Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)=O)([O-:3])=[O:2].C([SiH](CC)CC)C.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[N+:1]([CH2:4][CH2:5][CH2:6][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCc1ccc(C(=O)CC[N+](=O)[O-])cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCc1ccc(CCC[N+](=O)[O-])cc1
Temperature: -5 °C
Yield: 200.6 %

Procedure:
3-nitro-1-(4-octylphenyl)propan-1-one (20 g) and dichloromethane (100 mL) are charged into a round bottom flask at 25-30° C. and stirred. The mixture is cooled to −10° C. to 0° C. and triethylsilane (19.9 g) is added. A solution of titanium tetrachloride (19.57 g) in dichloromethane (100 mL) is added over a period of 15 minutes and the obtained reaction mixture is maintained at −10 to 0° C. for 5 hours. Water (200 mL) precooled to 0-10° C. is slowly added to the reaction mixture over a period of 20 minutes and the temperature is allowed to raise to 25-30° C. The reaction mixture is stirred for about 1 hour, organic layer is separated, washed with 5% sodium bicarbonate solution (100 mL), followed by 20% brine solution (100 mL), the organic layer is concentrated under vacuum at 45° C. to obtain 38.2 g of crude 1-(3-nitropropyl)-4-octylbenzene. Toluene (200 mL) and crude 1-(3-nitropropyl)-4-octylbenzene (38.2 g) are charged into the round bottom flask at 25-30° C. and stirred. Potassium carbonate (18.96 g) and paraformaldehyde (7.21 g) are charged and the reaction mixture is stirred at the same temperature for about 6 hours. The reaction mixture is filtered and washed with toluene (40 mL). The obtained filtrate, water (200 mL) and ethyl acetate (60 mL) are charged into a round bottom flask and stirred for 2 hours. The organic layer is separated, washed with 5% hydrochloric acid solution (100 mL), 5% sodium bicarbonate solution (100 mL) and followed by 5% brine solution (100 mL). The resultant organic layer is concentrated under vacuum at below 45° C. n-Hexane (100 mL) is added to the obtained compound and stirred. The obtained mixture is cooled to 0 to 5° C., maintained at the same temperature for about 60 minutes, filtered and washed with n-hexane (20 mL). The obtained wet compound and toluene (80 mL) are charged into a round bottom flask, heated to 40-45° C. and maintained at the same temperature for about 15 minutes. The reaction mixture is cooled to 0-5° C., maintained for about 45 minutes, filtered and washed the product with toluene (40 mL) precooled to 0-5° C. and the product obtained is dried under vacuum at 25-30° C. to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:10]([CH2:12]O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS([Cl:31])(=O)=O>ClCCl>[Cl:31][CH2:12][C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1nc(-c2ccccc2)oc1-c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1nc(-c2ccccc2)oc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of (2-phenyl-5-(pyridin-3-yl)oxazol-4-yl)methanol (210 mg, 832 μmol) and triethylamine (253 mg, 348 μL, 2.5 mmol) in dichloromethane (4 mL) was added at 0-5° C. methanesulfonyl chloride (191 mg, 130 μL, 1.66 mmol). The ice bath was removed after 10 min and the reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (1×25 mL) and brine (1×25 mL), dried over MgSO4 and concentrated in vacuo to give the product as light brown solid (197 mg, 728 μmol, 87.4%) which was used without further purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=O)=[CH:29]3)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([C:12](=[CH:35][C:30]4[NH:31][C:32]5[C:28]([CH:29]=4)=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:34][CH:33]=5)[C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2ccc(-c3ccc(F)cc3)cc2N1
Product: O=C1Nc2cc(-c3ccc(F)cc3)ccc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
6-(4-Fluoro-phenyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[OH:26])#[CH:19]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]#[C:18][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]2[OH:26])[CH:3]=1)=[O:17]
Reactant: C#CC1CCCCC1O
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Product: O=C(NCCCc1cccc(C#CC2CCCCC2O)c1)C(F)(F)F

Procedure:
Sonogashira coupling of bromide 3 with 2-ethynylcyclohexanol followed by flash chromatography (5-50% EtOAc/hexanes gradient), gave 2,2,2-trifluoro-N-(3-(3-((2-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamide as a yellow oil. Yield (1.2 g, 43%): 1H NMR (400 MHz, CDCl3) δ 7.18-7.28 (m, 3H), 7.06-7.30 (m, 3H), 6.33 (brs, 1H), 3.48-3.57 (m, 1H), 3.36 (app q, J=6.8 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.38-2.46 (m, 1H), 2.32 (brs, 1H), 2.02-2.10 (m, 2H), 1.91 (quint, J=7.2 Hz, 2H), 1.74-1.82 (m, 1H), 1.66-1.74 (m, 1H), 1.40-1.52 (m, 1H), 1.16-1.40 (m, 4H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1.Cl>O>[C:9]([O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: Cc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Meta-cresol (1 g, 9.0 mmol) and acetic anhydride (1.1 g, 10.8 mmol) were mixed in the presence of pyridine (3 ml) as a base at 0° C., and gradually heated to room temperature. After 30 minutes, 10˜15 ml of water is added thereto, and the mixture was neutralized by adding 1N HCl (30 ml) in three portions. The resultant mixture was extracted with organic solvent, washed, dried and purified by using column chromatography (eluent: hexane/ethyl acetate=6/1) to obtain 1.3 g (96%) of compound (3).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]=[CH:9][CH2:8]2)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(O)=[O:20].[OH-].[Na+]>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]1[O:20][CH:9]1[CH2:8]2)(=[O:3])[CH3:2]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CC(=O)Oc1ccc2c(c1)CC=CC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)CC1OC1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.8 %

Procedure:
A solution of 15.12 g of 1,4-dihydro-6-naphthol acetate in 160 ml of dichloromethane is cooled to 0° C while 10.5 g of m-chlorobenzoic acid is added over 10 minutes. The mixture is stirred overnight at room temperature and then poured into a slurry of 100 g of ice and 50 ml of 10% aqueous sodium hydroxide. The layers are separated, the aqueous layer re-extracted with dichloromethane (two 100 ml portions), and the combined extracts are washed with water, dried, and evaporated in vacuo to give 16 g of the title compound as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:24](=O)OC(C)(C)C)[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][S:5][N:6]=1.[H-].[Na+].I[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:24]([NH:23][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:3]2[C:2]([CH3:1])=[N:6][S:5][N:4]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:22]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: Cc1nsnc1C(=NOCc1cccc(NC(=O)OC(C)(C)C)n1)c1ccccc1
Reactant: CCCCCCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCCCNc1cccc(CON=C(c2ccccc2)c2nsnc2C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a stirred solution of tert-butyl {6-[({[(4-methyl-1,2,5-thiadiazol-3-yl)(phenyl)methylene]-amino}oxy)methyl]pyridin-2-yl}carbamate (104 mg, 0.24 mmol) in dry DMF (5 mL) was added sodium hydride (60 wt.-% in mineral oil, 11 mg, 0.27 mmol). After stirring at room temperature for 15 min, 1-iodohexane (62 mg, 0.29 mmol) was added, and the mixture stirred at room temperature for 16 h. After dropwise addition of trifluoroacetic anhydride (1 mL, 13 mmol), the mixture was stirred at 50° C. for 8 h. The cooled reaction mixture was poured into sat. aq. NaHCO3 (40 mL), extracted with ethyl acetate (2×30 mL), the organic layer was washed with water, dried (MgSO4) and concentrated in vacuo. Purification on silica gel afforded N-hexyl-6-[({[(4-methyl-1,2,5-thiadiazol-3-yl)(phenyl)methylene]amino}-oxy)methyl]pyridin-2-amine as an orange oil [79 mg, yield 75%; HPLC/MS: m/z=410 (M+H); log P(HCOOH)=3.11].
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([CH3:20])[C:11]=1[CH:21]([C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[C:27]([Cl:33])[N:26]=[C:25](Cl)[C:24]=1[Cl:35])[OH:22]>CO.[C].[Pd]>[CH3:8][O:9][C:10]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([CH3:20])[C:11]=1[CH:21]([C:23]1[C:24]([Cl:35])=[CH:25][N:26]=[C:27]([Cl:33])[C:28]=1[C:29]([F:30])([F:32])[F:31])[OH:22]
Reactant: COc1cc(C)c(C(O)c2c(Cl)c(Cl)nc(Cl)c2C(F)(F)F)c(OC)c1OC
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(C)c(C(O)c2c(Cl)cnc(Cl)c2C(F)(F)F)c(OC)c1OC
Reaction time: 14 h
Yield: 24 %

Procedure:
2.7 ml (19 mmol) of triethylamine and 0.9 g of 5% palladium carbon were added to a solution having 2,3,4-trimethoxy-6-methylphenyl)(2,3,6-trichloro-5-trifluoromethyl-4-pyridyl)methanol obtained in Step (a) dissolved in 200 ml of methanol, followed by stirring under a hydrogen atmosphere for 14 hours. The mixture was subjected to filtration, 30 ml of water was added, and methanol was distilled off under reduced pressure. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 2.38 g (yield: 24%) of (2,3,4-trimethoxy-6-methylphenyl)(2,5-dichloro-3-trifluoromethyl-4-pyridyl)methanol (melting point 162 to 165° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[N:19]=[C:20]([NH:23][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[S:21][CH:22]=1
Reactant: COc1ccc(Sc2cc(C)c(-c3csc(N)n3)c(Cl)c2)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COc1ccc(Sc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(Cl)c2)cc1
Yield: 47315.8 %

Procedure:
Compound 3 was synthesized from the reaction of 3-4 (70 mg, 0.19 mmol) with DMAP (46 mg, 0.38 mmol) and isonicotinoyl chloride hydrochloride (44 mg, 0.25 mmol). The reaction provided compound 3 (42 mg, 89.9 mmol) in 47% yield: 1H NMR (500 MHz, CDCl3) δ 8.82 (d, J=6.0 Hz, 2 H), 7.70 (d, J=6.0 Hz, 2 H), 7.46 (d, J=8.8 Hz, 2 H), 6.96 (d, J=8.8 Hz, 2 H), 6.92 (s, 1 H), 6.86 (s, 1 H), 6.82 (s, 1 H), 3.86 (s, 3 H), 2.01 (s, 3 H); ESI-MS: m/z 466.1 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]1[CH2:36][C@@:34]2([CH3:35])[C@@H:30]([CH2:31][CH2:32][C@@H:33]2[OH:37])[C@@:29]2([CH:38]=[CH2:39])[C@H:20]1[C:21]1[CH:22]=[CH:23][C:24]([OH:40])=[CH:25][C:26]=1[CH2:27][CH2:28]2>>[N:1]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]2[CH2:36][C@@:34]3([CH3:35])[C@@H:30]([CH2:31][CH2:32][C@@H:33]3[OH:37])[C@@:29]3([CH:38]=[CH2:39])[C@H:20]2[C:21]2[CH:22]=[CH:23][C:24]([OH:40])=[CH:25][C:26]=2[CH2:27][CH2:28]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCCl)C[C@@]1(C)[C@H]2CC[C@@H]1O
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCN1CCCC1)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with pyrrolidine (10 equivalents) with the addition of sodium carbonate analogously to instructions 17.2, 32 mg of mixture 30b yields 33 mg of amine 33b as a colorless foam (GC-MS: m/z theor.: 451, pract.: 451).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].[Br:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:16][CH2:17][CH2:18][CH2:19][C:20]([O:1][CH2:2][CH:3]([NH:8][C:9]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:15])[CH2:4][CH:5]([CH3:7])[CH3:6])=[O:21]
Reactant: O=C(O)CCCBr
Reactant: CC(C)CC(CO)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)CC(COC(=O)CCCBr)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
tert-Butyl 1-hydroxy-4-methylpentan-2-ylcarbamate (2.00 g, 9.20 mmol) and 4-bromo-butyric acid (2.57 g, 15.38 mmol) were dissolved in CH2Cl2 (40 ml) and the mixture was cooled to 0° C. EDC (4.20 g, 21.90 mmol) and DMAP (0.27 g, 2.21 mmol) were added and the reaction was slowly warmed to room temperature and stirred overnight. Then the reaction was treated with a solution of 5% aqueous NaH2PO4 (100 ml). The organic layer was washed with a solution of 10% aqueous Na2CO3 (100 ml) and brine, dried over Na2SO4, filtered and concentrated. The obtained crude clear oil corresponding to the title compound (3.30 g) was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Clc1ccc(Cl)c(I)n1
Solvent: Cc1ccccc1
Product: Clc1ccc(Cl)c(-c2ccccn2)n1
Yield: 75.6 %

Procedure:
The mixture of 3,6-dichloro-2-iodopyridine (21 g, 77% purity, 58.8 mmol), 2-(tributylstannyl)pyridine (37 g, 80% purity, 80 mmol) in toluene (300 mL) was degassed, then Pd(PPh3)4 (730 mg) was added, the mixture was degassed again and stirred at reflux under N2 overnight. The mixture was concentrated and the residue was purified via silica gel column (petroleum ether:EtOAc=10:1˜5:1) to give title compound (10 g, 76%) as a gray solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:12]([CH2:13][CH2:14]Cl)=[C:11](Cl)[C:10]2[C:5](=[C:6]([O:17][CH3:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([CH3:28])[CH:22]=1>CC(O)C>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([N:25]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([O:17][CH3:18])[C:5]=4[N:4]=[C:3]([CH3:2])[C:12]=3[CH2:13][CH2:14]2)=[C:23]([CH3:28])[CH:22]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: COc1cccc2c(Cl)c(CCCl)c(C)nc12
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(N2CCc3c(C)nc4c(OC)cccc4c32)c(C)c1
Yield: 18.9 %

Procedure:
A mixture of 2-methyl-3-(2-chloroethyl)-4-chloro-8-methoxyquinoline hydrochloride (15.33 g, 50 mmol), 4-methoxy-2-methylaniline (9.0 ml. 70 mmol) and 2-propanol (200 ml) was heated at reflux for 2 days, then evaporated. The crude product was triturated with ether then recrystallised twice from aqueous ethanol to give the title compound (3.16g), m.p. 163°-167°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][NH:12][CH3:13].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:12]([CH3:13])[CH3:11])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(Br)cn1

Procedure:
To a solution of 5-bromopyridine-2-carboxylic acid (1.5 g, 7.4 mmol), dimethyl amine (1.3 gm, 16 mmol), diisopropylethyl amine (excess) in DMF (10 mL) was added a solution of HATU in DMF (5 mL). After stirring the reaction for 14 hours at room temperature, the solvent was removed under reduced vacuum. The residue was taken up in ethyl acetate, washed with 1 N HCl (2×), brine (2×), 1 N NaOH (2×), brine (3×), dried over MgSO4, and concentrated. The crude was product was used in subsequent steps without further purification.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][Si:5]([CH3:15])([CH3:14])[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Br>C(N(CCCC)CCCC)CCC.O>[CH3:4][Si:5]([CH3:15])([CH3:14])[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][C:1]#[N:2]
Reactant: [C-]#N
Reactant: C[Si](C)(C)c1cccc(CBr)c1
Agent: [K+]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: C[Si](C)(C)c1cccc(CC#N)c1
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of KCN (5.5 g, 84 mmol), m-trimethylsilylbenzylbromide (5.31 g, 21.8 mmol), tributylamine (0.11 g, 0.59 mmol) and water (12.5 cm3) was stirred overnight. The product was extracted with dichloromethane (3×30 cm3), the extract was filtered through a silica plug (5g) and the solvent was removed under reduced pressure. The residue was distilled to give the product (2.27 g, 55%) as a colorless liquid.
Reaction SMILES: C[Si](I)(C)C.C[O:7][C:8](=[O:54])[C@H:9]([O:23][C:24]1[C:29]([Br:30])=[CH:28][C:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]4[CH:52]=[CH:51][CH:50]=[CH:49][C:39]=4[S:40][C:41]=3[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:33][CH:32]=2)=[CH:26][C:25]=1[Br:53])[CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].C(Cl)Cl>O>[CH2:42]([C:41]1[S:40][C:39]2[CH:49]=[CH:50][CH:51]=[CH:52][C:38]=2[C:37]=1[C:34]1[CH:33]=[CH:32][C:31]([C:27]2[CH:28]=[C:29]([Br:30])[C:24]([O:23][C@H:9]([CH2:10][CH2:11][N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[C:8]([OH:54])=[O:7])=[C:25]([Br:53])[CH:26]=2)=[CH:36][CH:35]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COC(=O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Agent: C[Si](C)(C)I
Solvent: O
Solvent: ClCCl
Product: O=C(O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Temperature: 50 °C
Reaction time: 24 h
Yield: 85.3 %

Procedure:
Trimethylsilyl iodide (0.29 mL, 2.07 mmol) was added into a mixture of (2R)-2-[4′-(2-benzyl-benzo[b]-thiophen-3-yl)-3,5-dibromo-biphenyl-4-yloxy]-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (1.1 g, 1.38 mmol), and methylene chloride (10 mL). The reaction mixture was stirred at 50° C. for 24 hours. An additional 0.29 mL of trimethylsilyl iodide was added and the mixture was stirred for 48 hours, poured into water and extracted with ethyl acetate. The organic extracts were washed with aqueous sodium bisulfite and dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexanes/EtAOc 2:1) gave white solid (0.92 g, 94% yield): mp 113-115° C.; MS m/e 778 (M−H)+;
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:33]([C:34]#[N:35])=[C:32]([S:36][CH2:37][C:38]3[N:39]=[C:40]([C:43]4[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=4)[S:41][CH:42]=3)[N:31]=[C:30]([N:50]3[CH2:53][CH2:52][CH2:51]3)[C:29]=2[C:54]#[N:55])=[CH:24][CH:23]=1)=[O:17])[CH3:15])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[C:33]([C:34]#[N:35])=[C:32]([S:36][CH2:37][C:38]3[N:39]=[C:40]([C:43]4[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=4)[S:41][CH:42]=3)[N:31]=[C:30]([N:50]3[CH2:51][CH2:52][CH2:53]3)[C:29]=2[C:54]#[N:55])=[CH:26][CH:27]=1)=[O:17])[CH3:15])=[O:12]
Reactant: C[C@H](NC(=O)CCNC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)CCN)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
90 mg (0.113 mmol) of 2-{4-(2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyanopyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-beta-alanyl-L-alaninate (Example 4A) were initially charged in 3.5 ml of dichloromethane. 0.347 ml (4.502 mmol) of trifluoroacetic acid was added, and the reaction solution was then stirred at RT overnight. The reaction solution was concentrated by evaporation and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). For further purification, the product was once more purified by preparative HPLC (column material: XBridge; mobile phase: acetonitrile/0.1% aq. ammonia=65/35). This gave 51 mg (65% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:9][C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(c1cccc(F)c1)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(c1cccc(F)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
A solution of ethyl 3,3-bis(3-fluorophenyl)propionate (39.08 g, 134.8 mmol) in absolute ethanol (500 mL) was treated with 5N NaOH (500 mL) and stirred at ambient temperature for 16 hr. After this time the reaction mixture was concentrated (removal of ethanol) on a rotary evaporator and diluted with water (1 L). The aqueous mixture was washed once with diethyl ether (500 mL) and the remaining aqueous mixture acidified (pH˜1) by the addition of concentrated HCl. The aqueous phase was extracted with methylene chloride (4×250 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to afford 31.76 g (90%) of the title compound as a white solid. GC/EI-MS analysis gave a single component: Rt=6.60 min, m/z (rel. int.) 262 (M+, 13), 243 (1), 216 (40), 203 (85), 201 (54), 183 (100), 170 (11), 121 (31), 101 (43), 96 (24), and 75 (45).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH2:38]([OH:43])[CH2:39][CH2:40][CH2:41][CH3:42]>>[CH2:38]([O:43][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)[CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CCCCCO
Agent: [Li]CCCC
Product: CCCCCOc1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (30 mg, 0.06 mmol) was reacted with 2 equivalents each of n-butyl lithium and n-pentanol by the procedure described in Reference Examples 6 and 7 to afford the title compound: HPLC/MS: m/e=514 (M++1); Rt'4.48 min. 1H-NMR 400 MHz (CDCl3): δ 0.89-0.91 (t, 3H), 1.26-1.40 (m, 4H), 1.69-1.76 (m, 2H), 4.19-4.22 (t, 2H), 7.15-7.28 (m, 6H), 7.35 (d, J=2 Hz, 1H), 7.40-7.43 (m, 1H), 7.58-7.61 (m, 1H), 8.52-8.55 (m, 2H).