Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([CH:10]=[C:11]([C:16]4[CH:17]=[C:18]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[N:19]5[C:24]=4[C:23]([NH2:25])=[N:22][CH:21]=[N:20]5)[CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=N[CH2:37][CH2:38][CH2:39][N:40](C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.CN([CH:66]=[O:67])C>>[NH2:40][C:39]1([C:66]([N:29]2[CH2:30][CH2:31][CH:26]([C:18]3[N:19]4[C:24]([C:23]([NH2:25])=[N:22][CH:21]=[N:20]4)=[C:16]([C:11]4[CH:12]=[CH:13][C:14]5[C:9]([CH:10]=4)=[N:8][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:15]=5)[CH:17]=3)[CH2:27][CH2:28]2)=[O:67])[CH2:37][CH2:38]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(C)C=O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(-c5ccccc5)nc4c3)c12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnn2c(C3CCN(C(=O)C4(N)CC4)CC3)cc(-c3ccc4cn(-c5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 8 %

Procedure:
A mixture 5-(2-phenyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (120 mg, 0.29 mmol), 1-(Boc-amino)-cyclopropyl-1-carboxylic acid (65 mg, 0.32 mmol), EDCl (62 mg, 0.32 mmol), HOBt (44 mg, 0.32 mmol), and N,N-diisopropylethylamine (115 μL, 0.85 mmol) in DMF (1.5 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated. To a solution of the residue in MeOH (1 mL) was added 4M HCl in dioxane (500 μL). The mixture was stirred at rt for 16 h. The mixture was concentrated and the residue was dissolved in 3:1 CHCl3/isopropanol (15 mL). The mixture was washed with saturated aqueous NaHCO3 (15 mL), brine, dried (Na2SO4) and concentrated to dryness. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to afford 11 mg (8%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1 H), 8.10 (d, 2 H), 7.93 (s, 1 H), 7.84 (d, 1 H), 7.69 (s, 1 H), 7.54-7.64 (m, 2 H), 7.45 (t, 1 H), 7.22 (dd, 1 H), 6.68 (s, 1 H), 3.36-3.51 (m, 1 H), 3.01-3.06 (m, 2 H), 2.21-2.37 (m, 2 H), 1.98-2.09 (m, 2 H), 1.51-1.72 (m, 2 H), 0.77-0.88 (m, 2 H), 0.59-0.74 (m, 2 H); ES-MS m/z 493.36 [M+H]+, HPLC RT (min) 2.07.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[C:16]([NH:24][NH2:25])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.C(O)C>[C:16]([NH:24][NH:25][C@@H:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]1[OH:14])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: NNC(=O)c1ccccc1
Solvent: CCCCCC
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NNC(=O)c2ccccc2)[C@@H]1O
Yield: 54.1 %

Procedure:
The procedure of Reference Example 2 was repeated except that 1.3 g of 6-cyano-3,4-epoxy-3,4 dihydro-2,2-dimethyl-2H-1-benzopyran and 1.0 g of benzoylhydrazine was used, and 1.18 g of trans-4-(2-benzoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol was obtained as white crystals, m.p. 197°-199° C. (recrystallized from hexane-ethanol).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[N:5]=1.[CH2:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:29]Cl)[CH2:16][CH3:17].[I-].[Na+]>CN(C=O)C.O>[CH2:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:29][N:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:6]1[N:5]=[C:4]([F:3])[CH:9]=[CH:8][CH:7]=1)[CH2:16][CH3:17]
Reactant: CCCn1c(CCl)nc2cc(C#N)ccc21
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(Cn2ccnc2-c2cccc(F)n2)nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring suspension of sodium hydride (2.25 g of 60% in oil) in DMF (10 mL) at 0° a solution of 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine (7.7 g, 47.2 mmol) in DMF (20 mL) is added. After stirring for 5 minutes, a solution of 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole (11 g, 47.2 mmol) and sodium iodide (20 mg) in DMF (80 mL) is added. The reaction mixture is stirred for 6 h, gradually warmed to room temperature. The reaction mixture is cooled, water added, the solid collected, rinsed with water and dried to afford the title compound, 1-Propyl-2-{[2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole. Method B
Reaction SMILES: [OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(O)C>ClCCl>[OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)[C@H](O)C(=O)O
Reactant: COc1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(COC(=O)[C@@H](O)C(C)C)cc1

Procedure:
2-hydroxy-3-methyl-(S)-(+)-butyric acid (1.77 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-1, step a. The title compound (3.10 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.50.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([S:18][C:19]4[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C1(O)C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([S:18][C:19]4[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccc(Br)cc3)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: Oc1ccccc1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Sc3ccc(Br)cc3)CS[C@H]12
Reaction time: 1.5 h
Yield: 79 %

Procedure:
To a solution of (7R)-7-[(phenylacetyl)amino]-3-(4-bromophenylthio)-3-cephem-4-carboxylate, benzhydryl ester (80 mg, 0.12 mmol) in phenol (230 mg) at 45° was added trifluoroacetic acid (9 μL). After 1.5 h, the volatiles are removed with a rotary evaporator, and the residue was triturated with isopropanol/hexane. The resulting white solid was washed with ether and dried in vacuo, affording 48 mg (79%) of the title compound. 1H NMR (acetone-d6) δ3.67 (d, 1H, J=16), 3.75 (d, 1H, J=16), 3.64 (d, 1H, J=18), 3.67 (d, 1H, J=18), 5.25 (d, 1H, J=5), 5.92 (d, 1H, J=5), 7.2-7.7 (m, 9H); IR (KBr) 1347, 1386, 1606, 1756, 3276 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:18])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(OC)c1

Procedure:
A solution of 25.0 g (150 ml) of (3-methoxyphenyl)acetic acid in dry methanol (250 ml) was mixed with 2 ml of conc. sulfuric acid and heated under reflux for 16 h. The cooled reaction solution was concentrated in vacuo, added to ice-water and extracted four times with 70 ml of ethyl acetate each time. The combined organic extracts were washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed in vacuo. Yield: 28.3 g (100%) of colorless oil
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29].C(N(C(C)C)C(C)C)C.[CH:40]1([CH2:43][N:44]2[CH2:49][CH2:48][N:47]([CH:50]3[CH2:55][CH2:54][CH:53]([NH2:56])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)[CH2:42][CH2:41]1>CN(C)C=O>[CH:40]1([CH2:43][N:44]2[CH2:49][CH2:48][N:47]([C@@H:50]3[CH2:55][CH2:54][C@H:53]([NH:56][C:21](=[O:22])[C:20]4[CH:24]=[CH:25][C:17]([NH:16][C:13]5[N:14]=[CH:15][C:5]6[N:4]([CH3:28])[C:3](=[O:29])[C:2]([F:30])([F:1])[CH2:8][N:7]([CH:9]([CH3:10])[CH3:11])[C:6]=6[N:12]=5)=[C:18]([O:26][CH3:27])[CH:19]=4)[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)[CH2:41][CH2:42]1.[CH:40]1([CH2:43][N:44]2[CH2:49][CH2:48][N:47]([C@H:50]3[CH2:55][CH2:54][C@H:53]([NH:56][C:21](=[O:22])[C:20]4[CH:24]=[CH:25][C:17]([NH:16][C:13]5[N:14]=[CH:15][C:5]6[N:4]([CH3:28])[C:3](=[O:29])[C:2]([F:30])([F:1])[CH2:8][N:7]([CH:9]([CH3:10])[CH3:11])[C:6]=6[N:12]=5)=[C:18]([O:26][CH3:27])[CH:19]=4)[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)[CH2:41][CH2:42]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Reactant: NC1CCC(N2CCN(CC3CC3)CC2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@H]2CC[C@@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.08 g (0.19 mmole) of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-292), 0.20 mL (1.2 mmole) of ethyldiisopropyl amine and 0.072 mg (0.21 mmole) of a cis/trans mixture of 4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexylamine with trihydrochloride in 2.0 mL of dimethylformamide was added 0.090 g (0.21 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-70:30) gave 0.024 g of N-[cis-4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexyl]-4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-301) (Rf: 0.58 in dichloromethane:methanol 7:3) as a white solid and 0.061 g of N-[trans-4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexyl]-4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-302) (Rf: 0.46 in dichloromethane:methanol 7:3) as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.Cl[CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CCCCCCC>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][NH:10][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)CCl
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: C[Si](C)(C)CNCc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
(3-(Trifluoromethyl)phenyl)methanamine (25 g, 143 mmol), (chloromethyl)trimethylsilane (19.92 mL, 143 mmol), and triethylamine (23.87 mL, 171 mmol) were combined neat and the resultant mixture was refluxed overnight. The reaction was cooled to room temperature and 150 mL of heptane was added. The HCl salts were removed by filtration and washed with heptane. The solvent was removed by placing under house vacuum and then high vacuum. N-(3-(Trifluoromethyl)benzyl)-1-(trimethylsilyl)methanamine was isolated by vacuum distillation (bp 70-90° C./3.2 torr): 1H NMR (300 MHz, CDCl3) δ ppm 7.59 (s, 1H), 7.53-7.38 (m, 3H), 3.86 (s, 2H), 2.04 (s, 2H), 1.34 (s, 1H), 0.06 (s, 9H).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH2:6]([O:16][CH2:17][CH:18]([OH:30])[CH2:19][N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28][CH2:29][N:20]1[CH2:19][CH:18]([O:30][S:2](=[O:4])(=[O:3])[OH:5])[CH2:17][O:16][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCCCOCC(O)CN1CCc2ccccc2C1
Product: CCCCCCCCCCOCC(CN1CCc2ccccc2C1)OS(=O)(=O)O

Procedure:
2-Decyloxymethyl-oxirane (1 equiv.), prepared according to Example 1 (except 1-decanol is substituted for 2-ethylhexanol), is dissolved in acetonitrile and warmed to 70° C. Stannic chloride (0.1 equiv.) is added to the reaction, which is maintained at 70° C. with stirring for 24-48 hours to give the oxazolidine. The reaction is cooled to from about 20° C. to about 25° C. and chlorosulfonic acid (1 equiv.) is added to the reaction at a temperature of from about 20° C. to about 25° C. to yield the product, through sulfation of the putative intermediate 1-Decyloxy-3-(3,4-dihydro-isoquinolin-2-yl)-propan-2-ol.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:42]3[CH2:43][CH2:44][CH2:45][CH:40]([CH2:39][OH:38])[CH2:41]3)=[O:36])[C:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCC1CCCNC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCCC(CO)C1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 3-hydroxymethyl-piperidine (Aldrich) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C34H42N5O3Cl2 [(M+H)+] 638.2659, observed 638.266.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].O.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20](S(O)(=O)=O)=CC=1.C1(=O)CCCC1>C1(C)C=CC=CC=1>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:20]4([CH2:21][CH2:22][CH2:17][CH2:27]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=C1CCCC1
Product: O=C1NC2(CCCC2)Nc2cc(-c3ccncc3)sc21
Yield: 186.6 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (150 mg, 0.68 mmol), p-toluenesulfonic acid monohydrate (50 mg) and cyclopentan-1-one (10 ml) in toluene (20 ml) was heated to reflux overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel (MeOH: dichloromethane=1:9) to afford the title compound (140 mg, yield 72%) as an orange solid:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29]([C:32](=O)[CH2:33][CH3:34])[S:30][CH:31]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br-].[C:37]([CH2:40][CH2:41][CH2:42][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:39])=[O:38].CC(C)([O-])C.[K+]>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:32](/[CH2:33][CH3:34])=[CH:42]/[CH2:41][CH2:40][C:37]([OH:39])=[O:38])[S:30][CH:31]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCC(=O)c1cc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)cs1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Product: CC/C(=C\CCC(=O)O)c1cc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)cs1

Procedure:
In a manner similar to that of Example 6(i), by reaction of 3 g (5.6 mmol) of 1-{4-[2-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl)ethyl]-2-thienyl}-1-propanone with 3.6 g (8.4 mmol) of (3-carboxy-propyl)triphenylphosphonium bromide and 1.9 g (17 mmol) of potassium tert-butoxide, the desired product is obtained in the form of a yellow oil (m=1.7 g, Y=50%).
Reaction SMILES: [Br-].[CH3:2][CH2:3][CH2:4][C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:14])=[O:13])[CH:8]=[CH:7][C:6]=1[OH:15].[C:16]([O-:19])([O-])=[O:17].[K+].[K+].[CH2:22]([C:24]([CH3:26])=[O:25])[CH3:23]>>[C:12]([C:9]1[CH:8]=[CH:7][C:6]([O:15][CH2:7][CH2:8][CH2:9][O:25][C:24]2[CH:26]=[CH:2][C:3]([C@H:4]3[O:19][C:16](=[O:17])[CH2:6][C@H:5]3[CH3:10])=[CH:23][CH:22]=2)=[C:5]([CH2:4][CH2:3][CH3:2])[C:10]=1[OH:11])(=[O:13])[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CCC(C)=O
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: [Br-]
Agent: [K+]
Product: CCCc1c(OCCCOc2ccc([C@H]3OC(=O)C[C@H]3C)cc2)ccc(C(C)=O)c1O

Procedure:
The bromide from Example 12 (4.5 g, 14.4 mmol) was reacted with 2,4-dihydroxy-3-propylacetophenone (2.9 g, 15.0 mmol) in methyl ethyl ketone (45 ml) containing anhydrous K2CO3 (4.0 g, 29.0 mmol) at reflux temperature for 6 hours in an atmosphere of nitrogen. The mixture was filtered, concentrated in vacuo and the residue was purified by chromatography on silica gel to provide the title compound, m.p. 88.5°-89.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[F:8].CO.C([Cl:18])(=O)C.[NH3:19]>C1(C)C=CC=CC=1>[ClH:18].[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[NH:19])[NH2:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: N#CCCc1ccc(F)c(Br)c1
Reactant: CC(=O)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: Cl
Product: N=C(N)CCc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a solution of 3-(3-bromo-4-fluorophenyl)propanenitrile (5.0 g, 21.05 mmol) in toluene (20 mL) and methanol (6.32 mL, 156 mmol) at 0° C. was added acetyl chloride (7.51 mL, 105 mmol) dropwise over 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was cooled to 0° C. by an ice bath, to which ammonia (30.1 mL, 210 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated to give a crude product. Recrystallization from toluene/methanol (1:1) then afforded the title compound as a white solid (5.2 g, 93% yield). LCMS: rt=1.18 min, [M+H+]=245
Reaction SMILES: C([Sn]1(CCCC)[O:14][CH2:13][C:8]2([CH2:12][CH:11]=[CH:10][CH2:9]2)[CH2:7][O:6]1)CCC.[CH2:19]([C:21]1([CH2:28][CH3:29])[CH2:26][O:25][C:24](=S)[O:23][CH2:22]1)[CH3:20]>>[CH2:19]([C:21]1([CH2:28][CH3:29])[CH2:26][O:25][C:24]2([O:6][CH2:7][C:8]3([CH:9]=[CH:10][CH2:11][CH2:12]3)[CH2:13][O:14]2)[O:23][CH2:22]1)[CH3:20]
Reactant: CCCC[Sn]1(CCCC)OCC2(CC=CC2)CO1
Reactant: CCC1(CC)COC(=S)OC1
Product: CCC1(CC)COC2(OCC3(C=CCC3)CO2)OC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
To the above solution of 8,8-dibutyl-7,9-dioxa-8-stannaspiro[4.5]dec-2-ene 4 was added 5,5-diethyl-1,3-dioxane-2-thione 1 (10.1 g, 60.3 mmol) in several small portions at room temperature over a period of 20 min. The resulting mixture was allowed to stir at room temperature for 24 hours. The reaction was monitored by TLC (silica gel, 25% ether/hexanes). The reaction mixture was then concentrated under reduced pressure and the residue taken up with ethyl ether (white suspension formed upon standing). The ether solution was filtered and concentrated under reduced pressure to give light yellowish oil. The crude material was purified by column chromatography (silica gel, 10-15% ethyl ether/hexanes). The desired 11,11-diethyl-7,9,13,14-tetraoxadispiro[4.2.5.2]pentadec-1-ene (DECP 5) was obtained as white solid in 72% yield. Mp (DSC) 95.19° C., 1H-NMR (CD13, 300 MHz) δ5.60 (s, 2H), 3.80 (s, 4H), 3.69 (s, 4H), 2.27 (s, 4H), 1.45-1.37 (q, 4H, J-7.8 Hz), 0.82-0.77 (t, 6H, J=7.8 Hz); 13C-NMR (CD13, 300 MHz) δ128.52, 114.39, 71.04, 69.48, 39.76, 34.33, 23.16, 7.12; FT-IR (Kbr pellet) (cm1) 3053, 2968, 1619, 1457, 1360, 1266, 1212, 1178, 1001, 938; Anal. Calcd for C1H2404: C, 67.14; H, 901; Found: C, 67.44; H, 9.22.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]([C:10]2[C:11](=[O:22])[NH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][CH:15]=2)[CH:6]=[CH:7][C:8]=1[OH:9].[C:23](OC(=O)C)(=[O:25])[CH3:24].[CH2:30]([O:32]CC)[CH3:31]>N1C=CC=CC=1>[C:23]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]2[C:11](=[O:22])[NH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][CH:15]=2)=[CH:4][C:3]=1[O:2][C:30](=[O:32])[CH3:31])(=[O:25])[CH3:24]
Reactant: O=c1[nH]c(-c2ccccc2)ncc1-c1ccc(O)c(O)c1
Reactant: CC(=O)OC(C)=O
Reactant: CCOCC
Agent: Br
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cnc(-c3ccccc3)[nH]c2=O)cc1OC(C)=O

Procedure:
5-(3,4-Dihydroxyphenyl)-2-phenyl-4(3H)-pyrimidinone hydrobromide (6.0 g) (21.4 mmol) are dissolved in 100 ml of pyridine and treated at room temperature while stirring with 5.2 g (51 mmol) of acetic anhydride. After 1.5 hours 200 ml of diethyl ether are added thereto and the precipitated product is filtered off. The solid is washed with diethyl ether and dried in a high vacuum at 35° C. There are obtained 7.1 g of 4-(3,4-dihydro-4-oxo-2-phenyl-5-pyrimidinyl)-o-phenylene diacetate as white crystals of m.p. 240° C.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@H:17]2[CH2:25][CH2:24][C@@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[C@@H:18]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[C:35]1(=O)[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@H:17]2[CH2:25][CH2:24][C@@H:23]3[C@@H:19]([CH2:20][N:21]([C:35]4[CH2:39][CH2:38][C:37](=[O:40])[CH:36]=4)[CH2:22]3)[C@@H:18]2[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: O=C1CCC(=O)C1
Reactant: C[C@@H](O[C@H]1CC[C@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of 12.3 mg (0.26 mmol) of (3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}4-(4-fluorophenyl)octahydro-1H-isoindole (Example 2) in ˜2 mL dry toluene was added 2.7 mg (0.028 mmol) cyclopentane-1,3-dione and a catalytic amount (˜0.5 mg) of PTSA. The resulting mixture was heated at reflux for 16 hr. The solvent was removed vacuum and the residue was purified by prep TLC eluting with EtOAc/MeOH (95/5) to afford the title compound. 1H-NMR (CDCl3): δ: 7.73 (1 H, s), 7.20 (2 H, s), 7.03-6.90 (2 H, m), 4.98, 4.80 (1 H, s), 4.50 (1 H, m), 3.62-3.18 (2 H, m), 3.30-3.18 (3 H, m), 3.15, 2.97 (1 H, d, J=11.2 Hz), 2.68 (2 H, m), 2.55-2.40 (4 H, m), 2.17 (1 H, m), 2.20 (1 H, m), 2.00 (1 H, m), 1.85 (1 H, m), 1.62 (1 H, m), 1.33 (3 H, d, J=6.2 Hz). MS: (MH)+ 556.0.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[CH2:22]=O>C1COCC1>[C:1]([NH:4][C:5]([CH2:22][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: C1CCNCC1
Reactant: C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CN1CCCCC1)(NC(C)=O)C(=O)OCC
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a solution of diethyl acetamidomalonate XC (1.75 g, 8.05 mmol) in THF (20 mL) was added piperidine (0.62 mL, 6.7 mmol) and 36% aqueous solution formaldehyde (0.23 mL, 8.25 mmol). The reaction mixture was stirred at 60° C. for 5 min. The mixture was cooled to −5° C. and kept at this temperature overnight. The precipitate was filtered to produce 1,3-diethyl 2-acetamido-2-(piperidin-1-ylmethyl)propanedioate XCI as a white crystallized solid (1.01 g, 3.21 mmol, 40% yield). 1H NMR (CDCl3) 1.15-1.30 (m, 6H), 1.31-1.56 (m, 6H), 2.03 (s, 3H), 2.30-2.51 (m, 4H), 3.25 (s, 2H), 4.13-4.32 (m, 4H), 6.99 (brs, 1H); ESIMS found for C15H26N2O5 m/z 315 (M+H).