Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@@H:8]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]([OH:11])=O)=[O:6])[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:33][NH:34][O:35][CH3:36].C(N(CC)CC)C>O1CCCC1>[CH3:19][C:2]([CH3:1])([O:4][C:5]([NH:7][C@@H:8]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]([N:34]([O:35][CH3:36])[CH3:33])=[O:11])=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
To a solution of (S)-α-[[(1,1-dimethylethoxy)-carbonyl]amino]cyclohexanepropanoic acid (93 g., 343 mmole) in dry tetrahydrofuran (1 1.) was added a 20% molar excess of 1,1'-carbonyldiimidazole over a period of less than 10 minutes with very efficient stirring to keep the internal temperature below 30° . After stirring for 30 minutes, N,O-dimethylhydroxylamine hydrochloride (36.8 g., 377 mmole) was added, followed by triethylamine (38.2 g., 377 mmole). After stirring at room temperature for 4 hours, the reaction mixture was filtered and the resulting filtrate was concentrated in vacuo. The amber colored residue (100 g.) was dissolved in ether (900 ml.) and poured into 1N HCl (1 l.). The acidic aqueous phase was separated, further extracted with ether and the combined ethereal solutions were washed with water, saturated sodium bicarbonate, water, and brine, then dried (MgSO4) to give (S)-α-[[(1,1-dimethylethoxy)-carbonyl]amino]-N-methoxy-N-methylcyclohexane-propanamide as a colorless oil. [α]D =-12.9° (c=1, methanol). TLC (silica gel; 1:1, ethyl acetate:hexanes) Rf =0.58.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]2=[O:16])=[CH:4][CH:3]=1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1.Cl>CN(C)C=O>[C:17]([Si:21]([CH3:23])([CH3:22])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]2=[O:14])=[CH:6][CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C1NC(=O)C(c2ccc(O)cc2)C(=O)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2C(=O)NC(=O)NC2=O)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 5-(4-hydroxyphenyl)barbituric Acid (1.9 g) and tertbutyl dimethylsilyl chloride (4.68 g) in 20 ml of anhydrous dimethylformamide are added 4.4 g of imidazole and the mixture is heated to 55° C. for 5 hours. The temperature is then brought to room temperature and the reaction mixture is poured into 1 N hydrochloric acid and extracted twice with ethyl acetate. The pooled organic extracts are washed with water and dried over sodium sulfate. By concentration of the solution a white solid separates, which is kept at 0° C. overnight, then it is filtered to give 2.185 g of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)Cl.C(OCC)(=O)C.[CH:21]([NH2:23])=O>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:23][CH:21]=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC=O
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 0 °C
Yield: 82 %

Procedure:
A solution of 2-amino-4-fluorobenzoic acid (3 g, 19.3 mmol) in formamide (30 ml) was heated at 150° C. for 6 hours. The reaction mixture was poured onto ice/water (1/1) (250 ml). The precipitated solid was collected by filtration, washed with water and dried to give 7-fluoro-3,4-dihydroquinazolin-4-one (2.6 g, 82%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][OH:9])=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])=[CH:13][CH:12]=2)[C:5]([CH2:31][CH2:32][CH3:33])=[N:4]1)[CH3:2].C[N+]1([O-])CCOCC1.C(#N)C>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([N:3]1[C:7]([CH:8]=[O:9])=[C:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][S:24]([C:27]([F:29])([F:28])[F:30])(=[O:25])=[O:26])=[CH:15][CH:16]=2)[C:5]([CH2:31][CH2:32][CH3:33])=[N:4]1)[CH3:2]
Reactant: CCCc1nn(CC)c(CO)c1Cc1ccc(-c2ccccc2NS(=O)(=O)C(F)(F)F)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCCc1nn(CC)c(C=O)c1Cc1ccc(-c2ccccc2NS(=O)(=O)C(F)(F)F)cc1
Yield: 70.1 %

Procedure:
Tetra-n-propylammonium perruthenate (46 mg) was added to a mixture of the product of Example 86 (630 mg), N-methylmorpholine N-oxide (0.46 g) and 4A molecular sieves (2.5 g) in dichloromethane (10 ml) and dry acetonitrile (10 ml) and the reaction left for 5 min. The reaction was filtered, solvent removed in vacuo and the residue adsorbed onto silica. The material was purified by chromatography eluting with System A (4:1) to give the title compound as a yellow gum (0.44 g).
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C@@H:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])[CH2:3][CH2:4][C:5](O)=[O:6].[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH3:1][N:2]([C:8]([O:10][C@@H:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[NH:33][CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CN(CCC(=O)O)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)CNC(=O)CCN(C)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To a mixture of benzyl 2(S)-[N-methyl-N-(2-carboxyethyl)aminocarbonyloxy]-3-phenylpropionate (460 mg) and isobutylamine (143 ml) in anhydrous methylene chloride (10 ml) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (274 mg) portionwise at 0°-5° C. After being stirred at the same temperature for 3 hours, the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (30 ml). The solution was washed with 0.5 N hydrochloric acid (30 ml), water (30 ml), aqueous sodium bicarbonate (30 ml), water (30 ml) and brine (30 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave benzyl 2(S)-[N-methyl-N-(2-isobutylcarbamoylethyl)aminocarbonyloxy]-3-phenylpropionate (440 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[C:25]([CH3:34])[C:24]=2[CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:36])[NH:17]2)(=[O:11])=[O:10].[Li+].[OH-]>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[C:25]([CH3:34])[C:24]=2[CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:36])[NH:17]2)(=[O:10])=[O:11]
Reactant: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(C)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2c(NS(=O)(=O)c3ccc(Cl)cc3Cl)c(Oc3ccc(CC(=O)O)c(C)c3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under an N2 atmosphere, methyl 2-(4-(4-(2,4-dichlorophenylsulfonamido)-2-methyl-1H-indol-5-yloxy)-2,3-dimethylphenyl)acetate (0.194 g, 0.354 mmol) was dissolved in tetrahydrofuran (2.5 mL) and 1N LiOH (aq) was added. The reaction was allowed to stir at room temperature for 2.5 h. The reaction was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was made acidic with citric acid to pH 4 and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. Flash column chromatography of the residue, eluting with 0% to 8% methanol in dichloromethane, afforded the title compound. LC-MS EST (neg.) m/z: 531.1 (M−H). 1H NMR (400 MHz) (DMSO-d6) δ 10.94 (s, 1H); 9.75 (s, 1H); 7.53 (d, J=8.5 Hz, 1H); 7.48 (d, J=2.0 Hz, 1H); 7.20 (dd, J=8.5 Hz and 2.0 Hz, 1H); 7.07 (d, J=8.6 Hz, 1H); 6.72 (d, J=8.4 Hz, 1H); 6.27 (d, J=8.4 Hz, 1H); 6.13 (s, 1H); 5.99 (d, J=8.4 Hz, 1H); 3.50 (s, 2H); 2.35 (s, 3H); 2.09 (s, 3H); 1.92 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][C:19](O)=[O:20])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][S:29](=[O:32])(=[O:31])[NH2:30].CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:23][O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][S:29](=[O:31])(=[O:32])[NH:30][C:19](=[O:20])[CH2:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:22])[N:8]2[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(OCC(=O)O)cccc2n1Cc1ccccc1
Reactant: COC(=O)CCCS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCS(=O)(=O)NC(=O)COc1cccc2c1cc(C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1-benzyl-2-methyl-1H-indol-4-yloxy)-acetic acid (5) (0.189 g, 0.64 mmole) in dichloromethane (15 mL), 4-sulfamoyl-butyric acid methyl ester (0.232 g, 1.28 mmole), EDCI (0.122 g, 0.64 mmole) and DMAP (0.078 g, 0.64 mmole) were added. The mixture was stirred at room temperature for 18 h. The dichloromethane was evaporated to half of the original volume and the mixture was washed with water (2×10 mL). The organic layer was separated and evaporated. The residue was purified by column chromatography (10:1 CHCl3:MeOH) to afford intermediate (6) as a solid. Yield: 0.15 g, 51%
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C(#N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)ccc2[N+](=O)[O-])CC1

Procedure:
2,4-Difluoronitrobenzene (10.0 g, 62.9 mmol), t-butyl piperazine-1-carboxylate (11.7 g, 62.9 mmol) and N,N-diisopropylethylamine (8.10 g, 62.9 mmol) were stirred at room temperature in dry acetonitrile (100 mL) for 16 h. The solvent was removed by rotary evaporation and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was removed by rotary evaporation to collect the title compound (19.0 g, 93%). 1H NMR (400 MHz, CDCl3): δ 7.91 (dd, 1H), 6.75 (m, 2H), 3.60 (m, 4H), 3.03 (m, 4H), 1.48 (s, 9H); MS (ESI) m/z: Calculated for C15H20FN3O4Na: 348.13; Observed: 348.1 (M++Na).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[Ni].C1COCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(CCC(=O)c2ccccc2)cc1

Procedure:
A mixture of 3-(4-nitro-phenyl)-1-phenyl-prop-2-en-1-one (24.9 g, 98.3 mmol), Raney nickel (7.0 g), MeOH (100 mL), and THF (400 mL) was shaken in a hydrogen atmosphere of 51 psi at 20° C. for 18.5 hours. The catalyst was filtered, and the filtrate was concentrated. The residue was recrystallized from 95% EtOH, to give the title compound, m.p. 76°-78° C. 1H NMR (CDCl3) δ 2.98 (t, 2 H), 3.25 (t, 2 H), 3.62 (bs, 2 H), 6.65 (d, 2 H), 7.05 (d, 2 H), 7.40-7.61 (m, 3 H), 7.96 (d, 2 H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](Cl)(=[O:14])=[O:13].O.C(OCC)(=O)C>O1CCCC1>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:2]([CH3:3])[CH3:1])(=[O:14])=[O:13]
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1S(=O)(=O)N(C)C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
72 ml (144 mmol, 3 eq) of a 2 M solution of dimethylamine in tetrahydrofuran were added dropwise to a solution of 9.90 g (47.9 mmol, 1 eq) of 2-methoxybenzenesulfonyl chloride in 300 ml of tetrahydrofuran at 0° C. under nitrogen. After 30 minutes, the reaction medium was hydrolyzed with water, and ethyl acetate was added. The organic phase was again washed with water, and then dried over anhydrous sodium sulfate, filtered and concentrated. 8.78 g of product were obtained in the form of a brown oil. Yield=85%.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[CH2:10][CH2:11][CH:12]([CH:27]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:13](N1C(C2C=CC=CC=2)COC1=O)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.O.O.O.[F-].C([NH+](CCCC)CCCC)CCC.C(O)(=O)C>COC(C)(C)C>[Si:1]([O:8][CH:9]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[CH2:10][CH2:11][CH:12]1[CH:27]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[N:35]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[C:13]1=[O:14])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCC(C(=O)N1C(=O)OCC1c1ccccc1)C(Nc1ccc(F)cc1)c1ccc(O)cc1)c1ccc(F)cc1
Agent: CCCC[NH+](CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [F-]
Solvent: O
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(O)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.63 g of 3-{5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-2-[(4-fluorophenyl-amino)-(4-hydroxyphenyl)methyl]pentanoyl}-4-phenyloxazolidin-2-one are suspended in 60 ml of tert-butyl methyl ether. 3.22 ml of bis(trimethylsilyl)acetamide and 122 mg of tributylammonium fluoride trihydrate are then added. The reaction mixture is stirred at room temperature for 3 h, and 0.6 ml of glacial acetic acid are then added. The reaction mixture is concentrated using a rotary evaporator and the residue is purified by column chromatography (SiO2; ethyl acetate/heptane 1:4). The product is obtained as clear crystals. C30H35F2NO3Si (523) MS (ESI): M+−131
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15](O)=[O:16])=[C:13]([CH3:18])[N:12]=[CH:11][CH:10]=2)=[C:4]([F:19])[CH:3]=1.C[CH2:21][N:22](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.CN>CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15]([NH:22][CH3:21])=[O:16])=[C:13]([CH3:18])[N:12]=[CH:11][CH:10]=2)=[C:4]([F:19])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nccc(-c2cc(F)c(Cl)cc2F)c1C(=O)O
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2cc(F)c(Cl)cc2F)ccnc1C
Reaction time: 0.17 h
Yield: 52.8 %

Procedure:
To the stirred solution of 4-(4-chloro-2,5-difluorophenyl)-2-methylnicotinic acid (1.7 g, 4.02 mmol) in DMF (0.5 mL) was added DIEA (2.81 mL, 16.06 mmol), HOBT (1.230 g, 8.03 mmol), EDC (1.155 g, 6.02 mmol) at 0° C. followed by addition of methylamine hydrochloride (0.488 g, 7.23 mmol). After stirring for 10 min, the ice bath was removed and the reaction mixture was allowed to stir overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (10 mL) and washed with water (10 mL) followed by brine (10 mL). The organic layer was separated and dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford 4-(4-chloro-2,5-difluorophenyl)-N,2-dimethylnicotinamide (1 g, 2.123 mmol, 53% crude yield) as a brown solid which was taken to the next step without purification. LC/MS (ESI) m/e 297.3 [(M+H)+, calcd for C14H12ClF2N2O 297.1]; LC/MS retention time (method B): tR=0.76 min.
Reaction SMILES: [NH2:1][C@H:2]([CH:21]([CH3:23])[CH3:22])[C:3]([N:5]1[CH2:10][CH2:9][C@@:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([CH3:20])([CH3:19])[CH2:6]1)=[O:4].[CH3:24][N:25]1[C:29]([C@@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32]([C:36](O)=[O:37])[CH2:31]2)=[N:28][N:27]=[N:26]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C@@:8]2([OH:11])[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:36]([C@H:32]3[CH2:33][CH2:34][CH2:35][C@@H:30]([C:29]4[N:25]([CH3:24])[N:26]=[N:27][N:28]=4)[CH2:31]3)=[O:37])[CH:21]([CH3:23])[CH3:22])[CH2:6][C:7]2([CH3:19])[CH3:20])=[CH:17][CH:16]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: Cn1nnnc1[C@@H]1CCC[C@H](C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)[C@H]1CCC[C@@H](c2nnnn2C)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Yield: 98.5 %

Procedure:
(R)-2-Amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one (25 mg, 0.067 mmol), (±)-cis-3-(1-methyl-1H-tetrazol-5-yl)cyclohexanecarboxylic acid (17 mg, 0.080 mmol), HOBT (12 mg, 0.080 mmol), EDC (15 mg, 0.080 mmol) and triethylamine (0.019 mL, 0.133 mmol) were mixed in methylene chloride (3 mL) at 25° C. with stirring. The reaction was stirred for 20 hours then washed with sat'd sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and concentrated in vacuo to give a white glass which was purified over silica gel (1:1 Hexanes/EtOAc to 100% EtOAc to 4:1 methylene chloride) to obtain (±)-cis-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-(1-methyl-1H-tetrazol-5-yl)cyclohexanecarboxamide (35 mg, 0.066 mmol, 99% yield) as a white glass. MS found: (M+H)+=531.46.
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18].Cl.NO.N1C=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:2]=[C:3]([NH2:18])[C:4]([NH2:15])=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: c1ccncc1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 50 mL round bottom flask was charged with a suspension of 1 (680 mg, 2.5 mmol), hydroxylamine HCl (191 mg, 2.75 mmol), and pyridine (0.25 mL, 3.0 mmol) in ethanol (10 mL) and stirred at RT overnight. Crude product concentrated and absorbed onto silica gel, then chromatographed using 97:3 CH2Cl2/MeOH to give 2 as an orange solid. LCMS m/z 289.2 (MH+), Rt 2.06 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12].[H-].[Na+].[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1.O>CN(C)C=O>[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:21]=1
Reactant: Brc1cncc(Br)c1
Reactant: OCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cncc(OCc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.6 %

Procedure:
A solution of 2-naphthylmethanol (1.58 g) in dimethylformamide (20 ml) was added to a slurry of sodium hydride (55% w/w dispersion in oil, 0.48 g) in dimethylformamide (2 ml) and the mixture was stirred at ambient temperature for 20 minutes. 3,5-Dibromopyridine (2.37 g) was added and the solution was heated to 120° C. for 5 hours and then allowed to stand at ambient temperature overnight. The mixture was poured into water (160 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with increasingly polar mixtures of petrol (b.p. 60°-80° C.) and ethyl acetate to give 3-bromo-5-(naphth-2-ylmethoxy)pyridine (1.4 g), m.p. 108°-109° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>CCOCC>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]2=[O:24])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)COc3ccccc32)CC1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1COc2ccccc2N1C1CCNCC1
Yield: 135.1 %

Procedure:
4-(3-Oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (17 g, 51 mmol) and 1:1 TFA/CH2Cl2 (40 mL) were combined and set stirring. After 45 min the mixture was evaporated to give a clear brown oil. The oil was set stirring and Et2O was added (300 mL). A solid formed and was filtered, washed with Et2O and air dried to give 16 g (90%) of a light beige solid. MS (electrospray): exact mass calculated for C13H16N2O2, 232.12. m/z found, 233.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.44 (dd, J=6.5, 1.4 Hz, 1H), 7.20-7.7.10 (m, 3H), 4.58 (s, 2H), 4.55-4.45 (m, 1H), 4.65-4.55 (m, 2H), 3.27 (dt, J=13.0, 2.3 Hz, 2H), 3.05 (dd, J=12.3, 4.1 Hz, 2H), 2.15 (d, J=13.8 Hz, 2H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: BrCc1ccccc1Br
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1Br

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-bromobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25](O)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25]([NH:37][CH2:31][C:32]4[O:36][CH:35]=[CH:34][CH:33]=4)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)O)c1
Reactant: NCc1ccco1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)NCc2ccco2)c1
Yield: 10.5 %

Procedure:
To solution of 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-nicotinic acid (40 mg, 0.098 mmol), furfuryl amine (19.11 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.4 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-furan-2-ylmethyl-nicotinamide as a colorless solid (5 mg, 25.3% yield).