Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[C:6]=1[CH3:13].[C:14]1(=[O:20])[NH:18][C:17](=[O:19])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:12][C:7]1[C:6]([CH3:13])=[C:5]([O:4][CH2:3][CH2:2][N:18]2[C:14](=[O:20])[CH2:15][CH2:16][C:17]2=[O:19])[CH:10]=[CH:9][N+:8]=1[O-:11]
Reactant: O=C1CCC(=O)N1
Reactant: Cc1c(OCCCl)cc[n+]([O-])c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1c(OCCN2C(=O)CCC2=O)cc[n+]([O-])c1C
Yield: 22.7 %

Procedure:
A mixture comprising 0.40 g (2 mmol) of 4-(2-chloroethoxy)-2,3-dimethylpyridine N-oxide, 0.30 g (3 mmol) of succinimide, 0.48 g (3.5 mmol) of potassium carbonate and 30 ml of methyl ethyl ketone was heated under reflux for 2 hours, cooled by allowing to stand and filtered. The filtrate was evaporated to dryness to remove the methyl ethyl ketone. The obtained residue was purified by silica gel column chromatography (solvent: CHCl3 /MeOH=19:1) to obtain 0.12 g of 2,3-dimethyl-4-(2-succinimidoethoxy)pyridine N-oxide as a white crystal.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]#[N:34])=[CH:23][CH:22]=1>CN(C)C=O>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:1][C:2]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=2)=[CH:26][CH:25]=1)#[N:34]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCOC(=O)c1cn(C)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)nc1NCc1ccc(-c2ccccc2C#N)cc1
Yield: 75.5 %

Procedure:
To a mixture of ethyl 3-amino-1-methylpyrazole-4-carboxylate (P. Schmidt et al. Hel. Chim. Acta., 1959, 41, 349.) (2.30 g) and potassium carbonate in N,N-dimethylformamide (70 ml), was added portionwise 4-bromomethyl-2'-cyanobiphenyl (4.81 g). The solvent was distilled under reduced pressure. To the residue was added ice-water and an aqueous solution of potassium carbonate. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, which was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give crude crystals, which were recrystallization from ethyl acetate-isopropylether to afford the title compound as white crystals (3.7 g, 76%), m.p. 151°-152° C.
Reaction SMILES: [C:1](=[O:42])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]1[CH2:7][C@H:6]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[C@H:5]([CH2:30][CH3:31])[CH2:4]1.[CH:43]1([NH2:46])[CH2:45][CH2:44]1.[OH-].[Na+]>O1CCOCC1>[CH:43]1([NH:46][C:1](=[O:42])[O:2][C@H:3]2[CH2:7][C@H:6]([C:8]3[N:12]4[C:13]5[CH:19]=[CH:18][NH:17][C:14]=5[N:15]=[CH:16][C:11]4=[N:10][N:9]=3)[C@H:5]([CH2:30][CH3:31])[CH2:4]2)[CH2:45][CH2:44]1
Reactant: CC[C@@H]1C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@@H](OC(=O)NC2CC2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a scalemic mixture enriched in (1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl 4-nitrophenyl carbonate (0.211 g, 0.357 mmol) in 1,4-dioxane (1.5 mL) was added cyclopropanamine (0.102 g, 1.786 mmol). After about 1 h, aqueous NaOH (1N, 1.5 mL, 1.5 mmol) was added and the reaction mixture was heated at about 60° C. for about 30 min then cooled to ambient temperature. The reaction mixture was extracted with DCM (3×5 mL). The combined organic solvents were concd under reduced pressure. The residue was purified using silica gel chromatography eluting with 0-100% EtOAc:MeOH (9:1) in EtOAc to give (1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl cyclopropylcarbamate (0.0847 g, 67%): LC/MS (Table 1, Method b) Rt=1.73 min; MS m/z: 355 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]=[C:28]=[O:29]>O1CCCC1>[CH3:26][NH:27][C:28](=[O:29])[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:14]=1
Reactant: CN=C=O
Reactant: Oc1cccc(C2CCCN2Cc2ccncc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2Cc2ccncc2)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a stirred solution of 3-[1-(4-pyridinylmethyl)-2-pyrrolidinyl]phenol (0.60 g) in dry tetrahydrofuran (16 ml) was added milled potassium carbonate (0.36 g), followed by methyl isocyanate (0.15 ml), dropwise, at ambient temperature, under nitrogen, with stirring. The mixture was stirred for 17 hrs and filtered through a pad of celite. The filter cake was washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, ether). The appropriate fractions were collected and concentrated to afford 0.63 g (86%) of product. Trituration of the residue with petroleum ether gave the analytical sample, mp 92°-105° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:30])=O.[OH-].[Na+]>>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:30])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: N#Cc1c(N)nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(N)nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2c1Cl
Temperature: 120 °C
Reaction time: 6 h

Procedure:
The mixture of 14 g of 2-amino-3-cyano-4-hydroxy-6-(4-benzylpiperazin-1-yl)quinoline and 28 mL of phosphoryl chloride is stirred at 120° C. for 6 hours. The cooled reaction mixture is poured onto 500 g of ice, the pH of the mixture is adjusted to 8 with 10% NaOH solution, and the precipitated material is filtered off. After drying 14.5 g of the title compound is obtained, m.p.: 206° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([NH:29][CH3:30])=[CH:22][C:21]=2F)=[CH:14][C:13]=1[Cl:33].[F:34][CH2:35][CH2:36][OH:37]>C1COCC1>[Cl:33][C:13]1[CH:14]=[C:15]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([NH:29][CH3:30])=[CH:22][C:21]=2[O:37][CH2:36][CH2:35][F:34])[CH:16]=[CH:17][C:12]=1[F:11]
Reactant: OCCF
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CNc1cc(OCCF)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
KHMDS (0.320 g, 1.60 mmol) is added to an ice-cooled mixture of N-(4-fluoro-3-chloro-phenyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (500 mg, 1.46 mmol), 2-fluoroethanol (0.129 ml, 2.19 mmol) and 30 ml THF. After 30 min the temperature is raised to 60° C. for 4.5 h, then it is stirred at rt overnight. Additional 2-fluoroethanol (0.129 ml, 2.19 mmol) and KHMDS (0.160 g, 0.80 mmol) are added and it is stirred for 4.5 h at 60° C. Then the mixture is diluted with satd. aq. NaHCO3-solution and the precipitate is filtered off, washed with water and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.C(N(C(C)C)C(C)C)C.Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(OCC)C>[CH3:15][O:14][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:7][C:2]([NH:1][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:3][CH:4]=1
Reactant: COc1ccc(N)cc1-c1ccccc1
Reactant: CCOC(=O)CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCOC(=O)CCCNc1ccc(OC)c(-c2ccccc2)c1
Reaction time: 4 h

Procedure:
29.5 g of 5-amino-2-methoxybiphenyl, 19.2 g of ethyldiisopropylamine and 28.9 g of ethyl 4-bromobutyrate are heated together (while stirring) for 4 hours at 125°. After cooling, the resulting reaction product is stirred with diethyl ether and filtered from the precipitated salt. The residue (remaining after evaporating off the ether) is recrystallized from isopropyl alcohol to obtain 22.5 g (48.5% of theory) of ethyl 4-(6-methoxybiphenyl-3-yl)amiobutyrate, MP 71° to 72.
Reaction SMILES: [Br:1][C:2]1[C:7](F)=[CH:6][CH:5]=[CH:4][C:3]=1[F:9].[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN(C)C1C=CN=CC=1>[C:19]([O:18][C:16]([N:10]1[CH2:15][CH2:14][N:13]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([F:9])[C:2]=2[Br:1])[CH2:12][CH2:11]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: Fc1cccc(F)c1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2Br)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A mixture of 2-bromo-1,3-difluorobenzene (0.2 g, 1.03 mmol) and tert-butyl piperazine-1-carboxylate (0.39 g, 2.07 mmol), and N,N-dimethylpyridin-4-amine (0.06 g, 0.52 mmol) was stirred at 120° C. overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give 4-(2-bromo-3-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.06 g, 16%). 1H NMR (CDCl3, 400 MHz): δ 7.25 (m, 1H), 6.87 (m, 1H), 6.81 (d, J=8.4 Hz, 1H), 3.63 (t, J=4.8 Hz, 4H), 3.01 (t, J=4.8 Hz, 4H), 1.5 (s, 9H). LC/MS (Table 1, Method 2) Rt=1.300 min; MS m/z: 303 [M+H−56]+ and 305 [M+H−56]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:23])[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:24][O:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].O>N1C=CC=CC=1>[CH2:16]([N:11]1[CH2:10][CH:9]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:28]([CH2:27][CH2:26][O:25][CH3:24])(=[O:30])=[O:29])[CH:7]=[CH:6][CH:5]=3)([OH:23])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCCS(=O)(=O)Cl
Reactant: Nc1cccc(C2(O)C3CCC2CN(Cc2ccccc2)C3)c1
Solvent: O
Solvent: c1ccncc1
Product: COCCS(=O)(=O)Nc1cccc(C2(O)C3CCC2CN(Cc2ccccc2)C3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-(3-Amino-phenyl)-3-benzyl-3-aza-bicyclo[3.2.1]octan-8-ol (1.63 g, 5.28 mmol) stirred in pyridine (20 ml) at 0° C. was charged with 2-methoxy-ethanesulfonyl chloride (1.26 g, 7.93 mmol) dropwise causing a color change from yellow to bright orange. The reaction was warmed to room temperature and judged complete by TLC after 1 h. Following addition of water (20 ml), the product was extracted with EtOAc (4×30 ml), washed with saturated aqueous NaCl solution (6×30 ml), dried over Na2SO4, filtered and concentrated to a crude red oil (2.37 g, >100%). 1H NMR (400 MHz, CDCl3) δ 7.35–7.10 (m, 4H), 3.78 (ddd, J=7.5, 3.3, 2.1 Hz, 2H), 3.59 (s, 2H), 3.36 (d, J=2.5 Hz, 3H), 3.17, (m, 2H), 2.85 (d, J=16.3 Hz, 3H), 2.61 (d, J=8.3 Hz, 2H), 2.36 (s, 2H), 1.79 (d, J=7.0 Hz, 2H), 1.37 (d, J=10.0 Hz, 2H); APCI MS m/z 431.2 (M+1)+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:22]>O.[Cu]Br>[Br:22][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: Br
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a mixture of 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (10 g, 39 mmol) in 40% HBr (100 mL) was added dropwise a solution of sodium nitrite (3.2 g, 46 mmol) in water (10 mL). The mixture was stirred for 20 minutes before it was poured into a solution of copper(I) bromide (8.4 g, 59 mmol) in 40% HBr (100 mL) at 0° C. The resulting dark brown mixture was stirred for 30 minutes and was then diluted with water. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by chromatography on silica gel (5-10% ethyl acetate in petroleum ether) to afford 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (7.1 g, 57%). 1H NMR (300 MHz, CDCl3) δ 7.60 (s, 4H), 3.58 (s, 1H). MS (ESI) m/z (M−H+) 321.0.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15](ON1C(=O)CCC1=O)=[O:16]>CN(C=O)C>[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:16]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Yield: 151.8 %

Procedure:
After 109.2 g (0.27 mol) of H-Arg-CHA.2HCl was dissolved in 290 ml of DMF, 70.2 ml (0.54 mol) of NEM was added to the solution. Further 81.7 g (0.3 mol) of BOC-Gly-OSu was added thereto at 0° to 5° C. The resulting mixture was reacted at room temperature for 18 hours. After completion of the reaction, DMF was distilled under reduced pressure. The residue was dissolved in 500 ml of MeOH and the solution was reprecipitated in 8 liters of AcOEt. The precipitated crystals were taken by filtration and dried to give 135.8 g (100%) of BOC-Gly-Arg-CHA.HCl.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH:21]=O)[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:21][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH3:28])=[C:18]([O:17][CH2:15][CH3:16])[CH:19]=2)[CH2:10][CH2:9]1)[CH3:16]
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: NCCCN1CCN(CCCN)CC1
Product: CCOc1ccc(CNCCCN2CCN(CCCNCc3ccc(OCC)c(OCC)c3)CC2)cc1OCC
Yield: 80 %

Procedure:
The title compound was prepared by a similar way as in Preparation Example 1, except that 1,4-bis(3-aminopropyl)piperazine was used instead of trans-1,2-cyclohexane diamine and 3,4-diethoxybenzaldehyde was used instead of veratraldehyde.
Reaction SMILES: CO[C:3]1[CH:19]=[C:18]([NH:20][C:21]2[C:22]3[N:23]([CH:32]=[CH:33][N:34]=3)[C:24]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)=[CH:25][N:26]=2)[CH:17]=[CH:16][C:4]=1C(NCC1C=NC(C)=CC=1)=O.BrC1N2C=CN=C2C(NC2C=CC([CH:52]3[CH2:57][CH2:56][N:55]([CH:58]([CH3:60])[CH3:59])[CH2:54][CH2:53]3)=CC=2)=NC=1>>[CH:58]([N:55]1[CH2:56][CH2:57][CH:52]([C:4]2[CH:3]=[CH:19][C:18]([NH:20][C:21]3[C:22]4[N:23]([CH:32]=[CH:33][N:34]=4)[C:24]([C:27]4[CH:28]=[N:29][NH:30][CH:31]=4)=[CH:25][N:26]=3)=[CH:17][CH:16]=2)[CH2:53][CH2:54]1)([CH3:60])[CH3:59]
Reactant: CC(C)N1CCC(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: COc1cc(Nc2ncc(-c3cn[nH]c3)n3ccnc23)ccc1C(=O)NCc1ccc(C)nc1
Product: CC(C)N1CCC(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ccnc34)cc2)CC1

Procedure:
This step may be performed using the same methods as described for Compound 184, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(1-isopropylpiperidin-4-yl)-phenyl]amine. LCMS: Rt 0.78 min (100%) m/z (ESI) 402 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([CH3:15])([S:7]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:9])=[O:8])[CH3:6])C.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:15][C:5]([S:7]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:9])=[O:8])([CH3:6])[C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)CCC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CCS(=O)(=O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
To a solution of 3.78 g (15.09 mol) of 2-methyl-2-(3-methyl-butane-1-sulfonyl)-propionic acid ethyl ester in THF/water (4/1, 50 mL) are added 1.58 g (37.74 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 18 h. The reaction mixture is concentrated under reduced pressure and the residue dissolved in DCM (20 mL) and extracted with water (50 mL). The aqueous layer is cooled in an ice bath and then acidified with 6M aqueous HCl solution to pH 1. The resulting precipitate is isolated by filtration, and dried under reduced pressure at 50° C. to afford 3.35 g of 2-methyl-2-(3-methyl-butane-1-sulfonyl)-propionic acid as white crystalline solids. Yield: 100%; ES-MS: m/z 221 [M−H].
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.CN1CC[O:11][CH2:10][CH2:9]1.C(Cl)(=O)C.[OH-].[Na+]>C(Cl)Cl>[NH:1]1[C:5]([NH:6][C:10](=[O:11])[CH3:9])=[CH:4][CH:3]=[N:2]1
Reactant: Nc1ccn[nH]1
Reactant: CN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccn[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.7 %

Procedure:
To a solution of 1H-pyrazol-5-amine (50 g, 0.602 mol) and N-methylmorpholine (160 mL, 1.44 mol) in CH2Cl2 (2 L) was added acetyl chloride (99 mL, 1.38 mol) dropwise at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 1 d. Some di-acylated product was observed in an LCMS. The reaction mixture was concentrated in vacuo and the resulting solid was suspended in MeOH (2 L) and cooled to 0° C. 4 M NaOH solution (aq., 440 mL, 1.75 mol) was added slowly and the mixture allowed to warm to room temperature over 1.5 h. The MeOH was removed in vacuo and the solid was collected by filtration, washed with minimal cold water and dried in vacuo to provide the title compound as a solid (60 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[F:21][C:22]1[CH:36]=[CH:35][C:25]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>O1CCCC1>[CH:9]1([CH:15]([C:26]([C:25]2[CH:35]=[CH:36][C:22]([F:21])=[CH:23][CH:24]=2)([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[OH:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)CC1CCCCC1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C1CCCCC1)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 813.5 %

Procedure:
Lithium diisopropylamide (56 mL of 1.8M, 100 mmol) was added to a solution of ethyl cyclohexylacetate (16.0 g, 100 mmol) in 50 mL tetrahydrofuran at -40° C. and the solution stirred for 0.5 hour. After further cooling to -70° C., 4,4'-difluorobenzophenone (10.9 g, 50 mmol) was added and the solution stirred for 1 hour at -70° C. and then allowed to warm to -10° C. during the next 2 hrs. The reaction was quenched with 2N hydrochloric acid and extracted with diethyl ether. The extracts were dried with magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 158 g of the title compound; m.p. =118°-119° C.
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[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.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:32])[CH2:30]Br)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C.Cl>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:32])[CH2:30][S:20][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In this example, heterocylic-protected glycine is synthesized by first forming an Nα-(auxiliary group)-substituted glycine, followed by deprotection and then cyclization by reaction with formalehyde. Triphenylmethyl mercaptan (Aldrich), 4 mmol, and 4′-methoxy-2-bromoacetophenone (Aldrich), 4 mmol, are dissolved in 2 mL DMF, after which 4 mmol DIEA is added. The mixture is stirred at room temperature for 1 hour, after which it is poured in diluted HCl, extracted with ethylacetate, and dried over sodium sulfate. The resulting oil is dissolved in ethylacetate and precipitated by addition of petroleum ether, which after evaporation gives a white solid, 4′-methoxy-2-(triphenylmethylthio)-acetophenone. This compound, 1.44 mmol, and aminoxyacetic acid, 4.3 mmol, are dissolved in 20 mL of trimethylorthoformate (TMOF), after which 0.047 mL of methanesulfonic acid is added as a catalyst. After incubation at room temperature for 48 hours, the solvent is evaporated and the residue taken up in ethylaceetate, washed with 1M monohydrogenpotassium sulfate and dried over sodium sulfate, after which the crude product is purified with silica gel chromatography and an oxime complex is isolated. 0.556 mmol of the oxime complex is dissolved in 2 mL of tetrahydrofuran (THF) and 1.67 mL of 1 M BH3/THF complex is added. After 24 hours, 3 mL of water and 1.5 mL of 10 N sodium hydroxide is added and the mixture is refluxed for 1 hour, after which the mixture is extracted with ethylacetate (4×) and dried over sodium sulfate. The final product of 1-amino-1-(4-methoxyphenyl)-2-(triphenylmethylthio)-ethane, is purified using silica gel chromatography. The 1-amino-1-(4-methoxyphenyl)-2-(triphenylmethylthio)-ethane is then reacted with BrNα-glycine in the presence of a base to give the Nα-(auxiliary group)-substituted glycine, preferably attached to a solid phase support. After deprotecting the sulfhydryl of this compound by treatment with TFA/TIS as described above, the cyclization reaction is carried out by treatment with formaldehyde. The final product is cleaved from the solid phase support by conventional means.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:10]([SH:12])[CH3:11].C1(O)C=CC=CC=1>>[CH2:10]([S:12][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:11]
Reactant: CCS
Reactant: OCc1ccc(O)cc1
Solvent: Oc1ccccc1
Product: CCSCc1ccc(O)cc1
Temperature: 85 °C
Yield: 65 %

Procedure:
A mixture of 62 g (0.5 mol) of 4-hydroxymethyl-phenol, 37 g (0.6 mol) of ethylmercaptan and 230 g of phenol was first heated, in a flask equipped with stirrer and reflux condenser, under normal pressure to about 85° C. in the course of about 15 minutes, and was then heated further in such a way that there was always a moderate reflux and that ultimately a final temperature of about 130° C. in the flask was reached. After a reaction time of 18 hours at 85°-130° C., the mixture was cooled and worked up by distillation. 4-Ethylthiomethyl-phenol was obtained in a yield of 65% of theory.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.OO.FC(F)(F)C(O)=[O:15]>C(O)(=O)C>[NH:1]1[C:9]2[CH:8]=[CH:7][N+:6]([O-:15])=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: c1cc2[nH]cnc2cn1
Reactant: O=C(O)C(F)(F)F
Agent: OO
Solvent: CC(=O)O
Product: [O-][n+]1ccc2[nH]cnc2c1
Temperature: 73 °C
Reaction time: 72 h

Procedure:
1H Imidazo[4,5-c]pyridine (4.0 g, 33.6 mmol) was dissolved in 60 ml of fresh acetic acid, heated to 73° C.±1° C. and to the solution was added 8.8 ml of 30% H2O2 (78 mmol). After stirring and heating at 73° C. for 24 hrs, an additional 5 ml of H2O2 was added as well as 1 ml of trifluoroacetic acid. Heating at 73° C. was continued for an additional 3 days. After concentrating, an aliquot NMR (D2O) shows a 2:1 product: starting material mixture. Concentration of the main reaction mixture was followed by trituration of the residue with 50 ml of acetonitrile. The filtered insolubles 1.6 g (35%) are pure N-oxide by TLC, (reverse phase, 9:1 H2O:THF) 200 MHz NMR (D2O, δ from TSP): 7.82 (1H, d, J=7 Hz) 8.21 (1H, d of d, J=7 Hz, J=1 Hz) 8.52 (1H, s) 8.84 (1H, d, J=1).