Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:15]([CH3:17])[CH3:16])=[C:11]([CH2:13]I)[N:12]=1.[C-:18]#[N:19].[Na+].O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:15]([CH3:17])[CH3:16])=[C:11]([CH2:13][C:18]#[N:19])[N:12]=1
Reactant: CC(C)c1oc(-c2ccccc2Cl)nc1CI
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1oc(-c2ccccc2Cl)nc1CC#N
Temperature: 25 °C
Yield: 8.7 %

Procedure:
In acetone (2 mL) was dissolved 2-(2-chlorophenyl)-4-iodomethyl-5-isopropyloxazole (590 mg, 1.63 mmol). Sodium cyanide (88 mg, 1.63 mmol) was added, and the resulting mixture was heated under reflux for 22 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography on silica gel (hexane/ethyl acetate=5/1), to obtain the desired compound (37 mg, 82%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH:24]([OH:26])[CH3:25])[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([C:24](=[O:26])[CH3:25])[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: COC(=O)C(NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxybutanoate (1.5 g, 4.22 mmol) in DCM (25 mL) was added portionwise Dess-Martin periodinane (1.790 g, 4.22 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with DCM and a 1:1 2M sodium carbonate (aq) and saturated sodium sulphite solution (aq) were added and stirred at room temperature for 15 minutes. The layers were separated and the organic layer dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][C:28]([CH:34]=O)=[CH:29][CH:30]=2)[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:28]3[CH:27]=[C:26]4[C:31]([CH2:32][CH2:33][C:24](=[O:23])[NH:25]4)=[CH:30][CH:29]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(c1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(c4)NC(=O)CC5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To 20 mL of a chloroform solution containing 176 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 102 mg of 2-oxo-1,2,3,4-tetrahydroquinoline-7-carbaldehyde, 34 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 200 mg of sodium triacetoxyborohydride was added, and stirred for 2.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=100:1] to give 178 mg of 7-methoxy-1-(2-(4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl)amino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a pale brown foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[OH-].[K+].[Cl:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C(=O)([O-])O.[Na+].Cl>CO.CN(C)C=O>[ClH:21].[C:13]1([C:6]2[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:29][CH2:30]4)=[CH:3][CH:4]=3)[NH:9][C:8](=[O:12])[CH:7]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClCCCN1CCC(c2ccccc2)CC1
Reactant: O=c1cc(-c2ccccc2)c2ccc(O)cc2[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1cc(-c2ccccc2)c2ccc(OCCCN3CCC(c4ccccc4)CC3)cc2[nH]1
Yield: 58 %

Procedure:
2.4 Grams of 7-hydroxy-4-phenylcarbostyril and 0.8 g of potassium hydroxide were mixed with 60 ml of methanol and concentrated under a reduced pressure to dryness. To the residue thus obtained was added 60 ml of dimethylformamide and well mixed, then 5 g of 1-(3-chloropropyl)-4-phenylpiperidine was added to the mixture and heated at 70°-80° C. for 8 hours under stir ring condition. The reaction mixture was concentrated under a reduced pressure to dryness, and to the residue thus obtained was added 60 ml of 5% sodium hydrogen-carbonate aqueous solution and extracted with chloroform. The chloroform layer was washed with water, dried and the chloroform was removed by distillation. To the residue thus obtained was added 30 ml of methanol and 5 ml of concentrated hydrochloric acid, and concentrated under a reduced pressure. The residue was crystallized with ethanol then recrystallized from methanol to obtain 2.8 g (58%) of 4-phenyl-7-[3-(4-phenyl-1-piperidyl)propoxy]carbostyril monohydrochloride as in the form of colorless needle-like crystals. Melting point: 238°-241° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH3:43])([CH3:42])[CH2:22][N:23]4[C:26](=[O:41])[CH2:27][N:28]([CH:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)C(=O)OC(C)(C)C)=[CH:19][CH:18]=3)[C:10]2=[O:44])[CH:5]=[CH:4][N:3]=1.[CH3:45][N:46]([CH3:50])[C:47]([NH2:49])=[O:48].CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:36]1([NH:28][CH2:27][C:26]([N:23]2[C:24]3[C:20](=[CH:19][CH:18]=[C:17]([N:11]4[C:12](=[O:16])[C:13]([CH3:15])([CH3:14])[N:9]([CH2:8][C:6]5[CH:5]=[CH:4][N:3]=[C:2]([NH:49][C:47](=[O:48])[N:46]([CH3:50])[CH3:45])[CH:7]=5)[C:10]4=[O:44])[CH:25]=3)[C:21]([CH3:42])([CH3:43])[CH2:22]2)=[O:41])[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CN(C)C(N)=O
Reactant: CC(C)(C)OC(=O)N(CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)cc21)C1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: CN(C)C(=O)Nc1cc(CN2C(=O)N(c3ccc4c(c3)N(C(=O)CNC3CCCC3)CC4(C)C)C(=O)C2(C)C)ccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.8 %

Procedure:
To a solution of 0.312 g of tert-butyl [2-(6-{3-[(2-chloropyridin-4-yl)methyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]cyclopentylcarbamate obtained in stage l) below in 12 mL of dioxane are successively added, under argon, 0.066 g of N,N-dimethylurea, 0.028 g of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) (Xantphos), 0.022 g of palladium acetate and 0.65 g of caesium carbonate. The reaction mixture is refluxed for 4 hours and then filtered and concentrated under reduced pressure. The residue is taken up in 10 mL of dioxane and then 12 mL of a 4N solution of hydrogen chloride in dioxane are added and the reaction mixture is stirred at room temperature for 15 hours. After concentrating under reduced pressure, the residue is taken up in 40 mL of water, neutralized by addition of sodium hydrogen carbonate and extracted with three times 20 mL of dichloromethane. The combined organic phases are then washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (90/10 by volume) to give 0.08 g of 3-[4-({3-[1-(N-cyclopentylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl}methyl)pyridin-2-yl]-1,1-dimethylurea, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:11][Si](C=[N+]=[N-])(C)C>O1CCCC1CO>[NH2:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC1(C(=O)O)CCCCC1
Solvent: OCC1CCCO1
Product: COC(=O)C1(N)CCCCC1
Yield: 52 %

Procedure:
To a solution of 1-aminocyclohexanecarboxylic acid (600 mg) in tetrahydrofuran-methanol was added dropwise trimethylsilyl diazomethane (4.2 mL) under ice-cooling and stirring, and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo, and to the residue were added successively diethylether-hexane (1/1) and a solution of 4N hydrochloric acid in ethyl acetate (1.05 mL). The precipitates were collected by filtration and dried to give methyl 1-amino-cyclohexanecarboxylate (423 mg, yield: 52%) as a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[N+:13]([O-])=O.Cl>C(O)C.[Pd]>[NH2:13][C:4]1[CH:5]=[C:6]([O:11][CH3:12])[C:7]([O:9][CH3:10])=[CH:8][C:3]=1[NH:2][CH3:1]
Reactant: CNc1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNc1cc(OC)c(OC)cc1N

Procedure:
A solution of 0.5 g (2.4 mmol) N-methyl-4,5-dimethoxy-2-nitroanilin in 150 ml ethanol was added 1 ml 4N hydrochloric acid, and the mixture was hydrogenated at atm. pressure by using 5% Pd-C (0.1 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo to give 2-amino-4.5-dimethoxy-N-methylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[NH:11][C:12]2[C:13]3[N:26]=[N:25][N:24]([CH:27]4[CH2:31][CH2:30][CH:29]([OH:32])[CH:28]4[OH:33])[C:14]=3[N:15]=[C:16]([S:18]([CH2:21][CH2:22][CH3:23])(=O)=O)[N:17]=2)=[CH:4][CH:3]=1.[CH2:34](S)CCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[NH:11][C:12]2[C:13]3[N:26]=[N:25][N:24]([CH:27]4[CH2:31][CH2:30][CH:29]([OH:32])[CH:28]4[OH:33])[C:14]=3[N:15]=[C:16]([S:18][CH2:21][CH2:22][CH2:23][CH3:34])[N:17]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)c1nc(NC2CC2c2ccc(Cl)cc2)c2nnn(C3CCC(O)C3O)c2n1
Reactant: CCCCS
Product: CCCCSc1nc(NC2CC2c2ccc(Cl)cc2)c2nnn(C3CCC(O)C3O)c2n1

Procedure:
The title compound was prepared as described in Example 8 using the product from step b) and butanethiol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[CH2:11][C@:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)([CH2:14][CH2:15][CH3:16])[N:13]=1)(C)(C)C.[F:27][C:28]([F:36])([F:35])[C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[NH2:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[CH2:11][C@:12]([C:17]2[CH:18]=[C:19]([NH:23][C:32]([C:29]3([C:28]([F:36])([F:35])[F:27])[CH2:31][CH2:30]3)=[O:33])[CH:20]=[CH:21][CH:22]=2)([CH2:14][CH2:15][CH3:16])[N:13]=1
Reactant: CCC[C@@]1(c2cccc(N)c2)CC(=O)N(C)C(NC(=O)OC(C)(C)C)=N1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Product: CCC[C@@]1(c2cccc(NC(=O)C3(C(F)(F)F)CC3)c2)CC(=O)N(C)C(N)=N1

Procedure:
The coupling of [(S)-4-(3-amino-phenyl)-1-methyl-6-oxo-4-propyl-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F5) and 1-trifluoromethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=397.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC([NH:23][C@@H:24]([CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][C@@H:24]([CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:26]
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCc1ccccc1)C(=O)O
Product: N[C@@H](CCCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 21 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-fluorophenoxy)aniline and (S)-2-(tert-butoxycarbonylamino)-5-phenylpentanoic acid, gave (S)-2-amino-N-(4-(4-fluorophenoxy)phenyl)-5-phenylpentanamide (165 mg, 21%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH:21]=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH3:24][O:25][CH2:26][CH2:27][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(COCC=C)C1)=O)CCC>>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH:21]=[CH:27][CH2:26][O:25][CH3:24])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1Cc2ccccc2N(C(=O)OCc2ccccc2)C1
Agent: C=CCOCC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCC)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Product: COCC=CC1Cc2ccccc2N(C(=O)OCc2ccccc2)C1

Procedure:
The title compound is prepared in a manner analogous to that described in Example 137b) starting from 1.50 g of N-benzyloxycarbonyl-3(R,S)-formyl-1,2,3,4-tetrahydroquinoline, 3.1 g of methoxyethyl-triphenylphosphonium bromide and 2.0 g of sodium bis(trimethylsilyl)amide: Rf (A)=0.55.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:11]O.P(Br)(Br)[Br:14]>ClCCl>[Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:11][Br:14]
Reactant: CC(C)(C)n1ncc(CO)c1Br
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(C)(C)n1ncc(CBr)c1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
A solution of (5-bromo-1-tert-butyl-1H-pyrazol-4-yl)methanol (460 mg, 1.97 mmol) in dichloromethane (25 mL) was cooled to 0° C. and then treated with phosphorus(III)bromide (0.37 mL, 3.46 mmol), dropwise, over 5 minutes. The mixture was stirred 30 minutes at 0° C. and then 1 hour at room temp. The mixture was quenched slowly with water (50 mL), stirred 30 minutes, and then extracted with ethyl acetate (2×50 mL). The organic phase was washed with saturated aqueous sodium bicarbonate (50 mL), dried over sodium sulfate, filtered and concentrated to yield 362 mg of 5-bromo-4-(bromomethyl)-1-tert-butyl-1H-pyrazole as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 7.54 (s, 1H), 4.39 (s, 2H), 1.74 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[CH:2]1.[N:9]1[C:17]([NH2:18])=[C:16]2[C:12]([N:13]=[CH:14][NH:15]2)=[N:11][CH:10]=1>N1C=CC=CC=1>[CH:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([NH:18][C:17]1[N:9]=[CH:10][N:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[N:13]2)=[O:7]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=C(Cl)c1ccsc1
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2nc[nH]c12)c1ccsc1
Yield: 60 %

Procedure:
62.6 g (0.439 mole) of thiophene-3-carbonyl chloride are added to a suspension of 19.7 g (0.146 mole) of adenine in 100 ml of dry pyridine. The mixture is refluxed for 10 hours, the pyridine is distilled off, the residue is taken up in chloroform, the solution is washed with dilute sodium bicarbonate solution and dried over sodium sulfate, and the solvent is then stripped off in a rotary evaporator. The solid residue is stirred repeatedly with cyclohexane and then recrystallized from ethanol and dried at about 40° C. under reduced pressure. 6-(3-Thenoylamino)-purine is obtained in a yield of 60%.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(O)C.CCOCC.C(Cl)(Cl)(Cl)Cl>[Br:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: O=C(Cl)c1cc(F)c(F)cc1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.2 %

Procedure:
Magnesium ribbon (7.3 g) is suspended in absolute ethanol (15 ml), and thereto is added carbon tetrachloride (1.5 ml), and thereto is added dropwise a mixture of diethyl malonate (48 g), absolute ethanol (30 ml) and anhydrous ether (120 ml) over a period of one hour. After the addition, the mixture is refluxed for 2 hours. After cooling till room temperature, a solution of 2-bromo-4,5-difluorobenzoyl chloride (92 g) in anhydrous ether (50 ml) is added dropwise to the mixture. After the addition, the mixture is allowed to stand overnight at room temperature. A mixture of ice-water (120 ml) and conc. sulfuric acid (8 ml) is added dropwise to the reaction mixture under ice-cooling. After the addition, the mixture is extracted with ether. The ether layer is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give diethyl (2-bromo-4,5-difluorobenzoyl)malonate (123 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]1([CH3:23])[CH2:12][C:11]2[C:13]([CH3:22])=[C:14]([NH:19]C=O)[C:15]([CH3:18])=[C:16]([CH3:17])[C:10]=2[O:9]1>O>[NH2:19][C:14]1[C:15]([CH3:18])=[C:16]([CH3:17])[C:10]2[O:9][C:8]([CH3:7])([CH2:23][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:12][C:11]=2[C:13]=1[CH3:22]
Reactant: C1CCNC1
Reactant: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CBr)O2
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCCC1)O2
Temperature: 160 °C
Yield: 83.5 %

Procedure:
Pyrrolidine (20 ml) was added to 2-bromomethyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (3.0 g, 9.6 mmol) and the mixture was heated at 160° C. in an autoclave for 15 hours. After the reaction mixture was cooled, the mixture was diluted with water and the product was extracted with ethylacetate. The extract was washed with water and dried and then the solvent was distilled off. The residue was purified by column chromatography on silica gel (chloroform-methanol, 9:1) and recrystallized from hexane to obtain the desired compound (2.2 g, yield: 83.5%), m.p. 85°-86° C. (dec.).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[C:14]([CH2:30][C:31]([OH:33])=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=1[C:19]2([CH3:27])[CH3:26].[CH:34]1[C:46]2[CH:45]([CH2:47][O:48][C:49](N3C(=O)CCC3=O)=[O:50])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.O>[CH:34]1[C:46]2[CH:45]([CH2:47][O:48][C:49]([NH:8][CH2:9][C:10]3[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]4[C:11]=3[O:12][C:13]3[C:14]([CH2:30][C:31]([OH:33])=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=3[C:19]4([CH3:27])[CH3:26])=[O:50])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: O=C1CCC(=O)N1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccc2c(c1CN)Oc1c(ccc(OC)c1CC(=O)O)C2(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1CNC(=O)OCC1c3ccccc3-c3ccccc31)Oc1c(ccc(OC)c1CC(=O)O)C2(C)C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
1.58 g (34.35 mmol) of 5-aminomethyl-3,6-dimethoxy-9,9-dimethylxanthene-4-acetic acid trifluoroacetate were suspended in a mixture of 7 ml of dioxan and 7 ml of water together with 1.13 g (3.35 mmol) of N-(9-fluorenylmethoxycarbonyl)-succinimide, whereupon 0.9 ml (5.03 mmol) of ethyldiisopropylamine was added at 0°. The mixture was stirred at 0° for 2 hours and thereafter at room temperature for 4 hours. The solid obtained was filtered off, washed with water, dried and chromatographed on silica gel with chloroform/methanol. The fractions containing the desired product were combined, washed with dilute potassium hydrogen sulphate solution and thereafter with water, dried over magnesium sulphate and concentrated, whereby 1.17 g of 5-[(9-fluorenylmethoxyformamido)methyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetic acid were obtained as a colourless powder of m.p. 134°-136°; IR 1727, 1703, 1606, 1495 cm-1.
Reaction SMILES: S1C2C=CC=CC=2N=C1NN=CC1OC([N+]([O-])=O)=CC=1.[N+:21]([C:24]1[S:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22].[NH:31]([C:33]1[S:34][C:35]2[CH:41]=[C:40]([O:42][C:43]([F:46])([F:45])[F:44])[CH:39]=[CH:38][C:36]=2[N:37]=1)[NH2:32]>>[F:46][C:43]([F:44])([F:45])[O:42][C:40]1[CH:39]=[CH:38][C:36]2[N:37]=[C:33]([NH:31][N:32]=[CH:29][C:27]3[S:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[S:34][C:35]=2[CH:41]=1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: NNc1nc2ccc(OC(F)(F)F)cc2s1
Agent: O=[N+]([O-])c1ccc(C=NNc2nc3ccccc3s2)o1
Product: O=[N+]([O-])c1ccc(C=NNc2nc3ccc(OC(F)(F)F)cc3s2)s1

Procedure:
The compound 3j was prepared according procedure described for 3a by employing 5-nitrothiophen aldehyde (157 mg, 1 mmol) and 2-hydrazino-6-trifluoromethoxy-benzothiazole (249 mg, 1 mmol) at 70° C. for 2 h (yield 219 mg, 75%).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>CN(C=O)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:29]3[C:25](=[O:35])[C:26]4[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:28]3=[O:30])=[CH:4][C:5]=2[N:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.3 %

Procedure:
To a solution of 6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 (0.3 g, 0.9 mmol) in DMF (10 mL) was added K2CO3 (0.2 g, 1.3 mmol), and phthalimide (0.1 g, 0.9 mmol). The resulting solution stirred 20 h at room temperature. The reaction was concentrated in vacuo and diluted with water (10 mL). The heterogeneous mixture was filtered to afford 2-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)isoindoline-1,3-dione 31 (0.3 g, 75%). MS (Q1) 415 (M)+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.O>CN1CCCC1=O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:2]3[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=3)[C:8]#[N:9])[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: N#Cc1ccnc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccnc(N2CCN(c3ccc(F)cc3)CC2)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 85.5 %

Procedure:
2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved in N-methylpyrrolidone (2.0 ml), and 1-(4-fluorophenyl)piperazine (1.0 g, 5.6 mmol) was added thereto. The reaction mixture was stirred at 100° C. for 10 hrs, combined with water to give precipitates, which were collected by filtration to give the titled compound (0.70 g, 86%).