Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH:16]1([C@@:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:24]2[N:28]=[CH:27][NH:26][N:25]=2)[OH:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][N:26]2[CH:27]=[N:28][C:24]([C@:22]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)([OH:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:25]2)[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: O[C@](c1ccccc1)(c1nc[nH]n1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2cnc([C@](O)(c3ccccc3)C3CCCCC3)n2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
Tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (6.75 g, 24.2 mmol) was dissolved in DMF (62 ml) and (R)-cyclohexyl(phenyl)1H-1,2,4-triazol-3-ylmethanol (Preparation 2, 5.2 g, 20 mmol) added, followed by potassium carbonate (5.58 g, 40.4 mmol). After stirring at 70° C. for 18 hours the solvent was removed in vacuo, and the residue partitioned between ethyl acetate (150 ml) and water (150 mL). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate:heptane, (1:4 to 1:1, by volume) to furnish the title compound as a white foam, in 51% yield, 4.7 g (contains 10% of the other riazole regio-isomer).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24]2)=[N:21][CH:22]=1.[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([O:52][CH3:53])[C:38]=1[OH:54]>>[NH2:28][CH:25]1[CH2:26][CH2:27][N:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:41]5[CH:40]=[C:39]([O:52][CH3:53])[C:38]([OH:54])=[C:37]([Cl:36])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12](=[O:15])[CH2:13][CH3:14])=[CH:18][CH:19]=2)[CH2:24]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(OC)c3)cc2c1Nc1ccc(N2CCC(N)C2)nc1
Yield: 25.7 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-propionylquinolin-4-ylamino) pyridin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (80 mg, 0.28 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (24 mg, 27% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.28 (s, 1H), 8.29-8.23 (m, 2H), 8.06-7.98 (m, 2H), 7.78 (dd, J=9.1, 2.7 Hz, 1H), 7.02 (d, J=2.2 Hz, 1H), 6.92 (d, J=9.1 Hz, 1H), 6.70 (d, J=2.2 Hz, 1H), 4.14-4.06 (m, 1H), 4.04-3.96 (m, 1H), 3.91 (s, 3H), 3.87-3.77 (m, 1H), 3.75-3.66 (m, 2H), 3.23 (q, J=7.1 Hz, 2H), 2.62-2.51 (m, 1H), 2.32-2.22 (m, 1H), 1.27 (t, J=7.1 Hz, 3H); ESI MS m/z 518 [C28H28ClN5O3+H]+; HPLC 98.5% (AUC), tR=9.79 min.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[CH2:6][CH2:5][C:4]=2[CH:3]=1.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C([O-])(=O)C.[K+]>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)CCc1cc(Br)ccc1-2
Agent: CC(=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Brc1ccc2c(ccc3cc(Br)ccc32)c1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
The mixture of 2,7-dibromo-9,10-dihydro-phenanthrene (2.4 g, 7.1 mmol), NBS (1.4 g, 7.8 mmol), and benzoyl peroxide (0.2 g) in carbon tetrachloride (300 ml) was refluxed for 2 hours. Potassium acetate (3.6 g) and acetic acid (3.2 ml) were added, and the refluxing was continued for additional 2 hours. The mixture was cooled and diluted with EtOAc. The organic phase was washed with water, saturated sodium bicarbonate, and brine, and was dried with sodium sulfate. Concentration gave 2,7-dibromo-phenanthrene (2.3 g).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N(OC(C)(C)C)=O.C(I)[I:22]>>[I:22][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1cc(CO)cc(C(F)(F)F)c1
Reactant: ICI
Agent: CC(C)(C)ON=O
Product: OCc1cc(I)cc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
[3-amino-5-(trifluoromethyl)phenyl]methanol (500 mg, 5.2 mmol) was suspended in CH2I2 (5 mL) and t-butyl nitrite (622 μL, 5.2 mmol) was added dropwise by syringe. The reaction was heated slowly to 100° C. and was maintained at this temperature for 30 minutes. The reaction was then cooled to room temperature, diluted with hexanes (50 mL), loaded on a silica gel column, and purified with 100% hexanes to 25% EtOAc/hexanes to afford [3-iodo-5-(trifluoromethyl)phenyl]methanol. Rf=0.19 (15% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 7.91 (s, 1H), 7.87 (s, 1H), 7.59 (s, 1H), 4.73 (d, J=4.9 Hz, 2H), 1.86 (t, J=5.6 Hz, 1H).
Reaction SMILES: [CH:1]1([CH2:5][CH:6](C(O)=O)[C:7]([OH:9])=[O:8])[CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.CO>[CH:1]1([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCC1)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=C(O)CCC1CCC1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
2-Cyclobutylmethyl-malonic acid (1.20 g, 6.9 mmol) was heated at 195° C. for 2 h. After this time, the resulting brown solution was cooled to 25° C. and diluted with a 90/10 methylene chloride/methanol solution (50 mL). The organics were then washed with a saturated aqueous sodium chloride solution, concentrated in vacuo and azeotroped with acetonitrile (2×10 mL) to afford 3-cyclobutyl-propionic acid (770 mg, 85%) as brown oil. The material was used without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:67][NH:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>ClCCl>[CH2:69]([N:68]([CH3:67])[C:19](=[O:21])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12]2)[CH:17]=1)[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1
Reactant: O=C(O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Reactant: CNCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccccc1)C(=O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
The compound (0.10 g) prepared in step (c) was dissolved in dichloromethane (2 ml). A BOP reagent (0.10 g) and diisopropylethylamine (0.052 ml) were added to the solution. The mixture was stirred at room temperature for 30 min. N-Methylbenzylamine (0.039 ml) was then added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=1:1) to give 0.072 g (57.3%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:20][NH2:21].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([NH:21][CH2:20][C:19]1[CH:18]=[C:17]([F:16])[CH:24]=[C:23]([F:25])[CH:22]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)O
Reactant: NCc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)C(=O)NCc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a solution of 2.92 g (20 mmol) methyl-malonic acid monoethyl ester in 100 ml of tetrahydrofuran 2.86 g (20 mmol) of 3,5-difluorobenzylamine, 3.83 g (20 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 2.70 g (20 mmol) of 1-hydroxybenzotrizole hydrate and 2.58 g (20 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. After concentration in vacuo 0.5 N HCl (50 ml) was added and the mixture was extracted with dichloromethane (three times 50 ml). The combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution, dried (MgSO4) and evaporated on the rotary evaporator. The residue was purified by flash chromatography (hexane/ethyl acetate=3:1) to yield 4.29 g (79%) of the tide compound as white crystalline solid.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:7][S:8]([C:11]1[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14])(=[O:10])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([NH:7][S:8]([C:11]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])(=[O:9])=[O:10])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)c1cc(C(=O)O)ccc1C(=O)O

Procedure:
At 50° C., 45.0 g (1.13 mol) of sodium hydroxide in 600 ml of water were added dropwise to a solution of 106.0 g (0.32 mol) of dimethyl tert-butylsulfamoylterephthalate in 1600 ml of methanol. The mixture was stirred at reflux temperature for 2 h and evaporated, the residue was taken up in approximately 500 ml of water and a pH of 1 was established using conc. hydrochloric acid. The precipitated solid was filtered off with suction and dried. This gave 87.4 g (90% of theory) of tert-butylsulfamoylterephthalic acid of m.p. 210-213° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[O:11])=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: Nc1ccc(Br)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Br)cc1)Nc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
3,4-Difluorophenyl isocyanate (0.74 g, 4.8 mmol) was added to a solution of 4-bromo aniline (0.75 g, 4.36 mmol) in THF (20 mL) and stirred at room temperature for 2 hr. The solvent was removed under reduced pressure and the residue was triturated with chloroform (60 mL) to afford title compound (0.6 g, 42%) as solid. 1H NMR (300 MHz, DMSO-d6): δ 8.9 (s, 1H), 8.87 (s, 1H), 7.64 (m, 1H), 7.47-7.41 (m, 4H), 7.39 (m, 1H), 7.2 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:14])(=[O:13])[NH:9][CH:10]2[CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=O)=[C:23]([O:31][CH3:32])[CH:22]=2)[N:16]=1.[F:33][C:34]([F:43])([F:42])[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:13])(=[O:14])[NH:9][CH:10]2[CH2:11][CH2:12]2)=[CH:4][C:3]=1[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[C:35]([C:34]([F:33])([F:42])[F:43])[CH:36]=3)=[O:27])=[C:23]([O:31][CH3:32])[CH:22]=2)[N:16]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(S(=O)(=O)NC4CC4)ccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3cc(S(=O)(=O)NC4CC4)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-5-(N-cyclopropylsulfamoyl) phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenz oate (Intermediate-40, 0.040 g, 0.08 mmol), 3-(trifluoromethyl)aniline (0.020 g, 0.12 mmol), trimethyl aluminium (2M solution in toluene) (1 ml) and dry toluene (5.0 mL) to afford 0.015 g of crude product, which was purified by washing with methanol:DCM:DEE to afford 0.015 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 0.42 (s, 2H), 0.54 (d, J=5.4 Hz, 2H), 2.20 (m, 1H), 3.96 (s, 3H), 7.45 (d, J=7.5 Hz, 1H), 7.61 (t, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.80-7.84 (m, 211), 7.96 (s, 3H), 8.18 (m, 211), 8.26 (s, 1H), 10.40 (s, 1H), 12.88 (br s, 1H); MS (m/z): 606.13 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][S:5][C:6]=1[NH:7][C@H:8]([C:13]([NH:15][CH2:16][C:17]#[N:18])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:17]([CH2:16][NH:15][C:13](=[O:14])[C@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH:7][C:6]1[S:5][N:4]=[CH:3][C:2]=1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:29]1[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]1)#[N:18]
Reactant: CC(C)C[C@H](Nc1sncc1Br)C(=O)NCC#N
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](Nc1sncc1-c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)C(=O)NCC#N
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A mixture of N2-(4-bromoisothiazol-5-yl)-N1-(cyanomethyl)leucinamide (91 mg, 0.27 mmol), 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenylboronic acid (100 mg, 0.33 mmol, prepared as described in Example 1), PdCl2(dppf) (5 mg, 0.006 mmol) and 2.0 M Na2CO3 aqueous solution (0.17 mL, 0.34 mmol) were heated to 85° C. in N,N-dimethylformamide (0.80 mL) under a nitrogen atmosphere for a total of 8 h. During this period additional catalyst (5 mg) was introduced at the 2 h, 4 h and 6 h time points. The reaction mixture was then cooled to rt, diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with saturated sodium chloride solution, dried (Na2SO4) and concentrated. Flash chromatography of the residue on silica eluting with a mixture of acetone and benzene (1:4) afforded 63 mg of N1-(cyanomethyl)-N2-[4-(4-(tert-butoxycarbonyl)piperazin-1-ylphenyl)isothiazol-5-yl]leucinamide as a faint-tan foam.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:3]=1.[C:20]([O:23][CH2:24][CH:25]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:27]I)(=[O:22])[CH3:21]>>[C:20]([O:23][CH2:24][CH:25]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:27][N:6]1[C:5]2[C:9](=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:8]=[CH:7]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OCC(CCI)COC(C)=O
Reactant: Cc1ccc(CSc2nc(N)nc3nc[nH]c23)cc1
Product: CC(=O)OCC(CCn1cnc2nc(N)nc(SCc3ccc(C)cc3)c21)COC(C)=O
Yield: 10 %

Procedure:
Using the previously described procedure 2-amino-6- [(4-methylphenyl)methylthio]purine (25 g) and 2-acetoxymethyl-4-iodobut-1-yl acetate (29 g) gave the title compound 33.3 g (79%) m.p. 102°-103°, and 4.2 g (9.9%) of 7-(4-acetoxy-3-acetoxymethylbut-1-yl)-2- amino-6-[(4-methylphenyl)methylthio]purine
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([NH:18][NH:19][C:20](=O)[C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=2)=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33].O>O1CCCC1>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[S:33][C:20]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=3)=[N:19][N:18]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCCCOc1ccc(CCC(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOc1ccc(CCc2nnc(-c3ccc(C(=O)OC)cc3)s2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 126.7 %

Procedure:
A suspension of 1-[3-(4-n-hexyloxyphenyl)propanoyl]-2-(4-methoxycarbonylbenzoyl)hydrazine (1.0 g) and diphosphorus pentasulfide (730 mg) in tetrahydrofuran (20 ml) was stirred for 1 hour at 60° C. To a reaction mixture was added water and the mixture was stirred for 1 hour at room temperature. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give methyl 4-[5-[2-(4-n-hexyloxyphenyl)ethyl]-1,3,4-thiadiazol-2-yl]benzoate (883 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])[CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:27])[CH3:26]
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cccc(OCC(F)(F)F)c1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1nccc(C(=O)NC(C)c2cccc(OCC(F)(F)F)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pyrimidine-4-carboxamide (15 mg, 0.04 mmol, Step-1, single enantiomer) and acetyl chloride (10 mg, 0.13 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([F:16])[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1.CCN(CC)CC.Cl>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([F:16])[CH:12]=[C:13]([CH:23]=[CH:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1ccc(C=Cc2cc(F)cc(OCc3ccccc3)c2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 90.9 %

Procedure:
A mixture of 5-benzyloxy-3-fluorophenyl Bromide (2.81 g, 10 mmol), Pd(OAc)2 (0.067 g, 0.3 mmol), tri-o-tolylphosphine (0.18 g, 0.6 mmol), 4-fluorostyrene (1.53 g, 12.5 mmol), and Et3N (1.26 g, 12.5 mmol) in 20 ml dry DMF was stirred at 100° C. for 24 hours under N2. The dark mixture was distributed between EtOAc and 1N HCl. The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered, and evaporated. After flash column, the desired product (2.93 g, 91%) was obtained. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.49-7.34 (m, 7H), 7.08-6.81 (m, 6H), 6.60 (dt, 1H), 5.08 (s, 2H); 19F NMR (CDCl3, 282 MHz) δ-31666.54 (t), −32136.54 (t). HRMS (EI+) found 322.1169 M+, calcd 322.1169 for C21H16F2O.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.Cl.[CH:15]1([C:18]2[S:22][C:21]([NH:23][C:24](=[O:30])[CH:25]([NH2:29])[CH2:26][CH2:27][CH3:28])=[N:20][N:19]=2)[CH2:17][CH2:16]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[CH:15]1([C:18]2[S:22][C:21]([NH:23][C:24](=[O:30])[C@@H:25]([NH:29][CH:7]3[CH2:6][CH2:5][C:4]4[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=4)[CH2:8]3)[CH2:26][CH2:27][CH3:28])=[N:20][N:19]=2)[CH2:16][CH2:17]1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCCC(N)C(=O)Nc1nnc(C2CC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1nnc(C2CC2)s1
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
A mixture of 6,8-difluoro-3,4-dihydro-1H-naphthalen-2-one (182 mg, 1.0 mmol), 2-amino-pentanoic acid (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide HCl (277 mg, 1.0 mmol) in methylene chloride (25 mL) was treated with triethyl amine (0.14 mL), then acetic acid (0.27 mL) and sodium sulfate. After stirring for 15 min, 95% pure sodium triacetoxy borohydride (424 mg, 2.0 mmol) was added and the resulting mixture was stirred at rt overnight. The mixture was quenched with dilute water and extracted with methylene chloride. The organic layer was washed with dilute sodium bicarbonate to pH 8, separated, dried and concentrated to give 306 mg of the title compound as a yellow glass foam, LC-MS, RT=1.9 min, M+1=407.0. The glass foam was purified by HPLC to give the trifluoroacetic acid salt of the title compound as a beige solid, LC-MS, RT=2.1 min, M+1=407.0.
Reaction SMILES: [CH3:1][N:2]1[C:15]2([CH2:17][CH2:16]2)[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[C:15]2([CH2:17][CH2:16]2)[CH2:14][C:5]2[N:6]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C1(CC1)C3
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CC2(CC2)N(C)C1

Procedure:
The title compound is prepared from a mixture of 2′,8′-dimethyl-1′,2′,4′,5′-tetrahydrospiro[cyclopropane-1,3′-pyrido[4,3-b]indole], 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[CH:8]1([Mg]Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH4+].[Cl-]>C1COCC1.CCOCC.C(OCC)(=O)C>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Br[Mg]C1CCCCC1
Reactant: BrCCCCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: BrCCCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 1,5-dibromopentane (16 gm, 69.97 mmol) in THF (20 ml) and a solution of (Li2CuCl4 in ether, 14 ml) under nitrogen at 5-10° C. was stirred for 25 minutes and then cyclohexyl magnesium bromide (10 gm, 69.97 mmol) was added dropwise over 30 minutes. The reaction was stirred at 0° C. for another 1 h, then at room temperature for 12 hr. The reaction mixture was cooled to 0° C., saturated with NH4Cl solution (20 ml), diluted with ethyl acetate (100 ml) and the combined organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography using hexane as an eluent. The pure product was an oily liquid (12.84 gm). 1H NMR (CDCl3): 0.8 (t, 2H, J=10.2 Hz), 1.00-1.38 (m, 9H), 1.52-168 (m, 6H), 1.70-1.80 (m, 2H), 3.38 (t, 2H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([C:13]([O:15]CC)=[O:14])[C:5]([F:18])=[C:4]([F:19])[C:3]=1[CH:20](C(OCC)=O)[C:21]([O:23]CC)=[O:22].Cl>C(O)(=O)C>[F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:13]([OH:15])=[O:14])[C:5]([F:18])=[C:4]([F:19])[C:3]=1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1c(F)c(F)c(C(C(=O)OCC)C(=O)OCC)c(F)c1C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1c(F)c(F)c(C(=O)O)c(C(=O)O)c1F
Yield: 84.3 %

Procedure:
To 50 g of diethyl 2-(2,5,6-trifluoro-3,4-bis(ethoxycarbonyl)phenyl)malonate were added 60 ml of conc. hydrochloric acid and 60 ml of acetic acid, and the mixture was refluxed overnight. The ethyl acetate in the reaction solution was distilled off under reduced pressure, and the solution was refluxed for 2 days. The acid in the reaction solution was distilled off, and hexane was added to the residue. The solid content was collected by filtration and dried to obtain 27 g of the title compound in crude form.