Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:15]([O:17]CC)=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH:27]([CH3:29])[CH3:28].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:15]([OH:17])=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CBr
Reactant: CCOC(=O)c1sc(-c2ccc(O)c(Br)c2)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(OCC(C)C)c(Br)c2)sc1C(=O)O
Temperature: 70 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
340 mg of the phenol derivative prepared in step (1) was suspended in 5 ml of N,N-dimethylformamide, 690 mg of anhydrous potassium carbonate and 690 mg of isobutyl bromide were added thereto, and the mixture was stirred at 70° C. for 24 hours. After the completion of the reaction, the reaction product was poured into water, and the mixture was extracted with ether. The organic layer was concentrated to give a crystalline product. This product was hydrolyzed by a conventional process and purified by recrystallization to give 310 mg of 2-(3-bromo-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: Nc1ccc2ncccc2c1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc2ncccc2c1
Temperature: 110 °C
Yield: 85.7 %

Procedure:
A mixture of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (141 mg, 0.5 mmol), 6-aminoquinoline (72.2 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 0.5 h. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide (DMF) and ether to give 169 mg (85%) of yellow solid. MS (ESI) m/z 394.0, 396.0 (M+H)+1
Reaction SMILES: [C:1]1([C@@H:13]2[C:17](=S)[NH:16][C:15](=[O:19])[C@H:14]2[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[C:29]1([C@H:41]2[C@H:45]([C:46]3[C:54]4[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=4)[NH:48][CH:47]=3)[C:44](=S)[NH:43][C:42]2=[O:56])[C:39]2=[C:40]3[C:35](=[CH:36][CH:37]=[CH:38]2)[CH2:34][CH2:33][CH2:32][N:31]3[CH:30]=1>CO.[Ni]>[C:1]1([C@@H:13]2[CH2:17][NH:16][C:15](=[O:19])[C@H:14]2[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[C:29]1([C@H:41]2[C@H:45]([C:46]3[C:54]4[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=4)[NH:48][CH:47]=3)[CH2:44][NH:43][C:42]2=[O:56])[C:39]2=[C:40]3[C:35](=[CH:36][CH:37]=[CH:38]2)[CH2:34][CH2:33][CH2:32][N:31]3[CH:30]=1
Reactant: O=C1NC(=S)[C@@H](c2c[nH]c3ccccc23)[C@@H]1c1cn2c3c(cccc13)CCC2
Reactant: O=C1NC(=S)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccccc12
Agent: [Ni]
Solvent: CO
Product: O=C1NC[C@@H](c2c[nH]c3ccccc23)[C@@H]1c1cn2c3c(cccc13)CCC2
Product: O=C1NC[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
A solution of (3R,4R)-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-5-thioxo-pyrrolidin-2-one and (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-5-thioxo-pyrrolidin-2-one (0.070 g, 0.181 mmol) in methanol (15 mL) was treated with excess Raney nickel. The mixture was stirred at room temperature for 15 min. The reaction mixture was filtered over a pad of celite under N2 and the solvent removed under reduced pressure. The residue was purified by flash chromatography (ethyl acetate:methanol; 98:2) giving a mixture (1/1) of regio isomers (3R,4R)-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-pyrrolidin-2-one and (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidin-2-one (22 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ: 10.84 (d, J=13.6 Hz, 1H), 7.91 (brs, 1H), 7.46 (dd, J=7.7 and 13.6 Hz, 1H), 7.30-7.16 (m, 4H), 7.02 (m, 1H), 6.90 (m, 1H), 6.84-6.78 (m, 3H), 4.04 (brs, 2H), 4.0 (m, 1H), 3.72 (m, 1H), 3.35 (brs, 2H), 2.86 (brm, 2H), 2.07 (brm, 2H). LCMS: 356 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]>CCO.CN(C=O)C.[Pd]>[NH2:1][C:2]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: Nc1c(CO)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1cccc(CO)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 2-amino-3-nitrobenzyl alcohol (1.4 g) and 10% Pd/C (140 mg) in EtOH (40 ml) and DMF (10 ml) was stirred under an atmosphere of hydrogen at ambient temperature for 18 h. The catalyst was removed by filtration through Celite, the filtrate reduced in vacuo and azeotroped with toluene (2×50 ml) to give 2,3-diaminobenzyl alcohol (1.15 g) as a dark brown solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[O:8])[CH3:7].CCN(C(C)C)C(C)C.[CH3:18][Si:19]([CH2:22][CH2:23][O:24][CH2:25]Cl)([CH3:21])[CH3:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:18][Si:19]([CH3:21])([CH3:20])[CH2:22][CH2:23][O:24][CH2:25][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)c1ncc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1nccn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(1H-imidazol-2-yl)ethanone (550 mg, 4.99 mmol), 3.18 mmol) in DCM (20 mL) was added DIPEA (1.74 ml, 9.99 mmol) and SEM chloride (0.87 ml dissolved in 5 mL DCM, 4.99 mmol). The resulting mixture was stirred at RT for 1 hr. Saturated aqueous sodium bicarbonate (10 mL) was then added and the aqueous phase was extracted with DCM (3×10 mL extractions). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title intermediate as a yellow oil: 1H NMR (500 MHz, CDCl3) delta 0.00 (9H, s), 1.03-0.82 (2H, m), 2.66 (3H, s), 3.66-3.38 (2H, m), 5.76 (2H, s), 7.18 (1H, s), 7.28 (1H, s); LC-MS: m/z=+241.00 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].Cl.O1CCOCC1>C(O)(=O)C.[Zn]>[NH2:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [Zn]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1ccc(N)cc1C(=O)O
Temperature: 30 °C
Reaction time: 1 h
Yield: 290.6 %

Procedure:
Cycloartenyl ester of 2-methoxy-5-nitrobenzoic acid (34.0 g, 0.056 mole) prepared according to the procedure of Example 170 was suspended in acetic acid (1.2 l) at 20° C., and thereto 6N-HCl-dioxane (19 ml, 2 equivalent) and zinc powder (68 g) were added. The mixture was stirred at 30° C. for 1 hour. Then, zinc powder was removed by filtration, and the filtrate was concentrated under reduced pressure and the residue was extracted with chloroform. The chloroform extracts were washed successively with water and saturated aqueous NaHCO3 solution, then dried, concentrated, and the residual crystals were recrystallized from methylene chloride-hexane (1:4, v/v), giving cycloartenyl ester of 5-amino-2-methoxybenzoic acid (27.2 g) in a 84.4% yield. m.p. 180°-182° C.
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[C:9]1([C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:20][C:21]1[C:22]([C:26]2C=CC=C[CH:27]=2)=NNC=1>>[CH:8]1([CH:2]([N:17]2[CH:18]=[CH:19][C:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[N:16]2)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[CH2:27][CH2:26][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: CC(Cl)C(=O)N(C)C
Reactant: c1ccc(-c2cc[nH]n2)cc1
Product: CN(C)C(=O)C(C1CCCCC1)n1ccc(-c2ccccc2)n1

Procedure:
Following the procedure of Example 1, but substituting α-bromo-N,N-dimethyl-1-cyclohexaneacetamide for 2-chloro N,N-dimethylpropionamide and 3-phenylpyrazole for 4-methyl-3-phenylpyrazole there was obtained α-cyclohexyl-N,N-dimethyl-3-phenylpyrazole-1-acetamide having a melting point of 87.5°-90° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][CH2:15][O:16][C:17]1[C:18]([CH3:34])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][CH:22]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:20]2.[CH2:35](Br)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>O1CCCC1.CCCCCC>[CH3:13][O:14][CH2:15][O:16][C:17]1[C:18]([CH3:34])=[C:19]2[C:24](=[C:25]([CH3:28])[C:26]=1[CH3:27])[O:23][C:22]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:20]2
Reactant: CCOC(=O)C1CCc2c(C)c(OCOC)c(C)c(C)c2O1
Reactant: CCCCCCCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCC1(C(=O)OCC)CCc2c(C)c(OCOC)c(C)c(C)c2O1
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
7.8 ml of a hexane solution containing 1.62 mmole/ml of butyllithium were added dropwise to a mixture of 2 g of diisopropylamine and 80 ml of tetrahydrofuran under a nitrogen stream at a temperature from -60° to -50° C. The resulting mixture was then allowed to stand for 10 minutes at room temperature, after which about 10 ml of tetrahydrofuran containing 4 g of ethyl 6-methoxymethoxy-5,7,8-trimethylchroman-2-carboxylate (prepared as described in Preparation 11) were added and the mixture was stirred for 1 hour at -60° C. About 20 ml of tetrahydrofuran containing 5 g of octyl bromide were added, and the mixture was stirred for 1 hour at -60° C. and then for 1 hour at room temperature, after which it was heated for 1 hour at 50° C. The reaction mixture was then poured into ice-water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography eluted with benzene, to give the title compound.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]([CH2:12][CH3:13])[C:9](O)=[O:10].S(Cl)([Cl:22])=O>>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]([CH2:12][CH3:13])[C:9]([Cl:22])=[O:10]
Reactant: CCC(Cc1ccccc1-c1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCC(Cc1ccccc1-c1ccccc1)C(=O)Cl
Yield: 106.3 %

Procedure:
A 100-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a thermometer and a NaOH trap was charged with 13.3 g (52.4 mmol) of 3-(2-biphenylyl)-2-ethylpropionic acid and 25.9 ml (355 mmol) of thionyl chloride, and the resulting mixture was stirred under reflux for 2.5 hours under a nitrogen atmosphere. After the reaction was completed, the unreacted thionyl chloride was distilled off under reduced pressure to obtain 15.2 g of a crude product as a yellow-orange liquid. The thus obtained acid chloride was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([CH:11]([F:13])[F:12])[C:3]=1[C:4]#[N:5].C([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])C.[C:21]([N:28]1[CH2:33]CC(N)C[CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(O)C>[C:24]([O:23][C:21](=[O:22])[N:28]([CH:33]1[CH2:18][CH2:17][N:16]([C:8]2[CH:7]=[C:6]([CH:11]([F:13])[F:12])[C:3]([C:4]#[N:5])=[C:2]([Cl:1])[N:9]=2)[CH2:19][CH2:20]1)[CH3:29])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCN(CC)CC
Reactant: N#Cc1c(C(F)F)cc(Cl)nc1Cl
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2cc(C(F)F)c(C#N)c(Cl)n2)CC1
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of the above nicotinonitrile (2.4 g, 10.8 mmol) in ethanol (40 mL) was cooled in a dry ice/acetone bath. Triethylamine (1.5 mL, 11.0 mmol) and N-methyl, N-boc-4-aminopiperidine were added and the reaction mixture was allowed to warm gradually to room temperature overnight. The reaction was concentrated, taken up in ethyl acetate (200 mL) and washed with 1 N HCl (2×100 mL). The organic phase was dried (magnesium sulfate) and concentrated to provide a 4 to 1 mixture of addition products to the 6 and 2 position, respectively. These regioisomers were separated by silica gel chromatography using a gradient of ethyl acetate in hexanes as the mobile phase to provide 1.3 g (30%) of (6′-chloro-5′-cyano-4′-difluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-methyl-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[OH:2].[CH3:11][O:12][CH2:13][CH:14]=O.C1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:11][O:12][CH2:13][CH:14]1[O:10][CH2:9][C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:1][O:2]1
Reactant: OCC1(CO)CCCCC1
Reactant: COCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: COCC1OCC2(CCCCC2)CO1
Yield: 97 %

Procedure:
A mixture of 288 g (2 moles) of 1,1-dimethylolcyclohexane, 191 g (2.2 moles) of 85% strength methoxyacetaldehyde and 250 ml of cyclohexane was heated with 2 g of p-toluenesulfonic acid under a water separator until water no longer separated off. The resulting solution was washed with dilute sodium hydroxide solution, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 388 g (97% yield) of 3-methoxymethyl-2,4-dioxaspiro[5.5]undecane of boiling point 95° C./1 mbar were obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45](O)=[O:46].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:46]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cc1cccc(C)c1OCC(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)COc1c(C)cccc1C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
A solution containing the product from Example 23S (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S. Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-80% ethyl acetate/chloroform to give the title compound (0.016 g, 61% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.86 (s, 9 H), 1.63 (m, 2 H), 2.07 (s, 6 H), 2.78 (m, 4 H), 3.51 (s, 3 H), 3.62 (m, 1 H), 3.94 (m, 3 H), 4.25 (m, 2 H), 4.87 (d, J=5.15 Hz, 1 H), 6.89 (m, 4 H), 7.19 (m, 5 H), 7.31 (m, 3 H), 7.61 (d, *8.46 Hz, 1 H), 7.84 (m, 5 H), 8.62 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@@H:10]([CH2:25][OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.C[O+](C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@@H:10]([CH2:25][O:26][CH3:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Agent: C[O+](C)C
Solvent: ClCCl
Product: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 0.58 h
Yield: 69.9 %

Procedure:
(2R,5R)-2-Hydroxymethyl-5-methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (25 g, 68 mmol) in DCM (823 mL) was cooled to 4° C. (ice bath). 1,8-bis(dimethylamino)naphthalene (72 g, 337 mmol) was added in one portion followed by trimethyl oxonium tetrifluoroborate (50 g, 337 mmol) portionwise over 5 min. The mixture was stirred for 35 min at 5° C., the ice bath removed, then warmed from 5-17° C. over 1 h. After stirring for a further 20 min., saturated aqueous ammonium chloride (300 mL) was added slowly and reaction stirred for 10 min. The organic layer was separated and the aqueous phase extracted with DCM (2×300 mL). The combined organic extracts were washed with 1.0 M HCl (3×1.5 L), saturated sodium bicarbonate solution (3×1.5 L), dried over sodium sulfate, filtered and concentrated. The oil was dissolved in DCM and petrol added until precipitation of 1,8-bis(dimethylamino)naphthalene occurred. Purification by column chromatography (silica gel, 0-0%, 0-100%, EtOAc/petrol) gave an oil which contained 1,8-bis(dimethylamino)naphthalene as a contaminant. The remaining 1,8-bis(dimethylamino)naphthalene was captured during filtration through a SCX-2 column eluting with MeOH, to give the title compound (18 g, 52% over two steps) as a pale yellow oil. 1H NMR (Me-d3-OD): 7.46-7.26 (5H, m), 5.26-5.07 (2H, m), 4.31 (2H, d), 4.04-3.85 (1H, m), 3.79 (1H, d), 3.46 (2H, s), 3.28-3.09 (2H, m), 1.48 (9H, s), 1.15 (3H, dd).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]3[CH:14]=[N:15][C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=4[O:28][CH3:29])=[N:17][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[NH2:54][CH:55]1[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]1.C(N(CC)CC)C>ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]3[CH:14]=[N:15][C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH:54][CH:55]5[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]5)=[O:25])=[CH:21][C:20]=4[O:28][CH3:29])=[N:17][C:6]2=3)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC1)CCC(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 24.3 %

Procedure:
A mixture of 0.059 g (0.00015 mole) of 4-(9-cyclobutyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-23), 0.07 g (0.000185 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.05 mL (0.0004 mole) of 4-amino-1-methylpiperidine, 0.1 mL of triethylamine and 3 mL of dichloromethane was stirred for 2.5 hours at ambient temperature. The mixture was concentrated under reduced pressure and the residue purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (10:90-100:0) to give 0.018 g of 4-(9-cyclobutyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-24).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:5])[CH3:4].[OH-].[Na+].I[CH2:9][CH:10]=[CH:11][C:12]1[CH2:13][S:14][C@@H:15]2[CH:35]([NH:36][C:37](=[O:67])/[C:38](=[N:64]\[O:65][CH3:66])/[C:39]3[N:40]=[C:41]([NH:44]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:42][CH:43]=3)[C:34](=[O:68])[N:16]2[C:17]=1[C:18]([O:20]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19]>C(OCC)(=O)C.CCCCCC>[NH2:44][C:41]1[S:42][CH:43]=[C:39](/[C:38](=[N:64]/[O:65][CH3:66])/[C:37]([NH:36][CH:35]2[C:34](=[O:68])[N:16]3[C:17]([C:18]([O-:20])=[O:19])=[C:12](/[CH:11]=[CH:10]/[CH2:9][N+:3]([CH3:5])([CH3:4])[CH3:2])[CH2:13][S:14][C@H:15]23)=[O:67])[N:40]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(/C=C/C[N+](C)(C)C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylamine hydrochloride (6.31 g, 66 mmole) was added to an aqueous NaOH solution (2N, 33 ml) covered with ethyl acetate (100 ml). The organic layer was separated, dried over NaOH pellets, and added to a suspension of diphenylmethyl 3-(3-iodo-1-propen-1-yl)-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (X-1, 32 g, 33 mmole) in a mixture of ethyl acetate and n-hexane (300 ml/150 ml). The mixture was stirred for one hour at room temperature and then filtered to give the blocked title compound, which was treated with trifluoroacetic acid (50 ml) and anisole (10 ml) for one hour at room temperature. The mixture was concentrated under reduced pressure and the residue was triturated with ether to give 10.3 g of dark brown solid, which was treated with water (100 ml) at room temperature. After removal of insolubles by filtration, the filtrate was chromatographed on a column of HP-20 (200 ml) by eluting with 30% aqueous methanol. The eluate was concentrated and lyophilized to give 2.3 g of the crude title compound, which was purified by preparative HPLC (Waters Associates, System 500, PrepPAK 500/C18, 15% CH3OH) to afford 880 mg (5%) of the title compound I-1D. Estimated purity 75% (by HPLC).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8]=O.CO[C:12](=[O:30])[C:13]([OH:29])=[CH:14][C:15](=[O:28])[N:16]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[O:17][CH3:18]>C(O)(=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][N:16]([O:17][CH3:18])[C:15]([C:14]1[CH2:8][N:1]([CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:12](=[O:30])[C:13]=1[OH:29])=[O:28]
Reactant: NCCCC(=O)O
Reactant: C=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(Cl)c(Cl)c1)OC
Solvent: CC(=O)O
Product: CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
To a solution of 4-amino butyric acid (0.093 g, 0.90 mmol) in acetic acid (0.5 mL) at 55° C. was added paraformaldehyde (0.027 g, 0.90 mmol). After stirring for 10 min, 3-[(3,4-dichloro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (0.2978 g, 0.89 mmol) was added and the mixture was stirred at 55° C. for 1 h. The clear yellow solution was cooled, concentrated and purified by preparative HPLC (C18, ODS-A, S-75 μm, 10%–40% acetonitrile/water/0.5% HCl) to give the title compound as a yellow foam (0.129 g, 34% yield). HRMS (M+H) calcd for C17H19N2Cl2O6: 417.06203; found: 417.0607.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH2:12])=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])C.Br[C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1>>[CH3:27][C:25]1[N:26]=[C:22]([NH:21][C:4]([C:6]2[C:11]([NH:12][C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=2)=[O:5])[S:23][CH:24]=1
Reactant: Cc1csc(N)n1
Reactant: Brc1cncnc1
Reactant: CCOC(=O)c1nc(C)cnc1N
Product: Cc1csc(NC(=O)c2nc(C)cnc2Nc2cncnc2)n1

Procedure:
The title compound, MS: m/e=328.3 (M+H+), was prepared in accordance with the general method of example 10 from 3-amino-6-methyl-pyrazine-2-carboxylic acid ethyl ester (Example C), 5-bromopyrimidine and 2-amino-4-methylthiazole