Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10](Cl)[CH:9]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:3]1=[O:27].C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C)C=O>[CH3:1][C:2]1([CH3:28])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:9]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:3]1=[O:27]
Reactant: C1COCCN1
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc(N2CCOCC2)c1
Temperature: 210 °C
Reaction time: 0.83 h

Procedure:
A sealed 2.5 ml tube containing 0.05 g of 5,5-dimethyl-1-(2-chloropyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione, 0.5 ml of dimethylformamide, 0.034 g of potassium carbonate and 0.021 ml of morpholine is placed in a Personal Chemistry Emrys Optimiser microwave oven. The mixture is irradiated with magnetic stirring at 210° C. for about 50 minutes. The reaction mixture is placed on a Bond Elut Varian cartridge of reference 1225-6053 containing 2 g of SCX phase conditioned with dimethylformamide. The cartridge is washed with methanol and then eluted with 2M ammoniacal methanol. The ammoniacal fractions are concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography using a cartridge 16 mm in diameter packed with 2 g of conditioned 15-35 μm silica, and then eluted with a mixture (cyclohexane/ethyl acetate)(8/2)(v/v) at a flow rate of 10 ml/minute. The fractions between 160 and 260 ml are concentrated to dryness under reduced pressure. 0.01 g of 5,5-dimethyl-1-(2-morpholinopyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained in the form of a powder, the characteristics of which product are as follows:
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[NH:14][N:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CN(C)C=O.[Pd]>[CH2:8]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][N:13]=[CH:12]2)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]ncc2cc(C=Cc3ccccc3)ccc12
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=c1[nH]ncc2cc(CCc3ccccc3)ccc12

Procedure:
A slurry of 11.2 gm 6-(2-phenylethenyl)-1(2H)-phthalazinone, from the previous example, in 115 ml dimethylformamide was hydrogenated with 1.0 gm 10% palladium on carbon catalyst at 50 psig for 3 hours. The catalyst was filtered off and rinsed with a little dimethylformamide. The filtrate was added to 5 volumes of water, stirred for a few minutes, filtered, washed with water and air dried. Wt=7.8 gm, m.p.=190°-193°. After recrystallization from 80 ml n-butanol the product weighed 6.4 gm and melted at 192°-193°.
Reaction SMILES: [H-].[Na+].[C:3]([SH:7])(=[S:6])[CH2:4][CH3:5].[CH2:8]([O:11][C:12]([N:14]1[CH2:18][C@H:17](OS(C)(=O)=O)[CH2:16][C@H:15]1[CH2:24][O:25][CH2:26][CH2:27][F:28])=[O:13])[CH:9]=[CH2:10]>O1CCCC1>[CH2:8]([O:11][C:12]([N:14]1[CH2:18][C@@H:17]([S:6][C:3](=[S:7])[CH2:4][CH3:5])[CH2:16][C@H:15]1[CH2:24][O:25][CH2:26][CH2:27][F:28])=[O:13])[CH:9]=[CH2:10]
Reactant: CCC(=S)S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COCCF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](SC(=S)CC)C[C@H]1COCCF
Temperature: 0 °C
Yield: 60 %

Procedure:
To a suspension of sodium hydride (60% in oil, 2.0 g) in anhydrous tetrahydrofuran (50 ml) was added propanedithioic acid (5.0 g) with ice-cooling. A solution of (2S,4R)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)-4-methylsulfonyloxypyrrolidine (16.25 g) in anhydrous tetrahydrofuran (50 ml) was added dropwise to the mixture and the mixture was heated at 60°-70° C. for 4 hours. The solution was poured into ice-water (100 ml) and extracted with diethyl ether. The organic layer was washed with 1N aqueous sodium hydroxide solution (50 ml) and brine, dried, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel [n-hexane-ethyl acetate (10:1, V/V)] to afford (2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)-4-[(1-thioxopropyl)thio]pyrrolidine (9.47 g).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([Li])CCC.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>C1COCC1>[CH2:27]([C:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])(=[O:6])=[O:5])[CH2:2][CH2:3]1)[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=[CH2:21]
Reactant: C=CCCCCCBr
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCCCCC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.3 %

Procedure:
To a solution of tert-butyl cyclopropylsulfonylcarbamate (885 mg, 4 mmol) in THF (20 mL) at −78° C. was added n-Butyllithium (3.36 mL, 8.40 mmol) (2.5 M in hexanes) dropwise. The formed solution was warmed up to r.t. and stirred for 1.5 h. Cooled this light yellow solution back to −78° C. 7-Bromo-1-heptene (1.219 mL, 8.00 mmol) was added dropwise. The final solution was allowed to warm up to r.t. over the period of 16 h. Quenched with sat. NH4Cl, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by Biotage column, eluted with gradient 5%˜40% EtOAc-Hexane to afford the desired product tert-butyl 1-(hept-6-enyl)cyclopropylsulfonylcarbamate (625 mg, 1.772 mmol, 44.3% yield) as a viscous oil, which solidified upon standing on bench. 1H NMR (400 MHz, CHLOROFORM-D) ppm 0.88-1.02 (m, 2 H) 1.26-1.49 (m, 6 H) 1.53 (s, 9 H) 1.60-1.71 (m, 2 H) 1.82-1.94 (m, 2 H) 2.06 (q, J=6.94 Hz, 2 H) 4.81-5.08 (m, 2 H) 5.68-5.88 (m, 1 H) 6.88 (b, NH). LC-MS (retention time: 2.76 min, Method A), MS m/z 218 (M+H-Boc).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]([N:19]([CH:29]([CH3:33])[C:30](=O)[CH3:31])[C:20](=[O:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1)[CH3:10]>O>[CH3:8][C:9]([N:19]1[CH:29]([CH3:33])[C:30]([CH3:31])=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:20]1=[O:28])([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1)[CH3:10]
Reactant: CC(=O)C(C)N(C(=O)Cc1ccccc1)C(C)(C)c1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cc(Cl)cc(Cl)c2)C1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To 15 ml of toluene were added 2.2 g of N-[1-methyl-1-(3,5-dichlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)-2-phenylacetamide and 3.5 g of 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), followed by stirring at room temperature for 1 hour. After water was added, the solution was extracted with ethyl acetate, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the solution was subjected to silica gel column chromatography to obtain 1.1 g of the desired 1-[1-methyl-1-(3,5-dichlorophenyl)ethyl]-4,5-dimethyl-3-phenyl-3-pyrroline-2-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19]([NH2:21])=[O:20])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[CH:22]1[CH:27]=CC=C[CH:23]=1.CCCBr>C(N(CC)CC)C>[CH2:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19]([NH2:21])=[O:20])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][CH3:27]
Reactant: c1ccccc1
Reactant: NCCCCC1(C(N)=O)c2ccccc2-c2ccccc21
Solvent: CCCBr
Solvent: CCN(CC)CC
Product: CCCNCCCCC1(C(N)=O)c2ccccc2-c2ccccc21

Procedure:
A solution of 9-(4-aminobutyl)-9-aminocarbonylfluorene in benzene containing one equivalent of n-propyl bromide and triethylamine is stirred for several hours. Removal of the reaction solvent and distillation of the product affords 9-(4-n-propylaminobutyl)-9-aminocarbonylfluorene.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]#[N:30].[I-].[K+]>CC(C)=O.O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:28][C:29]#[N:30])[CH:3]=1
Reactant: O=c1c(-c2ccccc2Cl)coc2cc(O)cc(Cl)c12
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#CCOc1cc(Cl)c2c(=O)c(-c3ccccc3Cl)coc2c1
Yield: 88.7 %

Procedure:
In 50 ml of acetone was dissolved 1.4 g of 5-chloro-3-(2-chlorophenyl)-7-hydroxy-4-oxo-4H-1-benzopyran, and 0.7 g of anhydrous potassium carbonate, 0.38 g of chloroacetonitrile and 0.15 g of potassium iodide were added to the solution, followed by refluxing for 8 hours. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol gave 1.4 g of the entitled compound having a melting point of 174° to 175° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[CH3:20][NH:21][CH3:22].O.Cl>O1CCCC1.C(O)C>[CH3:20][N:21]([CH3:22])[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2
Reactant: ClCCC=C1c2ccccc2COc2ccccc21
Reactant: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CN(C)CCC=C1c2ccccc2COc2ccccc21
Yield: 73.4 %

Procedure:
5.4 g (0.02 mol) of the 11-(3-chloropropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine, prepared according to (c) above, in 20 mL tetrahydrofuran and 5.5 g (0.12 mol) dimethylamine in 20 mL ethanol is heated together for 3 hours using a glass autoclave and a temperature of 95-100° C. (boiling water bath). Water and 6 N hydrochloric acid are added to the contents of the autoclave and the mixture is extracted with ether. The separated, aqueous-acid components are then made alkaline with dilute caustic soda solution, and the oil thereby separated is taken up in ether. The ether residue, after distillation in a high vacuum, produces 4.1 g (73.5% of theory) of 11-(3-dimethylamino-propylidene)-6,11-dihydrodibenzo-[b,e]-oxepine, having a B.P.0.1 147-150° C. The melting point of the hydrochloride is 182-184° C. (recrystallized from isopropanol).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=C(CC(N)=O)C=CC=1OC.[C:24]1([C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([CH2:34][CH:35]=O)[CH2:31][CH:32]=O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)(CC=O)CC=O>>[C:1]([N:9]1[CH:32]=[CH:31][C:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:35]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=CCC(CC=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(CC=O)CC=O
Agent: COc1ccc(CC(N)=O)cc1OC
Product: O=C(c1ccccc1)N1C=CC(c2ccccc2)(c2ccccc2)C=C1

Procedure:
The title compound was prepared using the method of Example 2b after substituting equivalent quantities of benzamide for (3,4-dimethoxyphenyl)acetamide and 3,3-diphenylglutaraldehyde (the compound of Example 4a) for 3,3-dimethylglutaraldehyde as starting materials. The crude product was purified by silica gel flash chromatography eluting with a 7% ethyl acetate/hexane solution. The eluate was evaporated in vacuo to yield a clear oil which, after triturating with methanol, gave the title compound as a white solid, mp 91°-93° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH3:67])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][CH:60]5[CH2:65][CH2:64][N:63]([CH2:66][CH3:67])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CCN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(CC)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino 1-N-ethyl piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47-2.04 (m, 16 H) 2.32 (q, J=7.07 Hz, 3 H) 2.88 (d, J=11.62 Hz, 2 H) 3.28 (s, 3 H) 3.67-3.87 (m, 3 H) 3.94 (s, 3 H) 4.87 (d, J=8.34 Hz, 1 H) 5.30-5.45 (m, 2 H) 6.01 (ddd, J=17.43, 12.88, 10.86 Hz, 1 H) 7.46 (d, J=1.77 Hz, 2 H) 7.82 (s, 1 H) 8.12 (s, 2 H) 8.30 (d, J=8.08 Hz, 1 H). [M+H] calc'd for C30H40FN7O3, 566; found 566.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[N:11][C:10]2[C:9](O)=[N:8][CH:7]=[N:6][C:5]=2[CH:4]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:27].O>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:27][C:9]1[C:10]2[N:11]=[CH:12][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2cc(C(F)(F)F)cnc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: FC(F)(F)c1cnc2c(Cl)ncnc2c1
Temperature: 115 °C

Procedure:
7-Trifluoromethyl-pyrido[3,2-d]pyrimidin-4-ol (300 mg, 1.39 mmol) was dissolved in toluene (5 ml). DIPEA (541 mg, 4.18 mmol) and POCl3 (641 mg, 4.18 mmol) were added and the reaction mixture was heated to 115° C. (external temperature). The reaction was cooled to rt and partioned between water (50 ml) and EtOAc (50 ml). The phases were separated and the aq phase was extracted twice with EtOAc (25 ml). The combined organic layer was washed with NaHCO3 solution and brine, treated with MgSO4 and filtered. The filtrate was concentrated, redissolved in DCM and filtered over silica and again concentrated to give the desired product as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[CH2:10][CH3:11].P(Br)(Br)[Br:14]>>[Br:14][CH:9]([C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH2:10][CH3:11]
Reactant: CCC(O)c1cc(F)ccc1F
Reactant: BrP(Br)Br
Product: CCC(Br)c1cc(F)ccc1F

Procedure:
rac-2-(1-Bromo-propyl)-1,4-difluoro-benzene was prepared from rac-1-(2,5-difluoro-phenyl)-propan-1-ol and phosphorus tribromide in analogy to Example 23 b): colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)[N:9]2[CH:20]=[CH:21][N:22]=[C:8]2[NH:7][C:6]=1[CH3:23])=[O:4]>[C].[Pd].C(O)(=O)C>[NH2:17][C:13]1[CH:12]=[C:11]([CH:10]2[N:9]3[CH:20]=[CH:21][N:22]=[C:8]3[NH:7][C:6]([CH3:23])=[C:5]2[C:3]([O:2][CH3:1])=[O:4])[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C1=C(C)Nc2nccn2C1c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)Nc2nccn2C1c1cccc(N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
A mixture of 20.0 g of 6-methoxycarbonyl-7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine, 200 ml of acetic acid and 3.0 g of 10 palladium-carbon is stirred at room temperature for 5 hours under hydrogen gas. After an insoluble material is filtered off, the filtrate is neutralized with sodium bicarbonate, and extracted with chloroform. The extract is dried and the solvent is distilled off under reduced pressure. The precipitated pale yellow crystals are collected by filtration and recrystallized from methanol to give 11.0 g of 5-(3-aminophenyl)-6-methoxycarbonyl-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 224°-225° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:20]([O:22][C:23]([CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:6][CH:7]=1)=[O:26])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Yield: 52.3 %

Procedure:
To 40 ml of methyl ethyl ketone were added 2.6 g of 2-(p-hydroxyphenyl)imidazo[2,1-b]benzothiazole, 1.7 g of monobromoacetic acid ethyl ester, and 1.5 g of potassium carbonate and the mixture was refluxed overnight. After the reaction was over, the reaction mixture was cooled, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure to provide solid materials, which were recrystallized from toluene-n-hexane to provide 1.8 g of 2-(p-ethoxycarbonylmethoxyphenyl)imidazo[2,1-b]benzothiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6]C(CO)=[CH:4][N:3]=1.[C:10]([O:13][C:14](=O)[CH3:15])(=[O:12])[CH3:11]>N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH3:6])=[CH:15][C:14]([O:13][C:10](=[O:12])[CH3:11])=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(CO)cn1
Solvent: c1ccncc1
Product: CC(=O)Oc1cnc(C)c(C)c1

Procedure:
2-Methyl-5-hydroxymethylpyridine (0.1 mole) is stirred in pyridine (50 ml.) with acetic anhydride (0.15 mole) at room temperature overnight. The mixture is concentrated to dryness, and the residue is dissolved in 70 ml. of water and extracted with 3 × 25 ml. of chloroform. After drying over magnesium sulfate, the chloroform is concentrated to dryness to give 2-methyl-5-acetoxy-methylpyridine.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]([F:35])([F:34])[O:20][C:21]1[CH:33]=[CH:32][C:24]([CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[F:34][C:19]([F:18])([F:35])[O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]([NH:5][C@@H:6]3[CH2:11][O:10][C:9]4=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]4[CH2:7]3)=[O:4])[CH2:28][CH2:27]2)=[CH:32][CH:33]=1
Reactant: FC(F)(F)Oc1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: O=C(CN1CCC(Cc2ccc(OC(F)(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 62.1 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(trifluoromethoxy)benzyl)piperidine (259 mg, 1.0 mmol) as crude materials, 150 mg title compound was generated and yield was 62%.
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1.[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:70])([F:69])[F:68])[CH:62]=4)=[S:59])=[CH:53][CH:52]=3)[CH:48]=2)[C:43]1=[O:71])[C:38]([O:40]C)=[O:39]>>[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:51]3[CH:52]=[CH:53][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:69])([F:70])[F:68])[CH:62]=4)=[S:59])=[CH:55][CH:56]=3)[CH:48]=2)[C:43]1=[O:71])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Yield: 77 %

Procedure:
The compound of example 283 was prepared analogous to compound of example 257 by hydrolysis of compound of example 282.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21].O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21]
Reactant: O=c1c2cc(Br)ccc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 47.4 %

Procedure:
Prepared according to Procedure C using Intermediate 2b (200 mg, 0.519 mmol), 6-mercaptopurine monohydrate (97 mg, 0.570 mmol), K2CO3 (79 mg, 0.572 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 123 mg of an off-white solid (47%), mp 212-242° C. (gradually decomposes). 1H NMR (DMSO-d6) δ: 13.07 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 8.24 (d, J=2.3 Hz, 1H); 8.06 (dd, J=2.3, 8.7 Hz, 1H); 7.76 (dd, J=1.9, 7.4 Hz, 1H); 7.70 (d, J=8.7 Hz, 1H); 7.66 (d, J=8.1 Hz, 1H); 7.51 (dd, J=2.1, 7.9 Hz, 1H); 7.46 (dd, J=1.9, 7.9 Hz, 1H); 4.47 (s, 2H). 13H NMR (DMSO-d6) ppm: 159.7, 156.8, 153.6, 151.5, 146.1, 143.6, 138.5, 134.0, 132.1, 131.8, 131.5, 130.5, 130.2, 129.9, 128.9, 128.8, 122.2, 120.3, 32.0. MS (ES): m/z 499.0 (M+). Anal. calcd. for C20H12ClBrN6OS∘0.2C2H6O∘0.05KCl: C, 47.79; H, 2.59; N, 16.39; S, 6.25. Found: C, 47.56; H, 2.54; N, 16.25; S, 6.58.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.P(Cl)(Cl)Cl.C(Cl)Cl.CO>ClC1C=CC=CC=1>[SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:6]
Reactant: O=C(O)c1cccnc1S
Reactant: NCc1cccs1
Solvent: ClCCl
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(NCc1cccs1)c1cccnc1S
Temperature: 145 °C
Yield: 24.1 %

Procedure:
A suspension of 8.0 g (51.5 mmol) of 2-mercaptonicotinic acid, 5.8 g (51.5 mmol) of 2-(aminomethyl)-thiophene and 3.5 g (25.8 mmol) of phosphorus trichloride in chlorobenzene (260 ml) was heated for 3 h under reflux (145° C.). When the reaction solution had cooled to 60° C., filtration with suction was carried out at that temperature. The solid obtained was taken up in a DCM/MeOH mixture (3:1, vv, 300 ml) and washed with water (2×50 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. Crystallization of the residue from ethyl acetate yielded 3.1 g (12.4 mmol, 24%) of 2-mercapto-N-(thiophen-2-ylmethyl)nicotinamide.