Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([O:13][CH3:14])=[N:4][C:5]([CH3:12])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C(OC)(C)(C)C>CN(C=O)C.C(N(CC)C(C)C)(C)C.[Cu]I.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>[CH3:14][O:13][C:3]1[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[C:7]([C:8]([F:11])([F:10])[F:9])[N:6]=[C:5]([CH3:12])[N:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1nc(C)nc(C(F)(F)F)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1nc(C)nc(C(F)(F)F)c1C#C[Si](C)(C)C
Temperature: 50 °C
Yield: 116.9 %

Procedure:
5-Iodo-4-methoxy-2-methyl-6-trifluoromethylpyrimidine (5.0 g) was dissolved in DMF (50 ml) and N,N-diisopropylethylamine (6.5 g), copper(I) iodide (0.3 g), dichlorobis(triphenylphosphine)palladium(II) (1.12 g) and trimethylsilylacetylene (15.4 g) was added at room temperature with stirring. The mixture was heated (50° C.) in nitrogen atmosphere for 7 hr and cool to room tempeature. The reaction mixture was added methyl tert-butyl ether (MTBE) (200 ml). The insoluble matter was removed by filtration through Celite and the filtrate was washed with water and brine, respectively. The MTBE solution was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give crude 4-methoxy-2-methyl-6-trifluoromethyl-5-trimethylsilylethynylpyrimidine (5.3 g) as pale yellow oil. This crude 4-methoxy-2-methyl-6-trifluoromethyl-5-trimethylsilylethynylpyrimidine (5.2 g) was dissolved in THF (100 ml) and tetrabutylammonium fluoride (1M THF solution, 18 ml) was added under ice cooling with stirring. After stirring 30 min at this temperature, the reaction mixture was added water in one portion under ice cooling and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane ethyl acetate) to give 5-ethynyl-4-methoxy-2-methyl-6-trifluoromethylpyrimidine (1.92 g) as colorless crystalline solid, mp 77° C.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH3:21])[CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[K+].[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:27]=[S:28])[C:14]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([CH3:21])[CH2:16]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC1CCCN(c2cc3nc(C(C)(C)C)sc3cc2N)C1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC1CCCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)C1
Reaction time: 0.5 h

Procedure:
To a cooled mixture of 1.5 g of 6-amino-2-tert-butyl-5-[3-methylpiperidin-1-yl]benzothiazole and 1.5 g of potassium bicarbonate in 50 ml of chloroform is added dropwise 0.6 g of thiophosgene in 5 ml of chloroform under stirring. The stirring is continued for 30 minutes maintaining the temperature at 0°-2°. The solid is filtered and the filtrate is evaporated. The residue thus obtained is dissolved in chloroform and filtered through a silica gel column. The filtrate is evaporated to give 2-tert-butyl-6-isothiocyanato-5-[3-methylpiperidin-1-yl]benzothiazole, melting at 47°-52°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[C:4](Cl)[N:3]=1.[I-].[Na+].[NH2:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:23][C:21]1[NH:20][N:19]=[C:18]([NH:17][C:4]2[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=2)[CH:22]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CCOC(=O)Cc1cc(Cl)nc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(Nc2cc(C)[nH]n2)nc(Cl)n1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A solution of ethyl 2-(2,6-dichloropyrimidin-4-yl)acetate (1.0 g, 4.25 mmol), sodium iodide (0.637 g, 4.25 mmol), 3-amino-5-methylpyrazole (0.413 g, 4.25 mmol), and N,N-diisopropylethylamine (0.96 ml, 5.53 mmol) was heated at 90° C. until reaction was complete (˜3 h). Reaction mixture was then cooled to room temperature, diluted with ethyl acetate (100 ml), washed with sat. sodium hydrogen carbonate solution (1×30 ml), water (3×30 ml), brine (30 ml), dried (MgSO4), filtered and evaporated in vacuo to leave an orange oil. Crude product was purified by flash chromatography (SiO2, 60-100% EtOAc/Petrol) to give title compound as a red sticky oil (0.520 g, 41%). 1H NMR (CDCl3) 1.29 (3H, t), 2.41 (3H, s), 3.52 (2H, s), 4.23 (2H, q), 5.20-4.60 (2H, very broad signal); ES+296.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][C:39]=2[S:41](Cl)(=[O:43])=[O:42])[CH:34]=[CH:33][CH:32]=1>>[C:25]1([S:22]([NH:21][C:3]2[CH:4]=[C:5]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][S:41]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:40]=2[N:31]=[CH:32][CH:33]=[CH:34]3)(=[O:42])=[O:43])(=[O:24])=[O:23])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: O=S(=O)(Nc1cc(N2CCNCC2)ccc1NS(=O)(=O)c1cccc2cccnc12)c1ccccc1

Procedure:
N-[2-[(Phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-8-quinolinesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 8-quinolinesulfonylchloride (54 mg, 0.239 mmol) according to general method 3 to give 50 mg of a purple solid. MS (posES-FIA) m/z=Found: 524.2; Calcd: 524.13; 1H NMR δ 9.34 (dd, 1H), 8.79 (dd, 1H), 8.37 (dd, 1H), 8.25 (dd, 1H), 7.92 (dd, 1H), 7.73 (t, 1H), 7.57–7.40 (m, 5H), 7.17 (d, 1H), 6.71 (dd, 1H), 6.14 (d, 1H), 3.23–3.08 (m, 8H).
Reaction SMILES: [CH3:1][N:2]([CH3:53])[CH:3]1[CH2:6][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]3[C@H:16]([CH3:39])[C@@H:17]4[C@@H:34]([C@H:35]([OH:37])[CH3:36])[C:33](=[O:38])[N:18]4[C:19]=3[C:20]([O:22]CC3C=CC([N+]([O-])=O)=CC=3)=[O:21])[CH2:11][N:10]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:8])[CH2:4]1.[H][H]>O1CCCC1.O.[Pd]>[CH3:53][N:2]([CH3:1])[CH:3]1[CH2:4][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]3[C@H:16]([CH3:39])[C@@H:17]4[C@@H:34]([C@H:35]([OH:37])[CH3:36])[C:33](=[O:38])[N:18]4[C:19]=3[C:20]([OH:22])=[O:21])[CH2:11][NH:10]2)=[O:8])[CH2:6]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(N(C)C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC(N(C)C)C4)C3)[C@H](C)[C@H]12

Procedure:
0.75 g of 4-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-(3-dimethylaminoazetidin-1-ylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in Example 129(1)] was dissolved in a mixture of 21 ml of tetrahydrofuran and 14 ml of water, and 0.75 g of a 10% w/w palladium-on-carbon catalyst was added to the resulting solution, after which the mixture was hydrogenated at room temperature for 1.5 hours in an atmosphere of hydrogen. At the end of this time, the catalyst was removed by filtration and the filtrate was washed with diethyl ether. The resulting aqueous solution was then concentrated by evaporation under reduced pressure, after which the residue was subjected to reverse phase column chromatography (Cosmosil 75C18 -prep, 25 g, manufactured by Nacalai Tesque). Of the fractions obtained by elution with 7% by volume aqueous acetonitrile, the fraction containing the title compound was concentrated by evaporation under reduced pressure and freeze-dried, to obtain 171 mg of the title compound as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:37]B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH3:37])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(C)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 86.2 %

Procedure:
A mixture of 6-bromo-2-(4-tert-butoxycarbonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (500 mg), methylboronic acid (270 mg), tetrakis(triphenylphosphine)palladium(0) (110 mg), potassium carbonate (380 mg), toluene (6 ml) and THF (4 ml) was stirred at 100° C. for 6 hrs. under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (380 mg).
Reaction SMILES: C(O)C.Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7](=C=O)[C:6]=1OCC.[H][H].C1C(=O)[N:28](I)[C:26](=[O:27])C1>[Pd].O.C(N(CC)CC)C>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:26]([NH2:28])=[O:27])=[CH:5]2
Reactant: CCOC1=C(Cl)c2cc(OC)ccc2NC1=C=O
Reactant: O=C1CCC(=O)N1I
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(C(N)=O)cc2c1
Temperature: 45 °C
Reaction time: 96 h
Yield: 71 %

Procedure:
380 l of ethanol are added to 49.2 kg of 4-chloro-3-ethoxy-carbonyl-6-methoxyquinoline. The suspension is heated at 45° C. for 30 minutes and then cooled to 20° C. 18.65 kg of triethylamine are added under nitrogen, followed by 1.91 kg of palladium-on-charcoal at 5% (at 60% water content). A stream of hydrogen is passed through under 0.5-0.8 bar at 33° C. for 48 hours. At this time, an HPLC1 control shows that the reaction is complete. The reactor is then vented with nitrogen and the reaction medium is then filtered to remove the catalyst. The filter is then rinsed with ethanol. The filtrate is poured over 750 kg of an aqueous ammonia solution. The reaction medium is then stirred at 25° C. over a period of 4 days. The ethanol is then removed by distillation under reduced pressure at a temperature not exceeding 40-45° C. The suspension thus obtained is cooled to 0-5° C. and stirred for 3 hours at this temperature. The precipitate is filtered off, washed with cold water, and then dried at 60-65° C. under reduced pressure until a constant weight is obtained. 26.5 kg (71%) of 6-methoxyquinoline-3-carboxamide are obtained in the form of a white solid which melts at 93.7-95.7° C. (HPLC% NIS=98.3%).
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C:4]1([CH3:26])[S:8][C@@H:7]2[C@H:9]([NH:12][C:13]([C@H:15]([NH2:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:14])[C:10](=[O:11])[N:6]2[C@H:5]1[C:23]([OH:25])=[O:24].O.O.O>O>[CH3:3][C:4]1([CH3:26])[S:8][C@@H:7]2[C@H:9]([NH:12][C:13]([C@H:15]([NH2:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:14])[C:10](=[O:11])[N:6]2[C@H:5]1[C:23]([O-:25])=[O:24].[Na+:2]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Yield: 98.7 %

Procedure:
6 ml of an aqueous 1N sodium hydroxide solution (6 millimols of NaOH) which had been cooled to about 0° C. was added dropwise over a period of 5 minutes to a suspension of 2.42 gm (6 millimols) of ampicillin trihydrate in 24 ml of water at about 0° C., while cooling and vigorously stirring. The resulting clear solution was immediately sterile-filtered, that is, filtered to remove suspended particles, and the filtrate was without delay frozen in bulk by the shell-freezing process. Thereafter, the frozen filtrate was lyophilized, yielding 2.2 gm of white sodium ampicillin having a residual moisture content of 1.35% by weight and a microbiological activity of 94% (U.S.P. standard).
Reaction SMILES: COC(C1C([C:11]2[N:12]=[C:13](C3C=CC=CC=3)[S:14][CH:15]=2)C(C(OC)=O)=C(C)NC=1C)=O.[CH:28]([O:31][C:32]([C:34]1[CH:39](C2N=C(C3C=CC=CC=3)SC=2)[C:38]([C:51]([O:53][CH:54]([CH3:56])C)=[O:52])=[C:37]([CH3:57])[NH:36][C:35]=1[CH3:58])=[O:33])([CH3:30])[CH3:29]>>[CH:28]([O:31][C:32]([C:34]1[CH:39]([C:13]2[S:14][CH:15]=[CH:11][N:12]=2)[C:38]([C:51]([O:53][CH2:54][CH3:56])=[O:52])=[C:37]([CH3:57])[NH:36][C:35]=1[CH3:58])=[O:33])([CH3:29])[CH3:30]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1csc(-c2ccccc2)n1
Reactant: CC1=C(C(=O)OC(C)C)C(c2csc(-c3ccccc3)n2)C(C(=O)OC(C)C)=C(C)N1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1nccs1

Procedure:
The following compounds were obtained in an analogous manner: (b) 2,6-dimethyl-4-thiazol-2-yl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl ester and (c) 2,6-dimethyl-4-thiazol-2-yl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl 5-propyl ester.
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH2:6][O:5]1>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:16][S:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH2:6][O:5][C:4](=[O:3])[CH:8]=2)=[CH:10][CH:11]=1
Reactant: CSc1ccc(C2COC(O[Si](C)(C)C)C2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CSc1ccc(C2=CC(=O)OC2)cc1
Reaction time: 10 h

Procedure:
To a solution of 4 g of Pd(OAc)2 in 100 mL of acetonitrile is added dropwise the crude product from Step 1 (5 g) under nitrogen at r.t. After 10 h at r.t., the mixture is condensed under reduced pressure and the residue is purified by flash chromatography on silica gel eluted with 2:1 hexane/EtOAc to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[C:28]([OH:38])=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:30]=[C:31]([Cl:33])[CH:32]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:26][C:27]1[C:28]([OH:38])=[C:29]([S:34]([N:7]([CH2:8][C:9]2[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[CH:11][CH:10]=2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=2)(=[O:36])=[O:35])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNCc2ccc(F)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 212.1 %

Procedure:
To a solution of tert-butyl 4-((4-fluorobenzylamino)methyl)benzylcarbamate (654 mg, 1.90 mmol, Aldrich) in CH2Cl2 (5 mL) were added 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (497 mg, 0.50 mmol, Aldrich) and diisopropylethylamine (1.34 mL, 9.50 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with methylene chloride (100 mL) and washed with saturated aq sodium bicarbonate solution and brine, dried over MgSO4, concentrated and purified by flash column chromatography on silica gel eluting with CH2Cl2/EtOAc to give the title compound (604 mg, 53%) as a white solid. MS (ESI): m/z 566.9.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][CH2:3][CH2:2]1.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]2[O:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]=2[CH:11]=1)([O-:15])=[O:14]
Reactant: O=C1NCCOc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1NCCOc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 22.2 %

Procedure:
To 2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one (30.34 g, 190 mmol) in conc. sulfuric acid (600 ml) at 0° C. was added potassium nitrate (20.82 g, 206 mmol) portionwise. The mixture was stirred for 20 minutes at 0° C. and then for 4 h at room temperature. The mixture was poured onto ice (21) and the solids were collected by filtration. The solids were taken up in hot ethyl acetate and then cooled to yield the title compound (8.79 g, 22%), MS m/z 209 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[C:21]2[CH3:25])[N:16]=[N:17][CH:18]=1>>[ClH:12].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[C:15]([CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[N:16]=[N:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: COc1ccc(-c2cnnc(Cn3ccnc3C)c2)cc1
Product: Cl

Procedure:
The title compound, MS: m/e=281.2 (M+H+), was prepared from 4-methoxybenzeneboronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][NH:25][C:26](=O)[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>CC#N>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]1[O:23][C:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[N:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NNC(=O)Cc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCCn2c1nc(-c1nnc(Cc3ccc(F)cc3)o1)c(OCc1ccccc1)c2=O
Reaction time: 4 h
Yield: 97.3 %

Procedure:
To stirred solution of 3-(benzyloxy)-N′-(2-(4-fluorophenyl)acetyl)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbohydrazide (0.075 g, 0.16 mmol), Ph3P (0.074 g, 0.28 mmol) and DIEA (0.16 mL, 0.91 mmol) in anhydrous CH3CN (3 mL) was added hexachloroethane (0.048 g, 0.20 mmol) all at once at room temperature. After 4 h, the resulting greenish-yellow reaction mixture was purified by preparative HPLC on a C18 column using water/MeOH containing 0.1% TFA as eluent to afford title compound (0.072 g, 86% yield) as a yellow solid. 1HNMR (500 MHz, CDCl3) δ: 7.42-7.40 (2H, m), 7.30-7.28 (3H, m), 7.24 (2H, dd, J=8.2, 5.55.34 (2H, s), 4.20 (2H, s), 4.07-4.01 (4H, m), 1.64 (6H, s). Hz)), 6.99 (2H, t, J=8.6 Hz), HRMS (M+H) calcd for C25H24N4O4F: 463.1782. found: 463.1788.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=O)=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].O>CCO>[Br:1][C:2]1[CH:3]=[C:4]([S:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OSc1cnc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-Bromo-6-chloro-pyridine-3-sulfonyl chloride (2.5 g, 8.6 mmol), sodium sulfite (2.0 g, 16.1 mmol), and sodium bicarbonate (1.4 g, 16.9 mmol) were dissolved into water (8 mL) and EtOH (3 mL). The reaction mixture was allowed to stir at RT for 12 hours. TLC analysis showed loss of SM and formation of a very polar new spot. Reaction mixture was concentrated in vacuo resulting in a white solid and was used without further purification. ESI-MS (m/z): Calcd. for C5H3BrClNO2S: 255.8 (M+H); found: 256.0. 1H-NMR (CD3OD): δ 8.55 (m, 1H), 8.29 (m, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[S:5][C:6]2[CH2:7][C:8]3[C:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[N:13][NH:12][C:9]=3[C:10]=2[CH:11]=1.[CH3:23][Si:24]([CH2:27][CH2:28][O:29][CH2:30]Cl)([CH3:26])[CH3:25]>C1COCC1>[Br:3][C:4]1[S:5][C:6]2[CH2:7][C:8]3[C:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[N:13][N:12]([CH2:30][O:29][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[C:9]=3[C:10]=2[CH:11]=1
Reactant: COc1ccc(-c2n[nH]c3c2Cc2sc(Br)cc2-3)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
At 0° C., NaH (60 percent, 1.3 g, 33.0 mmol) was added to a THF solution (40 mL) containing 2-Bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (8.3 g, 24.0 mmol). Then SEM-Cl (5.6 mL, 28 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% ETOAc in hexane) to give 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (9.0 g, 18 mmol) as brown solid in 75% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[N:7][CH2:6][CH2:5]2.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl>O1CCOCC1>[Cl-:13].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N+:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][C:11]([CH3:12])=[C:2]([CH3:1])[CH:3]=2)[CH:8]=1
Reactant: Cc1cc2c(cc1C)CCN=C2
Reactant: ClCc1ccccc1Cl
Solvent: C1COCCO1
Product: Cc1cc2c(cc1C)CC[N+](Cc1ccccc1Cl)=C2
Product: [Cl-]

Procedure:
The title compound is prepared analogously to Example A from 6,7-dimethyl-3,4-dihydroisoquinoline and 2-chlorobenzyl chloride in dioxan. Melting point: 127°-129° C.