Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C(OCC[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[C:9]=1[NH2:15])C.[N:16]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1)=[C:17]=[S:18].[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:31]([O:30][CH2:34][CH2:33][NH:14][C:10]1[C:9]([NH:15][C:17]([NH:16][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)=[S:18])=[CH:8][CH:13]=[CH:12][N:11]=1)[CH3:32]
Reactant: CCOCCc1ccnc(N)c1N
Reactant: C1CCOC1
Reactant: CCOC(=O)N1CCC(N=C=S)CC1
Agent: N#N
Product: CCOCCNc1ncccc1NC(=S)NC1CCN(C(=O)OCC)CC1
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A mixture of 25 parts of N2 -(2-ethoxyethyl)-2,3-pyridinediamine, 43 parts of ethyl 4-isothiocyanato-1-piperidinecarboxylate and 450 parts of tetrahydrofuran was stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in trichloromethane. The organic layer was washed twice with water, dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane. The product was filtered off and dried, yielding 35 parts (73.7%) of ethyl 4-[[[[2-[(2-ethoxyethyl)amino]-3-pyridinyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate as a residue (interm. 10).
Reaction SMILES: [CH2:1]=O.[NH2:3][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:5][OH:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>[OH-].[Na+]>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:3]2[C@@H:4]([C:7]([OH:9])=[O:8])[CH2:5][O:6][CH2:1]2)=[O:19])=[CH:13][CH:12]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: C=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H]1COCN1C(=O)Nc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2.1 1.49 ml (20.0 mmol) of 37% aqueous formaldehyde solution are added to a solution of 2.10 g (20.0 mmol) of D-serine in 10 ml of 1N aqueous sodium hydroxide solution. The resultant solution is left at 5° C. for 18 hours. The solution is heated to 80° C., 6.14 g (40 mmol) of 4-chlorophenyl isocyanate are added, and the mixture is stirred at this temperature for one hour. The mixture is allowed to cool, and the precipitate formed is filtered off. The filtrate is acidified using 1N HCl, and the precipitate formed is filtered off and dried, giving (R)-3-(4-chlorophenylcarbamoyl)oxazolidine-4-carboxylic acid as a colourless solid; ESI 271. 2.2 498 mg (2.60 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) are added to a solution of 541 mg (2.00 mmol) of (R)-3-(4-chlorophenylcarbamoyl)oxazolidine-4-carboxylic acid and 384 mg (2.00 mmol) of 4-(4-aminophenyl)morpholin-3-one in 4 ml of dimethylformamide (DMF), and the mixture is stirred at room temperature for 18 hours. The reaction mixture is added to saturated sodium hydrogencarbonate solution, and the precipitate formed is filtered off, giving 3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(R)-oxazolidine-3,4-dicarboxamide (“A2”) as a colourless solid; ESI 461.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:22][CH2:21][CH2:20][O:19][CH3:18])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: COCCN
Solvent: CCO
Product: COCCNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), 2-methyoxyethanamine (0.50 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 319 (M+, 0.3), 141 (17), 88 (bp), 72 (29), 58 (12), 56 (16).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Li+].Cl[CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)=[N:18][C:17]=1[CH2:16][S:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: O=S([O-])c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C(F)(F)F)cc3)c(C)o2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A mixture of lithium 4-(trifluoromethyl)benzenesulfinate (700 mg, 3.24 mmol, 1.72 equiv, 100%), methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (500 mg, 1.89 mmol, 1.00 equiv) and potassium carbonate (0.35 g) in N,N-dimethylformamide (25 mL) was stirred overnight at 70° C. The reaction mixture was cooled to room temperature then quenched by the addition of 60 mL of water and ice. The solid was collected by filtration, washed with 2×20 mL of water and dried in a vacuum oven to yield 0.7 g (85%) of methyl 4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate as a white solid. LC-MS: (ES, m/z): 481 [M+CH3CN+H]+, 440 [M+H]+, 271, 146, 105.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.O1CCOCC1.CCN(C(C)C)C(C)C.[CH2:27]([SH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:27]([S:34][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: SCc1ccccc1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 88.2 %

Procedure:
A screw cap vial was charged with 4-bromo-2-nitroaniline (7.00 g, 32.3 mmol), xantphos (0.933 g, 1.613 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.738 g, 0.806 mmol), 1,4-Dioxane (32.3 ml), and DIPEA (11.22 ml, 64.5 mmol). The vial was purged with Argon, sealed and heated to 80° C. for 10 minutes. The reaction was cooled to room temperature and benzyl mercaptan (4.01 ml, 33.9 mmol) was added and the reaction heated at 80° C. for 3 hours. The reaction was cooled to room temperature, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 4-(benzylthio)-2-nitroaniline (7.43 g, 28.5 mmol, 88% yield). m/z (ESI) 261.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[S:16][C:15]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:14][C:13]=2[CH3:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br.O.C(OCC)(=O)C>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[S:16][C:15]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:14][C:13]=2[CH3:21])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)c2sc(S(N)(=O)=O)cc2C)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(S(N)(=O)=O)sc1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
5-(4-methoxyphenylsulfonyl)-4-methylthiophene-2-sulfonamide (9.75 g, 0.028 mol) was suspended in methylene chloride (150 ml) and a 1.0M solution of boron tribromide in methylene chloride (90 ml, 0.09 mol) was added dropwise over 1/2 hour, at 0° C. Then the solution was stirred at ambient temperature for 5 hours. The solution was added to ice and water (500 ml) and ethyl acetate (500 ml) was added. The organic layer was separated, washed with saturated NaCl, saturated NaHCO3 and again with saturated NaCl, dried, filtered and concentrated in vacuo. A yellow oil was obtained which crystallized from ethyl acetate-n-butyl chloride. Yield was 67%. The recrystallized white solid melted at 170°-172° C. Purity and structure were confirmed by C, H, N, analyses, HPLC and NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:11]1([C:17]([OH:24])([C:21]([NH2:23])=[O:22])[C:18]([NH2:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.[Zn+2]>[C:11]1([C:17]([O:24][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:10])([C:21]([NH2:23])=[O:22])[C:18]([NH2:20])=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: NC(=O)C(O)(C(N)=O)c1ccccc1
Agent: CCCCCCCC(=O)[O-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: NC(=O)C(OC(=O)Nc1cccc(Cl)c1)(C(N)=O)c1ccccc1
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
0.5 g of zinc octoate and 4.45 g of 3-chlorophenyl isocyanate were added to 8.2 g of phenylhydroxymalonic acid diamide in 30 ml of ethyl acetate and the mixture was kept at 50° C. for 30 minutes. After cooling, the precipitate was filtered off with suction and recrystallised from acetone. 5.6 g of phenyl-(3-chlorophenylaminocarbonyloxy)-malonic acid diamide of melting point 196°-198° C. were obtained.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[S:10](=[O:14])(=[O:13])([OH:12])[OH:11].[NH2:15]C1C=CN=NN=1>>[NH:1]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[S:10](=[O:12])(=[O:11])([OH:14])[O-:13].[NH4+:15]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccnnn1
Agent: O=c1[nH]c(=O)[nH]c(=O)[nH]1
Product: O=S(=O)([O-])O
Product: [NH4+]

Procedure:
digesting the cyanuric acid in a second aqueous solution containing sulfuric acid, wherein the stoichiometric ratio of sulfuric acid to aminotriazine compounds is greater than 1, to produce a purified cyanuric acid in an ammonium bisulfate solution.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:30])OC3C=CC=CC=3)=[CH:15][CH:14]=2)[CH:5]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[N:7]=1)[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH:41][C:22]([NH:21][CH2:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([N:4]3[CH:5]=[C:6]([C:8]4[S:9][CH:10]=[CH:11][N:12]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:14][CH:15]=2)=[O:30])(=[O:39])=[O:40])=[CH:36][CH:37]=1
Reactant: CCc1nc(-c2nccs2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: CCc1nc(-c2nccs2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[2-ethyl-4-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]phenyl}ethylcarbamate and 4-chlorobenzenesulfonamide. MS (ESI) m/z 516 [M+H]+, 514 [M−H]−, 1H-NMR (CDCl3)δ1.22 (3H, t, J=7.5 Hz), 2.69 (2H, q, J=7.5 Hz), 2.88 (2H, t, J=6.8 Hz), 3.49-3.56 (2H, m), 6.64 (1H, br), 7.21-7.30 (4H, m), 7.48 (2H, d, J=8.8 Hz), 7.58 (1H, s), 7.77 (2H, d, J=3.3 Hz), 7.80 (2H, d, J=8.8 Hz)
Reaction SMILES: [CH2:1]([Li])CCC.C(N(C(C)C)CC)(C)C.[CH2:15]([O:17][C:18]([C:20]1([C@H:23]2[CH2:27][N:26]([C@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])[C:25](=[O:36])[CH2:24]2)[CH2:22][CH2:21]1)=[O:19])[CH3:16].CI.[Cl-].[NH4+]>O1CCCC1>[CH2:15]([O:17][C:18]([C:20]1([C@H:23]2[CH2:27][N:26]([C@H:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH3:29])[C:25](=[O:36])[C@@H:24]2[CH3:1])[CH2:21][CH2:22]1)=[O:19])[CH3:16]
Reactant: [Li]CCCC
Reactant: CCOC(=O)C1([C@@H]2CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@@H]2C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
The following reaction was carried out under a nitrogen atmosphere. At -78° C., n-butyl lithium (5.39 ml, 1.68 N, n-hexane solution, 9.06 mmol) was added dropwise to a tetrahydrofuran solution (40 ml) of diisopropylethylamine (1.37 ml, 9.75 mmol), and the mixture was warmed to 0° C. and stirred for 30 minutes. At -78° C., to this was further added dropwise a tetrahydrofuran solution (20 ml) of (4S)-4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-1-phenylethyl]-2-pyrrolidone (2.10 g, 6.97 mmol). After an additional 15 minutes of stirring, methyl iodide (2.17 ml, 34.8 mmol) was added dropwise thereto, and the mixture was stirred for 30 minutes while warming to 0° C. After completing the reaction, this was cooled in an ice bath and mixed with a saturated ammonium chloride aqueous solution (150 ml) and then tetrahydrofuran was evaporated. The resulting residue was extracted with chloroform (150 ml×3), and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent, the resulting residue was purified by a silica gel column chromatography (silica gel, 160 ml; ethyl acetate:hexane=2:3), to thereby obtain 1.90 g (87%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC(C(F)(F)F)=O.[NH2:21][C@@H:22]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([NH:21][C@@H:22]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H](Cc1ccccn1)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccn1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
To (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (495 mg, 2.62 mmol) was added (S)-benzyl 2-amino-3-(pyridin-2-yl)propanoate TFA salt (0.82 g, 2.22 mmol), HOBt (482 mg, 3.57 mmol), HBTU (1.35 g, 3.57 mmol), and ACN (10 mL). The mixture was cooled to 0° C. and DIEA (1.46 mL, 8.88 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated to provided crude (S)-benzyl 2-((S)-2-((tert-butoxycarbonyl)amino)propanamido)-3-(pyridin-2-yl)propanoate as a colorless solid (0.46 g) that was carried forward without further purification. MS (EI) for C23H29N3O5, found 428.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:30][CH2:31][N:32]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:3]=3)[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCc2cccnc2)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile (example 49a) was treated with the 4-(4-fluorophenyl)-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, light brown; MS: [M+H]+=448.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:12])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1
Reactant: CCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of the crude carboxylic acid (652 mg, 3.00 mmol) and NMM (0.50 ml, 4.5 mmol) in THF (12 ml) was added isobutyl chloroformate (0.45 ml, 3.5 mmol) and the resulting mixture was stirred at 0° C. for 5 minutes. A solution of aniline (0.45 ml, 4.9 mmol) in THF (3 ml) was then added dropwise. The reaction was warmed to room temperature and stirred for 66 hours. The reaction was diluted with 1M HCl (30 ml) and was extracted with Et2O (25 ml×3). The organic solution was washed with brine (50 ml), was dried (Na2SO4), filtered and concentrated under reduced pressure, giving crude ((R)-1-phenylcarbamoyl-butyl)-carbamic acid tert-butyl ester as an oily, light yellow foam.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:20]=[N:21][N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH:23]=1)(=[O:10])[CH3:9].Br[CH:34]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[F:46])[C:35]([CH:37]1[CH2:39][CH2:38]1)=[O:36].C(N(CC)CC)C.[Cl-].[Na+]>C(#N)C>[C:8]([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:34]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[C:35]([CH:37]2[CH2:38][CH2:39]2)=[O:36])[CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:20]=[N:21][N:22]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH:23]=1)(=[O:10])[CH3:9]
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Reactant: COc1ccc(Cn2cc(/C=C3\CNCCC3SC(C)=O)nn2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2cc(/C=C3\CN(C(C(=O)C4CC4)c4ccccc4F)CCC3SC(C)=O)nn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-{[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]methylidene}piperidine hydrogen trifluoroacetate (6.03 g) in acetonitrile (100 ml) were added 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (5.0 g) and triethylamine (3.5 ml). The resulting mixture was stirred at room temperature for 15 minutes. Then, the reaction was stopped by addition of a saturated aqueous sodium chloride solution, and the products were extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (1:1:1) as the eluent to afford the title compound as a pale yellow amorphous solid (5.11 g, yield: 75%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O.O>C(Cl)(Cl)Cl>[Cl:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)NC(C)(C)c1ccc(CO)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of N-(1-(4-hydroxymethylphenyl)-1-methylethyl)acetamide (18.24 g) in chloroform (180 ml) was added dropwise thionyl chloride (7.07 ml) over 10 min under ice-cooling and the mixture was stirred at room temperature for 20 hr. The reaction mixture was poured into water (1000 ml) and the organic layer was separated. The organic layer was washed with aqueous sodium hydrogencarbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (19.17 g) as pale-yellow crystals, m.p.=124-125° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([NH:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([O:13][C@@H:22]2[CH:23]3[CH2:26][CH2:27][N:20]([CH2:25][CH2:24]3)[CH2:21]2)=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C(Nc1cccc(F)c1)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cccc(F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
2-(3-Fluorophenylamino)-2-phenylacetic acid hydrochloride (I40) (1.34 g, 4.74 mmol), (R)-quinuclidin-3-ol (3.01 g, 23.7 mmol), DCC (1.95 g, 9.47 mmol), and HOBt (1.45 g, 9.47 mmol) were dissolved in THF (60 ml). The reaction was stirred at room temperature overnight. The solvent was evaporated, and the crude product was taken up with EtOAc and washed with NaHCO3 and then with brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/1) to give (R)-quinuclidin-3-yl 2-(3-fluorophenylamino)-2-phenylacetate (1.17 g, 68.9% yield).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:25][CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].CCOCC>C(#N)C>[Br-:25].[C:30]1([NH:29][C:27]([CH2:26][N+:1]23[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:28])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: O=C(CBr)Nc1ccccc1
Solvent: CCOCC
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.2 %

Procedure:
To 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (50 mg) in acetonitrile (1 mL) was added 2-bromo-N-phenylacetamide (Example 21a) (36 mg). The reaction mixture was stirred at room temperature for 3 days. Ether was added to the reaction mixture and the resultant solid was collected by filtration and dried to afford the title compound as a colourless solid (39 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([CH:22]=[CH2:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CCO.CCOC(C)=O.[Pd]>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([CH2:22][CH3:23])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1c(OCc2ccccc2)ccn(Cc2ccccc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1c(OCc2ccccc2)ccn(Cc2ccccc2)c1=O
Yield: 62.6 %

Procedure:
To a solution of 1-benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one (0.5 g, 1.6 mmol) in EtOH (10.0 mL) and EtOAc (10.0 mL) was added Pd/C (10%, 0.25 g) and stirred in an atmosphere of hydrogen gas at 30 psi for 16 h. The catalyst was removed by filtration, the filtrate was concentrated to dryness and the resulting residue was purified by silica gel flash chromatography using EtOAc/hexanes (1:1, v/v) to afford the title compound (0.32 g, 64%) as a pale yellow powder: 1H-NMR (CD3OD) δ: 7.52 (d, 1H, J=7.6 Hz), 7.39-7.2 (m, 10H), 6.41 (d, 1 h, J=7.6 Hz), 5.18 (s, 2H), 5.15 (s, 2H), 2.58 (q, 2H, J=7.2 Hz), 1.03 (t, 3H, J=7.2 Hz), ER-MS m/z=320 (MH+) HR-MS m/z calcd C21H22NO2 320.1651, found 320.1648.