Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Br[CH2:45][CH2:46][CH2:47][Cl:48].BrCC1OC(C(F)(F)F)=CC=1>>[Cl:48][CH2:47][CH2:46][CH2:45][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: ClCCCBr
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: O=C1N(CCCCl)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 1-bromo-3-chloropropane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (22%) as a colorless solid: mp 144-146° C.; 1H NMR (300 MHz, CDCl3) δ 7.31 (dt, 1H), 7.14-7.12 (m, 2H), 7.01 (t, 1H), 6.65 (s, 1H), 6.23 (s, 1H), 5.89 (s, 2H), 4.68 (ABq, 2H), 3.85-3.79 (m, 2H), 3.67 (t, 2H), 2.06 (t, 1H); 13C NMR (75 MHz, DMSO-d6) δ 177.2, 155.8, 148.7, 142.9, 142.2, 132.4, 129.3, 124.1, 123.3, 120.3, 109.3, 103.6, 101.7, 80.3, 57.8, 43.4, 30.6; MS (ES+) m/z 358.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[N:18]1([CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[ClH:1].[ClH:1].[N:18]1([CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)=[CH:4][N:3]=3)[CH2:31][CH2:32]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: C1CCN(CCCN2CCNCC2)CC1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nc2)cc1
Product: Cl
Product: FC(F)(F)c1ccc(-c2ccc(N3CCN(CCCN4CCCCC4)CC3)nc2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(4-trifluoromethylphenyl)pyridine and 1-(3-piperidinopropyl)piperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:25]([O-])=O)[C:21]([O:23][CH3:24])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([NH2:25])[C:21]([O:23][CH3:24])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)OC(COS(=O)(=O)c1ccc(C)cc1)CO2

Procedure:
To a mixture of 3.74 g (9.40 mmole) of [(2S)-7-nitro-6-methoxy-2,3-dihydro-1,4-benzodioxin-2y]methyl 4-methylbenzenesulfonate and 2.5 mL of 4 N isopropanolic HCl in 200 mL of ethyl acetate was added 0.45 g of 10% palladium on carbon and the mixture treated with 50 psi of hydrogen on a Parr apparatus for 15 hours. The catalyst was then removed by filtration through celite and the filtrate concentrated in vacuum to give 3.41 g of the (R)-enantiomer of the title compound as beige solid hydrochloride salt. 1H-NMR (DSMO-d6): broad singlet 9.8 δ (2 H); doublet 7.8 δ (2 H); doublet 7.45 δ (2 H); singlet 6.85 δ (1 H); singlet 6.75 δ (1 H); multiplet 4.2-4.45 δ (4 H); multiplet 4.0 δ (1 H); singlet 3.8 δ (3 H); singlet 2.5 δ (3 H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:11][CH:12]=C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]=[O+][O-]>CO.ClCCl>[C:1]([O:5][C:6]([C:8]1([CH2:11][CH:12]=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=CCC1(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)C1(CC=O)CC1

Procedure:
A solution of 5.7 g (31.3 mmol) of 1-allyl-cyclopropanecarboxylic acid tert-butyl ester in 50 mL methanol and 50 mL dichloromethane under nitrogen was taken to −78° C. where ozone was bubbled in for 1 hour. Nitrogen was bubbled in until the familiar blue color dissipated. Three drops of pyridine followed by 2 mL of dimethyl sulfide were added and the cooling bath removed. After 2 hours the reaction was poured into aqueous saturated ammonium chloride solution, extracted with dichloromethane, dried and concentrated to deliver a quantitative yield of the desired aldehyde as an oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].O.[CH3:8]O.[CH2:10](O)[CH3:11]>CC(C)=O>[CH3:8][C:10]1([CH3:11])[O:4][CH:3]([CH2:5][OH:6])[CH2:2][O:1]1
Reactant: CCO
Reactant: CO
Reactant: OCC(O)CO
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)OCC(CO)O1

Procedure:
A similar experiment to that of example 1 is carried out using this time 2 kg of crude product comprising 42% by weight of glycerol, 14% by weight of water and a large amount of volatile products (methanol, ethanol). The acetone is used in the same molar ratio as is for example 1 and the 2,2-dimethyl-1,3-dioxolane-4-methanol obtained has a purity of 98%.
Reaction SMILES: C(NC1C=CN([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C(=O)N=1)(=O)C1C=CC=CC=1.[NH:26]1[C-:30]=[N:29][N:28]=[N:27]1.P([O-])([O-])[O-].[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[C-:43][C:38]=2[N:37]=[N:36]1>C(#N)C>[NH:26]1[CH:30]=[N:29][N:28]=[N:27]1.[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1
Reactant: [c-]1nnn[nH]1
Reactant: [c-]1cccc2[nH]nnc12
Agent: O=C(Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1)c1ccccc1
Agent: [O-]P([O-])[O-]
Solvent: CC#N
Product: c1ccc2[nH]nnc2c1
Product: c1nnn[nH]1

Procedure:
N-Benzoylcytidine linked from the 3' hydroxyl group via a hemisuccinate bridge to aminopropyl-substituted HPLC-grade silica (Vydac) was used as the solid-phase support. Samples (100 mg each; 10 micromoles) were shaken in sealed test tubes in acetonitrile (1 ml) with each of the four 5'-dimethoxytrityl-deoxynucleoside-3'-dimethylaminophosphoramidites and either tetrazole (1 mmole) or benzotriazole (600 micromoles) to form the tetrazolide or benzotriazolide-phosphite active species, the latter being a compound of this invention. After thorough washing by repeated centrifugation and subsequent decanting, and oxidation with 0.01M iodine, the support was treated with 2.75% (w/v) trichloroacetic acid in methylene chloride (10 ml) for 5 minutes. Spectrophotometric assay of the dimethoxytrityl carbonium ion produced in the supernatant demonstrated that all couplings had proceeded to greater than 95% of theoretical yield.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:20])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:21])[N:5]=1)[CH3:3].[NH2:22][C:23]1[C:28]([I:29])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C.O>CC(O)C>[NH2:22][C:23]1[N:24]=[CH:25][N:26]=[C:27]([NH:1][C@H:2]([C:4]2[N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:12](=[O:20])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[Cl:21])[N:5]=2)[CH3:3])[C:28]=1[I:29]
Reactant: Nc1ncnc(Cl)c1I
Reactant: C[C@H](N)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1I)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (400 mg, 1.33 mmol) (prepared according to the procedure in Example 2a.A above) and 4-amino-6-chloro-5-iodopyrimidine (338 mg, 1.32 mmol) in IPA (5 mL) was added Hunig's base (0.4 mL). After stirring at 90° C. for 2 hours in a microwave reactor, water was added and the mixture was extracted with EtOAc (3×50 mL), dried (MgSO4), and concentrated. The residue was purified on a reverse phase system run from 0 to 95% ACN in water (0.1% TFA) to give (S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one. ES/MS m/z=519.0 (M+), 521.0(M+2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=2)([CH3:16])[CH2:9][CH2:10][C:11](OCC)=[O:12])=[CH:4][C:3]=1[CH3:25].[OH-].[NH4+:27]>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=2)([CH3:16])[CH2:9][CH2:10][C:11]([NH2:27])=[O:12])=[CH:4][C:3]=1[CH3:25]
Reactant: CCOC(=O)CCC(C)(c1ccc(O)c(C)c1)c1ccc(O)c(C)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(C)(CCC(N)=O)c2ccc(O)c(C)c2)ccc1O

Procedure:
A solution of ethyl 4,4-bis(4-hydroxy-3-methylphenyl)pentanoate (69.00 grams, 0.201 mole) and 29% aqueous ammonium hydroxide (1500 milliliters) was stirred at room temperature for 144 hours. The resulting slightly cloudy, emerald green solution was diluted with water and extracted with ethyl acetate (4×500 milliliters). The combined organic fractions were washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was removed in vacuo leaving the amide, 4,4-bis(4-hydroxy-3-methylphenyl)pentanamide, as a tan powder (45.1 grams, 72% yield).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[N:6][O:7][C:8]=1[CH3:9])([OH:3])=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26]([NH:28][C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)=[O:27])[CH:22]=[CH:23][CH:24]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:36][O:35][C:33]1[CH:34]=[C:29]([NH:28][C:26](=[O:27])[CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][C:1]([C:4]3[C:5]([C:10]4[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=4[F:17])=[N:6][O:7][C:8]=3[CH3:9])=[O:3])[CH:20]=2)[CH:30]=[C:31]([O:39][CH3:40])[C:32]=1[O:37][CH3:38]
Reactant: Cc1onc(-c2c(F)cccc2F)c1C(=O)O
Reactant: COc1cc(NC(=O)Cc2cccc(N)c2)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)Cc2cccc(NC(=O)c3c(-c4c(F)cccc4F)noc3C)c2)cc(OC)c1OC
Yield: 52.8 %

Procedure:
4-Carboxy-5-methyl-3-(2,6-difluorophenyl)isoxazole (0.120 g, 0.50 mmol), 2-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamide (0.174 g, 0.55 mmol), EDCI (0.161 g, 1.00 mmol), DMAP (0.012 g, 0.10 mmol), and dichloromethane (5 ml) were allowed to react for 16 h in a fashion similar to that for example 5. Column chromatography (silica gel, hexanes/ethyl acetate gradient) afforded the title compound (0.142 g, 53%).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[F:18].[Cl-].[NH4+].[CH3:21][C:22]([CH3:24])=[O:23]>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH2:21][C:22](=[O:23])[CH3:24])=[CH:12][C:11]=1[F:18]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: CC(C)=O
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)CC(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
Proline (23 mg, 0.20 mmol) was added to a solution of 4-chloro-3-fluorobenzaldehyde (159 mg, 1.00 mmol) in acetone (2.5 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then treated with saturated ammonium chloride. After partitioning, the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:4) to afford 4-(4-chloro-3-fluorophenyl)-4-hydroxybutan-2-one (160 mg, 73% yield) as a solid. 1H NMR (500 MHz, CDCl3) δ 7.36 (m, 1H), 7.19 (m, 1H), 7.06 (m, 1H), 5.13 (t, J=6.5 Hz, 1H), 3.43 (br s, 1H), 2.82 (d, J=6.5 Hz, 1H), 2.21 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[C:13](=[O:27])[NH:12][C:11]([CH3:28])=[C:10]2[C:29]([O:31][CH3:32])=[O:30])[CH:5]=[CH:6][C:7]=1[F:8].[N:33]1(CCCN)[CH2:38][CH:37]=[CH:36][CH:35]=[C:34]1[C:39]1[CH2:40][CH2:41][NH:42][CH2:43][CH:44]=1.C(Cl)[Cl:50]>>[ClH:50].[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15](=[O:16])[NH:12][CH2:11][CH2:10][CH2:9][N:42]3[CH2:43][CH:44]=[C:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=4)[CH2:40][CH2:41]3)[C:13](=[O:27])[NH:12][C:11]([CH3:28])=[C:10]2[C:29]([O:31][CH3:32])=[O:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1=C(C)NC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Reactant: ClCCl
Reactant: NCCCN1CC=CC=C1C1=CCNCC1
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCN2CC=C(c3ccccn3)CC2)C1c1ccc(F)c(F)c1
Product: Cl
Yield: 89 %

Procedure:
A solution of 6-(3,4-difluorophenyl)-4-methyl-5-methoxycarbonyl-1-(4-nitrophenoxy)carbonyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine (20 mg, 0.045 mmol) and 3-(3′, 6′-dihydro-2′H-[2,4′]bipyridyl-1-yl)propylamine (9.7 mg, 0.045 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 3 days. The solvent was removed in vacuum. The residue was separated on preparative TLC (CHCl3/MeOH=100/15) to get the title compound (21mg, 89% yield) as a yellow solid. Hydrochloride salt was made with HCl in ether. M.P. of the salt: 242-244° C. Calcd for C27H29N5O4F2+2.0 HCl+1.05 CHCl3+1.05 ether: C, 48.32%; H, 5.35%; N, 8.74%. Found: C, 48.10%; H, 5.13%; N, 8.72%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1)[CH3:2].[CH3:11][N:12]1[C@H:26]2[C@@H:16]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:27]=3[C:24]([CH2:25]2)=[CH:23][NH:22]4)[CH2:15][C:14](=O)[CH2:13]1>[Pd]>[CH3:11][N:12]1[C@H:26]2[C@@H:16]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:27]=3[C:24]([CH2:25]2)=[CH:23][NH:22]4)[CH2:15][CH:14]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=2)[CH2:13]1
Reactant: CN1CC(=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CCOc1ccc(N)cn1
Agent: [Pd]
Product: CCOc1ccc(NC2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cn1

Procedure:
The following compounds (isomers Ia and Ib) are obtained in a manner analogous to that described in Example 3, from 2-ethoxy-5-aminopyridine and 6-methyl-8-oxo-ergoline in the presence of palladium:
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:33])[CH:21]([NH:22][C:23](=[O:32])[CH2:24][O:25][C:26]3[S:27][C:28]([CH3:31])=[N:29][N:30]=3)[C@H:8]2[S:7]1>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:33])[CH:21]([NH:22][C:23](=[O:32])[CH2:24][O:25][C:26]3[S:27][C:28]([CH3:31])=[N:29][N:30]=3)[C@H:8]2[S:7]1
Reactant: Cc1nnc(OCC(=O)NC2C(=O)N3C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]23)s1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1nnc(OCC(=O)NC2C(=O)N3C(C(=O)O)=CC(C)S[C@H]23)s1
Reaction time: 1.5 h
Yield: 41.1 %

Procedure:
Acetic acid (8 ml) and zinc powder (6 g) were added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylate (6.60 g) in anhydrous dimethylformamide (40 ml), and the mixture was stirred for 1.5 hours. After the reaction, zinc powder was filtered and washed with dimethylformamide. The filtrate and the washings were combined, and the combined solution was poured into an ice-cooled mixture of ethyl acetate and 2 to 3% hydrochloric acid, and then extracted. The extract was extracted with a sodium bicarbonate aqueous solution and the aqueous solution was acidified with hydrochloric acid, and then extracted with ethyl acetate. The aqueous layer was saturated with sodium chloride, and then extracted, four times with ethylacetate (80 ml), after which the both ethyl acetate extract was combined. After the combined extracted was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was crystallized by adding ether to give dimethylformamide adduct of 2-methyl-7-[2-(5 -methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylic acid (2.0 g), mp 113° to 116° C.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:33]([C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)#[N:34].O>CS(C)=O>[C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:5][CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)=[CH:37][CH:36]=1)#[N:34]
Reactant: CS(=O)(=O)OCCCC1CCN(CCCOc2ccc(C#N)cc2)CC1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(OCCCC2CCN(CCCOc3ccc(C#N)cc3)CC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Into a solution of 91.9 g of 3-{1-[3-(4-cyanophenoxy)propyl]-4-piperidinyl}propyl methanesulfonate in 460 mL of dimethylsulfoxide, 66.9 g of potassium carbonate and 28.8 g of 4-cyanophenol were added at room temperature, and the solution was stirred at 60° C. for 2 hours. To the reaction mixture, after being cooled down to room temperature, 640 mL of water was dropped over 20 min, and then the mixture was stirred at room temperature for 35 min, and under water cooling for 30 min. The solid matter was collected by filtration, and washed twice with 180 mL of water and then 360 mL of 2-propanol to obtain 90.0 g of 4-(3-{4-[3-(4-cyanophenoxy)propyl]-1-piperidinyl}propoxy)benzonitrile as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)([CH3:7])=[O:6].[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10]1>C(Cl)Cl>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:5](=[O:6])[CH3:7])=[CH:17][C:12]=2[CH2:11][CH2:10]1
Reactant: c1ccc2c(c1)CCO2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCO2
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
AlCl3 (12.4 g, 93.0 mmol) was added in small portions to a stirred solution of AcCl (12.6 mL, 177.7 mmol) in dry DCM (100 mL) at −10° C. and the mixture stirred until homogeneous (15 min). The solution was added, via a cannula, to a stirred solution of 2,3-dihydro-1-benzofuran (190) (11.2 g, 93.0 mmol) in dry DCM (100 mL) at −10° C. and the solution stirred for 30 min at −10° C., and then poured into ice/cHCl (5:1 v/v, 1 L). The mixture was stirred for 2 h, extracted with DCM (3×100 mL), the combined organic fraction dried, and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (10-20%) of EtOAc/pet. ether, to give ketone 191 (14.23 g, 94%) as a white solid: mp 59-60° C. [lit. (Dun, J. P., et al., J. Med. Chem. 1986, 29, 2326-2329.) mp 60° C.]; 1H NMR δ 7.85 (d, J=1.9 Hz, 1H, H-4), 7.79 (dd, J=8.5, 1.9 Hz, 1H, H-6), 6.80 (d, J=8.5 Hz, 1H, H-7), 4.65 (t, J=8.7 Hz, 2H, H-2), 3.18 (br t, J=8.7 Hz, 2H, H-3), 2.13 (s, 3H, CH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:38][C:39]1[C:43]([S:44](Cl)(=[O:46])=[O:45])=[C:42]([CH3:48])[O:41][N:40]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:44]([C:43]2[C:39]([CH3:38])=[N:40][O:41][C:42]=2[CH3:48])(=[O:46])=[O:45])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(C)c1S(=O)(=O)N(Cc1ccc(-c2ncccn2)cc1)Cc1cccc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
To a solution of {3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (83.3 mg, 0.2054 mmol), prepared in Step A of Example 13o, in CH2Cl2 was added triethylamine (0.94 mL, 0.68 mmol) and 3,5-dimethyl-isoxazole-4-sulfonyl chloride (44.2 mg, 0.226 mmol) and the reaction was heated at reflux overnight. After cooling to room temperature, additional triethylamine (0.94 mL) and 3,5-dimethyl-isoxazole-4-sulfonyl chloride (44 mg) was added. The reaction was heated at reflux for 72 h and was cooled to room temperature. The organic solution was washed sequentially with 5.5% aqueous HCl, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3:MeOH 99:1) provide the title compound of Step A (61 mg). MS 565 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][CH2:8][O:9][C:10]([CH2:12][C:13]([CH2:15][C:16](OCC)=[O:17])=O)=[O:11].Cl>C(O)(=O)C>[CH2:8]([O:9][C:10]([CH2:12][C:13]1[CH:15]=[C:16]([OH:17])[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=1)=[O:11])[CH3:7]
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc(O)n2ncnc2n1
Temperature: 25 °C
Yield: 96 %

Procedure:
A suspension of 3-amino-s-triazole (28 g) and diethyl acetonedicarboxylate (100 g) in 100 ml of acetic acid was refluxed for six hours. After cooling to room temperature, 150 ml of concentrated hydrochloric acid was added under ice cooling, the crystals thus formed were collected by filtration, and washed twice with 100 ml of ethanol, then once with 100 ml of ether, affording 71 g of the objective compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[C:25]2[C:21](=[N:22][O:23][N:24]=2)[CH:20]=[C:19](CC)[C:18]=1[C:28]#N)(=[O:15])=[O:14].[OH-:31].[K+].[CH2:33]([OH:35])[CH3:34]>O>[CH3:1][N:2]([CH3:30])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[C:25]2[C:21](=[N:22][O:23][N:24]=2)[CH:20]=[C:19]([CH2:18][CH3:28])[C:34]=1[C:33]([OH:31])=[O:35])(=[O:15])=[O:14]
Reactant: [OH-]
Reactant: CCO
Reactant: CCc1cc2nonc2c(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)c1C#N
Agent: [K+]
Solvent: O
Product: CCc1cc2nonc2c(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)c1C(=O)O
Reaction time: 8 h

Procedure:
A solution of 1 g of 5-dimethylamino-N-(5-cyano-6-ethyl-2,1,3-benzoxadiazol-4-yl)-1-naphthalenesulfonamide and 0.7 g of potassium hydroxide in 20 ml of ethanol and 5 ml of water is bailed with stirring for 8 hours. The solvents are removed, the residue is dissolved in water and treated with hydrochloric acid and 5-dimethylamino-N-(5-carboxy-6-ethyl-2,1,3-benzoxadiazol-4-yl)-1-naphthalenesulfonamide is obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][O:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:16](=[O:17])[CH2:15][O:14][CH3:13]
Reactant: OCCCBr
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)OCCCBr
Temperature: 0 °C
Reaction time: 17.5 h
Yield: 106.1 %

Procedure:
1-Bromopropan-3-ol (1.32 mL, 14.6 mmol) was dissolved in anhydrous methylene chloride and cooled to 0° C. under nitrogen atmosphere. The solution was treated with triethylamine (2.2 mL, 15.8 mmol) and methoxyacetyl chloride (1.42 mL, 15.5 mmol) then warmed to room temperature. The reaction mixture was stirred for 17.5 h. It was then diluted with methylene chloride (150 mL) and extracted with saturated sodium bicarbonate (2×50 mL). The aqueous phase was back extracted with methylene chloride (100 mL) and the organic phases were combined and concentrated in vacuo to yield a crude, pale yellow oil (3.27 g). 1H NMR δ 4.25 (t, 2H, J=6.1), 4.05 (s, 2H), 3.45 (s, 3H), 3.22 (t, 2H, I=6.9), 2.18 (quint, 2H, J=6.6). The product was used as such in the following reaction.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:12]2[N:13]=[C:14]([CH2:16][O:17][CH3:18])[N:15]=[C:11]2[N:10]=[C:9]([CH3:19])[CH:8]=1>CN(C)C1C=CC=CC=1>[Cl:3][C:7]1[N:12]2[N:13]=[C:14]([CH2:16][O:17][CH3:18])[N:15]=[C:11]2[N:10]=[C:9]([CH3:19])[CH:8]=1
Reactant: COCc1nc2nc(C)cc(O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COCc1nc2nc(C)cc(Cl)n2n1
Reaction time: 1 h

Procedure:
To a mixed solution of 300 ml of phosphorus oxychloride and 50 ml of N,N-dimethylaniline was added 38.8 g of 7-hydroxy-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidine, and the mixture was stirred at 50° to 60° C. for one hour. After removing phosphorus oxychloride, the residue was dissolved in 500 ml of chloroform and stirred by adding ice. The chloroform layer was separated and washed with water, and then dried over anhydrous magnesium sulfate and distilled the solvent to obtain crystals. The crystals were collected by filtration and washed with water, and then dried to obtain the title compound.