Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.Cl[C:31]1[N:40]=[C:39]([N:41]([CH3:43])[CH3:42])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1>C1COCC1.CC(O)C>[NH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:31]2[N:40]=[C:39]([N:41]([CH3:43])[CH3:42])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)[CH2:9][CH2:10]1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN(C)c1nc(N2CCC(N)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60.1 %

Procedure:
To a solution of 1-benzyl-piperidin-4-ylamine (2.00 g, 10.5 mmol) in THF (20 mL) was added (Boc)2O (2.52 g, 11.5 mmol). The mixture was stirred at ambient temperature for 40 min, and concentrated. To a solution of the residue in MeOH (20 mL) was added 20% Pd(OH)2 (400 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 20 hr. Additionally, 20% Pd(OH)2 (400 mg) was added and the mixture was stirred at ambient temperature under hydrogen atmosphere for 7 hr, at 50° C. for 4.5 hr, and at ambient temperature for 12 hr, filtered through a pad of celite, and concentrated to give a white solid. A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (1.10 g, 5.30 mmol) and the above solid (1.27 g, 6.34 mmol) in 2-propanol (11 mL) was stirred at reflux for 20 hr. The precipitate was collected by filtration, washed with 2-propanol, dissolved in 50% MeOH in CHCl3 (60 mL). The solution was poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, EtOAc to CHCl3) to give [2-(4-amino-piperidin-1-yl)-quinazolin-4-yl]-dimethyl-amine (864 mg, 68%) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10].[N+:18]([O-])([OH:20])=[O:19]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([N+:18]([O-:20])=[O:19])=[C:8]([CH:7]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OC)c(OCCCCl)c1
Product: COC(=O)c1cc(OCCCCl)c(OC)cc1[N+](=O)[O-]
Yield: 86 %

Procedure:
Methyl 3-(3-chloropropoxy)-4-methoxybenzoate (6.65 g, 25.7 mmol) was reacted with nitric acid as described in Example 16A Step 2 to give methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate (6.70 g, 22.1 mmol, 86%). 1H NMR (300 MHz, DMSO-d6) δ 7.65 (s, 1H), 7.37 (s, 1H), 4.26 (t, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 3.76 (t, 2H), 2.26-2.18 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25]CC)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:32]1[CH2:33][CH2:34][N:29]([CH3:28])[C:30](=[O:35])[CH2:31]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1=O
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)(C)O
Product: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CC1=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
A mixture of ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylate (250 mg, 0.58 mmol), 1-methylpiperazin-2-one (130 mg, 1.2 mmol), Pd(OAc)2 (20 mg), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (41 mg, 0.087 mmol), and K3PO4 (490 mg, 2.3 mmol) in tert-butyl alcohol (8 mL) was purged with nitrogen then heated at 100° C. in a sealed vial for 3 h. The mixture was then allowed to cool and EtOAc and water were added. The resulting layers were separated and organic layer was concentrated under reduced pressure. To the resulting bright-yellow solid, 2 mL of dioxane, 2 mL of 2 M NaOH were added. The mixture was heated in 80° C. oil bath with stirring for 0.5 h, then allowed to cooled and neutralized with 4 mL of with 1 M HCl. The red solid formed was collected by filtration and air-dried overnight to give the sub-title compound (24 mg, 9.5%). LCMS calc. for C26H33N8O2 [M+H]+: m/z=489.3. found: 435.2.
Reaction SMILES: [CH2:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[C:10]([N+:15]([O-])=O)=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:6]([O:20][CH3:21])[CH:5]=1)[CH2:2][CH3:3].C.O.NN>CO>[CH3:21][O:20][C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:19]=[CH:18][C:7]=1[O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCc1ccc(Oc2cccnc2[N+](=O)[O-])c(OC)c1
Agent: NN
Solvent: CO
Solvent: O
Product: CCCc1ccc(Oc2cccnc2N)c(OC)c1
Yield: 91.7 %

Procedure:
To a stirred solution of 3-(4-propyl-2-methoxyphenoxy)-2-nitropyridine (1.1 g, 3.8 mmol) in methanol (15 ml) was added anhydrous Ferric chloride (55 mg, 5% by wt) and activated charcoal (55 mg, 5% by wt). The resulting mixture was heated to reflux and hydrazine hydrate (570 mg, 11.45 mmol) was added dropwise. The reaction was allowed to stir under reflux condition overnight, then filtered through celite. The filtrate was concentrated under reduced pressure, taken in ethyl acetate (150 ml). The organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was passed through silica column (eluant ethylacetate/pet ether 1:3 to get 900 mg (91.3%) of title compound as a pale yellow solid.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[C:22]=1[CH3:23])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:9])[CH3:6].CCCCC.[C:29](Cl)([CH3:32])([CH3:31])[CH3:30]>>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[C:22]=1[CH3:23])=[CH:19][C:18]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17][CH:16]=3)=[O:9])[CH3:6]
Reactant: CC(C)(C)Cl
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCC
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(C)(C)C)cc3c2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of aluminum trichloride is added to a suspension of 500 mg of 4-methyl-β-carboline-3-carboxylic acid ethyl ester in 15 ml of tert-butyl chloride. The mixture is stirred for 2 hours at room temperature and thereafter combined with 50 ml of pentane. The supernatant solution is removed by decanting, and the precipitate is combined with 10 ml of ethanol and 30 ml of water. After setting the pH at 3, the mixture is extracted repeatedly with ether. The collected organic phases are dried, filtered, and concentrated. Recrystallization from ether yields 250 mg of 6-tert-butyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester, mp 201°-203° C. From the mother liquor, 100 mg of 6,8-di-tert-butyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester can be isolated, mp 260°-263° C.
Reaction SMILES: C(=O)CCCCCC.ClC(Cl)(Cl)C([O-])=O.[Na+].C(=O)([O-])[O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:20]([Cl:23])([Cl:22])[Cl:21].[Na+]>O>[Cl:21][C:20]([Cl:22])([Cl:23])[CH:19]([OH:18])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCC(OC(=O)[O-])C(Cl)(Cl)Cl
Agent: O=C([O-])C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC=O
Product: CCCCCCC(O)C(Cl)(Cl)Cl
Reaction time: 8 h

Procedure:
The contents of a flask charged with n-heptanal (2.5 mmol), sodium trichloroacetate (2.7 mmol) and a solvent (10 g) were stirred for 16 hours. At the end of this period, when the reaction mixture contained sodium 1,1,1-trichloro-2-octyl carbonate (compound 24), ##STR35## water (50 ml) was added and the mixture was extracted with two portions (each of 25 ml) of n-pentane. Six experiments were thus carried out, each with another solvent. Table I shows which solvents and temperatures were used and presents the conversion of the n-heptanal and the selectivity to the title alcohol. These conversions and selectivities were already obtained after one hour stirring, stirring being continued overnight.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:32]([O-])=O)[C:5]([NH:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)=[C:14]([O:30][CH3:31])[CH:13]=2)[CH2:10][CH3:11])=[N:6][CH:7]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[I:1][C:2]1[CH:3]=[C:4]([NH2:32])[C:5]([NH:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:21]=[N:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=3)=[C:14]([O:30][CH3:31])[CH:13]=2)[CH2:10][CH3:11])=[N:6][CH:7]=1
Reactant: CCC(Nc1ncc(I)cc1[N+](=O)[O-])c1ccc(OCc2ccc(C(F)(F)F)nc2)c(OC)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCC(Nc1ncc(I)cc1N)c1ccc(OCc2ccc(C(F)(F)F)nc2)c(OC)c1
Temperature: 125 °C
Reaction time: 0.17 h
Yield: 101.4 %

Procedure:
To a stirred suspension of 5-iodo-N-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)-3-nitropyridin-2-amine (1.25 g, 2.12 mmol) in acetic acid (20 mL) was added iron (0.714 g, 12.77 mmol). The yellow mixture was heated to 125° C. As the mixture was heated, the yellow color faded and a gray suspension formed. After 10 min, the mixture was allowed to cool to room temperature and was diluted with ethyl acetate (75 mL). The suspension was filtered through Celite with the aid of ethyl acetate (50 mL). The filtrate was washed with water (2×30 mL) and then with concentrated ammonium hydroxide (2×30 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 1.20 g (>100%) of 5-iodo-N2-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)pyridine-2,3-diamine as a brown oil.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[O:14]=[C:4]1[C:5]2[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[S:1][CH:2]=[CH:3]1
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1c2ccccc2c2sccc(=O)c21

Procedure:
-- By the same method as described in Example 7, 4.8 g of thiopyrano[3,2-b]indol-4(5H)-one is alkylated with ethyl bromoacetate to give 6.0 g of product, mp 163°-165° C, after recrystallization from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:21]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=3[F:19])=[C:2]([NH2:1])[N:3]=2)[CH2:30][CH2:31]1)=[O:25])[CH3:22]
Reactant: COc1ccc(F)c(F)c1C(=O)c1ccc(Cl)nc1N
Reactant: CCOC(=O)N1CCC(N)CC1
Product: CCOC(=O)N1CCC(Nc2ccc(C(=O)c3c(OC)ccc(F)c3F)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 39) and ethyl4-amino-1-piperidine carboxylate (Aldrich 96%) using the procedure described in Step B. Example 6. HRMS, observed: 435.1841, Calcd for (M+H)+: 435.1839.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.C(OC(C1(N)C=[CH:58][C:57]([NH2:60])=[CH:56][CH2:55]1)=O)(C)(C)C>>[NH2:60][C:57]1[CH:58]=[CH:24][C:23]([NH:22][C:20]([C@H:19]([NH:18][C:16]([N:13]2[C:14](=[O:15])[CH:8]([CH2:7][C:6]3[CH:34]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:35][CH3:36])[CH2:9][NH:10][C:11](=[O:33])[CH2:12]2)=[O:17])[CH2:31][CH3:32])=[O:21])=[CH:55][CH:56]=1
Reactant: CC(C)(C)OC(=O)C1(N)C=CC(N)=CC1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccc(N)cc1

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, 1-(tert-butoxycarbonyl)-1,4-phenylenediamine was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14].N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]\[C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14]
Reactant: [H][H]
Reactant: NC(=O)C#Cc1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: NC(=O)/C=C\c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reaction time: 1.75 h
Yield: 85 %

Procedure:
A mixture of 3-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}prop-2-ynamide (12.2 mg, 0.033 mmol), 0.005 mL quinoline, and 4 mg Lindlar catalyst in 1.5 mL EtOAc was reacted under a balloon of hydrogen. After 1.75 hours, an additional catalytic amount of Lindlar catalyst was added and the reaction continued for an additional 1 hour. The reaction mixture was partitioned between EtOAc and dilute aqueous HCl, the EtOAc layer washed with H2O, brine, dried with Na2SO4 and evaporated. The crude material was chromatographed eluting with hexane/acetone to give the title compound as a white solid (10.3 mg, 84%). 1H NMR (Acetone-d6) δ: 8.79 (d, J=7.9 Hz, 1H), 8.69 (br. s., 1H), 8.37 (br. s., 1H), 7.75 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.35-7.43 (m, 2H), 6.93 (br. s., 1H), 6.64 (d, J=12.9 Hz, 1H), 6.41 (br. s., 1H), 5.97 (d, J=12.9 Hz, 1H)
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].ON1C(=O)C2=CC=CC=C2C1=O.O=O.OO>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(#N)C>[CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CC#N
Product: CCCCCCC(C)=O
Yield: 53 %

Procedure:
A mixture of 5 mmol of 2-octanol, 0.5 mmol of N-hydroxyphthalimide, 0.0005 mmol of cobalt(II) acetate, and 5 ml of acetonitrile was stirred at 75° C. in an oxygen atmosphere (1 atm) for 24 hours. An iodometric analysis of a reaction mixture revealed that hydrogen peroxide was formed in yield of 21% (selectivity: 35%). Separately, a gas chromatographic analysis of the reaction mixture revealed that the conversion rate from 2-octanol was 60%, and 2-octanone was formed in yield of 53%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:10][C:11]([CH3:21])([CH3:20])[C:12]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[O:13].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl.O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([NH:10][C:11]([CH3:21])([CH3:20])[C:12]([NH:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[O:13])[N:7]=1
Reactant: CC(C)(N)C(=O)NCC(F)(F)F
Reactant: Clc1cnnc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(Nc1cnnc(Cl)n1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a Dioxane (12.0 ml) solution of 3,5-dichloro-1,2,4-triazine I-15a (846 mg, 5.64 mmol) was added 2-amino-2-methyl-N-(2,2,2-trifluoroethyl) propanamide hydrochloride (1,242 mg, 5.64 mmol) followed by diisopropylethylamine (2.96 ml, 16.92 mmol). Dichloromethane (2 mL) was added and the reaction stirred for 2 hours at room temp. The reaction was diluted with dichloromethane and poured into saturated sodium bicarbonate. A precipitate formed. The solid was filtered washed with dichloromethane and then dried under reduced pressure to afford the product I-15 (1.02 g, 60.3%). LRMS (ESI) m/z 297.9 [(M+H)+; calcd for: C9H11ClF3N5O: 298.1].
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:15]=[C:14]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:28])[CH:12]=2)[CH:7]=1)C.O.[OH-].[Li+]>O1CCCC1.O>[F:28][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH2:5][C:4]([OH:29])=[O:3])[CH:15]=[C:14]2[C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(C)(=O)=O)cc2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(=O)c2cc(CC(=O)O)cc3ccc(F)cc23)cc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a solution of [6-fluoro-4-(4-methanesulfonyl-benzoyl)-naphthalen-2-yl]-acetic acid ethyl ester (0.63 g, 1.52 mmol) in tetrahydrofuran (6 mL) and water (6 mL) was added lithium hydroxide monohydrate (0.83 g, 1.98 mmol). The reaction mixture was heated at reflux for 3 hours. After cooling to room temperature, more water was added, and tetrahydrofuran was removed under reduced pressure. The pH was adjusted to 2 with ca. 2 mL of 4 N hydrochloric acid. The resulting light tan solid was collected by filtration to give pure [6-fluoro-4-(4-methanesulfonyl-benzoyl)-naphthalen-2-yl]-acetic acid (0.53 g, 90%).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[Cu](C#N)[C:13]#[N:14].C(OC(C)C)(=O)C>C(#N)CC.[Cl-].[Na+].O>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:13]#[N:14])=[N:3][CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCC#N
Solvent: O
Solvent: CC(=O)OC(C)C
Product: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
The compound of Step 1 (1 eq) was suspended in propionitrile (3 vol). Copper cyanide (1.1 eq) was added and the mixture was heated to 90° C. and aged for about 17 h. The reaction mixture was cooled to room temperature and isopropyl acetate (12 vol) and saturated brine (8 vol) were added. The mixture was stirred for 15 min and the layers were cut. The top organic layer was washed with brine (4×6 vol). The batch concentrated under reduced pressure to yield the desired product.
Reaction SMILES: [CH2:1]([O:4][C@H:5]([C@H:12]([CH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([N:27]2[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[CH3:33])[N:21]=1)[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:6](OC(C)C)=[O:7])[CH:2]=[CH2:3].CC(C[Al]CC(C)C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C@@H:5]([CH:6]=[O:7])[C@H:12]([CH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([N:27]2[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[CH3:33])[N:21]=1)[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H](C(=O)OC(C)C)[C@H](Cc1cc(C)cc(-n2c(C)ccc2C)n1)C(=O)OC(C)C
Agent: CC(C)C[Al]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C=CCO[C@@H](C=O)[C@H](Cc1cc(C)cc(-n2c(C)ccc2C)n1)C(=O)OC(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
To a solution of diisopropyl ester 10 (140 mg, 0.31 mmol) in toluene (5 mL) at −78° C. was added dropwise a solution of Dibal-H (1.0 M in toluene, 620 μL, 0.62 mmol) along the side of the flask over a period of 15 min. The reaction was maintained at −78° C. during the addition and allowed to react at the same temperature for 7 h. To the resulting solution at −78° C., MeOH (100 μL) was added dropwise along the side of the flask to quench the reaction. The reaction mixture was warmed to −20° C. and poured directly onto a vigorously stirring Rochelle's solution (potassium sodium tartrate solution, 5 mL). The viscous solution was allowed to stir for an additional 30 min then settled down to two clear phases. The organic layer was separated, and the aqueous layer was extracted with ether (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (EtOAc/hexanes, 1:9-1:4) to give 16 (75 mg, 0.19 mmol, 62%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 1.11-1.13 (d, J=6.0, 3H), 1.16-1.18 (d, J=6.5, 3H), 2.11 (s, 6H), 2.40 (s, 3H), 3.01-3.04 (dd, J=6.5, 14.5 Hz, 1H), 3.28-3.33 (dd, J=8.0, 15.0 Hz, 1H), 3.60-3.73 (ddd, J=4.0, 7.0, 11.5 Hz, 1H), 3.85-3.86 (dd, J=1.0, 4.5 Hz, 1H), 4.03-4.06 (dd, J=6.0, 13.0 Hz, 1H), 4.21-4.25 (dd, J=6.0, 12.5 Hz, 1H), 4.96-4.98 (m, 1H), 5.19-5.22 (dd, J=1.5, 10.5 Hz, 1H), 5.24-5.28 (dd, J=2.0, 17.5 Hz, 1H), 5.86-5.91 (m, 3H), 6.88 (s, 1H), 7.03 (s, 1H), 9.75-9.77 (d, J=1.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 13.5, 21.2, 22.0, 35.4, 46.8, 69.1, 72.7, 83.1, 106.9, 107.0, 118.6, 120.7, 123.7, 128.7, 133.9, 149.9, 151.9, 158.5, 171.0, 202.5; LCQ-MS (M+H+) calcd for C23H31N2O4 399. found 399; LC-TOF-MS (M+H+) calcd for C23H31N2O4 399.22838. found 399.22859.
Reaction SMILES: [C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:38][N:10]3[C:11](=[O:37])[C@@H:12]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26](O)=[O:27])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:62]1([S:65]([NH2:68])(=[O:67])=[O:66])[CH2:64][CH2:63]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[C:1]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:38][N:10]3[C:11](=[O:37])[C@@H:12]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26](=[O:27])[NH:68][S:65]([CH:62]4[CH2:64][CH2:63]4)(=[O:67])=[O:66])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:3][CH:2]=1
Reactant: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Reactant: NS(=O)(=O)C1CC1
Agent: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-(butylthio)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (15 mg, 0.022 mmol) and CDI (7.05 mg, 0.043 mmol) in tetrahydrofuran (1 mL) was heated to gentle reflux for 3 h. Cooled down to rt, cyclopropanesulfonamide (5.27 mg, 0.043 mmol) and DBU (9.83 μL, 0.065 mmol) were added and the reaction continued at r.t. overnight. Removed the solvent in vacuo. The residue was purified by prep-HPLC to afford the desired product tert-butyl (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-2-(butylthio)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (11 mg, 0.014 mmol, 63.8% yield) as a white solid. 1H NMR (500 MHz, MeOD) δ ppm 0.84 (t, J=7.32 Hz, 3 H) 1.00-1.06 (m, 1 H) 1.09-1.17 (m, 2 H) 1.27-1.38 (m,5 H) 1.38-1.47 (m, 5 H) 1.46-1.63 (m, 14 H) 1.70 (dd, J=8.09, 5.34 Hz, 1 H) 1.86-2.00 (m, 2 H)2.24-2.33 (m, 1 H) 2.39-2.48 (m, 2 H) 2.50-2.58 (m, 1 H) 2.63 (s, 1 H) 2.88-2.97 (m, 2 H) 3.98-4.07 (m,2 H) 4.46 (d, J=9.46 Hz, 1 H) 5.08 (t, J=9.31 Hz, 1 H) 5.28 (d, J=10.38 Hz, 1 H) 5.65-5.75 (m, 1 H) 7.36 (t, J=7.48 Hz, 1 H) 7.46 (t, J=7.63 Hz, 2 H) 7.59 (d, J=8.55 Hz, 4 H) 7.79 (t, J=9.00 Hz, 2 H). LC-MS (retention time: 3.48 min, method C), MS m/z 793(M+H).