Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C@H:24]1[NH:29][C@@H:28]([CH3:30])[CH2:27][N:26]([CH2:31][C:32]2[C:33]([CH3:40])=[C:34]([CH:38]=O)[NH:35][C:36]=2[CH3:37])[CH2:25]1>C(O)C.N1CCCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:38]\[C:34]1[NH:35][C:36]([CH3:37])=[C:32]([CH2:31][N:26]2[CH2:25][C@H:24]([CH3:23])[NH:29][C@H:28]([CH3:30])[CH2:27]2)[C:33]=1[CH3:40])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CN1C[C@@H](C)N[C@@H](C)C1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1C[C@@H](C)N[C@@H](C)C1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-((3R,5S)-3,5-dimethyl-piperazin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde in ethanol and piperidine to give the tiled compound.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([NH:7][C:8]1([C:12](O)=O)[CH2:11][CH2:10][CH2:9]1)=[O:6])[CH3:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[CH3:45][O:46][C:47](=[O:58])[C:48]1[CH:53]=[C:52]([NH:54][CH3:55])[C:51]([NH2:56])=[CH:50][C:49]=1[CH3:57]>C(Cl)Cl>[CH3:45][O:46][C:47]([C:48]1[C:49]([CH3:57])=[CH:50][C:51]2[N:56]=[C:12]([C:8]3([NH:7][C:5]([O:4][C:2]([CH3:15])([CH3:3])[CH3:1])=[O:6])[CH2:11][CH2:10][CH2:9]3)[N:54]([CH3:55])[C:52]=2[CH:53]=1)=[O:58]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Reactant: CNc1cc(C(=O)OC)c(C)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(cc1C)nc(C1(NC(=O)OC(C)(C)C)CCC1)n2C
Reaction time: 20 h
Yield: 58.1 %

Procedure:
1-((1,1-Dimethylethoxycarbonyl)amino)cyclobutanecarboxylic acid (1.40 g, 6.5 mmol) was dissolved in CH2Cl2 (45 mL) and reacted with TBTU in the presence of Et3N for a period of 30 min to pre-activate the acid. A solution of 4-amino-2-methyl-5-(methylamino)benzoic acid methyl ester 6-8 from Example 6 (1.33 g, 6.85 mmol) in CH2Cl2 (10 mL) was added slowly over a period of 30 min and stirring of the reaction mixture was continued for 20 h. The reaction mixture was concentrated to dryness, and the residue was re-dissolved in AcOH (10.0 mL) and stirred at 70° C. for 2 h to achieve cyclization of the benzimidazole ring. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc (˜250 mL), extracted with aqueous saturated NaHCO3 (2×100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4 and evaporated to dryness. The residue was purified by flash column chromatography (using a solvent gradient from 40% to 50% EtOAc in hexane) to obtain the pure 2-(1-tert-butoxycarbonylaminocyclobutyl)-3,6-dimethyl-3H-benzoimidazole-5-carboxylic acid methyl ester 7-1 as a beige solid (1.41 g, 55% yield) and recover some of the unreacted diamino starting material.
Reaction SMILES: C(Cl)(Cl)Cl.CC([O:8][CH2:9][C:10]1[CH2:29][S:28][CH:13]2[C@H:14]([NH:17][C:18]([CH2:20][CH2:21][CH2:22][CH:23]([NH2:27])[C:24]([OH:26])=[O:25])=[O:19])[C:15](=[O:16])[N:12]2[C:11]=1[C:30]([O-:32])=[O:31])=O.[Na+].CC(OCC1CS[C@@H]2[C@H](NC(CCC[C@@H](N)C(O)=O)=O)C(=O)N2C=1C(O)=O)=O.C>C(O)C>[CH2:29]1[S:28][C@@H:13]2[C@H:14]([NH:17][C:18]([CH2:20][CH2:21][CH2:22][C@@H:23]([NH2:27])[C:24]([OH:26])=[O:25])=[O:19])[C:15](=[O:16])[N:12]2[C:11]([C:30]([OH:32])=[O:31])=[C:10]1[CH2:9][OH:8]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)CCCC(N)C(=O)O)C2SC1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(=O)O)[C@H]2SC1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N[C@H](CCCC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)C(=O)O
Reaction time: 0.5 h

Procedure:
To the wet mycelia (10 g) was added a small volume of chloroform. The mixture was allowed to stand at ambient temperature for 30 minutes. To the mixture was added distilled water (20 ml). After allowing to stand at ambient temperature for a day, the mixture was centrifuged to give enzyme extracts (20 ml). The enzyme extracts was added to an aqueous solution (300 ml) containing cephalosporin C sodium.dihydrate (25 mg/ml). The reaction mixture was stirred at pH 4.5 and 30° C. for 10 hours until cephalosporin C in the mixture disappeared. To the resultant mixture was added activated charcoal (3 g) and the mixture was filtered. The filtrate was adjusted to pH 7.0 and concentrated under reduced pressure to give crystals, to which was added a small volume of 75% aqueous ethanol and the mixture was triturated. The crystals were separated by filtration and dried in vacuo to give crystalline deacetylcephalosporin C (3.6 g).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[CH:27]12[CH2:36][CH:30]([CH2:31][CH:32]1[C:33]([OH:35])=[O:34])[CH:29]=[CH:28]2>[Cl-].C[N+](C)(C)C>[CH:27]12[CH2:36][CH:30]([CH2:31][CH:32]1[C:33]([O:35][CH2:9][CH:8]([OH:10])[CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[O:34])[CH:29]=[CH:28]2
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: O=C(O)C1CC2C=CC1C2
Agent: C[N+](C)(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Product: C=C(C)C(=O)OCC(O)COC(=O)C1CC2C=CC1C2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Glycidyl methacrylate (43 g), containing 0.13 g of 2,6-di-tert. butyl-p-cresol and 0.26 g of tetramethylammonium chloride, was heated to 100° C. and bicyclo[2.2.1]hept-2-ene-6-carboxylic acid (41.8 g) was added slowly over about 1 hour, so that the temperature of the mixture did not exceed 105° C. Heating at 100° C. was continued for a further three hours, by which time the epoxide content of the product was negligible. The above-mentioned ester was a colourless mobile liquid.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[C@@H:3]([NH:8][C:9]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:17]=2[C:16]2[C:15](=[O:23])[NH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)[C:4]([F:7])([F:6])[F:5].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][CH:2]([CH3:24])[C@@H:3]([NH:8][C:9]1[C:18]2[CH:19]=[CH:20][N+:21]([O-:33])=[CH:22][C:17]=2[C:16]2[C:15](=[O:23])[NH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)[C:4]([F:6])([F:5])[F:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)[C@@H](Nc1nc2cc[nH]c(=O)c2c2cnccc12)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@@H](Nc1nc2cc[nH]c(=O)c2c2c[n+]([O-])ccc12)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 6-{[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino}pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one (20 mg, 0.059 mmol) in CH2Cl2 (8 mL) at 0° C. was added m-CPBA (60 mg, 0.268 mmol, 77% max) and allowed to stir for 2 hr. 10% sodium thiosulfate and sat. sodium bicarbonate were added to the reaction solution and stirred for 30 min. The layers were separated, the organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified on reverse phase HPLC 100% H2O to 100% MeCN to afford 6-{[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino}pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one 9-oxide. 1H NMR (600 MHz, CD3OD) δ 10.80 (s, 1H), 8.50 (d, 1H), 8.35 (d, 1H), 7.48 (d, 1H), 6.60 (d, 1H), 5.39 (m, 1H), 2.33 (m, 1H), 1.14 (d, 3H), 1.06 (d, 3H). LRMS (ESI) calc'd for (C16H16F3N4O2) [M+H]+, 353.1; found 353.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]1[CH2:28][C@@H:8]1[CH2:9][O:10][C:11]1[C:12]([O:25]C=O)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14]2.O>O1CCCC1>[OH:7][CH2:28][C@@H:8]1[O:25][C:12]2=[C:13]3[C:17](=[CH:18][CH:19]=[C:11]2[O:10][CH2:9]1)[NH:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14]3
Reactant: CCOC(=O)c1cc2c(OC=O)c(OC[C@H]3CO3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc2c3c(ccc2[nH]1)OC[C@H](CO)O3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Saturated aqueous potassium carbonate solution (200 ml) was added to a stirred solution of ethyl (R)-5-(2,3-epoxypropoxy)-4-formyloxyindole-2-carboxylate (22.0 g; prepared in a similar manner to that described above) in tetrahydrofuran (250 ml) and the mixture was stirred at room temperature for 72 hours. The mixture was poured into water (1000 ml) and extracted with ethyl acetate (4×400 ml). The combined extracts were dried over sodium sulphate and the solvent evaporated under reduced pressure to give ethyl (S)-2,3-dihydro-2-(hydroxymethyl)-7H-1,4-dioxino[2,3-e]indole-8-carboxylate (17.65 g) as a pale purple solid; m.p. 152-153° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([C:20]3([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=4)[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH2:15]2)=[O:13])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[Cl:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20]([CH:16]3[CH2:17][CH2:18][CH2:19][N:14]([C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=4)=[O:13])[CH2:15]3)([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)[C:21](=[O:30])[NH:22]2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of rac-5-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-pyridine-2-carboxylic acid methyl ester (67 mg, 0.12 mmol) (from Example 83 d supra) in tetrahydrofuran (2 mL) was added the suspension of lithium hydroxide monohydrate (51 mg, 1.2 mmol) (Aldrich) in water (2 mL). The mixture was stirred at room temperature for overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to “pH”<5 with dilute HCl, then extracted with ethyl acetate several times. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated to give rac-5-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-pyridine-2-carboxylic acid as a white solid. (Yield 45 mg, 69.2%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26].C(OCC)(=O)C>C(Cl)Cl>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCOC(=O)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccsc2)SCC(N)C1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccsc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
0.66 g of t-butyl α-[6-amino-5-oxo-2-(3-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [synthesized as described in Example 42(g)] was N-alkylated using 0.86 g of butyl 2-bromo-4-phenylbutyrate by the same procedure as is described in Example 42(h). The reaction product was subjected to silica gel column chromatography using a 1:20 by volume mixture of ethyl acetate and methylene chloride, to give two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na+:12].[OH-].[Na+].O.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+:12]
Reactant: ClCc1ccccc1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])c1ccc(OCc2ccccc2)cc1
Reaction time: 5 h
Yield: 72.3 %

Procedure:
To a suspension of sodium p-hydroxybenzenesulfonate (40 g, 0.17 mole) in a solution of NaOH (9.61 g, 0.24 mole) and H2O (55 ml), a solution of benzyl chloride (27.6 g, 0.22 mole) in ethanol (35 ml) was added dropwise, and continued to stir for 5 hours under reflux. After standing at room temperature overnight, the precipitate was filtered, washed with H2O and dried to afford 35.2 g of sodium p-benzyloxybenzenesulfonate as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[CH:8]=[O:9].O.[SH-:12].[Na+].[BH4-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([SH:12])[C:7]=1[CH2:8][OH:9]
Reactant: [SH-]
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1c(S)cncc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under argon atmosphere a mixture of 3,5-dichloro-pyridine-4-carbaldehyde (3.00 g, 17.05 mmol) and sodium hydrosulfide hydrate (flakes 70%, 1.37 g, 17.05 mmol) in DMF (20 mL) was stirred at 0° C. for 15 min. NaBH4 (8.52 g, 17.05 mmol) was added. After 30 min at 0° C. the solution was filtered and the solvent was removed in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 176.0 [M+H+].
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([CH3:6])[CH:3]=[CH:4]I.C([Li])CCC.[CH3:19][Sn:20](Cl)([CH3:22])[CH3:21].O>O1CCCC1>[CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([CH3:6])[CH:3]=[CH:4][Sn:20]([CH3:22])([CH3:21])[CH3:19]
Reactant: C[Sn](C)(C)Cl
Reactant: CC(C)(C=CI)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C=C[Sn](C)(C)C)c1ccc(Cl)cc1
Temperature: -90 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A stirring solution of 4.8 grams (0.016 mole) of 3-methyl-3-(4-chlorophenyl)-1-iodo-1-butene in 50 mL of tetrahydrofuran is cooled to about -90° C., and 6.9 mL (0.018 mole) of n-butyllithium (2.5M in hexane) is added dropwise at a rate to maintain the reaction mixture temperature at about -85° to -90° C. Upon completion of the addition, the reaction mixture is stirred at -90° C. for 30 minutes. After this time, a solution of 3.7 grams (0.019 mole) of trimethyltin chloride in 10 mL of tetrahydrofuran is added dropwise at a rate sufficient to maintain the reaction mixture temperature at about -85° to -90° C. Upon completion of addition, the reaction mixture is again stirred at -90° C. for 30 minutes. After this time, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 18 hours. The reaction mixture is then poured into 150 mL of water and extracted with 150 mL of diethyl ether. The ether extract is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 4.8 grams of 3-methyl-3-(4-chlorophenyl)-1-trimethylstannyl-1-butene. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]([NH2:22])=[O:21])=[CH:4][CH:3]=1.CO[C:27](OC)([N:29](C)C)[CH3:28]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]2[O:21][N:29]=[C:27]([CH3:28])[N:22]=2)=[CH:23][CH:24]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C(N)=O)n2Cc1ccc(F)cc1
Product: Cc1noc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)n1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-fluorobenzyl)-5-methanesulfonylindole-2-carboxamide (63 mg) and dimethylacetamide dimethylacetal (1 ml) was stirred at 110° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. A mixture of the resulting residue, hydroxylamine hydrochloride (25 mg), a 2N aqueous sodium hydroxide solution (0.18 ml), 1,4-dioxane (0.4 ml) and acetic acid (0.4 ml) was stirred at 90° C. for 2 hours. Water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 50 mg of the desired product as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[O:14][C:12](=O)[C:11]3=[CH:17][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:11](=[CH:17][CH:18]=2)[C:12](=[O:14])[N:25]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:15]3=[O:16])=[O:7])=[CH:19][CH:20]=1
Reactant: NCc1cccnc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(=O)OC2=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(=O)N(Cc1cccnc1)C2=O
Yield: 97.1 %

Procedure:
To a mixture of 870 mg of 4-(4-chlorobenzoyl) phthalic acid anhydride, 10 ml of acetic acid and 10 ml of toluene was added 394 mg of 3-aminomethylpyridine, and the resultant mixture was refluxed under heating for 2 hours. The reaction mixture was concentrated in vacuo, and the resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 1.11 g of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[CH:11]([N:14](CC)C(C)C)(C)[CH3:12].BrCC#N>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][CH2:12][C:11]#[N:14])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CCNCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 4-fluorophenethylamine (1.4 g) in acetonitrile (20 mL) was added dropwise N,N-diisopropylethylamine (2.6 mL) and bromoacetonitrile (0.84 mL). After stirring at room temperature for 50 minutes, the solution was diluted with ethyl acetate, the solution was washed with water, then with saturated sodium chloride water. After drying with anhydrous sodium sulfate, the solvent was removed by evaporation to provide the title compound (2.12 g) as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([Cl:24])[CH:26]=2)=[O:8])[N:6]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(Cl)c2)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 3-Chloro-benzoic acid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCC1>CO>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]2([CH2:1][C:2](=[O:3])[C:4]3[C:5](=[CH:6][CH:7]=[C:8]([Br:10])[CH:9]=3)[O:11]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCN(Cc3ccccc3)CC2)Oc2ccc(Br)cc21
Reaction time: 11 h
Yield: 66.6 %

Procedure:
A mixture of 2-hydroxy-5-bromoacetophenone (5.85 g, 27.2 mmol), N-benzyl-4-piperidone (5.14 g, 27.21 mmol) and pyrrolidine (1.11 ml, 13.60 mmol) in MeOH (100 ml) was heated to reflux. After 11 h, the solvent was removed under vacuum and the crude mixture was purified by column chromatography (eluent: hexane/AcOEt 90:10 to 70:30) to give 1′-benzyl-6-bromo-spiro[chromane-2,4′-piperidine]-4-one (7.0 g) as a yellow solid.
Reaction SMILES: CN(C=O)C.[CH2:6]([Cl:8])Cl.C(Cl)(=O)C(Cl)=O.[N:15]1[C:20]2[S:21][CH:22]=[CH:23][C:19]=2C(=O)[NH:17][CH:16]=1>O>[Cl:8][C:6]1[C:19]2[CH:23]=[CH:22][S:21][C:20]=2[N:15]=[CH:16][N:17]=1
Reactant: ClCCl
Reactant: O=c1[nH]cnc2sccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc2sccc12
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of DMF (90 μL) and CH2Cl2 (2 mL) at 0° C. under N2, oxalyl chloride (148 mg, 1.2 mmol) is added slowly and stirred for 10 min. 3H-Thieno[2,3-d]pyrimid-4-one (81 mg, 0.52 mmol) is added as a solid to the solution and warmed with a heat gun until the solid dissolves. The reaction is stirred at 25° C. for 12 h under N2. The reaction mixture is poured into water and extracted with CH2Cl2 . The phases are separated and the organic layer is dried (Na2SO4) and stripped under reduced pressure to yield 4-chlorothieno[2,3-d]pyrimidine (87.6 mg, 97%) as a solid. 1H NMR (DMSO) δ 8.96 (1H, s), 8.17 (1H, d, J=6.0 Hz), 7.62 (1H, d, J=6.0 Hz).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[N+](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-]>C(OCC)C.CCCCC.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH:2]([CH:3]1[CH2:4][CH:7]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH2:1]
Reactant: C=CC=C
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CCCCC
Product: C=CC1CC1C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Butadiene (200 ml , Aldrich) condensed at -70° was transferred to a glass lined autoclave vessel and ethyl diazoacetate (20 g, 0.175 mol, Aldrich) and rhodium acetate dimer (0.3 g, Aldrich) added. The suspension was stirred in a sealed autoclave for 24 hours at ambient temperature. The contents were diluted with 2% diethyl ether in pentane and passed through a silica pad (50 g). The pad was washed with a little ethanol and further ether-pentane. The eluant containing ethanol was treated separately. The organic phases were concentrated at reduced pressure (<5°) and subjected to short path bulb to bulb disillation (90-105° at 12 mm) to give the product as a colourless liquid (14.6 g).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH2:3]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].OS(O)(=O)=O>>[C:10]([N:7]1[CH:2]([CH3:1])[CH2:3][C:4](=[O:9])[NH:5][C:6]1=[O:8])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(=O)NC(=O)N1
Agent: O=S(=O)(O)O
Product: CC(=O)N1C(=O)NC(=O)CC1C

Procedure:
In the manner described above, 65 gm (0.5 mol) of 6-methyl-5,6-dihydrouracil were reacted with 8 mols of acetic acid anhydride in the presence of 2 ml of H2SO4. The product recrystallized from isopropanol had a melting point of 107° C to 109° C and the following analysis values:
Reaction SMILES: C([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([O:30][CH3:31])=[C:14]([O:19][CH:20]3[CH2:29][CH2:28][C:23]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:22][CH2:21]3)[CH:15]=2)[N:10]=[CH:9]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[O:24]1[C:23]2([CH2:28][CH2:29][CH:20]([O:19][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][C:13]=3[O:30][CH3:31])[N:10]=[CH:9][NH:8][C:17]4=[O:18])[CH2:21][CH2:22]2)[O:27][CH2:26][CH2:25]1
Reactant: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1OC1CCC2(CC1)OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2nc[nH]c(=O)c2cc1OC1CCC2(CC1)OCCO2

Procedure:
27.20 g of 3-benzyl-6-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-7-methoxy-3H-quinazolin-4-one are dissolved in 270 ml glacial acetic acid, combined with 2.70 g palladium on activated charcoal (10%) and hydrogenated at 60° C. until the uptake of hydrogen has ended. Then the glacial acetic acid is distilled off using the rotary evaporator and evaporated off with toluene. The flask residue is mixed with water and made alkaline with saturated sodium hydrogen carbonate solution. The precipitate formed is suction filtered and dried.