Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[NH:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Br:27])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:33].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]([C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Br:27])[CH:21]=1)[CH3:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: Cc1cccc(OCCCC(=O)OC(C)(C)C)c1NC(=O)c1ccc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(OCCCC(=O)OC(C)(C)C)c1N(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of 4-[2-(3-bromo-4-chloro-benzoylamino)-3-methyl-phenoxy]-butyric acid tert-butyl ester (10.2 g, 21.3 mmol) in dry DMF (100 mL) at 0° C. under N2, NaH (60% in mineral oil, 1.7 g, 42.6 mmol) was added in several portions with stirring. 10 minutes later, iodomethane (2.0 mL, 32.1 mmol) was added. The mixture was warmed to room temperature by removal of ice bath and stirring was continued for 1 hr. Water (10 mL) was then added and organics were extracted by ethyl acetate, which was then washed by water and brine, and was dried over MgSO4. After concentration, the crude product was purified by silica gel chromatography eluting with ethyl acetate/hexane (1/4) to yield 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-3-methyl-phenoxy}-butyric acid tert-butyl ester (9.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1.I[C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reactant: Ic1cnccn1
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4cnccn4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene and iodo-pyrazine.
Reaction SMILES: [NH:1]([CH2:6][CH2:7][C:8]#[N:9])[CH2:2][CH2:3][C:4]#[N:5].CO.C([BH3-])#N.[Na+].[C:16](#N)[CH3:17]>>[C:4]([CH2:3][CH2:2][N:1]([CH2:6][CH2:7][C:8]#[N:9])[CH2:16][CH3:17])#[N:5]
Reactant: CC#N
Reactant: N#CCCNCCC#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CCC#N)CCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a stirred mixture of 3,3'-iminodipropionitrile (14.4 g, 0.117 mol), acetaldelyde (25.7 g, 0.584 mol), methanol 50 mL), and acetonitrile (400 mL) was added sodium cyanoborohydride (9.6 g, 0.152 mol). The mixture was allowed to stir at room temperature overnight. The solvent was evaporated. The resulting residue was partitioned between dichloromethane and H2O. The dichloromethane layer was washed with water, dried, and evaporated to give a yellow oil, which was distilled by a Kugelrohr apparatus to give the title compound (9.2 g, 52%). 1H NMR (CDCl3, 200 MHz) 2.86 (t, J=7.0 Hz, 4H), 2.64 (q, J=7.0 Hz, 4H), 2.48 (t, J=7.0 Hz, 4H), 1.08 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[CH3:7].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:7][C:6]1[S:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[NH:1][S:17]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COC(=O)c1cc(N)c(C)s1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2cccs2)c(C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
To a mixture of methyl 4-amino-5-methylthiophene-2-carboxylate (20 g) and pyridine (100 mL) was added 2-thiophen-sulfonyl chloride (23.5 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give methyl 5-methyl-4-[(2-thienylsulfonyl)amino]thiophene-2-carboxylate (35.7 g, yield 96%) as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.C([Li])CCC.[C:13](=[O:15])=[O:14].Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:13]([OH:15])=[O:14]
Reactant: O=C=O
Reactant: COc1ccsc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccsc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methoxythiophene (4.81 g, 42.1 mmol) in ether (20 mL) at −78° C., butyllithium (17 mL, 47.6 mmol) was added. The reaction mixture was stirred at −78° C. for 1 hour, then it was warmed to 0° C. for 3 hours. After to recooling −78° C. the reaction mixture was poured into a beaker filled with crushed dry ice (14.5 g) and allowed to stand until the excess dry ice had completely sublimed. Then the reaction mixture was poured into a mixture of ice (10 g) to which conc. HCl (24 mL) had been added. The product was purified by precipitation from ether and filtering (6.42 g, 96%). EI-MS m/z 159 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+:12]([O-:15])(O)=[O:13].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:12]([O-:15])=[O:13])(=[O:18])[CH3:17]
Reactant: O=[N+]([O-])O
Reactant: Nc1cccc2c1CCCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1c([N+](=O)[O-])ccc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1-amino-5,6,7,8-tetrahydronaphtalene (5 ml; 30 mmol) in acetic anhydride (75 ml) was stirred at ambient temperature for 30 min. After cooling to 15° C. nitric acid (1.5 ml, 65%) was added and the mixture was allowed to warm to room temperature. Stirring was continued overnight. The mixture was poured into ice-water and the oily precipitate was filtered off, washed with water and dried. This crude product was purified by column-chromatography on silica gel, using a mixture of ethyl acetate and ligroin (1:1) as the eluent. Yield: 2.5 g (30%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH:5]([N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Clc1ccc(C(Cl)c2cccc(Br)c2)cc1
Solvent: ClCCl
Product: CN1CCN(C(c2ccc(Cl)cc2)c2cccc(Br)c2)CC1
Temperature: 25 °C

Procedure:
The benzhydryl chloride from above (8.33 g, 26.4 mmol) in 10 mL of N-methylpiperazine was heated to 110° for 12 hours under nitrogen. After cooling to room temperature, the residue was dissolved in 75 mL of methylene chloride and washed with 40 mL of 1M sodium hydroxide and two 50 mL portions of water. After drying over sodium sulfate, the solvent was removed in vacuo to give 10.2 g of 1-(3-bromo-4'-chlorobenzhydryl)-4-methylpiperazine as a dark oil. A portion of the oil was dissolved in ether and converted to the dihydrochloride salt with ethanolic hydrogen chloride. Recrystallization from 2:1 ethanol:methanol gave white powdery crystals, m.p. 229°-231°. Calc. for C18H20BrClN2.2HCl: C, 47.76; H, 4.90; N, 6.19. Found: C, 47.55; H, 4.91; N, 6.13.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6].[N+:13]([O-])([OH:15])=[O:14].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)Nc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Nc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 6.5 °C
Reaction time: 8 h

Procedure:
A solution of 2′-chloro-4′-fluoroacetanilide (85.5 g, 456 mmol) in concentrated sulfuric acid is cooled to 0° C., treated slowly with 70% nitric acid (32 mL, 502 mmol) while maintaining the temperature from 5-8° C., stirred at room temperature overnight and poured into water. The resultant aqueous mixture is filtered to obtain a solid which is recrystallized from ethanol to give the title product as pale, yellow plates (27.0 g, mp 158-160° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.CCCCCC.[I:29]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[C:16]([I:29])=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: Cc1cccc(C(=O)Nc2cccc(Cl)c2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(I)c(C(=O)Nc2cccc(Cl)c2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A solution of 6-Methyl-pyridine-2-carboxylic acid-(3-chloro-phenyl)-amide (1.96 g, 7.9 mmol) in THF (20.0 ml) was cooled to −78° C. A 1.6 M solution of n-BuLi in hexane (11.0 ml, 17.6 mmol, 2.2 equiv.) was added dropwise and the reaction was stirred for 30 min at −78° C. A solution of 2.02 g (7.9 mmol) of iodine in THF (20.0 ml) was added dropwise maintaining the temperature below −75° C. After 5 min, the reaction mixture was allowed to warm up to r.t. The mixture was quenched by the addition of sat. ammonium sulfate soln. (5 ml) and 40% sodium hydrogensulfite solution (5 ml). The pH of the solution was adjusted to 8 by the addition of sat. bicarbonate soln. The mixture was then extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated in vaccuo. The dark brown residue (2.66 g) was purified by flash chromatography (heptane/ethyl acetate 9:1) to yield a the title compound as a beige solid (total 1.42 g, 48%), MS (ISP): m/e=373.0, 375.0 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[N:7][N:6]=[C:5]2[C:9]2[N:14]=[C:13]([NH:15]C(=O)OCC3C=CC=CC=3)[CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1>[Pd]>[CH:1]1([N:4]2[CH:8]=[N:7][N:6]=[C:5]2[C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1cccc(-c2nncn2C2CC2)n1)OCc1ccccc1
Agent: [Pd]
Product: Nc1cccc(-c2nncn2C2CC2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A mixture of benzyl 6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-ylcarbamate (660 mg, 1.96 mmol, 1.0 eq) and Pd/C (80 mg 10% Pd loading, 40 mg/mmol) was loaded into a flask and purged with nitrogen. Ethanol (0.4 M) was added and the flask was charged with hydrogen (1 atm—balloon pressure). The reaction was stirred at room temperature for 90 minutes, and judged to be complete by TLC. The reaction mixture was filtered through celite, and concentrated under reduced pressure to give 395 mg (95%) of 6-(4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridin-2-ylamine. C10H11N5. 202.1 (M+1). 1H NMR (DMSO) d 8.14 (s, 1H), 7.54 (t, J=8 Hz, 1H), 7.46 (d, J=7 Hz, 1H), 6.60 (d, J=8 Hz, 1H), 4.70 (br s, 2H), 3.85-3.88 (m, 1H), 1.04-1.07 (m, 2H), 0.85-0.88 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:26]([O:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH2:27][CH3:28]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:33][CH2:32][CH2:31][CH2:30][O:29][CH2:26][CH2:27][CH3:28])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCCOCCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: CCCOCCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-propoxypropylamine employing methods similar to those described in Example 2 and was obtained a white solid: 1H NMR (d6-DMSO) δ 11.83 (1H, br s), 10.26 (1H, br s), 8.48 (1H, br s), 7.43 (1H, s), 7.30-7.26 (2H, m), 7.16-7.11 (2H, m), 4.09 (2H, s), 3.42-3.38 (4H, m), 3.30-3.28 (2H, m), 1.76-1.71 (2H, m), 1.49 (2H, q, J=7 Hz), 0.83 (3H, t, J=7.3 Hz); HRMS calcd for C22H24FN3O4+H+: 414.1829. Found 414.1844.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12](=[CH2:17])[C:13]([O:15][CH3:16])=[O:14])=[N:9][C:8]([O:18][CH3:19])=[CH:7][CH:6]=2.[C:20]1([CH2:26][O:27][C:28](=[O:37])[NH:29][C@H:30]2[CH2:35][CH2:34][NH:33][CH2:32][C@H:31]2[F:36])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.BrC1C2OCCOC=2C=C(C=O)C=1.O1C2=CN=C(CO)C=C2C=C1>CN(C)C(N(C)C)=N.CN(C=O)C>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([CH2:17][N:33]1[CH2:34][CH2:35][C@H:30]([NH:29][C:28]([O:27][CH2:26][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:37])[C@H:31]([F:36])[CH2:32]1)[C:13]([O:15][CH3:16])=[O:14])=[N:9][C:8]([O:18][CH3:19])=[CH:7][CH:6]=2
Reactant: O=C(N[C@H]1CCNC[C@H]1F)OCc1ccccc1
Reactant: C=C(C(=O)OC)c1c(F)cnc2ccc(OC)nc12
Agent: CN(C)C(=N)N(C)C
Agent: O=Cc1cc(Br)c2c(c1)OCCO2
Agent: OCc1cc2ccoc2cn1
Solvent: CN(C)C=O
Product: COC(=O)C(CN1CC[C@H](NC(=O)OCc2ccccc2)[C@H](F)C1)c1c(F)cnc2ccc(OC)nc12
Temperature: 80 °C
Yield: 100 %

Procedure:
A solution of methyl 2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-propenoate (953 mg, 3.63 mmol), cis-phenylmethyl[3-fluoro-4-piperidinyl]carbamate Enantiomer 2 (for a synthesis see WO2004058144, prepared by analogy to Examples 142(b), (c) and (d) from the Enantiomer 2 of Example 142(a)) (1.1 g, 4.35 mmol) and 1,1,3,3-tetramethylguanidine (6 drops) in DMF (3.5 ml) was heated at 80° C. under argon for 3 hours, cooled and evaporated. Chromatography, eluting with 1% methanol/dichloromethane, gave the product in 100% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[CH2:11][CH2:10]1.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([C:33]3[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=3)=[CH:29][NH:30]2)=[CH:26][CH:25]=1.C(N(CC)CC)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:36]2[CH2:37][CH:38]=[C:33]([C:28]3[C:27]4[C:31](=[CH:32][C:24]([F:23])=[CH:25][CH:26]=4)[NH:30][CH:29]=3)[CH2:34][CH2:35]2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C(=O)CCCCCBr)CC1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C(=O)CCCCCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)CC1
Yield: 65.2 %

Procedure:
Following the same procedure reported in the Step 2 of EXAMPLE 13, the reaction of 1-(2-methoxyphenyl)-4-(6-bromohexanoyl)piperazine (2.37 mmol) with 6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (2.37 mmol) and triethylamine (2.87 mmol) gave the alkylation product (780 mg, 65%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:14])[CH:8]=[C:9]([C:12]#[N:13])[C:10]=1[I:11])=[O:5])[CH3:2].[B-](F)(F)(F)[F:16].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O.C(Cl)Cl>C(#N)C>[C:12]([C:9]1[C:10]([I:11])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]([CH3:14])[C:8]=1[F:16])#[N:13]
Reactant: CCOC(=O)c1c(I)c(C#N)cn1C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(I)c(C#N)c(F)n1C
Temperature: 80 °C

Procedure:
Dissolve 4-cyano-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.69 mmol, prepared in preparation 34) and SELECTFLUOR® (4.04 mmol, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-(tetrafluoroborate)) in acetonitrile (27 mL). Heat the mixture at 80° C. for 16 h. Add H2O (30 mL) and methylene chloride (30 mL) into the reaction mixture. Extract with methylene chloride (3×30 mL). Combine the organic layers, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography to provide the title compound. Mass spectrum (m/e): 318.9 (M−1). Rf=0.5 (50% Et2O in hexanes).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.N1C=CC=CC=1.[C:52](Cl)(=[O:56])[CH2:53][CH2:54][CH3:55].Cl>C(Cl)Cl>[F:43][C:40]([F:41])([F:42])[C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:52](=[O:56])[CH2:53][CH2:54][CH3:55])[CH2:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCCC(=O)Cl
Reactant: CCNc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (100 mg) and pyridine (19 μl) are dissolved in methylene chloride (1 ml) and thereto is added butyryl chloride (19 μl) at room temperature. The reaction solution is stirred at room temperature for 30 minutes, and thereto are added methylene chloride and 1N-hydrochloric acid, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (84 mg). MS (m/z): 723 [M+H]+
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][CH2:11]I)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1C=CC=CC=1.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:5]([O:8][CH2:9][CH2:10][CH2:11][C:20]([C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=1)=[O:21])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
A mixture of Zn—Cu couple (2.68 g, 41.3 mmol) and tert-butyl(3-iodopropoxy)dimethylsilane (8.26 g, 27.5 mmol) in benzene (55 mL) and DMF (3.6 mL) was stirred vigorously at room temperature for 1 hour, heated to 60° C. for 4 hours, cooled to room temperature, and treated with a solution of 4-nitrobenzoyl chloride (3.4 g, 18.3 mmol) and (Ph3P)4Pd (0.847 g, 0.73 mmol) in benzene (36 mL) by cannula. The mixture was stirred for 1 hour, filtered through diatomaceous earth (Celite™), and partitioned between saturated NH4Cl and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% ethyl acetate/hexanes to provide 2.81 g of the desired product. MS(ESI(−)) m/e 322 (M−H)−.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:46]=2[N:47]=[CH:48][N:49]=1)[C@@H:15]1[O:45][C@H:19]([CH2:20][O:21]C(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:50](O[C@@H]1[C@@H](CO)O[C@@H](N2C3N=C(NC(=O)C(C)C)NC(=O)C=3N=C2)C1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]>>[Si:50]([O:18][C@@H:17]1[C@@H:19]([CH2:20][OH:21])[O:45][C@@H:15]([N:14]2[C:46]3[N:47]=[CH:48][N:49]=[C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:11]=3[N:12]=[CH:13]2)[CH2:16]1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO

Procedure:
This compound was prepared from N6 -benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyadenosine by the same procedure used for the preparation of 3'-O-t-butyldimethylsilyl-N2 -isobutyryl-2'-deoxyguanosine.
Reaction SMILES: C([C:4]([CH:13]([F:15])[F:14])([CH2:10][CH:11]=[CH2:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)N.C(#[N:18])C>O>[NH2:18][C:4]([CH:13]([F:15])[F:14])([CH2:10][CH:11]=[CH2:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C=CCC(C(N)=O)(C(=O)OCC)C(F)F
Reactant: CC#N
Solvent: O
Product: C=CCC(N)(C(=O)OCC)C(F)F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 2-carbamoyl-2-difluoromethyl-4-pentenoate prepared as in Step B (2.3 g) and iodo-benzene ditrifluoroacetate (3.5 g) in acetonitrile (14 mL) and water (14 mL) is stirred at 80° C. for 16 hours. Water (20 mL) is added and the mixture is extracted with ether (3×20 mL). The aqueous phase is concentrated and the residue suspended in saturated aqueous sodium bicarbonate (10 mL). The suspension is extracted with diethyl ether (3×20 mL). The organic layers are combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-amino-2-difluoromethyl-4-pentenoate (0.6 g) as an oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@H:18]([CH3:24])[CH2:19][O:20]C(=O)C)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].ClCCl>C(O)C.O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C@H:18]([CH3:24])[CH2:19][OH:20])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC[C@@H](C)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: C[C@H](CO)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 65 °C
Yield: 56.5 %

Procedure:
5.64 g of crude (S)-acetic acid 3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-2-methyl-propyl ester (asserted 14.1 mmol) were stirred in 26.6 ml of ethanol. A solution of 2.83 g of sodium hydroxide in 6 ml of water was added and the reaction was heated at 60-70° C. for 5 h. After cooling to room temperature, 50 ml of water and 50 ml of dichloromethane were added. The dichloromethane layer was separated and the aqueous phase was extracted with a further portion dichloromethane. The combined dichloromethane extracts were washed with water, dried over magnesium sulfate, filtered and evaporated under vacuum to give an orange oil. The crude product was purified by flash column chromatography eluting with dichloromethane-methanol (9:1). The fractions containing the product were combined and evaporated to give an orange oil (2.76 g).