Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].C[N+](C)(C)[CH2:4][CH:5]1[CH2:11][CH2:10][S:9][C:8]2[S:12][CH:13]=[CH:14][C:7]=2[C:6]1=[O:15].[C-:18]#[N:19].[K+]>CO.O>[O:15]=[C:6]1[CH:5]([CH2:4][C:18]#[N:19])[CH2:11][CH2:10][S:9][C:8]2[S:12][CH:13]=[CH:14][C:7]1=2
Reactant: [C-]#N
Reactant: C[N+](C)(C)CC1CCSc2sccc2C1=O
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CCC1CCSc2sccc2C1=O
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a suspension of 59.5 g of N,N,N-trimethyl-N-[(4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-yl)methyl]ammonium iodide in 400 ml of methanol is added a solution of 25.2 g of potassium cyanide in 100 ml of water with stirring at room temperature. The mixture is stirred for 1.5 hours at the same temperature, poured into 500 ml of water and then extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and the chloroform is distilled off. The resulting crystals are recrystallized from ethanol to give 32 g of 4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-acetonitrile as white crystals, melting at 68°-70° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH3:15])=[CH:10][CH:9]=1.FC1C=CC=CC=1C1C=CC(CC(CC2C=CC(C3C=CC=CC=3F)=CC=2)=O)=CC=1.[BH4-].[Na+].[SH:49][CH2:50][C:51]([OH:53])=[O:52].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:49][CH2:50][C:51]([OH:53])=[O:52])[CH3:15])=[CH:10][CH:9]=1
Reactant: CC(O)c1ccc(-c2ccccc2F)cc1
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(Cc1ccc(-c2ccccc2F)cc1)Cc1ccc(-c2ccccc2F)cc1
Agent: [BH4-]
Solvent: CO
Solvent: c1ccccc1
Product: CC(SCC(=O)O)c1ccc(-c2ccccc2F)cc1

Procedure:
50 gm (0.23 mol) of 1-(2'-fluoro-4-biphenylyl)-1-hydroxy-ethane, m.p. 88° C., (prepared from 2'-fluoro-4-biphenylyl-methyl-ketone by reduction with sodium borohydride in methanol) were dissolved in 500 ml of benzene, 32.2 gm (0.276 mol) of 80% mercapto-acetic acid and 1 gm of p-toluenesulfonic acid were added, and the mixture was heated at its boiling point for 1 hour, using an apparatus equipped with a water trap. 20.5 ml of water were separated. The benzene solution was washed with water after cooling, dried and evaporated. The crystalline residue was recrystallized from benzene/cyclohexane (2:1), whereby 38.0 gm (61.5% of theory) of the title compound, m.p. 125°-127° C., were obtained.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=1)[CH3:8].Br[CH2:21][CH2:22]Br>CN(C=O)C>[CH2:7]([O:9][C:10]([C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:21][CH2:22][O:18][C:13]=2[CH:12]=1)=[O:19])[CH3:8]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a suspension of Cs2CO3 (270 g, 1.49 mol) in DMF (1000 mL) were added 3,4-dihydroxybenzoic acid ethyl ester (54.6 g, 0.3 mol) and 1,2-dibromoethane (54.3 g, 0.29 mol) at room temperature. The resulting mixture was stirred at 80° C. overnight and then poured into ice-water. The mixture was extracted with EtOAc (200 mL×3). The combined organic layers were washed with water (200 mL×3) and brine (100 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by column (Petroleum Ether/Ethyl Acetate 50:1) on silica gel to obtain 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (18 g, 29%). 1H NMR (300 MHz, CDCl3) δ 7.53 (dd, J=1.8, 7.2 Hz, 2H), 6.84-6.87 (m, 1H), 4.22-4.34 (m, 6H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8]C[C@@H](O)[C@@H:11]2[N:14]2CCC[CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CS(Cl)(=O)=O.CN.[Cl-].[Na+].[OH-].[Na+].[CH2:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH3:32]>O1CCCC1.C(O)C.O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:32][C@@H:31]([N:33]3[CH2:36][CH2:37][CH2:35][CH2:34]3)[C@@H:11]2[NH:14][CH3:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)[C@@H](N1CCCC1)[C@H](O)CC2
Reactant: CCN(CC)CC
Agent: CN
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CN[C@@H]1c2cc([N+](=O)[O-])ccc2CC[C@H]1N1CCCC1

Procedure:
Using the procedure of Step B of Example 1, 1.31 g of the product of Step A, 10 ml of tetrahydrofuran, 0.90 m of triethylamine and 0.52 ml of methanesulfonyl chloride in 1.3 ml of tetrahydrofuran which is added at -20° C. were reacted. 7 ml of methylamine in solution at 33% in ethanol were used and after 1 hour of stirring, the solvent was evaportated. 50 ml of water saturated with sodium chloride and 2 ml of sodium hydroxide at 33% were added and extraction was done with methylene chloride. The organic phase was washed with water, dried and the solvent was evaporated to obtain 1.55 g of the expected product which was crystallized from isopropanol to obtain 1.03 g of product melting at 85° C.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[F:43][C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O.ClCCl>[F:43][C:44]1[CH:49]=[C:48]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([C:10]3[CH:9]=[C:8]([CH3:40])[C:7]([OH:6])=[C:12]([CH3:13])[CH:11]=3)([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[C:26]([CH3:39])[CH:25]=3)[C:15]2=[O:23])[CH:47]=[CH:46][CH:45]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(c3cccc(F)c3)c3ccccc32)cc(C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.563 g, 0.935 mmol), 3-fluorophenylboronic acid (0.262 g, 1.87 mmol), copper (II) acetate (0.169 g, 0.935 mmol), triethylamine (0.26 mL, 1.87 mmol), 4 angstrom molecular sieves, and dichloromethane (15 mL). Stir at room temperature overnight under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 70% dichloromethane in hexanes and concentrate. Dissolve the resulting compound (0.508 g, 0.730 mmol), in THF (4 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (1.70 mL). Stir for 1 h. Add 1N aqueous HCl(10 mL), water(40 mL), and add ethyl acetate (50 mL). Separate the layers and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with ethyl acetate to give 0.259 g (59%) of the title compound: mass spectrum (FAB): m/z=468(M+1); 1H NMR(DMSO-d6): δ8.30 (s, 2H), 7.69-7.63 (m, 1H), 7.47 (dt, 1H), 7.40-7.35 (m, 3H), 7.31 (td, 1H), 7.18 (td, 1H), 6.93 (d, 1H), 6.80 (s, 4H), 2.13 (s, 12H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[NH2:12][C:13]1([C:26](O)=[O:27])[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>O>[NH2:12][C:13]1([CH2:26][OH:27])[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1
Reactant: NC1(C(=O)O)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC1(CO)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
Lithium aluminum hydride (1.94 g, 51.2 mmol) was added to a THF (100 mL) solution of 4-amino-1-benzylpiperidine-4-carboxylic acid [Albert, J. S. et al. J. Med. Chem. 2002, 45, (18), 3972-3983] (390) (3.00 g, 12.8 mmol). The resulting mixture was stirred for 1.5 h at reflux. The reaction was cooled to room temperature and the following additions were made slowly: 2 mL of water followed by 2 mL of 1 N NaOH, and finally 4 mL of water. The mixture was then filtered and concentrated to give compound 391 as a thick clear oil (2.22 g, 79% yield). The material was used in the next step without further purification. LCMS-ESI (POS), M/Z, M+1: Found 221, Calculated 221.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[CH:4]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C(#N)C>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[N:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[CH:4]=2)=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1cc(CBr)n(-c2ccccc2Cl)n1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: FC(F)(F)c1cc(COc2ccc(Br)cc2)n(-c2ccccc2Cl)n1

Procedure:
Into a 25 mL flask was weighed 1.52 g (4.48 mmol) of 5-bromomethyl-1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole, 854 mg of 4-bromophenol, 584 mg of sodium carbonate, then 5 mL of DMF, and 5 mL of acetonitrile were added. The resulting suspension was stirred and heated at 80-850C for 20 h then was washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Biotage, 80 g Silica gel, gradient elution from 100% hexanes to 40% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo to afford the product as a colorless solid, yield: 1.917 g (99%); 1H NMR (400 MHz, DMSO-d6): δ 7.82 (m, 2H), 7.70 (dt, J=1.5, 7.5 Hz, 1H), 7.62 (dt, J=1.5, 7.5 Hz, 1H), 7.49 (d, J=9 Hz, 2H), 7.27 (s, 1H), 6.92 (d, J=9 Hz, 2H), 5.12 (s, 2H); MS (ES): 431 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][C:34]([OH:36])=[O:35])[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]([CH2:18][N+:19]4([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.C(=O)(O)[O-].[Na+].C([O:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][C:54]=1[O:55]C(=O)C)[C:49](Cl)=[O:50])(=O)C>CC(C)=O.O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][C:34]([OH:36])=[O:35])[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]([CH2:18][N+:19]4([CH3:25])[CH2:20][CH2:21][N:22]([C:49](=[O:50])[C:48]5[CH:52]=[CH:53][C:54]([OH:55])=[C:46]([OH:45])[CH:47]=5)[CH2:23][CH2:24]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Reactant: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4nsc(N)n4)[C@H]3SC2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4nsc(N)n4)[C@H]3SC2)CCN(C(=O)c2ccc(O)c(O)c2)CC1
Yield: 39.2 %

Procedure:
The solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (540 mg) in acetone (5 ml) and water (5 ml) was adjusted to pH 7.0 with a saturated aqueous solution of sodium bicarbonate. To the mixture was added 3,4-diacetoxybenzoyl chloride (308 mg) at pH 6.5-7.0. The mixture was stirred for an hour and evaporated in vacuo to remove acetone. The residue was adjusted to pH 8.5 with a saturated aqueous solution of sodium bicarbonate and then stirred for 2 hours at room temperature. The mixture was adjusted to pH 3.5 with 3N hydrochloric acid and then filtered. The filtrate was subjected to column chromatography on Diaion HP-20 using 5% aqueous isopropyl alcohol as an eluent. The eluate was evaporated in vacuo to remove isopropyl alcohol and then lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-[1-methyl- 4-(3,4 -dihydroxybenzoyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (265 mg).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH:4]=[CH2:5].C(OC(Cl)=O)C.C(N(CC)CC)C.Cl.[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[CH2:22]([O:29][NH:30][C:1](=[O:7])[CH2:2][CH2:3][CH:4]=[CH2:5])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=CCCC(=O)O
Reactant: NOCc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCCC(=O)NOCc1ccccc1

Procedure:
This compound was prepared in several steps. 4-pentenoic acid(1.2.6.4) was reacted with ethylchloroformate in the usual way to obtain the active mixed anhydride. To a solution of the mixed anhydride in chloroform was added triethylamine and O-benzylhydroxylamine hydrochloride to obtain O-benzyl-4-pentenohydroxamic acid(1.2.6.5). The double bond was oxidized using osmium tetroxide/N-methylmorpholine oxide to give the diol(1.2.6.6). The terminal hydroxyl group was then protected with t-butyldimethylsilylchloride in the usual way to yield (1.2.6.7). The secondary hydroxyl group was tosylated using pyridine/p-toluenesulfonyl chloride. Cyclization of (1.2.6.8) to the corresponding pyrrolidone(1.2.6.9) was effected by using sodium carbonate in methanol. The protecting silyl group was removed by treatment with tetraethylammonium fluoride. The title compound (1.2.6.3) was prepared by reacting the latter compound (1.2.6.10) with pyridine/p-toluenesulfonyl chloride in the usual way.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN1CCCC1=O.CCOC(C)=O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1ncnc2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3ccc(Br)cc23)CC1
Temperature: 80 °C

Procedure:
A solution of the crude product from Step 1 (1.5 g), piperazine-1-carboxylic acid tert-butyl ester (2.29 g, 12.3 mmol) and triethylamine (2.15 mL, 15.4 mmol) in N-methylpyrrolidinone (50 mL) was stirred and heated at 80° C. for 2 hours. The solution was cooled to room temperature, diluted with EtOAc (200 mL), washed with water (3×200 mL) and dried over Na2SO4. The mixture was purified by silica gel column chromatography (50% EtOAc/hexanes) to give 4-(6-bromo-quinazolin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a colorless oil (1.5 g, 3.8 mmol, 85% from Step 1.) MS (APCI+) [M+H]+ 394.9 and 392.9. 1H NMR (CDCl3, 400 MHz) δ 8.76 (1H, s), 8.02 (1H, s), 7.84-7.78 (2H, m), 3.74 (4H, s), 3.66 (4H, s), 1.51 (9H, s.)
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O.CCCCCC.C(OCC)(=O)C.C(OCC)C.O1CCCC1>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([CH3:9])[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: Cc1cc(OCc2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
After dissolving 4-amino-3-cresol (10 g, 81.20 mmol) in dimethylsulfoxide (80 ml), sodium hydride (3.25 g, 81.20 mmol, 60% in oil) was added and the mixture was stirred for 15 minutes at room temperature under a nitrogen atmosphere. Benzyl bromide (4.83 ml, 40.60 mmol) was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Water was added to the reaction solution, extraction was performed with diethyl ether/tetrahydrofuran, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was adsorbed onto silica gel, purified by silica gel column chromatography (hexane-ethyl acetate-ethanol) and then by NH silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (6.55 g, 30.72 mmol, 75.64%) as a violet oil.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][O:11][C@@H:12]1[O:17][C@@H:16]([CH2:18][CH2:19]/[CH:20]=[CH:21]\[C@@H:22]([C@@H:24]2[C@@H:29]([CH3:30])[CH2:28][O:27][CH:26]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[O:25]2)[CH3:23])[C@@H:15]([CH3:39])[C@H:14]([O:40][CH2:41][O:42][CH3:43])[C@H:13]1[CH3:44].C(N(CC)C(C)C)(C)C.S(=O)(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CS(C)=O.C(OCC)C>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:26][O:25][C@@H:24]([C@@H:22]([CH3:23])/[CH:21]=[CH:20]\[CH2:19][CH2:18][C@H:16]2[C@@H:15]([CH3:39])[C@H:14]([O:40][CH2:41][O:42][CH3:43])[C@@H:13]([CH3:44])[C@H:12]([O:11][CH3:10])[O:17]2)[C@@H:29]([CH3:30])[CH:28]=[O:27])=[CH:36][CH:35]=1
Reactant: COCO[C@@H]1[C@@H](C)[C@H](OC)O[C@@H](CC/C=C\[C@H](C)[C@H]2OC(c3ccc(OC)cc3)OC[C@@H]2C)[C@H]1C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)=O
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COCO[C@@H]1[C@@H](C)[C@H](OC)O[C@@H](CC/C=C\[C@H](C)[C@H](OCc2ccc(OC)cc2)[C@@H](C)C=O)[C@H]1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
DIBAL (1.0 M in hexane, 2.1 mL, 2.1 mmol) was added dropwise to a solution of the acetal 35 (329 mg, 0.67 mmol) in dry CH2Cl2 (6.7 mL) at 0° C. After stirring for 2 h, the reaction was quenched with saturated aqueous sodium tartrate (20 mL) followed by vigorously stirring for several hours. The aqueous phase was extracted with CH2Cl2 (3×10 mL) and the combined organic layers were washed with brine (10 mL). The residue obtained after drying over MgSO4 and evaporation under vacuum was dissolved in anhydrous CH2Cl2 (6 mL) and DMSO (12 mL), treated with N,N-diisopropylethylamine (0.52 mL, 3 mmol), cooled to 0° C. and treated with pyridinium sulfur trioxide (477 mg, 3 mmol). The reaction mixture was stirred at ambient temperature for 1 h, diluted with ethyl ether (50 mL) and washed with aqueous HCl (0.5 N, 50 mL) and brine (10 ml). The separated organic layer was dried over MgSO4. Filtration and concentration followed by short flash column chromatography (hexane/EtOAc 4:1) provided the crude aldehyde 37 (270 mg, 0.55 mmol) as a colorless oil which was used without further purification.
Reaction SMILES: C([N:3](CC)CC)C.[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=O)[CH2:21][CH2:20]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C:25]([C@H:22]1[CH2:23][CH2:24][C@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:20][CH2:21]1)(=[O:27])[NH2:3]
Reactant: O=C(N[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Triethylamine (1.4 ml, 10.1 mmol) was added to an N,N-dimethylformamide (120 ml) solution of trans-4-{[(benzyloxy)carbonyl]amino}cyclohexanecarboxylic acid (1.40 g, 5.10 mmol), ammonium chloride (0.54 g, 10.1 mmol), 1-hydroxybenzotriazole (0.39 g, 2.50 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.35 g, 7.10 mmol) and the resulting mixture was stirred at room temperature for 19 hours. Water was added and the precipitated solid was collected by filtration to give 1.20 g (86%) of the title compound as a colorless solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[CH2:6][NH:7][CH:8]1[C:17]2[N:12]([C:13](=[O:30])[C:14]3[CH:27]=[C:26]([CH3:28])[C:25]([CH3:29])=[CH:24][C:15]=3[C:16]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10][CH2:9]1.[CH2:35]=O.[BH4-].[Na+]>>[CH3:28][C:26]1[C:25]([CH3:29])=[CH:24][C:15]2[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:17]3[N:12]([C:13](=[O:30])[C:14]=2[CH:27]=1)[CH2:11][CH2:10][CH2:9][CH:8]3[N:7]([CH2:6][C:5]1[CH:4]=[C:3]([CH3:2])[CH:33]=[C:32]([CH3:34])[CH:31]=1)[CH3:35]
Reactant: C=O
Reactant: Cc1cc(C)cc(CNC2CCCn3c2c(-c2ccccc2)c2cc(C)c(C)cc2c3=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cc(C)cc(CN(C)C2CCCn3c2c(-c2ccccc2)c2cc(C)c(C)cc2c3=O)c1

Procedure:
The compound obtained in Example 233 and formalin were reacted and treated with sodium borohydride in the same manner as in Example 233 to yield the title compound as colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K]>CC(C)=O>[Br:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:14]1[C:10](=[O:20])[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]1=[O:15]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCCCBr
Agent: [K]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCBr
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a stirred solution of 1,7-dibromoheptane (11) (13.90 g, 53.9 mmol) in acetone (100 mL) was added potassium phthalimide (5.00 g, 27.0 mmol). The resulting mixture was refluxed for 16 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. MPLC purification of the residue (Hexanes:EtOAc/70:30) gave 12 as a colorless oil (6.62 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.83-7.84 (m, 2H), 7.69-7.72 (m, 2H), 3.67 (t, J=7.6 Hz, 2H), 3.39 (t, J=7.2 Hz, 2H), 1.82-1.84 (m, 2H), 1.67 (m, 2H), and 1.35 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 168.55, 134.06, 132.30, 123.32, 38.06, 34.12, 32.85, 28.67, 28.48, 28.19, and 26.83.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(NC(C)C)(C)C.[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1.O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=2)[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(Cl)cc(Nc2cc(C)n[nH]2)n1
Temperature: 50 °C
Yield: 67.5 %

Procedure:
To a stirred solution of 4,6-dichloro-2-(methylthio)pyrimidine (25 g, 0.128 mol) in DMF (100 ml) was added diisopropylamine (19.8 g, 0.154 mol) followed by 3-amino-5-methylpyrazole (13.7 g, 0.154 mol) portionwise over 10 minutes. The solution was heated to 50° C. for 16 hours, after which time all of the starting material had reacted (by LC/MS analysis). The mixture was cooled to ambient and poured into water (250 ml). The precipitate was filtered and the wet solid slurried in diethyl ether (300 ml). The solid was again filtered and re-slurried in methanol (100 ml). The filtered product was air dried on the sinter, then further dried under vacuum to afford the title compound as an off-white solid (22.1 g, 66% yield). 1H NMR (DMSO D6, 400 MHz) δ 2.22 (3H, s), 3.31 (3H, s), 6.00-7.50 (2H, br m), 10.17 (1H, s), 12.10 (1H, s); MS (ES+) 256, (ES−) 254.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[CH2:9]1[O:12][CH:10]1[CH3:11]>>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([CH2:9][CH:10]([OH:12])[CH3:11])[CH2:5]1
Reactant: CC1CO1
Reactant: CC1CNCC(C)O1
Product: CC(O)CN1CC(C)OC(C)C1

Procedure:
The compound 2,6-dimethyl-N-(2-hydroxypropyl) morpholine was prepared by the method of Example 1 from 100.56 grams 2,6-dimethylmorpholine (0.87 moles) and 50.53 grams of propylene oxide (0.87 moles). Distillation of the reaction mixture gave 116.1 grams (76.8%) of the alcohol as a pale yellow oil, bp 70°-72° C. at 0.25 mm of Hg. The following elemental analysis was obtained: calc. 62.4 C, 11.1 H, 8.1 N; found 62.0 C, 10.8 H, 8.0 N.