Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([C:29](O)=[O:30])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)(Cl)=O.[CH2:36]([NH2:39])[CH2:37][NH2:38].Cl>C1(C)C=CC=CC=1.C(Cl)Cl.CN(C=O)C>[NH2:38][CH2:37][CH2:36][NH:39][C:29]([C:24]1[CH:23]=[CH:22][C:21]2[C:26](=[CH:27][CH:28]=[C:19]([C:13]3[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([C:1]45[CH2:10][CH:5]6[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]6)[CH2:8]4)[CH2:2]5)[CH:12]=3)[CH:20]=2)[CH:25]=1)=[O:30]
Reactant: NCCN
Reactant: COc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3cc(C(=O)NCCN)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthalenecarboxylic acid (3 g, 7.27 mmoles) in dry toluene (20 mL) was added thionyl chloride (0.6 mL, 8.22 mmoles) and DMF (0.04 mL) under argon. The reaction mixture was heated to 100° C. for ten minutes and another 0.04 mL of DMF was added. After 30 minutes, more thionyl chloride (0.1 mL, 1.37 mmoles) was added and the reaction mixture was heated to 110° C. for 60 minutes. The solvent and excess thionyl chloride were removed in vacuo. The resulting solid was stirred with 100 mL dry methylene chloride under argon. This was added to a mixture of ethylene diamine (5.25 mL, 70 mmoles) in dry methylene chloride under argon at 0° C. while stirring rapidly. The solution was allowed to warm to ambient temperature while stirring rapidly during one hour. The reaction mixture was poured carefully into 350 mL of 1N aqueous HCl while stirring, and the methylene chloride was removed in vacuo. The resulting precipitate (hydrochloride salt of the product) was washed with 1N HCl, water, THF, and methylene chloride. Yield of hydrochloride salt: 2.76 g, 77%. The free base was generated by neutralizing with aqueous sodium bicarbonate and extracting the product into tetrahydrofuran, drying the organic layer over sodium sulfate, and removing the solvent. MS 455 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10][CH3:11])[CH:5]=[O:6].[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[S:10][CH3:11]
Reactant: CSc1ccc(C=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSc1ccc(CO)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
The mixture of 3-fluoro-4-(methylsulfanyl)benzaldehyde (19.44 g, 114.2 mmol) and sodium borohydride (2.1 g, 55.46 mmol) in methanol (200 mL) was stirred at room temperature for 2 hour. Water was added to the mixture, and the mixture was evaporated, diluted with ethyl acetate (300 mL), washed with water (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/4) to provide the subtitle compound (19.91 g, 100% yield) as an oil.
Reaction SMILES: [CH2:1]([C:10]1[CH:11]=[C:12]([CH3:17])[C:13]([OH:16])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:18]=[O:19]>CC1C=CC(O)=CC=1.CC1C=CC(O)=CC=1.CC1C=CC(O)=CC=1.CC1C=CC(O)=CC=1.[Ti].C1(C)C=CC=CC=1>[CH3:17][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]=[C:14]([CH:18]=[O:19])[C:13]=1[OH:16]
Reactant: CCCCCCCCCc1ccc(O)c(C)c1
Reactant: C=O
Agent: [Ti]
Agent: Cc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1cc(C)c(O)c(C=O)c1
Temperature: 215 °C
Reaction time: 0.33 h
Yield: 69.7 %

Procedure:
To toluene (500 mL) in a 2-I Parr pressure reactor at 220° C. was added a slurry of 4-nonyl-2-cresol (1a) (234 g, 1 mol), titanium(IV) cresylate (2 mL) and powder paraformaldehyde (83 g, 2.8 mol) for 10 mins. maintaining the temperature at 210-220° C. The reaction was kept for additional 20 mins. Crude product was collected in an expansion tank and the residue in the pressure reactor washed with toluene (200-mL×2). Combined toluene phases were concentrated in vacuo. The resulting viscous dark amber liquid was distilled in vacuo to obtain 3-methyl-5-nonylsalicylaldehyde (183 g) in 70% yield.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]2[C:11]=1[C:12]([CH3:22])([CH3:21])[CH2:13][CH2:14][S:15]2>C(Cl)Cl>[C:5]([C:19]1[C:10]([Cl:9])=[C:11]2[C:16](=[C:17]([Cl:20])[CH:18]=1)[S:15][CH2:14][CH2:13][C:12]2([CH3:22])[CH3:21])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC1(C)CCSc2c(Cl)ccc(Cl)c21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2c(c1Cl)C(C)(C)CCS2
Temperature: 0 °C
Yield: 55.7 %

Procedure:
1.26 Grams (9.45 mmol) of anhydrous aluminum chloride was suspended in 10 ml of methylene chloride, and a solution of 0.74 g (9.45 mmol) of acetyl chloride in 5 ml of methylene chloride was dropwise added with cooling with ice. The mixture was stirred until the reaction mixture was homogeneous, then, a solution of 1.95 g (7.88 mmol) of 5,8-dichloro-4,4-dimethylthiochroman in 5 ml of methylene chloride was added, and the mixture was allowed to react at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was poured into ice water and extracted with methylenechloride. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The methylene chloride was distilled off under reduced pressure, and the resultant oily substance was purified by silica gel column chromatography to give 1.27 g (yield 56%) of 6-acetyl-5,8-dichloro-4,4-dimethylthiochroman.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([NH:20][CH2:19][CH2:18][CH2:17][N:8]1[CH:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:32]
Reactant: O=C=Nc1ccccc1Cl
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)Nc1ccccc1Cl

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 2-chlorophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][C@H:3]1[CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:1][C@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[CH2:15][NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](CNC(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CNCC[C@@H]1O)OCc1ccccc1
Reaction time: 1 h
Yield: 84 %

Procedure:
To a flask containing 1,1-dimethylethyl (3R,4S)-4-hydroxy-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-piperidinecarboxylate (for a preparation see Example 135(e)) (1 g; 2.74 mmol) was added 100 mL of TFA/DCM (50%). The reaction mixture was stirred for 1 h and then concentrated. The crude product was made basic by the addition of 6N NaOH and extracted into 10% MeOH/DCM (2×50 mL). The organic fractions were dried with anhydrous sodium sulfate, filtered and concentrated to obtain the product as a clear oil (607 mg; 84%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OC([C:26]2[CH:38]=[CH:37][C:29]3[N:30]=[C:31]([NH:33]C(=O)C)[S:32][C:28]=3[CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:33][C:31]1[S:32][C:28]2[CH:27]=[C:26]([C:2]3[N:7]=[C:6]([NH:8][S:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)(=[O:11])=[O:10])[CH:5]=[CH:4][CH:3]=3)[CH:38]=[CH:37][C:29]=2[N:30]=1
Reactant: O=S(=O)(Nc1cccc(Cl)n1)c1ccccc1
Reactant: CC(=O)Nc1nc2ccc(C3OC(C)(C)C(C)(C)O3)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc2ccc(-c3cccc(NS(=O)(=O)c4ccccc4)n3)cc2s1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
N-(6-Chloropyridin-2-yl)benzenesulfonamide (0.480 g, 1.90 mmol) was dissolved in 1,4-dioxane (6 mL). Then N-(6-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.7 g, 2 mmol), 2M Na2CO3 (2 mL, 4 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.3 g, 0.2 mmol) was added to the mixture. The flask was fit with a reflux condensor, then placed into a pre-heated (95° C.) bath and allowed to stir under inert atmosphere overnight. The flask was removed from the heat bath and allowed to cool to ambient temperature. The mixture was filtered through a fritted funnel and the crude filtrate was purified by reverse-phase HPLC. This gave N-(6-(2-aminobenzo[d]thiazol-6-yl)pyridin-2-yl)benzenesulfonamide. MS (ESI pos. ion) m/z: 383 (MH+). Calculated exact mass for C18H14N4O2S2: 382. 1H NMR (400 MHz, acetone-d6): 8.19 (s, 1H), 8.08 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H), 7.53-7.64 (m, 4H), 7.44 (d, J=8.5 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.98 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:13][NH:17][CH:14]([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: COC(=O)C(CNC(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(4-chlorophenyl)acrylate (1.00 g, 5.09 mmol) was added as a solution in THF (2.5 mL) to a stirring solution of i-PrNH2 (650 uL, 7.63 mmol) in THF (10 mL) The reaction was allowed to stir at room temperature overnight to completion by LCMS analysis. The solvent was removed under reduced pressure to give methyl 2-(4-chlorophenyl)-3-(isopropylamino)propanoate (LCMS (APCI+) [M-Boc+H]+ 256.1, Rt: 1.97 min), which was re-dissolved in DCM (15 mL) at room temperature. The Boc2O (1.29 mL, 5.59 mmol) was added to the stirring amine via pipette followed by a catalytic amount (1 mg) of DMAP. The reaction was allowed to stir overnight to completion by LCMS and TLC analysis of the mixture. The solution was concentrated in vacuo to afford methyl 3-(tert-butoxycarbonyl(isopropypamino)-2-(4-chlorophenyl)propanoate as an oily residue (LCMS (APCI+) [M-Boc+H]+ 256.1, Rt: 4.13 min) which was re-dissolved in THF (12.0 mL) and water (4.0 mL). The solution was treated with LiOH—H20 (1.07 g, 25.4 mmol) and allowed to stir for 4 hours to completion by LCMS analysis. The solution was diluted with water and washed with diethyl ether (discarded). The aqueous was treated with 1M HCl solution until a pH of about 2 to about 3 was achieved and extracted with ethyl acetate several times. The organics were combined, washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid as an oil (1.04 g, 60%). LCMS (APCI+) [M-Boc+H]+ 242.0.
Reaction SMILES: [C:1]([C:3]1([N:10]2[CH2:15][CH2:14][N:13]([C:16](OCC)=O)[CH2:12][CH2:11]2)[CH2:9][CH2:8][CH:7]=[CH:6][O:5][CH2:4]1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:16][N:13]1[CH2:12][CH2:11][N:10]([C:3]2([CH2:1][NH2:2])[CH2:9][CH2:8][CH:7]=[CH:6][O:5][CH2:4]2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)N1CCN(C2(C#N)CCC=COC2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1CCN(C2(CN)CCC=COC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
To a solution of ethyl 4-(3-cyano-2,3,4,5-tetrahydrooxepin-3-yl)piperazine-1-carboxylate (320 mg, 1.146 mmole) in dry THF (5 ml) was added LAH (1.75 ml, 3.50 mmole) at 0° C. After 30 min the mixture was warmed to RT. After 16 hr the mixture was cooled to 0° C. and slowly quenched with 2M NaOH until gas evolution had ceased and a fine white precipitate formed. Anhydrous Na2SO4 was added and the mixture stirred for 15 min. The slurry was filtered through a pad of Celite washing with THF. The filtrate was concentrated to give the title compound as a clear oil (250 mg, 97%) which was used in the next step without purification. 1H-NMR (CDCl3, 500 MHz) d 6.23 (d, J=6.83 Hz, 1 H), 4.60 (m, 1 H), 4.11 (dd AB, J=12.46 and 58.83 Hz, 2 H), 2.77 (s, 2 H), 2.70 (m, 4 H), 2.43 (m, 4 H), 2.27 (s, 3 H), 2.13 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[C:16]=1[CH3:25]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:23][C:15]([CH3:14])=[C:16]([CH3:25])[C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: Cc1sc2c(c1C)C(C)NCC2
Product: Cc1sc2c(c1C)C(C)N(C(=O)c1cc3ncc(Cl)cn3n1)CC2
Yield: 57 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,3,4-Trimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:34]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.[W]>[Br:1][C:2]1[C:3]([CH2:15][Br:34])=[C:4]([NH:8][C:9](=[O:14])[C:10]([F:11])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NC(=O)C(F)(F)F
Reactant: BrBr
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1cccc(Br)c1CBr)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-(3-bromo-2-methyl-phenyl)-2,2,2-trifluoro-acetamide (2.1 g, 7.4 mmol) and benzoyl peroxide (100 mg) in carbon tetrachloride (50 mL) was heated to reflux under irradiation (150 W tungsten lamp). A solution of bromine (0.55 mL, 10.4 mmol) in carbon tetrachloride (3 mL) was then added drop-wise to the refluxing solution, and heating was pursued for 16 h. The reaction mixture was left to cool to RT and diluted with DCM. The organic layer was washed with sodium thiosulfate, and evaporated to dryness to give N-(3-bromo-2-bromomethyl-phenyl)-2,2,2-trifluoro-acetamide as a brown residue which was used without further purification (2.9 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([OH:33])=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:35])([F:34])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:37]1[C:46]([CH2:47][CH3:48])=[N:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1.CN(C=O)C.CCC([O-])(C)C.[Na+]>CC#N.Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:37]3[C:46]([CH2:47][CH3:48])=[N:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([OH:33])=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:35])([F:34])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](O)CN2C1=O
Reactant: CCc1nc2ccccc2nc1Cl
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCc1nc2ccccc2nc1O[C@@H]1C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.5 %

Procedure:
To (2R,6S,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-12,12-difluoro-2-hydroxy-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (Example 7j, 87.4 mg, 0.174 mmol) was added 2-chloro-3-ethylquinoxaline (47.7 mg, 0.247 mmol) and DMF (868 μl). To this solution was added sodium tert-pentoxide (48.9 mg, 0.444 mmol) at room temperature, and the mixture turned dark purple (slightly exothermic). The reaction mixture was stirred at room temperature for 17 h. Additional 2-chloro-3-ethylquinoxaline (18.1 mg, 0.094 mmol) and sodium tert-pentoxide (24.2 mg, 0.202 mmol) were added, and the reaction mixture was stirred for 22 h. The reaction mixture was diluted with CH3CN and neutralized with HCl (1 N, 0.7 ml) and evaporated under reduced pressure. The residue was purified by reverse phase HPLC (CH3CN/H2O (0.1%TFA), gradient=20/80-85/15) to provide the title compound as a light brown solid, (2R,6S,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-2-(3-ethylquinoxalin-2-yloxy)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (66 mg, 57% yield).
Reaction SMILES: [OH:1][C:2]1([CH2:26][OH:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.C=O.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:6][CH2:7]2)[CH2:26][O:27][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CO)CC3)c(F)c2)C(=O)O1
Agent: C=O
Solvent: c1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)COCO4)c(F)c2)C(=O)O1
Yield: 57 %

Procedure:
The compound was prepared by reacting (S)-N-{3-[4-(4-hydroxy-4-hydroxymethyl-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.3 mmol), paraformaldehyde (0.3 mmol), p-toluene sulfonic acid (0.3 mmol), 4° A molecular sieves (0.5 g) in benzene (10 ml) and by purifying on silica gel column chromatography to provide title compound in 57% yield.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:4]([CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:27].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])=[C:4]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:27]
Reactant: CCOC(=O)C(O)c1c(C)c(Br)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)c1c(C)c(Br)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A solution of ethyl 2-(4-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (crude, 1.22 g, ˜2.60 mmol) in DCM (60 mL) was treated with Dess-Martin periodinane (1.32 g, 3.12 mmol) at 23° C. After 30 min, 10% Na2S2O3 (30 mL) was added at 23° C. The system was diluted with H2O (20 mL) and extracted with DCM (3×30 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was treated with benzene, filtered, and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (1.18 g, 98% yield over 2 steps from ethyl 2-(4-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate). 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=8.6 Hz, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.77 (dd, J=8.6, 8.2 Hz, 1H), 7.71 (dd, J=8.6, 8.6 Hz, 1H), 4.42 (q, J=7.0 Hz, 2H), 2.57 (s, 3H), 1.39 (t, J=7.0 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ−73.3 (s).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1.[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30].C(N(CC)CC)C.[OH-].[Na+]>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])=[CH:7][C:6]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1
Reactant: COc1nccc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: CCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c3c(OC)nccc23)c1
Temperature: 80 °C

Procedure:
A mixture of Example 2D (0.05 g, 0.131 mmol), ethanesulfonyl chloride (0.051 g, 0.393 mmol), and triethylamine (0.080 g, 0.787 mmol) in dichloromethane (3 mL) was stirred at ambient temperature for 2 hours. The solvent was removed, and the residue was treated with sodium hydroxide (0.656 mL, 1.31 mmol) and dioxane (3 mL). The reaction mixture was heated at 80° C. for 3 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][NH:13][N:14]=2)[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1.F[B-](F)(F)F.[CH3:26][O+](C)C>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][N:13]([CH3:26])[N:14]=2)[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1
Reactant: C[O+](C)C
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nn[nH]n2)n1
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nnn(C)n2)n1

Procedure:
Treat a solution of (S)-2-sec-butylamino-6-(2H-tetrazol-5-yl)-isonicotinic acid methyl ester (350 mg, 1.26 mmol) in ethyl acetate (8 mL) with trimethyloxonium tetrafluoroborate at room temperature for 3 h. Dilute with ethyl acetate (50 mL) and wash with saturated sodium bicarbonate and saturated aqueous sodium chloride. Dry (sodium sulfate) and concentrate to give the title compound which is used directly in the next step without further purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44](Cl)(=[O:47])[CH2:45][CH3:46]>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:44]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:47])[CH2:45][CH3:46]
Reactant: CCC(=O)Cl
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)NC1CCN(CCNC(=O)c2nn(C(C)C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.310 g, 0.94 mmol) and triethylamine (0.13 mL, 0.94 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise propionyl chloride (0.08 mL, 0.94 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to an oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.168 g colorless crystals. Mp 169° C. Mass spectrum, m+ =385. Anal (C23H33N5O6) theory C, 58.09; H, 6.99; N, 14.73; found C, 57.79; H, 6.93; N, 14.46.