Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C(O[C:5](=O)[CH:6]([CH3:12])[C:7]([O:9]CC)=[O:8])C.[Br:14][C:15]1[CH:16]=[C:17]([C:20]([Br:23])=[CH:21][CH:22]=1)CBr.[OH-].[K+]>C(O)C.O>[Br:14][C:15]1[CH:16]=[CH:17][C:20]([Br:23])=[CH:21][C:22]=1[CH2:5][CH:6]([CH3:12])[C:7]([OH:9])=[O:8]
Reactant: BrCc1cc(Br)ccc1Br
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Cc1cc(Br)ccc1Br)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A total of 6.10 g (0.27 mol) of sodium metal were dissolved in 150 ml of dry ethanol in a three-necked round-bottom 1000 ml flask equipped with a reflux condenser, dropping funnel with pressure-equalization, and magnetic stirring bar. To the resulting solution, 45.5 g (0.26 mol) of diethylmethylmalonate in 50 ml of dry ethanol were added dropwise within 10 min. This mixture was stirred for 15 min; then 84.3 g (0.26 mol) of 3,6-dibromobenzylbromide were added by vigorous stirring at such a rate, so the reaction mixture maintained at gentle reflux. Additionally, this mixture was refluxed for 4 h and, then, cooled to room temperature. A solution of 52.1 g of KOH in 140 ml of water was added and the resulting mixture was refluxed for 3 h to saponificate the ester formed. Ethanol and water were distilled off. To the residue, 200 ml of water and, then, 12 M HCl (to pH 1) were added. The substituted methylmalonic acid precipitated, was separated, washed with 3×100 ml of cold water and dried overnight on a watch glass. Crude 3-(2,5-dibromophenyl)-2-methylpropanoic acid was obtained after decarboxylation of this substituted methylmalonic acid by heating it for 2 h at 160° C. This product was used without further purification. A mixture of this acid, 70 ml of SOCl2, and 100 ml of CH2Cl2 was stirred for 3 h at reflux. Thionyl chloride and CH2Cl2 were distilled off. The residue was dried in vacuum and, then, dissolved in 95 ml of CH2Cl2. To a suspension of 47.0 g (0.35 mol) of AlCl3 in 470 ml of CH2Cl2 the above-obtained solution of 3-(2,5-dibromophenyl)-2-methylpropanoyl chloride was added dropwise with vigorous stirring for 1 hour at −20° C. This mixture was refluxed for 3 h, cooled to ambient temperature, and, then poured on 500 cm3 of ice. The organic layer was separated. The aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and evaporated to dryness. The crude 4,7-dibromo-2-methyl-1-indanone was purified by flash chromatography on Silica Gel 60 (40-63 μm, d 50 mm, h 250 mm; eluent: hexanes/methyl-tert-butyl ether (1:1, vol.)). Yield 54.1 g (70%).
Reaction SMILES: Cl(O)(=O)(=O)=O.CO[CH:8]=[C:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1.Cl.[CH2:18]([O:20][NH2:21])[CH3:19]>C(Cl)(Cl)Cl.CO.O>[CH2:18]([O:20][N:21]=[CH:8][CH:9]1[CH:14]2[CH2:13][CH2:12][N:11]([CH2:16][CH2:15]2)[CH2:10]1)[CH3:19]
Reactant: COC=C1CN2CCC1CC2
Reactant: CCON
Agent: Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CCON=CC1CN2CCC1CC2
Reaction time: 1 h

Procedure:
4.8 cm3 of a 70% aqueous solution of perchloric acid is added at ambient temperature to 2 g of 3-methoxy methylidene quinuclidine in solution in 20 cm3 of chloroform. After agitating for one hour, 1.4 g of O-ethylhydroxylamine hydrochloride in 2.5 cm3 of methanol and 2.5 cm3 of water are added, and the reaction medium is maintained in this way for one night. After concentrating, alkalizing with sodium hydroxide, extracting with ethyl acetate, and distilling at 135° C. under 0.05 mbar, 2.05 g of expected product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=3[CH3:27])[CH:13]=[CH:12][C:11]=2[O:28][CH3:29])=O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(Cl)Cl.FC(F)(F)C(O)=O.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=3[CH3:27])[CH:13]=[CH:12][C:11]=2[O:28][CH3:29])=[CH:6][CH:7]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.2 g (5.55 mmol) of (4-fluorophenyl)[2-methoxy-5-(2,6-dimethyl-4-nitrophenoxy) phenyl]methanone in 10 ml methylene chloride and 3 ml trifluoroacetic acid is added 2.1 g (18.0 mmol) of triethylsilane. The solution is stirred overnight at room temperature, then diluted with ether (100 ml) and washed with water, 5% aqueous sodium carbonate, water, dried (CaSO4) and evaporated. The residual oil is flash chromatographed to give 1-[(4-fluorophenyl)methyl]-2-methoxy-5-(2,6-dimethyl-4-nitrophenoxy)benzene, m.p. 105°-110°.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[CH3:28][CH:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[CH3:30].[OH-].[Na+].[ClH:44]>CS(C)=O.C(OCC)(=O)C.C(Cl)(Cl)Cl>[ClH:1].[ClH:44].[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:41][C:38]4[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][CH2:32][NH:31][CH:29]([CH3:28])[CH3:30])=[CH:36][CH:37]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: CC(C)NCCCc1ccc(O)cc1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)NCCCc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1

Procedure:
Using the conditions described above in method A, 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (13.9 g) and 4-[3-(1-methylethyl)aminopropyl]phenol (7.0 g) were reacted in the presence of 9.25 ml 4.0N sodium hydroxide in 100 ml dimethylsulfoxide. The crude free base, isolated by extraction using chloroform, was dissolved in ethyl acetate and treated with hydrogen chloride in ethyl acetate to give the crude trihydrochloride salt. Crystallization from methanol-isopropanol yielded 10.8 g of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-[2-[4-[3-(1-methylethyl)aminopropyl]phenoxy]ethyl]piperazine trihydrochloride, mp 215°-225°.
Reaction SMILES: [OH-].[Na+].C(OC([C:8]1([CH2:23][C:24]([O:26]CC)=[O:25])[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]1)=O)C>O.C1COCC1>[C:19]([O:18][C:16]([N:11]1[CH2:12][CH2:13][C:14](=[O:15])[CH:8]([CH2:23][C:24]([OH:26])=[O:25])[CH2:9][CH2:10]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(CC(=O)O)CC1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
23.3 g sodium hydroxide in 218 mL water was added to 38 g 4-ethoxycarbonylmethyl-5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 155 mL THF. The reaction was stirred over night at RT, THF was removed and the mixture was extracted with dichlormethane. The aqueous part was acidified with 3M HCl to pH 3 at 0° C. The aqueous solution was extracted with dichloromethane, dried over magnesium sulfate, concentrated under reduced pressure to give 18.2 g of the desired product. (M+H)+=272
Reaction SMILES: [CH3:1][C:2]1NC(=O)N[C:4](=[O:9])[CH:3]=1.N1[CH:15]=[CH:14][C:13](=O)NC1=O.C[Si](C)(C)CCO[CH2:23][Cl:24]>>[CH2:4]([O:9][CH2:23][Cl:24])[C:3]1[CH:2]=[CH:1][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Product: ClCOCc1ccccc1

Procedure:
In a similar manner to the procedures described in Reference Example 3, reactions were carried out using 6-methylpyrimidine-2,4-dione, instead of pyrimidine-2,4-dione, and using 2-(trimethylsilyl)ethoxymethyl chloride, instead of benzyloxymethyl chloride, to give the title compound (yield 56%) as a white powder.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1.CCOC(C)=O>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[C:20]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1
Reactant: Oc1ccc(Cl)cc1C1CCCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2C2CCCCC2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (10 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-chloro-2-cyclohexylphenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (80ml), washed with H2O (2×40 ml) and brine (60 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-chloro-2-cyclohexylphenoxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[O:5][N:4]=1.C(N(C(C)C)C(C)C)C.Br[CH2:35][C:36]1[C:37]([CH2:42]Br)=[CH:38][CH:39]=[CH:40][CH:41]=1.C(Cl)[Cl:45]>>[ClH:45].[F:22][C:20]1[CH:19]=[CH:18][C:17]2[N:11]3[CH:10]=[N:9][C:8]([C:6]4[O:5][N:4]=[C:3]([CH2:2][N:1]5[CH2:42][C:37]6[C:36](=[CH:41][CH:40]=[CH:39][CH:38]=6)[CH2:35]5)[N:7]=4)=[C:12]3[CH2:13][N:14]([CH3:24])[C:15](=[O:23])[C:16]=2[CH:21]=1
Reactant: CN1Cc2c(-c3nc(CN)no3)ncn2-c2ccc(F)cc2C1=O
Reactant: BrCc1ccccc1CBr
Reactant: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1Cc2c(-c3nc(CN4Cc5ccccc5C4)no3)ncn2-c2ccc(F)cc2C1=O
Product: Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 32 %

Procedure:
A suspension of 328 mg (1.0 mmol) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 5 ml of methylene chloride was treated under argon with 0.38 ml (2.2 mmol) of N-ethyldiisopropylamine and 317 mg (1.2 mmol) of α,α'-dibromo-o-xylene and stirred at room temperature under argon for 5 hrs. The solution was washed once with 5 ml of water, dried with sodium sulfate, filtered and evaporated. The crude product was purified by chromatography on 30 g of silica gel (methylene chloride/acetone 4:1, then 2:1). The eluates were evaporated and the residue was taken up in 2.5 ml of methanol. The solution was acidified with ethereal hydrochloric acid and the solvent was removed in a vacuum. The residue was taken up in 6 ml of hot methanol; then cooled to about 0° and the white crystals were isolated by suction filtration. There were obtained 150 mg (32%) of 8-fluoro-3-(3-isoindolin-2-ylmethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (1:1) of m.p. 229°-233° (dec.).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[S:11][C:12]([CH:15]=O)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:26][OH:27]>O>[CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[S:11][C:12]([CH:15]=[N:26][OH:27])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)Oc1ccc(Oc2ncc(C=O)s2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(Oc2ncc(C=NO)s2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.5 %

Procedure:
To a solution of Example 1C (2.5 g, 0.0095 mol) in pyridine (15 mL, 0.19 mol) was added hydroxylamine hydrochloride (6.6 g, 0.095 mol) portion wise and the mixture was stirred at room temperature for 5 minutes and it solidified. The mixture was then heated at 70° C. for 0.5 hours. Water (300 mL) was added and the reaction was stirred for 20 minutes. The solid was filtered and air-dried to give 2.26 g of product as a white solid (85% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.28 (d, J=5.49 Hz, 6H) 4.54-4.68 (m, 1H) 7.00 (d, J=9.16 Hz, 2H) 7.28 (d, J=9.16 Hz, 2H) 7.68 (s, 1H) 7.77 (s, 1H) 11.89 (s, 1H). MS (ESI), m/z 279.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6](CC#N)[CH:7]=1.[OH-:13].[Na+].[CH2:15]([OH:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([CH2:16][C:15]([OH:13])=[O:17])[CH:7]=1
Reactant: CCO
Reactant: [OH-]
Reactant: COc1cc(Br)cc(CC#N)c1
Agent: [Na+]
Product: COc1cc(Br)cc(CC(=O)O)c1

Procedure:
A mixture of 5-bromo-3-methoxyphenylacetonitrile (22.6 g, 0.1 m) and 10% aqueous sodium hydroxide (300 ml) in ethanol (225 ml) is heated to 95° for 18 hours. The mixture is concentrated in vacuo, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed, dried with sodium sulfate and concentrated in vacuo to give 5-bromo-3-methoxyphenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:27])[C:12]3[CH:19]=[C:18]([CH2:20][NH:21][CH2:22][CH:23]([OH:26])[CH2:24]Cl)[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[SH:38].[CH:39](N(C(C)C)CC)(C)C.[Na+].[Cl-]>CCO>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:27])[C:12]3[CH:19]=[C:18]([CH2:20][N:21]([CH2:22][CH:23]([OH:26])[CH2:24][S:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][CH3:30])[CH3:39])[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccccc1S
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CNCC(O)CCl)oc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1SCC(O)CN(C)Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(((3-chloro-2-hydroxypropyl)amino)methyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 63, 0.181 g), 2-methoxythiophenol (0.058 mL), and diisopropylethylamine (0.097 mL) in absolute EtOH (16 mL) was heated to reflux overnight. The reaction was poured into 50% saturated aqueous NaCl (50 mL) and extracted with CHCl3. The combined organic layers were dried and concentrated. The crude product was purified by column chromatography (acetone/CHCl3/NH4OH; 1/2/0.5%) and triturated with Et2O/hexanes. The resulting solid was collected and dried overnight to yield 0.10 g of the title compound as a white solid. Physical characteristics. M.p. 145-147° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.66, 8.52, 7.40, 7.34, 7.22, 7.13, 6.89, 4.96, 4.55, 3.84-3.64, 3.02, 2.84, 2.55, 2.44, 2.29; 13C NMR (DMSO-d6) δ 174.1, 165.7, 157.4, 154.5, 152.7, 143.1, 140.0, 132.8, 130.5, 129.8, 128.1, 127.4, 126.8, 122.3, 116.6, 115.2, 112.0, 107.2, 68.8, 62.1, 56.9, 55.0, 44.3, 42.7, 38.8, 37.5. Anal. Found: C, 60.38; H, 5.56; N, 7.45.
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=2)[C:13]([OH:28])=[C:12]([C:29](OCC)=[O:30])[C:11]1=[O:34].[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>>[O:35]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=2)[C:13]([OH:28])=[C:12]([C:29]([NH:40][CH2:39][CH2:38][O:37][CH3:36])=[O:30])[C:11]1=[O:34]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCS2(=O)=O)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCS2(=O)=O)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 202 and was obtained as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1 H), 8.55 (s, 1 H), 7.85 (s, 1 H), 7.23 (m, 2 H), 6.99 (t, J=8.7 Hz, 2 H), 4.37 (t, J=7.2 Hz, 2 H), 4.10 (s, 2 H), 3.64 (q, J=5.2 Hz, 2 H), 3.58 (m, 2 H), 3.43-3.35 (m, 4 H), 3.41 (s, 3 H), 2.95 (t, J=6.1 Hz, 2 H), 2.17 (m, 2 H), 1.57 (m, 2 H); MS m/z 533 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][C:14]=1[NH2:22].[SH:23][C:24]1[N:28]([CH3:29])[CH:27]=[N:26][N:25]=1>>[CH3:29][N:28]1[CH:27]=[N:26][N:25]=[C:24]1[S:23][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:22][C:14]1[S:15][C:16]2[C:21]([N:13]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Nc1nc2cccnc2s1
Reactant: Cn1cnnc1S
Product: Cn1cnnc1Sc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1

Procedure:
The compound of Example 6 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, thiazolo[5,4-b]pyridin-2-yl-amine and 3-mercapto-4-methyl-1,2,4-triazole.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([N:24]4[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[C:25]4=[O:31])=[C:19]([CH3:32])[CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1CCCC1=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([N:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:34][CH2:35][Cl:36])[C:25]4=[O:31])=[C:19]([CH3:32])[CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc(C)c1-n1cccc(O)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc(C)c1-n1cccc(OCCCl)c1=O
Temperature: 60 °C
Reaction time: 15 h

Procedure:
900 mg (1.89 mmol) of the compound from Example 72A and 1.36 g (9.49 mmol) of 1-bromo-2-chloroethane are dissolved in 30 ml of 1-methyl-2-pyrrolidone. 1.55 g (4.75 mmol) of caesium carbonate are added to the solution, and the mixture is stirred at 60° C. for 15 hours. Water is then added, and, after phase separation, the aqueous phase is extracted three times with tert-butyl methyl ether and three times with dichloromethane. The combined organic phases are washed successively with 1N aqueous sodium hydroxide solution and saturated sodium chloride solution and then dried over sodium sulphate. The drying agent is filtered off and the solvent is removed completely on a rotary evaporator. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:5). This gives 464 mg (45% of theory, purity according to LC-MS 74%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:18][C:19]1[NH:23][N:22]=[CH:21][CH:20]=1.[CH2:24]1[CH:26]([CH2:27][C:28]([NH2:30])=[O:29])[CH2:25]1.[CH3:31][C:32]1([CH3:40])[CH2:39][C:37](=O)[CH2:36][C:34](=[O:35])[CH2:33]1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[C:36]4[C:34](=[O:35])[CH2:33][C:32]([CH3:40])([CH3:31])[CH2:39][C:37]=4[NH:18][C:19]4[NH:23][N:22]=[CH:21][C:20]3=4)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:25]1[CH:26]([CH2:27][C:28]([NH2:30])=[O:29])[CH2:24]1
Reactant: O=C/C=C/c1ccc(-c2cccc(F)c2)cn1
Reactant: Nc1ccn[nH]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: NC(=O)CC1CC1
Solvent: CCO
Product: CC1(C)CC(=O)C2=C(C1)Nc1[nH]ncc1C2/C=C/c1ccc(-c2cccc(F)c2)cn1

Procedure:
According to general procedure A, a mixture of 50 mg of (E)-3-[5-(3-fluorophenyl)pyridin-2-yl]propenal, 40 mg of 5-amino-1H-pyrazole-3-cyclopropylmethylcarboxamide, 31 mg of dimedone and 5 ml of ethanol is boiled under reflux for 2 hours. After cooling, the mixture is concentrated and purified by column chromatography (silica gel, methanol:DCM=5:95).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:12])[CH:11]=1.ClC(Cl)C(O)=O.[I:35]N1C(=O)CCC1=O>C(#N)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:12])[C:11]=1[I:35]
Reactant: COC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)cc2=O)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C(O)C(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(I)c2=O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a suspension of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (2.53 g, 6.55 mmol) and dichloroacetic acid (0.27 mL, 3.27 mmol) in acetonitrile (20 mL) was added N-iodosuccinimide (1.62 g, 7.20 mmol). Stirred at ambient temperature for 3.5 h. Cooled reaction mixture (0° C.), filtered solid, washed with cold acetonitrile, and dried in vacuo overnight. Obtained product as white solid (2.72 g, 81%). 1H NMR (CD3OD/400 MHz) δ8.24 (s, 1H), 8.07 (m, 1H), 7.93 (s, 1H), 7.63 (q, 1H, J=8.4 Hz), 7.54 (d, 1H, J=8.0 Hz), 7.01 (t, 2H, J=8.4 Hz), 5.57 (s, 2H), 3.90 (s, 3H), 2.19 (s, 3H). ESHRMS m/z 513.0143 (M+H calculated for C20H16F2IN2O4 requires 513.0117).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:10]1([C@@H:9]2[N:7]3[C:6](=[O:8])[CH2:5][CH2:4][CH:3]3[CH2:2][O:1]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(CO)N1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCC2CO[C@H](c3ccccc3)N12
Reaction time: 9 h
Yield: 86 %

Procedure:
A mixture of 5-hydroxymethyl-2-pyrrolidone (85.0 g), benzaldehyde (98.0 g), p-toluenesulfonic acid (1.6 g) and toluene (500 ml) was heated to reflux using a Dean-Stark water separator and an oil bath, with vigorous stirring. After nine hours, the collection of water stopped and the cooled reaction mixture was washed with 5% sodium bicarbonate solution (2×50 ml), saturated sodium bisulfite solution (4×50 ml), water (2×50 ml) and brine (1×50 ml). The toluene solution was dried over anhydrous magnesium sulfate and the solvent removed on a rotary evaporator. The residue obtained was distilled, 145°-150° C./0.1 mm Hg to give the title compound as an oil (129.0 g). [α]D =+269.6° (chloroform; c=1). TLC single spot at Rf =0.5 (silica gel, ethyl acetate-hexane; 4:1 UV and iodine).