2.96(m)(--CH2CH3 and 6,7-methylen proton), 4.12(s) (OCH3), 5.50(d.d) (c-6 proton), 7.03(d) (c-9 proton), 7.36(d) (Hβ -vinyl proton), 7.68(d) (Hα -vinyl proton), 7.18-7.70 (m) (4 phenyl protons), 8.26 (d) (c-8 proton), JHαHβ =16 Hz.