Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)(OC(C)(C)C)[NH2:10].Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]([C:28]2[CH:33]=CC(Br)=[CH:30][CH:29]=2)=[O:27])=[O:25])=[CH:20][CH:19]=1.CN[CH2:37][CH2:38][NH:39]C>[Cu]I.C1COCC1>[NH2:10][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]([C:28]2[CH:33]=[CH:37][C:38]([NH2:39])=[CH:30][CH:29]=2)=[O:27])=[O:25])=[CH:20][CH:19]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(N)=O
Reactant: CNCCNC
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)C(=O)c2ccc(N)cc2)cc1
Temperature: 90 °C

Procedure:
A Schlenk flask was thoroughly flame-dried under vacuum and then under nitrogen atmosphere (three cycles each). To this was added copper (I) iodide (4.14 g, 22 mmol), tribasic potassium phosphate (46.2 g, 220 mmol), and t-butyl carbamate (13.92 g, 119 mmol). These reagents were dried under vacuum and back-filled with nitrogen (three cycles). To this was added 4,4′-dibromobenzil, 1 (20 g, 54 mmol), N,N′-dimethylethylenediamine (3.82 g (4.7 mL), 43 mmol) and anhydrous THF (100 mL). The reaction flask was sealed under nitrogen and heated at 90° C. for 24 h. After bringing down to room temperature, the reaction mixture was passed through silica gel to remove the copper salts. The product was extracted with ethyl acetate and purified by column chromatography using 1:4 mixtures of ethyl acetate and hexane as eluant to obtain yellow crystalline solid. Yield: 17.5 g (73%). Mp. 207° C. 1H NMR (acetone-d6, 400 MHz): 1.50 (s, 18H), 7.78 (m, 4H), 7.89 (m, 4H), 8.98 (bs, 2H). 13C NMR (acetone-d6, 100 MHz): 194.5, 153.2, 146.9, 131.3, 128.0, 118.5, 81.1, 28.4. FT-IR (cm−1): ν 3332, 2925, 1682, 1598, 1509, 1455, 1414, 1368, 1313, 1221, 1169, 1144, 1050, 996, 914, 885, 830, 771. HRMS-FAB: mlz M+ calcd 440.1947. found 440.1938.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=2[F:14])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:14][C:8]1[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[S:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cccc(-c2csc(Br)n2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(F)c3F)cs2)CC1
Yield: 45.1 %

Procedure:
A solution of 2-bromo-4-(2,3-difluorophenyl)-1,3-thiazole (6.74 g, 24.4 mmol), tert-butyl piperazine-1-carboxylate (9.09 g, 48.4 mmol) and potassium carbonate (3.37 g, 24.4 mmol) in dimethylformamide (80 ml) was stirred at 120° C. for 13 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and crystals were collected by filtration to give 4.20 g (45.1%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[O:9][B:10](OC)[O:11]C.C([Li])(C)(C)C>C(OCC)C.CCCCC>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([B:10]([OH:11])[OH:9])[CH:3]=1
Reactant: COB(OC)OC
Reactant: Brc1cccnc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: OB(O)c1cccnc1
Temperature: 25 °C

Procedure:
A solution of 4.0 ml (6.56 g, 42 mmol) of 3-bromopyridine and 9 ml (8 mmol) of trimethylborate in 100 ml of diethyl ether was cooled to -70° C. then treated slowly with 33 ml (83.8 mmol) of a 2.54M tert-butyllithium in pentane solution. After allowing the resulting slurry to warm to room temperature the solvents were evaporated under vacuum. The residual oil was treated carefully with 50 ml of a 1M hydrochloric acid solution. Several milliters of methylene chloride were added and the mixture was stirred until the oil had dissolved. The aqueous layer was washed with fresh methylene chloride. The pH of the aqueous solution was raised to 12 with 5M sodium hydroxide solution and the washing was repeated. The pH of the aqueous solution was then lowered to 6.5 with concentrated hydrochloric acid solution. After chilling, this solution was filtered, saturated with sodium chloride, then extracted several times with a 2:1 mixture of diethyl ether and isopropanol. Evaporation of these extracts produced a colorless solid. This material was further purified by dissolving in methanol, evaporating to a thick paste, adding a few milliliters of water, concentrating further under vacuum, then chilling and collecting the crystalline product. Additional product in the aqueous mother liquor was isolated by repeating this process. Thorough drying of this hydrated product at 0.1 mm pressure afforded a fine powder weighing 2.2 g. Elemental analysis and a mass spectrum indicated the product so isolated was primarily the anhydride (tripyridylboroxane).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC[N:15]=C=NCCCN(C)C.[CH2:24]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:24]([CH:31]1[CH2:36][CH2:35][N:34]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][C:6]([C:10]([NH2:15])=[O:12])=[CH:7][CH:8]=3)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CCN=C=NCCCN(C)C
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2c1
Reaction time: 20 h
Yield: 48 %

Procedure:
Indole-5-carboxylic acid (1.61 g, 10 mMol) was reacted with EDAC (1.92 g, 10 mMol) in 40 mL dry DMF for 15 minutes. 4-Benzylpiperidine (1.75 g, 10 mMol) was added followed by DMAP (20 mg, catalyst) and the reaction mixture was stirred for 20 h. The mixture was poured into water and extracted with methylene chloride (3×100 mL). The combined extract was washed with dilute hydrochloric acid, saturated sodium bicarbonate and water and dried over MgSO4. After evaporation of the solvent, the residue was chromatographed with methylene chloride-methanol (0 to 2% methanol, gradient) to yield 1.60 g (50%) of the product after recrystallization from ether-Hexane. MS (ESI) m/e 318 (M+), (317+−H). 1HNMR (CDCl3) δ=8.5 (s, 1H); 7.7 (s, 1H); 7.4–7.15 (m, 8H); 6.8 (s, 1H); 4.8–4.6 (br, m, 1H); 4.1–3.9 9br, m, 1H); 3.1–2.7 (br, m, 2H); 2.6 (d, 2H); 1.9–1.7 (br, m, 3H); 1.4–1,2 (br, m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCN(Cc4ccccc4)CC3)cc2)nc1
Reaction time: 15 h
Yield: 56.7 %

Procedure:
Combine 6-(4-formyl-phenoxy)-nicotinamide (from step 1 above) (0.300 g, 1.24 mmol) and 1-benzylpiperazine (0.35 mL, 2.01 mmol) in methanol (12 mL) and stir at ambient temperature. After 15 h, add sodium borohydride (0.108 g, 2.85 mmol) and stir. After 1 h, filter the white precipitate and dry under vacuum to give 0.283 g (57%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C24H27N4O2 403.2134, found 403.2128: 1H NMR (DMSO-d6): 8.63 (d, 1H, J=1.5 Hz), 8.27 (dd, 1H, J=2.4, 8.3 Hz), 8.05 (s br, 1H) 7.50 (s br, 1H), 7.39-7.23 (m, 7H), 7.15-7.06 (m, 3H), 3.48 (m, 4H), 2.41 (s br, 8H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([O:20]CC=C)[CH:13]=2)[O:9][N:8]=1.B(Cl)(Cl)Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([OH:20])[CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[O:9][N:8]=1
Reactant: C=CCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-allyloxy-5-cyanophenyl)-1,2,4-oxadiazole (1.0 g, 3.4 mmol) and tetrabutylammonium iodide (1.4 g, 3.8 mmol) in dichloromethane (18 mL) at −78° C., under argon, was treated with a solution of 1M boron trichloride in dichloromethane (22 mL, 22 mmol). After 5 minutes at −78° C. the reaction mixture was stirred at ambient temperature for 1 hour. The reaction was then quenched with ice water and stirred for 30 minutes. The mixture was then washed with saturated sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using a gradient of 10% ethyl acetate in hexanes to 80% ethyl acetate in hexanes afforded 460 mg (51%) of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3/MeOD): δ-8.81 (d, 1H), 8.23 (d, 1H), 8.01 (s, 1H), 7.95 (m, 1H), 7.92 (m, 1H), 7.54 (m, 1H), 7.35 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1([N:17]([CH3:19])[CH3:18])[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]([Cl:35])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[CH2:1]([C:8]1([N:17]([CH3:19])[CH3:18])[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][CH3:16])[C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:35].[CH2:1]([C:8]1([N:17]([CH3:19])[CH3:18])[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][CH3:16])[C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNC1CCC(Cc2ccccc2)(N(C)C)CC1
Agent: CN(C)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C(=O)c1ccccc1)C1CCC(Cc2ccccc2)(N(C)C)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.00 g 1-benzyl-N′-ethyl-N,N-dimethyl-cyclohexane-1,4-diamine were dissolved in 50 ml methylene chloride, and 1.68 ml triethylamine and approx. 10 mg DMAP were added. 1.40 ml benzoyl chloride were added dropwise, while cooling in an ice/methanol bath, and the reaction mixture was then stirred overnight, while warming to room temperature. For working up, 50 ml five molar KOH solution and 50 ml water were added, the mixture was stirred for ten minutes and extracted three times with 50 ml methylene chloride each time, the combined extracts were dried over magnesium sulfate and filtered and the filtrate was concentrated. The crude product obtained (4.05 g) was chromatographed over silica gel with methanol/ether 1:1. 1.09 g of the polar diastereomer of N-(4-benzyl-4-dimethylamino-cyclohexyl)-N-ethyl-benzamide were obtained, from which 1.01 mg of the corresponding hydrochloride were prepared as described for example 1 with water and chlorotrimethylsilane in 2-butanone.
Reaction SMILES: C[O-].[Na+].CN(C)C([S:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][CH3:21])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=O>CO>[CH2:20]([O:19][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([SH:8])[CH:18]=1)[CH3:21]
Reactant: CCOc1ccc(C(=O)OC)c(SC(=O)N(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOc1ccc(C(=O)OC)c(S)c1
Yield: 86.7 %

Procedure:
Methanolic sodium methoxide (4.9M. 22.4 mL, 0.11 mol) was added via syringe to a solution of methyl 2-[(dimethylamino)carbonylthio]-4-ethoxybenzoate (crude. ca. 28.3 g, 0.10 mol) in methanol (100 mL) under nitrogen. The reaction mixture was heated at reflux for 30 minutes, then cooled with the aid of a water bath. Rotary evaporation yielded a solid. This was partitioned between dichloromethane (100 mL) and water (100 mL). The aqueous layer was washed with dichloromethane (3×40 mL), acidified to PH <1 with concentrated hydrochloric acid, and then extracted with dichloromethane (3×40 mL). These dichloromethane extracts were combined dried (Na2SO4), and filtered. Rotary evaporation yielded methyl 4-ethoxy-2-mercaptobenzoate as an oil (18.4 g) that on standing formed a crystalline solid melting at 42°-44° C. PMR (CDCl3, 200 MHz): δ7.97 (d, 1H. H ortho to CO2CH3); 6.78 (d, 1H. H ortho to SH); 6.64 (dd, 1H, H para to SH); 5.06 (s, 1H, SH); 4.05 (q. 2OCH2CH3); 3.88 (s. 3H, CO2CH3); 1.42 (t, 3H, OCH2CH3). TR (Nujol): 1686 (vs, C=O)cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[NH:12][C:13]2[S:14][CH:15]=[C:16]([C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[S:26]1[CH2:32][C:30](=[O:31])[N:29]([CH2:33][C:34]([OH:36])=[O:35])[C:27]1=[S:28].[Cl-].[NH4+].N>C(O)C>[CH3:27][N:29]([CH3:33])[CH:30]=[O:31].[CH3:27][N:29]([CH3:33])[CH:30]=[O:31].[CH2:22]([O:21][C:19]([C:18](=[C:32]1[S:26][C:27](=[S:28])[N:29]([CH2:33][C:34]([OH:36])=[O:35])[C:30]1=[O:31])[C:16]1[N:17]=[C:13]([NH:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:25])[S:14][CH:15]=1)=[O:20])[CH3:23]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc([N+](=O)[O-])cc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccc([N+](=O)[O-])cc2)n1
Product: CN(C)C=O

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 3.7 g of ethyl 2-(3-p-nitrophenylureido)thiazol-4-ylglyoxylate, 1.9 g of rhodanine-3-acetic acid, 1 g of ammonium chloride, 1 ml of 28% v/v aqueous ammonia and 40 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: C(O[C:4](=[O:26])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](C(F)(F)F)[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([Br:25])[CH:6]=1)C.[CH3:27][NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Br:25][C:7]1[CH:6]=[C:5]([C:4]([N:28]([CH3:27])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:26])[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]=1[O:21][CH2:22][CH2:23][OH:24]
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: CNCCCCCCCCc1ccccc1
Product: CN(CCCCCCCCc1ccccc1)C(=O)c1cc(Br)c(OCCO)c(-c2ccccc2)c1

Procedure:
5-bromo-6-(2-hydroxyethoxy)-N-methyl-N-(8-phenyloctyl) [1,1′-biphenyl]-3-carboxamide was prepared as a colorless oil (0.200 g, 56%) from 3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester and N-methyl-N-(8-phenyloctyl)amine using a procedure similar to step 2 of Example 175. 1H NMR (CDCl3) δ7.87-7.54 (m, 5H); 7.38-7.12 (m, 6H); 3.65 (m, 4H); 3.50 and 3.03 (2bt, 2H); 3.03 (2s, 3H); 2.58 (m, 2H); 1.98 (bs, 1H); 1.60 (m, 4H); 1.40-1.22 (m, 8H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.Cl[C:22]1C=CC(C2C(C=O)=CC=CC=2)=CC=1>>[O:14]1[CH2:19][CH2:18][CH:17]([N:4]2[CH2:3][CH2:2][CH2:22][C@H:6]([NH:1][C:7](=[O:8])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH2:5]2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Reactant: O=C1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(C2CCOCC2)C1

Procedure:
The title compound was prepared by substituting (S)-tert-butyl piperidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate and dihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[C:6](#[N:9])[CH:7]=[CH2:8].[OH-].[Na+]>O1CCOCC1.C1(C=CC(O)=CC=1)O>[CH3:3][C:2]([CH3:4])([CH:1]=[O:5])[CH2:8][CH2:7][C:6]#[N:9]
Reactant: CC(C)C=O
Reactant: C=CC#N
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C=O)CCC#N
Temperature: 65 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
To a stirred solution of isobutyraldehyde (6.3 mL, 69.3 mmol), hydroquinone (25 mg) and acrylonitrile (5.7 mL, 86.7 mmol) in 1,4-dioxane (25 mL) was added 5% sodium hydroxide (4.6 mL). The reaction was heated at 65° C. for 2.5 hours and then stirred at ambient temperature for 16 hours. The dioxane was removed in vacuo and the residue was taken up in dichloromethane (80 mL). The dichloromethane was washed with water (3×80 mL), dried (magnesium sulfate), concentrated in vacuo and then distilled to afford the title compound (5.4 g, 63%) as a colorless liquid; bp 70° C. (0.8 mm);
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([F:12])[C:6]([C:7]([OH:9])=O)=[C:5]([F:13])[CH:4]=1)#[N:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[N:49]1([CH2:55][CH:56]([N:60]2[CH:64]=[C:63]([C:65]3[C:66]4[CH:73]=[CH:72][N:71](COCC[Si](C)(C)C)[C:67]=4[N:68]=[CH:69][N:70]=3)[CH:62]=[N:61]2)[CH2:57][C:58]#[N:59])[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>CN(C=O)C.C(OCC)(=O)C>[C:58]([CH2:57][CH:56]([N:60]1[CH:64]=[C:63]([C:65]2[C:66]3[CH:73]=[CH:72][NH:71][C:67]=3[N:68]=[CH:69][N:70]=2)[CH:62]=[N:61]1)[CH2:55][N:49]1[CH2:50][CH2:51][N:52]([C:7]([C:6]2[C:5]([F:13])=[CH:4][C:3]([C:1]#[N:2])=[CH:11][C:10]=2[F:12])=[O:9])[CH2:53][CH2:54]1)#[N:59]
Reactant: N#Cc1cc(F)c(C(=O)O)c(F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC(CN1CCN(C(=O)c2c(F)cc(C#N)cc2F)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 16 h

Procedure:
4-Cyano-2,6-difluorobenzoic acid (82 mg, 0.32 mmol), Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (110 mg, 0.00025 mol) and triethylamine (180 uL, 0.0013 mol) were stirred together in DMF (0.5 mL) for 15 minutes. 4-Piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (125 mg, 0.211 mmol; from Example 12, Step 2) was added and the reaction stirred for 16 hours. To push the reaction to completion, additional 4-cyano-2,6-difluorobenzoic acid (82 mg, 0.32 mol) and triethylamine (58.9 uL, 0.000422 mol) were mixed, in a separate vial, in N,N-Dimethylformamide (1.6 mL) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (110 mg, 0.25 mmol) was added. This mixture was stirred separately for 15 minutes, and then was added to the incomplete original reaction mixture. The reaction was continued for 1.5 hours, then was diluted with a large quantity of ethyl acetate. The solution was washed with three portions of water, once with brine, dried over sodium sulfate and concentrated. The residue was stirred in a mixture of 1:1 dichloromethane (DCM):TFA for one hour, was concentrated, then was stirred in methanol (3 mL) containing ethylenediamine (0.5 mL) until deprotection was complete as evidenced by LCMS. Two successive purifications vial HPLC-MS (eluting first with a gradient of MeCN/H2O containing 0.1% TFA, then repurification eluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded clean product (46 mg, 43%). 1H NMR (400 MHz, d6-dmso): δ 12.11 (br s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7.98-7.91 (m, 2H), 7.60 (d, 1H), 6.97 (d, 1H), 5.02-4.93 (tt, 1H), 3.66-3.54 (m, 2H), 3.25-3.16 (m, 4H), 2.91-2.78 (m, 2H), 2.63-2.54 (m, 1H), 2.52-2.38 (m, 2H), 2.37-2.28 (m, 1H); LCMS (M+H)+: 502.1.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][NH2:14])[NH:10][CH:11]=2)=[CH:3][CH:2]=1.[S:21](Cl)([OH:24])(=O)=[O:22].[CH3:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][NH:14][S:21]([CH2:26][CH2:27][CH2:28][CH3:29])(=[O:24])=[O:22])[NH:10][CH:11]=2)=[CH:3][CH:2]=1
Reactant: NCCc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Reactant: O=S(=O)(O)Cl
Reactant: CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)NCCc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Temperature: 23 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
A mixture containing 2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylamine (obtained in Stage 32.2 of Example 32; 660 mg; 0.0025 mol) and n-butane sulphochloride (390 mg; 0.0025 mol) in 20 ml of DMF is stirred for two hours at 23° C. Potassium carbonate (345 mg; 0.0025 mol.) is then added, then stirring is continued for two hours. The solvent is evaporated off and the reaction mixture is taken up in water and dichloromethane. The organic phase is washed with a saturated solution of sodium chloride then dried. The solvent is evaporated off and the residue obtained is purified on a silica column (eluent: CH2Cl2-MeOH/93-07). A light beige-coloured powder is obtained with a yield of 19%. Melting point: 168.5° C.
Reaction SMILES: C(N(CC)CC)C.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][OH:25])[CH2:22][S:23][C@H:18]12)=[O:15].[C:31]1(=[O:41])[O:36][C:34](=[O:35])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12>ClCCl>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][O:25][C:31](=[O:41])[C:32]3[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=3[C:34]([OH:36])=[O:35])[CH2:22][S:23][C@H:18]12)=[O:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3C(=O)O)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
In dichloromethane (25 ml) was dissolved 7β-(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (3.60 g), followed by addition of phthalic anhydride (1.80 g). The mixture was stirred at room temperature for 2 hours, after which time it was treated in a manner similar to that described in Example 8. The procedure provided 7β-(2-thienylacetamido)-3-(2-carboxybenzoyloxy)methyl-3-cephem-4-carboxylic acid (3.44 g).
Reaction SMILES: [Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:21])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Solvent: ClCCl
Product: O=C(Cl)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Reaction time: 8 h

Procedure:
4-(2-Bromotetrafluoroethoxy)benzoic acid prepared as in Example 18 (26.6 g, 0.083 mol) is transferred to a 250 mL round-bottomed flask along with 150 mL of methylene chloride. Oxalyl chloride (11.64 g, 0.92 mol) is added and the mixture is stirred under nitrogen overnight to form a turbid solution which is concentrated by rotary evaporation and distilled at 80°-90° C./0.1 mmHg to yield 20.88 g of 4(2-bromotetrafluoroethoxy)benzoyl chloride as a colorless liquid, leaving 6.16 g of unreacted acid (76.8% conversion, 96.5% yield). The benzoyl chloride is added slowly with stirring to 8 mL of cold ammonium hydroxide (0.12 mol). The product amide precipitates as fine white needles which are filtered and dried under vacuum to yield 14.74 g of 4-(2-bromotetrafluoroethoxy)benzamide (75% conversion, 99% yield, m p. 150.5°-151.5° C.), along with 4.8 g of 4-(2-bromotetrafluoroethoxy)benzoic acid which is recovered from the mother liquor (24.3% recovery).