Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:55])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:54])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C@@H:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=4[Cl:53])[CH3:46])=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:57])[CH3:56])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[Cl:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C@H:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]12[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]1[C@@H:25]1[C@@:20]([CH3:54])([CH2:21][CH2:22]2)[C@@:19]2([CH3:55])[C@@H:28]([C@:29]3([CH3:32])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:56])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:58])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[CH3:46]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2ccccc2Cl)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2ccccc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((R)-1-(2-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (200 mg, 0.101 mmol) in dichloromethane (6 mL) stirred at room temp was added TFA (3 ml, 38.9 mmol). The reaction mixture was stirred at 25° C. for 2 h. The product was extracted with DCM (20 mL*2) and the combined organic phase was washed with H2O (20 mL*2) and brine (30 mL), dried. Then, the solvent was removed under reduced pressure. The residue was purified by preparative-HPLC to give the title compound (70 mg, 0.092 mmol, 91%) was collected as white solid. 1H NMR (400 MHz, METHANOL-d4) δ=8.69 (d, J=7.3 Hz, 1H), 7.50-7.17 (m, 4H), 6.83 (d, J=16.1 Hz, 1H), 6.03 (d, J=15.8 Hz, 1H), 5.52-5.35 (m, 1H), 4.50 (dd, J=5.1, 11.2 Hz, 1H), 3.32-3.26 (m, 1H), 3.00-2.80 (m, 1H), 2.73-2.49 (m, 2H), 2.35-0.77 (m, 50H); LC/MS: m/z calculated 761.4. Found 762.3 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17]CC2C=CC=CC=2C)[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])[CH3:5]>C1COCC1.C(O)C.[Pd]>[OH:17][C:15]1[CH:14]=[C:9]([CH:8]=[C:7]([O:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2C)cc(C(=O)OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Yield: 100.5 %

Procedure:
Methyl 3-{(1S)-2-methoxy-(1-methylethyl)oxy}-5-{[(2-methylphenyl)methyl]oxy}benzoate (50 g, 0.152 mol) was dissolved in THF/ethanol (1:1, 600 ml) and 10% Palladium on carbon (5.0 g) was added. The mixture was hydrogenated under normal pressure at room temperature. The catalyst was filtered off, and the filtrate concentrated in vacuo to give the desired compound (36.7 g, 99%).
Reaction SMILES: [C:1]([CH2:5][C:6]([OH:8])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:52][CH2:53][C:54]1[O:58][C:57]([C:59]2[CH:64]=[CH:63][C:62]([C:65]3[C:70]([CH3:71])=[CH:69][CH:68]=[C:67]([C:72]([NH:74][CH:75]4[CH2:77][CH2:76]4)=[O:73])[CH:66]=3)=[CH:61][CH:60]=2)=[N:56][N:55]=1>CN(C=O)C>[CH:75]1([NH:74][C:72]([C:67]2[CH:66]=[C:65]([C:62]3[CH:63]=[CH:64][C:59]([C:57]4[O:58][C:54]([CH2:53][NH:52][C:6](=[O:8])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:55][N:56]=4)=[CH:60][CH:61]=3)[C:70]([CH3:71])=[CH:69][CH:68]=2)=[O:73])[CH2:77][CH2:76]1
Reactant: CC(C)(C)CC(=O)O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC(=O)CC(C)(C)C)o2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
t-Butylacetic acid (10 mg) and HATU (33 mg) in DMF (1 ml) were stirred for 10 minutes at room temperature. To this solution was added HOBt (11.6 mg), DIPEA (0.45 ml) and 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) in DMF (3 ml) and the reaction stirred at room temperature for 72 hours. The solvent was evaporated under vacuum and the residue dissolved in DCM and washed with water (2×5 ml). The organic phase was reduced to dryness and the residue purified by bond-elut (silica, 5 g) eluting with an ethyl acetate/cyclohexane gradient and then by preparative HPLC to give, after evaporation of the solvents, N-cyclopropyl-4′-(5-{[(3,3-dimethylbutanoyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(OCC)=O)C.[H-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:22][CH:23]=[C:24]([CH:32]=O)[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:17][CH:16]=1.O>O1CCCC1>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[NH:22][CH:23]=[C:24]([CH:32]=[CH:9][C:10]#[N:11])[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:19][CH:20]=1
Reactant: O=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.7 %

Procedure:
2.92 ml (18.02 mmol) of diethylphosphonoacetonitrile were added to 16 ml of tetrahydrofuran and the resulting solution was added to a suspension of 786 mg (18.02 mmol) of 55% sodium hydride in 60 ml of tetrahydrofuran with ice-cooling, and the resulting mixture was then stirred at room temperature for 1.5 hours. At the end of this time, a suspension of 4.00 g (15.02 mmol) of 2-(4-fluorophenyl)-4-formyl-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in step (iii) above] in 30 ml of tetrahydrofuran was added to this mixture and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to afford a solid which was washed with diethyl ether to give 2.94 g (yield 68%) of the title compound as a pale brown powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[C:13]([S@@:17](/[N:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36]([NH2:38])=[O:37])=[CH:35][C:30]=2[O:29][N:28]=1)=[O:18])([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+]>O1CCCC1>[CH3:15][C:13]([CH3:16])([S@@:17]([NH:19][C@H:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36]([NH2:38])=[O:37])=[CH:35][C:30]=2[O:29][N:28]=1)[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:18])[CH3:14]
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccccc1-c1noc2cc(C(N)=O)ccc12
Reactant: Cc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(C(N)=O)ccc12
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 48.7 %

Procedure:
To a solution of 2-picoline (22.6 mL, 21.3 g) in tetrahydrofuran (280 mL) cooled under nitrogen to −72° C. was added a 2.5M in hexanes solution of n-butyl lithium (98 mL) dropwise over 40 min keeping the internal temperature less than −70° C. The mixture was stirred at this temp for 45 min then a solution of 3-(2-((E)-((S)-tert-butylsulfinylimino)methyl)phenyl)benzo[d]isoxazole-6-carboxamide (Compound 10) (28.2 g) in tetrahydrofuran (280 mL) was added dropwise over 45 min (the internal temperature less than −70° C.) then stirred at this temp for 30 min. Reaction mixture allowed to warm to −30° C. and saturated aqueous ammonium chloride (500 mL) added. The layers were separated and aqueous layer washed with ether (3×300 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and the solvents removed. Flash chromatography on silica eluting with ethyl acetate then 1 to 5% methanol in ethyl acetate gave three fractions of product that were crystallised from the minimum of ethyl acetate to give the title product (17.2 g).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]([NH:41][NH:42][C:43](=O)[CH2:44][CH:45]1[CH2:48][N:47]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46]1)=[O:40])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[O:40][C:43]([CH2:44][CH:45]2[CH2:48][N:47]([C:49]([O:51][C:52]([CH3:55])([CH3:53])[CH3:54])=[O:50])[CH2:46]2)=[N:42][N:41]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Cc2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)C1
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
To s solution of PPh3 (2.2 g, 8.2 mmol) in dry DCM (60 mL) was added I2 (2.1 g, 8.2 mmol). After I2 was dissolved completely, TEA (1.7 g, 16.4 mmol) was added quickly at rt. The mixture was stirred for 15 mins. Tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)azetidine-1-carboxylate (2.0 g, 4.1 mmol) was added. The mixture was stirred at rt for 1 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (gradient elution 0-40% EtOAc/petroleum ether) to afford tert-butyl 3-((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)azetidine-1-carboxylate (1.3 g, 66%) as a white solid. ESI-MS (Er, m/z): 470 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH:12]([CH2:17][NH:18][C:19]([N:21]=[N+]=[N-])=[O:20])[N:11]3[CH:24]=2)[CH:5]=[CH:6][CH:7]=1.[OH-:25].[Na+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH:12]([CH2:17][NH:18][C:19]([NH:21][CH2:17][CH:12]4[N:11]5[CH:24]=[C:8]([C:4]6[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=6)[CH:9]=[C:10]5[C:15](=[O:25])[NH:14][CH2:13]4)=[O:20])[N:11]3[CH:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC(=O)NCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21)NCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Step b 71 mg (0.206 mmol) of {[7-(3-chlorophenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]methyl}carbamic azide were dissolved in 10 ml of dry THF, NaOH 1N (2 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction was diluted with EtOAc and extracted with water, the organic layer was mixed with HCl 2N (5 ml) for 10 minutes, and then discarded; the aqueous solution was brought to pH 10 with NaOH 23% (10 ml) and portioned between EtOAc (10 ml) and THF (10 ml). The organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give the title compound 50 mg (89%) as a light yellow solid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([C:8]#[N:9])[CH2:2]1.I[CH2:11][CH2:12][CH2:13][CH3:14]>C(#N)C>[CH2:11]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([C:8]#[N:9])[CH2:2]1)[CH2:12][CH2:13][CH3:14]
Reactant: N#CC1CCCCNC1
Reactant: CCCCI
Solvent: CC#N
Product: CCCCN1CCCCC(C#N)C1

Procedure:
To 50 mL of acetonitrile is added 1 g (8.0 mmol) of hexahydro-1H-azepine-3-carbonitrile and 2.7 g (15 mmol) of iodobutane. Heat the reaction under reflux and monitor the reaction by thin-layer chromatography. Upon completion remove the solvent in vacuo and add 50 mL sat. sodium bicarbonate and 50 mL methylene chloride. Separate the organic layer and dry over Na2SO4. Filter off the drying agent and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[I:9]N1C(=O)CCC1=O.O>CS(C)=O>[I:9][C:7]1[C:2]([NH2:1])=[N:3][C:4]([NH2:8])=[CH:5][CH:6]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(I)c(N)n1
Temperature: 25 °C
Yield: 23 %

Procedure:
2,6-Diaminopyridine (100 g) was dissolved in DMSO (400 mL), and N-iodosuccinimide (100 g) was added thereto all at once under stirring at room temperature. The reaction solution was stirred for 10 minutes at room temperature, after which water (3.5 L) was added thereto and the precipitated solids were filtered off. The aqueous layer thus obtained was extracted with ethyl acetate (1.3 L) 3 times. The ethyl acetate layers were combined, and which was concentrated under a reduced pressure, and the residue thus obtained was purified by silica gel chromatography (heptane:ethyl acetate=2:3) to obtain the titled compound (24 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH:15]=1.[Cl:17][C:18]1[CH:31]=[CH:30][C:21]2[S:22][C:23]([S:26](Cl)(=[O:28])=[O:27])=[C:24]([CH3:25])[C:20]=2[CH:19]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:26]([C:23]2[S:22][C:21]3[CH:30]=[CH:31][C:18]([Cl:17])=[CH:19][C:20]=3[C:24]=2[CH3:25])(=[O:28])=[O:27])=[CH:5][C:4]=1[C:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH:11]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COc1ccc(N)cc1C1=CCN(C)CC1
Product: COc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1C1=CCN(C)CC1

Procedure:
The title compound (E130) was prepared from 4-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenylamine (free base of D39) (100 mg, 0.46 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (129 mg, 0.46 mmol) using the method of Example 1 (177 mg, 77%). MH+=463/465.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([C:15]([O:17][CH3:18])=[O:16])[C:9]([CH3:19])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCOCC1.O>[CH3:18][O:17][C:15]([C:10]1[C:9]([CH3:19])=[CH:8][C:3]([C:4]([OH:6])=[O:5])=[C:2]([CH3:1])[C:11]=1[N+:12]([O-:14])=[O:13])=[O:16]
Reactant: COC(=O)c1cc(C)c(C(=O)OC)c([N+](=O)[O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c(C)cc(C(=O)O)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
Dimethyl 2,5-dimethyl-3-nitroterephthalate (2.27 g, 8.50 mmol) was dissolved in 1,4-dioxane (20 mL) and was cooled in an ice bath. 1N Sodium hydroxide (8.5 mL) was added dropwise, and the mixture was stirred at ambient temperature for 2.25 h. Additional 1N sodium hydroxide (0.5 mL) was added drop-wise and the mixture was stirred at ambient temperature for a further 1 h at which point another 0.5 mL aliquot of 1N aqueous sodium hydroxide was added and stirring was continued for an additional 1 h. The reaction mixture was diluted with water and was washed with ether. The aqueous portion was acidified with 1N hydrochloric acid to pH ˜2 and then was extracted with ethyl acetate (2×). The combined ethyl acetate portion was dried over sodium sulfate, then filtered and concentrated to provide 4-(methoxycarbonyl)-2,5-dimethyl-3-nitrobenzoic acid (quantitative yield). 1H NMR (400 MHz, d6-DMSO): δ 13.8 (br s, 1H), 7.93 (d, 1H), 3.81 (s, 3H), 2.38 (s, 3H), 2.37 (s, 3H); MS (EI) for C11H11NO6: 252 (M−H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[I:25]I>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([I:25])=[CH:4][CH:3]=1
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
To a solution of N-(6-chloropyridin-2-yl)pivalamide (15.8 g, 74.2 mmol) in anhydrous THF (150 mL) at −78° C. under a nitrogen atmosphere, is added 1.7 M t-butyllithium in pentane (96 mL, 163 mmol, 2.2 eq.) dropwise (dropping funnel) over 0.5 h. The reaction mixture is then stirred at −78° C. for 3 h before iodine (22.6 g, 89 mmol, 1.2 eq.) in THF (60 mL) is slowly added in one portion. After 10 min., the cooling bath is removed and the reaction is allowed to warm to rt and stirred for 2 h. Hydrochloric acid (1 M, 75 mL) is then added to the reaction mixture. The reaction mixture is concentrated in vacuo (rotary evaporator) to remove the THF, the resulting mixture is extracted with ethyl acetate (800 mL). The phases are separated and the organic layer is washed with aqueous 1 M Na2S2O3 (100 mL), brine (300 mL×2), water (300 mL), dried over MgSO4, and evaporated. The crude product is recrystallized from DCM/hexanes (1:4) and the solid that forms collected by filtration to provide N-(6-chloro-3-iodopyridin-2-yl)pivalamide as a white crystalline solid (17.2 g). The filtrate is evaporated and the residue chromatographed on a silica gel column (hexanes/EtOAc, 9/1) to provide an additional product (2.5 g). Overall 19.7 g (78% yield) of N-(6-chloro-3-iodopyridin-2-yl)pivalamide is obtained. 1H NMR (300 MHz, DMSO-d6), δ 9.86 (s, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 1.23 (s, 9H). LCMS-ESI (m/z): calcd for C10H12Cl1N2O 337.9; [M+H]+ found 339.0.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:11][O:10][CH2:9][C@H:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:6]([CH3:28])[O:5][C:4]1=[O:29].[OH:30][C:31]1[C:32]([C:39](O)=[O:40])=[N:33][CH:34]=[CH:35][C:36]=1[O:37][CH3:38].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:13]([O:12][C@@H:8]1[C@@H:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:6]([CH3:28])[O:5][C:4](=[O:29])[C@H:3]([NH:2][C:39](=[O:40])[C:32]2[C:31]([OH:30])=[C:36]([O:37][CH3:38])[CH:35]=[CH:34][N:33]=2)[CH2:11][O:10][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H]1OC(=O)[C@H](N)COC[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: COc1ccnc(C(=O)O)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@@H]2COC[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](C)OC2=O)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
To a mixture of (3R,7S,8S,9R)-3-amino-7,8-bis(benzyloxy)-9-methyl-1,5-dioxonan-2-one hydrochloride (85.0 mg, 0.2015 mmol) and 3-hydroxy-4-methoxypicolinic acid (54.0 mg, 0.321 mmol) in DCM (1.20 mL) was added 4-methylmorpholine (0.141 mL, 1.29 mmol) followed by HATU (135.0 mg, 0.343 mmol) and the mixture was stirred at room temperature for 4 h. The reaction mixture was directly purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to yield the title compound as a colorless oil (65.4 mg, 61%): IR (neat) 3368, 2933, 1748, 1648, 1527, 1242, 1066 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.98 (s, 1H), 8.86 (d, J=8.0 Hz, 1H), 8.01 (d, J=5.2 Hz, 1H), 7.41-7.27 (m, 10H), 6.86 (d, J=5.2 Hz, 1H), 5.36 (qd, J=6.7, 3.1 Hz, 1H), 5.06 (ddd, J=8.0, 6.1, 1.9 Hz, 1H), 4.71 (d, J=11.4 Hz, 1H), 4.68 (d, J=11.8 Hz, 1H), 4.60 (d, J=11.3 Hz, 1H), 4.58 (d, J=11.8 Hz, 1H), 4.16 (dd, J=12.2, 3.6 Hz, 1H), 4.12 (dd, J=9.4, 2.2 Hz, 2H), 3.98 (dd, J=11.7, 6.1 Hz, 1H), 3.94 (s, 3H), 3.71 (dd, J=11.9, 1.7 Hz, 1H), 3.57-3.50 (m, 1H), 1.38 (d, J=6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.86, 169.07, 155.41, 148.82, 140.81, 138.27, 138.10, 130.51, 128.58, 128.54, 128.14, 128.05, 128.00, 127.85, 109.64, 78.70, 75.15, 74.37, 72.35, 71.55, 56.21, 53.37, 15.28; HRMS-ESI (m/z) [M]+ calcd for C29H32N2O8, 536.2159; found, 536.2162.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:15][CH2:16][C:17]#[CH:18])[C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5](Cl)=[O:6].O.[NH3:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:15][CH2:16][C:17]#[CH:18])[C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5]([NH2:20])=[O:6]
Reactant: C#CCOc1cc(C(=O)Cl)cc(Cl)c1OCC#C
Reactant: N
Solvent: O
Solvent: Cc1ccccc1
Product: C#CCOc1cc(C(N)=O)cc(Cl)c1OCC#C
Temperature: 0 °C

Procedure:
A solution of 3-choro-4,5-dipropargyloxybenzoyl chloride (1.00 g) in 30% ammonia water (20 ml) and toluene (10 ml) was stirred under reflux for 10 minutes, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a residue. The residue was further washed with hexane to give 3-chloro-4,5-dipropargyloxybenzamide (0.88 g). m.p. 122°-125° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([O:10][CH3:11])[CH:9]=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[CH3:11][O:10][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH2:1]
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1-c1ccccc1
Yield: 99 %

Procedure:
2.6 g of 10% by weight of palladium on charcoal is added to a solution of 11.2 g of the product obtained in Stage A in 150 ml of ethyl acetate. The suspension obtained is agitated under 1.3 atmospheres of hydrogen. After the absorption of hydrogen has stopped, the reaction medium is returned to normal atmospheric pressure, followed by filtration and evaporation under reduced pressure in order to obtain 9.64 g of sought product melting at 56° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18]2)=[N:5][CH:4]=1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Reactant: O=C(NC[C@@H]1CCCNC1)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC[C@@H](CNC(=O)OCc4ccccc4)C3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.250 g, 1.15 mmol) in 1:1 (MeOH/CHCl3) (25 mL) were added phenylmethyl [(3R)-3-piperidinyl-methyl]carbamate (0.210 g, 0.90 mmol) and Na2SO4 (0.100 g) and the resulting solution stirred at ambient temperature for 18 hours. Na(OAc)3BH (0.57 g, 2.7 mmol) was added and solution stirred an additional 2 hours. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column) [0-100% Hexanes/EtOAc] to yield a colorless oil. (0.207 g, 51%) LCMS: m/z 451 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:20])[NH:12][C@H:13]1[CH2:17][C@@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11]([NH:12][C@@H:13]1[CH2:17][C@H:16]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[CH:14]1)=[O:20])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1C=C[C@@H](COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (0.76 mL, 9.8 mmol) was added to a solution of cis-(4-hydroxymethyl-cyclopent-2-enyl)-carbamic acid tert-butyl ester (2 g, 9.4 mmol) and triethyl amine (1.96 mL,14.1 mmol) in CH2Cl2 (30 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. After filtration CH2Cl2 was added, and the organic phase was washed with 1M HCl, dried and concentrated under reduced pressure to yield of cis- methanesulfonic acid 4-tert-butoxycarbonylamino-cyclopent-2enylmethyl ester (2.64 g, 96%).