Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][CH:9]1[CH2:15][O:16][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC2CC(F)(F)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To a stirred mixture of 1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethanol (600 mg, 2.53 mmol), methyl 4-hydroxybenzoate (462 mg, 3.03 mmol), Ph3P (795 mg, 3.03 mmol) in THF (10 ml) was added DIAD (597 ul, 3.03 mmol) at room temperature. The mixture was heated at reflux for 3 h with stirring. After cooling to room temperature, the mixture was concntrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (4:1) as eluent to give methyl 4-[1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethoxy]benzoate (831 mg, 88%) as a colorless oil. 1H-NMR (CDCl3) δ1.48 (s, 9 H), 2.53-2.61 (m, 2 H), 3.63-4.41 (series of m, total 8 H), 6.94 (d, J=8.8 Hz, 2 H), 7.99 (d, J=8.8 Hz, 2 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([CH3:12])[CH2:7]1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH3:12][N:8]1[CH2:7][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:22]2[CH2:23][CH2:24][N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)[CH2:20][CH2:21]2)[O:10][C:9]1=[O:11]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CN1CC(CCCCCl)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CN1CC(CCCCN2CCN(c3ccccn3)CC2)OC1=O

Procedure:
Following the procedure of Example 1, the title compound is prepared from a mixture of 5-(4-chlorobutyl)-3-methyl-2-oxazolidinone (5.0 g, 0.0262 mol), 1-(2-pyridinyl)piperazine (4.56 g, 0.0279 mol) and potassium carbonate (8.5 g, 0.0614 mol) in 1-butanol (50 ml) to obtain 3.4 g (41% yield) of solid. Recrystallization from ethyl acetate/petroleum ether followed by drying in vacuo gave 1.46 g of the title compound, mp 69°-72° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][CH:27]([F:44])[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:32]2[CH:33]=[CH:34][C:29]([O:28][CH:27]([F:44])[F:26])=[CH:30][CH:31]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN(Cc1cc(-c2ccc(OC(F)F)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 111.5 %

Procedure:
tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), 2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (348 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (174 mg) were suspended in dimethoxyethane (10 mL) and water (4 mL), and the mixture was stirred under a nitrogen atmosphere at 105° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 550 mg, quantitative yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:25]#[N:26])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].CO>O.C(OCC)(=O)C.[Fe]>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:22][CH2:23][CH3:24])[N:12]=[CH:11][C:10]([C:25]#[N:26])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCOc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1N

Procedure:
A mixture of 2.5 g (6 mmol) of 4-[(3-bromophenyl)amino]-7-ethoxy-6-nitro-quinoline-3-carbonitrile, 2.4 g (45 mmol) of ammonium chloride, and 1.5 g (27 mmol) iron was stirred at reflux in 40 ml of water and 40 ml of methanol for 4 hours. The mixture was diluted with 500 ml of hot ethyl acetate and the hot mixture was filtered. The filtration was washed with saturated sodium chloride solution and then the organic layer was dried over sodium sulfate. The solution was concentrated and 1.5 of beige solid was collected: mass spectrum (electrospray, m/e): M+H 382.8 and 384.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:12]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[N:11][NH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(-c2cn[nH]c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A suspension of 4-(4-fluorophenyl)-1-trityl-1H-pyrazole (0.370 g) was suspended in a mixture solution of trifluoroacetic acid (5 ml)/methylene chloride (10 ml) and stirred for 10 min at room temperature, followed by irradiating microwaves thereto at 70° C. for 20 min to induce a reaction. After the reaction was terminated, the solution was diluted in methylene chloride (20 ml), neutralized with 1N sodium hydroxide (20 ml), and washed with distilled water (30 ml) and then with brine (20 ml). The washed organic layer thus formed was dried over anhydrous magnesium sulfate and concentrated by evaporation in a vacuum. The residue thus obtained was separated using silica gel chromatography to give 4-(4-fluorophenyl)-1H-pyrazole (Yield 81%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](OCC3C=CC=CC=3)=O)[CH2:25][CH2:24]2)[N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[H][H]>CO.C(O)(=O)C.[Pd]>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][N:11]2[C:10]([CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[C:12]2[CH3:13])=[CH:21][CH:20]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)cc(C2CCN(C(=O)OCc3ccccc3)CC2)n1CCc1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(C(=O)OC(C)(C)C)cc(C2CCN(C)CC2)n1CCc1ccc(F)cc1

Procedure:
A 340 mg portion of benzyl 4-{4-(tert-butoxycarbonyl)-1-[2-(4-fluorophenyl)ethyl]-5-methyl-1H-pyrrol-2-yl}piperidine-1-carboxylate was dissolved in 7 ml of methanol, and 159 μl of 37% formalin, 3 drops of acetic acid and 45 mg of 10% palladium-activated carbon were added, followed by stirring at room temperature for 2 hours in an atmosphere of hydrogen. The reaction liquid was filtered through celite, the filtrate was concentrated under a reduced pressure, 50 ml of a saturated sodium bicarbonate aqueous solution was added to the residue, and the resulting solid was collected by filtration to obtain 232 mg of tert-butyl 1-[2-(4-fluorophenyl)ethyl]-2-methyl-5-(1-methylpiperidin-4-yl)-1H-pyrrole-3-carboxylate as a colorless solid.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:55][O:56][C:57]1[CH:65]=[C:64]2[C:60]([CH2:61][CH2:62][C:63]2=[O:66])=[CH:59][CH:58]=1>CO.ClCCl>[Br:1][CH:62]1[CH2:61][C:60]2[C:64](=[CH:65][C:57]([O:56][CH3:55])=[CH:58][CH:59]=2)[C:63]1=[O:66]
Reactant: [Br-]
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(Br)C2

Procedure:
49.2 g (102 mmol) of tetra-n-butylammonium tribromide are added in fractions over the course of 15 minutes, at room temperature, to 16.2 g (100 mmol) of 6-methoxy-indan-1-one dissolved in 400 ml of methanol and 1 liter of dichloromethane, and the mixture is then stirred overnight at room temperature. After evaporation, the residue is taken up in 500 ml of dichloromethane and washed twice with 250 ml of N hydrochloric acid. Drying over magnesium sulphate and concentration, and then rapid filtration over 500 g of silica (eluant: dichloromethane) yield 23.4 g of the desired product.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[N+:5]([C:8]1[CH:16]=[C:12]([C:13](O)=[O:14])[C:11](N)=[CH:10][CH:9]=1)([O-:7])=[O:6]>O>[N+:5]([C:8]1[CH:16]=[C:12]2[C:11](=[CH:10][CH:9]=1)[NH:4][C:2](=[O:3])[NH:1][C:13]2=[O:14])([O-:7])=[O:6]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 150 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
Urea (9.89 g, 0.165 mol) and 5-nitroanthranilic acid (6.00 g, 32.9 mmol) were heated to 200° C. with vigorous stirring for 1 h. The melt was allowed to cool to 150° C., and water (150 mL) was slowly added. The resulting slurry was sonicated for 1 h and stirred vigorously for an additional 2 h. It was then cooled to 0° C., and the precipitate was collected and rinsed with water to yield the titled compound (6.43 g, 94% yield). This material was dried in a vacuum oven and used without further purification. This compound did not yield MS data.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[OH:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[C:23](=[O:24])[CH2:22][CH2:21][C:20]2=[O:25])=[CH:15][CH:14]=1.N12CCN(CC1)CC2>O1CCCC1>[O:25]=[C:20]1[CH2:21][CH2:22][C:23](=[O:24])[N:19]1[C:16]1[CH:15]=[CH:14][C:13]([O:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:18][CH:17]=1
Reactant: O=C1CCC(=O)N1c1ccc(O)nc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: CN(C(=O)Oc1ccc(N2C(=O)CCC2=O)cn1)c1ccccc1
Yield: 84.5 %

Procedure:
A solution of N-methyl-N-phenyl carbamoyl chloride (170 mg, 1.00 mmol), 1-(6-hydroxy-pyridin-3-yl)-pyrrolidine-2,5-dione (192 mg, 1.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (112 mg, 1.00 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 4 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 80:20) yielding the title compound (275 mg, 85% yield) as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[N:6]1)[CH2:2][C:3]#[CH:4].B1C2CCCC1CCC2.[C:19]([O:23][C:24](=[O:33])[NH:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CN(C)C=O.C(OCC)(=O)C>[C:19]([O:23][C:24](=[O:33])[NH:25][C:26]1[CH:27]=[CH:28][C:29]([CH:4]=[CH:3][CH2:2][CH2:1][N:5]2[CH:9]=[CH:8][N:7]=[N:6]2)=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: C#CCCn1ccnn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(C=CCCn2ccnn2)cc1
Reaction time: 2 h
Yield: 32.8 %

Procedure:
A solution of 1-but-3-ynyl-1H-[1,2,3]triazole (0.76 g, 6.3 mmol) in anhydrous THF (50 ml) is treated with 9-BBN (0.5 M in THF, 27.6 ml, 13.8 mmol) at 0° C. and stirred for 2 h. This mixture is added to a solution of (4-iodo-phenyl)-carbamic acid tert-butyl ester (2 g, 6.3 mmol), [Pd(PPh3)2]Cl2 (0.51 g, 0.63 mmol) and aqueous potassium carbonate (3M, 6.3 ml, 18.8 mmol) in N,N-dimethyl formamide (50 ml) and stirred for 2 h at 70° C. After cooling to room temperature ethyl acetate (100 ml) is added and the solution extracted with water (2×50 ml). The organic layer is concentrated and the crude product purified by flash column chromatography (ethyl acetate/heptane 3:1) and washing with diethyl ether to yield [4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenyl]-carbamic acid tert-butyl ester as beige solid (0.65 g, 33%).
Reaction SMILES: CN([CH:4]=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:20]=[CH:19][C:16](C=O)=[CH:15][CH:14]=1.[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O>[CH2:21]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:19][C:20]=1[CH:4]=[O:5])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CN(C)C=O
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCCCOc1ccccc1C=O
Yield: 80 %

Procedure:
To 250 ml of DMF containing 207 g of anhydrous potassium carbonate (1.5M) was added 122 g of 4-hydroxybenzaldehyde and 181.6 g of hexylbromide. The resultant mixture was heated at reflux temperature overnight after which it was poured into cold water and extracted with ethylacetate. The extracts were dried and evaporated in vacuo to afford the desired subtitled intermediate (80% yield), b.p. 110°-115° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:54]1([C:60]2[CH:68]=[CH:67][C:63]([C:64](O)=[O:65])=[CH:62][CH:61]=2)[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:64](=[O:65])[C:63]1[CH:67]=[CH:68][C:60]([N:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)=[CH:61][CH:62]=1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 21.8 %

Procedure:
DIPEA (188.6 mg, 0.25 mL, 1.45 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (282.2 mg, 0.8 mmol) in DMF (4 mL). HOBT (108 mg, 0.8 mmol) and EDCI (279.7 mg, 1.45 mmol) were then added at room temperature. After 2 minutes, 4-piperidin-1-yl-benzoic acid (150 mg, 0.729 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 80 mg (21.7% yield) N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-benzamide. LCMS Purity: 94.74%. 1H NMR (DMSO-d6): δ 8.2 (s, 1H), 7.9-7.5 (m, 6H), 7.0-6.9 (d, 2H), 4.2-4.0 (d, 2H), 3.8-3.5 (m, 4H), 3.35-3.2 (m, 4H), 3.2-3.0 (m, 4H), 1.7-1.5 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]1(=[O:17])[CH2:15][CH2:14][CH2:13][C:12](=O)[CH2:11]1.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](=[NH:25])[NH2:24])[CH3:19]>C(O)C>[CH2:18]([O:20][C:21]([C:22]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Br:1])[C:11]2[C:10](=[O:17])[CH2:15][CH2:14][CH2:13][C:12]=2[NH:24][C:23]=1[NH2:25])=[O:26])[CH3:19]
Reactant: O=C1CCCC(=O)C1
Reactant: O=Cc1ccccc1Br
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1ccccc1Br
Yield: 46 %

Procedure:
Upon boiling a solution of 9.3 g of 2-bromobenzaldehyde, 5.6 g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 6 hours, 2-amino-4-(2-bromopheny)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 245°C (ethanol) is obtained. Yield: 46% of theory.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:23][C:24]([O:26][CH2:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2)=[O:25])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([O:21]C)=O)=[CH:15][CH:16]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:39][C:40]1[NH:41][CH2:42][CH2:43][CH2:44][N:45]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:23][C:24]([O:26][CH2:27][C:28]12[CH2:29][CH:30]3[CH2:36][CH:34]([CH2:33][CH:32]([CH2:31]3)[CH2:37]1)[CH2:35]2)=[O:25])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:21])[NH:39][C:40]2[NH:45][CH2:44][CH2:43][CH2:42][N:41]=2)=[CH:15][CH:16]=1)=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)s1
Reactant: NC1=NCCCN1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.5 %

Procedure:
1.37 g (2.5 mmol) of the product obtained in step b) were dissolved in 12 ml of anhydrous dimethylformamide, and after addition of 1.24 g of 2-amino-1,4,5,6-tetrahydropyrimidine the mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo and the residue was chromatographed (silica gel; ethyl acetate/methanol (1/1; v/v)) to give 1.1 g of the title compound.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[N:34]([CH3:36])[CH3:35])[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[C:23]([C:22]1[CH:31]=[CH:32][C:33]([N:34]([CH3:36])[CH3:35])=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:21]=1)(=[O:24])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2)cc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: CN(C)c1ccc(C(=O)c2ccccc2)cc1NC(=O)c1ccn2c1CSC2c1cccnc1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 25.7 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 70° and 76° C., to a solution of 3-amino-4-dimethylaminobenzophenone (4.8 g) and triethylamine (4.05 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 70° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 7 hours and 10 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 1N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (10.1 g) is thereby obtained, which is dissolved in boiling acetonitrile (80 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 20° C. for 2 hours. The crystals formed are separated by filtration, washed twice with acetonitrile (50 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(5-benzoyl-2-dimethylaminophenyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (2.4 g) in the form of yellow crystals, m.p. 186° C., is thereby obtained.
Reaction SMILES: CC1C=C(C)C=C(C)C=1O.[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1O.[C:22]1([NH:28]C(=O)CCl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C1(C)C=CC=CC=1.CN(C)C=O>[C:22]1([NH:28][C:15]2[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: O=C(CCl)Nc1ccccc1
Agent: Cc1cc(C)c(O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cccc(Cl)c1Nc1ccccc1
Yield: 91 %

Procedure:
37.6 g of 2,4,6-trimethyl phenol and 11 g of sodium hydroxide were dissolved in 30 ml of water and mixed with 150 ml of toluene. The toluene recovered from heating was mixed with 139 ml of N,N-dimethylformamide to obtain a N,N-dimethylformamide solution. 40 g of 2,6-dichlorophenol was dissolved in 130 ml of toluene, followed by the addition of 9.8 g of sodium hydroxide in 20 ml of water, 41.5 g of N-phenyl chloroacetamide and 8.7 ml of N,N-dimethylformamide, and refluxed in a oil bath at 140°-150° C. for 15 h. The toluene was recovered from the reflux, and mixed with the above N,N-dimethylformamide solution and reacted for 3 h. Recovering N,N-dimethylformamide from the reacted mixture with distillation under reduced pressure (145°-150° C., 8 mm Hg) resulted in the formation of 53 g of N-phenyl 2,6-dichloroaniline and the product yield was 90.75%.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:15]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(Cc2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(Cc2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
A mixture of hydroxylammonium chloride (6.23 g), sodium hydrogen carbonate (10.1 g) and dimethyl sulfoxide (30 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-6-oxo-4-propyl-1-(pyridin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.6 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (1.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.99 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (2.07 g, 70%).