Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:15]=[O:16])[C:9]=2[CH:8]=[CH:7]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:23]([O:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:15]=[O:16])[C:9]=2[CH:8]=[CH:7]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cccc2c1ccn2CC(O)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=Cc1cccc2c1ccn2CC(OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.3 %

Procedure:
There was suspended 26.4 mg of 60% sodium hydride in 5 ml of dimethylformamide, followed by addition of a solution of 1-(2-hydroxy-2-phenylethyl)indole-4-carbaldehyde (160 mg) in dimethylformamide (2 ml) with ice-cooling. After stirring at room temperature for 15 minutes, the mixture was ice-cooled, then a solution of benzyl bromide (115.2 mg) in dimethylformamide (2 ml) was added thereto and stirred at room temperature for 3 hours. The reaction system was poured into 50 ml of a 10% ammonium chloride aqueous solution and extracted with ethyl acetate (50 ml×2). The resulting organic phase was washed with, in order, a 10% citric acid aqueous solution, a saturated sodium hydrogen carbonate aqueous solution and a saturated common salt solution, dried over anhydrous sodium sulfate and the solvent was removed through evaporation under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 170 mg of 1-(2-benzyloxy-2-phenylethyl)indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 80%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C(N(CC)CC)C.[C:31]([C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([NH:38]O)=[NH:37])#[N:32]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:15][N:38]=[C:36]([C:35]2[CH:40]=[CH:41][CH:42]=[C:33]([C:31]#[N:32])[CH:34]=2)[N:37]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1cccc(C(=N)NO)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2cccc(C#N)c2)no1
Temperature: 120 °C
Yield: 44 %

Procedure:
(S)-2-[3-(3-Cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (698 mg, 44%) was prepared according to the procedure in Example 25 from (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.00 g, 4.66 mmol) with isobutyl chloroformate (0.64 mL, 4.9 mmol) and triethylamine (1.6 mL, 11.5 mmol) in THF (14 mL). Then 3-cyano-N-hydroxy-benzamidine (753 mg, 4.67 mmol) and DMF (15 mL) were added and the mixture was heated at 120° C. for 18 h.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=1)[O:35][CH2:36][C:37]([OH:39])=[O:38])=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=3)[O:35][CH2:36][C:37]([OH:39])=[O:38])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1cccc(OCC(=O)O)c1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)COc1cccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and (3-formyl-phenoxy)-acetic acid according to the procedure of Example 66. MS (ESI) m/z 557.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([Br:14])[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[CH3:15])=[O:4].[Li+].[OH-].Cl>C1COCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]2[O:7][C:6]([CH3:15])=[C:5]([C:3]([OH:4])=[O:2])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1c(C)oc2ccc(Br)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1oc2ccc(Br)cc2c1C(=O)O

Procedure:
350 mg (1.30 mmol) 5-bromo-2-methyl-benzofuran-3-carboxylic acid methyl ester was dissolved in 10 mL THF and treated with 5.0 mL 1 M aqueous LiOH solution at 60° C. for 12 h. The reaction mixture was acidified with 1 M aqueous hydrochlorid acid. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[BH3-]C#N.[Na+].[F:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.CS(O)(=O)=O>CO>[F:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:1][C@H:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])=[CH:20][CH:19]=1
Reactant: N[C@H]1CCNC1=O
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cc1
Agent: CS(=O)(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C1NCC[C@@H]1NCc1ccc(OCc2cccc(F)c2)cc1
Reaction time: 0.17 h

Procedure:
To a 2M solution of (S)-3-aminopyrrolidin-2-one (1.47 g, 14.6 mmol), prepared as described in Example 5, in anhydrous methanol 2.0 g of 3 Å molecular sieves and 0.77 g NaBH3CN (12 mmol) were added; after 10 minutes, 3.4 g (14.8 mmol) of 4-(3-fluorobenzyloxy)benzaldehyde in 40 ml of anhydrous methanol were added. The reaction was carried out for 3 hours, then the mixture filtered, the solution was evaporated yielding a residue which was directly flash-chromatographed on silica gel (eluant: CHCl3:CH3OH:NH3 (30%) 97:3:0.3, v:v:v) to give a white solid (3.4 g; 74%). The free base thus obtained was treated with a stoichiometric amount of methanesulfonic acid to give the title compound m.p. 140.5-143.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:17]=O)=[C:12]3[C:16]=2[O:15][CH:14]=[CH:13]3)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].CO.N1C=CC=CC=1>CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:17]=[N:20][OH:21])=[C:12]3[C:16]=2[O:15][CH:14]=[CH:13]3)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccc(O)cc2)c2occc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: CCOCC
Product: ON=Cc1ccc(-c2ccc(O)cc2)c2occc12
Temperature: 68 °C

Procedure:
To a 15 ml round bottom flask was added 7-(4-hydroxyphenyl)-benzofuran-4-carbaldehyde (250 mg, 1.05 mmol), hydroxylamine hydrochloride (146 mg, 2.10 mmol), anhydrous MeOH (6.5 ml), and anhydrous pyridine (0.17 ml, 2.10 mmol). The flask was then sealed and heated to 68° C. for 1 h, cooled to room temperature, dilute with ether, and the layers separated. The ether layer was washed with water, dried over anhydrous Na2SO4, passed through a silica plug, and concentrated to 250 mg (94%) clean product as a yellow solid. Further purification was done by chromatography (1:1 EtOAc/hexanes) for analytical analysis: mp 216–217° C.; 1H NMR (300 MHz, DMSO-d6): δ 6.92 (2H, d, J=8.7 Hz), 7.36 (1H, d, J=2.1 Hz), 7.49 (2H, app s), 7.74 (2H, d, J=8.6 Hz), 8.14 (1H, d, J=2.1 Hz), 8.42 (1H, s), 9.73 (1H, s) 11.36 (1H, s); MS (ESI) m/z 254 ([M+H]+).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:36][C:35]([CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[N:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>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.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[S:36][C:35]([CH:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[N:34][CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Brc1cnc(C2CCOCC2)s1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2cnc(C3CCOCC3)s2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 52.3 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one (100 mg, 0.243 mmol), 5-bromo-2-(tetrahydro-2H-pyran-4-yl)thiazole (65.5 mg, 0.264 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.60 mL, 0.60 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (11.6 mg, 0.01 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give off-white solids, 57.5 mg (yield 52.3%). 1H NMR (300 MHz, DMSO-d6) δ 8.12 (s, 1H), 8.08 (s, 1H), 7.60 (s, 1H), 7.40 (d, J=1.2 Hz, 1H), 7.07 (d, J=1.3 Hz, 1H), 4.85 (p, J=5.9 Hz, 1H), 4.00-3.88 (m, 2H), 3.76-3.62 (m, 1H), 3.55-3.42 (m, 2H), 3.42-3.36 (m, 1H), 3.28-3.14 (m, 1H), 2.88-2.71 (m, 1H), 2.41-2.19 (m, 2H), 2.06-1.93 (m, 2H), 1.85-1.65 (m, 2H), 1.31 (d, J=6.0 Hz, 3H), 1.14-1.06 (m, 2H), 1.06-0.96 (m, 2H) ppm; MS (ESI+) m/z 453.09 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[S:29]([CH3:28])(=[O:31])=[O:30])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ccccc3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(C)(=O)=O)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-(3-{[(biphenyl-4-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 12m, and methanesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 4H), 7.44-7.23 (m, 6H), 7.14 (m, 3H), 4.35 (s, 2H), 4.33 (s, 2H), 3.64 (s, 3H), 2.92 (t, 2H), 2.78 (s, 3H), 2.59 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1N.[CH3:10][S:11]SC.N(OC(C)(C)C)=O>C(#N)C>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[S:11][CH3:10]
Reactant: CSSC
Reactant: Nc1cc(Cl)ccc1Br
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CSc1cc(Cl)ccc1Br
Temperature: 60 °C
Yield: 66.3 %

Procedure:
2-Bromo-5-chloroaniline (85.2 g, 0.41 mol) was dissolved in 1 L of acetonitrile followed by the addition of dimethydisulfide (30.0 mL, 0.33 mol). The flask was immersed in a water bath warmed to 60° C., equipped with a reflux condenser, and tert-butyl nitrite (54.0, 0.45 mol) was added in portions over 15 minutes. Once the addition was complete, the reaction was refluxed for 2 hours. After cooling to room temperature, the acetonitrile was evaporated, followed by re-dissolving in dichloromethane and subsequent concentration to remove remaining acetonitrile. The residue was re-dissolved in a minimal amount of dichloromethane and diluted with hexanes until precipitation was initiated. The mixture was filtered through a plug of silica and washed with hexanes. The filtrate was then concentrated in vacuo and crystallized upon cooling. 1-Bromo-4-chloro-2-methylsulfanylbenzene (52.0 g, 53%) was isolated via suction filtration.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:19]4[CH:18]=[CH:17][N:16]=[C:15]([O:20]C)[C:14]=4[C:13]([C:22]4[CH:23]=[C:24]([C:27]([NH2:29])=[O:28])[S:25][CH:26]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:19]4[CH:18]=[CH:17][NH:16][C:15](=[O:20])[C:14]=4[C:13]([C:22]4[CH:23]=[C:24]([C:27]([NH2:29])=[O:28])[S:25][CH:26]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: NC(=O)c1cc(-c2nn(C3CCC4(CC3)OCCO4)c3cc[nH]c(=O)c23)cs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
To a solution of 4-(1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (20.0 mg) in acetonitrile (5 mL) were added sodium iodide (18.1 mg) and chloro(trimethyl)silane (0.027 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (3.4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1.C(O)(=O)C=CC1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:18]=[CH:17][C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2Cl)cc1
Agent: O=C(O)C=Cc1ccccc1
Product: O=C(O)CCc1ccc(-c2ccccc2Cl)cc1

Procedure:
when p-(2-chlorophenyl)cinnamic acid is replaced by the cinnamic acid compounds of Table II, Example 1 then the corresponding propionic acid is prepared.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[Cl:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]>>[Cl:10][C:11]1[CH:18]=[C:17]([S:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]
Reactant: CCc1cccc(S)c1
Reactant: O=Cc1ccc(F)cc1Cl
Product: CCc1cccc(Sc2ccc(C=O)c(Cl)c2)c1

Procedure:
3-Ethylbenzenethiol and 2-chloro-4-fluorobenzaldehyde were reacted according to the same experiment procedures as in Reference Example 1 of the pamphlet of WO 03029205 to obtain the target product as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][CH2:12][OH:13])[N:9]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1.I[CH3:20].[H-].[Na+].[Cl-].[NH4+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][CH2:12][O:13][CH3:20])[N:9]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1
Reactant: CCOC(=O)c1cc(CCCCCl)n(CCO)n1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CCCCCl)n(CCOC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 5-(4-chlorobutyl)-1-(2-hydroxyethyl)-1H-pyrazole-3-carboxylate (165 g, 0.600 mol) and iodomethane (187 mL, 3.00 mol) in THF (1.2 L) was cooled to 0° C. Sodium hydride (28.8 g of a 60% dispersion in mineral oil, 0.720 mol) was added slowly while maintaining the temperature below 10° C. The reaction was allowed to warm to ambient temperature and stirred overnight. Aqueous ammonium chloride and water were added, and the mixture was extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide ethyl 5-(4-chlorobutyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylate as a dark brown oil.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[NH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9][C:8]1=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:1][CH:2]([CH3:6])[C:3]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:7][C:8](=[O:17])[NH:9][CH2:10]2)=[O:4]
Reactant: CC(Br)C(=O)Br
Reactant: O=C1NCc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc2c(c1)CNC(=O)N2

Procedure:
2-Bromopropionyl bromide (10.6 g) is added dropwise to a stirring mixture of 3,4-dihydro-2(1H)-quinazolinone (3.2 g) and anhydrous aluminum chloride (7.9 g) in carbon disulfide (60 ml). The reaction mixture is refluxed for four hours, the carbon disulfide decanted and the residue treated with aqueous hydrochloric acid (6N). The acidic residue is poured into ice water, and the precipitate filtered, washed with water and dried, affording the desired product as a solid, which is used in the next step without further purification.
Reaction SMILES: FC1C=C(N)C=CC=1OC1C=CN=C2C=C(C3N(C)C=CN=3)SC=12.[CH2:25]([N:27]1[CH:31]=[C:30]([C:32]2[S:40][C:39]3[C:34](=[N:35][CH:36]=[CH:37][C:38]=3[O:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-])=O)=[CH:44][C:43]=3[F:51])[CH:33]=2)[N:29]=[CH:28]1)[CH3:26]>>[CH2:25]([N:27]1[CH:31]=[C:30]([C:32]2[S:40][C:39]3[C:34](=[N:35][CH:36]=[CH:37][C:38]=3[O:41][C:42]3[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][C:43]=3[F:51])[CH:33]=2)[N:29]=[CH:28]1)[CH3:26]
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1

Procedure:
Following the procedure described for compound 9 (example 2, step 5) but substituting nitro compound 8 for the compound 14, title compound 15 was obtained as a yellow solid (86% yield). MS (m/z): 402.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:23]=[CH:22][C:21]3[C:20](=O)[CH2:19][CH2:18][C:17]([CH3:26])([CH3:25])[C:16]=3[CH:15]=2)=[CH:8][C:7]=1[F:27])[CH3:2].ClCCl.[CH:32]1([NH2:35])[CH2:34][CH2:33]1.C([BH3-])#N.[Na+]>CCCCCC.C(OCC)(=O)C.C(O)(=O)C.C(#N)C>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:23]=[CH:22][C:21]3[CH:20]([NH:35][CH:32]4[CH2:34][CH2:33]4)[CH2:19][CH2:18][C:17]([CH3:26])([CH3:25])[C:16]=3[CH:15]=2)=[CH:8][C:7]=1[F:27])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1F
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3NC2CC2)cc1F

Procedure:
Following general procedure G and using [2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl) phenyl]acetic acid ethyl ester (Compound 14, 0.258 g, 0.68 mmol), dichloromethane (4 mL), acetonitrile(2 mL), cyclopropyl amine(1 mL, 14.45 mmol), acetic acid (1 mL) and sodium cyanoborohydride (0.266 g, 4.23 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 16-20-25% ethyl acetate in hexane as the eluent, the title compound was obtained as a pale yellow oil (0.21 g, 73%).
Reaction SMILES: C([NH:3][C@@H:4]1[C:27](=[O:28])[N:6]2[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]3[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=3)[CH2:9][S:10][C@H:5]12)=O.[ClH:29].C(OCC)(=O)C>CO>[ClH:29].[ClH:29].[NH2:3][C@@H:4]1[C:27](=[O:28])[N:6]2[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]3[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=3)[CH2:9][S:10][C@H:5]12
Reactant: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC=O)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a cooled suspension of 7β-formamido-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate (1.225 g) in methanol (12 ml) was added dropwise conc. hydrochloric acid (0.83 ml) at 10° C. The mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was poured into ethyl acetate (300 ml) and the precipitates were collected by filtration, washed with ethyl acetate and diisopropyl ether and dried in vacuo. The powder was dissolved in cold water (10 ml) and the resulting solution was chromatographed on Diaion HP-20 (10 ml) at 5° C. and the elution was carried out with cold water. To the eluate (24 ml) was added dropwise isopropyl alcohol (12 ml) under cooling and the mixture was allowed to stand overnight in a refrigerator. The resultant crystal was collected by filtration, washed with a cold mixture of isopropyl alcohol and water (10:1) and cold isopropyl alcohol, and dried in vacuo to give 7β -amino-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4carboxylate dihydrochloride (440 mg).
Reaction SMILES: [OH-].[K+].C([CH2:5][NH:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[N:15]=2)[C:10](=[O:18])[C:9]([C:19]([O:21]CC)=[O:20])=[CH:8]1)=O>O.C(O)C>[CH3:17][C:14]1[N:15]=[C:16]2[C:11]([C:10](=[O:18])[C:9]([C:19]([OH:21])=[O:20])=[CH:8][N:7]2[NH:6][CH3:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cn(NCC=O)c2nc(C)ccc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNn1cc(C(=O)O)c(=O)c2ccc(C)nc21
Temperature: 0 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
A solution of 85% potassium hydroxide (2.25 g, 0.035 m) in 7.8 ml of water was added to a refluxing solution of 4.5 g (0.016 m) of ethyl 1-(N-formylmethylamino)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate in 141 ml of absolute ethanol. The reaction mixture was heated at reflux for one hour, then allowed to stand at room temperature for three days, and poured into 100 ml of ice-water and filtered. The filtrate while cold was acidified with acetic acid, and the solid product was collected by filtration, washed with water and dried at 50° C. in vacuo to yield 3.3 g of 1,4-dihydro-7-methyl-1-methylamino-4-oxo-1,8-naphthyridine-3-carboxylic acid, beige solid, m.p. 215°-217° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19](O)=[C:18]([F:23])[C:17]=2[F:24])=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:25][C:26]([F:53])([C:49]([F:52])([F:51])[F:50])[C:27]([F:48])([F:47])[C:28]([F:46])([F:45])[O:29][C:30]([F:44])([F:43])[C:31]([F:42])([F:41])[C:32]([F:40])([F:39])[CH2:33][O:34][CH2:35][CH2:36][CH2:37]Br>>[CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([F:39])([F:40])[C:31]([F:41])([F:42])[C:30]([O:29][C:28]([F:45])([F:46])[C:27]([F:47])([F:48])[C:26]([F:25])([F:53])[C:49]([F:51])([F:52])[F:50])([F:44])[F:43])=[C:18]([F:23])[C:17]=2[F:24])=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)COCCCBr
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)c(F)c2F)nc1
Product: CCCCCCCCOc1cnc(-c2ccc(CCCOCC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyloxy-2-[4-hydroxy-2,3-difluorophenyl]pyrimidine (1.5 g, 4.7 mmol) with 3-(4-(nonafluorobutoxy)-2,2,3,3,4,4-hexafluorobutoxy)propyl bromide (2.45 g, 5.1 mmol, prepared from 1,3-dibromopropane and 4-(nonafluorobutoxy)-2,2,3,3,4,4-hexafluorobutanol). The reaction mixture was quenched with water, and the resulting crude product was further purified by recrystallization from ethanol, followed by Kugelrohr distillation (210° C. at 0.5 torr), to provide a yield of 2.6 g.