Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:4]([CH:5](OC(=O)C)[C:6](Cl)([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[Cl-].[NH4+]>CN(C=O)C.[Zn]>[CH3:1][C:2]1([CH3:22])[CH:4]([CH:5]=[C:6]([Cl:11])[C:7]([F:8])([F:9])[F:10])[CH:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C1C(C(OC(C)=O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(C=C(Cl)C(F)(F)F)C1(C)C
Temperature: 50 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
To a solution of 183 mg (0.500 mmol) of ethyl 2,2-dimethyl-3-(1-acetoxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 9, in 0.5 ml of DMF, 35 mg (0.54 mmol) of zinc powder was added, and the mixture was stirred at 50° C. for 4 hours. After an addition of 1 ml of a saturated ammonium chloride aqueous solution, the mixture was extracted with diethyl ether (1 ml×5 times). The extract was dried over anhydrous magnesium sulfate, then filtered and concentrated under reduced pressure. The product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/3) to obtain 116 mg of ethyl 2,2-dimethyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-cyclopropane carboxylate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=1.Br[C:24]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:25]=1[CH2:26][OH:27]>>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:6]=[C:7]([C:24]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:25]=2[CH2:26][OH:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester and 2-bromo-5-(trifluoromethyl)benzyl alcohol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:34](=[O:39])([O:36][CH2:37][CH3:38])[NH2:35]>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:35][C:34](=[O:39])[O:36][CH2:37][CH3:38])[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Cl)c3)C(C)(C)C2=O)cc1
Reactant: CCOC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1
Temperature: 105 °C
Yield: 45.3 %

Procedure:
To a solution of 3.5 g of 3-(4-tert-butylphenyl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage a) of Example 7 in 90 mL of dioxane are successively added, under argon, 406 mg of palladium diacetate, 1.1 g of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine)[xantphos], 12.9 g of caesium carbonate and 1.86 g of ethyl carbamate. The reaction mixture is heated at 105° C. for 7 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of cyclohexane and ethyl acetate (60/40 by volume) to give 1.8 g of ethyl (4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]methyl}pyridin-2-yl)carbamate, the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([NH:21][C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[CH:9]=2)=[CH:4][CH:3]=1.[Si]([O:34][CH2:35][CH2:36]Br)(C(C)(C)C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:34][CH2:35][CH2:36][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([NH:21][C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1ccc(-n2nc(NC(=O)N(C)C)cc2-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(NC(=O)N(C)C)cc2-c2ccc(OCCO)cc2)cc1
Temperature: 75 °C
Reaction time: 7 h
Yield: 83.9 %

Procedure:
A mixture of N′-[5-[4-(hydroxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea (121.9 mg), 2-(tert-butyl-dimethylsilyloxy)ethyl bromide (166 mg), and K2CO3 (95.6 mg) in DMF (1.5 ml) was stirred at 75° C. for 7 hours. 2-(tert-butyldimethylsilyloxy)ethyl bromide (83 mg) and KI (57.4 mg) was added to the reaction mixture, and the mixture was stirred at 75° C. overnight. The mixture was allowed to cool to ambient temperature, and was partitioned between ethyl acetate and H2O. The aqueous layer was reextracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by 5% MeOH/CHCl3. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give N′-[5-[4-(2-hydroxyethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea (115 mg) as an amorphous powder. 84.3 mg of amorphous powder was crystallized from AcOEt-IPE to give N′-[5-[4-(2-hydroxyethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea (79.5 mg) as a white powder.
Reaction SMILES: [CH2:1]([CH2:8][C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C1(CS(O)(=O)=O)C=CC=CC=1.C1(CS(N[C@H](C(O)=O)CC(C)C)(=O)=O)C=CC=CC=1.C(N[C@H](C(O)=O)CC(C)C)(=O)C>C1C=CC=CC=1.C(O)C>[CH2:12]([NH:19][C@H:9]([CH3:10])[CH2:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: NCc1ccccc1
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)O
Agent: CC(C)C[C@H](NS(=O)(=O)Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)Cc1ccccc1
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: C[C@H](CCc1ccccc1)NCc1ccccc1
Temperature: 25 °C

Procedure:
In an apparatus fitted with a Dean Stark trap, reflux a solution of 1.0 kg (6.75 mol) of benzylacetone, 725 g (6.75 mol) of benzylamine and 5.0 g of α-toluenesulfonic acid hydrate in 7 liters of benzene for 14 hours. Remove the solvent in vacuo, and dissolve the residue in 6.5 liters of methanol. With cooling and stirring, carefully add 125 g of NaBH4 and stir the mixture for 16 hours at room temperature. Remove the methanol in vacuo, and add 2 liters water and 4 liters benzene, and extract the product into the benzene. After drying (MgSO4), filter and distill (b.p. 145°-150° C./0.5 mm). Dissolve 1,028 g (4.288 mol) of the distillate and 1.23 kg (4.328 mol) of N-α-toluenesulfonyl-(L)-leucine in 7.2 liters of boiling ethanol and allow to cool to room temperature without agitation. Wash the precipitate with a small amount of ice-cold ethanol, recrystallize from 4.8 liters of ethanol, wash with ice-cold ethanol and filter off the solid product that is highly enriched with the salt of the undesired S enantiomer. Combine the mother liquor from the original precipitation and that from the recrystallization, remove the solvent and recover the free base by basifying with 500 ml of 20% aqueous NaOH and extracting with benzene. After drying (MgSO4), filtering and removing the benzene, dissolve the residue [487 g (2.04 mol)] and 346 g (2.06 mol) of N-acetyl-(L)-leucine in 2.0 liters of boiling ethanol and allow the solution to cool to room temperature. Filter and recrystallize once from 1.8 liter of ethanol followed by recrystallization from 4.0 liters of acetonitrile to obtain the desired R salt, m.p. 151°-152° C. Basify with 400 ml of aqueous 2.5N NaOH, extract with ether, dry (MgSO4), filter and remove the solvent in vacuo to obtain the product (2), [α]D26 =+4.5° (c=5.0, ethanol).
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16].C(CC(C)(C)C)(C)C>ClCCl>[O:7]([C:1]1[CH:2]=[CH:3][C:4]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Product: O=S(=O)(O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.3 %

Procedure:
To a stirred solution of 42.5 g (0.25 mol) of phenyl ether in 200 mL of dichloromethane at -20° C. under argon was slowly added 23.3 g (0.20 mol) of chlorosulfonic acid. After the addition was complete, the reaction was allowed to slowly warm to room temperature. After 16 hours, 150 mL of isooctane was added, and the solution was concentrated to an oily residue. Redissolution in 200 mL of 1:3 dichloromethane/isooctane and reconcentration with cooling to about 100 mL gave a solid. The supernatant was decanted, and the solid was triturated with additional isooctane and then dried in vacuo to give 55.2 g of crude 4-phenoxybenzene sulfonic acid. The crude acid was dissolved in 200 mL of dichloromethane, and 22 mL (32 g, 0.25 mol) of oxalyl chloride was added, followed by 2.5 mL of N,N-dimethylformamide. After 2 days, the reaction solution was poured into 200 mL of ice water, and extracted with 400 mL of hexane. The organic layer was washed with 100 mL of water and 100 mL of brine, dried over magnesium sulfate, and concentrated. Recrystallization of the residue from dichloromethane/isooctane gave 38.5 g of 4-phenoxybenzenesulfonyl chloride as a white solid: mp 41.5° C.; 1H--NMR (CDCl3) δ 7.10 (apparent t, 4 H, J=7 Hz), 7.28 (t, 1H, J=7 Hz), 7.46 (t, 2H, J=8 Hz), 7.98 (d, 2H, J=8.8 Hz).
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:3][CH2:4][CH2:5][NH2:6].[C:22]([NH:24][C:25](=[N:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH:39]=1)OC1C=CC=CC=1)#[N:23]>>[C:22]([NH:24][C:25]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH2:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH3:1])=[N:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]2)[CH:39]=1)#[N:23]
Reactant: CN(CCCN)CCC(c1ccccc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: CN(CCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.57 g (2 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,3-propanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; IR (KBr): 2164 cm-1 (C≡N).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[C@@H:22]([CH3:23])[CH2:21][CH2:20][C@@H:19]3[CH3:24])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][C@H:19]1[CH2:20][CH2:21][C@H:22]([CH3:23])[N:18]1[C:14]1[N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H]1CC[C@H](C)N1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CC[C@H](C)N1c1cccc(Nc2cc(-c3ccccc3)nn3ccnc23)n1
Temperature: 90 °C
Reaction time: 0.15 h
Yield: 7.6 %

Procedure:
A mixture of 6-chloro-N-(6-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.668 g, 1.95 mmol), phenylboronic acid (0.261 g, 2.14 mmol), Pd2(dba)3 (0.224 g, 0.39 mmol), X-phos (0.372 g, 0.78 mmol) and Na2CO3 (0.62 g, 5.85 mmol) in dioxane (30 mL) and water (10 mL) was heated to 90° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min). The fractions containing product were acidified by the addition of concentrated HCl and concentrated in vacuo to afford N-(6-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine (57 mg, 9% over two steps) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 8.87 (s, 1H), 8.35 (s, 1H), 7.95-7.92 (m, 3H), 7.59-7.47 (m, 4 h), 6.48 (d, 1H, J=7.8 Hz), 6.17 (d, 1H, J=8.1 Hz), 4.23 (s, 2H), 2.25 (s, 2H), 1.64-1.62 (m, 2H), 1.09 (s, 3H), 1.07 (s, 3H). LC-MS: [M+H]+, 385, tR=2.023 min, HPLC: 96.85% at 214 nm, 96.97% at 254 nm, tR=8.147 min.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)=S.[N:16]#[C:17][NH2:18].[Pb]>>[C:17]([NH:18][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)#[N:16]
Reactant: N#CN
Reactant: CNC(=S)NCCSCc1csc(N)n1
Agent: [Pb]
Product: CNC(=NCCSCc1csc(N)n1)NC#N

Procedure:
Reaction of N-methyl-N'-[2-((2-amino-4-thiazolyl)-methylthio)ethyl]thiourea with lead cyanamide by the procedure of Example 91, refluxing for 24 hours, gives the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:20](=O)[CH3:21])[C:15](OCC)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][NH2:24]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15](=[O:16])[NH:23][NH:24][C:20]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NN
Product: Cc1[nH][nH]c(=O)c1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A solution of 595 mg (1.9 mmol) of ethyl 2-(R/S)-(1-tert-butoxycarbonyl-piperidin-4-yl)-3-oxo-butanoate (from Step B) and 0.06 mL (1.9 mmol) of hydrazine in 10 mL of xylenes was heated at reflux for 2 h. The resulting mixture was cooled to rt and the solid that precipitated was filtered and dried to afford the title compound. 1H-NMR (500 MHz, CD3OD) δ 1.45 (s, 9H), 1.60 (app d, J=12.0, 2H), 1.83 (dq, J=4.0, 13.0, 2H), 2.14 (s, 3H), 2.52–2.58 (m, 1H), 2.65–2.85 (br s, 2H), 4.13 (d, J=13.5, 2H), 4.81 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:36]=[CH:35][C:13]3[N:14]([C:17]4[CH:18]=[C:19]([NH:31]C(=O)C)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])[CH:22]=4)[CH:15]=[N:16][C:12]=3[CH:11]=2)[N:7]=[N:6]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:36]=[CH:35][C:13]3[N:14]([C:17]4[CH:18]=[C:19]([NH2:31])[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])[CH:22]=4)[CH:15]=[N:16][C:12]=3[CH:11]=2)[N:7]=[N:6]1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CCN(C)C)nn4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-c3ccc(F)cc3F)c2)nn1
Temperature: 85 °C
Yield: 77 %

Procedure:
To a solution of the compound of Example 20 (450 mg, 0.9 mmol) in ethanol (10 ml) was added aqueous solution of NaOH (450 mg, 11.25 mmol, 12.5 eq.) and the mixture was heated at 85° C. for 2 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 77% yield (0.32 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][CH2:15][CH3:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[BH4-].[Na+]>C1COCC1.O.CCOC(C)=O>[CH2:15]([O:14][CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][OH:11])[CH3:16]
Reactant: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-ethoxypropanoic acid (1.81 g, 7.76 mmol) in THF (20 mL) at −15° C. was added isobutyl chloroformate (1.015 mL, 7.76 mmol) in THF (5 mL) and 4-methylmorpholine (0.853 mL, 7.76 mmol) in THF (5 mL). After stirring for 10 min at −15° C., the mixture was slowly added to a solution of sodium borohydride (0.881 g, 23.28 mmol) in H2O (7 mL). The mixture was stirred at −15° C. for 30 min and was diluted with EtOAc. The organic layer was washed with saturated aq NaHCO3 and brine and dried. The residue was carried to next step without further purification (1.6 g, 94%). [M+H] calc'd for C10H21NO4, 220. found, 220.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.C1(CCCN)CCCCC1>O1CCOCC1>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][NH2:12])[CH2:5][CH2:4]1
Reactant: COc1ccc(CCCN)cc1
Agent: NCCCC1CCCCC1
Solvent: C1COCCO1
Product: COC1CCC(CCCN)CC1

Procedure:
A solution of 1.18 g (7.1 mmol) 3-(4-methoxy-phenyl)propylamine in 50 mL of dioxane was hydrogenated at 138 bar and at 160° C. for 16 h in the presence of 0.5 g of 5% Ru/Al2O3. The catalyst was removed by filtration and the filtrate was concentrated to dryness. Preparative HPLC of the crude product by elution with 10% (10% concd NH4OH in MeOH)--CH2Cl2 furnished 723.5 mg (59%) of the cis/trans mixture of cyclohexylpropylamine (c/t=~3:1 by 1H NMR): 1H NMR (CDCl3, cis-isomer only) δ3.37 (br s, 1H), 3.27 (s, 3H), 2.64 (t, J=7.0 Hz, 2H), 2.10-0.87 (M, 15H); FDMS 172 (M+1).
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S+:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Pb+2].[CH2:31]([S:35]([OH:38])(=[O:37])=[O:36])[CH2:32][CH2:33][CH3:34]>CO>[CH2:31]([S:35]([O-:38])(=[O:37])=[O:36])[CH2:32][CH2:33][CH3:34].[C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S+:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][CH:8]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CCCCS(=O)(=O)O
Agent: CC(C)(C)Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Product: CCCCS(=O)(=O)[O-]
Temperature: 40 °C

Procedure:
In 36 g of methanol was dissolved 3.3 g (0.009 mol) of (4-tert-butoxyphenyl)diphenylsulfonium chloride. 1.7 g (0.0063 mol) of lead carbonate and 1.4 g (0.010 mol) of butanesulfonic acid were added to the solution, which was heated at 40° C. After cooling, the precipitate was filtered off and the filtrate was evaporated. 100 g of chloroform was added to the residue, the solution was washed with 100 g of water, and the solvent layer was evaporated again, obtaining 3.5 g (two-steps yield 64%) of (4-tert-butoxyphenyl)diphenylsulfonium butanesulfonate with 97% purity.
Reaction SMILES: [CH:1]12[NH:8][C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH:16][C:17]1[O:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)=[CH:20][N:21]=1.F[C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:40]([C:37]1[CH:38]=[CH:39][C:34]([N:8]2[CH2:5][CH:4]3[CH2:6][CH2:7][CH:1]2[C@@H:2]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH:16][C:17]2[O:18][C:19]([C:22]4[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:30])[F:32])=[CH:26][CH:27]=4)=[CH:20][N:21]=2)[CH2:3]3)=[CH:35][CH:36]=1)([O-:42])=[O:41]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: FC(F)(F)Oc1ccc(-c2cnc(N[C@@H]3CCCC[C@H]3NC3CC[C@H]4CCC3N4)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CC3CCC2[C@@H](N[C@@H]2CCCC[C@H]2Nc2ncc(-c4ccc(OC(F)(F)F)cc4)o2)C3)cc1
Temperature: 80 °C
Yield: 16.5 %

Procedure:
To a solution of (1R,2R)—N1-((5R)-8-azabicyclo[3.2.1]octan-2-yl)-N2-(5-(4-(trifluoromethoxy)phenyl)oxazol-2-yl)cyclohexane-1,2-diamine (28 mg, 0.062 mmol) and 4-fluoronitrobenzene (9.65 mg, 0.069 mmol) in DMF (0.38 ml) was added K2CO3. The reaction mixture was then heated at 80° C. for 4 hrs. The reaction mixture was partitioned between EtOAc and water. The organic phase was separated, dried over MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC using method A with two isomers were separating. The fractions with the desired product, which eluted later than the undesired isomer, were concentrated to give (1R,2R)—N1-((6S)-2-(4-nitrophenyl)-2-azabicyclo[2.2.2]octan-6-yl)-N2-(5-(4-(trifluoromethoxy)phenyl)oxazol-2-yl)cyclohexane-1,2-diamine (5.82 mg, 0.0102 mmol, 16.4% yield) as a yellow solid. Anal. Calcd. for C29H32F3N5O4 m/z 571.2, found: 572.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 11.04 (1 H, br. s.), 7.88 (2 H, d, J=9.3 Hz), 7.55 (2 H, d, J=8.2 Hz), 7.30 (2 H, d, J=8.2 Hz), 7.02 (1 H, s), 6.78 (2 H, d, J=9.3 Hz), 6.38 (1 H, br. s.), 4.65 (1 H, d, J=6.0 Hz), 4.36 (1 H, d, J=6.0 Hz), 4.33-4.20 (1 H, m), 3.80-3.73 (1 H, m), 3.40-3.27 (1 H, m), 2.26-1.65 (13 H, m), 1.65-1.30 (3 H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]([CH:35]([CH3:37])[CH3:36])[N:8]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17](OS(C(F)(F)F)(=O)=O)[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].[CH3:41][Sn](C)(C)C>CN(C)C=O.C1(P([Pd](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:38])[C@@H:7]([CH:35]([CH3:36])[CH3:37])[N:8]([CH2:30][CH2:31][CH:32]([CH3:33])[CH3:34])[S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:41])[CH:18]=2)[CH:13]=1)(=[O:10])=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCN([C@@H](C(=O)OC(C)(C)C)C(C)C)S(=O)(=O)c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc2cc(S(=O)(=O)N(CCC(C)C)[C@@H](C(=O)OC(C)(C)C)C(C)C)ccc2c1
Temperature: 80 °C
Yield: 48.5 %

Procedure:
To a solution of N-isoamyl-N-(6-trifluoromethanesulfonyloxy naphthalene-2-sulfonyl)-D-valine tert-butyl ester (1.1 g, 1.89 mmol) in N,N-dimethylformamide (20 mL) is added lithium chloride (0.40 g, 9.5 mmol), tetramethyl tin (0.525 mL, 3.79 mmol), and bistriphenylphosphino palladium dichloride (0.066 g, 0.095 mmol). The reaction is heated to 80° C. for 16 h. The reaction is allowed to cool to ambient temperature and filtered through Celite. The filtrate is poured over water and extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography (4% hexanes-ethyl acetate) to afford the title compound as a white solid (0.41 g, 50% yield).