Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Br[CH2:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12]>C(Cl)Cl>[OH:5][CH2:4][CH2:3][N:2]([CH2:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])[CH3:1]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CNCCO
Solvent: ClCCl
Product: CN(CCO)Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To a solution of 2-(methylamino)ethanol (4 mL, 51 mmol) and TEA (4 mL, 28.05 mmol) in DCM (75 mL) under N2, was added 3-(bromomethyl)benzonitrile (5 g, 25.50 mmol) at 0° C. and the mixture was stirred at RT for 30 min. After this time, reaction mixture was concentrated under reduced pressure and the remaining residue was dissolved in DCM and washed with water to give the title compound as a colorless liquid (4.9 g, 100%). 1H NMR (DMSO-d6, 400 MHz) δ 7.76 (s, 1H), 7.69-7.71 (m, 2H), 7.63-7.65 (m, 1H), 7.49-7.53 (m, 1H), 4.41-4.43 (m, 1H), 3.47-3.51 (m, 2H), 3.32 (m, 2H), 2.40-2.43 (m, 2H), 2.13 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:33]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:34])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(Cl)C1CCCCC1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)C5CCCCC5)c4)CC3)cccc2n1
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and cyclohexanecarbonyl chloride.
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][C:8]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])([CH2:12][OH:13])[CH:9]([F:11])[F:10])(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[Cl:29][CH:30](C)[C:31](Cl)=O>Cl.O1CCOCC1.ClCCl>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([F:21])=[C:14]([C:8]([NH:7][C:6](=[O:22])[CH:30]([Cl:29])[CH3:31])([CH2:12][OH:13])[CH:9]([F:10])[F:11])[CH:19]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)(c1cc(Br)ccc1F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(Cl)C(=O)NC(CO)(c1cc(Br)ccc1F)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[1-(5-Bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester [Example 42 step c)](2.21 g, 5.75 mmol) was dissolved in 20 mL HCl solution 4 mol/L in dioxane and stirred at room temperature for 60 minutes. The reaction mixture was evaporated to give a white solid which was directly taken up in 15 mL dichloromethane. 20 mL aqueous Na2CO3 solution (10% w/w) was added and the emulsion was cooled to 0-5° C. Racemic 2-chloro-propionyl chloride (787 mg, 6.20 mmol) was added dropwise and the reaction mixture was slowly warmed to room temperature. After 30 minutes, the layers were separated and washed with dichloromethane. The organic layers were combined, dried over Na2SO4 and evaporated. The crude product was purified on a silica gel column by eluting with heptanes/EtOAc 3/1->2/1 to give 632 mg of the first eluting and 619 mg of the second eluting diastereomer.
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)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:30][CH2:29][CH2:28][CH:25]2[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: CC1CCC(CCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC2CCC(C)CC2)ccc1Oc1ccc(C(N)=O)cn1
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.100 g, 0.367 mmol), 2-(4-methylcyclohexyl)ethylamine (0.0571 g, 0.404 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give 6-(2-methoxy-4-{[2-(4-methylcyclohexyl)ethylamino]methyl}phenoxy)nicotinamide (0.0958 g, 65.6%). Dissolve the compound in dichloromethane (2.5 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to afford the title compound: TOF MS ES+ 398.2 (M+H)+, HRMS calcd for C23H32N3O3 398.2444 (M+H)+, found 398.2440, time 0.52 min; Anal. Calcd for C23H31N3O3.0.5H2O: C, 57.35; H, 7.22; N, 8.36. Found: C, 57.33; H, 6.94; N, 8.34.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16]C2C=CC=CC=2)[C@@H:13]([O:23][CH2:24]C2C=CC=CC=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)(OC)[O:11][C:10]1([CH2:55][OH:56])[CH2:53][OH:54])C1C=CC=CC=1.F[C:58](F)(F)[C:59](O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:13]([O:23][CH2:24][C:59]2[CH:58]=[CH:14][CH:9]=[CH:10][CH:53]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]([F:50])([F:52])[F:51])=[CH:45][CH:46]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:55][OH:56])[CH2:53][O:54]2)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reaction time: 1 h

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 7k (100 mg, 0.13 mmol) was dissolved in 10 mL dichloromethane, followed by addition of 0.1 mL trifluoroacetic acid. The reaction mixture was stirred for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 7m (22 mg, white solid), yield: 22.9%. MS m/z (ESI): 778.3 [M+18].
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1>>[NH:25]1[C:21]([C:17]2[CH:16]=[C:15]([NH:14][S:10]([C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[CH:3]=3)(=[O:12])=[O:11])[CH:20]=[CH:19][CH:18]=2)=[N:22][N:23]=[N:24]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cc2ccccc2s1
Yield: 60 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 1-benzothiophene-2-sulfonyl chloride (12.8 mg, 0.055 mmol) and 5-(3-amino-phenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 60% yield (10.8 mg). MS (ESI+) calcd mass for C15H11N5O2S2 357.035416, found 357.036256.
Reaction SMILES: [C:1](O)(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+:14].CC(O[CH2:19][C:20]1[CH2:37][S:36][C@@H:23]2[C@H:24]([NH:27][C:28]([CH2:30][C:31]3[S:35][CH:34]=[CH:33][CH:32]=3)=[O:29])[C:25](=[O:26])[N:22]2[C:21]=1[C:38]([OH:40])=[O:39])=O.[H-].[Na+]>O>[Na+:14].[S:35]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:30][C:28]([NH:27][CH:24]1[C:25](=[O:26])[N:22]2[C:21]([C:38]([O-:40])=[O:39])=[C:20]([CH2:19][C:1](=[S:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:37][S:36][C@H:23]12)=[O:29]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: OC(=S)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)[O-])=C(CC(=S)c3ccccc3)CS[C@H]12
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Thiobenzoic acid (1.41 g, 10.2 mmol) and sodium bicarbonate (0.857 g, 10.2 mmol) were stirred in 30 ml of H2O and heated to 50° C. The mixture was filtered through silica gel, and the filtrate was added to cephalothin (1.43 g, 3.4 mmol) in 20 ml of H2O. The reaction mixture was stirred for 20 hours at 50° C. 7-Thiophenylacetamido-3-thiobenzoylmethyl-3-cephem-4-carboxylic acid (0.791 g) was collected by filtration. 50 mg of this material was dissolved in DMF (2 ml). Sodium hydride (4.4 mg. 0.11 mmol) was added, and the mixture was stirred for two hours, filtered, and dried under vacuum. The residue was dissolved in water, refiltered and lyophilized to yield pure 7-thiophenylacetamido-3-thiobenzoylmethyl-3-cephem-4-carboxylate sodium salt.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[C:3](O)=[O:4].C([O:24][N:25]1C2C(=CC=CC=2)[C@H](C)[C@H](NC(=O)OC(C)(C)C)C1=O)C1C=CC=CC=1.C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>B(Cl)(Cl)Cl>[NH2:1][CH:2]1[CH2:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[N:25]([OH:24])[C:3]1=[O:4]
Reactant: NC(Cc1cccc2ccccc12)C(=O)O
Reactant: C[C@H]1c2ccccc2N(OCc2ccccc2)C(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: NC1Cc2c(ccc3ccccc23)N(O)C1=O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 10 %

Procedure:
Benzyl[4-(benzyloxy)-3-oxo-1,2,3,4-tetrahydrobenzo[t]quinolin-2-yl]carbamate (54, prepared from 2-amino-3-(1-naphthyl)propanoic acid according to the general procedure for synthesis of tert-butyl (3S,4S)-1-(benzyloxy)-4-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (33) in Example 7) (35 mg, 0.077 mmol) was dissolved in a solution of boron trichloride in DCM (1.0 M, 5.00 mL, 5.00 mmol), and the reaction was heated at 50° C. for 1 h. After being quenched with MeOH (10 mL), the reaction was stirred for 15 min, then treated with silica gel impregnated with p-toluenesulfonic acid (0.68 mEq/g, 2 g, 1.36 mmol). After 1.5 hours, the silica was filtered off and rinsed with MeOH; the silica was then slurried with a 2N solution of ammonia in MeOH for 20 minutes, and filtered. The solids were rinsed with MeOH and the combined filtrates were concentrated in vacuo to afford a solid, which was triturated with Et2O to provide the product as a solid (2 mg, 10%). LCMS m/z 229.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.07 (dd, J=15, 15 Hz, 1H), 3.82 (dd, J=16, 6.5 Hz, 1H), 4.00 (dd, J=14, 6 Hz, 1H), 7.45 (dd, J=7, 7 Hz, 1H), 7.58 (dd, J=8, 8 Hz, 1H), 7.67 (d, J=9 Hz, 1H), 7.88 (m, 2H), 8.01 (d, J=9 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12](=[O:27])[C@H:13]([CH:24]([CH3:26])[CH3:25])[NH:14][C:15]([O:17]C1C=CC=CC=1)=O.N#N>O1CCOCC1>[CH3:10][O:11][C:12](=[O:27])[C@@H:13]([NH:14][C:15]([N:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:17])[CH:24]([CH3:25])[CH3:26]
Reactant: COC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Reactant: CNCc1ccccn1
Agent: N#N
Solvent: C1COCCO1
Product: COC(=O)[C@@H](NC(=O)N(C)Cc1ccccn1)C(C)C
Yield: 92.5 %

Procedure:
A solution of 2.68 g (22.0 mmol) of 2-(methylaminomethyl)-pyridine, from step 3a above, and 5.02g (20.0 mmol) of phenoxycarbonyl-L-valine methyl ester, from step 3b above, in 20 mL of 1,4-dioxane was purged with N2. The solution was then heated at reflux for four hours under a N2 atmosphere, then the solution was concentrated in vacuo. The resulting residue was dissolved in ethyl ether and extracted into 1N HCl. The aqueous layer was adjusted to about pH 9 with solid sodium carbonate and extracted twice with methylene chloride. The organic layers were combined and washed with 0.2M phosphate buffer at pH 7.0. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo, affording 5.17 g of the title product as a light yellow oil. NMR (CDCl3)δ0.95 (dd,3H), 2.19 (m, 1H), 3.03 (s,3H), 3.72 (s,3H), 4.42 (dd, 1H), 4.54 (s,2 H), 6.14 (bs,1H), 7.26 (m,2H), 7.70 (dt,1H), 8.56 (m, 1H) .
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[C:9]([F:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][CH3:14])[C:5]=1[F:15].[OH-].[Na+]>C(O)C>[F:10][C:9]1[C:8]([O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([F:15])[C:4]=1[C:3]([OH:16])=[O:2]
Reactant: COC(=O)c1c(F)c(OC)cc(OC)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(F)c(C(=O)O)c1F
Yield: 82.2 %

Procedure:
A suspension of 115 g (0.49 mol) of 2,6-difluoro-3,5-dimethoxy benzoic acid methyl ester and 42.9 g (1.07 mol) of solid sodium hydroxide in 1.4 L of anhydrous ethanol was refluxed for 24 hours. The ethanol was concentrated in vacuo and the solid residue was dissolved in water and extracted two times with ethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and a white precipitate was filtered, washed with cold water and dried in vacuo to give 87.9 g (81%) of the title compound. MS (APCI) (m+1)/z 219.1.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH3:12])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:13]([NH:16][NH2:17])([NH2:15])=[S:14].O>C(O)(=O)C>[OH:1][N:2]=[C:3]([CH3:12])[C:4](=[N:17][NH:16][C:13]([NH2:15])=[S:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=NO)C(=O)c1ccccc1
Reactant: NNC(N)=S
Solvent: CC(=O)O
Solvent: O
Product: CC(=NO)C(=NNC(N)=S)c1ccccc1
Temperature: 60 °C
Yield: 86.6 %

Procedure:
A mixture of 2-hydroxyiminopropiophenone (150 g) and thiosemicarbazine (90 g) in acetic acid (500 ml) was heated at 60° C. for 60 hours with stirring. After cooling, water was added to the reaction mixture. The resultant precipitates were collected by filtration, washed successively with water, methanol and diisopropyl ether, and dried to give 2-hydroxyiminopropiophenone thiosemicarbazone (188.2 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].[Br:13]N1C(=O)CCC1=O>S(=O)(=O)(O)O.O>[Br:13][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1ccc(CC(=O)O)c(Br)c1
Reaction time: 18 h
Yield: 70.5 %

Procedure:
A solution of 4-cyanophenylacetic acid (1.6 g, 9.93 mmol) in 50% aqueous sulfuric acid (10 mL) was treated with N-bromosuccinimide (1.8 g, 10.11 mmol). The mixture was stirred in the dark for 18 h then diluted with water and extracted with diethyl ether to give 2-bromo-4-cyanophenylacetic acid (2.1 g, 7.00 mmol, 70.5% yield) as a white solid containing about 25% of starting material.
Reaction SMILES: [CH3:1][C:2](=[CH:4][C@H:5]([OH:10])[C@H:6]([OH:9])[CH2:7][CH3:8])[CH3:3].[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1.COC(OC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:12][C:11]1([CH3:16])[O:10][C@@H:5]([CH2:4][CH:2]([CH3:3])[CH3:1])[C@@H:6]([CH:7]=[CH2:8])[O:9]1
Reactant: CC[C@@H](O)[C@@H](O)C=C(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)OC
Solvent: ClCCl
Product: C=C[C@H]1OC(C)(C)O[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the crude alcohol resulting from Example 9A dissolved in dichloromethane was added p-toluenesulfonic acid (500 mg) and 2,2-dimethoxypropane. The reaction was stirred at ambient temperature for 24 hours and poured into saturated sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate and concentrated by distillation to give the title compound. 1H NMR (CDCl3, 300 MHz) δ0.92 (d, J=6 Hz, 3H), 0.96 (d, J-6 Hz, 3H), 1.17 (ddd, J=4.5, 9.0, 15 Hz, 1H), 1.38 (s, 3H), 1.48 (s, 3H), 1.75 (m, 1H), 4.24 (ddd, J=3, 6, 9 Hz, 1H), 4.48 (m, 1H), 5.22 (ddd, J=1, 2, 9 Hz, 1H), 5.27 (ddd, J=1, 2, 17 Hz, 1H), 5.81 (ddd, J=7.5, 9, 17 Hz, 1H).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:18][C@@H:7]2[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@@H:6]2[CH2:5]1>CO>[OH:3][CH:4]1[CH2:18][C@@H:7]2[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:10][C@@H:6]2[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(=O)C[C@H]2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H]2CC(O)C[C@H]2C1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Sodium borohydride (0.15 g, 4.00 mmol), was added to a solution of 1,1-dimethylethyl (3aR,6aS)-5-oxo-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.45 g, 2.00 mmol) in 10 mL methanol at 0° C. and the reaction mixture was stirred for 1 h at this temperature. The solvent was evaporated, the crude mixture was diluted with 100 mL ethyl acetate and washed with water (30 mL), 1M aqueous hydrochloric acid and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 1,1-dimethylethyl (3aR,6aS)-5-(hydroxy)-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.44 g, 98%). 1H NMR (400 MHz, d6-DMSO): 4.08 (m, 1H), 3.40 (m, 2H), 3.30 (m, 2H), 2.50 (m, 2H), 1.98 (m, 2H), 1.40 (s, 9H), 1.30 (m, 2H). MS (EI) for C12H21NO3: 228 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH:23]=2)=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:44]1[CH:49]=[CH:48][C:47]([S:50]([CH:53]([CH3:55])[CH3:54])(=[O:52])=[O:51])=[CH:46][N:45]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[CH:23]=2)=[CH:20][C:19]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([CH:53]([CH3:55])[CH3:54])(=[O:51])=[O:52])=[CH:46][N:45]=2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(-c2cc(-c3cc(B4OC(C)(C)C(C)(C)O4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)cc1
Reactant: CC(C)S(=O)(=O)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A mixture of tert-butyl N-tert-butoxycarbonyl-N-[3-[3-(p-tolyl)isoxazol-5-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]carbamate (426 mg, 0.7377 mmol) and 2-bromo-5-isopropylsulfonyl-pyridine (233.8 mg, 0.8852 mmol) in DMF (10 mL) was degassed and placed under an atmosphere of nitrogen. Pd(PPh3)2Cl2 (30.51 mg, 0.07377 mmol) was added and the reaction again degassed. 2M aqueous Na2CO3 (1.106 mL, 2.213 mmol) was added and the reaction was stirred at 95° C. for 2 hours. The reaction mixture was partitioned between EtOAc and brine and the aqueous layer extracted with EtOAc (×3). The combined organic extracts were washed with water (×3) and brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, eluting with 0 to 50% EtOAc/Petroleum Ether, loaded in DCM) to give the sub-title product as a yellow solid (344 mg, 74% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.24 (d, J=6.8 Hz, 6H), 1.29 (s, 18H), 2.40 (s, 3H), 3.64 (sept, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.63 (s, 1H), 7.83 (d, J=8.1 Hz, 2H), 8.47 (dd, 1H), 8.58 (d, 1H), 9.12 (d, J=2.2 Hz, 1H), 9.17 (d, 1H) and 9.42 (d, J=2.2 Hz, 1H) ppm; MS (ES+) 635.2.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:46])[C:14]([CH3:45])([CH3:44])[CH2:15][NH:16][C:17]([C:19]1[C:20]([OH:43])=[C:21]2[C:26](=[CH:27][N:28]=1)[N:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24](=[O:36])[C:23]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[CH:22]2)=[O:18])(C)(C)C>C(Cl)Cl>[CH2:29]([N:25]1[C:26]2[C:21](=[C:20]([OH:43])[C:19]([C:17]([NH:16][CH2:15][C:14]([CH3:45])([CH3:44])[C:13]([OH:46])=[O:12])=[O:18])=[N:28][CH:27]=2)[CH:22]=[C:23]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:24]1=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O)C(=O)O
Reaction time: 2 h
Yield: 59.6 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a mixture of 3-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-2,2-dimethyl-propionic acid tert-butyl ester (22 mg, 0.042 mmol) and CH2Cl2 (3 mL), and the resulting mixture was stirred for 2 h. Solvent was evaporated in vacuo, and the residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 11.8 mg of the title compound as a light yellow solid. MS: (+) m/z 472.34 (M+1).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].[OH-:15].[Na+].II>O.C(O)C>[O:15]=[C:4]([N:6]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])[CH2:3][CH2:2][S:1][S:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=C1C[C@@H](C(=O)O)N(C(=O)CCS)C1
Reactant: [OH-]
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1C[C@@H](C(=O)O)N(C(=O)CCSSCCC(=O)N2CC(=O)C[C@H]2C(=O)O)C1

Procedure:
The product from Example 2 is dissolved in water and the pH adjusted to 6.5 by the addition of 1 N sodium hydroxide. To this stirred solution is added dropwise a 0.5 M iodine solution in 95% ethanol (6.34 g. iodine/50 ml. solution) while maintaining the pH at 5.5 to 6.5 with 1 N sodium hydroxide. Excess iodine is removed with dilute sodium thiosulfate and the solution is concentrated, cooled and acidified with 1:1 hydrochloric acid. Solvent is added and the layers are separated. The organic layer is dried MgSO4) and the solvent evaporated to yield as a residue 1,1'-[dithiobis(1-oxo-3,1-propanediyl)]bis[4-oxo-L-proline].