Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24]([OH:26])=[O:25])[CH:20]=[CH:21][CH:22]=1.Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>O1CCCC1>[Br:16][C:17]1[CH:18]=[C:19]([CH:23]([CH2:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[C:24]([OH:26])=[O:25])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(CC(C(=O)O)c2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of n-butyl lithium (95 ml, 15% solution in hexane, 147 mmol) and 2,2,6,6-tetramethylpiperidine (24.9 ml, 147 mmol) in tetrahydrofurane (220 ml) was added a solution of (3-bromo-phenyl)-acetic acid (15.05 g, 70 mmol) in tetrahydrofuran (80 ml) at −78° C. The reaction mixture was stirred for 60 minutes at that temperature. Then 4-bromomethyl-benzonitrile (13.72 g, 70 mmol) in tetrahydrofuran (160 ml) was added. The reaction mixture was stirred for 2 hours at −78° C., then warmed up to room temperature and quenched with ammonium chloride solution (240 ml), 3 N hydrochloric acid (50 ml), and ethyl acetate (300 ml). The organic layer was washed with ammonium chloride solution and brine, dried, and evaporated in vacuo. The residue was solved in ethyl acetate and stirred with methyl-tert-butylether. The precipitate was sucked off and dried in vacuo to give 19.0 g of the desired product (82% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[O:22]=[C:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33](C(OC(C)(C)C)=O)[CH:32]=[CH:31]2>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:33]3[C:34]4[C:30](=[CH:29][C:28]([N:24]5[CH2:25][CH2:26][CH2:27][C:23]5=[O:22])=[CH:36][CH:35]=4)[CH:31]=[CH:32]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(N3CCCC3=O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(N5CCCC5=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and tert-butyl 5-(2-oxopyrrolidin-1-yl)-1H-indole-1-carboxylate (intermediate-27) (0.011 g, 6%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][C@H:31]2[C@H:36]([OH:37])[CH2:35][O:34][CH2:33][CH2:32]2)[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][C@H:31]3[C@H:36]([OH:37])[CH2:35][O:34][CH2:33][CH2:32]3)=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: O=C1N=C(N[C@@H]2CCOC[C@H]2O)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2CCOC[C@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 75 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.05 g) in 2-propanol (20 mL) were added 1,5-anhydro-2,3-dideoxy-3-[(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)amino]-threo-pentitol (1.00 g) and piperidinium acetate (457 mg). The reaction mixture was stirred at 75° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, methanol/ethyl acetate), and the obtained powder was washed with diisopropyl ether to give the title compound (571 mg).
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:27]1[N:31]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)[N:30]=[CH:29][CH:28]=1)CCC>>[CH3:21][C:3]1[C:2]([C:27]2[N:31]([C:32]3[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=3)[N:30]=[CH:29][CH:28]=2)=[CH:7][N:6]2[N:8]=[CH:9][N:10]=[C:5]2[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1
Reactant: Cc1c(Br)cn2ncnc2c1-c1cccc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2ncnc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (Int. 6, 100 mg, 0.281 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 193 mg, 0.421 mmol) using a similar method to that used in Example 1 (Step 4) (91 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)(=[O:34])[CH3:33]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Reactant: CC(=O)Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A155) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([N:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1)[C:4](=[NH:7])SC)#N.[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[N:31]1C=CC=C[CH:32]=1>>[CH2:22]([NH:30][C:4](=[N:7][C:32]#[N:31])[NH:3][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:12][CH:13]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCc1ccccc1
Reactant: CSC(=N)N(C#N)c1ccc(C2=NNC(=O)CC2C)cc1
Reactant: c1ccncc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=NC#N)NCCc2ccccc2)cc1

Procedure:
A stirred mixture of 6-(4-(N-cyano-S-methylisothioureido)phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone, (2 g), phenethylamine (8.4 ml) and pyridine (40 ml) was heated under reflux for 3 hours. The mixture was evaporated under reduced pressure to yield an oil, which on trituration with one normal acetic acid (17 ml) gave 1.1 g of a solid, m.p. 209°-210° C. Recrystallisation from ethanol gave the pure title compound, 0.64 g, m.p. 215°-217° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:16]=[CH:17][CH:18]=3)[CH2:13][NH:12]2)[O:9][C:8](=[O:32])[NH:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[F:36][C:34]1[CH:33]=[C:4]([CH:3]=[C:2]([F:1])[CH:35]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:23]([CH3:24])[CH3:25])[CH:26]([CH3:27])[CH3:28])[CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2[CH:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:9][C:8](=[O:32])[NH:7]1
Reactant: CC(C)[Si](Oc1cccc2c1CN[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2)(C(C)C)C(C)C
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)[Si](Oc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2)(C(C)C)C(C)C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution of (4S,5R)-4-(3,5-difluorobenzyl)-5-((R)-8-(triisopropylsilyloxy)-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one Step F (12), 120 mg, 0.23 mmol) in acetonitrile (2 mL) were added potassium carbonate (64 mg, 0.46 mmol) and bromodiphenylmethane (91 mg, 0.37 mmol). This mixture was put on microwave at 75° C. for 2 h and 15 min. Solvent was removed and the crude mixture was purified by silica gel Flash Chromatography to give 120 mg of the title compound (75% yield): 1H NMR (CDCl3, 500 MHz) δ 0.90 (18H, m), 1.06 (3H, m), 2.47 (1H, m), 2.76 (1H, d, J=20 Hz), 3.16-3.23 (2H, m), 3.69 (1H, d, J=20 Hz), 3.75 (1H, m), 4.02 (1H, m), 4.18 (1H, d, J=20 Hz), 4.72 (1H, m), 4.80 (1H, s), 4.92 (1H, s), 6.61 (1H, d, J=10 Hz), 6.76-6.80 (4H, m), 7.03-7.06 (1H, m), 7.17-7.30 (6H, m), 7.39 (4H, t, J=5 Hz). MS (ESI) (M+H)+ 683.31.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27]1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O.C(OCC)(=O)C>[C:6]([C:5]1[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:10][C:2]([N:26]2[CH2:31][CH2:30][CH2:29][C@@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:27]2)=[N:3][CH:4]=1)(=[O:7])[NH2:8]
Reactant: NC(=O)c1cnc(Cl)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cc(Nc3ccc(C(=O)N4CCOCC4)cc3)c(C(N)=O)cn2)C1
Temperature: 120 °C
Yield: 41.9 %

Procedure:
A solution of 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (230 mg, 0.637 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (166 mg, 0.829 mmol) in N-methyl-2-pyrrolidinone (2 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (107 mg, 0.829 mmol) in a vial, sealed and heated in a heating block at 120° C. for 2 days. The mixture was diluted with ethyl acetate and washed with water. Concentrated and the dark residue was chromatographed (ISCO Companion 12 g silica gel column and eluted with ethyl acetate) to give 140 mg of (R)-tert-butyl 1-(5-carbamoyl-4-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate as a white solid. LCMS: (M+H)+=525.21. 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9H) 1.50-1.65 (m, 2H) 1.68-1.81 (m, 1H) 1.91 (d, J=10.77 Hz, 1H) 3.16-3.36 (m, 2H) 3.55-3.80 (m, 10H) 3.88 (dd, J=12.85, 3.41 Hz, 1H) 4.68 (d, J=6.81 Hz, 1H) 5.75 (s, 2H) 6.41 (s, 1H) 7.30 (d, J=8.57 Hz, 2H) 7.44 (d, J=8.57 Hz, 2H) 8.32 (s, 1H) 10.33 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH3:12])[CH2:2][CH3:3].Br[N:14]1C(=O)CC[C:15]1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CNN>CCOCC.C(Cl)(Cl)(Cl)Cl>[CH2:2]([C:1]1[N:14]([CH3:15])[C:10]([CH2:11][CH3:12])=[C:5]2[C:4]=1[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1ccccc1CCC
Agent: CNN
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCc1c2ccccc2c(CC)n1C

Procedure:
A mixture of 0.374 mole of o-dipropylbenzene, 146 g. (0.822 mole) of N-bromosuccinimide, 0.1 g. of benzoyl peroxide, and 800 ml. of carbon tetrachloride is heated under reflux with stirring and ultraviolet irradiation until the reaction is complete. The precipitated succinimide is filtered, washed with carbon tetrachloride, and the filtrate is evaporated to dryness under reduced pressure. The residual α,α'-dibromo-o-dipropylbenzene is dissolved in 800 ml. of absolute ether. To the stirred solution under nitrogen is added dropwise a solution of 40 g. (0.87 mole) of methyl hydrazine in 50 ml. of absolute ether. A gummy precipitate separates. After 3 hours of stirring and an overnight period of standing, the ether is decanted. The residue dissolved in 625 ml. of water is treated with 375 ml. of 40% sodium hydroxide solution and the mixture is stirred at reflux for 1.5 hours. After cooling, the precipitate of the crude product is collected, washed with water, and dissolved in 600 ml. of ether. The ether solution is washed repeatedly with water and dried over anhydrous magnesium sulfate with stirring and cooling in an ice bath. The filtered solution is evaporated under reduced pressure and the residual dark yellow solid is triturated with petroleum ether, filtered and dried in vacuo to yield 1,3-diethyl-2-methylisoindole.
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21]C)=O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:41][CH2:42][CH2:43][CH2:44][NH2:45]>ClCCl>[NH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:19]([C:17]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)=[C:10]([NH:9][CH2:8][CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:18]=1)=[O:21]
Reactant: NCCCN
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCCN)nc32)[C@H](O)[C@@H]1O
Temperature: 100 °C
Yield: 58.4 %

Procedure:
A mixture of methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylate (Preparation 9) (0.35 g, 0.64 mmol) and 1,3-diaminopropane (0.45 g, 6.1 mmol) was heated at 100° C. for 3 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (80:20:1.2, by volume) changing to dichloromethane:methanol:concentrated aqueous ammonia (88:12:2, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.22 g, 58%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[CH:18]([NH:20][NH2:21])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:16]1[N:17]=[CH:18][NH:20][N:21]=1)[C:30]1[CH:29]=[CH:28][CH:33]=[CH:32][CH:31]=1
Reactant: N#CCc1cccc(OCc2ccccc2)c1
Reactant: NNC=O
Reactant: CCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(COc2cccc(Cc3nc[nH]n3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a stirring solution of 3-benzyloxyphenylacetonitrile (5.0 g, 0.022 mole) in methanol (100 mL) was added formic hydrazide (2.69 g, 0.060 mole) and solid potassium carbonate (9.9 g, 0.027 mole). The reaction was heated at reflux and stirred overnight. The mixture was cooled to RT, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 75% ethyl acetate:hexane as eluent to afford 1.8 g (30% yield) of the title compound as an oil: MS (ESI) 266.0 (M+H+).
Reaction SMILES: FC(F)(F)C([NH:5][C@@H:6]([C@H:10]([CH3:13])[CH:11]=[CH2:12])[C:7]([OH:9])=[O:8])=O.[OH-].[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O>[CH2:22]([O:21][C:19]([NH:5][C@@H:6]([C@H:10]([CH3:13])[CH:11]=[CH2:12])[C:7]([OH:9])=[O:8])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=C[C@@H](C)[C@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C[C@@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
A mixture of 25.16 g (112 mmol) of (2S,3R)-2-trifluoroacetylamino-3-methyl-4-pentenoic acid and 112 mL of 2 N aqueous sodium hydroxide is stirred at 80° C. for 1.5 h. The mixture is then allowed to cool to 25° C. and is further chilled to 0° C. 2 N aqueous sodium hydroxide (112 mL) is added followed by dropwise addition of 18 mL (126 mmol) of benzyl chloroformate. After 45 min at 0° C. and 5 h at 25° C. the mixture is added to 150 mL of water and is treated with aqueous sodium hydroxide until an orange solution resulted. The mixture is extracted with ether. The aqueous phase is acidified with 6 N HCl to pH 1 and is extracted with ether. Drying over magnesium sulfate and concentration in vacuo affords 22.61 g (77%) of (2S,3R)-2-benzyloxycarbonylamino-3-methyl-4-pentenoic acid as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:12][S:13][CH2:14][CH2:15][CH:16]=O>>[CH3:12][S:13][CH2:14][CH:15]=[CH:16][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCNC1
Reactant: CSCCC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSCC=CN1CCCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
To a dry 1 L round bottom flask equipped with a magnetic stir bar, liquid addition funnel, thermometer, and nitrogen inlet were added potassium carbonate (33.2 g, 240 mmol) and pyrrolidine (136.5 g, 160 mL, 1.92 mol), and the resulting suspension was cooled to 0° C. in an ice bath. 3-(Methylthio)propionaldehyde (K) (50 g, 480 mmol) was added dropwise via the addition funnel at a rate which maintained the reaction temperature at 0-7° C. The resulting light yellow mixture was warmed to room temperature and stirred for 16 hours. The residual potassium carbonate was removed by filtration, the filter cake washed with Et2O, and the filtrate concentrated on the rotary evaporator to give the crude enamine as a viscous, light yellow oil. Fractional distillation (108-110° C. at 4 mm Hg) afforded 63.3 g (83.8%) of 1-[3-(methylthio)prop-1-enyl]pyrrolidine (L) as a colorless liquid. 1H NMR (CDCl3) δ 6.29 (d, 1H), 4.06 (dt, 1H), 3.16 (d, 2H), 3.03 (m, 4H), 2.04 (s, 3H), 1.85 (m, 4H). GC-MS (EI) m/z 157 (M+).
Reaction SMILES: [NH2:1][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]([N:14]([CH3:16])[CH3:15])([CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH3:4].[CH3:23][C:24]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:3]([CH3:4])([CH2:5][O:6][Si:7]([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9])[CH:2]([NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[C:24]=1[CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)C(C)(CO[Si](C)(C)C(C)(C)C)C(N)c1ccccc1
Reactant: Cc1cccc(C(=O)O)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC(c2ccccc2)C(C)(CO[Si](C)(C)C(C)(C)C)N(C)C)c1C
Yield: 30 %

Procedure:
The title compound (64 mg; 30%) was prepared from [2-amino-1-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-methyl-2-phenylethyl]dimethylamine D48 (150 mg; 0.46 mmol), 2,3-dimethylbenzoic acid (75 mg; 0.5 mmol), PL-dicyclohexylcarbodiimide (385 mg; 0.5 mmol; Polymer Labs 1.3 mmol/g), 1-hydroxybenzotriazole (77 mg; 0.5 mmol) in DCM (5 ml) in a similar manner to that described in E1. Mass spectrum (Electrospray LC/MS): Found 455 (MH+), C27H42N2O2Si requires 454. Ret. time 2.57 and 2.61 min.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=[C:19]=[O:20])[CH:13]=1>ClCCl>[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]2)=[O:20])[CH:13]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)Nc2cccc(C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a solution of ethyl piperazine-1-carboxylate (1.0 g, 6.32 mmol) in dichloromethane (30 ml) was added m-tolylisocyanate (0.90 mg, 6.95 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and washed with water, brine and dried over Na2SO4. After removing the solvents, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (1.6 g, 87%).
Reaction SMILES: C[O:2][C:3]([CH:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[C:6](OC)=[O:7])=O.[Li+].[BH4-].CO>C1COCC1>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:5]([CH2:3][OH:2])[CH2:6][OH:7])=[CH:22][CH:21]=1
Reactant: COC(=O)C(CCCCCCOc1ccc([N+](=O)[O-])cc1)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(OCCCCCCC(CO)CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Compound 17 (1.19 g, 3.4 mmol) was dissolved in dry THF (50 mL). LiBH4 (0.44 g, 20.2 mmol) was added and the mixture was refluxed overnight. The mixture was allowed to cool to r.t. and MeOH (10 mL) was added. The reaction mixture was stirred for 30 min at r.t. The mixture was evaporated to dryness. Saturated aqueous NaHCO3 was added and the mixture was refluxed for one hour. The mixture was allowed to cool to r.t. and then filtered. The precipitate was washed with water and purified on silica gel (10% MeOH/CH2Cl2), yielding 0.60 g (67%) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:24]2[NH:36][C:34](=[O:35])[NH:33][C:8]([C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=3)[C:13]#[N:14])=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH3:19]
Reactant: N#Cc1cccc(C(=O)Cc2ccccc2)c1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cccc(C#N)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 8.9 %

Procedure:
To a solution of 3-(2-phenylacetyl)benzonitrile (Intermediate 23) (100 mg, 0.45 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (89.1 mg, 0.45 mmol), and urea (82.3 mg, 1.35 mmol) in 5 mL of ethanol was added 0.2 mL of concentrated HCl, the mixture was refluxed for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 53 (18.2 mg, yield 8.8%). 1H NMR (DMSO-d6 400 MHz) δ 10.27 (s, 1H), 8.86 (s, 1H), 7.71 (t, J=12.4 Hz, 2H), 7.57 (s, 1H), 7.44 (m, 3H), 7.14-7.06 (m, 4H), 6.85 (d, J=6.8 Hz, 2H), 5.28 (s, 1H), 4.06 (m, 2H), 1.32 (t, J=6.8 Hz, 3H); MS (ESI): m/z 456.9 [M+1]+.