Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:43])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][C:37]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][CH:39]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([CH2:15][O:14][C:12]2[C:11]([C:19]([F:20])([F:21])[F:22])=[CH:10][C:9]3[NH:23][C:24](=[O:43])[CH2:25][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[CH:35]=[N:36][C:37]([CH:40]6[CH2:41][CH2:42]6)=[CH:38][CH:39]=5)[CH:29]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccc(C4CC4)nc3)c2)=Nc2cc(OCC3CC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (5-cyclopropylmethoxy-2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M178) (240 mg, 0.39 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (74 mg, 39%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:15]([OH:17])=O)=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:3])[CH3:2].[CH3:18][O:19][C:20]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[CH:24][C:23]([CH2:35][CH2:36][NH2:37])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[CH:24][C:23]([CH2:35][CH2:36][NH:37][C:15]([C:6]2[C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:14][C:13]3[C:8]([CH:7]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:17])=[CH:22][CH:21]=1
Reactant: COc1ccc(CCN)cc1-c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Oc1cc2ccccc2cc1C(=O)O
Product: COc1ccc(CCNC(=O)c2cc3ccccc3cc2OC(C)=O)cc1-c1ccc([N+](=O)[O-])cc1

Procedure:
Acetic acid 3-[2-(6-methoxy-4′-nitro-biphenyl-3-yl)-ethylcarbamoyl]-naphthalen-2-yl ester (108 mg) was prepared from 3-Acetoxy-naphthalene-2-carboxylic acid (58 mg, 0.25 mmol) and 2-(6-Methoxy-4′-nitro-biphenyl-3-yl)-ethylamine (68 mg, 0.25 mmol following the general procedure A.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Br:18][CH2:19][C:20](Br)=[O:21]>C1COCC1.C(=O)=O.CC(C)=O>[Br:18][CH2:19][C:20]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])=[O:21]
Reactant: O=C(Br)CBr
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C(CBr)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (4R)-4-phenyl-1,3-oxazolidin-2-one (100 g, 613 mmol) in THF (2 L) under a nitrogen atmosphere was cooled to −78° C. in dry ice-acetone bath. To the stirred solution was added n-BuLi (337 mL, 2 M solution in cyclohexane, 675 mmol) dropwise over a period of 30 min, followed by the addition of 2-bromoacetyl bromide (123.7 g, 613 mmol) over 15 min. The resulting solution was stirred at 25° C. for 2 h. The reaction was quenched with aqueous NH4Cl (500 mL), and the mixture was extracted three times with EtOAc (3×1 L). The combined organic extracts were washed with water (500 mL) and brine (500 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as a brown solid. The crude product was used directly in the next step.
Reaction SMILES: ClCCCC(OC(=O)C)CCCCC.ClCCCC(OC(=O)C)CCCCCCC.C([O:34][CH:35]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]CC)[CH2:36][CH2:37][CH2:38][N:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50]CC)=[O:49])[C:40]#[N:41])(=O)C>>[OH:34][C@H:35]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:36]#[C:37][CH2:38][N:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[C:40]#[N:41]
Reactant: CCCCCCCC(CCCN(C#N)CCCCCCC(=O)OCC)OC(C)=O
Agent: CCCCCC(CCCCl)OC(C)=O
Agent: CCCCCCCC(CCCCl)OC(C)=O
Product: CCCCC[C@@H](O)C#CCN(C#N)CCCCCCC(=O)O

Procedure:
The synthesis of this compound, initially, is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxyundecane (Example C, Step 3 ). The product of Step A is thus ethyl 7-[N-(4-acetoxyundecyl)cyanamido]heptanoate. The subsequent steps yield 7-[N-(4-hydroxyundecyl)cyanamido]heptanoic acid (B). This product then is treated as described in Example 3, Step A, to yield the subject compound 7-[1-(4-hydroxyundecyl)thioreido]heptanoic acid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:10]3[CH2:9]2)=[O:7])[CH2:2]1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O>C1COCC1>[Cl:27][C:22]1[CH:21]=[C:20]([C:15]2[C:16]([C:17]([NH2:19])=[O:18])=[C:10]3[CH2:9][N:8]([C:6]([NH:5][CH:3]4[CH2:2][N:1]([CH2:43][C:44]([F:47])([F:46])[F:45])[CH2:4]4)=[O:7])[CH2:13][CH2:12][N:11]3[N:14]=2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CN(C(=O)NC1CNC1)CC2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CN(C(=O)NC1CN(CC(F)(F)F)C1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.4 %

Procedure:
To a stirred solution of Intermediate 339B (100 mg, 0.255 mmol) in THF (10 mL) was added DIPEA (0.222 mL, 1.273 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (118 mg, 0.509 mmol) and stirred at RT for 16 h. The reaction mixture was quenched with a 10% aqueous solution of NaHCO3 and extracted with EtOAc (2×20 mL) The combined organic layer was dried over Na2SO4, filtered and the filtrate evaporated. The crude compound was purified by preparative HPLC to afford Compound 339 as an off-white solid (15 mg, 12%). HPLC retention times 10.73 min. and 11.90 min (Methods C and D). MS(ES): m/z=475 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.84 (dd, J=7.37, 2.08 Hz, 1H), 7.62-7.72 (m, 1H), 7.41-7.50 (m, 1H), 7.36 (br. s., 1H), 7.27 (d, J=6.80 Hz, 1H), 7.18 (br. s., 1H), 4.73 (s, 2H) 4.19-4.31 (m, 1H), 4.06-4.17 (m, 2H), 3.84 (d, J=5.67 Hz, 2H), 3.57-3.69 (m, 2H), 3.09-3.23 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]([CH3:11])([C:8]([OH:10])=O)[CH2:4][O:3]1.Cl.[CH3:14][NH:15][O:16][CH3:17].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O.CN(C=O)C>[CH3:17][O:16][N:15]([CH3:14])[C:8]([C:5]1([CH3:11])[CH2:4][O:3][C:2]([CH3:1])([CH3:12])[O:7][CH2:6]1)=[O:10]
Reactant: CNOC
Reactant: CC1(C)OCC(C)(C(=O)O)CO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)C1(C)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a mixture of 2,2,5-trimethyl-1,3-dioxane5-carboxylic acid (1.0 g, 5.74 mmol) and DMF (10 mL) were added N,O-dimethylhydroxylamine hydrochloride (0.84 g, 8.6 mmol), 1-hydroxybenzotriazole hydrate (1.32 g, 8.6 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloric acid (1.651 g, 8.61 mmol) and triethylamine (2.39 mL, 17.2 mmol) under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulphate, and concentrated in vacuo to give N-methoxy-N,2,2,5-tetramethyl-1,3-dioxane5-carboxylic acid amid (1.08 g, yield: 86%) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18](Cl)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:26][N:27]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[N:28]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18]([C:30]4[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=4)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COC(=O)C1(c2ccc(Nc3nc(-c4cnn(C)c4)nc4c3CCC4)cc2)CCC1
Temperature: 100 °C
Yield: 47.8 %

Procedure:
A glass tube was charged with 1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid methyl ester (0.5 g, 1.4 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.42 g, 2 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) (0.081 g, 0.1 mmol) and alternatively purged and backfilled with nitrogen. After addition of anhydrous toluene (10 mL), EtOH (5 mL), and sodium carbonate (2M, 2 mL) the glass tube was sealed and heated at 100° C. under stirring until the reaction was complete as evidenced by the disappearance of starting chloro compound (TLC). The resulting mixture was cooled to a temperature in the range of 15° C. to 40° C., diluted with ethyl acetate (20 mL), filtered through Celite, washed with ethyl acetate, and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel to afford the title compound as a light yellow solid (0.27 g, 48%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([Br:12])[C:4]=1[N:13]=[C:14]1[NH:18][CH2:17][CH2:16][NH:15]1>C(O)C.[Fe]>[NH2:9][C:7]1[CH:6]=[C:5]([Br:12])[C:4]([N:13]=[C:14]2[NH:18][CH2:17][CH2:16][NH:15]2)=[C:3]([Br:2])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(Br)c(N=C2NCCN2)c(Br)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cc(Br)c(N=C2NCCN2)c(Br)c1
Yield: 87.2 %

Procedure:
A solution of concentrated hydrochloric acid (2.8 ml, 0.028M) in aqueous ethanol (50%, 15 ml) was added dropwise to a stirred heated mixture of 2-(2,6-dibromo-4-nitro phenylimino)imidazolidine (4 g, 0.011M) and iron powder (1.9 g, 0.034M) in aqueous ethanol (50%). The mixture was heated under reflux for 3 hours after which time it was filtered hot and evaporated to a low volume. This residual solution was acidified with dilute hydrochloric acid and the resulting solid was removed. The solution was then basified with dilute aqueous sodium hydroxide yielding a solid which was collected. This solid was triturated with hot methanol which was then evaporated to leave a brown solid (3.2 g). This solid was chromatographed on alumina and eluted with a methanol in methylene chloride gradient. The fractions containing the required compound were combined and evaporated affording 2-(4-amino-2,6-dibromophenylimino)imidazoline dihydrochloride, mp>320° C. (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:25]=[CH:24][C:17]([C:18]([N:21]([CH3:23])[CH3:22])=[N:19][OH:20])=[C:16]([CH3:26])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].[OH-].S(OC)(O[CH3:37])(=O)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:28])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[CH:25]=[CH:24][C:17]([C:18]([N:21]([CH3:22])[CH3:23])=[N:19][O:20][CH3:37])=[C:16]([CH3:26])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=NO)N(C)C
Reactant: COS(=O)(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)N(C)C
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N′-hydroxy-2,N,N-trimethyl-benzamidine (200 mg) in DMF (5 mL) was added a solution of LiOH (31 mg) in water (2 mL), before adding dimethyl sulfate (0.21 mL, 0.27 g). The mixture was stirred at room temperature over night and poured onto water. The aqueous layer was extracted with MTBE and the combined organic layers were washed with water, dried (Na2SO4) and evaporated to yield the title compound (170 mg, 83%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]([Sn](CCCC)(CCCC)CC=C)[CH2:20][CH2:21]C>C(#N)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([CH2:21][CH:20]=[CH2:19])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Solvent: CC#N
Product: C=CCc1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C

Procedure:
A 9 g portion of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was combined with 11.1 g of tri-n-butyl-2-propenylstannane and 1.69 g of tetrakis(triphenylphosphene) palladium in 40 mL of acetonitrile in a sealable tube. Argon was bubbled through the mixture, the cap replaced, and the reaction heated at 90° for 18 h. Upon cooling, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was triturated with diethyl ether to obtain 4.23 g of crystalline product, and a second crop of 1.31 g of product was also obtained. mp 144°-146°; FDMS 255M+; Calcd for C17H21N1O2 :
Reaction SMILES: C(OC1C=CC(C#CC(C2CCCC2)(O)CC2OC(C)(C)OC(=O)C=2)=CC=1COC(=O)C)(=O)C.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C(C)(C)C#N)=C(F)C=2)CCCC1.[CH:66]1([C:71]2([CH2:79][CH2:80][C:81]3[CH:86]=[CH:85][C:84]([OH:87])=[C:83]([CH2:88][O:89]C)[CH:82]=3)[O:76][C:75](=[O:77])[CH2:74][C:73](=[O:78])[CH2:72]2)[CH2:70][CH2:69][CH2:68][CH2:67]1>>[CH:66]1([C:71]2([CH2:79][CH2:80][C:81]3[CH:86]=[CH:85][C:84]([OH:87])=[C:83]([CH2:88][OH:89])[CH:82]=3)[O:76][C:75](=[O:77])[CH2:74][C:73](=[O:78])[CH2:72]2)[CH2:70][CH2:69][CH2:68][CH2:67]1
Reactant: COCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Agent: CC(=O)OCc1cc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)ccc1OC(C)=O
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Product: O=C1CC(=O)OC(CCc2ccc(O)c(CO)c2)(C2CCCC2)C1

Procedure:
The title compound was prepared analogously to step 4 from Example A(97) where Acetic acid 2-acetoxy-5-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl) -3-hydroxy-but-1-ynyl]-benzyl ester (from step 2 below) was substituted in place of 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile. The product was obtained together with compound from Example A(194). 6-Cyclopentyl-6-[2-(4-hydroxy-3-methoxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione above 1H NMR (400 MHz, CDCl3): δ 1.30–1.80 (m, 9H), 1.83–1.86 (m, 2H), 2.15–2.18 (m, 1H), 2.49–2.54 (m, 2H), 2.67 (s, 2H), 3.33 (s, 2H), 4.76 (s, 2H), 6.71–6.91 (m, 3H). ESIMS (MH−): 331.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH3:12][CH:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17]Br>>[CH3:12][CH:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: OCCCCCCCCCBr
Reactant: CC(C)CCCCBr
Product: CC(C)CCCCCCCCCCCCCO
Yield: 55 %

Procedure:
14-methylpentadecan-1-ol was prepared from 9-bromononanol and 5-methylhexylbromide in 55% yield. The 1H NMR and MS-ESI data matched those reported by Yuasa et al. (Yuasa and Tsuruta (2004) Flavour and Fragrance Journal 19:199-204).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1
Reaction time: 12 h

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine (0.850 g, 3.4 mmol), Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (0.926 g, 4 mmol), in 1, 2 dichloroethane (10 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (1.33 g, 6 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2—CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 1.4 g (3.25 mmol, 93.2% yield) of a light yellow solid. MS (m/e): 433.4 (M+H+).
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH2:6][OH:7])[O:3][CH:2]=1.[CH2:8]([N:10]([CH2:17][CH3:18])[CH2:11]N(CC)CC)[CH3:9]>C(O)(=O)C>[CH2:8]([N:10]([CH2:11][C:2]1[O:3][C:4]([CH2:6][OH:7])=[CH:5][CH:1]=1)[CH2:17][CH3:18])[CH3:9]
Reactant: CCN(CC)CN(CC)CC
Reactant: OCc1ccco1
Solvent: CC(=O)O
Product: CCN(CC)Cc1ccc(CO)o1
Temperature: 0 °C
Reaction time: 17 h
Yield: 80.1 %

Procedure:
To a solution of 2-furfuryl alcohol (8.24 g; 84 mmol) in 55 ml of acetic acid was added dropwise a solution of N,N,N',N'-tetraethyl-methylenediamine (20 g; 126 mmol)in 25 ml of acetic acid, and the solution was stirred at 0° C. for 30 minutes and at room temperature for 17 hours. The above solution was concentrated in vacuo, the residue was basified with dropwise addition of 30% of NaOH solution at 0° C. (to pH=11), and the mixture was extracted with ethyl acetate. The mixture was filtered, the organic layer was dried over sodium sulfate and concentrated in vacuo to yield a brown oil. The oil was distilled with a Kugelrohr Apparatus to afford 12.33 g (80%) of 5-diethylaminomethyl-2-hydroxymethylfuran as a yellow oil, b.p. 140° C./1 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:20]([O:22][CH2:23][C:24](O)=O)[CH3:21].[OH-].[NH4+]>O>[CH2:20]([O:22][CH2:23][C:24]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:21]
Reactant: CCOCC(=O)O
Reactant: Nc1cnc2ccccc2c1NCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1Cc1ccccc1
Temperature: 120 °C
Yield: 104.4 %

Procedure:
3-Amino-4-(phenylmethylamino)quinoline (4 g, 16 mmol) was combined with ethoxyacetic acid (4.5 mL, 48 mmol) and heated at 120° C. for about 3 hours. The reaction mixture was cooled to room temperature, diluted with water and then made basic with ammonium hydroxide. The resulting precipitate was collected to provide 5.3 g of the desired product as a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.[H-].[Na+]>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH:16]3[CH2:17][O:18]3)=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCC1CO1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(OCC3CO3)cc2)cc1
Yield: 83.3 %

Procedure:
A procedure similar to that described in preparation 46 was repeated, except that 4.00 g of 4-phenylphenol, 3.97 g of epibromohydrin, 1.27 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 80 ml of anhydrous dimethylformamide were used, to give 4.43 g of the title compound, melting at 80.2° to 82.9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].CCCCC.S(O[CH2:33][CH2:34][C:35]1[O:36][CH:37]=[CH:38][CH:39]=1)(=O)(=O)C>CN(C)C=O>[O:36]1[CH:37]=[CH:38][CH:39]=[C:35]1[CH2:34][CH2:33][N:12]1[C:11](=[O:20])[CH2:10][C@@:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[C:13]1=[O:19]
Reactant: COc1cccc([C@@]23CCCC[C@H]2C(=O)NC(=O)C3)c1
Reactant: CS(=O)(=O)OCCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: COc1cccc([C@@]23CCCC[C@@H]2C(=O)N(CCc2ccco2)C(=O)C3)c1
Temperature: 0 °C

Procedure:
A solution of 5.0 g (18.5 mmoles) of 4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 100 ml of anhydrous dimethylformamide was added to a stirred suspension of 1.4 g (28 mmoles) of 50% sodium hydride in mineral oil (washed with pentane) in 75 ml of anhydrous dimethylformamide heated at 50° under nitrogen. The mixture was heated at 90° for 2 hours, then cooled to 35°. A solution of 7.1 g (37 mmoles) of freshly prepared 2-furylethyl mesylate (prepared according ot the procedure of Crossland and Servis, J. Org. Chem., 35, 3195 (1970)) in 10 ml of anhydrous dimethylformamide was added and the reaction mixture heated at 90° overnight. It was the cooled and poured into ice-water, and extracted with ether. Evaporation of the ether gave an oil which was purified by column chromatography (Silicar CC-7, eluting with acetone-benzene). The major fraction was identified as N-(2-furylethyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:19]([O:18][C:16]([CH2:15][NH:6][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:11]([CH3:13])[CH3:12])=[O:17])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1c(C(C)C)cccc1C(C)C
Reaction time: 72 h

Procedure:
Dissolve 2,6-diisopropylaniline (53.1 g, 0.30 mol) and ethyl bromoacetate (55.1 g, 0,33 mol) in 200 ml DMF. After 72 hours, pour onto aqueous NaHCO3 and extract with hexane. Wash the hexane twice with water. Dry, concentrate and distill to obtain as a fraction b.p. 130°-145° C./0.1 mm N-ethoxycarbonylmethyl-(2,6-diisopropyl)aniline.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].COC(N1[C:20](=[O:21])[CH:19]=[CH:18][C:17]1=[O:22])=O.O1CCCC1.Cl>C(=O)(O)[O-]>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][N:8]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]1=[O:22])[CH3:11]
Reactant: COC(=O)N1C(=O)C=CC1=O
Reactant: CCOC(CCCN)OCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCOC(CCCN1C(=O)C=CC1=O)OCC
Reaction time: 0.25 h

Procedure:
As shown in FIG. 2, to a solution of 4-aminobutyraldehyde diethylacetal (5 g, 31 mmol) in 100 ml of saturated bicarbonate was added N-methoxycarbonylmaleimide (4.91 g, 31.6 mmol) at 0° C. (icebath). After 15 minutes, tetrahydrofuran (100 ml) was added at room temperature and the resultant mixture stirred for 1 hour. The resultant mixture was then acidified with 1N hydrochloric acid to pH 6-7 and extracted with ethyl acetate (3×200 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo. The crude product was purified by chromatography on silica gel 60 eluting with ethyl acetate/petroleum ether 1:2 to yield 4-maleimidobutyraldehyde diethylacetal as a yellow oil (4.31 g; 58%), TLC Rf=0.65, ethyl acetate/hexane 1:1.