Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[C:6]([CH3:14])=[C:5]2[OH:15].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:15][C:5]1[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]=[C:7]([CH3:13])[C:6]=1[CH3:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nc2c(C)cc(Br)cc2c(O)c1C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(C)cc(Br)cc2c(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
26.6 Grams of 6-bromo-4-hydroxy-2,3,8-trimethylquinoline synthesized in the same way as that described in Example 1 was suspended in 70 ml of dimethylformamide, to which 4.4 g of 60% sodium hydride was added under cooling with ice and then the mixture was stirred at room temperature for 30 minutes. 19 Grams of benzyl bromide was added dropwise to the reaction mixture under cooling with ice and the mixture was allowed to react at room temperature overnight. After 50 ml of water was added, the reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate overnight. After the solvent was evaporated under reduced pressure, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (6:1) to obtain 24.3 g of 4-benzyloxy-6-bromo-2,3,8-trimethylquinoline.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH2:29][O:30][CH3:31]>C(Cl)Cl.O>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:21]([F:20])[CH:22]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COCCOc1ccc(NC(=O)Oc2ccccc2)cc1F
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COCCOc1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Reaction time: 16 h
Yield: 53.4 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (102 mg, 0.327 mmol, 1.0 eq.) in DCM (5.0 mL) was added TEA (1.36 mL, 0.981 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(2-methoxyethoxy)phenylcarbamate (100 mg, 0.327 mmol, 1.0 eq.) at RT and stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL) and brine (5 mL), dried over anhydrous Na2SO4, and the solvent evaporated under vacuum. The crude product obtained was purified by neutral alumina column chromatography using MeOH/CHCl3 (1:9) as eluent to yield 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(2-methoxyethoxy)-phenyl)urea (example A18) (85 mg, 53%) as a white solid (TLC system: MeOH/CHCl3 (1:9), Rf: 0.5).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:13]1[C:14](=[O:23])[O:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:12])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12>CN(C=O)C>[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH:63][C:10]([C:13]3[C:14](=[O:23])[O:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:12])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2ccccc2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2ccccc2oc1=O
Temperature: 25 °C
Yield: 84.3 %

Procedure:
DIEA (50.4 μL, 0.29 mmol) was added to 3-carboxy-coumarin (50.0 mg, 0.26 mmol) and HATU (110.0 mg, 0.29 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (55.0 mg, 0.26 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 83.6 mg of product in 85% yield: LCMS (ESI) m/z 382 (MH+).
Reaction SMILES: [CH3:1][Mg]Cl.[O:4]=[C:5]([CH3:32])[CH2:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O1CCCC1>[OH:4][C:5]([CH3:1])([CH3:32])[CH2:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C[Mg]Cl
Reactant: CCCCCCCCCCCCC(CC(C)=O)c1coc([Si](C)(C)C(C)(C)C)c1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(CC(C)(C)O)c1coc([Si](C)(C)C(C)(C)C)c1

Procedure:
A mixture of methylmagnesium chloride (a 3 M solution in tetrahydrofuran; 0.68 ml, 2.04 mmol) and 4-[1-(2-oxopropyl)tridecyl]-2-tert-butyldimethylsilylfuran (Compound 31, 429 mg, 1.02 mmol) in tetrahydrofuran (3 ml) was stirred at 0° at room temperature for 6 hours. The mixture was quenched with saturated ammonium chloride and extracted with ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was chromatographed on a silica column using 5% ethyl acetate/hexane to give the title alcohol.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][CH:9]=1>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][Si:2]([C:5]#[C:6][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:10][CH:9]=1)([CH3:4])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)C(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CC(C)(C)C(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.4 g Bis-(triphenylphosphine)-palladium dichloride and 0.19 g CuI are added, at room temperature, to a solution of 10.5 g trimethylsilylacetylene and 23.6 g 1-(4-bromophenyl)-2,2-dimethylpropan-1-one in 350 ml absolute diethylamine. The reaction mixture is stirred during 20 hours at room temperature, evaporated to dryness at the rotary evaporator and the residue extracted several times with toluene. The toluene is evaporated off and the remaining tacky oil chromatographed on a silica-gel column with hexane/toluene 2:1 as mobile phase to give 1-(4-trimethylsilylethynyl-phenyl)-2,2-dimethylpropan-1-one.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:36]=[CH:35][CH:34]=[CH:33][C:12]=1[CH2:13][C:14]1[C:21](=[O:22])[N:17]2[CH2:18][CH2:19][CH2:20][N:16]2[C:15]=1[C:23]1[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=1>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:10][C:11]1[CH:36]=[CH:35][CH:34]=[CH:33][C:12]=1[CH2:13][C:14]1[C:21](=[O:22])[N:17]2[CH2:18][CH2:19][CH2:20][N:16]2[C:15]=1[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:24]=1
Reactant: CS(=O)(=O)c1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(Cc2ccccc2Cl)c(-c2ccnc(Oc3ccccc3)n2)n2n1CCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of phenol (0.18 g, 1.00 mmol) in THF (4 mL) is added sodium hydride (0.10 g of a 60% dispersion in mineral oil, 1.60 mmol). After stirring 5 min at room temperature a solution of 2-(2-chloro-benzyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 8, (0.21 g, 0.50 mmol) in THF (5 mL) is added to the reaction mixture. After stirring 1.5 h at room temperature, the mixture is diluted with aqueous saturated NaHCO3. The aqueous phase is extracted three times with CHCl3 and the combined organic phases are washed with aqueous saturated NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (5% MeOH/CHCl3) to afford 100 mg of the desired product as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=5.4 Hz, 1H), 7.47 (t, J=7.8 Hz, 2H), 7.40 (d, J=5.4 Hz, 1H), 7.29-7.10 (m, 7H), 4.16 (t, J=6.9 Hz, 2H), 4.07 (s, 2H), 3.91 (t, J=6.9 Hz, 2H), 2.61 (dddd, J=6.9, 6.9, 6.9, 6.9 Hz, 2H); ESI+ MS: m/z (rel intensity) 418.9 (100, M++H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:30]=[CH:29][C:15]([CH2:16][NH:17][C:18]([NH:20][NH:21]C(OC(C)(C)C)=O)=[O:19])=[C:14]([F:31])[CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].O1CCOCC1.[ClH:38]>ClCCl>[ClH:38].[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:30]=[CH:29][C:15]([CH2:16][NH:17][C:18]([NH:20][NH2:21])=[O:19])=[C:14]([F:31])[CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(CNC(=O)NNC(=O)OC(C)(C)C)c(F)c2)cs1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(CCc2ccc(CNC(=O)NN)c(F)c2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of tert-butyl 2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}-2-fluorobenzyl)carbamoyl]hydrazinecarboxylate (141.6 mg, 0.314 mmol) in anhydrous dichloromethane (2 ml) was added 4M hydrogen chloride dioxane solution (2 ml). The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. Ethyl acetate (10 ml) was added to the residue, and the mixture was concentrated again under reduced pressure. This operation was repeated 3 times to remove hydrogen chloride gas azeotropically. The residue was suspended in a mixture of ethanol (2 ml) and ethyl acetate (4 ml), filtered, washed twice with ethyl acetate, and dried under reduced pressure to give N-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}-2-fluorobenzyl)hydrazinecarboxamide hydrochloride (123.6 mg, 0.319 mmol, quantitative) as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH:14]=O)[N:10]([CH2:16][CH:17]=[CH2:18])[C:9]=2[C:8](=[O:19])[N:7]([CH3:20])[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4].Cl.[NH2:23]O>N1C=CC=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([C:14]#[N:23])[N:10]([CH2:16][CH:17]=[CH2:18])[C:9]=2[C:8](=[O:19])[N:7]([CH3:20])[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C=O)nc2c1c(=O)n(C)c(=O)n2CCCC
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: C=CCn1c(C#N)nc2c1c(=O)n(C)c(=O)n2CCCC
Temperature: 50 °C

Procedure:
A solution of 3-butyl-1-methyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carbaldehyde in anhydrous pyridine (5 ml) was treated with hydroxylamine hydrochloride (63 mg, 0.91 mmol) and heated at 50° C. for 1 hour. The mixture was allowed to cool, concentrated, and treated with acetic anhydride (5 ml) then heated at 100° C. for 2.5 hours and 125° C. for 45 minutes. Again the mixture was allowed to cool then partitioned between water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to afford the title compound as a yellow residue (230 mg crude, 114%); m/z 288.3[MH+].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=O)OC(C)(C)C.C([O-])(=O)C.[Na+].COC1[CH2:27][CH2:26][CH:25](OC)O1.O1CCOCC1.[ClH:36]>C(O)(=O)C>[ClH:36].[N:8]1([C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[NH2:1])[CH:9]=[CH:27][CH:26]=[CH:25]1
Reactant: COC1CCC(OC)O1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: N[C@@H]1CCCC[C@H]1n1cccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
tert-Butyl N-[(1R,2R)-2-aminocyclohexyl]carbamate (1.06 g, 4.93 mmol), sodium acetate (1.70 g, 20.7 mmol) and 2,5-dimethoxytetrahydrofuran (764 μL, 5.91 mmol) were combined in acetic acid (10.6 mL). The reaction mixture was heated at 80° C. for 16 hours. The reaction mixture was then evaporated to dryness and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The layers were separated, and the organic layer was washed twice with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness to yield a brown solid. This solid was then dissolved in HCl in dioxane (10.3 mL of 4.0 M, 41.1 mmol) and was allowed to stand for 3 hours. The solvent was then removed to yield trans-2-(1H-pyrrol-1-yl)cyclohexanamine hydrogen chloride (989 mg, 99%) as a brown solid. ESI-MS m/z calc. 164.1, found 165.2 (M+1)+; Retention time: 0.27 minutes (4 min run).
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[C:22]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[C:23]([C:26]#[N:27])[C:24]#[N:25]>CCO>[C:26]([C:23]([C:24]#[N:25])=[C:22]([N:18]1[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CC(C#N)=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=C(C#N)C#N)c2ccccc2)CC1
Reaction time: 16 h

Procedure:
Triethyl amine (1 ml) was added into a solution of N-Boc piperazine (1 g) and 2-(chloro(phenyl)methylene)malononitrile (1 g) in EtOH (20 ml). After 16 hours at 115° C., the reaction mixture was cooled down and some of desired product, tert-butyl 4-(2,2-dicyano-1-phenylvinyl)piperazine-1-carboxylate, precipitated out from the solution. After filteration, the mother solution was concentrated to offer a residue which was purified using silica gel chromatography to afford more tert-butyl 4-(2,2-dicyano-1-phenylvinyl)piperazine-1-carboxylate. 1H NMR (500 MHz, DMSO-d6) □7.53 (m, 5H), 3.93 (b, 2H), 3.61 (b, 2H), 3.36 (b, 2H), 3.15 (b, 2H), 1.39(s, 9H); 13C NMR(125 MHz, DMSO-d6) □170.9, 153.6, 132.6, 131.7, 129.1, 129.0, 117.4, 116.7, 79.4, 51.5, 50.33, 42.9, 27.9. MS m/z: (M+H)+ calcd for C19H23N4O2 339.18, found 339.17. Retention time 1.46 min (column A).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Clc1nccc2cnccc12
Reactant: C1COCCN1
Product: c1cc2c(N3CCOCC3)nccc2cn1

Procedure:
To 1-chloro-2,6-naphthyridine (164.3 mg, 0.998 mmol) (prepared as described in Van den Haak et al, J. Org. Chem 1982, 47 (9), 1673–7) was added morpholine (15 mL) and the mixture was heated at reflux for 4 h. Removal of the volatile components gave 216.6 mg of 1-morpholin-4-yl-[2,6]naphthyridine as a beige solid.
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>ClCCl>[C:8]([CH:2]([NH:1][C:23]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:24])[C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:9]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCOC(=O)C(N)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)NC(=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 18.3 g (143 mmol) of ethyl amino(cyano)acetate in 500 mL of anhydrous dichloromethane were added 30 mL (214 mmol) of triethylamine and 23 mL (171 mmol) of cyclohexanecarbonyl chloride, and the mixture was stirred for 3 hours at 0° C. Then, saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with ethyl acetate to give the solid substance. The obtained solid substance was collected and the filtrate was removed under reduced pressure. The obtained residue was treated with ethyl acetate to give solid substance. This treatment was further repeated. The filtrate was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1) to give crude crystalline. The obtained crude crystalline was washed with ether and combined with the above all solid products to give 24.3 g (71%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[N:10]([CH3:35])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH2:33][CH3:34])[N:12]=2.[C:37](O)(=[O:41])[C@@H:38]([CH3:40])[OH:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:33]([C:25]1[N:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([CH2:8][N:3]4[CH2:4][CH2:5][N:6]([C:37](=[O:41])[C@H:38]([OH:39])[CH3:40])[CH2:7][C:2]4([CH3:1])[CH3:36])[N:10]3[CH3:35])=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNCC3(C)C)n(C)c2n1
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)[C@@H](C)O)CC3(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.9 %

Procedure:
A mixture of 8-(2,2-dimethylpiperazin-1-ylmethyl)-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.20 mmol), D-Lactic acid (20 mg, 0.22 mmol), HATU (85 mg, 0.22 mmol) and DIPEA (40 μL, 0.23 mmol) in DCM (2 mL) was allowed to stir at r.t. for 16 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 2%) affording 722 as a white solid (37 mg, 33%). LCMS (method I): RT 2.90 min, [M+H]+ 562.2. 1H NMR (CDCl3, 400 MHz): δ 8.04-7.99 (1 H, m), 7.77-7.76 (1 H, m), 7.35-7.25 (2 H, m), 4.47-4.45 (1 H, m), 4.34 (4 H, brd s), 4.02-3.98 (1 H, m), 3.91 (3 H, s), 3.86 (4 H, t, J=4.67 Hz), 3.82-3.68 (2 H, m), 3.50-3.49 (1 H, m), 3.40-3.31 (3 H, m), 3.27-3.16 (1 H, m), 2.57-2.55 (2 H, m), 1.45 (3 H, t, J=7.47 Hz), 1.39-1.28 (4 H, m), 1.27-1.15 (5 H, m)
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:35][CH3:36])=[C:10]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][S:23]([C:26]2[S:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH:27]=2)(=[O:25])=[O:24])(=[O:14])=[O:13])[CH:11]=1)(=[O:5])=[O:4])=[CH2:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1.C(Cl)Cl>[CH3:36][O:35][C:9]1[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH2:2][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)(=[O:4])=[O:5])=[CH:11][C:10]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[CH:27]=1)(=[O:25])=[O:24])(=[O:13])=[O:14]
Reactant: C1CCNC1
Reactant: C=CS(=O)(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)CCN2CCCC2)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid [2-(5-ethenesulfonyl-2-methoxybenzenesulfonylamino)phenyl]-amide (0.2 mmol, prepared as in Example 19) in dry THF (2 mL) was added 0.2 mL of pyrrolidine. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (10 mL) and was washed with saturated sodium chloride aqueous solution (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc then DCM/methanol/AcOH (100:2:1 to 100:10:2) to furnish 121 mg of benzo[b]thiophene-2-sulfonic acid {2-[2-methoxy-5-(2-pyrrolidin-1-yl-ethanesulfonyl)-benzenesulfonylamino]phenyl} amide. LC: Tr 0.94 min; MS: 636.8 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 1.68 (m, 4H), 2.38 (m, 4H), 2.78(t, 2H), 3.28 (t, 2H), 4.20 (s, 3H), 6.76 (d, 1H), 6.96 (d, 1H), 7.14 (t, 1H), 7.21 (d, 1H), 7.36 (d, 1H), 7.41 (t, 1H), 7.49(t, 1H), 7.60 (s, 1H), 7.79 (d, 1H), 7.83 (d, 1H), 8.07 (d, 1H), 8.26 (d, 1H) ppm.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH3:14])[CH:13]=[CH:2][C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccsc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccsc1

Procedure:
3-dimethylamino-1-thien-3-ylpropen-1-one was prepared from 3-acetylthiophene (15.0 g) and dimethylformamide dimethylacetal (47.5 mL, 357 mmol) as a yellow solid (14 g), m.p. 98°. δH (CDCl3) 7.90 (1H, dd, J 3.0, 1.0 Hz), 7.76 (1H, d, J 12.4 Hz), 7.53 (1H, dd, J 5.9,1.0 Hz), 7.28-7.25 (1H, m), 5.57 (1H,d, J 12.4 Hz) and 3.03 (6H, bs).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].[NH2:19][C@H:20]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1)[C@H:21]([OH:25])[C:22]([OH:24])=[O:23].O1CCOCC1>O>[Br:32][C:28]1[CH:27]=[C:26]([C@@H:20]2[C@@H:21]([C:22]([OH:24])=[O:23])[O:25][C:2](=[O:4])[NH:19]2)[CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@H](c1cccc(Br)c1)[C@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1N[C@H](c2cccc(Br)c2)[C@@H](C(=O)O)O1
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To triphosgene (36.5 mg, 0.123 mmol) and Na2CO3 (65.2 mg, 0.615 mmol) in Water (2.000 mL) at 0° C. was added dropwise a solution of (2S,3R)-3-amino-3-(3-bromophenyl)-2-hydroxypropanoic acid (20 mg, 0.077 mmol) in Water (0.5 mL)/1,4-Dioxane (0.5 mL). After 15 min, the ice bath was removed and stirring was continued for one hour. ethylacetate (1 ml) was added to the reaction mixture and after five minutes the ethylacetate layer was discarded and the aqueous layer was acidified to pH 2 and extracted with ethylacetate (5 mL×3). The combined organics were dried over magnesium sulfate, filtered and concentrated providing (4R,5S)-4-(3-bromophenyl)-2-oxooxazolidine-5-carboxylic acid (14.2 mg, 0.047 mmol, 61.3% yield) as a white solid. Mass spec.: 287.79 (MH)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[C:10]2([CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)[C:9](=[O:19])[NH:8][C:7]1=[O:20]>O>[CH3:5][N:6]1[C:10]2([CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[C:14]([N+:1]([O-:4])=[O:2])[CH:13]=3)[CH2:18]2)[C:9](=[O:19])[NH:8][C:7]1=[O:20]
Reactant: CN1C(=O)NC(=O)C12Cc1ccccc1C2
Reactant: O=[N+]([O-])O
Solvent: O
Product: CN1C(=O)NC(=O)C12Cc1ccc([N+](=O)[O-])cc1C2

Procedure:
To stirred fuming nitric acid (100 mL) was slowly added (±)-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (4.5 g, 20.9 mmol) in portions over 30 min. The reaction mixture was diluted with H2O (200 mL) and the precipitate was collected by filtration, washed with H2O and dried in vacuo to give the title compound. MS: m/z=262 (M+1).
Reaction SMILES: C(O[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6])C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:17][CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8])=[O:16])=[CH:13][CH:12]=1
Reactant: CCOC(O)C(F)(F)F
Reactant: NC(=O)c1ccc(Cl)cc1
Product: O=C(NC(O)C(F)(F)F)c1ccc(Cl)cc1

Procedure:
Trifluoroacetaldehyde ethyl hemiacetal and 4-chlorobenzamide were processed as described in Example 1 A to provide the desired product.