Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([N:10]([CH2:12][C:13]([OH:15])=O)[CH3:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.Cl.C[O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[NH2:23]>>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([S:7]([N:10]([CH2:12][C:13]([NH:23][C@H:22]([C:21]([OH:31])=[O:20])[CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:15])[CH3:11])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1cccnc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N[C@@H](Cc2cccnc2)C(=O)O)cc1
Yield: 17 %

Procedure:
N-(Toluene-4-sulfonyl)sarcosine was coupled to 3-(3-pyridyl)alanine methyl ester dihydrochloride using the procedure described in Method 3 to give N-(toluene4-sulfonyl)sarcosyl-β-(3-pyridyl)alanine (166 mg, 17%). The title compound was prepared via hydrolysis of the methyl ester using 1N aqueous NaOH in dioxane/water (129 mg, 100%).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[NH:23][Si](C)(C)C.C(N(CC)CC)C>O1CCOCC1.CCOC(C)=O>[CH3:17][N:13]1[C:14]2=[CH:15][NH:23][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]1=[O:18]
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1c(=O)c2c(-c3ccccc3)[nH]cc2n(C)c1=O
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 13.4a (Intermediate C) (2.33 g, 6.91 mmol), hexamethyldisilazane (2.90 mL, 13.82 mmol) and triethylamine (2.89 mL, 20.73 mmol) were combined in dioxane (20 mL) and the mixture heated at reflux for 22 hours. Further portions of hexamethyldisilazane (2.90 mL, 13.82 mmol) and triethylamine (2.89 mL, 20.73 mmol) were added to allow the reaction to run to completion. The reaction mixture was cooled to room temperature, diluted with EtOAc (150 mL) and washed with 1M HCl (aq) and brine. The organic phases was dried over sodium sulphate and evaporated under vacuum. The residue was triturated with DCM/diethyl ether/hexane to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.CCN(CC)CC.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](Cl)([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:31][CH:30]=1>ClCCl>[CH3:49][O:48][C:45]1[CH:44]=[CH:43][C:42]([C:35]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH:17][C:10]2[CH2:11][O:12][CH2:13][C:14]([F:16])([F:15])[C@:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:19])([CH3:18])[N:9]=2)=[CH:47][CH:46]=1
Reactant: C[C@]1(c2cc(Br)ccc2F)N=C(N)COCC1(F)F
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 2 h

Procedure:
To a solution of (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (9.0 mmol) in dichloromethane (150 ml) was subsequently added at 0° C. NEt3 (18.0 mmol) and 4,4′-dimethoxytriphenylmethyl chloride (9.9 mmol) and stirring was continued at 22° C. for 2 h. The mixture was washed with saturated aqueous NH4Cl, the organic layer was dried, evaporated and the residue was purified by chromatography on silica using cyclohexane/ethyl acetate to give pure (R)-N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (A8A) as a colorless foam. MS (ISP): m/z=639.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=2)[N:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:15][N:11]1[CH:12]=[CH:13][N:14]=[C:10]1[S:9][C:5]1[N:4]=[C:3]([C:1]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16](=[O:24])[N:2]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: Cn1ccnc1Sc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1ccnc1Sc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 5.5 %

Procedure:
2-Cyano-6-(1-methyl-1H-imidazol-2-yl)thiopyridine (1.56 g, 7.22 mmol) and methyl thiosalicylate (1.53 g, 9.10 mmol) were dissolved in toluene (100 ml), and triethylamine (1.70 ml, 12.1 mmol) was added thereto. The reaction mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.14 g, 5%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.C(=O)([O-])O.[Na+].[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>O1CCCC1>[CH:33]1([S:36]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:27]=2)(=[O:38])=[O:37])[CH2:35][CH2:34]1
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Reactant: O=S(=O)(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(NS(=O)(=O)C4CC4)cn3c2)c1
Temperature: 25 °C
Reaction time: 61 h
Yield: 22.6 %

Procedure:
To N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (150 mg, 0.417 mmol), tetrahydrofuran (10 mL) and aqueous sodium hydrogen carbonate solution (5 mL) was added cyclopropanesulfonyl chloride (348 μL, 2.48 mmol), and the mixture was stirred at room temperature for 61 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→70% ethyl acetate-hexane) to give the title compound (43.7 mg, 23%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]23[CH2:22][CH2:21][C:18]([CH2:23][CH2:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH2:19][CH2:20]2)[CH2:17][O:16]3)[CH:5]=[C:6]([O:8]C2CCCCO2)[CH:7]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[F:1][C:2]1[CH:3]=[C:4]([C:15]23[CH2:20][CH2:19][C:18]([CH2:23][CH2:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH2:21][CH2:22]2)[CH2:17][O:16]3)[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cc(O)cc(F)c3)(CC1)OC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
A mixture of tert-butyl 2-(2-(1-(3-fluoro-5-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate (400 mg, 0.861 mmol) and PPTS (65 mg, 0.258 mmol) in MeOH (10 mL) was stirred at 50° C. for 3 h. The reaction was cooled to rt, then concentrated in vacuo. The residual crude oil was purified by flash chromatography (SiO2) using a gradient from 0% to 30% EtOAc/hexane (10 min) to give the title compound (292 mg, 0.768 mmol, 89% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ: 6.71-6.66 (m, 1H), 6.66-6.61 (m, 1H), 6.42 (d, J=10.2 Hz, 1H), 5.96 (s, 1H), 3.96 (s, 2H), 3.88 (s, 2H), 3.58 (t, J=6.9 Hz, 2H), 2.04-1.92 (m, 4H), 1.80-1.70 (m, 4H), 1.57-1.49 (m, 11H); 19F NMR (471 MHz, CDCl3) δ: −112.25 (s, 1F).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[CH2:11]([N:13]([CH3:17])[C:14](Cl)=[O:15])[CH3:12]>>[CH2:11]([N:13]([CH3:17])[C:14]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:15])[CH3:12]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CCN(C)C(=O)Cl
Product: CCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Yield: 96.1 %

Procedure:
Using 3-amino-5-t-butylisoxazole and N-ethyl-N-methylcarbamoyl chloride, the reaction is carried out as in Example 1, whereby 1-ethyl-1-methyl-3-(5-t-butyl-3-isoxazolyl)urea is obtained. Yield is 96.1%. Melting point is 88.5° to 89.5° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[C:15]([C:31]([F:34])([F:33])[F:32])=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C@:24]3([CH3:30])[CH2:28][O:27]C(=O)[NH:25]3)[CH:18]=[CH:17]4)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].C(O)C.O>>[NH2:25][C@@:24]([C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][C@H:10]3[CH2:9][CH2:8][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:12][CH2:11]3)[C:15]=2[C:31]([F:33])([F:34])[F:32])[CH:20]=1)([CH3:30])[CH2:28][OH:27]
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@@H](c5ccccc5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@@H](c4ccccc4)CC3)ccc2c1
Yield: 50.1 %

Procedure:
The mixture of (R)-4-(6-(cis-4-phenyl-cyclohexyloxy)-5-trifluoromethylnaphthalen-2-yl)-4-methyloxazolidin-2-one (46.7 mg, 0.0000995 mol) and lithium hydroxide (26 mg, 0.0011 mol) in ethanol (2 mL, 0.04 mol) and water (0.4 mL, 0.02 mol) was heated to reflux overnight. LCMS showed reaction complete. The solvent was removed under vacuum and the residue was partitioned between water and CH2Cl2. The aqueous layer was extensively extracted with CH2Cl2. The combined organic phase was dried over Na2SO4. The concentrated residue was taken up into DCM and subjected to chromatographic purification with CH2Cl2/MeOH (10:90 to 80:20) to give the product as a white solid (22.1 mg, 50% yield). LCMS 427.26 ([M-NH2]+, 100%). 1H NMR (400 MHz, CD3OD) δ ppm 1.52 (s, 3 H), 1.67 (brd, J=11.8 Hz, 2 H), 1.82 (dd, J=13.4, 13.1 Hz, 2 H), 2.02 (ddd, J=13.1, 12.8, 3.0 Hz, 2 H), 2.20 (d, J=14.8 Hz, 2 H), 2.65 (ddd, J=12.2, 12.2, 3.8 Hz, 1H), 3.68 (d, J=10.9 Hz, 1H), 3.73 (d, J=10.9 Hz, 1H), 5.01 (brs, 1H), 7.14-7.30 (m, 5H), 7.50 (d, J=9.3 Hz, 1H), 7.71 (dd, J=9.3, 2.2 Hz, 1H), 7.95 (d, J=2.1 Hz, 1H), 8.08 (d, J=9.3 Hz, 1H), 8.16 (d, J=9.3 Hz, 1 H).
Reaction SMILES: OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:23][C:24]1[CH:33]=[CH:32][C:31]2[C:30]([C:34](O)=O)=[CH:29][CH:28]=[CH:27][C:26]=2[N:25]=1.[CH3:37][NH:38][C:39](=[S:42])[NH:40][NH2:41]>CN(C)C=O.C(N(CC)CC)C>[CH3:37][N:38]1[C:34]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:31]=2[CH:32]=[CH:33][C:24]([CH3:23])=[N:25]3)=[N:41][NH:40][C:39]1=[S:42]
Reactant: CNC(=S)NN
Reactant: Cc1ccc2c(C(=O)O)cccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3n[nH]c(=S)n3C)cccc2n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Hydroxybenzotriazole (7.8 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11 g) and triethylamine were successively added to a stirred solution of 2-methyl-5-quinolinecarboxylic acid (10g) and 4-methyl-3-thiosemicarbazide (6.1 g) in dimethylformamide (200 ml), at 0° C. Following the addiction the reaction mixture was allowed to reach room temperature, the stirred continued over night and then the solvent was evaporated under reduced pressure. The residue was treated with an aqueous sodium hydroxide solution (500 ml, 0.5N) and the mixture was stirred at 80° C. for 3 h, after which time the mixture was cooled to room temperature and the pH adjusted to pH 6 using a aqueous hydrochloridric acid solution (2M) and the resulting precipitatye was filtered and dried in vacuo to give the title compound (11 g) as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1([CH3:13])[CH:8]([CH3:9])[CH2:7][CH2:6][C:5]([CH2:11][CH3:12])([CH3:10])[NH:4]1)[CH3:2].Cl.[CH2:15]1[O:17][CH2:16]1>CO>[OH:17][CH2:16][CH2:15][N:4]1[C:5]([CH2:11][CH3:12])([CH3:10])[CH2:6][CH2:7][CH:8]([CH3:9])[C:3]1([CH2:1][CH3:2])[CH3:13]
Reactant: CCC1(C)CCC(C)C(C)(CC)N1
Reactant: C1CO1
Agent: Cl
Solvent: CO
Product: CCC1(C)CCC(C)C(C)(CC)N1CCO
Temperature: 100 °C

Procedure:
An autoclave is filled with 36.6 g 2,6-diethyl-2,3,6-trimethylpiperidine, 150 ml of methanol and 1 ml conc. hydrochloric acid. 11 g of ethylene oxide are added under a pressure of 2 atmospheres and the autoclave is heated to 100° C. for 24 hours. The methanol is distilled off and the residue is purified by fractional distillation which yields 1-(2-hydroxyethyl)-2,6-diethyl-2,3,6-trimethylpiperidine (Compound No. 8) boiling at 106° C./0.1 mm Hg.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5].CC([O-])(C)C.[K+:16]>CCOCC>[F:7][C:3]([F:8])([C:2]([F:10])([F:9])[F:1])[C:4]([O-:6])=[O:5].[K+:16]
Reactant: O=C(O)C(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=C([O-])C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Pentafluoropropionic acid (20.5 g, 183 mmol) was slowly added to a solution of KOtBu (29.9 g, 183 mmol) in ether (400 mL) at 0° C. After 30 minutes the ice bath was removed. After stirring at room temperature for 4 hours the suspension was filtered and the cake was washed with ether (200 mL). The fine white solid was placed under vacuum for 16 hours prior to use.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=2[F:30])[N:23]=[C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:21]=1[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=3[F:30])[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:21]=2[CH3:38])[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(-c2ncc(Br)cc2N)cn1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ncc(Br)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-6′-methoxy-2,3′-bipyridin-3-amine (226.0 mg, 0.81 mmol) in dry DMF (5 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (100.7 mg, 2.52 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (353.1 mg, 1.21 mmol) was added in portions. Upon complete addition, the mixture was warmed to 70° C. After 3 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted 5 times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-35% EtOAc in hexanes) to afford a yellow residue as mostly N-(5-bromo-6′-methoxy-2,3′-bipyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[C:18]1([CH2:24][N:25]([CH2:37][CH:38]=[CH2:39])[C:26](=[O:36])[CH2:27][NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[N:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]3[C:26](=[O:36])[N:25]([CH2:24][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:37][CH:38]3[CH2:39]2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(OCc2ccccc2F)cc1
Reactant: C=CCN(Cc1ccccc1)C(=O)CNCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C1C2C(CC(c3ccc(OCc4ccccc4F)cc3)N2Cc2ccccc2)CN1Cc1ccccc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 49.6 %

Procedure:
A solution of 4-{[(2-fluorophenyl)methyl]oxy}benzaldehyde (D92, 920 mg, 4.0 mmol), prepared by an analogous procedure to that described hereinabove, N1,N2-bis(phenylmethyl)-N1-2-propen-1-ylglycinamide (D90, 588 mg, 2.0 mmol) and DIPEA (0.68 ml, 4.0 mmol) in dry toluene (8 ml) were stirred at 120° C. for 72 h. After the reaction was terminated, it was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The residue was purified via flash chromatography affording the title compound (503 mg, 50%) as a racemate. Rf (cyclohexanes:ethyl acetate 1:1): 0.57.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][CH:14]([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:17]([Zn]CC)[CH3:18]>>[F:15][CH:14]([F:16])[CH2:13][O:12][C:3]1[C:2]([CH2:17][CH3:18])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: COC(=O)c1cnc(OCC(F)F)c(Br)c1
Reactant: CC[Zn]CC
Product: CCc1cc(C(=O)OC)cnc1OCC(F)F
Yield: 88 %

Procedure:
The title compound is prepared in 88% yield (660 mg, clear colorless oil) from methyl 5-bromo-6-(2,2-difluoroethoxy)nicotinate (900 mg, 3.0 mmol, Step-2) and diethylzinc instead of dimethylzinc by the similar manner in Step-3 of Amine-27.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N+:16]([O-:18])[CH3:17])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:5][CH:4]=1.[CH2:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CCCCCCCC>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:19][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:18][N:16]2[CH3:17])=[CH:5][CH:4]=1
Reactant: C=CCCCCCCCCCCCCCCCC
Reactant: COc1ccc(C(Cn2cncn2)=[N+](C)[O-])cc1
Product: CCCCCCCCC1CC(Cn2cncn2)(c2ccc(OC)cc2)N(C)O1

Procedure:
Derivative 3 (R=4-OCH3, n=7) is prepared by a procedure similar to that described in Example 1 by reacting 1-(4-methoxyphenyl)-N-methyl-2-(1H-1,2,4-triazol-1-yl)ethanimine N-oxide (1: R=4-OCH3) with 1-decene (2: n=7). The resulting diastereomeric mixture of cis- and trans-derivative 3 (R=4-OCH3, n=7) is flash-chromatographed on neutral silica gel using chloroform-methanol (99:1 by volume) as eluent. Isomer A has a melting point of 89°-91° C. (ethyl acetate).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([NH:9]C2C=CC=CC=2)[CH:6]=[CH:7][CH:8]=1.[C:18]([OH:22])(=[O:21])[CH:19]=[CH2:20].[OH-].[Na+]>O>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([NH:9][CH2:20][CH2:19][C:18]([OH:22])=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(Nc2ccccc2)c1
Reactant: C=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCNc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To an aqueous solution of 3-trifluoromethylphenyl aniline (5.0 g) in water (15.0 ml) was added acrylic acid (3.2 ml) and the resulting mixture was stirred at 100° C. for one hour. The reaction mixture was basified with 5N aqueous sodium hydroxide solution and extracted with ethyl acetate (100 ml×2). The resulting organic layer was washed with saturated saline (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 3-(3-trifluoromethylphenylamino)propionic acid (8.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:35].[CH3:37][NH:38][CH3:39].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][N:38]([CH3:39])[CH3:37])=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:14]=1[CH3:35]
Reactant: CNC
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and dimethylamine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 18 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the title compound (0.03 g, 26%). LCMS: 518.25 (M+1)+; HPLC: 89.16% (@ 254 nm) (Rt; 3.982; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.81 (s, 1H), 8.18 (t, 1H), 8.08 (d, 1H, J=8 Hz), 7.52 (d, 1H, J=8 Hz), 7.43 (s, 1H), 7.26 (s, 1H), 5.86 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.83-3.86 (m, 4H), 3.32 (2H merged in solvent peak), 3.03 (m, 1H), 2.64 (s, 3H), 2.50 (3H merged in solvent peak), 2.40 (bs, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.60 (bs, 4H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:19][C:32](=[O:33])[O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3ccccc3C(F)(F)F)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccccc3C(F)(F)F)c2O1)OCc1ccccc1
Yield: 94.2 %

Procedure:
Treatment of (±)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (0.813 g, 2.46 mmol) with diisopropylethylamine (0.478 g, 3.69 mmol) and benzyl chloroformate (0.462 g, 2.71 mmol) generally according to the procedure described for Intermediate 12 gave 0.99 g (94%) of (±)-benzyl {7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate as a pale yellow oil Rf=0.60 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C24H20F3NO3: C, 67.44; H, 4.71; N, 3.15. Found: C, 67.43H, 4.76; N, 3.15. Chiral HPLC separation of (±)-benzyl[7-(2-(trifluoromethyl))-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, isopropanol:carbon dioxide 3:17) provided two fractions. Fraction 1 (Rt=5.252 min, Chiralcel OJ, isopropanol:carbon dioxide 3:17); Fraction 2 (Rt=6.280 min, Chiralcel OJ, isopropanol:carbon dioxide 3:17).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:18][C@@H:19]([CH3:25])[C:20](OCC)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)=O.CC(C)=O.CO>CCCCCC.C(Cl)Cl>[CH2:11]([O:18][C@@H:19]([CH3:25])[CH:20]=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)[C@H](C)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: CO
Solvent: CCCCCC
Solvent: ClCCl
Product: C[C@@H](C=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.4 %

Procedure:
A solution of 1.0M DIBAL (diisobutylaluminum hydride) in hexane (10 ml) was added dropwise to a stirred solution of ethyl (S)-2-(benzyloxy)propionate (obtained in Preparation 7) (2.08 g) in methylene chloride (20 ml) at −78° C. (dry-ice/acetone) for 5 minutes under nitrogen atmosphere. After 20 minutes, methanol (1.6 ml) was added dropwise to the mixture at −78° C., and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was filtered through a pad of Celite, and the solid on the filter was washed with methylene chloride. The combined filtrates were concentrated in vacuo. The obtained residue was purified by silica gel (35 g) chromatography eluted with hexane/ethyl acetate (30:1) to give (S)-2-(benzyloxy)propionaldehyde (810 mg).