Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C(C)=CC(C)=CC=1C.[CH3:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH:29]=[C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=3)[C:22]3[CH2:23][CH:24]([CH2:26]O)[O:25][C:21]=3[CH:20]=2)=[O:18])=[N:12]1.CCN(S(F)(F)[F:47])CC>C(Cl)Cl>[CH3:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH:29]=[C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=3)[C:22]3[CH2:23][CH:24]([CH2:26][F:47])[O:25][C:21]=3[CH:20]=2)=[O:18])=[N:12]1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(CO)C3)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(CF)C3)n1
Reaction time: 8 h
Yield: 18.4 %

Procedure:
A solution of 2,4,6-collidine (0.0311 mL, 0.235 mmol) and 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (200) (50 mg, 0.11 mmol) in CH2Cl2 (3 mL) was cooled to −15° C. DAST (0.0307 mL, 0.235 mmol) was added drop wise. The mixture was stirred at −15° C. to room temperature overnight, then quenched with MeOH at 0° C., concentrated, and purified by column chromatography eluting with 25-75% EtOAc in hexanes to give a white solid (9 mg, 18% yield). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1 H) 7.78-8.03 (m, 2 H) 7.20-7.34 (m, 2 H) 7.02-7.20 (m, 3 H) 6.77 (d, J=2.27 Hz, 1 H) 5.01-5.19 (m, 1 H) 4.42-4.78 (m, 2 H) 3.79 (s, 3H) 3.25 (dd, J=16.55, 9.73 Hz, 1 H) 3.08 (s, 3 H) 2.99-3.06 (m, 1 H); LCMS for C21H20FN3O5S m/z 446.00 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C([Cl:27])=O>CN(C)C=O.ClCCl>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([Cl:27])=[O:23])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCc1nc2cnc3cccnc3c2n1CCCC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCc1nc2cnc3cccnc3c2n1CCCC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
One drop of N,N-dimethylformamide (DMF) was added to a solution of 4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyric acid (3.53 g, 11.3 mmol, 1.0 eq) in dichloromethane (55 mL). Oxalyl chloride (3.0 mL, 33.9 mmol, 3.0 eq) was added dropwise over 5 minutes to the reaction mixture, which was subsequently stirred for 2 hours at ambient temperature. The mixture was concentrated under reduced pressure to provide 4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyryl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[N:15]([CH3:35])[C:16](=[O:34])[C:17]2[CH:22]=[C:21]([S:23]CC[Si](C)(C)C)[CH:20]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:18]=2)=[C:4]([O:36][CH3:37])[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[N:15]([CH3:35])[C:16](=[O:34])[C:17]2[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([SH:23])[CH:22]=2)=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(SCC[Si](C)(C)C)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of N-(4-(4-fluoro-2-methoxyphenyl)-6-methylpyridin-3-yl)-N-methyl-3-(trifluoromethyl)-5-(2-(trimethylsilyl)ethylthio)benzamide (0.477 g, 866 μmol) in THF (10 mL) was added tetrabutylammonium fluoride (1M solution in THF, 4.55 mL, 4.55 mmol) and the clear, light yellow solution was stirred at room temperature for 75 minutes. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of CH2Cl2:MeOH (100:0 to 90:10). Light brown solid (93%). MS (ESI): m/z=449.10 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][CH3:34])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.Cl.C([O:39][C:40]1[C:45]([O:46]C(=O)C)=[CH:44][N:43]=[C:42]([C:50](Cl)=[O:51])[CH:41]=1)(=O)C.C(=O)(O)[O-].[Na+]>O.CC(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][CH3:34])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:24][CH2:23][N:22]([C:50]([C:42]5[CH:41]=[C:40]([OH:39])[C:45]([OH:46])=[CH:44][N:43]=5)=[O:51])[CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCNCC3)CS[C@H]12)c1nsc(N)n1
Reactant: CC(=O)Oc1cnc(C(=O)Cl)cc1OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4cc(O)c(O)cn4)CC3)CS[C@H]12)c1nsc(N)n1
Yield: 47.9 %

Procedure:
To a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (255 mg) in a mixture of water (5 ml) and acetone (5 ml) was added 4,5-diacetoxy-2-pyridinecarbonyl chloride hydrochloride (309 mg), with maintaining the pH of the solution to 8.0-8.5 by addition of saturated aqueous sodium bicarbonate. After stirring for 30-minutes, acetone was removed by evaporation in vacuo and the residue was adjusted to pH 8 and stirred for 2 hours. The mixture was adjusted to pH 3.0 with 1N hydrochloric acid and chromatographed on Diaion HP-20 (50 ml), and the elution was carried out with 10% aqueous isopropyl alcohol. The eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[1-methyl-4(4,5-dihydroxy-2-pyridylcarbonyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (155 mg).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[N:9]([CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[O:28][CH3:29])[C:8]1=[O:30]>N1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29])[C:8](=[O:30])[C:7]2([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[NH:6][C:1](=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: COC(=O)c1ccc(CN2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Solvent: c1ccncc1
Product: CCC(=O)NC1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)OC)cc2OC)c2ccc(Cl)cc21
Reaction time: 24 h
Yield: 87.8 %

Procedure:
0.52 g of propionyl chloride is added at RT to a solution of 1.323 g of the compound obtained in EXAMPLE 89 in 5 ml of pyridine and the mixture is stirred for 24 hours. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (90/10; v/v) as the eluent to give 1.3 g of the expected product.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]([C@H:9]1[CH2:13][C@H:12](Br)[CH2:11][N:10]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:8]>CN(C)C=O.O>[CH3:5][O:6][C:7]([C@H:9]1[CH2:13][C@@H:12]([N:1]=[N+:2]=[N-:3])[CH2:11][N:10]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:8]
Reactant: COC(=O)[C@H]1C[C@H](Br)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 72.5 °C
Yield: 100 %

Procedure:
Add sodium azide (157 g, 2.39 mol) to (2R,4S)-4-bromo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (370 g, 1.20 mol) in N,N-dimethylformamide (2.5 L) and heat at 70-75° C. for 16 h under nitrogen. Cool to room temperature, dilute with water (5 L), and extract with ethyl acetate (3 L). Wash with brine (2 L). Extract the brine layer with ethyl acetate (3 L), combine the organic layers, dry over sodium sulfate, filter and concentrate to obtain an oil (324.5 g). Dissolve the material in ether (2 L), wash with water (2×2 L), dry over sodium sulfate, filter, and concentrate to obtain 261.2 g of a dark yellow oil. Back-extract the aqueous layer with ether (2×2 L), dry over sodium sulfate, filter, and concentrate to obtain an additional 7.3 g of product. Overall yield 268.5 g (83%). [α]D20+39.5 (c=1.0 in methanol). 1H NMR (400 MHz, CDCl3) δ 1.40-1.41 (s, 9H), 2.09-2.13 (m, 1H), 2.40-2.44 (m, 1H), 3.37-3.45 (m, 1H), 3.61-3.65 (m, 1H), 3.67-3.69 (s, 3H), 4.09-4.15 (m, 1H), 4.25-4.38 (m, 1H).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([C:17]1[CH:18]=[C:19]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][CH:30]([CH3:37])[CH:31]3O)[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[C:13]([C:17]1[CH:18]=[C:19]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30]([CH3:37])=[CH:31]3)[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC1Cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cccc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=Cc2cccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2C1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A mixture of p-toluenesulfonic acid monohydrate (1.57 g, 8.26 mmol, 0.2 equiv), compound 10 (15 g crude, ˜41.32 mmol, 1.0 equiv) and toluene (300 mL) was refluxed for 1 hour. After cooling to room temperature, the mixture was washed sequentially with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified over silica gel (300 g) eluting with heptanes to give compound 11 (10.8 g, 82% overall yield for 2 steps) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].CO>O1CCCC1>[C:12]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
2-Amino-4-nitrophenol (10 g, 0.065 mol) was dissolved in tetrahydrofuran (100 ml) and, after cooling to 0° C., acetic anhydride (12.24 ml, 0.130 mol) was added dropwise, followed by stirring at room temperature for 2 h. Thereafter, methanol (10 ml) was added to the reaction mixture, which was then stirred at room temperature for 30 min and, thereafter, the solvent was evaporated and the resulting residue was diluted with diethyl ether and filtered. The solvent was evaporated off the filtrate and the resulting solids were dried to yield the end compound 2-acetamido-4-nitrophenol (12.21 g) as a pale brown solid mass.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19]([O:21][CH2:22][C:23]([NH2:25])=[O:24])[C:18]([C:26]#[N:27])=[C:17](S(C)=O)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19]([O:21][CH2:22][C:23]([NH2:25])=[O:24])[C:18]([C:26]#[N:27])=[C:17]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)c1cc(-c2ccccc2OCc2ccccc2)nc(OCC(N)=O)c1C#N
Reactant: C1COCCN1
Solvent: O
Product: N#Cc1c(N2CCOCC2)cc(-c2ccccc2OCc2ccccc2)nc1OCC(N)=O
Temperature: 130 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of 2-{[6-[2-(benzyloxy)phenyl]-3-cyano-4-(methylsulfinyl)-2-pyridinyl]oxy}acetamide (300 mg, 0.71 mmol) and morpholine (1.0 mL) was stirred at 130° C. for 1 hr, and then water was added. The resulting precipitates were collected by filtration and dried under reduced pressure to give 2-{[6-[2-(benzyloxy)phenyl]-3-cyano-4-(4-morpholinyl)-2-pyridinyl]oxy}acetamide as a yellow solid (304 mg, yield; 96%).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[O:11][C:12](=[CH:17][Br:18])[C:13]([CH3:16])([CH3:15])[N:14]=2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.S(=O)(=O)(O)[OH:20]>O>[Br:18][CH2:17][C:12](=[O:11])[C:13]([NH:14][C:10](=[O:20])[C:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[C:7]([Cl:9])[CH:6]=1)([CH3:16])[CH3:15]
Reactant: O=S(=O)(O)O
Reactant: CC1(C)N=C(c2cc(Cl)cc(Cl)c2)OC1=CBr
Agent: Br
Solvent: O
Product: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CBr
Temperature: 50 °C

Procedure:
N- (1',1'-dimethylpropynyl)-3,5-dichlorobenzamide (40 gm, 0.156 m) was dissolved in methylene chloride (600 ml) and bromine (25 gm, 0.156 m) in methylene chloride (100 ml) was added gradually with stirring at room temperature. After the complete addition of the bromine, the mixture was stirred for another 15 minutes and diluted with hexane (500 ml). The yellowish-white precipitate which formed was filtered and dried to yield 58 gm of 2-(3',5'-dichlorophenyl)-4,4-dimethyl-5-bromomethylenoxazoline hydrobromide. The oxazoline hydrobromide (55 gm, 0.13 m) was added to concentrated sulfuric acid (200 ml) and stirred to obtain a clear solution. Water (20 ml) was added and the mixture heated at about 50° C. for about 24 hours. The mixture was then poured into ice water (about 2000 ml) and the white precipitate which formed was filtered and dried. Recrystallization from isopropanol, ether and hexane (1:1:2) yielded 21 gm of pure product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:17][Zn+]>C1COCC1.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>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:17][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Fc1cc(F)cc(C[Zn+])c1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2cc(F)cc(F)c2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
Methyl 2-chloroisonicotinate (5.600 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen, then (3,5-difluorobenzyl)zinc(II) chloride (0.5 M in THF, 100 mL, 50.00 mmol) was added and the resulting solution was stirred at 60° C. for 3 h before it was cooled to room temperature and quenched with methanol (50.0 mL). The mixture was diluted with EtOAc and washed with satd NH4Cl. The organic phase was dried and concentrated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column, eluent isocratic heptane/EtOAc 8:2 for 2 CV, then a gradient from 20% to 50% of EtOAc in heptane over 6 CV was used as mobile phase. Methyl 2-(3,5-difluorobenzyl)isonicotinate (7.42 g, 86%) was isolated as an oil. 1H NMR (400 MHz, cdcl3) δ 3.94 (s, 3H), 4.18 (s, 2H), 6.66 (tt, 1H), 6.74-6.82 (m, 2H), 7.67-7.75 (m, 2H), 8.67-8.75 (m, 1H). MS m/z 264 (M+H)+
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:17]=[O:18]>>[CH2:13]([C:12]1[CH:11]=[C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:15]=[CH:14][C:17]=1[OH:18])[C:14]1[CH:15]=[C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:11]=[CH:12][C:13]=1[OH:16]
Reactant: C=O
Reactant: CCCCCCCCCc1ccc(O)cc1
Product: CCCCCCCCCc1ccc(O)c(Cc2cc(CCCCCCCCC)ccc2O)c1

Procedure:
2,2' methylenebis (4-nonylphenol) was prepared in a similar manner by replacement of the 1,1,3,3,-Tetramethylbutylphenol by 4-nonylphenol in the same mole ratio to formaldehyde.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][N:27]1[CH:31]=[N:30][N:29]=[C:28]1[SH:32]>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:32][C:28]3[N:27]([CH3:26])[CH:31]=[N:30][N:29]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Cn1cnnc1S
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nncn3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70) where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3 H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 4-methyl-4H-1,2,4-triazole-3-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.CC([O:19][B:20](OC(C)C)[O:21]C(C)C)C.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[C:33]#[N:34]>C1COCC1>[C:33]([C:32]1[C:31]([C:30]([F:39])([F:40])[F:29])=[CH:38][CH:37]=[CH:36][C:35]=1[B:20]([OH:21])[OH:19])#[N:34]
Reactant: N#Cc1ccccc1C(F)(F)F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1c(B(O)O)cccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 249.7 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (0.99 g, 7.02 mmol) in THF (25 ml) was added n-BuLi (2.80 ml, 2.5 M hexane solution, 7.02 mmol) at −10° C. After stirring for 10 min, this solution was cooled to −78° C., tris(1-methylethyl)borate (1.58 g, 8.4 mmol) was added, and the mixture was stirred for 5 min. To this solution was added a solution of 2-(trifluoromethyl)benzonitrile (1.00 g, 5.85 mmol) in THF (10 ml), and the mixture was stirred at −78° C. for 2 hr. The reaction solution was allowed to warm to room temperature, the reaction was quenched with acetic acid, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, the precipitated solid was filtered off, and the filtrate was concentrated to give the title compound (3.14 g) as a mixture. This was used for the next reaction without performing further purification and identification.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29](F)(F)F)=[CH:4][CH:3]=1.ClC1SC2C(=C(C#N)C=CC=2)[N:38]=1>>[NH2:28][C:12]1[C:11]([C:8]2[S:9][C:10]3[C:6](=[C:5]([C:29]#[N:38])[CH:4]=[CH:3][CH:2]=3)[N:7]=2)=[CH:16][C:15]([C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH:21]=2)=[CH:14][N:13]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Reactant: N#Cc1cccc2sc(Cl)nc12
Product: N#Cc1cccc2sc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)nc12

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-chloro-1,3-benzothiazole-4-carbonitrile and conducting the Suzuki coupling at 80° C. for 2 h, the title compound was obtained as a yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ=2.04-2.23 (m, 4H), 3.04 (m, 2H), 3.30 (m, 2H), 4.44 (mc, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.99 (s, 1H), 8.03 (dd, J=7.6, 1.0 Hz, 1H), 8.34 (s, 1H), 8.49 (dd, J=8.1, 1.0 Hz, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.86 (broad s, 1H), 9.03 (broad s, 1H). MS (ES′): m/z=402.15 [MH+]. HPLC: tR=2.28 min (ZQ3, polar—5 min).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15]([CH:19]=1)[C:16](O)=[O:17]>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15]([CH:19]=1)[C:16]([Cl:3])=[O:17]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of thionyl chloride (7.25 mL, 99.5 mmol) and N,N-dimethylformamide is added to a mixture of 5-chloro-2-nitrobenzoic acid in toluene. The reaction mixture is heated to and held at 80° C. for 16 hours, cooled to room temperature, concentrated in vacuo, diluted with toluene, concentrated in vacuo and diluted with toluene to obtain the title product as a 1 molar solution in toluene.
Reaction SMILES: [O:1]([CH2:8][C:9]([O:11][CH:12]1[C:23]2[C:24](=[O:25])[C:19]([O:26][Si](C(C)(C)C)(C)C)([CH2:20][CH2:21][CH:22]=2)[C:18]#[C:17][CH:16]=[CH:15][C:14]#[C:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.C(Cl)(Cl)Cl>[O:1]([CH2:8][C:9]([O:11][CH:12]1[C:23]2[C:24](=[O:25])[C:19]([OH:26])([CH2:20][CH2:21][CH:22]=2)[C:18]#[C:17][CH:16]=[CH:15][C:14]#[C:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC12C#CC=CC#CC(OC(=O)COc3ccccc3)C(=CCC1)C2=O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(COc1ccccc1)OC1C#CC=CC#CC2(O)CCC=C1C2=O
Reaction time: 72 h

Procedure:
To a solution of compound 11a in 26 mL of acetonitrile was added 4 mL of 48% HF. The solution was stirred for 72 h. The solution was diluted with chloroform and washed with water. The organic fraction was dried over MgSO4 and concentrated and the residue chromatographed over silica gel (5:1 hexane/ethyl acetate) to give 8-[(phenoxymethyl)carbonyloxy]-1-hydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyn-13-one (11b) (116 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:30][C:31](=[O:39])NC2C=CC=CC=2)[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][CH:15]=1>>[C:25]([O:24][C:23]([NH:22][CH2:21][CH:20]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)[CH2:30][C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)=[O:39])=[O:29])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCC(CC(=O)Nc1ccccc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)CC(CNC(=O)OC(C)(C)C)c2ccc(Cl)cc2)cc1
Yield: 72 %

Procedure:
The compound was prepared from 33 and ethyl 4-aminobenzoate in a similar manner as described for preparation of 34. Chromatography on silica gel (7:3 hexanes/ethyl (Rf 0.20) afforded 35 as a brown solid in 72% yield. 1H NMR (400 MHz, CD3OD) δ 1.35 (9H, s, C(CH3), 1.35 (3H, t, J 6.8 Hz, CH2CH3), 2.63 (1H, dd, J 8.6, 14.6 Hz, H—CHCO), 2.77 (1H, dd, J 6.2, 14.6 Hz, H—CHCO), 3.35-3.40 (1H, m, CH2CHCH2), 4.31 (2H, q, J 7.2 Hz, CH2CH3), 7.24 (2H, d, J 8.8 Hz, 2×Ar—H), 7.28 (2H, d, J 8.8 Hz, 2×Ar—H), 7.57 (2H, d, J 8.4 Hz, 2×Ar—H), 7.91 (2H, d, J 9.2 Hz, 2×Ar—H). 13C NMR (400 MHz, CDCl3) δ 14.56 (s) (CH2CH3), 28.56 (s) (C(CH3)3), 40.92 (s) (CH2CO), 42.77 (s) (CH2CHCH2), 45.97 (s) (CH2NH), 61.04 (s) (C(CH3)3), 80.56 (s) (CH2CH3), 119.07 (s) (2×CH, Ar), 125.90 (s) (C, Ar), 129.08 (s) (2×CH, Ar), 129.17 (s) (2×CH, Ar), 130.90 (s) (2×CH, Ar), 133.17 (s) (C, Ar), 140.35 (s) (C, Ar), 142.65 (s) (C, Ar), 157.54 (s) (C═O), 166.47 (s) (C═O), 170.32 (s) (C═O). νmax (pure sample)/(cm−1)), 3353 (md), 1685 (st) (C═O), 1685 (st) (C═O), 1661 (st) (C═O), 1524 (st), 1273 (st), 1249 (st), 1188 (st), 769 (md).