Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:9][C:8]=1[CH3:29].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.O>CN(C=O)C>[CH3:29][C:8]1[CH:9]=[C:10]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)[CH:11]=[C:12]([CH3:13])[C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCCBr)c(C)c3)nc2c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(4-bromo-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (494 mg, 1.07 mmol) in DMF (10 mL) was added pyrrolidine (609 mg, 8.57 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the product was extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous Na2SO4. Solvent was evaporated to give the title compound as a white solid. Yield: 278 mg (57%). MP 180-181° C. 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 2H), 6.83 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.83 (t, J=6.4 Hz, 2H), 2.56 (m, 6H), 2.36 (s, 6H), 1.88 (m, 2H), 1.79 (m, 6H). MS (ES) m/z: 452.21 (M+1).
Reaction SMILES: C(O[C:4](=[O:16])[CH:5]([O:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:6])C.[NH2:17][CH2:18][CH2:19][NH2:20]>C(O)C>[NH2:17][CH2:18][CH2:19][NH:20][C:4](=[O:16])[CH:5]([O:7][C:8]1[C:9]([Cl:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14])[CH3:6]
Reactant: NCCN
Reactant: CCOC(=O)C(C)Oc1c(Cl)cccc1Cl
Solvent: CCO
Product: CC(Oc1c(Cl)cccc1Cl)C(=O)NCCN
Yield: 76.7 %

Procedure:
42.0 g (=0.160 mols) of (+)-2-(2,6-dichlorophenoxy)-propionic acid ethylester are stirred for 6 hours at room temperature with 194.0 g (=3.228 mols) of 1,2-diaminoethane and, after working up, produce 34.0 g of (+)-2-(2,6-dichlorophenoxy)-propionic acid-N-(2-aminoethyl)amide, C11H14Cl2N2O2 [277.2] as a high viscosity oil, [α]D20 =+5.6° (c=1/ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.C(N=C=N[CH2:33][CH2:34][CH2:35][N:36](C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:36][CH:35]3[CH2:34][CH2:33][CH:5]([C:4]4[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=4)[CH2:6][CH2:7]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(c5ccccc5)CC4)cc3)c(Cl)cc21
Reaction time: 8 h

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.0899 g, 0.238 mmol), N,N-dimethylpyridin-4-amine (0.00291 g, 0.0238 mmol), and (1R,4R)-4-phenylcyclohexanamine (0.0627 g, 0.358 mmol) in DMF (1.25 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0549 g, 0.286 mmol), and the reaction was stirred overnight. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Biotage SP1 system eluting with a linear gradient of 5% to 50% EtOAc in hexanes to yield two isomers of the product. The first eluting isomer was collected and called isomer 1 (27 mg). The second eluting isomer was called isomer 2 (32 mg). The relative configurations of each of these isomers were not determined.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li][CH2:11]CCC.[C:15]([O:19][C:20]([NH:22][C@H:23]([C:29]([O:31][CH3:32])=[O:30])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:21])([CH3:18])([CH3:17])[CH3:16].CI>C1COCC1>[C:15]([O:19][C:20]([NH:22][C@H:23]([C:29]([O:31][CH3:32])=[O:30])[CH:24]([CH3:11])[C:25]([O:27][CH3:28])=[O:26])=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: [Li]CCCC
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of hexamethyldisilazane (88 mL, 0.421 mol), in THF (500 mL) at −30° C. was added BuLi (2.5M in hexanes, 169 mL, 0.423 mol) and the mixture stirred at this temperature for 15 minutes before cooling to −78° C. A solution of dimethyl N-(tert-butoxycarbonyl)-L-aspartate (Preparation 70, 50 g, 0.19 mol) in THF (200 mL) was added slowly over 15 minutes and the reaction stirred at −78° C. for 2 hours. MeI (14.3 mL, 0.23 mol) was added over 30 minutes and the reaction continued stirring at −78° C. for 18 hours. The reaction was quenched by pouring into an aqueous solution of KHSO4 (80 g in 600 mL, pH=3). THF was then removed in vacuo and the product extracted into EtOAc. The organic layer was collected, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% EtOAc in heptane to afford the title compound as a mixture of diastereomers in a ratio 7:3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][CH2:11]2)[C:5]([C:24]#[N:25])=[C:4]([SH:26])[N:3]=1.Cl[CH2:28][C:29]1[N:30]=[C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[S:32][CH:33]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C@H:10]2[CH2:11][CH2:12][C@H:13]([O:16][Si:17]([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:18])[CH3:19])[CH2:14][CH2:15]2)[C:5]([C:24]#[N:25])=[C:4]([S:26][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[S:32][CH:33]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2c(C#N)c(N)nc(S)c2C#N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
23 mg (0.06 mmol) of the compound from Example 12A (trans isomer), 17 mg (0.07 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 20 mg (0.24 mmol) of sodium bicarbonate are initially charged in 2 ml of dry DMF and stirred at RT for 20 h. The mixture is then directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1)[C:29](O)=[O:30]>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:29](=[O:30])[C:28]2[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=[C:26]([O:25][CH3:24])[CH:27]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc(OC)cc(C(=O)O)c1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: COc1cc(OC)cc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(Cl)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 3,5-dimethoxy-benzoic acid. LC-MS (basic): tR=0.92 min; [M+H]+=512.3.
Reaction SMILES: C([O:5]C(NOCC(O)=O)=O)(C)(C)C.C(OCC)(=O)C.[CH:20]1([N:26]=[C:27]=[N:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.ON1C(=O)CCC1=O>C(#N)C>[CH:29]1([NH:28][C:27]([NH:26][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:5])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)NOCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyloxycarbonylaminoxy acetic acid was dissolved in ice-cooled ethyl acetate or acetonitrile and treated with N,N′-dicyclohexylcarbodiimide (1.0 equivalent) and N-hydroxysuccinimide (1.0 equivalent). The reaction mixture was stirred at room temperature overnight. The N,N′-dicyclohexylurea formed was removed by filtration and the filtrate was evaporated to dryness in vacuo. The crude Boc-AOA-OSu was either used directly in the next step or purified by recrystallisation from chloroform. Adopted from Kurth et al. J. Med. Chem. 1993, 36, 1255.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:3]([NH:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].[C:28]([NH:38][C@H:39]([C:43](O)=[O:44])[CH:40]([CH3:42])[CH3:41])([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[C:7]([O:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:43](=[O:44])[C@H:39]([CH:40]([CH3:41])[CH3:42])[NH:38][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)ONC(=O)[C@@H](N)CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NOC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-amino-N-tert-butoxy-3-(4-phenoxyphenylsulfonyl)-propionamide (1.9 g) in methylene chloride (30 ml) was added CBZ-(S)-valine (1.6 g), 1-hydroxybenzotriazole (0.9 g), triethylamine (1 ml), and N'-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide (1.3 g). After stirring overnight at room temperature, the solution was partitioned between methylene chloride and water, and after the organic layer was dried over magnesium sulfate, solvent was removed under reduced pressure to give (R)-N-tert-butoxy-2-(CBZ-valinamido)-3-(4-phenoxyphenylsulfonyl)-propionamide, which was used without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:41])([F:40])[O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1.[Cl:42][C:43]1[C:44]([C:53]([F:56])([F:55])[F:54])=[N:45][N:46]([CH2:49][C:50](O)=[O:51])[C:47]=1[CH3:48]>>[Cl:42][C:43]1[C:44]([C:53]([F:55])([F:54])[F:56])=[N:45][N:46]([CH2:49][C:50]([N:37]2[CH2:36][CH2:35][N:34]([C:31]3[CH:32]=[CH:33][C:28]([O:27][C:26]([F:25])([F:40])[F:41])=[CH:29][CH:30]=3)[CH2:39][CH2:38]2)=[O:51])[C:47]=1[CH3:48]
Reactant: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Trifluoromethoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.20 (d, 2H), 7.04 (d, 2H), 5.38 (s, 2H), 3.60 (m, 4H), 3.27 (m, 2H), 3.17 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=471.1, found=471.0.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[S:4].N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:11][N:5]1[C:6](=[O:7])[CH:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[S:4]
Reactant: CN1C(=O)CC(=O)N(C)C1=S
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1C(=O)N(C)C(=S)N(C)C1=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
155 g (0.9 mol) of 1,3-dimethyl-2-thiobarbituric acid, 88,3 g (1.12 mol) of pyridine and 9 g of 4-dimethylaminopyridine are dissolved in 660 ml of dichloromethane and the solution is cooled to 0° C. Then 102 g (0.94 mol) of ethyl chloroformate are added dropwise over 1 hour. The mixture is subsequently stirred for 12 hours at 0° C., then allowed to warm to room temperature and worked up after a further 7 hours as follows. 600 ml of dichloromethane are added and the solution is washed with three 1000 ml portions of water, dried over Na2SO4 and the solvent is evaporated off. The crude product is recrystallised from ethanol. Melting point 90°-93° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.Br[CH2:36][C:37]([O:39][CH2:40]C)=[O:38].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:7]2[C:2](=[O:1])[N:3]([CH:29]3[CH2:30][CH2:31][N:32]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:34]3)[C:4]3[N:5]([N:26]=[CH:27][N:28]=3)[C:6]=2[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1)#[N:22]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCNCC2)c2ncnn12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(CC(=O)OC)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (453 mg), ethyl bromoacetate (184 mg), potassium carbonate (276 mg) and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=60/40→35/65 (volume ratio)] to give the title compound as a colorless amorphous compound (418 mg, 80%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:19][C:20]([CH3:27])([CH3:26])[C:21](=O)[CH2:22][C:23]#[N:24]>C(O)C>[C:20]([C:21]1[CH:22]=[C:23]([NH2:24])[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=1)([CH3:27])([CH3:26])[CH3:19]
Reactant: NNc1ccccc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Yield: 70 %

Procedure:
N,N-Diisopropylethylamine (1.7 mL, 7.99 mmol) was added to a mixture of phenyl hydrazine hydrochloride (1.5 g, 10.39 mmol) and 4,4-dimethyl-3-oxopentane nitrile (1.0 g, 7.99 mmol) in ethanol (15 mL) and the mixture was heated under reflux for 18 hours. The cooled mixture was then concentrated to low volume and partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with heptanes:ethyl acetate, 75:25, to afford the title compound as a pale orange oil that crystallised on standing (1.21 g, 70% yield).
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1.C1(S([CH:26]2[CH2:30][CH2:29][CH:28]([O:31][CH3:32])[O:27]2)(=O)=O)C=CC=CC=1>C1COCC1.[Zn+2].[Br-].[Br-]>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([CH:26]2[CH2:30][CH2:29][CH:28]([O:31][CH3:32])[O:27]2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(Br)cc1OC
Reactant: COC1CCC(S(=O)(=O)c2ccccc2)O1
Agent: [Br-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1ccc(C2CCC(OC)O2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
Magnesium (2.18 g, 0.091 M) was placed in a 3-necked flask containing dry THF (10 ml) and 1,2-dibromoethane (0.2 ml). A solution of 4-bromoveratrole (18.0 g, 0.086 M) in THF (50 ml) was added dropwise, warming to initiate reaction. The resulting solution was heated at reflux for 0.75 h then cooled to room temperature and cannulated into a 1M solution of ZnBr2 in THF (50 ml, 0.05 M) and stirred for 0.5 h at room temperature. A solution of 2-benzenesulphonyl-5-methoxytetrahydrofuran (10.0 g, 0.041 M) in THF (50 ml) was added dropwise to the pale yellow suspension and the mixture allowed to stir at room temperature for 20 h. Reaction was quenched by addition of 1N HCl (50 ml), and extracted with ether (2×100 ml). The organics were combined washed with water (50 ml) dried (Na2SO4) and evaporated. Flash column chromatography (flash silica gel, hexane:ethyl acetate (3:2)) gave 2-(3,4-dimethoxyphenyl)-5-methoxytetrahydrofuran (8.0 g, 82%) as a yellow oil (rf 0.28).
Reaction SMILES: C(O[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[C:21]([CH2:29][CH3:30])=[N:22][O:23][C:24]=3[C:25]=2[CH2:26][CH2:27][CH3:28])=[C:8](C)[C:7]=1[CH3:32])(=O)CC.[Li+].[OH-:34]>CO>[CH3:32][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[C:21]([CH2:29][CH3:30])=[N:22][O:23][C:24]=3[C:25]=2[CH2:26][CH2:27][CH3:28])[CH:10]=[CH:11][C:6]=1[CH:8]([CH3:7])[C:9]([OH:12])=[O:34]
Reactant: CCCc1c(OCCCOc2ccc(OC(=O)CC)c(C)c2C)ccc2c(CC)noc12
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(C)C(=O)O)c(C)c2)ccc2c(CC)noc12
Temperature: 50 °C

Procedure:
A solution of methyl-2-methyl-4-(3-(3-(Ethyl)-7-(propyl)-6-benz-[4,5]-isoxazoloxy)propyloxy)-phenyl propionate (11.5 mg, Step A) was dissolved in MeOH (0.5 mL)and 1M LiOH (0.10 mL) was added. The resulting solution was warmed to 50° C. for 2 hours, cooled and concentrated. The residue was partitioned between ethyl acetate and 1 M Hcl. The organic fraction was removed, dried and concentrated to give the title compound as a colorless oil (10.7 mg) NMR (CDCl3); δ 7.40 (d,2H), 7.11 (d,2H), 6.95 (d,2H), 6.85 (d,2H), 1.43 (t,3H), 1.18 (d,2H), 0.95 (t,3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:35])[NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[C:28]2[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=2[O:26][CH:25]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:9])[C:10]([NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[C:28]2[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=2[O:26][CH:25]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:35]
Reactant: COc1ccc2occ(CC3CCCN3C(=O)C(NC(=O)C(C)NC(=O)OC(C)(C)C)C(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2occ(CC3CCCN3C(=O)C(NC(=O)C(C)N)C(C)C)c2c1
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 33 (0.057 g, 0.11 mmol) in DCM (5 mL) was added TFA (1 mL) at ambient temperature. After 1 h, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (10% MeOH/DCM) to afford 0.015 g (35%) of 34 as a white solid. 1H NMR (CDCl3, 300 MHz) δ7.42 (m, 1H); 7.35 (d, 1H); 7.28 (m, 1H); 6.90 (dd, 1H); 4.60 (m, 1H); 4.48-4.45 (m, 1H); 3.89-3.76 (m, 4H); 3.65-3.56 (m, 2H); 3.31 (dd, 1H); 2.52-2.44 (m, 1H); 2.13-1.72 (m, 6H); 1.43-1.27 (m, 5H); 1.05-0.97 (m, 6H) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[NH:5][C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][N:9]1[C:10]2[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[NH:5][C:6]=2[N:7]=[CH:8]1)[CH3:25]
Reactant: Cn1c(=O)[nH]c2nc[nH]c2c1=O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2[nH]c(=O)n(C)c(=O)c21
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of 1-methyl xanthine (120, 1 g, 6.01 mmol) in DMF, potassium carbonate (0.91 g, 6.6 mmol) was added and the reaction mixture was heated to 90° C. and stirred for 1 h. A solution of ClCH2COOEt (0.36 g, 3.0 mmol) in DMF was then added dropwise to the reaction over 45 min. After stirring an additional 15 min, the reaction was cooled to room temperature and poured into ice cold 1N HCl (50 ml). The reaction was then extracted with chloroform (50×2 ml). The combined organic layers were washed with water (100 mL), dried over Na2SO4 and concentrated in vacuo. To the resulting solid was added 30% dichloromethane in hexanes (400 mL) and the resulting mixture was stirred for 15 min and filtered to yield compound 121 as a yellow solid (0.6 g, 40%). MS (APCI): m/z 253.32 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.[CH2:21](I)[CH3:22].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:21]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1)[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CCNCC2)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1-Dimethylethyl 4-(4-piperidinylmethyl)-1-piperidinecarboxylate (may be prepared as described in Description 2) (2 g), ethyl iodide (0.57 ml) and K2CO3 (1.96 g) were combined in acetonitrile (70 ml) and the reaction mixture was stirred at room temperature for 3 h. The reaction was filtered to remove solids and the solvent evaporated to give the title compound (D7) as a yellow solid (2.5 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].CO[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:23]2>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:25]2[CH:24]=[CH:23][C:22]3[C:27]([CH:26]=2)=[C:28]2[C:29]([CH2:4][CH2:3][CH2:7][CH2:6]2)=[CH:20][CH:21]=3)(=[O:32])=[O:31])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: COc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc4ccc5c(c4c3)CCCC5)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B, substituting 5,6,7,8-tetrahydrophenanthrene-3-sulfonyl chloride for 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc/CH2Cl2 to 30% EtOAc/CH2Cl2 to give the title compound as a white foam.
Reaction SMILES: NC([CH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:17][CH:16]=3)[C:11]2=[O:28])[CH2:6][CH2:5]1)=O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(#[N:52])C.O>>[NH2:52][CH:4]1[CH2:5][CH2:6][CH:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:17][CH:16]=3)[C:11]2=[O:28])[CH2:8][CH2:9]1
Reactant: COC(=O)CCCc1ccc(N2CCN(C3CCC(C(N)=O)CC3)C2=O)cc1
Reactant: CC#N
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: COC(=O)CCCc1ccc(N2CCN(C3CCC(N)CC3)C2=O)cc1

Procedure:
Prepared from 1-(4-aminocarbonyl-cyclohexyl)-3-[4-(3-methoxycarbonyl-propyl)-phenyl]-imidazolidin-2-one by treating with [bis-(trifluoroacetoxy) iodo]benzene in acetonitrile/water at ambient temperature.