Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Al].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>O.C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([C:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [Al]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1ccc(O)c(C2=CCCCC2)c1
Temperature: 100 °C
Yield: 27.4 %

Procedure:
15.0 g (0.10 mol) of 4-tert-butylphenol and 7.2 g (0.035 mol) of aluminium isopropylate are added to 100 ml of xylene under nitrogen. To remove the resulting isopropanol, 30 ml of solvent are distilled off. The reaction mixture is heated to 100° C. and charged with 9.8 g (0.10 mol) of cyclohexanone and is then refluxed for 20 hours. The reaction mixture is cooled and charged with 40 ml of water and 10 ml of concentrated hydrochloric acid. The organic phase is separated, washed with water, dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is chromatographed over silica gel using the solvent system hexane/ethyl acetate=19:1 and the pure fractions are crystallised from methanol, giving 6.3 g (27%) of 4-tert-butyl-2-cyclohexen-1-yl-phenol, m.p. 90-93° C. (compound (109), Table 1).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>CO>[CH:34]1([NH:37][CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:30])([F:29])[F:31])=[CH:25][CH:26]=2)[CH2:36][CH2:35]1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: NC1CC1
Solvent: CO
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNC2CC2)cc1)C(F)(F)F
Temperature: 140 °C
Yield: 65.9 %

Procedure:
A 20-mL microwave vial was charged with ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (1.0 g, 1.9 mmol, Intermediate B), cyclopropylamine (4.0 mL, 57 mmol, Alfa Aesar, Ward Hill, Mass.) and MeOH (10.0 mL). The vial was sealed and heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 30 min. After cooling to room temperature, the reaction mixture was concentrated and the crude product was purified by column chromatography (120 g of silica, 2 to 8% 2M NH3 in MeOH/CH2Cl2) to afford 2-(4-((2S)-2-((cyclopropylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.613 g) as mixture of two isomers.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(CC)CC)C.Cl.[CH:18]1([C:21](=N)OCC)[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>C(O)C>[CH:18]1([C:21]2[NH:3][C:4]3=[CH:5][S:6][CH:7]=[C:8]3[N:9]=2)[CH2:20][CH2:19]1
Reactant: Nc1cscc1N
Reactant: CCOC(=N)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1scc2[nH]c(C3CC3)nc12
Temperature: 25 °C
Reaction time: 70 h
Yield: 32 %

Procedure:
[step 1] 3,4-Diaminothiophene dihydrochloride (300 mg, 1.60 mmol) was suspended in ethanol (12 mL), triethylamine (0.45 mL, 3.21 mmol) and ethyl cyclopropanecarboimidate monohydrochloride (WO200970485; 528 mg, 3.53 mmol) were added, and the mixture was stirred at room temperature for 70 hr. To the mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-0/100 v/v) to give 2-cyclopropyl-1H-thieno[3,4-d]imidazole (84 mg, 32%).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1F.O1CCOCC1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(Cl)Cl.CN(C=O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: C1COCCN1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Br)c(N2CCOCC2)c1
Temperature: 150 °C
Yield: 36 %

Procedure:
A microwave vial charged with potassium phosphate (0.533 g, 2.51 mmol), 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (0.610 g, 2.51 mmol) and 1 mL dioxane, was treated with morpholine (0.437 ml, 5.02 mmol) and was heated to 150° C. in a microwave reactor for one hour. LC/MS showed mostly starting material, so the reaction mixture was treated with 1 mL DMF and was heated to 150° C. in an oil bath overnight. LC/MS showed product, so the reaction mixture was diluted with DCM, filtered through a syringe filter, and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 50% EtOAc/heptane) gave 4-(2-bromo-5-(trifluoromethyl)phenyl)morpholine (0.280 g, 0.903 mmol) as a clear oil. [M+H]+=312.0
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10])([CH3:5])[CH3:4])#[N:2].[Li+].[OH-]>C1COCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: COC(=O)c1cccc(C(C)(C)C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
To a solution of methyl 3-(2-cyanopropan-2-yl)benzoate (1 equiv.) in THF (0.10 M) was added 1M LiOH (2.5 equiv.) and allowed to stir at RT for 18 hrs. LCMS analysis indicated the formation of the desired product (MH+—190, Rt—0.60 min). The volatiles were removed in vacuo, and the aqueous phase was acidified to ˜pH3 with 1M HCl. A white precipitate was formed, filtered and dried. Isolated 3-(2-cyanopropan-2-yl)benzoic acid in 63% yield. LCMS (m/z) (M+H)=190.1, Rt=0.60. 1H NMR (400 MHz, <cd3od>) δ ppm 1.76 (s, 6H) 7.54 (t, J=7.83 Hz, 1H) 7.74-7.80 (m, 1H) 8.00 (d, J=7.43 Hz, 1H) 8.16-8.21 (m, 1H).
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([NH2:5])=[O:4].[NH2:14][C@H:15]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH3:16].C([BH3-])#N.[Na+]>>[NH2:5][C:3]([CH:2]([NH:14][C@H:15]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH3:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NC(=O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCc1ccccc1)C(N)=O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in example 26, one can condense 2-oxo-4-phenylbutyramide and L-alanyl-L-proline in the presence of sodium cyanoborohydride to yield N-(1-amino carbonyl-3-phenylpropyl)-L-alanyl-L-proline.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:28]OS(C)(=O)=O)[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH:36]([NH2:39])([CH3:38])[CH3:37]>>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][NH:39][CH:36]([CH3:38])[CH3:37])[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)N
Reactant: CS(=O)(=O)OCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Product: CC(C)NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1

Procedure:
A solution of methanesulfonic acid 4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]pyridine-2-ylmethyl ester (150 mg, 0.30 mmol) and isopropyl amine (5 mL) is stirred at rt for 2 h. The reaction is concentrated under reduced pressure and the residue separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give 5-[2-(isopropylamino-methyl)-pyridin-4-yloxy]-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 469.2 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.25-8.37 (m, 2H), 7.97 (s, 1H), 7.88 (d, J=3.8 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.30 (d, J=2.3 Hz, 1H), 7.00 (dd, J=9.0, 2.4 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.81 (dd, J=5.8, 2.3 Hz, 1H), 6.66 (d, J=3.8 Hz, 1H), 4.01 (s, 2H), 3.09-3.18 (m, 1H), 1.18 (d, J=6.6 Hz, 6H).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]=[O:17]>N1C=CC=CC=1.O>[OH:17][CH2:16][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]#[N:9]
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: C=O
Solvent: c1ccncc1
Solvent: O
Product: N#CC(CO)(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 40 h
Yield: 79.2 %

Procedure:
To a suspension of 2,2-diphenylacetonitrile (2.0 g, 10.35 mmol) and paraformaldehyde (1.242 g, 41.399 mmol) in pyridine (18 mL) was added Triton B (40% solution in water, 1.022 mL, 2.587 mmol) at 0° C. The suspension instantaneously changed color. The cooling bath was removed and the reaction was stirred at 23° C. for ˜40 hours. The reaction was then acidified with acetic acid (2 mL) and poured into water (150 mL). The aqueous phase was extracted with diethyl ether (2×) and the combined organic extracts were washed with water (2×), 1N HCl (2×) and saturated sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel Biotage chromatography (ethyl acetate/hexane 10% to 50%) to give the title material (1.83 g, 100%) as an oil. HPLC ret. time (Condition A): 1.682 min. 1H NMR (400 MHz, CDCl3) δ ppm: 2.21 (1H, t, J=7.20 Hz), 4.37 (2H, d, J=6.82 Hz), 7.35-7.44 (10H, m).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:32]=[C:31](C(O)=O)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:36])[CH:29]=2)[N:24]=1)([OH:16])=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>O>[CH3:36][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]([OH:16])=[O:15])[CH:32]=[CH:31]2
Reactant: Cc1ccc2nc(-c3ccccc3C(=O)O)cc(C(=O)O)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 160 °C
Yield: 46.7 %

Procedure:
To 1 ml of diphenyl ether were added 0.2 g of the 2-(2-carboxyphenyl)-6-methyl-4-quinolinecarboxylic acid obtained in Example 2. After adding 123 mg of p-toluenesulfonic acid, the mixture was heated at 160° C. for 1 hour. Then the reaction mixture was poured into water, made alkaline by adding sodium hydroxide and washed with ethyl acetate. The aqueous layer was neutralized with 3M hydrochloric acid until a precipitate was formed. After extracting with ethyl acetate, 80 mg of 2-(6-methylquinolin-2-yl)benzoic acid were obtained. NMR (270 MHz, CD3OD): δ 7.58-8.32 (m,9H); 2.58 (s,3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:22][C:23]([F:37])([F:36])[CH2:24][C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:29][C:25]([CH2:24][C:23]([F:37])([F:22])[F:36])=[CH:26][N:27]=3)[CH2:31][CH2:32]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)Cc1cnc(N2CCNCC2)s1
Agent: Cl
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(CC(F)(F)F)s2)CC1)C(F)(F)F
Yield: 54 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A15) and 1-[5-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine hydrochloride (Example 69(e)). The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 54%). MS (m/e): 546.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.BrN1C(=[O:18])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C1N2CN3CN(C2)CN1C3.[OH-].[Na+]>C1C=CC=CC=1.O.C(Cl)(Cl)Cl.C(O)(=O)C>[N:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([CH:1]=[O:18])[CH:3]=1
Reactant: Cc1cnc2cccnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: O=Cc1cnc2cccnc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.8 %

Procedure:
To a solution of 0.26 g of 3-methyl-1,5-naphthyridine in 4 mL of benzene, 0.35 g of N-bromosuccinimide and 29 mg of azobisisobutyronitrile were added, and the mixture was heated under reflux while stirring for 2 hours 15 minutes. Thereto was further added 0.13 g of N-bromosuccinimide, and the mixture was heated under reflux while stirring for 30 minutes. After cooling to room temperature, a solution of 0.50 g of hexamethylenetetramine in 1.5 mL of water was dropped to the reaction mixture under cooling with ice, thereto was added 1.5 mL of acetic acid, and the mixture was heated under reflux while stirring for 1 hour 20 minutes. After cooling to room temperature, chloroform and a 20% aqueous sodium hydroxide solution were added to the reaction mixture and the mixture was adjusted to pH 8.5. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by flash silica gel column chromatography using an eluent of hexane:ethyl acetate=1:1 to obtain 25 mg of 1,5-naphthyridine-3-carbaldehyde as a slightly yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15]N(C)[CH2:13][CH2:12]2)[CH:6]=[CH:5][C:4]=1[NH2:18].N1CC[O:22]CC1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:22][CH2:13][CH2:12]2)[CH:6]=[CH:5][C:4]=1[NH2:18]
Reactant: C1COCCN1
Reactant: COc1cc(CCN2CCN(C)CC2)ccc1N
Product: COc1cc(CCN2CCOCC2)ccc1N

Procedure:
2-Methoxy-4-(2-morpholin-4-yl-ethyl)-phenylamine was prepared in a similar manner as 2-Methoxy-4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamine of Example 488 replacing 1-Methyl-piperazine with morpholine. LC/MS (E/I+) 237.07 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:34])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:34])[C:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Yield: 67.6 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (2.3 g, 7.9 mmol) prepared in Example 26a, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in 1,2-dichloroethane (130 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2.7 g, 68%).
Reaction SMILES: [CH2:1]([CH:7]([O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(OCC)(=O)C.CN(C=O)C.[Ni]>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([O:30][C:31](=[O:41])[C:32]2[CH:33]=[CH:34][C:35]([NH2:38])=[CH:36][CH:37]=2)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:19])=[CH:26][CH:25]=1
Reactant: CCCCCCC(CCCCCCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1)OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCC(CCCCCCCCCCC(=O)Oc1ccc(N)cc1)OC(=O)c1ccc(N)cc1
Temperature: 62.5 °C
Reaction time: 4 h

Procedure:
To a solution of 4-Nitro-benzoic acid 1-hexyl-11-(4-nitro-phenoxy carbonyl)-undecyl ester (290 g) in a mixture of Ethyl acetate (1.5 L) and DMF (300 mL) taken in a pressure vessel was added Raney Nickel (80 g). The reaction mixture was stirred under an atmosphere of Hydrogen (8-10 Kg) for 4 hours at a temperature of 60-65° C. The catalyst was removed by filtration. 75% of the solvent was distilled off and poured into cold water (2 L). The resulting solid was filtered off and washed with chilled water (100 mL) and do the slurry with 1 lit diisopropylether and filtered off, then dried the material properly in vacuum oven at 60-80° C. to yield pure 4-amino-benzoic acid 11-(4-amino-phenoxycarbonyl)-1-hexyl-undecyl ester product as off white powder (190 g) with a melting point of 156-159° C. The resulting compound was characterized by 1H NMR (CDCl3) δ 0.83 (t, 3H, CH3), 1.2-1.65 (m, 26H, 13×CH2), 1.81 (m, 2H, CH2), 2.12 (t, 2H, COCH2), 3.50 (m, 1H, CH), 5.5-6.1 (m, 4H, 2×NH2) 6.8-7.2 (m, 4H, Ar), 7.2-7.8 (m, 4H, Ar). The hydrolytic degradation of the compound was carried out in pH 9.0 buffer solution. The study showed that 1% solution is 100% hydrolyzed in 15 hours at 50° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][CH:18]4[CH2:27][CH2:26][C:25]5[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=5)[C:19]4=[O:30])[CH2:13][CH2:12]3)[C:10](=[O:31])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH-].[Na+].OO.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][C@H:18]4[CH2:27][CH2:26][C:25]5[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=5)[C@H:19]4[OH:30])[CH2:13][CH2:12]3)[C:10](=[O:31])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc2c(c1)CCC(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)C2=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C([O-])[O-]
Agent: OO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@H](CN1CCC3(CC1)C(=O)NCN3c1ccccc1)[C@@H]2O
Temperature: -78 °C
Reaction time: 16 h

Procedure:
1-Phenyl-8-[(1,2,3,4-tetrahydro-6-methoxy-1-oxo-2-naphthalenyl)methyl]-1,3,8-triazaspiro[4.5]decan-4-one (5.4 g) dissolved in 60 ml of dry tetrahydrofuran is added dropwise to a flask charged with 2.1 equivalents of a 1 molar tetrahydrofuran solution of lithium tri-sec-butylborohydride which has been cooled to -78° C under an argon atmosphere. The resulting solution is stirred for 16 hours at room temperature. The reaction mixture is treated at 0° C with 15 ml of 3 molar sodium hydroxide followed by the addition of 15 ml of 30% hydrogen peroxide. The aqueous phase is saturated with potassium carbonate and the organic layer is separated and concentrated. The residue is dissolved in methylene chloride, washed with water, dried and concentrated producing the crude product. Two crystallizations of this material from absolute ethanol/methylene chloride yield 3.8 g of isomerically pure title compound, melting point 182°-183° C.
Reaction SMILES: C(C[O:4][C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([C:19]([O:21][CH3:22])=[O:20])=[C:7]([C:23]([F:26])([F:25])[F:24])[N:6]=1)#N.BrCC#N.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:4][C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([C:19]([O:21][CH3:22])=[O:20])=[C:7]([C:23]([F:25])([F:24])[F:26])[N:6]=1
Reactant: COC(=O)c1c(OCC#N)nc(C(F)(F)F)c(C(=O)OC)c1CC(C)C
Agent: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)nc(C(F)(F)F)c(C(=O)OC)c1CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This example illustrates the preparation of Compound 80, namely, dimethyl 2-(cyanomethoxy)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridine-dicarboxylate. A solution of 6.38 g (0.019 mol) of dimethyl 2-hydroxy-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (Compound 1) in 50 mL of dimethylformamide was prepared and to it was added 7.2 g (0.06 mol) of bromoacetonitrile and 8.3 g (0.06 mol) of anhydrous potassium carbonate. The mixture was stirred at room temperature overnight then suction filtered. The filtrate was diluted with 400 mL of water and extracted with four 50 mL portions of methylene chloride. The combined extracts were dried with magnesium sulfate and the solvent was removed by rotary evaporation giving 7.09 g (98.9% yield) of a dark amber oil. Silica gel chromatography with 10% ethyl acetate, 90% cyclohexane gave 3.51 g (49%) of Compound 80 as a clear colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]=3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH:18]=3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(C3=CCNCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.2 %

Procedure:
A mixture of 200c (1.0 g, 2.3 mmol) and 4 M HCl/dioxane (10 mL) was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure. The residue was basified with aqueous sodium hydroxide and extracted with dichloromethane. The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford 200d (650 mg, 84%) as a yellow solid. MS-ESI: [M+H]+ 363.0
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[C:17]1([C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:11]1([C@H:9]([NH:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([N:26]3[CH:27]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:24]=[CH:25]3)[N:7]=2)[CH3:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@@H](Nc1cncc(Cl)n1)c1ccccc1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Product: C[C@@H](Nc1cncc(-n2cnc(-c3ccccc3)c2)n1)c1ccccc1
Yield: 66.9 %

Procedure:
In a procedure analogous to example 2, reaction of 6-chloro-N-[(1R)-1-phenylethyl]pyrazin-2-amine (180 mg, 0.77 mmol) and 4-phenylimidazole (122 mg, 0.85 mmol) furnished the product (176 mg, 67%).