Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([F:41])[C:39]=1[F:40])[CH2:35]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:35][C:34]3[CH:33]=[C:32]([F:31])[C:39]([F:40])=[C:38]([F:41])[CH:37]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cc(CBr)cc(F)c1F
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2cc(F)c(F)c(F)c2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 3,4,5-trifluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.43 (m, 1 H), 7.24-7.17 (m, 1 H), 7.07 (t, J=3.0 Hz, 1 H), 6.97-6.87 (m, 3 H), 6.35 (dd, J=3.3, 11.3 Hz, 1 H), 5.60-5.42 (m, 3 H), 4.29 (t, J=4.8 Hz, 2 H), 2.92-2.80 (m, 2 H), 2.76 (s, 3 H), 2.15-2.07 (m, 2 H), 1.01-0.91 (s, 9 H); LC/MS (m/z) ES+=539.34 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[N+:13]([CH:15](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:16][CH3:17])#[C-:14].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:16]([C:15]1[N:13]=[CH:14][O:8][C:7]=1[C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1)[CH3:17]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: [C-]#[N+]C(CC)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1ncoc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A mixture of 4-(trifluoromethyl)benzaldehyde (3.60 mL, 27.0 mmol), 1-(1-isocyanopropylsulfonyl)-4-methylbenzene (6.02 g, 27.0 mmol), and K2CO3 (4.47 g, 32.4 mmol) in MeOH (100 mL) was heated to reflux. After 1.5 hr the reaction mixture was cooled to ambient temperature, and the volatiles evaporated at reduced pressure. The residue was partitioned between Et2O (100 mL) and H2O (100 mL). The separated aqueous phase was extracted with Et2O. The combined organic extract was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. Chromatography on silica gel (Analogix® Intelliflash 280™; SF40-150 g column; 10% to 30% EtOAc/hexanes eluant, 30 min) afforded 5.75 g (88%) of the title compound as a pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.90-7.78 (m, 4H), 2.79 (q, J=7.5, 2H), 1.23 (t, J=7.5, 3H). MS (DCI+) m/z 242 (M+H).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.C(Cl)CCl.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>ClCCl>[OH:9][C:8]1[CH:10]=[C:2]([CH:3]=[C:4]([OH:5])[C:6]=1[OH:7])[C:1]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:12]
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Nc1ccccc1-c1cc2ccccc2[nH]1)c1cc(O)c(O)c(O)c1

Procedure:
A 25-mL one-necked recovery flask equipped with a stirring bar and a septum was charged with gallic acid (176 mg; 1.03 mmol; 1.00 equiv). A clear, colorless solution was formed on addition of 5 mL of dichloromethane. Solid EDC (197 mg; 1.03 mmol; 1.00 equiv) and 2-(2-aminophenyl)indole (194 mg; 0.932 mmol; 0.904 equiv) were added sequentially as solids. The reaction was worked up after 24 h by extraction with 10 mL of NaHCO3 (satd aq). The organic layer was dried (anhydrous sodium sulfate), filtered and concentrated by rotary evaporation to yield a yellow oily paste. The crude was purified using DCM-MeOH (19:1) to yield a light yellow solid (230 mg; 68%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(C)(C)C.CCOCC>[N:13]1([C:2]2[C:3]3[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: N#Cc1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: N#Cc1c[nH]c2ncnc(N3CCCCC3)c12
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (54 mg/0.3 mmol) (prepared by the method of Townsend, et. al., J. Am. Chem. Soc., 1969, 91, 2102) suspended in 3.0 mL tert-Butanol was added piperidine (59 μL/0.60 mmol). The resulting mixture was then heated at reflux for 2.5 h and after cooling to room temperature, was transferred to a separatory funnel and diluted with ether (20 mL). The solution was extracted 2×10 mL with 1N HCl, the combined aqueous layers were adjusted to pH 7 with 2 N potassium hydroxide (KOH) solution forming a precipitate which was collected by filtration, washed with water and dried under reduced pressure to give 29 mg (42%) of the title compound as a colorless solid. Mp 209-211° C.; 1H NMR (400 MHz) (acetone-6) δ1.72-1.74 (m, 6H), 3.72-3.79 (m, 4H), 8.12 (s, 1H), 8.29 (s, 1H). LRMS: 228 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:16]3)[C:12]3[CH:11]=[CH:10][S:9][C:8]=3[NH:7][C:6]=2[CH:26]=1.C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:29])[C@@H:17]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:16]3)[C:12]3[CH:11]=[CH:10][S:9][C:8]=3[NH:7][C:6]=2[CH:26]=1
Reactant: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sccc32)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sccc32)CCN1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.1 %

Procedure:
Combine (S)-6-fluoro-10-[3-(3-methoxy-propyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (220.1 mg, 0.59 mmol), formaldehyde (52.5 μL, 0.64 mmol, 37% in water), and dichloromethane (8.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (186.8 mg, 6.88 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (90:10) to give 195.1 mg (86%) of the title compound: mass spectrum (ion spray): m/z=389.1 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:19])[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])(=[O:3])[CH3:2].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH3:22][CH2:2][C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:19])[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:3]
Reactant: CI
Reactant: CC(=O)Nc1scc(C)c1C(=O)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)Nc1scc(C)c1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 40.0 g of 2-acetylamino-3-(o-chlorobenzoyl)-4-methylthiophene in 800 ml of dimethylformamide is added 7.74 g of 63 % sodium hydride. The mixture is stirred at room temperature for 30 minutes. Then 61.34 g of methyl iodide in 184 ml of dimethylformamide is added thereto. The mixture is stirred at room temperature for 2 hours, then poured into water, and extracted with benzene. The benzene extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residual oil is chromatographed on silica gel, using chloroform as an eluent to give 2-(N-methylacetylamino)-3-(o-chlorobenzoyl)-4-methylthiophene as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]2=[O:13])=[CH:6][CH:5]=1)([O-])=O.C1CCCCC=1.[ClH:25]>C(O)C.[Pd]>[ClH:25].[ClH:25].[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]2=[O:13])=[CH:8][CH:9]=1
Reactant: O=C1NCCCCC1Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1=CCCCC1
Product: Nc1ccc(NC2CCCCNC2=O)cc1
Yield: 81 %

Procedure:
2 g (8 mmol) of α-N-(4-nitrophenyl)amino-ε-caprolactam are partially dissolved in 40 ml of 95° ethanol in a 150 ml three-necked flask equipped with a thermometer and a reflux condenser. 2 g of palladium-on-charcoal (10% active and 50% moisture) are then introduced, followed by 20 ml of cyclohexene. The mixture is brought to reflux for 3 hours and is then cooled, before being filtered through celite. After having run approximately 6 ml (˜3.5 eq) of 5N hydrochloric acid onto the filtrate, the latter is evaporated to dryness and the residue is taken up in ethanol and precipitated from acetone. After filtration, 1.9 g of a white product are obtained, i.e. a final yield of 81%.
Reaction SMILES: C[Al](C)C.[CH3:5][NH2:6].[OH:7][C@@H:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][O:22][CH3:23])[CH:10]=[C:9]1[C:24]([O:26]C)=O>C1(C)C=CC=CC=1>[OH:7][C@@H:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][O:22][CH3:23])[CH:10]=[C:9]1[C:24](=[O:26])[NH:6][CH3:5]
Reactant: COC[C@@H]1C=C(C(=O)OC)[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CNC(=O)C1=C[C@@H](COC)N(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 53.5 %

Procedure:
A dry 2 necked round bottomed flask was equipped with a magnetic stirrer and it was flushed with nitrogen twice. Then trimethylaluminum (0.191 ml, 0.38 mmol) was added followed by toluene (0.5 ml). The solution was cooled down to −10° C. and methanamine (0.183 ml, 0.37 mmol) was added slowly. The reaction mixture was stirred at that temperature for 20 minutes. A solution of (2S,5S)-1-tert-butyl 4-methyl 5-hydroxy-2-(methoxymethyl)-5,6-dihydropyridine-1,4(2H)-dicarboxylate (Intermediate 254, 100 mg, 0.33 mmol) in toluene (0.5 ml) was added slowly at room temperature. After stirring overnight the reaction was quenched with 1M HCl and allowed to stir for 15 minutes to complete the hydrolysis. The reaction mixture was extracted with ethyl acetate. The organics were washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (MeOH/DCM) afforded the title compound as a clear oil (53 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][C:36]=1[F:37]>>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[F:37])[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: Oc1ccc(F)c(F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(F)c(F)c3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3,4-difluorophenol: ESMS m/e: 511.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[N+]=[N-].F.[Al](F)(F)[F:16]>CCCCCC>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[C:7]([F:16])[CH:6]=[CH:5][C:4]=1[NH2:9]
Reactant: [N-]=[N+]=Nc1ccccc1C(F)(F)F
Reactant: F[Al](F)F
Agent: F
Solvent: CCCCCC
Product: Nc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C

Procedure:
A mixture of 13.58g. (0.07 mole) of 2-trifluoromethylphenylazide, 100 ml. of hexane, and 20 ml. of anhydrous hydrogen fluoride was treated with 1.0g. of AlF3, and the reaction mixture was then aged for 10 hours at room temperature with agitation. The reaction mixture was then cooled, vented, and rinsed from the bomb with 60 ml. of dichloromethane, followed by 50 ml. of water. After blowing off the hydrogen fluoride, the aqueous rinse was added to the residue, which was cooled to 0° C. and made alkaline (pH about 11) with KOH pellets. The residue was then extracted twice with 100 ml. of dichloromethane per extraction; and the extracts were dried over MgSO4, and then concentrated under reduced pressure to yield 9.68g. (77%) of a brown oil. Structure of the final product as 2-trifluoromethyl-4-fluoroaniline was confirmed by IR and NMR. The final product had a b.p. of 87°-90° C. at 40 mm. Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.[C:24]1([CH3:33])[C:25]([N:30]=[C:31]=[O:32])=[CH:26][CH:27]=[CH:28][CH:29]=1.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:33])=[O:32])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: Cc1ccccc1N=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccccc4C)c(F)c3)c2cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg) was dissolved in chloroform (3 ml), and o-toluyl isocyanate (30 μl) was then added to the solution. The mixture was stirred at 60° C. overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 17 mg (yield 24%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:37][N:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1.O>CN(C)C=O>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:26][C:27]5[CH:28]=[CH:29][C:30]([C:33](=[O:37])[CH2:34][C:35]#[N:36])=[CH:31][CH:32]=5)[C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: BrCc1ccc(-c2ccno2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(C(=O)CC#N)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a solution of 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.35 g, 1.20 mmol) in anhydrous N,N-dimethylformamide (20 mL) at 0° C. was added slowly sodium hydride (60% w/w dispersion in mineral oil, 0.072 g, 1.50 mmol). The solution was stirred at ambient temperature for 30 min, 5-(4-(bromomethyl)phenyl)isoxazole (Sasaki et al., Biorg. Med. Chem. Lett. (1998) δ:2241-2246) (0.24 g, 1.00 mmol) was added and the mixture was stirred for 16 h at ambient temperature. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (3×100 mL), dried over magnesium sulftate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes to afford 3-{4-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]phenyl}-3-oxopropanenitrile (0.33 g, 61%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.96-7.92 (m, 2H), 7.63-7.60 (m, 2H), 7.50-7.46 (m, 1H), 7.23-7.13 (m, 2H), 7.04 6.97 (m, 2H), 6.71-6.67 (m, 1H), 5.43-4.76 (m, 4H), 4.06 (s, 2H), 2.46 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([OH:23])[C:19]([F:22])([F:21])[F:20])=[C:14]([N:24]2[CH:28]=[CH:27][C:26]([CH3:29])=[N:25]2)[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:23][C@H:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=2[N:24]2[CH:28]=[CH:27][C:26]([CH3:29])=[N:25]2)[C:19]([F:22])([F:21])[F:20])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](O)C(F)(F)F)n1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2ccnc(Cl)c2)C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of 2-chloro-4-nitropyridine (200 mg, 1.00 mmol) in 1,4-dioxane (6 mL) was added. (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (368 mg, 1.27 mmol), and Cs2CO3 (828 mg, 2.54 mmol). The reaction was heated to 80° C. for 12 h, then cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (R)-2-chloro-4-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridine as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>[OH-].[Na+].O>[C:17]1([CH2:16][O:15][C:13]([NH:1][CH2:2][CH:3]2[CH2:4][CH2:5][CH:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]2)=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCC1CCC(C(=O)O)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid (10 g, 63.6 mmol, Aldrich) in 2N aqueous NaOH (65 ml) at 0° C. was added benzyl chloroformate (11.9 g, 70 mmol, Aldrich) and the reaction temperature was maintained below 10° C. The cloudy mixture was stirred at RT for 0.5 h. It was then diluted with H2O (100 ml). The clear solution was washed with ether (3×80 ml). The pH of the aqueous layer was adjusted to 2 by adding 6N HCl. The precipitates were filtered and dried in vacuo. 17.8 g of 23 was obtained as a white solid.
Reaction SMILES: [N:1]1([CH2:12][CH2:13][OH:14])[C:5]2[C:6]3[CH:11]=[CH:10][S:9][C:7]=3[CH2:8][C:4]=2[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][N:1]1[C:5]2[C:6]3[CH:11]=[CH:10][S:9][C:7]=3[CH2:8][C:4]=2[CH:3]=[N:2]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCn1ncc2c1-c1ccsc1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1ncc2c1-c1ccsc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 0.50 g of 2-(1,4-dihydrothieno[2′,3′:4,5]cyclopenta[1,2-c]pyrazol-1-yl)ethanol was dissolved in 15 ml of methylene chloride, 1.00 ml of triethylamine and 0.28 ml of methanesulfonyl chloride were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with chloroform. The organic layers were combined, washed with brine and then dried with anhydrous magnesium sulfate. After removal of the drying agent by filtration, the resulting filtrate was concentrated under a reduced pressure to give 0.75 g of 2-(1,4-dihydrothieno[2′,3′:4,5]cyclopenta[1,2-c]pyrazol-1-yl)ethyl methanesulfonate.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].Cl[S:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>C1COCC1>[C:10]([O:14][C:15]([NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=2)(=[O:27])=[O:26])[CH2:19][CH2:18]1)=[O:23])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.7 %

Procedure:
Diisopropylethylamine (10.9 ml, 62.4 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (5.0 g, 20.0 mmol) in THF (150 ml) at room temperature. To this mixture was added 4-(chlorosulfonyl)benzoic acid (5.52 g, 25.0 mmol) portion wise and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was concentrated and the resulting residue suspended in HCl (1M solution, 100 ml), the resulting solid precipitate was collected by filtration, washed with water and dried under vacuum give the title compound (9.2 g, 96% yield) as a white solid. Tr=1.28 min m/z (ES+) (M+Na+) 407.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25][OH:26])[CH2:23][S:24][C@H:19]23)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:39]=[C:40]1[O:44][C:42](=[O:43])[CH2:41]1>ClCCl>[C:8]1([CH2:14][C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25][O:26][C:42](=[O:43])[CH2:41][C:40](=[O:44])[CH3:39])[CH2:23][S:24][C@H:19]23)=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
In dichloromethane (50 ml) was dissolved 7β-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (4.49 g) and, at room temperature, triethylamine (0.51 g) and diketene (1.26 g) were added. The reaction was conducted for 2 hours, after which time the solvent was distilled off under reduced pressure. The residue was diluted with water and adjusted to pH 6.0. This aqueous solution was extracted twice with ethyl acetate, brought down to pH 2.0 with 4 N-HCl and extracted three times with ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous solution of sodium chloride, treated with magnesium sulfate and filtered. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate-ether. The above procedure provided 7β-phenylacetamido-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (4.16 g) (yield 96.3%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=[CH:24]1)=O.CNC>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine- 3-acetic acid (5.5 g, 0.0166 mole), 1,1'-carbonyldiimidazole (2.7 g, 0.0166 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 21/2 hours. The nitrogen flow was stopped and a solution of dimethylamine (0.5M in tetrahydrofuran) (66 ml) was added. The solution was stirred at room temperature, stoppered, for 16 hours. The reaction mixture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake was recrystallized from ethanol to give 3.78 g (63%) of white needles, mp 224°-225° C.