Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S)C=CC=CC=1.C(N(CC)CC)C.[N:15]([CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:27])[CH:20]=1)=[N+]=[N-]>C(#N)C>[NH2:15][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:27])[CH:20]=1
Reactant: N#Cc1ccc(CN=[N+]=[N-])cc1F
Agent: Sc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN)cc1F
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
To a suspension of stannous chloride dihydrate (0.45 g, 2.4 mmol) in 20 mL of acetonitrile under stirring was added thiophenol (1.07 g, 9.7 mmol) and triethylamine (0.726 g, 7.17 mmol). Thereafter was added a solution of 4-azidomethyl-2-fluorobenzonitrile (0.279 g, 1.58 mmol; see step (iv) above) in a few mLs of acetonitrile. After 1.5 h, the azide was consumed and the solvent was evaporated. The residue was dissolved in methylene chloride and washed three times with 2M NaOH. The organic phase was extracted twice with 1M HCl. The combined acidic aqueous phase washed with methylene chloride and then made alkaline with 2M NaOH and extracted three times with methylene chloride. The organic phase was dried (Na2SO4) and evaporated to give 0.172 g (72%) of the desired sub-title compound which could be used without purification.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH2:24]([CH2:28][C:29](=O)[CH3:30])[C:25]([CH3:27])=O.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.CCCCCC.C(O)C>[CH3:30][C:29]1[N:5]([S:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:17])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][CH:14]=2)(=[O:7])=[O:8])[C:25]([CH3:27])=[CH:24][CH:28]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NS(=O)(=O)c1ccc(CC(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1S(=O)(=O)c1ccc(CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
Thionyl chloride (25 mL, 0.34 mol) was added dropwise to ethanol (540 mL). The reaction was heated to reflux for 15 minutes and cooled. The solution was treated with 2-[4-aminosulfonylphenyl]-1-phenyl-ethan-1-one from Step 1 (20.0 g, 72.64 mmol) and acetonylacetone (12.8 mL, 108.96 mmol), and reheated to reflux for 30 minutes. After cooling to room temperature, the solution was poured into rapidly stirred saturated aqueous Na2CO3 and ice (1500 mL). The aqueous phase was extracted with ethyl acetate (2×700 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo, yielding a brown oil. The oil was diluted with ethyl acetate (200 mL) and hexane (2000 mL), dried with MgSO4, gravity filtered, then purified through a short silica gel column with hexane and ethyl acetate (1:1) as eluant. The material was concentrated in vacuo and crystallized from hexane/ethyl acetate. The solid was isolated by filtration and air dried to afford 2,5-dimethyl-1-[[4-(2-oxo-2-phenylethyl)phenyl]sulfonyl]-1H-pyrrole (12.2 g, 49%) as a brown solid: mp 94.6°-98.8° C. 1H NMR (DMSO-d6 /300 MHz) 8.05 (d, J=7.25 Hz, 2H), 7.76 (d, J=8.26 Hz, 2H), 7.65 (t, J=7.85 Hz, 1H), 7.54 (t, J=7.85 Hz, 1H), 7.44 (d, J=8.26 Hz, 2H), 7.30 (br s, 2H), 4.52 (s, 2H). Mass spectrum: M+H obs. at m/z=354.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[CH:6][CH:7]=1
Reactant: NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(CCCc1ccccc1)NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (236 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2) The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (501 mg, 76%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[C:15]([N:17]=[CH:18][O-])#[N:16]>C(#N)C>[C:15]([NH:17][CH:18]=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)#[N:16]
Reactant: N#CN=C[O-]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC#N
Product: CN(C)Cc1ccc(CSCCN=CNC#N)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.6 g of 5-[[(2-aminoethyl)thio]methyl]N,N-dimethylfuranmethanamine (prepared according to Belgian Pat. No. 857,388, hereby incorporated by reference) in 35 ml of acetonitrile are added dropwise 2.56 g of N-cyano-formimidate in 15 ml of acetonitrile, under cooling at 0° C. The mixture is maintained under stirring for 30 minutes and the acetonitrile is removed by vacuum evaporation. A solid residue is formed, which is crystallized from ethyl acetate. 2.1 g are obtained of N-cyano-N'-[2-[[[5-[(dimethyl-amino)methyl]-2-furanyl]methyl]thio]ethyl]formamidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:18][C:19]1([CH3:28])[CH2:24][C:23](=O)[CH2:22][C:21]([CH3:27])([CH3:26])[O:20]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:23]2[CH2:22][C:21]([CH3:27])([CH3:26])[O:20][C:19]([CH3:28])([CH3:18])[CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(O)c(Cl)c1
Reactant: CC1(C)CC(=O)CC(C)(C)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(Br)cc2)c2ccc(O)c(Cl)c2)CC(C)(C)O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.3 %

Procedure:
To a stirred suspension of zinc powder (0.59 g, 8.99 mmol) in THF (20 mL) was slowly added TiCl4 (0.50 mL, 4.50 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of (4-bromophenyl)(3-chloro-4-hydroxyphenyl)methanone (105) (0.35 g, 1.12 mmol) and 2,2,6,6-tetramethyl tetrahydro-4H-pyran-4-one (0.54 g, 3.37 mmol) in THF (6 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 1.5 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (20 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (25 mL). The combined organic phase washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as yellow viscous oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc:hexanes to give 0.47 g (96%) of compound 130 as a yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 1.20 (s, 6H), 1.22 (s, 6H), 2.18 (s, 2H), 2.22 (s, 2H), 5.47 (s, 1H), 6.90-7.00 (m, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.09 (d, J=1.6 Hz, 1H), 7.43 (d, J=8.3 Hz, 2H). LCMS (ESI), m/z 433 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2ccsc2)n1
Product: c1cn(CCCc2ccc(OCc3coc(-c4ccsc4)n3)cc2)cn1
Yield: 65 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(3-thienyl)oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(3-thienyl)oxazole. The yield was 65%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 102-103° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([N:26]([CH2:34][CH3:35])[C:27](=[O:33])[CH2:28][CH2:29][C:30](O)=[O:31])[CH3:25]>>[CH2:34]([N:26]([CH2:24][CH3:25])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:31])[CH3:35]
Reactant: CCN(CC)C(=O)CCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCN(CC)C(=O)CCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-(diethylamino)-4-oxobutanoic acid to yield (3aR,4S,7aR)-methyl 4-(4-(diethylamino)-4-oxobutanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=1.22 min; UPLC Method I
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[N:6][CH:7]=1.C(N(CC)CC)C.C(O)=O>C1(C)C=CC=CC=1>[CH:11]1([C:9]([NH:8][C:5]2[C:4]([N+:14]([O-:16])=[O:15])=[C:3]([CH3:17])[CH:2]=[CH:7][N:6]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: Cc1c(Br)cnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: Cc1ccccc1
Product: Cc1ccnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Yield: 72.3 %

Procedure:
Toluene (60 ml) was added to 3.0 g (10.0 mmol) of 5-bromo-2-cyclopropanecarboxamido-4-methyl-3-nitropyridine, 10% Pd--C (100 mg) and 2.9 g (28.6 mmol) of triethylamine, followed by stirring and heating under reflux. 1.9 g (41.3 mmol) of formic acid was dropwise added to this solution, followed by stirring for 5 hours. The reaction liquid was brought to room temperature and filtered to remove the catalyst. The filtrate was subjected to vacuum concentration. Chloroform (100 ml) and water (100 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) once. The organic phases were combined, dried over anhydrous magnesium sulfate'and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 1.6 g of the title compound (yield 72).
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].[Cl:10][CH2:11][C:12](Cl)=[O:13].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([N:3]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:12](=[O:13])[CH2:11][Cl:10])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCNC1CCCCC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(C(=O)CCl)C1CCCCC1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
N-Ethyl-cyclohexylamine (2.6 g) is dissolved in dry benzene (20 ml). To the solution are added dropwise with stirring chloroacetyl chloride (2.6 g) and triethylamine (2.4 g) under ice-cooling. The mixture is stirred under ice-cooling for one hour and further at room temperature for one hour. The reaction mixture is poured onto ice-water and extracted with ether. The ether layer is washed with an aqueous sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue is distilled under reduced pressure to give N-ethyl-N-cyclohexyl-chloroacetamide (3 g), b.p. 118°-120° C./0.2 mmHg.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:23][CH2:22]2)[CH:4]=[CH:3][CH:2]=1.C1(CN)C=CC=CC=1>CO.[Pd]>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(=O)CN1CCC(Nc2nc3ccccc3n2-c2cccc3cccnc23)CC1
Agent: [Pd]
Solvent: CO
Solvent: NCc1ccccc1
Product: CC(C)C(=O)CN1CCC(Nc2nc3ccccc3n2-c2cccc3c2NCCC3)CC1
Reaction time: 24 h
Yield: 27.1 %

Procedure:
A mixture of 1-[4-[[1-(8-quinolinyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-3-methyl-2-butanone (0.0222 mol) and benzenemethanamine (0.0666 mol) in methanol (250 ml) was hydrogenated at 40° C. under a 3 bar pressure for 24 hours with palladium on activated carbon (1.5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered through celite, washed with CH2Cl2 and CH3OH and the filtrate was evaporated. Palladium on activated carbon (1.5 g) and methanol (250 ml) were added again. Hydrogenation was continued at 40° C. under a 3 bar pressure for 24 hours. After uptake of hydrogen, the catalyst was filtered through celite, washed with CH2Cl2 and the filtrate was evaporated. The residue (22 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.1 and 85/15/1; 20-45 μm). Three pure fractions were collected and their solvents were evaporated, yielding 2.6 g 1-[4-[[1-(1,2,3,4-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-3-methyl-2-butanone (interm. 40) (fraction 1), 2.9 g of fraction 2 and 0.7 g of fraction 3. Fraction 2 and 3 were crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.82 g (±)-N-[1-[3-methyl-2-[(phenylmethyl)amino]butyl]-4-piperidinyl]-1-(1,2,3,4-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-amine; mp. 126° C. and 0.55 g of N-(4-piperidinyl)-1-(1,2,3,4-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-amine; mp. 205° C. (comp. 48).
Reaction SMILES: [C:1]1([O:11][C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23]>C1(C)C=CC=CC=1>[C:1]1([O:11][C:12]2[CH:18]=[CH:17][C:15]([NH:16][C:25]([NH:24][C:22](=[O:23])[C:21]3[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=3[Cl:19])=[O:26])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Nc1ccc(Oc2cccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1ccccc1Cl)Nc1ccc(Oc2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4.7 g (0.020 mol) of 4-(α-naphthoxy)-aniline in 100 ml of absolute toluene were added 3.65 g (0.020 mol) of o-chlorobenzoyl isocyanate. The reaction solution thus obtained was stirred at room temperature for 15 hours. During this time the product crystallized out. It was removed by suction filtration, washed with toluene, and dried.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[C:26]1(C)C=CC=CC=1>CO>[F:1][C:2]([F:20])([F:21])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([O:9][CH3:26])=[O:8]
Reactant: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: Cc1ccccc1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Yield: 98 %

Procedure:
A solution of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (20 g) and thionyl chloride (15.0 g) in methanol (100 ml) was stirred at 80° C. for 2 hours. The solvents were evaporated under vacuum to give an oil residue. Toluene (100 ml) was added to the residue and the solution was washed with saturated NaHCO3 (30 ml) solution followed by water (3×30 ml). The organic layer was concentrated under reduced pressure to give the product as a white solid (20.5 g, yield 98.0%).
Reaction SMILES: CC1(C)OC(=O)[CH:5]([CH2:9][C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:4](=O)[O:3]1.CCCCCC>C1(C)C=CC=CC=1>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C@H:10]2[CH2:9][CH2:5][C:4](=[O:3])[N:22]2[C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CC1C(=O)OC(C)(C)OC1=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1Cc1ccc(C(F)(F)F)cc1

Procedure:
(R)-tert-Butyl 3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (10.0 g, 22.5 mmol) in 100 mL toluene was heated at 105° C. for 3 hours. Hexane was added, and the mixture was sonicated. The resulting solid was filtered. The desired product was obtained as a white amorphous solid (21.0 g, yield 98%). No further purification was performed and the reaction was carried on to the next step.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:50]=[CH:49][C:12]([C:13]([N:15]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:27][N:26]=[C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=5)=[CH:30][CH:29]=4)[N:24]=3)=[CH:19][CH:18]=2)=[O:14])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:8][C:9]1[CH:50]=[CH:49][C:12]([C:13]([N:15]([CH2:41][C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[O:27][N:26]=[C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=5)=[CH:30][CH:29]=4)[N:24]=3)=[CH:21][CH:22]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2ccc(-c3noc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc(NC(=O)OC(C)(C)C)cc5)cc4)n3)cc2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(-c3noc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc(N)cc5)cc4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
Prepared using General Procedure 8. To a stirred solution of tert-butyl 2-(4-((tert-butoxycarbonyl)amino)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-63 (659 mg, 0.977 mmol) in DCM (15 mL) was added TFA (752 μL, 9.77 mmol) at room temperature. After 2 h additional TFA (752 μL, 9.77 mmol) was added and the reaction mixture stirred for a further 3 h at room temperature. The reaction mixture was diluted with toluene (20 mL) and the solvent removed in vacuo. The residue was diluted with EA (100 mL) and washed with NaHCO3 (30 mL). The organics were concentrated in vacuo and the crude product was purified by chromatography (EA/hexanes) to afford 284 mg (50%) of tert-butyl 2-(4-amino-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-64 as an off-white powder. LCMS-ESI (m/z) calculated for C35H34N4O4: 574; found 519 [M-t-Bu+H]+, 573 [M−H]−, tR=3.12 min (Method 10).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24](B5OC(C)(C)C(C)(C)O5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[NH2:36][C:37]1[CH:42]=[N:41][C:40](Br)=[CH:39][N:38]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:40]5[N:41]=[CH:42][C:37]([NH2:36])=[N:38][CH:39]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1
Reactant: Nc1cnc(Br)cn1
Reactant: Cc1ncnc(N2CCOc3ccc(B4OC(C)(C)C(C)(C)O4)cc3C2)c1Cc1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncnc(N2CCOc3ccc(-c4cnc(N)cn4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 95 °C
Reaction time: 16 h
Yield: 19.4 %

Procedure:
A solution of 4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.10 g, 0.21 mmol), 2-amino-5-bromopyrazine (40 mg, 0.21 mmol) and potassium carbonate (0.12 g, 0.84 mmol) in N,N-dimethylformamide (5 mL), and water (0.5 mL) was degassed by bubbling nitrogen gas for five minutes followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.021 mmol), then stirred at 95° C. for 16 hours. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (30 mL). The organic layer was separated, washed with brine, dried over sodium sulfate then filtered and concentrated. Purification by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) provided 5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyrazin-2-amine (18 mg, 20%). 1H NMR (400 MHz, d6-DMSO): 8.80 (s, 1H), 8.38 (s, 1H), 7.96 (s, 1H), 7.72 (d, 1H), 7.50 (br s, 1H), 7.25-7.14 (m, 4H), 6.93 (d, 1H), 4.90 (s, 2H), 4.32 (m, 2H), 4.00 (m, 4H), 2.22 (s, 3H). MS (EI) for C25H23FNO6: 443 (MH+).
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[CH2:1]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1CCc1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(NCc2ccccc2CCc2ccccc2)cc1

Procedure:
Methyl 4-[N-(2-(phenethyl)benzyl)amino]benzoate was prepared from 2-(phenethyl)benzaldehyde and methyl 4-aminobenzoate using a similar method to that of Example 4 paragraph (G).
Reaction SMILES: C(N[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1O)(=O)C.C([O-])(=O)C(C)=O.[Na+].[C:23]([NH:26][C@H:27]1[C@H:36]([C@@H:37]([C@@H:39]([CH2:41][OH:42])[OH:40])[OH:38])[O:35][C:30]([OH:34])([C:31](=[O:33])[O-:32])[CH2:29][C@@H:28]1[OH:43])(=[O:25])[CH3:24]>O>[C:23]([NH:26][C@H:27]1[C@H:36]([C@@H:37]([C@@H:39]([CH2:41][OH:42])[OH:40])[OH:38])[O:35][C:30]([OH:34])([C:31](=[O:32])[OH:33])[CH2:29][C@@H:28]1[OH:43])(=[O:25])[CH3:24]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)[O-])C[C@@H]1O
Agent: CC(=O)C(=O)[O-]
Agent: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: O
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Reaction time: 120 h
Yield: 39.8 %

Procedure:
To a pH 7.0˜7.5 solution of N-acetylmannosamine (2.7 g, 12.2 mmole) and sodium pyruvate (2.7 g, 24.5 mmole) in water (15 ml) was added a dialysis bag (cut off MW of 20,000) containing N-acetylneuraminate lyase [EC 4.1.3.3] (25 units) in a reaction mixture of N-acetylmannosamine (0.54 g) and sodium pyruvate (0.54 g) in water (3 ml) at pH 7.0-7.5. The reaction mixture was shaken at 60 r.p.m. at 30° C. for 5 days. The enzyme bag was removed and reused for new batch of reaction. The reaction mixture was diluted with water (15 ml), then passed through a column of Amberlite IRA-400 (HCOO− form) (150 ml). The resin was then washed with water (300 ml), eluted with 0.5M HCOOH solution. The eluate was collected and vacuum evaporated to dryness. The residue was dissolved in water (2 ml) then diluted with glacial acetic acid (10 ml) at 4° C. overnight, filtered the crystals, washed with EtOH, dried to afford N-acetylneuraminic acid as white crystalline powder (1.5 g, 39.8%).