Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1.C(NC(C)C)(C)C.O>CN(C=O)C>[N+:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cccc([N+](=O)[O-])c2)C1
Temperature: 75 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (450 mg), 1-(chloromethyl)-3-nitrobenzene (435 mg) in DMF (4.5 mL) was added N,N-diisopropylamine (463 uL), which was stirred at 75° C. for 4 hours. To the resultant was added H2O. The mixture was extracted with ethyl acetate. The organic phase was washed brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-1-(3-nitrobenzyl)-3-pyrrolidinyl]carbamate (, 757 mg) as a orange oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=2.Br[CH2:19][C:20]1[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1.[H-].[Na+].Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=3)[C:10]([CH3:11])=[C:2]2[CH3:1])=[CH:31][CH:30]=1
Reactant: COC(=O)COc1ccc(CBr)cc1
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(OCC(=O)OC)cc1
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of the allyl 2,3-dimethyl-1H-indole-5-carboxylate (500 mg, 2.2 mmol) in anhydrous DMF (20 mL) was added the methyl 2-(4-(bromomethyl)phenoxy)acetate (565 mg, 2.2 mmol) followed by NaH (131 mg, 3.3 mmol). The resulting solution was allowed to stir overnight under argon atmosphere. The remaining NaH was hydrolyzed by the careful addition of a 0.5 N HCl solution. The mixture was diluted with ethyl acetate, washed with a 0.5 N HCl solution and brine, dried on MgSO4, and concentrated. The crude residue was purified by chromatography on silica gel (Hexane/Ethyl acetate 5/5) to afford yellow oil (536 mg, 61%). ESI-MS (m/z): 408 [M+H]+
Reaction SMILES: OC1C2N=NNC=2C=CC=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@H:19]([CH3:23])[C:20]([OH:22])=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[C:40]1([C:46]2([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C@H:54]3[C@H:50]([CH2:51][NH:52][CH2:53]3)[C:49](=[O:55])[CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:56]1([C:46]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:54]3[C@H:50]([CH2:51][N:52]([C:20](=[O:22])[C@H:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][CH3:11])[CH3:23])[CH2:53]3)[C:49](=[O:55])[CH2:48][CH2:47]2)[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: COc1ccccc1[C@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1 h
Yield: 63.6 %

Procedure:
1H hydroxybenzotriazole (0.59 g) is added to a solution of 84% optically pure (S)-2-(2-methoxyphenyl)propionic acid (0.75 g), prepared according to T. Matsumoto et al., Bull. Chem. Soc. Jpn., 58, 340 (1985) in dry dimethylformamide (15 cc), and the solution is then cooled to 0° C. N,N'-Dicyclohexylcarbodiimide (0.91 g) is then added, the mixture is stirred for 1 hour at this temperature and a solution of (3aR, 7aR)-7,7-diphenylperhydro-4-isoindolone hydrochloride (1.44 g) and N,N-diisopropylethylamine (0.76 cc) in dimethylformamide (10 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, diluted with ethyl acetate (100 cc) and concentrated to dryness under reduced pressure (2.7 kPa) after the precipitate has been filtered off. The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 3 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and collecting 125-cc fractions. Fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by dissolution in boiling isopropyl ether (60 cc) to which hexane (30 cc) is added. The cooled solution is filtered and the filtrate concentrated to dryness under reduced pressure (2.7 kPa) to give (3aR, 7aR)-7,7-diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydro-4-isoindolone (1.2 g) in the form of a white meringue-like product containing (3aR, 7aR)-7,7-diphenyl-2-[(R)-2-(2-methoxyphenyl)propionyl]perhydro-4-isoindolone (10%); [α]D20 =-181° (c=0.81, chloroform).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7]C=[CH:5][C:4]=1O.C=O.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][CH2:18][NH2:19])=[CH:15][CH:14]=1.[O:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][CH2:18][N:19]2[CH2:7][C:8]3[CH:3]=[CH:4][CH:5]=[C:27]([O:22][CH3:23])[C:26]=3[O:25][CH2:24]2)=[CH:15][CH:14]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: C1COCCO1
Reactant: COc1ccccc1O
Agent: C=O
Product: COc1cccc2c1OCN(CCc1ccc(Cl)cc1)C2

Procedure:
To 20 ml. of dioxane are dissolved 5 g. of orthomethoxyphenol, 5 g. of para-formaldehyde and 12.6 g. of para-chlorophenethylamine. The solution is heated on reflux for 9.5 hours and distilled to remove the solvent. The residue is purified by column chromatography on silica gel with a mixture of acetone and benezene (1:4). Recrystallization of the resultant crude crystals from methanol yields 3-(4-chlorophenethyl)-8-methoxy-3,4-dihydro-2H-1,3-benzoxazine as colorless needles melting at 87-88° C. Yield: 4 g.
Reaction SMILES: [C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:28]([OH:37])(=[O:36])[C@@H:29]([C@H:31]([C:33]([OH:35])=[O:34])[OH:32])[OH:30]>>[C:33]([C@H:31]([OH:32])[C@@H:29]([OH:30])[C:28]([O-:37])=[O:36])([OH:35])=[O:34].[C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][NH+:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: C[NH+]1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)O
Yield: 85.7 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and L-(+)-tartaric acid (0.41 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium (2R,3R)-3-carboxy-2,3-dihydroxypropanoate as a crystalline white solid (1.2 g, 85% yield).
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([NH:28][C:29]1[N:34]=[C:33]([C:35]([OH:37])=O)[C:32]([Br:38])=[CH:31][CH:30]=1)(=[O:27])[CH3:26].C(N(CC)C(C)C)(C)C.Cl.CNOC>ClCCl>[C:25]([NH:28][C:29]1[N:34]=[C:33]([C:35]([N:9]([O:8][CH3:4])[CH3:10])=[O:37])[C:32]([Br:38])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1nc(NC(C)=O)ccc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (4.56 g, 12.0 mmol) was added to a solution of 6-acetamido-3-bromopicolinic acid (2.6 g, 10.0 mmol) and DIPEA (N,N-diisopropylethylamine)(5.2 ml, 30 mmol) in DCM (dichloromethane)(10 ml). After 10 minutes, N,O-dimethylhydroxylamine hydrochloride (1.5 g, 15.0 mmol) was added to the reaction. The reaction was stirred at room temperature for 5 min. The reaction mixture was partitioned between EtOAc (ethyl acetate) and saturated NH4Cl solution. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was used in the next step without further purification. MS (m/z) 302.1 [M+H]+. 1H NMR (400 MHz, cd3cl) δ 8.14 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 3.56 (s, 3H), 3.37 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: ClC([O:4][C:5](Cl)(Cl)Cl)=O.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([Cl:20])[C:11]=1[O:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1.[NH3:28].O>C(Cl)(Cl)Cl>[Cl:20][C:12]1[CH:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:15]=[C:10]([Cl:9])[C:11]=1[O:21][C:22]1[CH:26]=[C:25]([CH3:27])[N:24]([C:5]([NH2:28])=[O:4])[N:23]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.1 %

Procedure:
Trichloromethyl chloroformate (3.0 g, 15.0 mmol) was added to a solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (4.67 g, 15.0 mmol) in chloroform (50 ml) at 0° C., and while the mixture was allowed to have room temperature gradually, it was further stirred at room temperature for 4 hours. 30% ammonia solution (10 ml) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hour. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a white solid of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (2.82 g, yield: 53.1%). mp: 152-154° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.58 (d, J=0.4 Hz, 3H), 4.80-5.15 (br s, 1H), 5.80 (q, J=0.4 Hz, 1H), 6.45-6.80 (br s, 1H), 7.66 (s, 2H).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:33])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:36][C@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42]1[N:46]2[CH:47]=[C:48]([O:51][C@H:52]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[C@@H:55]([NH2:62])[CH2:54][CH2:53]3)[CH:49]=[CH:50][C:45]2=[N:44][N:43]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:62][C@@H:55]2[C:56]3[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=3)[C@H:52]([O:51][C:48]3[CH:49]=[CH:50][C:45]4[N:46]([C:42]([N:38]5[CH2:39][CH2:40][CH2:41][C@@H:37]5[CH3:36])=[N:43][N:44]=4)[CH:47]=3)[CH2:53][CH2:54]2)=[O:33])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:17]=2)[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(Cl)c(OCCOC3CCCCO3)c2)n1
Reactant: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(Cl)c(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Yield: 19.3 %

Procedure:
A solution of Intermediate 53b (238 mg, 0.41 mmol), Intermediate 78b (220 mg, 0.61 mmol) and DIPEA (158 μL, 0.91 mmol) in dioxane (2.5 mL) was heated at 60° C. for 18 h. The reaction mixture was cooled and diluted with DCM (5 mL). The organic layer was washed with water (2×5 mL), passed through a phase separator and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound (62 mg, 19%). LCMS (Method 3): Rt: 4.00 min, m/z 783/785 [MH+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5]1.C(Cl)Cl.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C([O-])(O)=O.[Na+]>CCOC(C)=O.CN(C=O)C>[C:31]([NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=2)[CH2:8][CH2:9]1)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (70 mg, 0.18 mmol) and TEA (123 μL, 0.881 mmol) in a 1:1 mixture of CH2Cl2:DMF (2 mL) was treated with pivaloyl chloride (42 mg, 0.35 mmol). The reaction mixture was stirred overnight then transferred to a test tube containing saturated aqueous NaHCO3 (4 mL) and EtOAc (4 mL). The biphasic mixture was mixed vigorously and allowed to separate for 15 min. After separation, the mixture was cooled to −20° C. until the aqueous layer was frozen. The organic layer was then poured off and the solvent was removed under reduced pressure at 50° C. The resulting residue was purified by HiTOPs.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[OH:11][CH2:12][CH2:13]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:11][CH2:12][CH2:13][O:6]2)[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: OCCO
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc(C2OCCO2)cc1Br
Yield: 90.1 %

Procedure:
3-Bromo-4-hydroxybenzaldehyde (2a, 10.0 g, 49.8 mmol) was heated at reflux with 1,2-dihydroxyethane (25 g, 0.4 mol) in toluene (150 mL) in the presence of p-toluenesulfonic acid (950 mg) for 48 h in an apparatus fitted with a Dean-Stark trap. The reaction mixture was concentrated by reduced pressure evaporation, washed with aqueous sodium hydrogen carbonate, water, brine, dried over Na2SO4, evaporated to dryness and then passed through a short silica gel column using a hexanes-ethyl acetate mixture (5:1) with a few drops of triethylamine as eluent to afford the protected product 3a (11.0 g, 95%) as a crystalline solid. Rf=0.38 (25% EtOAc-hexanes): mp 76-78° C. IR (neat) 3351, 2954, 2891, 1608, 1499, 1431, 1284, 1100 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=1.8 Hz, 1H), 7.28 (dd, J=8.4, 2.4 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 5.69 (s, 1H), 4.03 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 152.9, 131.5, 130.2, 127.5, 115.8, 110.0, 102.7, 65.2; CIMS (m/z, rel intensity) 247 (MH++2, 7), 245 (MH+, 7), 203 (100), 201 (100), 175 (4), 173(5), 94 (1).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C@@H:14]1[CH2:19][CH:18]([O:20][N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]=[C:22]2[CH3:46])[CH2:17][C@H:16]([CH3:47])[O:15]1>O>[CH3:13][C@@H:14]1[CH2:19][CH:18]([O:20][N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4[NH:3][C:4](=[O:7])[O:5][N:42]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]=[C:22]2[CH3:46])[CH2:17][C@H:16]([CH3:47])[O:15]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(OC2C[C@@H](C)O[C@@H](C)C2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(OC2C[C@@H](C)O[C@@H](C)C2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogen carbonate (2.2 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C. for 30 min, 4′-[(1-{[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.62 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 35%).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[Cl:13][C:14]1[S:15]C=C[C:18]=1[Cl:19].P([O-])(O)(O)=[O:21].[Na+]>O1CCCC1.CN(C)C=O>[Cl:19][C:18]1[CH:7]=[C:5]([CH:6]=[O:21])[S:15][C:14]=1[Cl:13]
Reactant: Clc1ccsc1Cl
Reactant: O=P([O-])(O)O
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)c(Cl)s1
Reaction time: 0.5 h

Procedure:
11.1 g of diisopropylamine in 100 ml of tetrahydrofuran were cooled to -60° C., 49 ml of n-butyllithium were added over 10 minutes. The mixture was stirred for 30 minutes and 10 g of 2,3-dichlorothiophene were added at -60° C. The mixture was stirred for 45 minutes and then 6 m1 of dimethylformamide and 10 ml of tetrahydrofuran were added. The mixture was stirred for 1 and a half hours, allowed to return to room temperature, poured into a saturated aqueous sodium dihydrogenphosphate solution and extracted with isopropyl ether. The solvent was evaporated and, after chromatography on silica (eluent: 95/5 hexane/ethyl acetate), 10.16 g of the expected product were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11])[C:5]#N.C(O)=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11])[CH:5]=[O:14]
Reactant: O=CO
Reactant: COc1c(F)cc(C#N)cc1F
Product: COc1c(F)cc(C=O)cc1F

Procedure:
3,5-Difluoro-4-methoxybenzonitrile (0.237 mol), Raney alloy (40 g) and 90% formic acid (400 ml) were reacted substantially as described in Example 7A above to obtain 22.9 g (56%) of a white, low melting solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:29]=[O:30]>O1CCCC1>[C:16]1([C@H:14]([N:10]2[CH2:11][CH2:12][O:13][C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([CH:29]=[O:30])=[CH:3][CH:4]=3)[CH2:9]2)[CH3:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Br)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C=O)cc2)C1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 101.9 %

Procedure:
To a solution of (2S)-2 (4-bromophenyl)-4 ((1R)-1-phenylethyl)morpholine (intermediate 1a, 63.3 g, 183 mmol) in tetrahydrofuran (450 ml) was added n-butyllithium (1.57 M in hexane solution, 175 ml, 275 mmol) at −78° C. and the mixture was stirred for 20 minutes. N,N-dimethylformamide (28.3 ml 365 mmol) was added and the mixture was stirred for 2 hours at −78° C. and then allowed to be warmed to −10° C. The reaction was quenched with aqueous ammonium chloride, and the resulting solution was partitioned between water and ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford crude 4-((2S)-4 ((1R)-1-phenylethyl) morpholin-2-yl)benzaldehyde (intermediate 14, 55.1 g). This compound was used without further purification.
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[O:17][CH2:18][CH:19]([OH:24])[CH2:20][N:21]([CH3:23])[CH3:22])#[N:4].Cl>C(O)C.C(Cl)Cl>[CH3:23][N:21]([CH3:22])[CH2:20][CH:19]([OH:24])[CH2:18][O:17][C:16]1[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([NH2:4])=[O:1]
Reactant: [OH-]
Reactant: CN(C)CC(O)COc1ccccc1CCCCc1ccccc1C#N
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CN(C)CC(O)COc1ccccc1CCCCc1ccccc1C(N)=O
Yield: 52.7 %

Procedure:
2 ml of an aqueous solution containing 1 g of sodium hydroxide were added to a solution of 430 mg of 1-{2-[4-(2-cyanophenyl)butyl]phenoxy}-3-dimethylamino-2-propanol [prepared as described in Example 9(b)] in 5 ml of ethanol, and the resulting mixture was heated under reflux for 15 hours. At the end of this time, the reaction mixture was neutralized by the addition of aqueous hydrochloric acid, after which it was concentrated by evaporation under reduced pressure. The resulting residue was mixed with ethanol, and insoluble materials were filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of methylene chloride and methanol as the eluent, to give a colorless oily material, which was dissolved in a small amount of methylene chloride and then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 238 mg (yield 62%) of the title compound as colorless crystals, melting at 149°-151° C.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([C:34]([F:37])([F:36])[F:35])[C:5]=1[OH:38])(=[O:3])[CH3:2].[N-:39]=[N+:40]=[N-:41].[Na+].Cl.C(N(CC)CC)C>>[OH:38][C:5]1[C:6]([C:34]([F:36])([F:35])[F:37])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:17]3[CH:24]=[CH:23][CH:22]=[C:19]([C:20]4[N:39]=[N:40][NH:41][N:21]=4)[CH:18]=3)=[CH:12][CH:11]=2)[CH:32]=[CH:33][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)c(C(F)(F)F)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(-c4nn[nH]n4)c3)cc2)c(C(F)(F)F)c1O
Yield: 96.2 %

Procedure:
Employing the procedure of Example 1 using 3-[[4-(4-acetyl-3-hydroxy-2-trifluoromethyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (384 mg, 0.731 mmol), sodium azide (475 mg, 7.31 mmol), and triethylamine hydrochloride (1.01 g, 7.31 mmol) to yield the title compound as a tan solid (400 mg, 96%): 1H NMR (CD3CN) δ1.44-1.91 (m, 6H), 2.56 (s, 3H), 3.44 (m, 1H), 3.78 (m, 1H), 4.66 (q, 1H), 5.23 (d, 2H), 5.91 (d, 1H), 6.73 (dd, 1H), 7.39-7.62 (m, 5H), 7.89-8.08 (m, 3H), 13.75 (s, 1H).