Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[SH:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][OH:24]>CN(C=O)C>[OH:24][CH2:23][CH2:22][C:21]([CH3:26])([S:20][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH3:25]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(S)CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(CCO)Sc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-fluoro-3-nitrobenzoic acid (2 g, 10.80 mmol) in DMF (50 ml) was added potassium carbonate (3.73 g, 27.0 mmol), and 3-mercapto-3-methylbutan-1-ol (1.450 ml, 11.88 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture had turned yellow over night. The DMF was removed under reduced pressure and the resulting slurry was diluted with EtOAc (100 mL) and extracted with H2O (100 mL). The aqueous layer was then treated with conc. HCl until a precipitate formed. The mixture was extracted with EtOAc (3×100 mL) and the combined organics were dried over Na2SO4 and concentrated in vacuo. The product was isolated as a yellow solid and used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH2:11][CH3:12])=[O:5])C.[OH-].[Na+].C(O)C>C(OCC)C>[CH2:11]([C:7]1[N:8]=[CH:9][O:10][C:6]=1[C:4]([OH:5])=[O:3])[CH3:12]
Reactant: CCOC(=O)c1ocnc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCc1ncoc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
4-Ethyl-oxazole-5-carboxylic acid ethyl ester (4.6 g) was stirred in a solution of 1N NaOH (25 ml) and ethanol (1 ml). The reaction mixture was then stirred at room temperature for 16 hours. Diethyl ether (25 ml) was added, and then the aqueous layer separated and acidified with 1N HCl (26 ml). A yellow solid formed that was collected by filtration, washed with water, then with n-pentane, providing the title compound (2.6 g) as a white solid.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:23]=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:47][C:48]1C=C(C=C[C:55]=1O)C=O.C(Br)CCCCCCC/C=C\CCCCCCCC.OC1C=C(C=CC=1O)C(OCC)=O>>[CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:23]([O:47][CH2:48][CH3:55])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CCCCCCCC/C=C\CCCCCCCCOc1ccc(C=O)cc1OCCCCCCCC/C=C\CCCCCCCC
Agent: CCCCCCCC/C=C\CCCCCCCCBr
Agent: CCOC(=O)c1ccc(O)c(O)c1
Product: CCCCCCCC/C=C\CCCCCCCCOc1ccc(C(=O)OCC)cc1OCCCCCCCC/C=C\CCCCCCCC

Procedure:
The first step was the synthesis of 3,4-di(oleyloxy)benzaldehyde 8a by the O-alkylation of 3,4-dihydroxy benzaldehyde 7a with oleyl bromide (Scheme 1 as shown in FIG. 3). Similarly, the bis-O-alkylation of ethyl 3,4-dihydroxybenzoate 7b with oleyl bromide was used to form ethyl 3,4-di(oleyloxy)benzoate 8b using the method of Safinya et al.,23,24 Subsequent cleavage of 8b with KOH was carried out to give the acid 8c (Scheme 1) followed by treatment with oxalyl chloride to give the desired acid chloride 8d.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[O:16][S:17](=[O:38])(=[O:37])[NH:18][C:19](=[O:36])[CH2:20][C:21]1[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:23][C:22]=1[CH:33]([CH3:35])[CH3:34])([CH3:3])[CH3:2].[H][H]>[Ni].O1CCCC1.C(OCC)(=O)C>[NH2:10][C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([O:16][S:17](=[O:38])(=[O:37])[NH:18][C:19](=[O:36])[CH2:20][C:21]2[C:22]([CH:33]([CH3:34])[CH3:35])=[CH:23][C:24]([CH:30]([CH3:31])[CH3:32])=[CH:25][C:26]=2[CH:27]([CH3:29])[CH3:28])=[C:6]([CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: [H][H]
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc([N+](=O)[O-])cc2C(C)C)c(C(C)C)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(N)cc2C(C)C)c(C(C)C)c1
Reaction time: 21 h
Yield: 89.5 %

Procedure:
22.0 g of [(2,4,6-Triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-4-nitro-phenyl ester and 6 g of Raney nickel were mixed in 110 mL tetrahydrofuran under 50 psi of hydrogen. After 21 hours, the reaction was filtered and concentrated to give an orange oil which was dissolved in ethyl acetate, filtered through a pad of silica, and concentrated to give an oily solid. Recrystallization from 53 diethyl ether/hexanes gave 18.60 g (89%) of the title compound as a cream colored solid; mp 153-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:24][C:25]([CH3:30])([CH3:29])[CH:26]([OH:28])[CH3:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:24][C:25]([CH3:30])([CH:26]([OH:28])[CH3:27])[CH3:29])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(Cl)cc21
Reactant: CC(O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)C(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.07 g, 0.3 mmol), 3-amino-3-methylbutan-2-ol (0.05 g, 0.49 mmol), EDCI (0.057 g, 0.3 mmol), DMAP (0.037 g, 0.3 mmol), HOBT (0.041 g, 0.3 mmol) and DIPEA (0.163 g, 1.26 mmol) in 10 mL of DMF was stirred at room temperature overnight. The solvent was removed under reduced pressure at 70° C., the residue was triturated with water and then purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 15% acetonitrile/75% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(3-hydroxy-2-methylbutan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.025 g, 28%) as a yellow solid. MS: (M+H)+=413; 1H NMR (300 MHz, DMSO): δ 12.85 (s, 1H), 9.12 (s, 1H), 8.66 (d, 1H, J=8.7 Hz), 8.41 (s, 1H), 8.00-7.96 (m, 1H), 7.33 (dd, 1H, J=8.7, 1.5 Hz), 5.17 (d, 1H, J=5.7 Hz), 4.20 (s, 1H), 4.04-4.00 (m, 1H), 1.48 (s, 6H), 1.17 (d, 3H, J=6.6 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]([CH:23]=[O:24])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(OCc2ccccc2)nc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccccc2)nc1
Reaction time: 1 h

Procedure:
To a solution of 2-benzyloxy-5-bromo-pyridine (1.64 g, 6.2 mmol) in tetrahydrofuran (25 mL, −78° C.) was added n-butyllithium (2.5 M in hexane, 2.61 mL, 1.05 equiv). After 1 h at −78° C., dimethylformamide (0.97 mL, 2 equiv) was added and the mixture stirred for 30 min. The reaction was quickly poured into a stirred solution of 5% aqueous sodium bicarbonate (50 mL) and extracted with diethyl ether (3×). The ethereal was washed with brine, dried over magnesium sulfate, and concentrated to give 1.16 g (quant.) which was used without purification. Mass spec.: 186.34 (MH)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH3:16][NH2+]C.C=O>>[C:1]([O:9][CH2:10][CH2:11][C:12](=[CH2:16])[CH:13]=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[NH2+]C
Reactant: O=CCCCOC(=O)c1ccccc1
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CCOC(=O)c1ccccc1

Procedure:
10 g (52 mmol) of 4-benzoyloxybutanal, 4.78 g (58.6 mmol) of dimethylammonium chloride and 4.6 ml (60.8 mmol) of formaldehyde solution (37%) are refluxed for one hour with stirring (bath temperature ~110° C.). The mixture is allowed to cool and is extracted three times with ether; the organic phases are combined, washed with saturated sodium chloride solution, dried over MgSO4, filtered and concentrated by evaporation. 4-benzoyloxy-2-methylenebutanal is obtained in the form of a yellowish oil which can be reacted without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10](O)=[O:11])[CH2:7][C:6]=2[CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:32]([CH3:34])[CH3:33])C2C=CC=CC=2N=N1.CNC.O1CCCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:32]([CH3:34])[CH3:33])=[O:11])[CH2:7][C:6]=2[CH:13]=1
Reactant: O=C(O)C1Cc2cc(Br)ccc2O1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CN(C)C(=O)C1Cc2cc(Br)ccc2O1
Yield: 87 %

Procedure:
A mixture of 5-bromo-2,3-dihydro-1-benzofuran-2-carboxylic acid (0.243 g, 1.00 mmol) (ParkWay, Cat. No. YB-162), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.464 g, 1.05 mmol) and 2.0 M dimethylamine in tetrahydrofuran (THF) (2.00 mL, 4.00 mmol) was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (gradient: 0-50%) to afford the desired product (0.235 g, 87%). LCMS (M+H)+=270.0/272.0.
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]=1[CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+]>CO>[CH2:18]([C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:16][CH3:17])=[CH:10][CH:9]=2)[CH2:14][CH2:15][C:6]=1/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC1=C(/C=C/C(=O)OC)CCc2cc(OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC1=C(/C=C/C(=O)O)CCc2cc(OC)ccc21
Yield: 94 %

Procedure:
As in Example 112, (E)-3-(1-butyl-3,4-dihydro-6-methoxy-2-naphthalenyl)-2-propenoic acid methyl ester (2.9 g) in methanol (12 mL) was treated with 2N sodium hydroxide solution (7 mL) at reflux for 1.5 hours. The usual work up provided 2.6 g of (E)-3-(1-butyl-3,4-dihydro-6-methoxy-2-naphthalenyl)-2-propenoic acid as an oil.
Reaction SMILES: C([O:8][C:9](=O)[CH2:10][C:11](=O)[CH2:12][O:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)C1C=CC=CC=1.Cl.[C:27]1([CH3:35])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][NH2:34].CCN(CC)CC.N12CCCN=C1CCCCC2>CCO.CN(C=O)C>[C:14]12([O:13][CH2:12][C:11]3[CH:10]=[C:9]([OH:8])[N:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH3:35])[N:34]=3)[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: Cc1ccccc1NN
Reactant: O=C(COC12CC3CC(CC(C3)C1)C2)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccccc1-n1nc(COC23CC4CC(CC(C4)C2)C3)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(adamantan-1-yloxy)-3-oxo-butyric acid benzyl ester (334 mg, 0.98 mmol), o-tolyl hydrazine hydrochloride (163 mg, 1.0 mmol), and NEt3 (140 μL, 1.0 mmol) in EtOH (6 mL) was stirred at room temperature for 1 hr. The mixture was evaporated and the residue partitioned between EtOAc (40 mL) and H2O (40 mL). The organic phase was separated, washed with brine (20 mL), and dried (MgSO4). Filtration and evaporation of the solvent gave the crude hydrazone. 1,8-Diazabicyclo[5.4.0]undec-7-ene (150 μl, 1.0 mmol) was added to a solution of the hydrazone in DMF (4 mL), and the solution stirred at room temperature for 17 h. The mixture was partitioned between 5% KHSO4 (60 mL) and EtOAc (60 mL). The organic layer was washed with brine (2×30 mL), and dried (MgSO4). Filtration and evaporation of the solvent gave the product as a solid which was triturated with ether, isolated by filtration and dried (170 mg, 51%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6](O)=[O:7])[CH2:3]1.C(Cl)(=O)C([Cl:13])=O>ClCCl>[CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6]([Cl:13])=[O:7])[CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)CC(C(=O)O)C1
Solvent: ClCCl
Product: CC1(C)CC(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,3-Dimethyl-cyclobutanecarboxylic acid (Parkway Scientific, New York, N.Y., USA) (500 mg, 3.90 mmol) was dissolved in dichloromethane (3 mL) and oxalyl chloride (1.02 mL, 11.7 mmol) was added. The solution was stirred at room temperature for 4 h before concentrating in vacuo to provide 3,3-dimethylcyclobutanecarbonyl chloride which was carried on without purification. 1H NMR (400 MHz, CDCl3) δ 3.49 (quin, J=8.9 Hz, 1H) 2.27-2.15 (m, 2H) 2.14-2.06 (m, 2H) 1.18 (s, 3H) 1.12 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH:13]=O)=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CS([Cl:21])(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1.CO>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][Cl:21])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CCl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of 5-formyl-2-thiophencarboxylic acid tert-butyl ester (5 g, 23.6 mmol) in tetrahydrofuran (50 mL) and methanol (5 mL), was added sodium borohydride (0.50 g, 13.0 mmol) at 0° C., and the mixture was stirred for 2 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 0.5N-hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was dissolved in dichloromethane (100 mL), methanesulfonyl chloride (1.9 ml, 24 mmol) and diisopropylethylamine (5.7 ml, 33 mmol) were added at 0° C., and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, 0.5N-hydrochloric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (5.3 g, 23 mmol).
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]([C:12]1[CH:13]=[C:14]([CH:18](O)[CH3:19])[CH:15]=[CH:16][CH:17]=1)=[O:11]>C1C=CC=CC=1>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]([C:12]1[CH:13]=[C:14]([CH:18]([Cl:3])[CH3:19])[CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cccc(C(=O)c2cccs2)c1
Solvent: c1ccccc1
Product: CC(Cl)c1cccc(C(=O)c2cccs2)c1
Reaction time: 1 h

Procedure:
5.5 parts of thionyl chloride is added dropwise to a stirred solution of 9.5 parts of α-hydroxy-α-methyl-m-tolyl 2-thienyl ketone in 40 parts of benzene while keeping the temperature below 20° C. Upon completion, stirring is continued for 1 hour at room temperature and for one additional hour at 30°-35° C. The reaction mixture is evaporated in vacuo. The residue is taken up in toluene and the latter is evaporated again. The residue is distilled, yielding α-chloro-α-methyl-m-tolyl 2-thienyl ketone; b.p. 168°-178° C at 0.7 mm pressure.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:31][N:32]4[CH2:37][CH2:36][N:35]([S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]4)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.CO>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH2:31][N:32]3[CH2:33][CH2:34][N:35]([S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])[CH2:36][CH2:37]3)[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(=O)(=O)N(C)C)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CN3CCN(S(=O)(=O)N(C)C)CC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N,N-dimethylpiperazine-1-sulfonamide (0.210 g, 0.278 mmol) in trifluoroacetic acid (5 mL, 67.3 mmol) and trifluoromethanesulfonic acid (0.2 mL, 0.278 mmol) was stirred at 80° C. for 2 h. The dark solution was cooled down to room temperature and concentrated to a slurry. The slurry was neutralized to pH 8 with aqueous NaHCO3. The precipitate was dissolved in DCM/MeOH and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 5% to 10% 2 M NH3.MeOH in CH2Cl2 to give 4-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N,N-dimethylpiperazine-1-sulfonamide (0.110 g, 0.214 mmol, 77% yield). 1H NMR (400 MHz, d6-DMSO) δ 11.75 (s, 1H); 8.70 (d, J=2.15 Hz, 1H); 8.55 (d, J=0.39 Hz, 1H); 8.19 (d, J=2.54 Hz, 2H); 8.17 (dd, J=8.90, 2.84 Hz, 1H); 7.86 (d, J=0.98 Hz, 1H); 7.71 (d, J=1.76 Hz, 1H); 6.82 (d, J=8.80 Hz, 1H); 3.84 (s, 3H); 3.47 (s, 2H); 3.31 (s, 2H); 3.16 (d, J=4.89 Hz, 3H); 2.75 (s, 6H); 2.47 (s, 2H); 2.44 (s, 3H). m/z (ESI, +ve ion) 515.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([C:21]([OH:23])=O)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:24]1[CH:28]=[CH:27][N:26]=[C:25]1[NH2:29].[Cl-].[NH4+]>>[O:24]1[CH:28]=[CH:27][N:26]=[C:25]1[NH:29][C:21]([C:16]1[C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:20][CH:19]=[CH:18][N:17]=1)=[O:23]
Reactant: Nc1ncco1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C(=O)Nc1ncco1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid (EXAMPLE 33 Step 2) and oxazol-2-amine instead of 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid and ammonium chloride.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH:20]=[CH2:21])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CCO.[Rh]>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH2:20][CH3:21])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: [Rh]
Solvent: CCO
Product: CCc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
To a solution of (S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-vinylnaphthalen-2-yl)acetic acid (4 mg, 0.010 mmol) in EtOH (1.5 mL) was added Rh/Al2O3 (cat. amount) and the resulting mixture stirred under hydrogen (1 atm, balloon) at room temperature for 2 h. The reaction mixture was filtered over Celite, concentrated in vacuo and the residue was purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to provide 0.8 mg of the desired product. 1H-NMR: 400 MHz, (CD3OD) δ: 7.81 (d, J=4.2 Hz, 1H), 7.77 (s, 1H), 7.58-7.53 (m, 3H), 7.44-7.41 (m, 1H), 7.33-7.20 (m, 3H), 5.20 (s, 1H), 3.14-3.08 (m, 1H), 2.93-2.87 (m, 1H), 1.34 (t, J=7.4 Hz, 3H), 0.98 (s, 9H). LCMS-ESI− (m/z): [M−H]− calcd for C24H24ClO3: 395.1. Found: 395.0.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[C:16]2[S:15][CH:14]=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[C:17]([O-])([O-])=[O:18].[Na+].[Na+]>CN(C=O)C>[CH3:6][O:7][C:8]1[C:16]2[S:15][CH:14]=[CH:13][C:12]=2[C:11]([CH:17]=[O:18])=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc2ccsc12
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c2ccsc12
Temperature: 100 °C

Procedure:
Phosphorous oxychloride (0.518 g, 17.7 mmol) was added to DMF (1.04 mL) under argon at rt. After 30 min 7-methoxybenzothiophene (0.5 g, 3.04 mmol) was added and the reaction was heated to 100° C. for 3.5 h. The reaction was cooled to rt and poured into a saturated Na2CO3 solution, extracted with ether (100 mL) and the organic phase dried (MgSO4). Solvent was removed in vacuo to give the title compound: RT=3.34 min; m/z (ES+)=193.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)(O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=[CH:7][C:6]=2[CH:24]=1>S(=O)(=O)(O)O.FC(F)(F)S(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=[CH:7][C:6]=2[CH:24]=1
Reactant: CN1CCC(C2(O)c3ccc(Cl)cc3C=Cc3cccnc32)CC1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: CN1CCC(=C2c3ccc(Cl)cc3C=Cc3cccnc32)CC1
Temperature: 70 °C
Yield: 94.3 %

Procedure:
A mixture of 847 mg (2.48 mmole) of 8-chloro-11-(1-methyl-4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol in 5 mL of concentrated sulfuric acid and 5 mL of trifluoromethane sulfonic acid was heated at 70° C. for 4 hr 10 min. The mixture was cooled to room temperature, poured into ice cold 30% aqueous KOH, and extracted three times with CH2Cl2The organic portions were combined, washed once with water, dried over MgSO4, filtered, and concentrated in vacuo to yield 755 mg (94%) of the title compound as a glass.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([O:30]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:29])=[C:15]([C:18]4[S:19][C:20]([CH2:24][C:25](=[O:27])[NH2:26])=[C:21]([CH3:23])[N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([OH:30])=[S:29])=[C:15]([C:18]4[S:19][C:20]([CH2:24][C:25](=[O:27])[NH2:26])=[C:21]([CH3:23])[N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nc(C2=C(C(=S)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)sc1CC(N)=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)sc1CC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a mixture of benzhydryl 7β-(2-phenylacetamido)-3-(5-carbamoylmethyl-4-methylthiazol-2-yl)thio-3-cephem-4-carboxylate (0.80 g), anisole (0.80 ml) and dichloromethane (2.40 ml) was added trifluoroacetic acid (1.60 ml) at 15° C. After stirring at room temperature for 1 hour, the solution was poured into diisopropyl ether. The resulting precipitate was collected by filtration, added to a mixture of tetrahydrofuran and water, and adjusted to pH 7.5 with an aqueous sodium bicarbonate. The separated aqueous solution was washed with ethyl acetate and adjusted to pH 3.0 with 1N-hydrochloric acid. The resulting crystal was collected by filtration and washed with water to give 7β-(2-phenylacetamido)-3-(5-carbamoylmethyl-4-methylthiazol-2-yl)thio-3-cephem-4-carboxylic acid (445 mg).