Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:16]1[O:17][CH2:18][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27](B4OC(C)(C)C(C)(C)O4)[CH:28]=3)[O:23][CH2:22][C:21]32[CH2:40][CH2:39]3)[N:20]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.Br[C:42]1[CH:43]=[C:44]2[CH:50]=[CH:49][NH:48][C:45]2=[N:46][CH:47]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:48]1[C:45]2=[N:46][CH:47]=[C:42]([C:27]3[CH:28]=[C:29]4[C:19]5([CH2:18][O:17][C:16]([NH2:8])=[N:20]5)[C:21]5([CH2:39][CH2:40]5)[CH2:22][O:23][C:24]4=[CH:25][CH:26]=3)[CH:43]=[C:44]2[CH:50]=[CH:49]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1OCC21CC1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=NC2(CO1)c1cc(-c3cnc4[nH]ccc4c3)ccc1OCC21CC1
Temperature: 100 °C
Reaction time: 7 h
Yield: 48.5 %

Procedure:
The mixture of di-tert-butyl[6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]imidodicarbonate (140 mg, 0.25 mmol), 5-bromo-1H-pyrrolo[2,3-b]pyridine (87 mg, 0.44 mmol), Pd(PPh3)4 (58 mg, 0.050 mmol), and Na2CO3 (80 mg, 0.76 mmol) in 1,4-dioxane-H2O (2.8 ml, 4:1) was stirred for 7 hours at 100° C. After dilution with EtOAc and H2O, the organic layer was washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (CHCl3:MeOH=100:0-85:15) to give white solid. The solid was washed by diisopropyl ether to give 6′-(1H-pyrrolo[2,3-b]pyridin-5-yl)dispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-amine (42 mg).
Reaction SMILES: F[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH2:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:11])[C:7]=1[N+:8]([O-:10])=[O:9].[C:19]([Si](C)(C)C)#[N:20]>C[N+]([O-])=O>[C:19]([C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH2:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:11])[C:7]=1[N+:8]([O-:10])=[O:9])#[N:20]
Reactant: C[Si](C)(C)C#N
Reactant: Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(F)c1[N+](=O)[O-]
Solvent: C[N+](=O)[O-]
Product: N#Cc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(N)c1[N+](=O)[O-]
Yield: 82 %

Procedure:
A solution of 5-fluoro-1,3-diamino-2,4,6-trinitrobenzene (F-DATB) (5.22 g, 20 mmol) and cyanotrimethylsilane (4.96 g, 50 mmol) in CH3NO2 (100 ml) was refluxed for two hours and then evaporated under vacuum to leave a solid residue. Recrystallization from acetonitrile (100 ml) gave 5-cyano-1,3-diamino-2,4,6-trinitrobenzene (4.4 g, 82%) as orange-brown crystals: mp 212°-217° C. dec. An additional recrystallization gave the analytical sample: mp 220°-221° C.; mass spectrum (CI, CH4) m/z 269 (M+1, 100).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=1.[H-].[Na+]>CN(C)C=O>[CH3:29][N:21]([C:19]1[CH:20]=[C:15]([O:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:18]=1[N+:30]([O-:32])=[O:31])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1[N+](=O)[O-]
Yield: 57.7 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-phenylphenol (4.0 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (6.5 g), sodium hydride (55 wt. %, 1.13 g) and anhydrous N,N-dimethylformamide (35 ml) and the reaction mixture was purified to give the title compound (5.5 g).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]([Sn](CCCC)(CCCC)CCCC)=[CH2:14])[CH3:11].[F-].[K+]>C(#N)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>[CH2:13]([O:12][C:10]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)=[CH2:11])[CH3:14]
Reactant: N#Cc1ccc(Br)nc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: C=C(OCC)c1ccc(C#N)cn1
Temperature: 25 °C
Yield: 190.5 %

Procedure:
Slurry 6-bromo-nicotinonitrile (8.0 g, 43.7 mmol), 1-ethoxyvinyl-tributylstannane (17.4 g, 48 mmol), and dichlorobis(triphenylphosphine)-palladium (1.5 g, 2.2 mmol) in acetonitrile (680 mL) at room temperature. Stir the mixture at reflux for 16 h under a nitrogen atmosphere. Cool the mixture to room temperature, add aqueous saturated potassium fluoride (100 mL), stir 30 min then filter and wash with EtOAc (200 mL). Wash the organic phase with water (250 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (14.5 g) that was used without further purification. MS (ES+) m/z: 175 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([Br:20])[CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[Br:21])O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([Br:20])[CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[Br:21])=[CH:27][CH:26]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cc(Br)c2nccc(Br)c2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(C(c2ccc(Cl)cc2)c2cc(Br)c3nccc(Br)c3c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To solution of bis(4-chlorophenyl)(4,8-dibromoquinolin-6-yl)methanol (175 mg, 0.325 mmol) and triethylsilane (0.208 mL, 1.3 mmol) in CH2Cl2 was added slowly TFA (0.35 mL, 4.57 mmol). The resulting mixture was stirred for 4 hr at room temperature. The reaction was diluted with CH2Cl2 and washed with Na2CO3 to make the aqueous layer basic. The organics were concentrated and purified by silica column (15% EtOAc/hexanes) chromatography to yield 6-(bis(4-chlorophenyl)methyl)-4,8-dibromoquinoline. (M+H)+: 520, 523, 528.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br)([O-:18])=[O:17]>O1CCCC1>[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(ccn2Cc2cccc([N+](=O)[O-])c2)c1
Reaction time: 0.5 h

Procedure:
Methyl indole-5-carboxylate (10 g) was dissolved in dry tetrahydrofuran (250 ml) and cooled in an ice-bath. To the stirred solution was added sodium hydride (60% suspension in oil) (2.57 g) in portions over 15 minutes. After stirring for a further 30 minutes, 3-nitrobenzyl bromide (11.55 g) in dry tetrahydrofuran (30 ml) was added dropwise over 20 minutes. Stirring was continued at 0° C. for 30 minutes, then at room temperature for 2 hours. Excess sodium hydride was destroyed by cautious addition of acetic acid, then the reaction mixture extracted from brine into ethyl acetate, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Recrystallisation from ethyl acetate/hexane afforded methyl 1-(3-nitrobenzyl)indole-5-carboxylate (m.p. 129°-130° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](Cl)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.CN(C)C=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccc(C)cc3)c2c1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCOc1ccc2nc(N3CCOCC3)n(-c3ccc(C)cc3)c2c1
Temperature: 110 °C
Reaction time: 7.5 h

Procedure:
240 mg of 6-[[2-chloro-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was mixed with 0.2 ml of N,N-dimethylformamide and 0.7 ml of morpholine, and the mixture was stirred for 7.5 hours at 110° C. Another 0.7 ml of morpholine was added and heated for another 4 hours at 110° C. It was mixed with water, extracted with ethyl acetate, the organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 7 mg was obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O>[CH2:19]([O:11][C:7]1[C:6]([Br:12])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[CH:9][C:8]=1[Br:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)c1cc(Br)c(O)c(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Br)c(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3,5-dibromo-4-hydroxyacetophenone from Example 45A (15 g, 51.2 mmol) in DMF (51 mL) was added K2CO3 (10.2 g, 74.1 mmol) and benzyl bromide (6.0 mL, 50.7 mmol). The reaction stirred at room temperature for 45 minutes. It was diluted with water (200 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were washed with 2M NaOH solution (2×75 mL), water (75 mL), and brine (75 mL) and then dried over MgSO4 and concentrated in vacuo to give 1-(4-benzyloxy-3,5-dibromo-phenyl)-ethanone as an off white solid (14.3 g, 37.2 mmol, 73% yield).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][C:8]=2[F:24])[CH2:2]1.Cl[C:26]1[N:35]=[C:34]2[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]2[CH:36]2[CH2:38][CH2:37]2)=[CH:28][C:27]=1[F:43].C[Si](C)(C)Cl.C(N(CC)CC)C>CN1CCCC1=O>[C:20]([NH:19][CH2:18][CH:16]1[O:15][C:14](=[O:23])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:3]3[CH2:4][N:1]([C:26]4[N:35]=[C:34]5[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]5[CH:36]5[CH2:38][CH2:37]5)=[CH:28][C:27]=4[F:43])[CH2:2]3)=[C:8]([F:24])[CH:9]=2)[CH2:17]1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3CNC3)c(F)c2)C(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)NCC1CN(c2ccc(OCC3CN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)C3)c(F)c2)C(=O)O1
Temperature: 150 °C
Reaction time: 0.12 h

Procedure:
A suspension of 179 mg N-{(5S)-3-[4-(Azetidin-3-ylmethoxy)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (MW: 337.35, 0.31 mmol), 100 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-Naphthyridine-3-carboxylic acid (MW: 282.66, 0.25 mmol), 0.134 ml trimethylchlorosilane (MW: 108.64, d=0.859, 1.059 mmol) and 0.197 ml triethylamine (MW: 101.19, d=0.726, 1.41 mmol) in 2 ml N-methyl-pyrrolidin-2-one was heated under stirring in a micro wave oven at 150° C. for 7 min. The N-methyl-pyrrolidin-2-one was evaporated, the residue was purified by chromatography. Yield: 82 mg, 40%. MS: 583.5 (M+H)+, Method ESI+. Molecular Weight=584
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:21][CH:22]=2)=[C:13]([F:31])[CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH:18]=2)=[C:13]([F:31])[CH:12]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(Cl)cc2F)CC1
Product: Fc1cc(Cl)ccc1C1=CCN(CCCc2onc3c2CCCCC3)CC1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]#[N:10].[CH2:11]([N:18]1[CH2:23][CH:22]2[CH2:24][CH:19]1[CH2:20][NH:21]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:23][CH:22]2[CH2:24][CH:19]1[CH2:20][N:21]2[CH2:8][C:9]#[N:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CCCl
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CCN1CC2CC1CN2Cc1ccccc1

Procedure:
Finely ground potassium carbonate, as well as 1.3 mL of freshly distilled chloroacetonitrile were added to a solution of 3 g of 2-benzyl-2,5-diazabicyclo[2.2.1]heptane in 40 mL of anhydrous toluene and refluxed for 10 hours with vigorous stirring. The solution was cooled, filtered and evaporated. Bulb tube distillation (boiling point: 110°–120° C. at 0.01 mbar) resulted in 3.57 g of 140 as a colorless oil (97% of the theoretical yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)[CH:5]=[C:4]([Cl:17])[N:3]=1.C(N(C(C)C)CC)(C)C.[C:27]1([C:33]2[CH:37]=[C:36]([CH2:38][NH2:39])[O:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)CCC>[Cl:17][C:4]1[N:3]=[C:2]([NH:39][CH2:38][C:36]2[O:35][N:34]=[C:33]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:37]=2)[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)[CH:5]=1
Reactant: CC(C)c1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Reactant: NCc1cc(-c2ccccc2)no1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(Nc2cc(Cl)nc(NCc3cc(-c4ccccc4)no3)n2)n[nH]1
Temperature: 90 °C
Reaction time: 30 h
Yield: 44.6 %

Procedure:
To a solution of 2,6-dichloropyrimidin-4-yl-(5-isopropyl-1H-pyrazol-3-yl)-amine (19.44 g, 71.7 mmol) in 1-butanol (200 mL) was added diisopropylethylamine (23.7 mL, 143 mmol) and 3-phenylisoxazol-5-ylmethylamine (15.0 g, 86.1 mmol). The mixture was stirred at 90° C. for 30 h, then concentrated on a rotary evaporator. The residue was taken up in 100 mL of methanol and boiled until the volume reached around 50 mL. The solution was allowed to cool to room temperature and then placed in the refrigerator overnight. The solid that formed was collected by filtration, while the filtrate was concentrated on a rotary evaporator, heated to boiling in methanol and cooled overnight in the refrigerator. This solid was collected and the filtrate was subjected to methanol recrystallization a third time. The three solids were combined to give the desired product (13.1 g, 45%) as a white solid.
Reaction SMILES: [CH3:1][C@@:2]1([OH:24])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:23]=[C:14]2[CH:15]=[CH:16][C:17]3[C:18](=[O:22])[NH:19][N:20]=[CH:21][C:12]([C:13]=32)=[N:11]1>CO.[Pd]>[CH3:1][C@@:2]1([OH:24])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:23]=[C:14]2[CH2:15][CH2:16][C:17]3[C:18](=[O:22])[NH:19][N:20]=[CH:21][C:12]([C:13]=32)=[N:11]1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c(=O)[nH]ncc(n1)c23
Agent: [Pd]
Solvent: CO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1C=C2CCC3=C2C(=N1)C=NNC3=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 59.8 %

Procedure:
A mixture of tricyclic nucleoside 6.6 (20 mg, 0.06 mmol) and 10% Pd/C (12.8 mg, 0.2 eq.) in 20 mL of MeOH under H2 pressure (32 psi) was shaken for 7 hr at room temperature. The mixture was filtered through 0.45 μM filter. The combined filtrates were evaporated and purified on a silica gel column with 5% MeOH in CH2Cl2. 12 mg of pure compound 8.1 was obtained (yield 60%). 1H NMR (300 MHz, DMSO-d6): δ 10.65 (br s, 1H, NH), 8.37 (s, 1H, H-4), 7.48 (s, 1H, H-1), 6.12 (s, 1H, H-1′), 5.05 (m, 3H, 3×OH), 3.89-3.12 (m, 4H, H-3′, H-4′, 2×H-5′), 2.86-2.74 (m, 4H, 2×H-8, 2×H-9), 0.64 (s, 3H, CH3); LCMS: ES-MS 393.6 (M+CH3COO).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH:32]C(=O)C)[CH:24]=2)([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=O)C.CO.[OH-].[Na+]>O>[NH2:4][C:5]1[CH:6]=[C:7]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH2:32])[CH:24]=2)([C:19]([F:20])([F:21])[F:22])[C:15]([F:18])([F:17])[F:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)Nc1cc(C(c2ccc([N+](=O)[O-])c(NC(C)=O)c2)(C(F)(F)F)C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cc(C(c2ccc([N+](=O)[O-])c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1[N+](=O)[O-]

Procedure:
160 g (0.31 mol) of 2,2-bis-(3-acetamido-4nitrophenyl) hexafluoropropane are heated under reflux for 15 minutes in a solution of 65 ml of water, 570 ml of methanol and 25 g of sodium hydroxide. The hot solution is diluted with 1,300 ml of hot water and then cooled to 0°-5° C. The solid is filtered off with suction, washed with water, dried at 80° C. and recrystallized from toluene. Yield 115 g (0.27 mol); yellow solid; m.p. 257°-259° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[N:17]=[CH:18][C:19]([CH:22]=O)=[N:20][CH:21]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH2:24]([O:26][C:27]([C@H:29]1[CH2:32][C@@H:31]([NH2:33])[CH2:30]1)=[O:28])[CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClC(Cl)C>>[CH2:24]([O:26][C:27]([CH:29]1[CH2:32][CH:31]([NH:33][CH2:22][C:19]2[CH:18]=[N:17][C:16]([C:13]3[N:12]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=4)[O:15][N:14]=3)=[CH:21][N:20]=2)[CH2:30]1)=[O:28])[CH3:25]
Reactant: CC(C)Cc1ccc(-c2nc(-c3cnc(C=O)cn3)no2)cc1
Reactant: CCOC(=O)[C@H]1C[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1CC(NCc2cnc(-c3noc(-c4ccc(CC(C)C)cc4)n3)cn2)C1

Procedure:
A solution of 5-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyrazine-2-carbaldehyde (0.100 g, 0.32 mmol), cis-3-amino-cyclobutanecarboxylic acid ethyl ester (0.056 g, 0.388 mmol), sodium triacetoxyborohydride (0.082 g, 0.388 mmol) and dichloroethane (5.0 mL) was stirred at room temperature for 12 hours. The reaction mixture was quenched with 1N NaOH (10 mL) and the organic layer was isolated, washed with H2O (2×10 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound as a crude solid.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[Br:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[CH2:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:24](=[O:25])[CH2:23][Br:22])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCCCNCc1ccccc1
Reactant: O=C(Cl)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCN(Cc1ccccc1)C(=O)CBr
Yield: 58.4 %

Procedure:
N-hexylbenzylamine (4.2 g, 21.953 mmol) and triethylamine (3.98 ml, 28.539 mmol) were mixed in DCM (20 ml) and cooled in an ice-bath. Bromacetyl chloride (3.455 mg, 21.953 mmol) in DCM (5 ml) was added. The mixture was stirred over weekend and the temperature was allowed going up to room temperature. The mixture was washed with water mixed with 1% hydrochloric acid (water phase pH˜4-5) and brine, dried with magnesium sulphate, and evaporated. Column chromatography of the residue on silica gel using ethyl acetate/heptane (10:90, then 20:80) as eluant gave 4.0 g desired product, yield 58%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][CH:10]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)=[O:20])[CH2:15]2)[CH2:9][CH2:8]1
Reactant: O=C1CCC(c2cnccn2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3cnccn3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-pyrazin-2-yl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([NH:22][C:23](=[O:27])[CH2:24][CH2:25]Cl)([CH3:21])([CH3:20])[CH3:19]>C(O)C>[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([N:8]([CH2:25][CH2:24][C:23]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:27])[NH2:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)(C)NC(=O)CCCl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(N(N)CCC(=O)NC(C)(C)C)cc1
Reaction time: 14 h
Yield: 64.3 %

Procedure:
To a solution of tert-butyl amine (1.0 gm, 13.6 mmol) in dichloromethane (50 ml) was added 3-chloropropionyl chloride (2.06 g, 16.3 mmol) and NaOH (650 mg, 16.25 in 2.0 ml H2O) solution simultaneously at −20 deg C. for 1 h. The reaction mixture was allowed to stir for 1 h at RT. The organic layer was washed with 5% HCl followed by 5% aqueous sodium bicarbonate. The organic layer was dried and concentrated to get 2.23 g (yield: 99%) N-tert-butyl-3-chloropropanamide as white solid. To a solution of p-Tolylhydrazine hydrochloride (500 mg, 3.16 mmol) in ethanol (15 ml) was added triethylamine (1.31 ml, 9.4 mmol) and N-tert-butyl-3-chloropropanamide (510 mg, 3.12 mmol). The resulting reaction mixture was heated at 90 deg C. for 14 hrs. The reaction mixture was concentrated to dryness and basified with aqueous saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to obtain the crude, which was purified by silica gel chromatography (Eluent: 10% MeOH in dichloromethane) to obtain 500 mg (yield: 63.3%) of 3-(1-p-tolylhydrazinyl)-N-tert-butylpropanamide. The amide obtained (500 mg, 2.0 mmol) and N-methyl-4-piperidone hydrochloride (298 mg, 2.0 mmol) were dissolved in ethanolic HCl (20 ml) and stirred at RT for 15 minutes. The solvent was removed in vacuo. The reaction mixture obtained was dissolved in ethanol and heated at 90 deg C. for 14 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated to dryness and basified with aqueous saturated sodium bicarbonate, extracted with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated. The crude obtained was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml) to obtain 10 mg (yield: 1.12%) of the desired product as TFA salt. 1H NMR (DMSO-D2O) TFA SALT 7.30-7.25 (d, 1H), 7.20 (s, 1H), 7.0-6.95 (d, 1H), 4.5 (m, 1H), 4.30-4.15 (m, 3H), 3.70-3.65 (m, 1H), 3.50-3.30 (m, 1H), 3.20-3.10 (m, 2H), 2.90 (s, 3H), 2.50-2.40 (d, 2H), 2.30 (s, 3H), 1.10 (s, 9H).