Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12](OC2C=CC([N+]([O-])=O)=CC=2)=[O:13])C=CC=CC=1.[CH3:36][O:37][C:38](=[O:44])[C@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1>>[CH3:36][O:37][C:38]([C@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:13])=[O:44]
Reactant: COC(=O)[C@H]1CCCN1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)[C@H]1CCCN1C(=O)SCCN
Yield: 103.8 %

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (675 mg) and D-proline methylester (0.18 g) were subjected to similar reactions to those described in References 2 and 4 to give 2-[(R)-2-methoxycarbonylpyrrolidino]carbonylthioethylamine (crude formate: 336 mg). The product was dissolved in anhydrous methanol (6 ml). To the solution were added triethylamine (1.01 ml) and mitomycin A (338 mg: 0.8 molar equivalent). The solution was then treated in a similar manner to that described in Example 1 to obtain Compound 32 (286 mg) in the form of grayish blue powders with a yield of 43%.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:13]([CH3:12])[CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CNCC1CCN(C)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(CN(C)C(=O)c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Yield: 64.9 %

Procedure:
4-cyanobenzoylchloride (200 mg, 1.21 mmol) was dissolved in anhydrous CH2Cl2 (4 mL) and cooled to 0° C. Methyl-(1-methyl-piperidin-4-ylmethyl)-amine (172 mg, 1.21 mmol) in anhydrous CH2Cl2 (1 mL) was added followed by N,N-diisopropylethylamine (0.63 mL, 3.62 mmol). The reaction mixture was allowed to warm to RT over 2 h. The reaction mixture was concentrated in vacuo and the crude product purified by reverse phase preparative HPLC-MS to obtain 4-cyano-N-methyl-N-(1-methyl-piperidin-4-ylmethyl)-benzamide as an off-white solid (213 mg, 65%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:17]1[C@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][C@H:19]([CH:28]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29]2)[C:18]1=[O:37])[C:10]([N:12]1[CH2:15][CH:14](O)[CH2:13]1)=[O:11].C(N(S(F)(F)[F:44])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:17]1[C@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][C@H:19]([CH:28]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29]2)[C:18]1=[O:37])[C:10]([N:12]1[CH2:13][CH:14]([F:44])[CH2:15]1)=[O:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N1CC(O)C1)c1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N1CC(F)C1)c1ccc(F)cc1F
Reaction time: 8 h

Procedure:
The azetidinol (Example 15) (57 mg) in anhydrous dichloromethane (2 mL) was stirred at −5° C. and diethylaminosulfur trifluoride (50 μL, excess) was added in one portion. The mixture was left at room temperature overnight and saturated aqueous sodium hydrogen carbonate (3 mL) was added. The mixture was diluted with dichloromethane (10 mL) and the organic phase was separated using a hydrophobic frit and blown down with nitrogen. The crude reaction mixture was purified using the mass-directed autoprep system to give (3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-(3-fluoroazetidin-1-yl)-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiiierazine-2,5-dione (26 mg) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](Cl)[CH:18]=2)[NH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22]1>C1C=CC=CC=1>[C:25]([CH2:24][CH2:23][CH2:22][C:21]([N:8]([CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:28])([OH:27])=[O:26]
Reactant: Clc1ccc2[nH]cc(CCNCc3ccccc3)c2c1
Reactant: O=C1CCCC(=O)O1
Solvent: c1ccccc1
Product: O=C(O)CCCC(=O)N(CCc1c[nH]c2ccccc12)Cc1ccccc1
Reaction time: 8 h

Procedure:
113 g (0.396 mol) of 3-(2-benzylaminoethyl)-5-chloroindole are dissolved in 500 ml of benzene. 45.27 g of glutaric anhydride are added in small amounts and the reaction mixture is heated at the reflux temperature for 2 hours and then left to stand overnight. It is evaporated to dryness. This gives the named product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])CCC.C[O:20][B:21](OC)[O:22]C.Cl>>[B:21]([OH:22])([OH:20])[C:6]1[CH:7]=[CH:2][C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:5]=1
Reactant: COB(OC)OC
Reactant: Brc1ccccc1-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Product: OB(O)c1ccc(-c2ccccc2)cc1
Temperature: -95 °C
Reaction time: 0.08 h

Procedure:
5 g of bromobiphenyl was dissolved in 100 mL of tetrahydrofuran(THF), and the solution was cooled to −95° C. Then, 20.2 mL of 1.6M butyllithium was added thereto and stirred for 5 minutes. 24.31 mL of trimethylborate was added thereto at −95° C., and the solution was stirred for 2 hours at −78° C., and for 12 hours at room temperature. Then, 10% HCl solution was added thereto at 0° C. to adjust the pH of the solution to be less than 6, and the solvent was distilled. The reaction product was extracted with ether to obtain biphenylboronic acid. Thereafter, as shown in the following reaction 4, 0.08 g of bromospiro-dimer, 0.034 g of biphenyl boric acid, 0.003 g of Pd(TPP)4 catalyst, 0.11 ml of 2M Na2CO3 were refluxed in 1,2-dimethoxyethane solvent while stirring for 24 hours (Suzuki coupling reaction) to obtain the target compound.
Reaction SMILES: [OH-].[K+].[CH3:3][C@H:4]1[CH2:13][CH:12]=[CH:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[C@H:5]1[C:14]([O:16]CC)=[O:15].[OH-].[Na+]>C(O)C>[CH3:3][CH:4]1[CH2:13][CH:12]=[CH:11][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH:5]1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)[C@H]1[C@@H](C)CC=CC12CCCC2
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CC=CC2(CCCC2)C1C(=O)O
Yield: 37.5 %

Procedure:
A solution of KOH (19.1 g, 289 mmol) in ethanol (60 ml) was treated with rel-(6S,7S)-ethyl 7-methylspiro[4.5]dec-9-ene-6-carboxylate (4.28 g, 19.2 mmol, prepared as described in Example 19) and after refluxing for 3 d, the resulting mixture was poured into cold 2N aqueous NaOH (100 ml), and extracted twice with cyclohexane (50 ml). The combined aqueous phases were acidified with conc. HCl, extracted twice with MTBE (50 ml), and the combined org. phases were washed with water (50 ml), with a saturated aqueous solution of NaCl (50 ml), dried (MgSO4), and concentrated. FC (300 g SiO2, hexane/MTBE 8:1) of the crude product (2.65 g) gave 7-methylspiro[4.5]dec-9-ene-6-carboxylic acid (1.4 g, 37%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(Oc2ncccn2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
A solution of N-BOC-L-tyrosine methyl ester (3.0 g, 10.2 mmol) in DMF (5 ml) was added to a suspension of NaH (60% in oil, 11.2 mmol, 447 mg) in DMF (10 ml). After 10 min, a solution of 2-chloropyrimidine (11.2 mmol, 1.28 g) in DMF (3 ml) was added and the mixture stirred overnight. The reaction was quenched with water, diluted EtOAc and washed with water and brine. The EtOAc layer was dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography [SiO2, EtOAc/hexane, 1:1] gave the title compound. δH (DMSO d6) 8.62 (2H, d, J 4.8 Hz), 7.37 (1H, d, J 8.1 Hz), 7.28 (2H, d, J 8.4 Hz), 7.24 (1H, t, J 4.8 Hz), 7.09 (2H, d, J 8.4 Hz), 4.18 (1H, m), 3.01 (1H, dd, J 13.8, 4.6 Hz), 1.33 (9H, s).
Reaction SMILES: Br[C:2]1[C:13](=[O:14])[N:12]([CH2:15][CH3:16])[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([N:12]1[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]1=[O:14])[CH3:16]
Reactant: CCn1c(=O)c(Br)cc2cnc(SC)nc21
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCn1c(=O)c(-c2ccccc2)cc2cnc(SC)nc21
Temperature: 120 °C
Yield: 82 %

Procedure:
6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (150 mg, 0.50 mmol), phenylboronic acid (183 mg, 1.50 mmol), K3PO4 (318 mg, 1.50 mmol) and Pd(PPh3)4 (29 mg, 0.02 mmol) were mixed as solids and placed under argon. Argon was bubbled through the mixture of dimethoxyethane:ethanol:water (1:1:1, 2.0 mL) for 20 min. The solvent was added to the solid and the suspension was heated under microwave irradiation at 120° C. for 1 h. After completion, the reaction mixture evaporated to dryness, the crude product was purified by silica gel column chromatography using dichloromethane:ethyl acetate (100:0.5) to yield 8-ethyl-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one as an off-white solid (121 mg, 0.41 mmol, 81%). ESMS m/z 298 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.59 (s, 1H), 8.03 (s, 1H), 4.55 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O:4][CH:5]1[CH2:22][CH2:21][C:20]2([CH3:23])[CH:7]([CH2:8][CH2:9][C:10]3([CH3:48])[CH:19]2[CH2:18][CH2:17][CH:16]2[C:11]3([CH3:47])[CH2:12][CH2:13][C:14]3([C:30](=[O:46])[NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:43][CH2:42][N:41]([CH2:44][CH3:45])[CH2:40][CH2:39]5)[CH2:33]4)[CH2:26][CH2:25][CH:24]([C:27]([CH3:29])=[CH2:28])[CH:15]32)[C:6]1([CH3:50])[CH3:49])(=O)C.C1COCC1.[OH-].[Na+]>CO>[CH2:44]([N:41]1[CH2:42][CH2:43][N:38]([CH2:37][C@H:34]2[CH2:35][CH2:36][C@@H:32]([NH:31][C:30]([C@:14]34[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]3[C@@H:16]3[C@@:11]([CH3:47])([CH2:12][CH2:13]4)[C@@:10]4([CH3:48])[C@@H:19]([C@:20]5([CH3:23])[C@@H:7]([CH2:8][CH2:9]4)[C:6]([CH3:49])([CH3:50])[C@@H:5]([OH:4])[CH2:22][CH2:21]5)[CH2:18][CH2:17]3)=[O:46])[CH2:33]2)[CH2:39][CH2:40]1)[CH3:45]
Reactant: C=C(C)C1CCC2(C(=O)N[C@@H]3CC[C@H](CN4CCN(CC)CC4)C3)CCC3(C)C(CCC4C5(C)CCC(OC(C)=O)C(C)(C)C5CCC43C)C12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCN(CC)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.4 %

Procedure:
1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3S)-3-((4-ethylpiperazin-1-yl)methyl)cyclopentylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 34, 0.5 g) in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.12 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature then completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.34 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.25-4.70 (m, 4H); 5.78 (s, 1H); MASS: 650 (100%).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1F)([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:18]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Cc1ccccc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccccc1NC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
0.990 g (4.356 mmol) of 4-hydroxy-2′-methylbenzanilide and 0.811 g (4.358 mmol) of 2,4-dinitrofluorobenzene were dissolved into 20 ml of acetone. The solution was stirred for one hour at reflux temperature after the addition of 0.6 g (4.3 mmol) of potassium carbonate. The reaction solution was filtered and precipitate was thoroughly washed with acetone. Filtrate was concentrated and purified through column chromatography (developing solvent: chloroform) to yield 1.553 g of 4-(2,4-dinitrophenoxy)-2′-methybenzanilide shown in the structural formula 11 above in light yellow solid (Yield: 90.63%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]3[CH2:15][CH2:14]3)[O:11][CH:12]=2)=[CH:4][CH:3]=1.[Cu](C#N)[C:17]#[N:18].[C-]#N.[Na+]>CN1C(=O)CCC1>[CH:13]1([C:10]2[O:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:17]#[N:18])=[CH:3][CH:4]=3)[N:9]=2)[CH2:15][CH2:14]1
Reactant: N#C[Cu]C#N
Reactant: Brc1ccc(-c2coc(C3CC3)n2)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(-c2coc(C3CC3)n2)cc1
Yield: 70.6 %

Procedure:
To a solution of 4-(4-bromophenyl)-2-cyclopropyl-1,3-oxazole (1.78 g, 6.74 mmol) in NMP (25 mL) was added copper cyanide (4.22 g, 47.12 mmol). The mixture was heated to 185C for 4 h. Upon cooling, the mixture was poured into a 0C solution of 5% aqueous sodium cyanide (60 ml). The aqueous phase was extracted with Et2O. The combined organic phases were washed with, 5% aqueous sodium cyanide, water, and brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (CH2Cl2/Hexanes, 2:3 to 10:0) to yield 4-(2-cyclopropy-1,3-oxazol-4-yl)benzonitrile as a yellow solid (1.00 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4].I[CH3:22]>CC(C)=O.[Ag]=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][CH3:22])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4]
Reactant: CI
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: O=[Ag]
Solvent: CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](OC)CN1C(=O)OCc1ccccc1
Temperature: 57 °C
Reaction time: 28 h
Yield: 95.2 %

Procedure:
To 2.00 g (7.16 mmol) of (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester in 20 mL of acetone was added 5.64 g of silver oxide (24.3 mmol) and 1.56 mL of iodomethane (25.0 mmol) and the mixture was stirred at 57° C. for 28 h. The solution was cooled to 25° C., filtered through celite and concentrated. Purification was through 50 mL of silica by eluting with EtOAc:Hexane (8:1) and the purified fractions were concentrated to give a 2.0 g (96%) of (2S,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester as a clear oil. HPLC: Rt 3.79 min. (100% area). 1H NMR (CDCl3, 400 MHz) δ: 7.31-7.23 (5H, m), 5.22-5.00 (2H, m), 4.44-4.40 (1H, m), 4.10-4.02 (1H, m), 3.76 (3H, s), 3.69-3.60 (1H, m), 3.54 (2H, s), 3.29 (3H, bs), 2.42-2.30 (1H, m). LCMS (ESI) (M+Na+) m/z: 316.1.
Reaction SMILES: CCO[CH2:4][CH3:5].[C:6]1([CH:12]2[CH2:17][CH2:16]C(=O)[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[C:6]1([CH:12]2[CH2:17][CH2:16][C:4](=[CH2:5])[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CCOCC
Solvent: ClCCl
Product: C=C1CCC(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
BDAM (3.00 grams) was suspended in 30 milliliters of dry CH2Cl2. Two molar equivalents of ether were added dropwise to the chilled suspension. After about 10 minutes of stirring, a homogeneous solution was formed. At this point, 1 molar equivalent of TMAL (1.1 milliliter) was added. The reaction mixture was stirred at room temperature for 15 minutes and 2.00 grams of 4-phenylcyclohexanone were added. Vigorous reflux which quickly subsided was noticed. The reaction mixture was stirred at room temperature for 3 hours and hydrolyzed as described in Example 1. The aqueous layer was acidified to help separate the organic layer. After the usual work up and column separation, 1.75 grams of 4-phenyl-1-methylenecyclohexane were isolated (88% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:38])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][O:22][C:30]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution comprising 10 g (33.7 mmol) of 1,4-dibenzyl-2-hydroxymethylpiperazine (prepared in accordance with the process described by Jucker and Rissi in Helv. Chem. Acta, 1962, 45, 2383-2402) in 9.5 ml (2.8 equivalents; 94.4 mmol) of triethylamine and 95 ml of dichloromethane (CH2Cl2) is placed in a 500 ml ground-necked conical flask on which is fitted an addition funnel, and is cooled in an ice bath. After dropwise addition of 6.4 g (1.25 equivalents; 42 mmol) of phenyl chlorocarbonate dissolved in 95 ml of CH2Cl2, the mixture is stirred at 0° C. for one hour and then at room temperature for 10 hours. At the end of the reaction, the solution is washed once with saturated sodium bicarbonate (NaHCO3), solution and then with water until a neutral pH is obtained, and it is dried over magnesium sulfate (MgSO4). After filtration on paper and evaporation of the CH2Cl2, the residue is chromatographed on a column of silica gel, using dichloromethane as eluent. 8 g of 1,4-dibenzyl-2-phenoxycarbonyloxymethylpiperazine are thus obtained in the form of a viscous product. Yield: 57%. Rf=0.52 (2/98 v/v MeOH/CH2Cl2,).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[C:15]([C:10]1([NH:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:14][CH2:13][CH2:12][CH2:11]1)#[N:16]
Reactant: N#CC1(N)CCCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)NC1(C#N)CCCC1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a stirred mixture of 20.2 g (0.2 mole) triethylamine and 200 ml chloroform cooled in an ice bath, 14.7 g (0.1 mole) 1-amino-1-cyanocyclopentane hydrochloride (the product of Example 14) were spooned in over ten minutes to give a red solution. To that mixture, 11.5 g (0.1 mole) methanesulfonyl chloride in 25 ml chloroform were added dropwise over 30 minutes. The reaction mixture was stirred 30 minutes. The reaction mixture was washed with 25 ml concentrated hydrochloric acid which had been diluted to 50 ml with ice water. The layers were phase separated. The organic layer was washed twice with 50 ml ice water, dried over magnesium sulfate and stripped to give 13 g of the above-identified amber oily product.
Reaction SMILES: [F:1][C:2]1[C:3](=[S:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C[O-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>CO>[CH2:15]([S:9][C:3]1[C:2]([F:1])=[CH:7][NH:6][C:5](=[O:8])[N:4]=1)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: O=c1[nH]cc(F)c(=S)[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCSc1nc(=O)[nH]cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
This material was prepared by the procedure described in Tetrahedron 1985, 41, 5289-5293. To a solution of 5-fluoro-4-thioxo-3,4-dihydropyrimidin-2(1H)-one (12.4 g, 84.9 mmol) and sodium methoxide (4.54 g, 84.9 mmol) in MeOH (100 mL) was added dropwise allyl bromide (10.27 g, 84.9 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. After removal of solvent, the residue was purified by normal phase chromatography (gradient, 10 to 33% EtOAc/hexane), to give 4-(allylthio)-5-fluoropyrimidin-2(1H)-one (6 g, 38%) as a white solid: mp 150-152° C.; 1H NMR (301 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.00 (d, J=4.5 Hz, 1H), 5.90 (ddt, J=16.8, 10.0, 6.8 Hz, 1H), 5.34 (dd, J=16.9, 1.4 Hz, 1H), 5.15 (dd, J=10.0, 0.7 Hz, 1H), 3.83 (d, J=6.8 Hz, 2H); ESIMS m/z 187 ([M+H]+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[C:14](Cl)[C:15]3[N:16]2[CH:19]=[CH:20][N:21]=3)=[CH:11][C:10]=1[C:23]([F:26])([F:25])[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([CH2:30][OH:31])[CH2:28][NH2:29].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[C:14]([NH:29][CH2:28][CH2:27][CH2:30][OH:31])[C:15]3[N:16]2[CH:19]=[CH:20][N:21]=3)=[CH:11][C:10]=1[C:23]([F:26])([F:25])[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCO
Reactant: FC(F)(F)c1cc2nc(Cl)c3nccn3c2cc1NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: OCCCNc1nc2cc(C(F)(F)F)c(NCc3ccccc3)cc2n2ccnc12
Yield: 84.8 %

Procedure:
A solution of N-benzyl-4-chloro-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-8-amine (30 mg; 0.079 mmol; 1 eq), 3-propanolamine (20 μl; 0.264 mmol; 3.3 eq) and diisopropylethylamine (15 μl; 0.088 mmol; 1.1 eq) in anhydrous 1,4-dioxane (0.5 ml) is stirred under argon at 100° C. for 16 h. Partition (ethyl acetate/aqueous ammonium chloride), washings of the organic phase (twice with aqueous ammonium chloride, once with brine), drying (magnesium sulfate) and concentration affords the title product (28 mg; 0.067 mmol; 86%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]2[C@H:29]([CH3:30])[C@H:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:27][C:26]2=[O:37])[CH:7]=1)[CH3:2].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]2[C@H:29]([CH3:30])[C@H:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:27][C:26]2=[O:37])[CH:7]=1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(O)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1
Product: CCOC(=O)Cc1ccc(OCc2ccccc2)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 3, using the following starting material: 2-{4-hydroxy-3-[2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid ethyl ester and benzyl bromide.