Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[C:3]1[C:7](=[O:8])[CH2:6][O:5][C:4]1=[O:9])=[N-].[CH3:10][CH:11]([CH:13]1[CH2:15][CH2:14]1)[OH:12]>C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH:13]1([CH:11]([O:12][C:3]2[C:4](=[O:9])[O:5][CH2:6][C:7]=2[OH:8])[CH3:10])[CH2:15][CH2:14]1
Reactant: CC(O)C1CC1
Reactant: [N-]=[N+]=C1C(=O)COC1=O
Agent: [Rh+3]
Agent: CC(=O)[O-]
Product: CC(OC1=C(O)COC1=O)C1CC1
Temperature: 130 °C

Procedure:
To the mixture of 3-diazo-2,4-(3H, 5H)-furandione (300 mg, 2.38 mmol; Example 207, Step 1) and a-methylcyclopropanemethanol (2.0 mL) was added rhodium acetate (30 mg). The mixture was heated at 130° C. for a period of 18 h. The excess of alcohol was evaporated under reduced pressure and the resulting crude mixture was purified by flash chromatography (10% to 20% MeOH in CH2Cl2) to provide 50 mg of the title compound.
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[I:1]
Reactant: II
Reactant: CC(=O)c1ccc(N)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CC(=O)c1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
Iodine (2.82 g; 11.10 mmol) was added to a stirred mixture of silver sulphate (3.46 g; 11.10 mmol) and 1-(4-aminophenyl)ethanone (1.50 g; 11.10 mmol) in ethanol (40 mL). The reaction mixture was then stirred at room temperature for 18 hours and filtered over celite. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulfate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to afford 0.514 g (18%) of the title compound as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[NH:4]1.C(N(CC)CC)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:24][C:23]([Si:20]([CH3:22])([CH3:21])[O:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[NH:4]1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1N[C@H](CO)CN2CCC[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCC[C@H]2C(=O)N1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.2 %

Procedure:
To a solution of (3S,8aS)-3-(hydroxymethyl) hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (1.49 g, 8.82 mmol) in dimethylformamide (20 mL) was added triethylamine (2.45 mL, 17.6 mmol) and 4-dimethylaminopyridine (90 mg, 0.882 mmol). The solution was cooled in an ice bath and tert-butyldimethylsilyl chloride (2.66 g, 17.6 mmol) was added. The mixture was warmed to room temperature and stirred for 14 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous portion was extracted twice with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a pale brown solid which was triturated with ethyl acetate to afford (3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl) hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one as an off-white solid (1.74 g, 5.84 mmol, 66% yield). 1H NMR (400 MHz, CDCl3): 6.09-5.90 (m, 1H), 3.86-3.76 (m, 1H), 3.63 (dd, 1H), 3.44 (dd, 1H), 3.25 (t, 1H), 3.10 (ddd, 1H), 2.98-2.90 (m, 1H), 2.68-2.60 (m, 1H), 2.52 (dd, 1H), 2.28-2.18 (m, 1H), 2.06-1.95 (m, 1H), 1.93-1.74 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H); MS (EI) for C14H28N2O2Si: 285 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[CH:6][CH:7]=1>[Pd].C(O)C>[N:3]1[CH:2]=[CH:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[N:4]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccc(Cl)nn2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2cccnn2)c1
Yield: 62.7 %

Procedure:
A suspension of 3-chloro6-(3-nitro-phenyl)pyridazine (0.34 g) in tetrhydrofuran (5 ml) and ethanol (5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 100 mg) under hydrogen atmosphere for 10 hours. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was diluted with ethyl acetate and an aqueous solution of sodium hydrogen carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 3-pyridazin-3-yl-phenylamine (155 mg, 62.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][C:20]([N+:25]([O-:27])=[O:26])([CH2:23]O)[CH2:21][OH:22].Cl.CN(C)CCCN=C=NCC.N(C(C)C)(C(C)C)CC>CN(C1C=CN=CC=1)C.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:23][C:20]([CH2:21][OH:22])([N+:25]([O-:27])=[O:26])[CH2:19][OH:18])=[O:15])[CH:7]=[CH:6]2
Reactant: O=[N+]([O-])C(CO)(CO)CO
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: COc1ccc2cc([C@H](C)C(=O)OCC(CO)(CO)[N+](=O)[O-])ccc2c1
Yield: 36.9 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.27 g, 18.5 mmol), 2-hydroxymethyl-2-nitro-1,3-propanediol (2.89 g, 19.1 mmol), N,N-dimethylaminopyridine (DMAP, 0.88 g, 7.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.86 g, 25.4 mmol) and NEt(i-Pr)2 (11 mL, 63.2 mmol) in acetone (100 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between 3N HCl (100 mL) and CH2Cl2 (200 mL×2). The combined organic layer was back washed with water and brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with ethyl acetate/hexane (gradient from 1:2 to 1:1, Rf=0.1 in 1:2) to give the title compound as a white solid (2.48 g, 39% yield). Mp 124-126° C. 1H NMR (300 MHz, 10% CD3OD/CDCl3) δ 7.73-7.64 (m, 3H), 7.37-7.33 (m, 1H), 7.17-7.12 (m, 2H), 4.44 (d, J=2.6 Hz, 2H), 3.92 (s, 3H), 3.9-3.7 (m, 5H), 3.4 (br, 2H), 1.58 (d, J=7.2 Hz, 3H), 13C NMR (75 MHz, 10% CD3OD/CDCl3) δ 174.1, 157.4, 134.5, 133.5, 129.0, 128.6, 127.0, 125.7, 118.8, 105.4, 92.4, 61.2, 60.1, 55.0, 45.0, 17.7.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10](=[O:19])[C:9]2=[O:20])(=[O:5])=[O:4].[Cl:22][C:23]1[CH:24]=[N+:25]([O-:48])[CH:26]=[C:27]([Cl:47])[C:28]=1[CH2:29][C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:41])[F:40])=[C:34]([O:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)[CH:33]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[N+:25]([O-:48])[CH:26]=[C:27]([Cl:47])[C:28]=1[CH2:29][C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:41])[F:40])=[C:34]([O:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)[CH:33]=1)[O:17][C:16](=[O:18])[CH2:15][N:11]1[C:12]2[C:8](=[CH:7][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:21])[CH3:1])=[CH:14][CH:13]=2)[C:9](=[O:20])[C:10]1=[O:19]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
A mixture of crude 2-(5-(N,N-dimethylsulfamoyl)-2,3-dioxoindolin-1-yl)acetic acid (0.178 g, 0.57 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol), EDC (0.274 g, 1.428 mmol) and DMAP (0.029 g, 0.238 mmol) in dry DCM (10 ml) was stirred at room temperature overnight. The mixture was washed with 1N HCl, aqueous 5% NaHCO3 and brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude was purified by silica gel flash chromatography (DCM:MeOH from 99.5:0.5 to 98:2) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N,N-dimethylsulfamoyl)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.128 g, 0.179 mmol, 37% yield). This product was further purified by crystallization from ethyl acetate/hexane 1/1 to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N,N-dimethyl sulfamoyl)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.052 g, 0.179 mmol, 15% yield). MS/ESI+ 714.11 [MH]+; [αD]=−37.09, c=0.488; MeOH; 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.15 (s, 2H), 8.06 (d, 1H), 8.00 (dd, 1H), 7.19 (d, 1H), 6.83-7.01 (m, 2H), 6.74 (d, 1H), 6.67 (t, 1H), 6.13 (dd, 1H), 4.53 (d, 2H), 3.91 (d, 2H), 3.58 (dd, 1H), 3.28 (dd, 1H), 2.79 (s, 6H), 1.09-1.43 (m, 1H), 0.55-0.84 (m, 2H), 0.18-0.52 (m, 2H)
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.[CH3:14][S:15][CH:16](SC)[CH2:17][N+:18]([O-:20])=[O:19].[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>CN(C)C=O>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:16]([S:15][CH3:14])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:6][CH:5]=1
Reactant: CSC(C[N+](=O)[O-])SC
Reactant: CNCc1ccc(CSCCN)o1
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Product: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])SC)o1
Yield: 26.6 %

Procedure:
A solution of 2-[[5-[(methylamino)methyl]-2-furanylmethyl]thio]ethanamine (6.0 g) and 1,1-bis-(methylthio)-2-nitroethane (19.8 g) in dry dimethylformamide (150 ml) was stirred for 1 hour at 0° and for 5 hours at room temperature. A solution of oxalic acid (4.0 g) in dry dimethylformamide (16 ml) was added and the solid which formed during 18 hours was filtered, washed with dimethylformamide, ethanol and ether and dried. The solid was suspended in water (200 ml) at 55° and on cooling was filtered, washed with water and dried to give the title compound (3.25 g) m.p. 158°-160° dec.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=3[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:7][C:6]=12.C(N([CH2:37][CH3:38])CC)C>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([C:38]#[C:37][Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:10][C:9]=3[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:7][C:6]=12
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(I)ccc32)c1Br
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(Br)n(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 10 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 263 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanylethoxymethyl)-7-iodo-2H-pyrazolo[4,3-c]isoquinoline in 1.5 ml of DMF and then 1.5 ml of triethylamine. After argon has been bubbled through the mixture for 10 min, 30 mg of bis(triphenylphosphene)palladium(II) dichloride, 8.7 mg of copper(I) iodide and 118 μl of ethynyltrimethylsilane are added. The mixture is stirred at RT for 2 h, poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of DCM and methanol (99.5/0.5 by vol.), to give 140 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanylethoxymethyl)-7-trimethylsilanylethynyl-2H-pyrazolo[4,3-c]isoquinoline (cream solid). MS (E/I): m/z=586 (M+) 1H NMR: −0.05 (s, 9 H) 0.23 (s, 9 H) 0.89 (m, 2 H) 3.72 (m, 2 H) 5.88 (s, 2 H) 7.4 (t, J=8.1 Hz, 2H) 7.6 (broad s, 1H) 7.75 (m, 1H) 8.01 (dd, J=8.3, 1.5 Hz, 1H) 8.52 (d, J=8.3 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C1COCC1>[C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: OCCCCc1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCCCc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product from Step A was dissolved in 100 ml of THF and the mixture was cooled in an ice-water bath. Triethylamine (7.5 ml, 54 mmol) was added followed by dropwise addition of 3.8 ml of acetyl chloride (54 mmol). The mixture was allowed to stir overnight at ambient temperature. The solution was filtered and concentrated on a rotary evaporator. The residue was partitioned between ethyl acetate and dilute, cold 1N HCl. The organic phase was washed with saturated NaHCO3 solution, brine and then dried (Na2SO4). Evaporation of the solvent left 10.48 g of the desired acetate (98%) the solvent left 10.48 g of the desired acetate (98%) as a light yellow oil. 1H-NMR (CDCl3)δ7.2-6.6 (3H, m); 2.9 (2H, t); 2.45 (2H, t); 2.15 (3H, s); 2.0 (4H, m).
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+]([C:7]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])([O-])=O>CC(C)=O>[CH3:1][S:2][C:7]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: C[S-]
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CSc1cc(C(F)(F)F)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Sodium thiomethoxide (366 g of a 21% aqueous solution, 1.1M) was added during 3 hours to a solution of 2-nitro-4-trifluoromethylbenzonitrile (220.5 g, 1.0M) in acetone (340 g) with stirring at 20-30° C. Stirring was continued for a further 1 hour and the two liquid phases separated. The upper layer (a solution of the product in acetone) was kept at 20° C. when 2-methylthio-4-trifluoromethylbenzonitrile crystallised (213 g), m.p.82° C. The yield was 97%, with product purity >96%.
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:19]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=3[CH3:35])[CH:20]=[C:21]([C:25](=[O:27])[CH:26]=2)[C:22]([OH:24])=[O:23])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1>O1CCOCC1.O.[C].[Pd]>[NH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:19]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=3[CH3:35])[CH:20]=[C:21]([C:25](=[O:27])[CH:26]=2)[C:22]([OH:24])=[O:23])[CH2:14][CH2:13]1
Reactant: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C1CCC(N)CC1
Reaction time: 3 h
Yield: 88.1 %

Procedure:
In a mixture of 10 ml of dioxane and 5 ml of water was dissolved 0.15 g of 6-(4-benzyloxycarbonylaminocyclohexyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid, and 0.03 g of 5% by weight palladium carbon was added. The above acid was hydrogenated under atmospheric pressure for 3 hours. The catalyst was removed by filtration and the solvent was then removed by distillation under reduced pressure. To the residue was added 3 ml of diethyl ether, and the precipitated crystals were collected by filtration and washed with 3 ml of diethyl ether to obtain 0.095 g of 6-(4-aminocyclohexyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 237°-250° C. (decomp.).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OS(O)(=O)=O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:42])([CH3:41])[C:28]([CH:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:31](OCC)=[O:32])=[O:29])=[CH:23][C:22]=1[F:43]>>[Cl:20][C:21]1[CH:26]=[C:25]2[C:24](=[CH:23][C:22]=1[F:43])[C:27]([CH3:41])([CH3:42])[C:28](=[O:29])[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:31]2[OH:32]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(Cl)c(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2cc(Cl)c(F)cc2C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
A suspension of P2O5 (33.0 g, 232 mmol) in concentrated H2SO4 (29.5 mL, 531 mmol) was cooled 0° C. At 0° C., the suspension was added to diethyl 2-(2-(4-chloro-3-fluorophenyl)-2-methylpropanoyl)malonate (2.90 g, 8.20 mmol), and the mixture was stirred at 25° C. for 1 hour. The reaction was quenched with ice. On melting, it was extracted with EtOAc (3×100 mL), washed with water (150 mL), and then with brine (100 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to give the title compound (1.349 g, 52.6% yield) as a tan solid. MS m/e=313.3 (M+H)+.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:29][C:28]([CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)=[N:27][N:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[NH2:32][CH2:31][CH2:30][C:28]1[O:29][C:25]([C@@H:20]2[CH2:19][CH2:18][C@@H:17]3[CH2:24][N:21]2[C:22](=[O:23])[N:16]3[O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:26][N:27]=1
Reactant: CC(C)(C)OC(=O)NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
TFA (0.5 mL) was added to a 0° C. solution of tert-butyl 2-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)ethylcarbamate (85 mg, 0.192 mmol) in CH2Cl2 (2.0 mL). The reaction mixture was stirred at 0° C. for 2 hrs and was then concentrated under vacuum to provide (2S,5R)-2-(5-(2-aminoethyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one TFA salt as a sticky oil, which was used directly in the next step. ESI-MS (EI+, m/z): 344.2 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:17][CH2:18][CH3:19])[CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=1)=[O:7].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]=O)=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[ClH:16].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][NH:2][C@@H:3]([CH2:17][CH2:18][CH3:19])[CH2:4][NH:5][C:6]([C:8]2[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=2)=[O:7])=[CH:24][CH:23]=1
Reactant: COc1ccc(CCC=O)cc1
Reactant: CCC[C@H](N)CNC(=O)c1nc(Cl)c(N)nc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCC[C@@H](CNC(=O)c1nc(Cl)c(N)nc1N)NCCCc1ccc(OC)cc1

Procedure:
A solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid ((S)-2-amino-pentyl)-amide hydrochloride (Example 4) (400 mg, 1.467 mmol), 3-(4-methoxyphenyl)propionaldehyde (181 mg, 1.103 mmol) and sodium triacetoxyborohydride (467 mg, 2.205 mmol) in DCM (150 mL) is heated at reflux overnight. The reaction mixture is allowed to cool, and 1 N NaOH solution (50 mL) and DCM (50 mL) are added. The organic phase is separated and the aqueous phase is extracted once with DCM. The combined organic phases are washed with sat. aq. NaCl solution, dried (MgSO4), and concentrated in vacuo to afford a yellow solid. Purification by flash column chromatography (SiO2, MeOH:DCM, gradient 2-10%+0.1% TEA) affords the title compound. [M+H]+ 421. 1H NMR (400 MHz, CDCl3) δ 8.69 (2H, br), 8.23 (1H, t), 7.25 (4H, br), 7.11 (2H, d), 6.84 (2H, d), 3.72 (3H, s), 3.55-3.45 (2H, m), 3.25-3.15 (1H, m), 3.03-2.92 (2H, m), 2.58 (2H, t), 1.85-1.73 (2H, m), 1.65-1.27 (4H, m), 0.89 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: C1COCCN1
Product: N#Cc1cc(Br)cc(N2CCOCC2)c1
Yield: 81 %

Procedure:
3-bromo-5-morpholinobenzonitrile was prepared according procedure M from 3-bromo-5-fluorobenzonitrile and morpholine in 81% yield.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=[O:15])[CH3:14]>>[CH2:7]([N:8]1[C:12]([CH:13]([OH:15])[CH3:14])=[N:11][CH:10]=[N:9]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC=O
Reactant: c1ccc(Cn2cncn2)cc1
Product: CC(O)c1ncnn1Cc1ccccc1
Yield: 86 %

Procedure:
1-(1-Benzyl-1H-1,2,4-triazol-5-yl)ethanol was synthesized in a manner similar to that of procedure 21B but using 1-(phenylmethyl)-1H-1,2,4-triazole and acetaldehyde as the starting materials. The product was isolated as a white solid in 86% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[S:8][C:5]2=[N:6][CH:7]=1.[Cl:20][CH:21]([Cl:40])[C:22]([NH:24][C@H:25]([CH2:38][F:39])[C@H:26]([OH:37])[C:27]1[CH:32]=[CH:31][C:30]([Sn](C)(C)C)=[CH:29][CH:28]=1)=[O:23].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(NC(=O)[O-])(C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O.O.C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:20][CH:21]([Cl:40])[C:22]([NH:24][C@H:25]([CH2:38][F:39])[C@@H:26]([C:27]1[CH:28]=[CH:29][C:30]([C:2]2[CH:3]=[C:4]3[N:10]=[C:9]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[S:8][C:5]3=[N:6][CH:7]=2)=[CH:31][CH:32]=1)[OH:37])=[O:23]
Reactant: CC(C)(C)OC(=O)NCc1nc2cc(Br)cnc2s1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Agent: CC(C)(C)NC(=O)[O-]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1nc2cc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc3)cnc2s1
Temperature: 65 °C
Reaction time: 3 h
Yield: 16.4 %

Procedure:
A mixture of tert-butyl ((6-bromothiazolo[5,4-b]pyridin-2-yl)methyl)carbamate (156 mg, 0.45 mmol), 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)-propan-2-yl)acetamide (200 mg, 0.45 mmol) and tris(2-furyl)phosphine (21 mg, 0.090 mmol) Tris(dibenzylideneacetone) dipalladium(0) (41 mg, 0.045 mmol) in dimethylformamide (2.5 mL) is heated at 65° C. for 3 hours under nitrogen. The mixture is then cooled, diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). Extracts are dried over Na2SO4 and concentrated to get crude title compound. m/z (CI) M+1 543. To a solution of crude tert-butylcarbamate (200 mg, 0.452 mmol) in DCM (3 mL) is added trifluoroacetic acid (0.5 mL) and stirred at room temperature for 3 hours. Reaction is diluted with toluene (10 mL), concentrated under vacuum, basified with saturated aq NaHCO3 and extracted using ethyl acetate (3×10 mL). Extracts are dried over Na2SO4, concentrated and crude compound adsorbed on celite and purified on silica gel column using 0 to 20% methanol in ethyl acetate to give the title compound (40 mg). 1HNMR (DMSO-d6): 4.17 (m, 2H). 4.27 (m, 1.5H), 4.43 (m, 0.5H), 4.59 (m, 0.5H), 4.70 (m, 0.5H), 4.93 (m, 1H), 6.01 (m, 1H), 6.54 (1H), 7.50 (d, 2H), 7.80 (d, 2H), 8.51 (m, 1H), 8.64 (d, 1H), 8.87 (d, 1H), m/z (CI) M+H 443.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:5]1[F:17])=[N+]=[N-]>CCO.[Pd]>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][CH:4]([NH2:1])[CH:5]([F:17])[CH2:6]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])C(F)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N)C(F)C1
Reaction time: 48 h

Procedure:
Pd/C 10% (12 g) was added to a solution of tert-butyl 4-azido-3-fluoropiperidine-1-carboxylate, 2.6 (62 g, 0.254 mol) in EtOH (600 mL). The reaction was stirred under a hydrogen atmosphere (balloon pressure) for 48 hours. The mixture was filtered through celite-bed and concentrated under reduced pressure to obtain the title compound tert-butyl4-amino-3-fluoropiperidine-1-carboxylate, 2.7 (42 g, 75% yield). LCMS: m/z 218.8 (M+1).