Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:19]=4[CH:20]=[CH:21][N:22]5S(C4C=CC(C)=CC=4)(=O)=O)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[K+]>CO>[NH:22]1[C:23]2[C:19](=[C:18]([CH2:17][NH:16][C:12]3[N:11]=[C:10]([NH:9][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[NH:8][N:7]=4)[CH:15]=[CH:14][N:13]=3)[CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CNc4nccc(Nc5cc(C6CC6)[nH]n5)n4)cccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2cc[nH]c2c1
Temperature: 100 °C

Procedure:
To a solution of 50 (330 mg, 0.73 mmol) in MeOH (5.0 mL) was added a solution of KOH (2.0 N, 5 mL). The mixture was heated in a sealed tube at 100° C. overnight then concentrated in vacuo. The residue was purified by preparative HPLC to afford 145 mg (57%) of I-38 as white solid.
Reaction SMILES: Cl.Cl[C:3]1[C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[N:6]=[CH:7][N:8]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOC(C)=O>[CH2:16]([NH:23][C:3]1[C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[N:6]=[CH:7][N:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1ncnc2c1[nH]c1ccccc12
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(CNc2ncnc3c2[nH]c2ccccc23)cc1
Reaction time: 6 h
Yield: 69 %

Procedure:
4-Chloroindolo[3,2-d]pyrimidine hydrochloride (240 mg, 1 mmol, and benzylamine (1 mL) are stirred under a dry nitrogen atmosphere at 150 C. for 6 hours, and then concentrated under reduced pressure to give an oily soft solid which is dissolved in EtOAc (20 mL), and washed with saturated sodium bicarbonate solution (20 mL), water (3×15 mL), and brine (20 mL). The solution is dried (MgSO4) and the solvent is removed under reduced pressure. Trituration of the residue with dichloromethane, gives 4-benzylaminoindolo[3,2-d]pyrimidine (190 mg, 69%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[NH2:33][C:34]([CH3:38])([CH3:37])[C:35]#[N:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:35]([C:34]([NH:33][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)([CH3:38])[CH3:37])#[N:36]
Reactant: CC(C)(N)C#N
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 10 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 30 mg, 0.070 mmol), 2-amino-2-methylpropanenitrile-HCl (12.58 mg, 0.104 mmol) [Ingate, S. T. et al., Tetrahedron, 53:17795-17814 (1997)], HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were dissolved in DMF (1 mL). After stirring 1 h, the mixture was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 40-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to provide single enantiomer N-(2-cyanopropan-2-yl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (3.7 mg, 0.007 mmol, 10.7% yield): LCMS=498.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.19 (2 H, m), 7.49-7.70 (7 H, m), 5.13 (1 H, s), 1.71 (3 H, s), 1.67 (3 H, s); HPLC peak RT=2.9 min (Method E).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23](=[O:43])[CH:24]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=2)C(OC)=O)[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(O)(O)O>>[CH2:16]([O:15][C:13]1[CH:12]=[C:11]([C:23](=[O:43])[CH2:24][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:34]=2)[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)C(C(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1)c1ccc(OCc2ccccc2)cc1
Agent: OB(O)O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
34.8 g of crude methyl 3-(3,5-dibenzyloxy-phenyl)-2-(4-benzyloxyphenyl)-3-oxopropionate prepared according to Example 2 (0.0608 mol) and 7.51 g of boric acid (0.121 mol) are introduced into a 250 ml round-bottomed flask. The medium is brought to 100° C. for 1 h, 120° C. for 1 h, 140° C. for 1 h and then 150-55° C. for 5 h while distilling off light products. The mixture is cooled to 60° C. and an aqueous solution of 8.5 g of sodium hydroxide pellets dissolved in 175 ml of water is added. The mixture is then brought to reflux for 3 h and brought back to 60° C., 250 ml of toluene are added, separation by settling is carried out, the organic phase is recovered and washed with 75 ml of water and then the toluene phase is concentrated on a rotary evaporator. 19.4 g of crude 1-(3,5-dibenzyloxyphenyl)-2-(4-benzyloxyphenyl)ethanone are recovered.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH2:21])[CH:9]=1)([CH3:3])[CH3:2].Cl[C:25]([O:27][CH3:28])=[O:26].C(N(CC)C(C)C)(C)C.O>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:11]=2[CH2:20][NH:21][C:25](=[O:26])[O:27][CH3:28])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)NCc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 25 °C

Procedure:
To a solution of 1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine (166 mg, 0.51 mmol) and methyl chloroformate (107 μL, 1.39 mmol) in CH2Cl2 (5 mL) was added N,N-diisopropylethylamine (485 μL, 2.79 mmol). The reaction was stirred at room temperature for twenty minutes and then was poured into H2O (50 mL). The mixture was extracted with EtOAc (100 mL), and the organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 2% to 20% EtOAc/hexanes afforded methyl {[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.29 (15% EtOAc/hexanes). LCMS=382.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.68 (s, 1H), 7.57 (d, J=8.0Hz, 1H), 7.31 (d, J=8.0Hz, 1H), 7.25 (dd, J=8.5, 2.5 Hz, 1H), 6.97 (d, J=2.5 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 4.17 (m, 2H), 3.75 (s, 3H), 3.65 (s, 3H), 2.89 (m, 1H), 1.25 (d, J=7.0 Hz, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.Br[CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>CN(C=O)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([CH2:7][N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)=[CH:9][CH:10]=1)#[N:13]
Reactant: c1cc[nH]c1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2cccc2)cc1

Procedure:
Using pyrrole and 4-(bromomethyl)benzonitrile and the method of Example 83A, except using DMF as the solvent, provided N-(4-cyanobenzyl)pyrrole. 1H NMR (CDCl3) δ7.62 (m, 2H), 7.14 (m, 2H), 6.69 (m, 2H), 6.24 (m, 2H), 5.15 (s, 2H). MS (DCl/NH3) (M+H)+ 183 and (M+H+NH3)+ 200.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9](O)[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.O>[N:1]([CH2:4][C@@H:5]1[C@@H:9]([N:22]2[C:18](=[O:28])[C:19]3[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:21]2=[O:23])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1CN=[N+]=[N-]
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](N2C(=O)c3ccccc3C2=O)[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a solution of the compound 5 (658 mg) in tetrahydrofuran (15 mL), phthalimide (600 mg), triphenylphosphine (1070 mg) and 2.2 mol/L of a solution (2.0 mL) of diethyl azodicarboxylate in toluene were added at 0° C. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was added water and extracted with ethyl acetate. The extract was washed with aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→4:1) to obtain the title compound (508 mg) having the following physical properties.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][CH:6]([F:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15](O)=[O:16])=[CH:10][CH:9]=1>>[F:5][CH:6]([F:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15]([Cl:3])=[O:16])=[CH:10][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)[C@H](C(=O)O)c1ccc(OC(F)F)cc1
Product: CC(C)[C@H](C(=O)Cl)c1ccc(OC(F)F)cc1
Yield: 95.2 %

Procedure:
Add 32.8 g (0.275 mole) of thionyl chloride to 42 g (0.17 mole) of the obtained (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyric acid, heat with stirring under reflux for 2 hours, and then distill off the unreacted thionyl chloride to give 42.5 g of (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyryl chloride.
Reaction SMILES: [C:1]1([S:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:20]>O>[C:1]1([S:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O-:14])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:20]
Reactant: O=C(O)c1ccccc1OCSc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1ccccc1OCSc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
126 g (0.48 mol) of 2-(phenylthio-methoxy)-benzoic acid were dissolved in 500 ml of water, with addition of 19.18 g (0.48 mol) of sodium hydroxide. The reaction mixture was stirred at room temperature for 30 minutes and then evaporated completely at 60° C. under reduced pressure. The colourless pulverulent product which remained was dried at 100° C. under reduced pressure for 16 hours. 133.5 g (98.6% of theory) of sodium 2-(phenylthio-methoxy)-benzoate of melting point 204°-207° C. were obtained in this manner.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH:5][CH:6]=[C:7]1[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]1=[O:16].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:28]([O:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH:5][CH:6]=[C:7]1[C:12](=[O:13])[O:11][C:10]([CH3:14])([CH3:15])[O:9][C:8]1=[O:16])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OCc1ccccc1
Temperature: 65 °C
Yield: 83.2 %

Procedure:
A mixture of 5-((3-hydroxy-4-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (20 g, 69 mmol), potassium carbonate (12.4 g, 90 mmol) and benzyl bromide (15.4 g, 90 mmol) in DMF (100 ml) was heated at 65° C. for 2 hours. Two thirds of the DMF was removed from the mixture by evaporation, the mixture was diluted with water, adjusted to pH4 with 5M hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water and then brine, dried (MgSO4) and the volatiles removed by evaporation. The solid residue was triturated with ether, and collected by filtration and dried under vacuum to give 5-((3-benzyloxy-4-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (22 g, 83%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[OH:12].[CH3:13][CH:14](O)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[C:3]([O:12][CH:14]([CH3:15])[CH3:13])=[CH:4][C:5]([F:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(O)cc1F
Reactant: CC(C)O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Oc1cc(F)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 22 h
Yield: 43.7 %

Procedure:
A mixture of 2-chloro-5-fluoro-4-nitrophenol (287 mg, 1.5 mmol), propan-2-ol (90 mg, 1.5 mmol), diphenyl-2-pyridylphosphine (592 mg, 2.25 mmol) and di-tert-butyl azodicarboxylate (518 mg, 2.25 mmol) in tetrahydrofuran (10 ml) was stirred at room temperature under argon for 22 hrs. The mixture was treated with 1M HCl/diethyl ether (10 ml) and stirred at room temperature for 1 hr, then concentrated under vacuum and the residue dissolved in diethyl ether (10 ml), treated with 5M HCl acid (10 ml) and stirred for 30 mins. The organic layer was separated, washed with 5M HCl acid (10 ml), then 10% Na2CO3 solution (2×10 ml), dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with 5-70% ethyl acetate/60-80 petrol ether to afford the title compound as a yellow solid (153 mg, 43%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]1([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[C:29]([F:46])=[C:30](/[CH:34]=[C:35](/[C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=2[F:45])\[C:36]#[N:37])[CH:31]=[CH:32][CH:33]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:34]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[C:29]=2[F:46])[C:35]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=2[F:45])([C:36]#[N:37])[CH:9]([CH2:10][C:11]2([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]2)[NH:8]1)=[O:26])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)C/N=C/CC1(C(C)(C)O[SiH2]C(C)(C)C)CC=CCC1
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C1NC(CC2(C(C)(C)O[SiH2]C(C)(C)C)CC=CCC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 53.7 %

Procedure:
In a manner similar to the method described in Example 100b, [2-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enyl]-eth-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 117a (3.5 g, 9 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.3 g, 7 mmol) prepared in Example 52a, AgF (1.4 g, 11 mmol), and triethylamine (2.6 mL, 19 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (9 ml) in tert-butanol (10 mL) at 100° C. for 2 h to give rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enylmethyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (2.6 g, 51%).
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[C:9]([Br:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:22])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CCOC(C)=O>[Br:10][C:9]1[CH:8]=[C:7]([Br:11])[CH:6]=[C:5]2[C:4]=1[C:3](=[O:23])[C:14]([CH3:15])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:13](=[O:22])[NH:12]2
Reactant: COC(=O)c1c(Br)cc(Br)cc1NC(=O)C(C)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)C(=O)Nc2cc(Br)cc(Br)c2C1=O
Yield: 64.6 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 4,6-dibromo-2-(2-phenyl-propionyl amino)-benzoic acid methyl ester (1.00 g, 2.27 mmol) and LiHMDS (6.81 mmol, 1M THF solution). After normal workup, the pure objective compound (0.60 g, 65%) was obtained as yellow solid by a flash column chromatography (Hex:EtOAc=4:1): 1H NMR (200 MHz, CDCl3) δ 1.64 (s, 3H, CH3), 7.04 (d, J=1.6 Hz, 1H, ArH), 7.17-7.37 (m, 5H, ArH), 7.46 (d, J=1.6 Hz, 1H, ArH), 9.35 (br s, 1H, NH); m.p. 202-203° C.; MS(EI) m/e 409 [M+], 288, 132, 104; HRMS m/e cacld. for C16H11Br2NO2 406.9157, found 406.9161.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@H:19]3[C:24](O)=[O:25])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:48]([O:52][C:53](=[O:65])[NH:54][CH2:55][C:56]1[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][C:57]=1[CH2:63][NH2:64])([CH3:51])([CH3:50])[CH3:49]>C(Cl)Cl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@H:19]3[C:24](=[O:25])[NH:64][CH2:63][C:57]3[CH:58]=[C:59]([Cl:62])[CH:60]=[CH:61][C:56]=3[CH2:55][NH:54][C:53]([O:52][C:48]([CH3:51])([CH3:49])[CH3:50])=[O:65])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN
Reactant: O=C(O)[C@@H]1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (S)-4-[{(9H-Fluoren-9-yl)methoxy}carbonyl]morpholine-3-carboxylic acid (2.96 g, 8.39 mmol, 1.0 eq) in CH2Cl2 (10 mL), EDCI (3.20 g, 16.68 mmol, 2 eq.), HOBT (2.20 g, 16.28 mmol) and tert-butyl[2-(aminomethyl)-4-chlorobenzyl]carbamate (2.20 g, 8.39 mmol) were added at 0° C. The resulting mixture was stirred for 5 h at room temperature. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed sequentially with saturated NaHCO3 solution (20 mL) and 0.5 M aqueous HCl (20 mL). The organic layer was separated, washed with brine solution (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; eluent: 40% EtOAc/hexanes) to afford the title compound as pale yellow semi solid (4.10 g)
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:7]4=[N:6][C:5]=3[CH3:16])[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: Cc1ccc2nc(C)c(CCCl)c(=O)n2c1
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(C)c(CCN3CCN(c4cccc(Cl)c4)CC3)c(=O)n2c1
Yield: 40.7 %

Procedure:
A mixture of 2.2 g of 3-(2-chloroethyl)-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 4.5 g of 1-(m-chlorophenyl)piperazine and 25 ml of toluene was refluxed for 30 hours. After completion of the reaction, the reaction mixture was then treated in the same manner as in Example 10. The crude crystals thus obtained were recrystallized from a mixture of ethanol and n-hexane to give 1.5 g of the desired compound as pale yellow powders, m.p. 127° - 128°C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.I[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:13][CH:14]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(-n2c(C)cc3ccccc32)cc1
Yield: 73.7 %

Procedure:
1-(4-Methoxyphenyl)-2-methyl-1H-indole was synthesized according to Buchwald et al. J. Am. Chem. Soc. 2001, 123, 7727. 2-Methylindole (157 mg, 1.2 mmol), 4-iodoanisole (234 mg, 1 mmol), copper(I) iodide (2 mg, 0.01 mmol), trans-1,2-diaminocyclohexane (11.4 mg, 0.1 mmol), and potassium phosphate tribasic (446 mg, 2.1 mmol) were stirred in dioxane (1 mL) at 90° C. overnight. The reaction mixture was filtered through a pad of silica and washed with ethyl acetate. SiO2 chromatography with 5-20% ethyl acetate/hexanes gave 175 mg of the desired product (74% yield). LC-MS (C16H15NO calc'd 237) m/z 238 (M+H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][C:14]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[CH2:15][N:16]=2)=[CH:8][C:7]=1[Br:35])(=O)C.C[O-].[Na+]>CO.C(OC)(C)(C)C>[F:34][C:31]([F:32])([F:33])[C:23]1[CH:22]=[C:21]([C:14]2([C:17]([F:18])([F:19])[F:20])[CH2:13][C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[C:7]([Br:35])[CH:8]=3)=[N:16][CH2:15]2)[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[N:24]=1
Reactant: CC(=O)OCc1ccc(C2=NCC(c3cc(C(F)(F)F)nc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Product: OCc1ccc(C2=NCC(c3cc(C(F)(F)F)nc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Br

Procedure:
4-{3-[2,6-bis(trifluoromethyl)pyridin-4-yl]-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl}-2-bromobenzyl acetate (0.5 g) and Sodium methoxide (0.005 g) in MeOH (10 ml) were stirred at room temperature for 30 minutes. The mixture was diluted with t-BuOMe, and washed with brine, and the organic layer was dried over MgSO4. After the solvent was evaporated under reduced pressure, the targeted product was obtained (0.4 g).
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28](C)[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].[CH3:32][O:33][C@H]1CC[C@H](N)CC1.C1(CCBr)C=CC=CC=1>C(OC(=O)C)C>[CH3:32][O:33][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:16]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CO[C@H]1CC[C@H](N)CC1
Agent: BrCCc1ccccc1
Solvent: CCOC(C)=O
Product: CO[C@H]1CC[C@H](N(CCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using trans-4-methoxy-cyclohexylamine (prepared as described in J. Med. Chem. 1977, 20, 279-290), 2-phenylethylbromide and 2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.