Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:12])=[CH:7][C:6]=1[O:14][CH3:15]
Reactant: COc1cc(C(C)=O)ccc1OCC(F)F
Reactant: CC(C)(C)[S@](N)=O
Product: COc1cc(C(C)N[S@](=O)C(C)(C)C)ccc1OCC(F)F
Yield: 97 %

Procedure:
The title compound is prepared in 97% yield (1.09 g, yellow oil) from 1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanone (0.77 g, 3.35 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][NH:9][S:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][NH:9][S:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1ccc(N)cc1
Reaction time: 6 h
Yield: 98.1 %

Procedure:
10% Pd/C (7 mg) was added to a solution tert-butyl N-(4-nitrobenzyl)sulfamoyl-carbamate (65 mg) in ethanol and tetrahydrofuran and charged with H2. After stirring the reaction mixture for 6 h, the mixture was filtered using celite and evaporated in vacuo to obtain tert-butyl N-(4-aminobenzyl)sulfamoylcarbamate (58 mg, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=2)[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][CH:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=2)[CH2:29][CH2:30]1
Reactant: COc1ccc(O)cc1OC
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Product: COc1ccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2F)cc1OC

Procedure:
Prepared by Procedure A and Scheme AN using 3,4-dimethoxyphenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 577.6 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=2)[C:15]([OH:17])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[NH:22][NH2:23]>>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=2)[C:15]([NH:23][NH:22][C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[O:17])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCc1ccccc1)Nc1cc(C(=O)O)ccn1
Reactant: NNC(=O)OCc1ccccc1
Product: O=C(CCc1ccccc1)Nc1cc(C(=O)NNC(=O)OCc2ccccc2)ccn1
Yield: 53 %

Procedure:
In the same manner as in Reference Example 1 and using 2-[(3-phenylpropanoyl)amino]isonicotinic acid instead of benzothiazole-6-carboxylic acid and benzyl carbazate instead of tert-butyl carbazate, the title compound (yield 53%) was obtained as colorless amorphous.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8](OC(=O)C)(=[O:10])[CH3:9]>O1CCCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: OCCNCCO
Solvent: C1CCOC1
Product: CC(=O)N(CCO)CCO

Procedure:
315 g of diethanolamine were dissolved in 500 g of tetrahydrofuran in a round-bottom flask. Then, 310 g of acetic anhydride were slowly added. The temperature was kept below 5° C. with the aid of a cooling bath. When, after the dropwise addition, exothermic heat was no longer detectable, heating was slowly carried out to 100° C. Tetrahydrofuran and acetic acid were removed under vacuum.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=[O:6].Cl[Si](C)(C)[CH3:12]>CO.COC(OC)(C)C>[CH3:12][O:6][C:5](=[O:7])[C:4](=[O:8])[CH2:3][CH:2]([CH3:9])[CH3:1]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)CC(=O)C(=O)O
Solvent: COC(C)(C)OC
Solvent: CO
Product: COC(=O)C(=O)CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-2-oxo-pentanoic acid (3.4 g, 26 mmol) in methanol (12 mL) and 2,2-dimethoxypropane (48 mL) is added chlorotrimethylsilane (0.38 mL). The reaction mixture is stirred at ambient temperature overnight. The reaction mixture is concentrated under reduced pressure to give the title compound as an oil, (3.8 g, quant.). 1H NMR (400 MHz, CDCl3): δ 3.86 (s, 3H), 2.72 (d, 2H), 2.16 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:11]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:19].C1C(=O)N([Br:27])C(=O)C1>C(Cl)Cl>[Br:27][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:19])[N:2]([CH3:1])[C:11]2([CH3:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN1C(=O)Nc2ccccc2C1(C)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN1C(=O)Nc2ccc(Br)cc2C1(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-Dimethyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (0.4 g, 1.59 mmol) in DCM (5 mL) is added NBS (0.28 g, 1.59 mmol). After the addition the mixture is stirred at room temperature overnight. The mixture is diluted with DCM, washed with H2O, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by chromatography on silica gel to give product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[C:17]([F:26])=[CH:18][C:19]2[CH2:23][O:22][B:21]([OH:24])[C:20]=2[CH:25]=1.N1C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([NH:15][C:16]1[C:17]([F:26])=[CH:18][C:19]2[CH2:23][O:22][B:21]([OH:24])[C:20]=2[CH:25]=1)(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c(F)c1
Reactant: Nc1cc2c(cc1F)COB2O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2cc3c(cc2F)COB3O)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a stirred solution of 2-fluoro-4-nitrobenzene-1-sulfonyl chloride (1.336 g, 5.57 mmol) and 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (0.93 g, 5.57 mmol) in 20 mL of ACN was added pyridine (900 uL, 11.14 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After quenched with water, the solvent was removed in vacuo. The residue was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na2SO4, and concentrated to give 1.84 g of the title compound as a yellow residue. MS calcd for (C13H9BF2N2O6S): 370.0. MS found (ESI negative): (M−H)−=368.9
Reaction SMILES: [CH3:1][CH:2]([CH3:40])[CH:3]([N:9]1[CH2:12][CH:11]([CH2:13][C:14]2[N:15]([CH3:39])[C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:19]=[C:18]([N:29]2[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[C:30]2[CH3:38])[N:17]=3)[CH2:10]1)[C:4]([O:6]CC)=[O:5].C(O)C.[OH-].[Li+].Cl>O>[CH3:1][CH:2]([CH3:40])[CH:3]([N:9]1[CH2:10][CH:11]([CH2:13][C:14]2[N:15]([CH3:39])[C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:19]=[C:18]([N:29]2[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[C:30]2[CH3:38])[N:17]=3)[CH2:12]1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C(C)C)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(C(=O)O)C(C)C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-methyl-2-(3-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)azetidin-1-yl)butanoate (0.180 g, 0.329 mmol) in ethanol (1.0 mL, 17 mmol) was added 1.0 M of lithium hydroxide in water (2.0 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 1M HCl and concentrated. The residue was re-dissolved in MeOH and loaded onto a SCX-2 column. The column was first washed with MeOH. The product was then eluted with 2M NH3 in MeOH and concentrated. LCMS m/z: 519.3 (MH+)
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:21]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])[C:22]2[C:23]([CH3:31])=[CH:24][C:25]([C:28]([NH2:30])=[O:29])=[N:26][CH:27]=2)=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:21]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])[C:22]2[C:23]([CH3:31])=[CH:24][C:25]([C:28]([NH2:30])=[O:29])=[N:26][CH:27]=2)(=[O:9])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1cc(C(N)=O)ncc1C(c1cc(F)ccc1F)S(=O)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C(N)=O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 52 %

Procedure:
3-Chloroperbenzoic acid (66 mg, 0.25 mmol) was added to a solution of 5-[[(4-chlorophenyl)sulfinyl](2,5-difluorophenyl)methyl]-4-methylpyridine-2-carboxamide (105 mg, 0.25 mmol) in methylene chloride (5 ml) at 0° C. After stirring for 5 days at room temperature, the reaction mixture was washed with 1 N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative thin-layer chromatography (developed with methylene chloride:methanol=40:1, and eluted with methylene chloride:methanol=4:1). The obtained fraction was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether and collected by filtration, thus to obtain the title compound (56 mg, 0.13 mmol, 51%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:21])=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:22][CH3:23]>C(Cl)Cl>[OH:21][C:15]1[C:14]2[C:19](=[CH:20][C:11]([O:10][CH2:9][CH2:8][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[C:12]([O:22][CH3:23])[CH:13]=2)[N:18]=[CH:17][N:16]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(O)ncnc2cc1OCCCl
Solvent: ClCCl
Product: COc1cc2c(O)ncnc2cc1OCCN1CCOCC1
Temperature: 100 °C
Yield: 46 %

Procedure:
To morpholine (5 mL) was added 7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ol (600 mg, 2.36 mmol) from Example 35A and the mixture heated at 100° C. for 4 hours. After cooling to room temperature, the mixture was diluted with DCM and filtered. The resulting solid was washed with MeOH and H2O to give 4-hydroxy-6-methoxy-7-(2-morpholinoethoxy)quinazoline (328 mg, 1.07 mmol, 46%). 1H NMR (300 MHz, DMSO-d6) δ 12.08 (br s, 1H), 7.98 (s, 1H), 7.44 (s, 1H), 7.17 (s, 1H), 4.23 (t, 2H), 3.87 (s, 3H), 3.58 (t, 4H), 3.41-3.32 (m, 4H), 2.75 (t, 2H); LC-MS (ESI) m/z 306 (M+H)+.
Reaction SMILES: [Cl-].[Cl:2][C:3](=[O:9])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[CH3:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][C:12]=1/[CH:17]=[C:18]1\[C:19](=[O:29])[N:20]([CH2:27][OH:28])[C:21]2[C:26]\1=[CH:25][CH:24]=[CH:23][CH:22]=2>>[Cl-:2].[CH3:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][C:12]=1/[CH:17]=[C:18]1\[C:19](=[O:29])[N:20]([CH2:27][O:28][C:3](=[O:9])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])[C:21]2[C:26]\1=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(CO)c3ccccc32)[nH]1
Reactant: C[N+](C)(C)CC(=O)Cl
Agent: [Cl-]
Product: Cc1cc(C)c(/C=C2\C(=O)N(COC(=O)C[N+](C)(C)C)c3ccccc32)[nH]1

Procedure:
Following the procedure of Example 2, the title compound was prepared from 2-chloro-N,N,N-trimethyl-2-oxoethanaminium chloride and (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-1-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (1).
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.[CH3:18]COCC.CO>>[C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O:10][CH3:18])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC(=O)C(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of phenylmalonic acid (3.6 g, 0.02 mol), boron trifluoride etherate (2.4 mL, 0.02 mol) and 0.8 mL of anhydrous methanol (0.02 mol) was refluxed and stirred for 24 hours. After cooling to room temperature, the reaction mixture was filtered and 20 mL of water was added.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([CH2:26][CH3:27])([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:20]([CH3:25])[CH:19]=3)([CH2:26][CH3:27])[CH2:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc2cc(C(=O)OC)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)OC)ccc2c1
Yield: 47.9 %

Procedure:
Stir a mixture containing 6-[1-ethyl-1-(4-hydroxy-3-methylphenyl)propyl]naphthalene-2-carboxylic acid methyl ester (0.87 g, 2.40 mmol), 1-bromopinacolone (0.64 g, 3.60 mmol), and potassium carbonate (1.0 g, 7.2 mmol) in acetone (15 mL) at RT for 16 h. Concentrate the reaction mixture and dilute the residue with EtOAc (100 mL) and water (50 mL). Adjust the pH of the mixture to 1 using 1 N HCl. Discard the aqueous layer and wash the organic layer with brine, dry over Na2SO4, then filter. Concentrate the filtrate and purify by silica gel radial chromatography (5:95 EtOAc:hex to 15:85 EtoAc:hex) to give the title compound as an off-white solid (0.53 g, 48%). MS (ES) m/e 461 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].O.[NH3:18]>O1CCOCC1>[NH2:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([NH2:18])=[O:8]
Reactant: COC(=O)c1cc(N)c([N+](=O)[O-])cc1OC
Reactant: N
Solvent: O
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])c(N)cc1C(N)=O
Reaction time: 40 h

Procedure:
To a solution of 5.66 g of methyl 5-amino-2-methoxy-4-nitrobenzoate in 200 ml of dioxane was added 50 ml of 28 % ammonia water, and then the mixture was allowed to stand at room temperature for 40 hours. The solvent was evaporated under reduced pressure, and the residue was recrystallized from dioxane to give the title compound, m.p. 250°-257° C., yield of 4.30 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[N:18]=[C:17]([NH2:24])[CH:16]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:24][C:17]2[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[N:18]=2)[CH:7]=1
Reactant: CCCc1cc(C)cc(N)n1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCCc1cc(C)cc(Nc2cc(Cl)nnc2C(=O)OCC)n1
Temperature: 130 °C
Yield: 28881.6 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (335 mg, 1.52 mmol) in acetonitrile (5 mL) was added 4-methyl-6-propylpyridin-2-amine (342 mg, 2.27 mmol) and the mixture heated in a sealed tube at 130° C. for 72 h. The mixture was cooled, concentrated in vacuo, and then purified by chromatography (silica, 10 to 35% ethyl acetate in hexanes) to give ethyl 6-chloro-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (147 mg, 439 mmol, 29%) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 10.61 (s, 1H), 9.26 (s, 1H), 6.74 (s, 1H), 6.61 (s, 1H), 4.58 (q, J=7.1 Hz, 2H), 2.76 (t, J=7.5 Hz, 1H), 2.35 (s, 3H), 1.84 (m, 2H), 1.53 (t, J=6.9 Hz, 3H), 1.03 (t, J=7.3 Hz, 3H), MS (EI/CI) m/z: 335.0 [M+H].
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34]([O:37][Si](C)(C)C)[C:35]#[CH:36].[SiH3]O[SiH3]>N1CCCCC1.[Cu]I.CCOCC>[CH3:12][C:9]1([CH3:13])[CH2:10][CH2:11][C:2]([CH3:14])([CH3:1])[C:3]2[CH:4]=[C:5]([C:36]#[C:35][CH2:34][OH:37])[CH:6]=[CH:7][C:8]1=2
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: C#CCO[Si](C)(C)C
Agent: [Cu]I
Agent: [SiH3]O[SiH3]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CC1(C)CCC(C)(C)c2cc(C#CCO)ccc21

Procedure:
114 g of crude 2-bromo-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (GC-purity: 76.5%) was dissolved in 250 ml of piperidine and successively treated with 4.80 g of ((Ph)3P)4Pd, 0.95 g of CuI, and 1.35 g of (Ph)3P. The internal temperature was then raised to 90°-95° C. and 150 ml of propargyloxy-trimethylsilane were added via dropping funnel within 4 hours. After 1 additional hour the reaction mixture was poured onto crashed ice/HCl conc. and vigorously stirred until TLC indicated that all silylether had been cleaved. EtOEt was added, the layers were separated and the organic phase washed with H2O and brine. Drying over Na2SO4, evaporation of the solvent and purification by flash chromatography (silica gel, hexane/AcOEt=85:15) afforded 60.6 g of 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-prop-2-yn-1-ol as ochre yellow crystals of m.p. 84°-85° C. (GC-purity >96%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:14]([CH:17]([OH:19])[CH3:18])=[CH:15][S:16][C@H:11]12)=[O:8].N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:21])[C:14]([CH:17]([O:19][C:44](=[O:46])[CH3:45])[CH3:18])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(C)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 99 %

Procedure:
A solution of 0.535 g. of benzhydryl 7-(2-thienylacetamido)-3-(1-hydroxyethyl)-2-cephem-4-carboxylate, 6 ml. of pyridine, and 2 ml. of acetic anhydride in 30 ml. of methylene chloride was refluxed at 42° C. for 2 hours. The reaction mixture was then evaporated in vacuo to dryness, and the resulting residue was dissolved in ethyl acetate and washed with 1N.HCl and brine, and dried over anhydrous sodium sulfate. Evaporation in vacuo of the dried solution to dryness provided 0.571 g. (99 percent) of the title product as a white froth. The product was identical to that prepared above via the reaction of ketene with the cephem carbinol.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[ClH:9].NC(CS)C[N:13]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:23][C:18]=2[CH2:17][N:16]([C:30]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)=[O:31])[CH2:15][CH2:14]1>>[ClH:9].[C:32]1([C:30]([N:16]2[CH2:17][C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:21]=[CH:20][C:19]=3[N:13]([CH2:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:15]2)=[O:31])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: O=Cc1cccnc1
Reactant: NC(CS)CN1CCN(C(=O)c2cccc3ccccc23)Cc2cc(-c3ccccc3)ccc21
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2cccnc2)c2ccc(-c3ccccc3)cc2C1

Procedure:
The title compound was prepared from nicotinaldehyde and the compound E of Example 2 by following the procedure described for the preparation of Example 6. MS (M+H): 470.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][P:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23][CH3:24])[CH:15]=1)(=[O:12])[O:7][CH2:8][CH2:9][O:10][CH3:11].[H][H]>CO.[Pd]>[CH3:11][O:10][CH2:9][CH2:8][O:7][P:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:23][CH3:24])[CH:15]=1)(=[O:12])[O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: [H][H]
Reactant: COCCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1)OCCOC
Agent: [Pd]
Solvent: CO
Product: COCCOP(=O)(Cc1ccc(N)c(OC)c1)OCCOC
Yield: 96.8 %

Procedure:
A mixture of bis(2-methoxyethyl)(4-nitro-3-methoxybenzyl)phosphonate (Compound 217D, 4.5 g, 12.4 mmol) and 5% Pd/C (2 g, wet) in MeOH (100 mL) was hydrogenated under 50 psi hydrogen pressure at 50° C. for 18 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product (4 g, 97%). 1H NMR (DMSO-d6, 400 MHz): δ=3.11 (d, J=21.2 Hz, 2H), 3.34 (s, 6H), 3.49 (m, 4H), 3.81 (s, 3H), 4.05 (m, 4H), 6.12 (d, J=8.4 Hz, 2H), 6.20 (dd, J=8.4 Hz, 1H), 6.78 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH2:15]([NH2:17])[CH3:16]>CC#N>[CH2:15]([NH:17][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)[CH3:16]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCN
Solvent: CC#N
Product: CCNc1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a 0° C. solution of ethyl 4-chloro-2(methylthio)pyrimidine-5-carboxylate (19 g, 82 mmol) in CH3CN (100 mL) was added a solution of aqueous ethylamine (70%, 8.1 g, 126 mmol). The resulting mixture was stirred at RT for 8 h. The organic solution was removed under reduced pressure, and the residue was partitioned between EtOAc and H2O. The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined organics were washed with brine, dried (MgSO4) and concentrated to give ethyl 4-(ethylamino)-2-(methylthio)pyrimidine-5-carboxylate (19.5 g, 99.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1 H), 8.26 (t, J=4.8 Hz, 1 H), 4.23 (q, J=7.2 Hz, 2 H), 3.48 (q, J=7.2 Hz, 2 H), 2.44 (s, 3 H), 1.26 (t, J=7.2 Hz, 3 H), 1.13 (t, J=7.2 Hz, 3 H).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][C:10](=O)[CH3:11])[O:3]1.[Cl:14][C:15]1[CH:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[CH:17][N:16]=1.O>O1CCOCC1>[Cl:14][C:15]1[CH:20]=[C:19]([N:21]2[C:10]([CH3:11])=[CH:9][C:4]([OH:3])=[CH:5][C:6]2=[O:8])[C:18]([CH3:22])=[CH:17][N:16]=1
Reactant: Cc1cnc(Cl)cc1N
Reactant: CC(=O)CC1=CC(=O)OC(C)(C)O1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(Cl)cc1-n1c(C)cc(O)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a screw top vial with rubber septa inset was added 2,2-dimethyl-6-(2-oxo-propyl)-[1,3]dioxin-4-one, prepared as described in Organic Letters, 11(21), 4910-4913; 2009, (500 mg, 2.7 mmol) and 2-chloro-5-methyl-pyridin-4-ylamine (575 mg, 4 mmol, 1.5 eq). The mixture was dissolved in anhydrous 1,4-dioxane (10 mL). Once the mixture was homogeneous the vial was placed on a stirrer/hot plate preset to 90° C. The reaction vessel was heated at this temperature for 3.5 h. The reaction vial was removed from heat and analyzed by HPLC which showed that the reaction was >95% complete. The vial was placed back on the hot plate. To the heated mixture was added H2SO4 (250 μL) and the reaction was heated for 1 h. The reaction vial was removed from the heat and after cooling to ambient temperature, the dioxane was removed by passing a stream of air over the top of the open vial to give a brown residue. Water (˜4 mL) was added to the vial, and the mixture was stirred for 30 min. The resulting tan solid was filtered off with washing from additional water and the diethyl ether to give the desired product (531 mg, 57% based on being the sulfate salt) as a tan solid which by HPLC was ˜95% pure: MS (ES) m/e 250 (M+H).