Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[Li]CCCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1>[C:22]([C:3]1[C:2]([NH:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11])=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:24])[CH3:23]
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cccnc1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
To a solution of N-(pyridin-2-yl)pivalamide (2.0 g, 11.22 mmoles) in THF at −78° C. was added 9.4 mL (2.1 eq) of n-BuLi. The resulting mixture was stirred at 0° C. for 3 hours. The reaction mixture was then cooled to −78° C. after which N-methoxy-N-methylacetamide (1.2 g, 1.1 eq) was added as a solution in THF. The resulting mixture was stirred at room temperature for 2 hours. It was then quenched into ice-H2O. The resulting mixture was extracted with CH2Cl2 (3×20 mL) and the combined organic extracts were washed with H2O (2×20 mL), brine (lx 20 mL), then dried over MgSO4. Concentration and purification by MPLC gave N-(3-acetylpyridin-2-yl)pivalamide (1.62 g, 65%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (s, 9 H) 2.65 (s, 3 H) 7.09 (dd, J=7.76, 4.83 Hz, 1 H) 8.17 (dd, J=7.76, 1.90 Hz, 1 H) 8.64 (dd, J=4.69, 2.05 Hz, 1 H) 11.49 (br. s., 1 H).
Reaction SMILES: [F:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:21])=[C:12]([CH:15]([OH:20])[C:16]([O:18][CH3:19])=[O:17])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].O>ClCCl>[F:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:21])=[C:12]([C:15](=[O:20])[C:16]([O:18][CH3:19])=[O:17])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1
Reactant: COC(=O)C(O)c1c(C)nc2c(ccn2Cc2cccc(F)c2F)c1I
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: COC(=O)C(=O)c1c(C)nc2c(ccn2Cc2cccc(F)c2F)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of methyl 2-(1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate (7.95 g, 14.65 mmol) in dichloromethane (DCM) (130 mL) at 0° C. was added in two portions Dess-Martin periodinane (6.83 g, 16.11 mmol) and the mixture was stirred at ambient temperature for 30 min and then a 20% Na2S2O3/water was added and stirring at ambient temperature continued for 20 min. The mixture was diluted with dichloromethane and the organic phase was washed with NaHCO3/water (2×), dried (Na2SO4), concentrated, purified by chromatography (silica gel, EtOAc/hexanes 0-20% then 100%, product eluted at 20-60%) to provide methyl 2-(1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxoacetate (5.8 g, 11.10 mmol, 76% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.54-2.64 (m, 3 H), 3.94 (s, 3 H), 5.53 (s, 2 H), 6.39 (d, J=3.71 Hz, 1 H), 6.84-6.95 (m, 1 H), 6.99 (m, 1 H) 7.10 (m, 1 H), 7.28 (d, J=3.52 Hz, 1 H); LCMS (m/z) ES+=471 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[OH-].[K+].[C:11]([O:15][C:16]([N:18]1[CH2:21][CH2:20][C@H:19]1[CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:22][C@@H:19]2[CH2:20][CH2:21][N:18]2[C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17])[CH:5]=[N:4][CH:3]=1
Reactant: Oc1cncc(F)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCN2C(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
A solution of 3-fluoro-5-hydroxypyridine (500 mg, 4.43 mmol, as prepared in step 10f below) in dimethylformamide (20 mL) was treated with ground KOH (400 mg, 7.10 mmol) and stirred for 30 minutes at 80° C. To this mixture was rapidly added the 1-(t-butyloxycarbonyl)-(2S)-p-toluene-sulfonyloxymethylazetidine (1.05 g, 4.39 mmol, as prepared in Step 10b below) dissolved in dimethylformamide (5 mL) and the reaction mixture was subsequently stirred for 16 h at 80° C. The mixture was concentrated to remove the dimethylformamide and the resultant residue diluted with water and extracted with EtOAc (3×). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo. This material was purified by flash chromatography (silica gel; hexane/EtOAc, 10:1) to give 5-fluoro-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (692 mg, 56%): 1H NMR (CDCl3, 300 MHz) δ1.40 (s, 9H), 2.30 (m, 2H), 3.92 (m, 2H), 4.16 (m, 1H), 4.40 (m, 1H), 4.54 (m, 1H), 7.05 (m, 1H), 8.20 (m, 2H); MS (CI/NH3) m/z: 283 (M+H)+. To 5-fluoro-3-(1-Boc-(2S)-azetidinylmethoxy)pyridine from above (320 mg, 1.14 mmol) was added HCl/Et2O in methylene chloride at 0° C., and the solution was stirred for 2 h. The solvent was removed and the residue was recrystallized from EtOH/Et2O to afford the title compound (250 mg): mp 165-167° C.; [α]D25 27.8 (c 0.56, MeOH); 1H NMR (D2O, 300 MHz) δ2.70 (m, 2H), 4.10 (m, 2H), 4.50 (d, J=4.5 Hz, 2H), 5.01 (m, 1H), 7.80 (tt, J=3 Hz, 1H), 8.42 (dd, J=3, 6 Hz, 2H); MS (CI/NH3) m/z 183 (M+H)+, 200 (M+NH4)+.
Reaction SMILES: [O:1]=[C:2]1[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:3]1[CH2:27][CH2:28][CH2:29][CH2:30][B:31]1[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]1.CN(CCN(C)C)C.[CH2:48](I)[CH:49]=[CH2:50].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl>C1COCC1.CCCCCCC>[CH2:50]([C@:3]1([CH2:27][CH2:28][CH2:29][CH2:30][B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)[C:2](=[O:1])[O:7][C@@H:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:49]=[CH2:48]
Reactant: C=CCI
Reactant: CC(C)(C)OC(=O)N1[C@H](CCCCB2OC(C)(C)C(C)(C)O2)C(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C=CC[C@]1(CCCCB2OC(C)(C)C(C)(C)O2)C(=O)O[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A solution of (3R,5R,6S)-tert-butyl 2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate (5.00 g, 9.34 mmol) and TMEDA (10 mL, 65 mmol, 7 equiv) in THF (51 mL, 0.2 M) was cooled to −78° C. and treated with allyl iodide (17 mL, 187 mmol, 20 equiv) and potassium bis(trimethylsilyl)amide (47 mL, 0.9 M in THF, 46.7 mmol, 5 equiv) drop wise and stirred for 30 min. Once the addition was complete, the cooling bath was removed and the mixture was stirred over night. Once complete by TLC, the reaction mixture was quenched with 0.5N HCl (5-10 equiv), diluted with heptane and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV) gave (3R,5R,6S)-tert-butyl 3-allyl-2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate as colorless oil (5.2 g, 96%). Rf 0.55 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.39-7.14 (m, 10H), 7.10 (dd, J1=5.4 Hz, J2=1.8 Hz, 1H), 6.08 (d, J=5.4 Hz, 1H), 5.95-5.80 (m, 1H), 5.27-5.17 (m, 2H), 3.30-3.15 (m, 1H), 2.89-2.76 (m, 1H), 2.20-2.07 (m, 2H), 1.54 (s, 9H), 1.35-1.21 (m, 4H), 1.78 (s, 12H), 0.46 (t, J=8.4 Hz, 2H); ESI-LCMS m/z calcd for C34H46BNO6: expected 575.3. found 574.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[CH:19]=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[I:28]N1C(=O)CCC1=O>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([I:28])=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)cnn3C2CCCCO2)c1F
Reactant: O=C1CCC(=O)N1I
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(I)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 5-6 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and N-iodosuccinimide. LCMS (M+H)+=418.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:31][C:32](=O)[CH2:33][C:34](=[O:46])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N:41]2[CH:45]=[CH:44][N:43]=[N:42]2)[CH:36]=1)C>>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH:14][C:32](=[O:31])[CH2:33][C:34](=[O:46])[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([N:41]3[CH:45]=[CH:44][N:43]=[N:42]3)[CH:36]=2)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
The title compound was prepared from [5-amino-2′-fluoro-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example J5) (200 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) (150 mg, 0.57 mmol) according to the general procedure M. Obtained as a light yellow solid (110 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and pyridine-2-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.905 min, m/z=435.2; 1H NMR (CDCl3) 1.22-1.37 (m, 1H), 1.49 (d, 3H), 1.60-1.70 (m, 2H), 1.80-1.97 (m, 2H), 2.07-2.31 (m, 3H), 2.85 (m, 1H), 3.50 (m, 2H), 5.65 (m, 1H), 6.97 (m, 4H), 7.20 (m, 3H), 7.57-7.70 (m, 4H), 8.60 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[NH:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>COCCO>[F:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)[N:9]([NH:12][CH3:13])[CH:8]=[C:7]([C:14]([OH:16])=[O:15])[C:6]2=[O:17]
Reactant: CN1CCNCC1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: COCCO
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Temperature: 127 °C

Procedure:
The compound of Example 1 was prepared on a still larger scale as follows: A mixture of 970 g of 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid, 1600 ml of N-methylpiperazine and 8 liters of 2-methoxyethanol was heated to reflux (about 127° C.) over a period of three hours. After 20 hours at reflux, the reaction mixture was cooled to 10° C. and filtered. The filter cake was washed with cold methoxyethanol, followed by methanol. The product was dried at 40° C., affording 925 g of 6-fluoro-1,4-dihydro-1-methylamino-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid which was purified in the form of its methanesulfonate salt.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@]1(CCO[Si](C)(C)C(C)(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO[Si](C)(C)C(C)(C)C)(C(=O)O)C1
Reaction time: 8 h

Procedure:
To a solution of the product of Step A (7.89 g, 19.74 mmol, 1 eq) in methanol (100 mL) at rt was added 1 N NaOH (59.2 mL, 59.2 mmol, 3.0 eq). After stirring overnight, the methanol was removed, 1 N HCl was added until the solution was acidic, the solution extracted with DCM, the organics combined, dried over MgSO4, and concentrated to afford the title compound of Step B. 1H NMR (CHLOROFORM-d) δ: 5.85 (br. s., 2H), 4.97 (br. s., 1H), 4.80 (br. s., 1H), 3.71 (br. s., 2H), 1.99-2.41 (m, 3H), 1.92 (br. s., 1H), 1.44 (br. s., 9H), 0.88 (s, 9H), 0.06 (br. s., 6H). ESI-MS (m/z): Calculated for C19H35NO5Si: 408.2 (M+23). found: 408.3.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:20])=[CH:8][C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.I[CH3:22]>CN(C=O)C>[CH3:22][O:3][CH2:4][C:5]1[O:6][C:7]([CH3:20])=[CH:8][C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CI
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1oc(C)cc(=O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a suspension of sodium hydride (0.48 g, 20 mmol, 2 eq.) in 30 ml dry DMF was added 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (2.46 g, 10 mmol, 1 eq.) followed by dropwise addition of iodomethane (4.26 g, 30 mmol, 3 eq.) at 0° C. under nitrogen. After stiming for 30 minutes at this temperature, the reaction mixture was poured into ice cold water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic fractions were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to yield the crude product (2.6 g,˜100%) as an orange oil which solidified on cooling. Recrystallisation from CH2Cl2/Pet. ether 40/60 afforded the pure product (2.35 g, 90%) as a white crystalline solid. m.p. 30-32° C.
Reaction SMILES: [CH3:1][N:2]1[C:14]2([CH2:19][CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][CH2:15]2)[C:6]2=[CH:7][CH:8]=[C:9]([S:10]([CH3:13])(=[O:12])=[O:11])[N:5]2[CH2:4][CH2:3]1>CCO.[C].[Pd]>[CH3:1][N:2]1[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:6]2=[CH:7][CH:8]=[C:9]([S:10]([CH3:13])(=[O:11])=[O:12])[N:5]2[CH2:4][CH2:3]1
Reactant: CN1CCn2c(ccc2S(C)(=O)=O)C12CCN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CCO
Product: CN1CCn2c(ccc2S(C)(=O)=O)C12CCNCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.5 %

Procedure:
To a solution of benzyl 2-methyl-6-methylsulfonyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (520 mg, 1.25 mmol) in EtOH (13 mL) was added 10% palladium-carbon (66 mg, 0.062 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h under a hydrogen atmosphere. The mixture was filtered through a plug of celite and the solvent was evaporated under reduced pressure to yield 2-methyl-6-methylsulfonyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine] (342 mg, 97%) as an off-white solid. ESI-MS m/z calc. 283.1, found 284.3 (M+1)+; Retention time: 0.30 minutes (3 min run).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[N+:12]([O-])=[CH:13][CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=2)[N+:7]([O-])=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.Cl.[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][N:7]=2)[CH:16]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(-c2cc([N+](=O)[O-])cc[n+]2[O-])c1
Agent: [Pd]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: Nc1ccnc(-c2cc(N)ccn2)c1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
1.34 g of 4,4′-dinitro-2,2′-bipyridine-1,1′-dioxide was suspended in 75 mL of methanol under argon. The mixture was cooled to 0° C. then 0.5 g of 5% Pd/C was added followed by portion wise addition of 1.82 g of sodium borohydride over 10 minutes. The mixture was allowed to warm to room temperature then stirred for 48 hours. The mixture was filtered through a two inch plug of Celite.® Rotary evaporation of the filtrate yielded an off-white solid that was dissolved in 100 mL of 20% HCl. Insoluble residue was removed by filtration then the solution was washed with 100 mL of ether followed by neutralization to pH=8 using 50% NaOH. Cooling to 4° C. yielded a white precipitate which was collected by filtration. The solid was dried under vacuum overnight to yield the desired product as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)[O:5][CH:6]1[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:6]([O:5][C:4]2[CH:17]=[CH:18][C:19]([CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[C:2]([F:1])[CH:3]=2)[CH2:7]1
Reactant: CN1CCN(Cc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(Cc2ccc(OC3CNC3)cc2F)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
A solution of 29C (0.9 g, 2.4 mmol) in DCM (20 mL) was treated with TFA (10 g, 88 mmol) and stirred at 0° C. for 4 h. The reaction mixture was concentrated and the residue was dissolved in aqueous NaHCO3 (sat.). The mixture was extracted three times with DCM and the organic solutions were filtered through a phase separator. The solvent was removed by evaporation. There was obtained 0.21 g (32%) of 29D as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.28 (s, 3H), 2.28-2.68 (bm, 8H), 3.52 (s, 2H), 3.69-3.85 (m, 2H), 3.85-4.02 (m, 2H), 4.88-5.03 (m, 1H), 6.36-6.58 (m, 2H), 7.15-7.27 (m, 1H).
Reaction SMILES: C(OCC)(=O)C.[N+:7]([C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[O:12][CH2:13][CH2:14][C:15]#[N:16])([O-])=O.[H][H]>[Pd]>[NH2:7][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[O:12][CH2:13][CH2:14][C:15]#[N:16]
Reactant: N#CCCOc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#CCCOc1ccccc1N
Reaction time: 4 h
Yield: 98 %

Procedure:
To palladium (0.00748 g, 0.0702 mmol) in a 50 mL flask with stirbar was added ethyl acetate (11.7 g, 133 mmol) under nitrogen, and then nitrile 83 (0.675 g, 3.51 mmol) was added (FIG. 18). The flask was fitted with a balloon containing hydrogen, and the nitrogen inlet was removed. The reaction was stirred vigorously for 4 hours, and then was filtered through celite, washing with ethyl acetate. The product 84 required no further purification, 98% yield. 1H NMR (500 MHz, CDCl3) δ 6.85-6.77 (m, 1H), 6.74-6.62 (m, 3H), 4.08 (t, J=6.1 Hz, 2H), 3.94-3.74 (m, 2H), 2.72 (t, J=6.1 Hz, 2H). LRMS m/z Calcd. for C9H10N2O: 162.07931, found: 163.1 [M+1].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.CCN(CC)CC.[Si:29]([O:36][C@@H:37]([CH3:63])[C@@H:38]([NH:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]#[N:60])=[C:55]([Cl:61])[C:54]=1[CH3:62])[C:39]([NH:41][NH:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][C:47]([I:50])=[CH:46][CH:45]=1)=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl>[Si:29]([O:36][C@@H:37]([CH3:63])[C@@H:38]([NH:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]#[N:60])=[C:55]([Cl:61])[C:54]=1[CH3:62])[C:39]1[O:51][C:43]([C:44]2[CH:45]=[CH:46][C:47]([I:50])=[CH:48][CH:49]=2)=[N:42][N:41]=1)([C:32]([CH3:34])([CH3:35])[CH3:33])([CH3:30])[CH3:31]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(I)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(I)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of triphenylphosphine (7.2 g, 27.5 mmol) in DCM (300 mL) was added I2 (7.0 g, 27.5 mmol) at 0° C. After I2 was dissolved completely, Et3N (7.7 mL, 55.2 mmol) was added, followed by a solution of N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-iodobenzohydrazide (8.6 g, 13.7 mmol) in DCM (100 mL). The reaction mixture was allowed to warm to room temperature and stirred for an additional 60 min. The reaction was quenched with saturated sodium thiosulfate (50 mL) and diluted with DCM (500 mL). The organic layer was separated and washed with water, brine, dried over Na2SO4 and filtered. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound (7.3 g, 88%). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.06 (d, J=8.6 Hz, 2H), 7.88 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 5.56 (d, J=8.8 Hz, 1H), 5.00 (dd, J=2.0, 8.8 Hz, 1H), 4.74 (m, 1H), 2.59 (s, 3H), 1.62 (d, J=6.3 Hz, 3H), 1.07 (s, 9H), 0.28 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]3)[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][CH:13]([OH:16])[CH2:14][CH2:15]3)[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1CCC(N2CCOc3cc(Br)ccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC(N2CCOc3cc(Br)ccc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A mixture of intermediate D25 (1.3 g, 4.191 mmol) and sodium borohydride (0.476 g, 12.573 mmol) in MeOH (15 ml) was stirred at room temperature for 3 h. Then, the resulting mixture was carefully quenched with NH4Cl (aqueous sat. solution) and extracted with DCM. The organic layer was separated, dried (Na2SO4), and evaporated in vacuo. The residue was triturated with a mixture of diisopropylether/diethylether to yield D26 (1.045 g, 63%) as cis/trans mixture of isomers (34% and 66% respectively)
Reaction SMILES: C1(C(C2C=CC=CC=2)[CH:8]2[O:12][C:11]3=[CH:13][C:14]4[O:15][CH2:16][C:17]5([C:31]=4[CH:32]=[C:10]3[CH2:9]2)[C:25]2[CH:24]=[C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]3=[CH:21][C:20]=2[NH:19][C:18]5=[O:30])C=CC=CC=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[O:26]1[C:23]2=[CH:24][C:25]3[C:17]4([CH2:16][O:15][C:14]5[CH:13]=[C:11]6[C:10](=[CH:32][C:31]4=5)[CH2:9][CH2:8][O:12]6)[C:18](=[O:30])[NH:19][C:20]=3[CH:21]=[C:22]2[O:29][CH2:28][CH2:27]1
Reactant: O=C1Nc2cc3c(cc2C12COc1cc4c(cc12)CC(C(c1ccccc1)c1ccccc1)O4)OCCO3
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cc3c(cc2C12COc1cc4c(cc12)CCO4)OCCO3
Yield: 22.5 %

Procedure:
To a solution of 6-(diphenylmethyl)-2′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′-[1,4]dioxino[2,3-f]indol]-7′(6′H)-one (0.5 g, 1.0 mmol) in trifluoroacetic acid (7 mL) was added triethylsilane (0.47 mL, 3.0 mmol). The reaction mixture was heated at reflux for 3.5 h and concentrated in vacuo. The residue was triturated in methanol to afford 2′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′-[1,4]dioxino[2,3-f]indol]-7′(6′H)-one (0.076 g, 23%) as a colorless solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 6.61 (s, 1H), 6.50 (s, 1H), 6.40 (s, 1H), 6.36 (s, 1H), 4.66 (ABq, J=36.8, 9.2 Hz, 2H), 4.54-4.44 (m, 2H), 4.24-4.11 (m, 4H), 3.02-2.92 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.8, 160.8, 160.4, 143.3, 138.7, 135.4, 125.1, 120.9, 119.5, 118.9, 113.0, 99.0, 92.2, 79.7, 72.0, 64.2, 63.7, 57.1, 28.3; MS (ES+) m/z 337.9 (M+1).