Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:12].[K+].[K+].S(=O)(=O)(O)O.[OH2:27]>C(O)(=O)C>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([F:10])[CH:4]=[CH:5][C:6]=1[C:9]([OH:12])=[O:27]
Reactant: O
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: Cc1ccc(F)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc(F)c(Cl)c1Cl
Temperature: 100 °C

Procedure:
2,3-dichloro-1-fluoro-4-methylbenzene (0.090 g, 0.5 mmol) was added to a stirred mixture of potassium dichromate (0.284 g, 1 mmol) in acetic acid (1 ml). 97% Sulphuric acid (0.5 ml) was then added slowly to the mixture which was subsequently heated at 100° C. for 2 hrs. After cooling to room temperature, water and ice were added and the green solid thus obtained was filtered off and washed with cold water to afford 2,3-dichloro-4-fluorobenzoic acid (0.056 g, 0.27 mmol) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Li])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.C1(OC(Cl)=O)C=CC=CC=1.[N].N1C=CC=CC=1>>[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:11]=1
Reactant: [Li]c1cccc(Br)c1
Reactant: Clc1ccncc1
Agent: O=C(Cl)Oc1ccccc1
Agent: [N]
Solvent: c1ccncc1
Product: Clc1ccnc(-c2cccc(Br)c2)c1

Procedure:
Starting from 3-bromophenyllithium, 4-chloropyridine and chloroformic acid phenyl ester (for the acylation of the pyridine nitrogen), the title compound is prepared analogously to J. Org. Chem. 50, 4410 (1985). A corresponding 1-acyl-1,2-dihydropyridine is formed as intermediate and is aromatised by reaction with o-chloroanil (=3,4,5,6-tetrachloro-1,2-benzoquinone) to form the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[I:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=O)=[CH:18][CH:19]=2)[N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:13]=1.N1CCCCC1>C(O)C>[I:11][C:12]1[C:20]2[C:15](=[CH:16][C:17](/[CH:21]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:18][CH:19]=2)[N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[N:13]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Solvent: C1CCNCC1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(I)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Oxindole (665 mg, 5 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (2 g, 5 mmol) were dissolved into ethanol (25 mL). Piperidine (0.1 mL) was added and the solution was heated to 70° C. for 2 h, cooled to rt and stirred overnight. The solvent was removed in vacuo to give an orange solid which was triturated with ethanol to give the title compound in quantitative yield. 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.86 (s, 1H), 7.62-7.55 (m, 3H), 7.24 (d, 1H, J=7.8 Hz), 6.91 (d, 1H, J=7.8 Hz), 6.86 (t, 1H, J=7.6 Hz), 5.75 (s, 2H), 3.62-3.58 (m, 2H), 0.93-0.89 (m, 2H), −0.04 (s, 9H); MS ESI 518.0 [M+H]+, calcd for [C22H24IN3O2Sii+H]+ 518.4.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH2:14]([N:21]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27](Br)[CH:28]=2)[N:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[CH2:14]([N:21]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:28]=2)[N:23]=[CH:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=c1c2cc(Br)ccc2ncn1Cc1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc2ncn(Cc3ccccc3)c(=O)c2c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 107.9 %

Procedure:
Under nitrogen atmosphere, 947 mg of trimethylsilylacetylene, 54.7 mg of copper iodide (I), 54.2 mg bis(triphenylphosphine) palladium dichloride (II) and 3 ml of triethylamine were added sequentially to 1.5 ml solution of dimethylformamide with 501 mg of 3-benzyl-6-bromo4-oxo-3,4-dihydroquinazoline, and the mixture was stirred at 100° C. for 14 hours. After distilling out the solvents under reduced pressure, water was added to the reaction solution, and extracted with ether. Ether layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by silicagel column chromatography (ethyl acetate/hexane=3/7) to obtain 570 mg of the above compound as a colorless oily matter.
Reaction SMILES: [N+:1]([C:4]1(O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:5]1O)([O-:3])=[O:2].[CH3:12][N:13]1[C:18]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:21][CH2:20]2)=[CH:17][C:16](=[O:29])[N:15]([CH3:30])[C:14]1=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=[O:54]>O1CCCC1>[CH3:12][N:13]1[C:18]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][O:28][C:9]3[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:7][C:8]=3[OH:54])[CH2:21][CH2:20]2)=[CH:17][C:16](=[O:29])[N:15]([CH3:30])[C:14]1=[O:31]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: Cn1c(N2CCN(CCCO)CC2)cc(=O)n(C)c1=O
Reactant: O=[N+]([O-])C1(O)C=CC=CC1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(N2CCN(CCCOc3cc([N+](=O)[O-])ccc3O)CC2)cc(=O)n(C)c1=O
Yield: 43.8 %

Procedure:
In 15 ml of anhydrous tetrahydrofuran were suspended 0.63 g of 2-nitrocatechol, 1.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound a) and 1.06 g of triphenylphosphine, and 0.71 g of diethyl azodicarboxylate was added to the resultant suspension. Afterward, the resultant mixture was treated in the same manner as in Reference Example 4 to obtain 0.65 g of light yellow crystals. The crystals were recrystallized from ethanol to obtain 0.55 g of crystalline 1,3-dimethyl-6-[4-(3-[2-hydroxy-5-nitrophenyloxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound y).
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[CH:26][C:24](N)=[N:23][C:21]2=[O:22])[CH2:17][CH2:16]1)([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].N([O-])=[O:29].[Na+].C(O)(=O)C>>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[CH:26][C:24](=[O:29])[NH:23][C:21]2=[O:22])[CH2:17][CH2:16]1)([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2]
Reactant: O=N[O-]
Reactant: Nc1ccn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1ccn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1

Procedure:
The derivative was synthesized via the unstable diazonium derivative starting with the commercially available 2′,3′-dideoxy-cytidine-5′-triphosphate (Boehringer Mannheim) by deamination with NaNO2/acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].Cl[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccnc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 92.6 %

Procedure:
Sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (154 mg, 0.50 mmol), 2-chloro-3-nitropyridine (79 mg, 0.50 mmol) and DMSO (2.5 mL) were combined and the resulting solution stirred at ambient temperature for 19 hours. The solution was partitioned between EtOAc (25 mL) and water (25 mL) and the organic layer was subsequently washed with brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo to afford semi-pure 2-{[6-(4-fluorophenyl)naphthalen-2-yl]sulfonyl}-3-nitropyridine as a yellow solid (189 mg) which was used directly in the following step. 1H NMR (500 MHz, d6-DMSO): δ 8.85 (1H, dd, J=1.3, 4.6 Hz), 8.75-8.73 (1H, m), 8.63 (1H, dd, J=1.3, 8.1 Hz), 8.38 (2H, t, J=7.7 Hz), 8.25 (1H, d, J=8.8 Hz), 8.06 (1H, dd, J=1.7, 8.6 Hz), 7.98-7.92 (4H, m), 7.39 (2H, t, J=8.8 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=O)[CH2:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[CH:5][CH:4]=[N:3]1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].Cl>CCO>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:8]([C:9]3[CH:13]=[CH:12][S:11][CH:10]=3)=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH3:16]
Reactant: Cn1nccc1C(=O)Cc1ccsc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccnn3C)=C2c2ccsc2)cc([N+](=O)[O-])c1O
Yield: 22.7 %

Procedure:
To a mixture of 1-(1-methyl-1H-pyrazol-5-yl)-2-(thiophen-3-yl)ethanone (Intermediate 72) (90 mg, 0.32 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (110 mg, 0.52 mmol) and urea (52 mg, 0.87 mmol) in EtOH (4 mL) was added concentrated HCl (0.1 mL). The reaction was refluxed overnight. Purified by column chromatography and preparative HPLC to give Compound 139 as a yellow solid (32 mg, yield: 16.7%). 1HNMR (DMSO-d6 400 MHz): δ 10.44 (s, 1H), 8.91 (s, 1H), 7.75 (s, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.34-7.36 (m, 2H), 7.06-7.07 (m, 1H), 6.39 (d, J=2.0 Hz, 1H), 6.21 (d, J=4.8 Hz, 1H), 5.42 (d, J=2.4 Hz, 3H), 4.14 (q, J=7.2 Hz, 2H), 3.62 (s, 3H), 1.42 (t, J=7.2 Hz, 3H); MS (ESI): m/z 442.0 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.O>[CH:18]1([O:1][C:2]2[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cccc(C=O)c1OC1CCCC1
Reaction time: 55 h
Yield: 615 %

Procedure:
A mixture of 2-hydroxy-3-methoxy-benzaldehyde (10 g, 6.57 mmoles), K2CO3 (18.16 g, 131 mmoles), cyclopentyl-bromide (14.05 ml, 131 mmoles) in absolute ethanol (150 ml) under nitrogen was refluxed under stirring for 55 hours. The mixture was diluted with water, thrice extracted in ethyl acetate, washed with water, anhydrified over Na2SO4 and evaporated to dryness, the yielded oil was purified by flash chromatography on silica gel (eluent petrolatum/ethyl acetate 95:5) to give 8.9 g of the title product (yield: 61%).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4][OH:5].[OH-].[K+].Br[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:28])=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:19]=1)=[O:17].Cl>O.CN1CCCC1=O>[C:24]([C:22]1[CH:23]=[C:18]([C:16](=[O:17])[CH2:15][O:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH:19]=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:21]=1[OH:28])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)=CCC/C(C)=C/COCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
A mixture of 9.6 g (62 mmol) of (E)-3,7-dimethyl-octa-2,6-dien-1-ol, 8.4 g (150 mmol) of potassium hydroxide and 20 ml of n-methylpyrrolidone are stirred for one hour at room temperature. Then 10.0 g (33 mmol) of 2-bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-ethanone is added in portions and stirring is continued at room temperature for 20 hours. After the addition of 30 ml of water the mixture is neutralized with 6N hydrochloric acid while cooling with an ice bath and then extracted with ethyl acetate. The organic phases are washed twice with brine, dried over sodium sulfate and evaporated. The residue is purified by column chromatography and crystallisation of the pure fractions from hexane gives 6.1 g (50%) of compound 116; m.p. 50° C.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:35][OH:36])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:38][C:39]([NH2:41])=[S:40].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>CN(C)C(=O)C>[NH2:41][C:39]1[S:40][CH:2]=[C:3]([C:4](=[N:35][OH:36])[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O:19][CH:20]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]23)=[O:6])[N:38]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]2SC1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 36.6 %

Procedure:
To a solution of benzhydryl 7-(4-bromo-2-hydroxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylate (48 g) in N,N-dimethylacetamide (200 ml) was added thiourea (7.0 g) at 5° C., and the mixture was stirred at ambient temperature for an hour. After the reaction mixture was poured into 3% aqueous sodium bicarbonate (2 liter), sodium chloride (150 g) was added thereto. The precipitates were collected by filtration and then dissolved in a mixture of acetone (200 ml) and ethyl acetate (500 ml). The separated organic layer was washed with an aqueous sodium chloride, followed by evaporation. The resultant precipitates were collected by filtration, washed with ethyl acetate and diethyl ether and dried in vacuo to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (16.9 g), mp 133°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH2:11]Br)[C:4]=1[CH2:13]Br.[SH:15][CH2:16][C:17]([O:19][CH2:20]C)=[O:18].C[O-].[Na+].CC[O-].[Na+]>C(Cl)Cl.CO>[C:17]([CH:16]1[CH2:13][C:4]2[C:5](=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:11][S:15]1)([O:19][CH3:20])=[O:18]
Reactant: COc1ccc(OC)c(CBr)c1CBr
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1Cc2c(OC)ccc(OC)c2CS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
1,4-dimethoxy-2,3-dibromomethylbenzene (10.0 g, 30.88 mmol) was dissolved in CH2Cl2 and MeOH (750 ml, 6:4) followed by addition of ethyl 2-mercaptoacetate (4.02 ml, 37.06 mmol) with stirring under argon. The mixture was then cooled to 0° C. followed by dropwise addition of sodium methoxide (4.37M, 8.5 ml, 37.06 mmol) over a period of 2 h using an automatic syringe pump. After 5 minutes the solvent was evaporated and the crude was redissolved in THF (400 ml) and cooled to 0° C. again. NaOEt (2.10 g, 30.88 mmol) was then added. The ice bath was removed and the reaction was stirred for 2 more hours. The reaction mixture was then quenched with NH4Cl (sat.) and extracted with ether. The organic phases were combined, dried over MgSO4, filtered and concentrated. The crude residue was then treated with NaOME in MeOH and THF at 0° C. for 2 hours. The reaction mixture was extracted with ether (100 ml×2). The combined organic phases were washed with H2O, dried over MgSO4, filtered and concentrated to a residue that was purified by flash chromatography to give title compound in 45% yield. 1H NMR (300 MHz, CDCl3, ppm) d:2.97 (dd, 1H, J=16.51, 8.79 Hz, HCHaCHC=O), 3.36 (dd, 1H, J=16.7, 5.1 Hz, HCHeCHC=O), 3.73 (m, 2H, HCHa,e--O), 3.75 (s, 3H, OCH3), 3.78 (s, 6H, 2×OCH3), 3.85 (m, 1H, HC--S), 6.69 (m, 2H, ArH).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:7]3[N:8]=[CH:9][C:4]4[CH:3]=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:5]=4[N:6]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CS(=O)c1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(Br)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Temperature: 120 °C
Yield: 21 %

Procedure:
Under a dry argon atmosphere were combined 6-bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.78 g, 2.19 mmol, prepared as in Example 107 of WO 98/33798 (incorporated herein by reference)) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.67 g, 2.4 mmol) without solvent. The flask was evacuated and heated to 120° C. for 1 hour. The mixture was purified by chromatography on silica gel, eluting with chloroform, to give a yellow foam, 0.288 g. Recrystalization from acetonitrile gave 4-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.266 g, 21%). MS (APCI); M++1: Calc'd, 570.17, Found, 570.0.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.[N+:29]([C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1)([O-:31])=[O:30]>C(Cl)Cl.[Cl-].[Na+].O>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([S:38]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=3)(=[O:39])=[O:40])[CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCn1c(=O)c2c(ncn2S(=O)(=O)c2cccc([N+](=O)[O-])c2)n(CCCC)c1=O
Temperature: 23 °C
Reaction time: 19 h
Yield: 79 %

Procedure:
To 404 mg (1.53 mmol) of 1,3-dibutyl-3,7-dihydro-purine-2,6-dione in 15 mL of CH2Cl2 at 23° C. was added 0.40 mL (296 mg, 2.29 mmol) i-Pr2NEt followed by 373 mg (1.68 mmol) of 3-nitrobenzenesulfonyl chloride. After stirring at 23° C. for 19 h, the reaction mixture was poured into 50 mL brine and extracted with 3×50 mL of EtOAc. The combined organics were successively washed with 1×50 mL sat. NaHCO3 solution, 1×50 mL H2O, 1×50 mL brine, dried over MgSO4, filtered and evaporated to an oily yellow solid. Flash chromatography on silica gel, eluting with CH2Cl2/EtOAc (40/1), gave a white solid. Recrystallization from hot hexanes/EtOAc gave 540 mg (1.20 mmol, a 79% yield) of the title compound as a white, crystalline solid. mp: 178-179° C.; 1H NMR (300 MHz, CDCl3); δ 0.88-0.98 (m, 6H), 1.22-1.42 (m, 4H), 1.50-1.61 (m, 2H), 1.63-1.75 (m, 2H), 3.92 (t, J=7.5 Hz, 2H), 4.07 (t, J=7.5 Hz, 2H) 7.86 (t, J=8.1 Hz, 1H), 8.34 (s, 1H), 8.55 (d, J=8.1 Hz, 1H), 8.77 (d, J=8.2 Hz, 1H), 9.01 (brt, 1H); IR (KBr, cm−1): 3142w, 2963m, 2935m, 2876w, 1716s, 1661s, 1538s, 1441m, 1396s, 1181s, 1130m, 761m, 670m; MS (ES) m/z (relative intensity): 450 (M++H, 100).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])[C:7]([CH3:20])([CH3:19])[CH2:6]1)[CH:2]=[CH2:3].[CH3:21][SiH:22]([CH3:24])[CH3:23]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[OH:18][C:15]([CH3:17])([CH3:16])[CH2:14][O:13][N:8]1[C:7]([CH3:20])([CH3:19])[CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH2:3][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH2:10][C:9]1([CH3:12])[CH3:11]
Reactant: C=CCOC1CC(C)(C)N(OCC(C)(C)O)C(C)(C)C1
Reactant: C[SiH](C)C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CC(C)(O)CON1C(C)(C)CC(OCCC[Si](C)(C)C)CC1(C)C

Procedure:
The title compound is prepared by reacting the compound prepared in Example 17 with trimethylsilane and hydrogen hexachloroplatinate(IV) in isopropyl alcohol.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([NH:15][CH3:16])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH:18]([C:24]([O:26]CC)=O)[C:19]([O:21]CC)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:24]([OH:26])=[C:18]([CH3:17])[C:19](=[O:21])[N:15]([CH3:16])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CNc1cc(=O)n(Cc2ccccc2)cn1
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1c(O)c2c(=O)n(Cc3ccccc3)cnc2n(C)c1=O
Yield: 76 %

Procedure:
3-Benzyl-6-(methylamino)pyrimidin-4(3H)-one (compound 5A) (10 g, 46.5 mmol, 1 eq) and diethyl methylmalonate (16 mL, 93 mmol, 2 eq) were heated in phenyl ether (20 mL, 127 mmol) at 240° C. for 3 hours. The solution was cooled and diethyl ether (100 mL) was added. A precipitate formed which was filtered and washed with ether to give 10.5 g of the title compound as a tan solid (76%). [M+H] calc'd for C16H15N3O3, 298; found, 298.
Reaction SMILES: [C:1]([C:3]1([CH2:6]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][CH2:4]1)#[N:2].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:27])=[C:23]([CH:26]=1)[CH:24]=[O:25].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH2:6][C:3]2([C:1]#[N:2])[CH2:5][CH2:4]2)=[C:23]([CH:24]=[O:25])[CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C#N)CC2)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(COc2ccc(Cl)cc2C=O)CC1
Temperature: 25 °C

Procedure:
To a solution of the crude toluene-4-sulfonic acid 1-cyano-cyclopropylmethyl ester in DMF (30 mL) was added 5-chloro-2-hydroxy-benzaldehyde (5.9 g, 38 mmol) and K2CO3 (10.5 g, 76 mmol) slowly. The reaction mixture was placed in a sealed tube and irradiated by microwave reactor at 75° C. for 30 min. After cooled to room temperature, the mixture was poured into water. The solution was diluted with EtOAc (200 mL), washed with water, dried and concentrated to give the title compound as a black oil (4.76 g). The oil was used for next step reaction directly without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH2:17][N:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[N:27][C:22]=2[N:21]2[CH2:28][CH2:29][CH2:30][CH:20]2[C:19]1=O.O1CCCC1>CCOCC>[CH3:16][O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[C:10]=1[CH2:17][N:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[N:27][C:22]=2[N:21]2[CH2:28][CH2:29][CH2:30][CH:20]2[CH2:19]1
Reactant: COc1cccc(OC)c1CN1C(=O)C2CCCN2c2ncccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(OC)c1CN1CC2CCCN2c2ncccc21
Yield: 67 %

Procedure:
Lithium aluminum hydride (1 g.) was dissolved in 100 ml. of anhydrous diethyl ether. To the stirred solution was added over a period of fifteen minutes a solution of 6a,7,8,9-tetrahydro-5-[(2,6-dimethoxyphenyl)methyl]pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1 g., 0.003 mole) in 50 ml. of dry tetrahydrofuran. The reaction mixture was refluxed for eighteen hours and was worked up by adding wet ether, filtering, drying and evaporating in vacuo. The residue (m.p. 110°-112° C.) was dissolved in ethanol and treated with diethyl ether saturated with hydrogen chloride. The separated solid was recrystallized from methanol to afford 0.7 g. (67% yield) of the title compound as the hydrochloride salt, m.p. 211°-213° C.