Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[CH:3]=[C:4](/[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)\SC)#[N:2].O.[NH2:21][NH2:22]>CCO>[NH2:2][C:1]1[NH:22][N:21]=[C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:3]=1
Reactant: NN
Reactant: CS/C(=C\C#N)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)[nH]n2)CC1
Temperature: 25 °C

Procedure:
A mixture of (Z)-tert-butyl 4-(2-cyano-1-(methylthio)vinyl)piperazine-1-carboxylate (5.94 g, 20.9 mmol) and hydrazine monohydrate (4.5 mL) in EtOH (50 mL) was heated to reflux for 14 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by column chromatography, eluting with 0-10% MeOH/CH2Cl2 to give tert-butyl 4-(5-amino-1H-pyrazol-3-yl)piperazine-1-carboxylate.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([OH:14])(=O)[CH2:9][C:10]([OH:12])=O.[CH3:15][NH:16][C:17]([NH2:19])=[O:18].CS(C)=O>C(O)(=O)C>[CH3:15][N:16]1[C:8](=[O:14])[CH2:9][C:10](=[O:12])[NH:19][C:17]1=[O:18]
Reactant: CNC(N)=O
Reactant: O=C(O)CC(=O)O
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)CC(=O)NC1=O
Temperature: 95 °C

Procedure:
Acetic anhydride (34 ml) was added to a solution of malonic acid (20 g) and methylurea (12.5 g) in acetic acid (46 ml). The mixture was heated to 95° C. for 3 hours then cooled to room temperature. The resulting solution was concentrated under reduced pressure and the residue as 20 mM stock solutions in dimethyl sulphoxide (DMSO, Sigma #D-5879) and serial dilutions were prepared from these solutions using DMSO, 2 μL of which were added to the wells. Activity at room temperature was measured by monitoring the increase in fluorescence using a TECAN Ultra platereader with 340 nm excitation and 465 nm emission filters. The compounds provided have measured IC50 of less then 400 μM
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([O:9][C:10](=[O:32])[NH:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][O:30][NH2:31])([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([O:9][C:10](=[O:32])[NH:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][O:30][N:31]=[C:2]([CH3:4])[CH3:1])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)NCCCn1c(CON)nc2c(N)nc3ccccc3c21
Solvent: CO
Product: CC(C)=NOCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetone (20 mL) was added to a solution of tert-butyl[3-(4-amino-2-aminooxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate (3.6 g) in methanol (70 mL). The reaction mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure to provide 4.12 g of tert-butyl[3-(4-amino-2-isopropylideneaminoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate as a light yellow foam.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[N:27]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[N:26]=[CH:25][N:24]=1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([N:27]3[C:23]([CH3:22])=[N:24][CH:25]=[N:26]3)=[CH:36][CH:35]=2)[CH2:2][CH2:3]1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1
Product: Cc1ncnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cc1

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=4.54 min; Mass spectrum (ESI+): m/z=489 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:5]([O:7][CH3:8])=[O:6])#[N:2].C([Sn]([N:33]=[N+:34]=[N-:35])(CCCC)CCCC)CCC>C1COCC1>[NH:33]1[C:1]([CH2:3][CH:4]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:5]([O:7][CH3:8])=[O:6])=[N:2][N:35]=[N:34]1
Reactant: COC(=O)C(CC#N)NC(=O)OCc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1nnn[nH]1)NC(=O)OCc1ccccc1
Yield: 85.8 %

Procedure:
2.5 g (9.54 mmol, 1 equiv.) of the compound of Example 51 (3-cyano-2-benzyloxymethanamidopropionic acid, methyl ester) was dissolved in 10 mL of dry THF and 3.0 g (9.54 mmol, 1 equiv.) of tri-n-butyltin azide was added. The reaction was refluxed for 72 hours followed by concentration in vacuo. 50 mL of 1M NaOH was added and the aqueous solution was extracted with ethyl acetate (3×50 mL). The aqueous solution was acidified to pH=1 with 4M HCl and extracted with ethyl acetate (4×60 mL). After drying over sodium sulfate, the organics were decanted and concentrated in vacuo to yield 2.5 g of the title compound. 1H-NMR (CDCl3): 7.3 p.p.m (m, 5H); 6.1 p.p.m. (m, 1H); 5.1 p.p.m. (s, 2H); 4.8 p.p.m. (m, 1H); 3.8 p.p.m. (s, 3H); 3.5 p.p.m. (m, 2H).
Reaction SMILES: [OH:1][P:2]([CH2:14][C:15]([N:17]1[CH:21]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:20][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:18]1)=[O:16])([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:3].CN(C)C=O.[C:43]([O:49][CH2:50]Cl)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:45][C:44]([CH3:47])([CH3:46])[C:43](=[O:48])[O:49][CH2:50][O:3][P:2]([CH2:14][C:15]([N:17]1[CH:21]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:20][C:19]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:18]1)=[O:16])([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:1]
Reactant: O=C(OCc1ccccc1)C1CC(c2ccccc2)=NN1C(=O)CP(=O)(O)CCCCc1ccccc1
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1N=C(c2ccccc2)CC1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 4.0 g. of the benzyl ester product from part (c) dissolved in 40 ml. of dry dimethylformamide under argon is treated at ambient temperature with 1.5 g. of chloromethyl pivalate and 1.8 g. of triethylamine. After stirring overnight, the solution is diluted with ethyl acetate and washed with 10% potassium dihydrogen sulfate, water, and saturated brine. The organic solution is dried (MgSO4) and concentrated in vacuo to give the crude product. Flash chromatography on silica gel and elution with ethyl acetate/dichloromethane (1:1) gives homogeneous (+)-4,5-dihydro-1-[[[(2,2-dimethyl-1-oxopropoxy)methoxy](4-phenylbutyl)phosphinyl]acetyl]-3-phenyl-1H-pyrazole-5-carboxylic acid, phenylmethyl ester as an oil.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:17]O>>[CH3:17][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=1[Br:6]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)cc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1Br
Temperature: 25 °C
Yield: 98 %

Procedure:
Concentrated sulfuric acid (5 mL) was added drop-wise to an ice-cold mixture of 2-bromo-4-chloro-benzoic acid (10.14 g, 0.0431 mol) and methanol (40 mL). The resulting mixture was heated at reflux for 17 hours. After this time, the reaction mixture was cooled to room temperature, and then poured into ice-cold water (150 mL), creating a white suspension. The suspension was extracted with ethyl acetate (150 mL). The organic phase was washed with saturated aqueous NaHCO3 (100 mL), followed by saturated aqueous NaCl (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-bromo-4-chloro-benzoic acid methyl ester (10.57 g, 98% yield) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12]([O:14][CH3:15])=[O:13].[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:16]1([NH:22][C:23]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[CH:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]2=[O:11])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)C1C(=O)Nc2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: COC(=O)C1C(=O)N(C(=O)Nc2ccccc2)c2ccc(Cl)cc21

Procedure:
To 6.0 g. (0.027 mole) of methyl 5-chlorooxindole-3-carboxylate in 200 ml. of toluene was added 5.25 ml. (0.048 mole) of phenylisocyanate and the resulting reaction mixture heated to reflux overnight. The reaction mixture was cooled and diluted with petroleum ether to give, after filtration and drying, 2.0 g. of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]1[CH2:18][C:17](=O)[CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH3:14])[CH:17]2[CH2:16][O:15][CH2:18]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1COC1
Reactant: CNCC1CN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN(CC1CN(C(=O)OC(C)(C)C)C1)C1COC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
A mixture of 3-(methylamino)methylazetidine-1-carboxylic acid tert-butyl ester (450 mg, 2.25 mmol), oxetan-3-one (135 mg, 1.88 mmol), in dichloromethane (10 mL) was stirred at RT for 1.5 h. Sodium triacetoxyborohydride (797 mg, 3.76 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 18 h. The mixture was diluted with water, the phases were separated and the aqueous phase was extracted with EtOAc (2×25 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvents reduced in vacuo The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 5:95) to afford the title compound as a colourless oil (330 mg, 69%). 1H NMR (400 MHz, CDCl3): δ 4.64 (2 H, t, J=6.58 Hz), 4.57 (2 H, t, J=6.26 Hz), 4.01 (2 H, t, J=8.40 Hz), 3.57-3.55 (3 H, m), 2.71-2.61 (1 H, m), 2.41 (2 H, d, J=7.57 Hz), 2.08 (3 H, s), 1.44 (9 H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[OH:9]O>ClCCl.C[Re](=O)(=O)=O.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[N+:4]([O-:9])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: [O-][n+]1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
3,5-Dibromopyridine (30.5 g, 0.12 mol) was dissolved in dichloromethane (80 mL) and methlytrioxorhenium (150 mg, 0.603 mmol) was added 30% hydrogen peroxide (27 mL) was added slowly over 5 minutes and the mixture was stirred at ambient temperature for 3 hours. An additional 40 mL of hydrogen peroxide was added and the reaction was stirred 16 hours. Manganese dioxide (100 mg) was added and the suspension was stirred 40 minutes. The mixture was extracted with dichloromethane, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate was added and the suspension was refluxed for 30 minutes until solids dissolved and then the mixture was allowed to cool to ambient temperature and aged 48 hours. 3,5-dibromopyridine 1-oxide (25.09 g, 82% yield) was collected by vacuum filtration as pale yellow needles. 1H NMR (CDCl3) δ 8.27 (s, 2 H), 7.56 (s, 1 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[NH:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]1.Cl.[N:19]([O-])=[O:20].[Na+]>>[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5](=[O:17])[NH:6][CH:7]1[CH2:8][C:9]([CH3:16])([CH3:15])[NH:10][C:11]([CH3:13])([CH3:14])[CH2:12]1
Reactant: O=N[O-]
Reactant: CC1(C)CC(NC(=O)NCCCl)CC(C)(C)N1
Agent: Cl
Agent: [Na+]
Product: CC1(C)CC(NC(=O)N(CCCl)N=O)CC(C)(C)N1
Reaction time: 1.5 h

Procedure:
To a solution of 1 g. of 4-[3-(2-chloroethyl)ureido]-2,2,6,6-tetramethylpiperidine in 8 ml. of 10% hydrochloric acid was added gradually 0.4 g. of sodium nitrite at 0° - 5° C. After completion of the addition, the reaction mixture was stirred at a temperature below 10° C. for additional 1.5 hours. The crystalline substances separated out in situ during the stirring were recovered by filtration, washed with a small amount of cold water and recrystallized from aqueous methanol to give 0.5 g. of the pure hydrochloride.monohydrate of the desired product having pale yellow color and a decomposition point of 159° - 163° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=[CH:16][CH:15]=2)=[N:13]1
Reactant: N#Cc1cccc(C(N)=O)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 71.7 %

Procedure:
A mixture of methyl thiosalicylate (1.1 g, 6.4 mmol), 6-cyano-2-pyridinecarboxamide (0.47 g, 3.1 mmol), triethylamine (1.0 ml, 7.1 mmol) and toluene (3 ml) was refluxed for 6 hrs as described in Example. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-ethanol to give the titled compound (0.63 g, 70%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(-c2ccc(F)cc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccc(F)cc2)c2ccccc2c1=O

Procedure:
The product of Example 129A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.71-11.73 (bs, 1H), 8.39-8.45 (m, 1H), 7.90-8.03 (m, 2H), 7.69-7.74 (m, 1H), 7.62-7.68 (m, 2H), 7.37-7.44 (m, 6H), 3.71 (s, 2H); MS (APCI+) M/Z 408 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(OC([NH:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)=O)(C)(C)C>>[NH2:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: NCc1ccccn1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Product: NCc1ccc(C(=O)NCc2ccccn2)cc1
Yield: 106 %

Procedure:
Use the General Procedure 6-2, using 2-(aminomethyl)pyridine (181 mg, 0.172 mL, 1.67 mmol) and 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (420 mg, 1.67 mmol) to give the title compound as a solid (427 mg, 100%). MS (ES+) m/z: 242 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.O(C)[Na].[BH4-].[Na+].Cl>C(O)C.CO.CCOC(C)=O>[ClH:1].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:16]2)[OH:10])=[CH:7][CH:8]=1
Reactant: Cc1ccc(C(=O)C2CCN(CCc3ccccc3)CC2)cc1
Agent: CO[Na]
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(C(O)C2CCN(CCc3ccccc3)CC2)cc1

Procedure:
A solution of (4-methylphenyl)[1-(2-phenylethyl)-4-piperidinyl]-methanone hydrochloride (9.5 g, 0.028 mol) in absolute ethanol (350 ml) was treated first by the addition of NaOCH3 (1.62 g, 0.03 mol) and then, portionwise, with sodium borohydride (2.27 g, 0.06 mol) and stirred at room temperature for 18 h. The reaction mixture was concentrated to a solid and stirred with 10% aqueous NaOH. The mixture was extracted with CH2Cl2 (3×50 ml). The CH2Cl2 solution was washed with water and then saturated NaCl solution, and dried over Na2SO4. After filtering off the Na2SO4, the filtrate was concentrated to a solid. This material was dissolved in EtOAc/Et2O (1:1, 200 ml) and treated with a solution of HCl (0.023 mol) in CH3OH/EtOAc (3:10, 13 ml). The resulting precipitate was twice recrystallized from butanone containing a small amount of CH3OH to give alpha-(4-methylphenyl)- 1-(2-phenylethyl)-4-piperidinemethanol hydrochloride, mp 181°-183° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:36])[CH2:14][CH2:15][C@:16]1([O:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH2:21][C@H:20]2[CH2:22][CH2:23][C@@H:17]1[CH:18]=[C:19]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCO.[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:36])[CH2:14][CH2:15][C@:16]1([O:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH2:21][C@H:20]2[CH2:22][CH2:23][C@@H:17]1[CH2:18][CH:19]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)C(=O)O[C@@]1(CCN(C)CCCc2nc3ccccc3[nH]2)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)O[C@@]1(CCN(C)CCCc2nc3ccccc3[nH]2)C[C@H]2CC[C@@H]1CC2c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 22 mg of rac-isobutyric acid (1R*,2R*,4R*)-2-(2-{[3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester dissolved in 0.6 mL EtOH (evacuated 3 times with N2) were added 10 mg of 10 wt % Pd/C. The reaction mixture was stirred under a H2 atmosphere (balloon) for 1 h, filtered over a pad of celite and the cake was washed with EtOH and concentrated in vacuo to provide crude isobutyric acid (1R*,2R*,4R*)-(5RS)-2-(2-{[3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-2-yl ester as mixture of 2 diastereoisomeric racemates. Purification by CC using EtOAc/MeOH 2/1 yielded 5 mg of racemate A and 6 mg of racemate B, both as colorless oils.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:7][C:8]([C:11]([OH:13])=O)=[N:9][N:10]=1.[NH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=2)=[N:18]1>>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][CH2:15][NH:14][C:11]([C:8]3[NH:9][N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[CH:7]=3)=[O:13])[N:18]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Reactant: O=C(O)C1=NN=C(c2ccco2)C1
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(-c4ccco4)n[nH]3)n2)cc1Cl
Yield: 35.6 %

Procedure:
The title compound was prepared using the method of Example 54 but starting from 5-(2-furyl)-4H-pyrazole-3-carboxylic acid (36 mg; 0.20 mmol) and 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (50 mg; 0.20 mmol). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-100% MeOH/DCM) to obtain 29 mg (36%) of the title compound. 1H-NMR (400 MHz; d1-CDCl3): δ 3.90-3.96 (m, 2H), 4.41 (t, 2H), 6.51-6.53 (m, 1H), 6.61 (d, 1H), 6.66 (d, 1H), 6.95 (s, 1H), 7.48-7.50 (m, 2H), 7.61 (broad s, 1H), 7.68 (d, 1H), 7.76-7.79 (m, 1H), 8.11 (s, 1H), 10.45 (broad s, 1H).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH3:2].[CH2:18](Br)[CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[CH2:20]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:5](=[N:4][O:3][CH2:1][CH3:2])[CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:12][CH:13]=1)[CH:19]=[CH2:18]
Reactant: CCON=C(CC(=O)OC)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOc1ccc(C(CC(=O)OC)=NOCC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of crude methyl 3-(ethoxyimino)-3-(4-hydroxyphenyl)propanoate obtained from Step A at 0° C. was added allyl bromide (0.65 mL) and potassium carbonate (781 mg) in DMF (5 mL), and the resulting suspension was stirred at 0° C. for 2 h. Ethyl acetate and water were added, the aqueous layer was extracted with ethyl acetate (×3), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the title compound as an oil. The crude product was used in Step C without purification. HPLC retention time: 1.88 min (method A). MS (ESI) (M+H)+ 278.14.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:39]2[C:44](=[O:45])[C:43]3[S:46][C:47]4[CH2:52][CH2:51][CH2:50][CH2:49][C:48]=4[C:42]=3[CH:41]=[N:40]2)[C:5]([CH2:34][O:35]C(=O)C)=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH2:24]4)[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.O[Li].O>C1COCC1.CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N:39]2[C:44](=[O:45])[C:43]3[S:46][C:47]4[CH2:52][CH2:51][CH2:50][CH2:49][C:48]=4[C:42]=3[CH:41]=[N:40]2)[C:5]([CH2:34][OH:35])=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH2:24]4)[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: C=CC(=O)N[C@H]1CCCN(c2cccc(Nc3cc(-c4cc(F)cc(-n5ncc6c7c(sc6c5=O)CCCC7)c4COC(C)=O)cn(C)c3=O)n2)C1
Agent: [Li]O
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=CC(=O)N[C@H]1CCCN(c2cccc(Nc3cc(-c4cc(F)cc(-n5ncc6c7c(sc6c5=O)CCCC7)c4CO)cn(C)c3=O)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
A mixture of 115a (73 mg, 0.1 mmol) and LiOH.H2O (40 mg, 1 mmol) in THF/i-PrOH/water (2.0 mL/1.0 mL/1.0 mL) was stirred at rt for 2 h. The mixture was extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give 115 (20 mg, 29%) as gray solid. 1H NMR (300 MHz, DMSO-d6, 80° C.): δ 8.42 (s, 1H), 8.40 (s, 1H), 8.00 (s, 1H), 7.77 (d, J=4.5 Hz, 1H), 7.41-7.29 (m, 5H), 6.44 (d, J=3 Hz, 1H), 6.25-6.17 (m, 2H), 5.55-5.50 (m, 1H), 4.35 (s, 2H), 3.98-3.76 (m, 3H), 3.61 (s, 3H), 3.09-2.87 (m, 7H), 1.93-1.87 (m, 6H), 1.71 (bs, 1H), 1.49-1.45 (m, 2H). ESI-LCMS: m/z=682 [C36H36FN7O4S+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH3:10][S-:11].[Na+].C1COCC1.C(OCC)(=O)C>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:11][CH3:10])=[N:3][CH:4]=1)#[N:9]
Reactant: C[S-]
Reactant: N#Cc1ccc(Cl)nc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C#N)cn1
Yield: 99.6 %

Procedure:
2-Chloro-5-cyanopyridine (2.10 g, 15.1 mmol) and sodium thiomethoxide (1.16 g, 16.5 mmol) were added to THF (30 ml). The reaction mixture was refluxed for 9 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (2.26 g, 100%) as pale yellow crystals.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]
Reactant: CN(C(=O)Oc1ccc(CCNC(=O)OC(C)(C)C)cc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Reaction time: 4 h

Procedure:
{2-[4-(Methyl-phenyl-carbamoyloxy)-phenyl]-ethyl}-carbamic acid tertbutyl ester(3.7 g; 10 mmol) from above was dissolved in CH2Cl2 (90 mL). Addition of TFA (6 mL) and stirring for 4 h. The reaction mixture was evaporated to dryness and dried in vacuo at 50° C. overnight producing the title compound as a TFA salt in quantitative yield as yellow hygroscopic crystals.