Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16](=[O:22])[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C@H:10]([CH3:15])[C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16](=[O:22])[N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)[C@H:10]([CH3:15])[C:11]([OH:13])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](C(=O)O)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of the product from Step A (0.404 g, 1.29 mmol) in THF (30 mL) and water (10 mL) was added lithium hydroxide (96.0 mg, 4.0 mmol). After stirring at room temperature for 3 h, the reaction was quenched with 1N hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo to give the desired product.
Reaction SMILES: C([C:4]([Cl:23])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([O:20][CH2:21][CH3:22])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)C.[OH-].[Ba+2].[OH-].Cl>C(O)C>[Cl:23][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([O:20][CH2:21][CH3:22])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(Cl)(Cc1ccc(OCC)c(OCC)c1)C(C)=O
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(Cl)Cc1ccc(OCC)c(OCC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
In 150 ml of ethanol is dissolved 14.0 g of the above ethyl 2-acetyl-2-chloro-3-(3,4-diethoxyphenyl)propionate, followed by addition of 3.5 g of anhydrous barium hydroxide. The mixture is stirred under ice cooling for 30 minutes, then poured into 300 g ice-40 ml 6N-HCl, and extracted with ether. The ethereal layer is washed with water, dried (over MgSO4) and distilled to remove the ether. The above procedure provides 12.0 g (97.6%) of ethyl 2-chloro-3-(3,4-diethoxyphenyl)propionate as oil.
Reaction SMILES: [I:1]I.Br[C:4]1[S:8][C:7]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1[C:18]1[O:19][CH:20]=[CH:21][CH:22]=1>>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:5]1[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][C:4]=1[I:1]
Reactant: II
Reactant: O=C(Nc1nc(-c2ccco2)c(Br)s1)c1ccccc1
Product: O=C(Nc1nc(-c2ccco2)c(I)s1)c1ccccc1
Yield: 55.9 %

Procedure:
In a manner similar to that in Example 92, by using iodine (26.3 g, 104 mmol) in place of DMF and using N-[5-bromo-4-(2-furyl)thiazol-2-yl]benzamide (10.3 g, 29.6 mmol) obtained in Step 1 in place of Compound h, the entitled Compound n (6.56 g, 56%) was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH2:15]>C(O)(C)C.[Cl-].[Na+].O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:15][CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CNCCOc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 4-nitro-(2-chloroethoxy)benzene (781 mg, 3.9 mmol) and aqueous methylamine (15 mL, 40 wt. %) in isopropyl alcohol (15 mL) is heated in a sealed tube at 100° for 4 hours. After cooling in an ice water bath, the mixtured is poured into brine and extracted 2× with dichloromethane, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-nitro-(2-methylaminoethoxy)benzene (697 mg).
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][C:20]=1[O:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:27])=[CH:21][C:20]=1[O:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: COc1cc(CC(=O)O)ccc1OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc(CC(=O)N2CCc3occc3C2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.33 g (1.2 mmol) of 4-benzyloxy-3-methoxyphenylacetic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) to yield the desired product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH:9]([CH:11]1[CH2:16][CH:15]2[CH2:17][CH:12]1[CH:13]=[CH:14]2)[OH:10].[C:18](OC(=O)C)(=[O:20])[CH3:19].C(Cl)Cl.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O>[C:18]([O:10][CH:9]([CH:11]1[CH2:16][CH:15]2[CH2:17][CH:12]1[CH:13]=[CH:14]2)[CH2:8][CH2:7][CH:2]1[O:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: OC(CCC1OCCCO1)C1CC2C=CC1C2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC(CCC1OCCCO1)C1CC2C=CC1C2
Yield: 95.8 %

Procedure:
To a mixture of 15.0 g of 3-(1,3-dioxan-2-yl)-1-(5-norbornen-2-yl)-1-propanol, 9.6 g of acetic anhydride, 100 mg of 4-dimethylaminopyridine and 50 ml of methylene chloride, 10.2 g of triethylamine was added dropwise over 30 minutes at 20° C. Stirring was continued for 30 minutes whereupon 10 g of water was added to stop reaction. Stirring was continued for a further 30 minutes whereupon water was added to the reaction solution, which was extracted with hexane. The organic layer was successively washed with water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was further purified by vacuum distillation, obtaining 16.9 g of 3-(1,3-dioxan-2-yl)-1-(5-norbornen-2-yl)-1-propyl acetate (boiling point 125° C./53 Pa, yield 96%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:40])[O:5][C@:6]1([C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@:27]([F:37])([C@@H:28]([O:32][Si](C)(C)C)[CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:38])[CH:23]=[CH:24]2)[CH2:19][CH2:18]3)[CH2:15][C@@H:14]1[CH3:39])[C:7](=[O:13])[CH2:8][O:9]C(=O)C)[CH3:2].Cl>CO.C(Cl)(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:40])[O:5][C@:6]1([C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@:27]([F:37])([C@@H:28]([OH:32])[CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:38])[CH:23]=[CH:24]2)[CH2:19][CH2:18]3)[CH2:15][C@@H:14]1[CH3:39])[C:7](=[O:13])[CH2:8][OH:9])[CH3:2]
Reactant: CCNC(=O)O[C@]1(C(=O)COC(C)=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCNC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
Solid (11β,16β)-21-(acetyloxy)-9-fluoro-16-methyl-3,20-dioxo-11-[(trimethylsilyl)oxy]-pregna-1,4-dien-17-yl ethylcarbamate (2.22 g, 3.84 mmol) was dissolved in 128 mL of a pre-mixed solution of methanol/chloroform/6N HCl (10:2:1) and stirred at room temperature. After 16 hours, an additional 2 mL of 6N HCl was added. After 5 hours more, the solution was partitioned between ethyl acetate and water. The organic phase was washed successively with sat. NaHCO3, water, and brine. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to give a pale yellow oil. Purification by flash chromatography through a column of 500 g of silica gel, eluting with hexane/ethyl acetate/dichloromethane/methanol (3:3:3:1) yielded 0.890 g of (11β,16β)-9-fluoro-11,21-dihydroxy-16-methyl-3,20-dioxopregna-1,4-dien-17-yl ethylcarbamate as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][OH:10])=[C:5]([CH3:13])[CH:4]=1)#[CH:2].Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.C(NC(C)C)(C)C>C1COCC1.[Cu]I>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:2]#[C:1][C:3]2[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][OH:10])=[C:5]([CH3:13])[CH:4]=2)=[N:16][CH:17]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#Cc1ccc(OCCO)c(C)c1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2ccc(Br)cn2)ccc1OCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.26 g (1.36 mmol) of CuI was added to a degassed solution of 11.98 g (68.00 mmol) of 2-(4-ethynyl-2-methylphenoxy)ethanol, 16.11 g (68.00 mmol) of 2,5-dibromopyridine, 0.96 g (1.36 mmol) of bis(triphenylphosphane)palladium (II) chloride, and 19.22 mL (136.00 mmol) of diisopropylamine in 500 mL of THF and the mixture was stirred for 4 hours at RT. The reaction mixture was evaporated down in vacuo and the residue taken up in 800 mL of EtOAc. The organic phase was with water and saturated aqueous NaCl solution washed, dried over sodium sulfate, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, gradient DCM/EtOAc 90:10→80:20). Yield: 13.20 g (58% of theoretical); C16H14BrNO2 (M=332.192); calc.: molpeak (M+H)+: 332/334 (Br); found: molpeak (M+H)+: 332/334 (Br); Rf value: 0.39 (silica gel, cyc/EtOAc 1:1).
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[S:21][CH:22]=[N:23][N:24]=3)(=[O:18])=[O:17])=[C:11]([F:36])[CH:10]=2)[C@@H:5]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[S:21][CH:22]=[N:23][N:24]=3)(=[O:17])=[O:18])=[C:11]([F:36])[CH:10]=2)[C@@H:5]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(C)c(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2nncs2)c(F)cc1O[C@H]1CC(F)(F)CC[C@@H]1c1ccnn1C
Yield: 80.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (78.8 mg, 0.124 mmol) prepared in Example 125b, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (48.6 mg, 81%) as a colorless solid.
Reaction SMILES: C(ON=O)(C)(C)C.C(#N)C.N[C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][C:13]=1[N+:29]([O-:31])=[O:30].[ClH:32]>C(OCC)(=O)C.[Cu](Cl)Cl>[Cl:32][C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][C:13]=1[N+:29]([O-:31])=[O:30]
Reactant: CCOC(=O)c1cccc(-c2cnc(N)c([N+](=O)[O-])c2)c1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cccc(-c2cnc(Cl)c([N+](=O)[O-])c2)c1
Temperature: 70 °C
Yield: 61 %

Procedure:
A solution of tert-butylnitrite (3.23 mL, 27.17 mmol), anhydrous copper(II) chloride (2.9 g, 21.74 mmol) and anhydrous acetonitrile (90 mL) was warmed to 70° C. Ethyl 3-(6-amino-5-nitropyridin-3-yl)benzoate (5.2 g, 18.11 mmol) was then added portionwise over a period 10 minutes to the reaction solution. The reaction mixture was maintained at 70° C. for 2 hours and then allowed to cool to room temperature. The reaction mixture was then poured into 110 mL of 20% aqueous HCl solution, followed by extraction with ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography using a 95:5 v/v hexane:ethyl acetate as solvent to afford ethyl 3-(6-chloro-5-nitropyridin-3-yl)benzoate (3.4 g, 61% yield) as a tan solid.
Reaction SMILES: [CH3:1][O:2][P:3]([CH3:7])(=[O:6])[O:4][CH3:5].[Li]CCCC.C[O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1>C1COCC1>[CH3:1][O:2][P:3]([CH2:7][C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:14])(=[O:6])[O:4][CH3:5]
Reactant: COC(=O)c1cccc(Cc2ccccc2)c1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1cccc(Cc2ccccc2)c1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a −78° C. THF solution(10 mL) of dimethylmethylphosphonate (0.423 mL, 3.9 mmol) was added 1.6M BuLi in hexanes (2.44 mL, 3.9 mmol). After 1 h a THF solution (5 mL) of 3-benzyl-benzoic acid methyl ester (589 mg, 2.6 mmol) was added. After 15 min. the reaction mixture was warmed to room temperature and stirred an additional 3 h. The reaction mixture was quenched with an aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated. The residue was subjected to column chromatography (18 ethyl acetate: 1 hexanes) to provide [2-(3-benzyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (677 mg, 2.12 mmol) as an oil.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]([N:34]([CH2:40][CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH3:33]>O1CCOCC1>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:34]([CH2:40][CH3:41])[CH2:32][CH3:33])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CCCCN
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCCC3)C2=O)c1F
Solvent: C1COCCO1
Product: CCN(CC)CCCCNc1ncc2c(n1)N(C1CCCC1)C(=O)N(c1c(F)c(OC)cc(OC)c1F)C2
Yield: 86 %

Procedure:
In a 1-L round bottom flask, 8.00 g (17.78 mmol) of 1-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one in 260 mL of dioxane was treated with 5.10 g (35.36 mmol) of 4-diethylamino-butylamine and heated at reflux for 10 hours under nitrogen atmosphere. The dioxane was evaporated in vacuo. The crude product was purified using medium-pressure chromatography eluting with a gradient of 9:0.5:0.25 to 9:1:0.5 ethyl acetate/methanol/triethylamine to give 8.14 g (86%) of the title compound as a pure partially crystalline solid. A 50 mg portion of the solid was recrystallized with 25% ethanol in hexanes to give 35 mg of title compound as pure crystalline solid: mp 132° C.–133° C. MS (APCI) (m+1)/z 533.3.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]#[N:22].C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[C:21]=1[NH2:22]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: COc1ccc(N=[N+]=[N-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nnc(-c3ccc(Cl)cc3Cl)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-4-methoxy-benzene (0.750 g, 1 eq) and commercial (2,4-dichloro-phenyl)-acetonitrile (1.12 g, 1.2 eq) in ethanol (10 ml) kept under nitrogen, a solution of sodium methoxide (0.408 g, 1.5 eq) in ethanol (10 ml) is added drop-wise (25 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (40 ml), washed with water (2×50 ml), dried over MgSO4 and evaporated to dryness. The yellow semisolid residue (0.842 g) is purified by flash chromatography using 60-120 mesh silica gel and eluting with 15% ethylacetate in hexane, to afford the title compound as a white solid (0.428 g, 24% yield). M.p. 154.6-163.9° C.
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:17])[CH:9]=1)[CH3:7])(=O)=O.[F:18][C:19]([F:26])([F:25])[C:20]1[CH:24]=[CH:23][NH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[CH3:17][C:10]1[CH:9]=[C:8]([CH:6]([N:22]2[CH:23]=[CH:24][C:20]([C:19]([F:26])([F:25])[F:18])=[N:21]2)[CH3:7])[CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cc(C(C)OS(C)(=O)=O)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1cc[nH]n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C(C)n2ccc(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 66.7 %

Procedure:
1-(3-Methyl-4-nitrophenyl)-ethyl methanesulfonate (2.59 g), 3-trifluoromethyl-1H-pyrazole (1.09 g), potassium carbonate (1.66 g) and 18-crown-6 (0.26 g) were refluxed in acetonitrile (100 ml) for 6 hours. After finishing the reaction, water (100 ml) was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and then dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel column chromatography to obtain 1-[1-(3-methyl-4-nitrophenyl)-ethyl]-3-trifluoromethyl-1H-pyrazole (1.60 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[C:11]([NH2:14])=[N:12][CH:13]=2)[CH:5]=[C:4](Cl)[N:3]=1.Cl.[C@H:21]12[CH2:27][C@H:24]([NH:25][CH2:26]1)[CH2:23][N:22]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)C(C)C)C.O>O1CCCC1>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:25]3[CH2:26][C@@H:21]4[CH2:27][C@H:24]3[CH2:23][N:22]4[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:5]=2)=[CH:9][C:10]=1[C:15]([F:18])([F:17])[F:16]
Reactant: Nc1ncc(-c2cc(Cl)nc(Cl)n2)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(-c2cnc(N)c(C(F)(F)F)c2)nc(Cl)n1
Temperature: 75 °C
Yield: 55.6 %

Procedure:
To a solution of 5-(2,6-dichloropyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine (300 mg, 0.84 mmol) in tetrahydrofuran (60 mL) was added (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate hydrochloride (197 mg, 0.84 mmol) and N-ethyl-N-isopropylpropan-2-amine (2 mL). The mixture was heated at 75° C. for 3 h. After cooling to room temperature, water (50 mL) was added to. The mixture was extracted with ethyl acetate (3×30 mL). The organic layer was dried over sodium sulfate, concentrated and purified by flash column chromatography (25% ethyl acetate in petroleum ether to 100% ethyl acetate) to provide (1S,4S)-tert-butyl 5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-chloropyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (220 mg, 48.1% yield). TLC (Thin layer chromatography) (petroleum ether (PE): ethyl acetate (EA)=3:1, Rf=0.3-0.4).
Reaction SMILES: CC([O-])(C)C.[K+].F[C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16].[CH2:17]([OH:20])[CH2:18][OH:19].CCOC(C)=O>CS(C)=O>[F:16][C:9]1[CH:10]=[C:11]([F:15])[C:12]([F:14])=[CH:13][C:8]=1[O:19][CH2:18][CH2:17][OH:20]
Reactant: OCCO
Reactant: Fc1cc(F)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OCCOc1cc(F)c(F)cc1F
Temperature: 80 °C

Procedure:
t-BuOK (3.0 g, 27 mmol) was added to a mixture of 1,2,4,5-tetrafluorobenzene (2.0 g, 13.3 mmol) and ethylene glycol (7.5 mL, 133 mmol) in DMSO (50 mL) and heated at 80° C. for 1 h and then at 60° C. overnight. EtOAc was added and the resulting solution was washed several times with water. The organic layer was dried (Na2SO4) and concentrated carefully in vacuo at 30° C. to furnish 1.5 g (containing ˜14% EtOAc) of the title compound as a white semisolid. NMR analysis supports the stated structure. This material was used directly in the next step.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:12].[Cl:25][CH2:26][CH2:27][C:28](=O)[CH3:29].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Cl-:25].[CH3:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:3]1[C:27]([CH3:26])=[C:28]([CH3:29])[S:12][CH:1]=1
Reactant: CC(=O)CCCl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1ccccc1NC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1-[n+]1csc(C)c1C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 164.6 %

Procedure:
A mixture of 8b (4.055 g, 30 mmol) and phosphorus pentasulfide (1.351 g, 3.04 mmol) in dry 1,4-dioxane (4 mL) was stirred at room temperature for 15 min under an argon atmosphere. 4-Chloro-2-butanone (2.131 g, 20 mmol) was added and the resulting slurry was heated at 100° C. The reaction mixture was refluxed for 50 min, initially becoming clear yellow and finally deep red. After cooling at room temperature, the crude mixture was diluted with H2O (20 mL). Na2CO3 was added to the reaction mixture until pH≈7. The solvent was evaporated under reduced pressure and the resulting solid was suspended in CH2Cl2 and purified by column chromatography (column packed with silica gel) eluting with EtOH/CH2Cl2 (15/85). Upon concentration of the last yellowish band, a viscous orange oil was obtained. This was solidified when washed under vigorous stirring with diethyl ether (3×2 mL) to afford 9b as a tan solid (1.20 g, 17%). 1H NMR (CD2Cl2, 300 MHz): δ=11.09 (s, 1H), 7.53-7.31 (m, 4H), 2.57 (s, 3H), 2.08 (s, 3H), 2.04 (s, 3H); 13C{1H} NMR (CD2Cl2, 75 MHz): δ=160.77, 142.05, 136.10, 134.60, 134.30, 132.23, 132.00, 128.08, 126.55, 17.23, 12.90, 11.98; HRMS (FAB+) calculated for C12H14NS [M]+ 204.0847, observed 204.0845.
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7]C(O)=O)=[CH:4][C:3]=2[O:2]1.[C:15](=O)([O-:17])[O-:16].[K+].[K+].[H][H]>[Pd]>[CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]([CH3:7])[C:15]([OH:17])=[O:16])=[CH:4][C:3]=2[O:2]1
Reactant: O=C([O-])[O-]
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Agent: [Pd]
Agent: [K+]
Product: CC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 95 %

Procedure:
To a solution of 50 g. of 3,4-methylenedioxycinnamic acid in 200 ml. of a 2 N potassium carbonate solution in a Parr shaker was added 0.5 g. of a five percent palladium on carbon catalyst. Hydrogen was introduced into the reactor to a pressure of 30 psig. The reaction was allowed to proceed until 0.26 moles of hydrogen were taken up (about 4 hours). At the completion of the reaction the mixture was filtered to remove the catalyst. Acidification of the mixture resulted in the precipitation of the desired 3,4-methylenedioxyphenylpropionic acid in 95 percent yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12][C:11]=2[C:19](O)=[O:20])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:19](=[O:20])[C:11]3[S:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:14][C:10]=3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NCc1cc(C(C)(C)C)sc1C(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1c(Br)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A 250-mL single-necked round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 102e (1.12 g, 2.93 mmol) and anhydrous methylene chloride (50 mL). Thionyl chloride (1.25 g, 10.5 mmol) was added and the reaction was stirred at ambient temperature. After 16 h the reaction was concentrated under reduced pressure. Purification of the resulting residue by column chromatography afforded a 65% yield (757 mg) of 102f as a white solid: mp 185-186° C.; 1H NMR (300 MHz, CDCl3) δ 7.56 (dd, 1H, J=6.6, 1.2 Hz), 7.20 (dd, 1H, J=6.3, 1.5 Hz), 7.11 (t, 1H, 7.8 Hz), 6.87 (s, 1H), 4.56 (s, 2H), 2.33 (s, 3H), 1.45 (s, 9H); MS (ESI+) m/z 364.2 (M+H).