Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:18])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:17])[N:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=1[F:29]>C1(C)C=CC=CC=1>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:5](=[O:18])[NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([N:14]([CH3:15])[CH3:16])=[O:17])=[CH:11][CH:12]=2)=[CH:24][C:23]=1[F:29]
Reactant: Nc1ccc(Br)c(F)c1
Reactant: CN(C)C(=O)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(Br)c(F)c2)cc1
Temperature: 110 °C
Yield: 44.6 %

Procedure:
To a 250 mL round bottom flask, 2,2,2-trichloroethyl(4-(dimethylcarbamoyl)phenyl)carbamate (30 g, 0.0885 mol), 4-bromo-3-fluoroaniline (20 g, 0.1062 mol), TEA (24.6 mL, 0.177 mol) and toluene (150 mL) was added. The reaction mixture was maintained at 110° C. for 12 h. The reaction mass was cooled to room temperature. The obtained precipitate was collected by filtration and dried under vacuum to get the desired product [15 g, 50%]. 1H NMR (300 MHz, DMSO-d6): δ 9.09 (s, 1H), 8.99 (s, 1H), 7.65-7.53 (m, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 1H), 2.93 (s, 6H); LC-MS (ESI): Calculated mass: 379.0; Observed mass: 382.1 (RT: 1.43 min).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH2:14][CH3:15])[CH:3]=1.[Cu](C#N)[C:17]#[N:18]>CN(C)C=O.O>[C:17]([C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH2:14][CH3:15])[CH:3]=1)#[N:18]
Reactant: CCc1cc(Br)cc(C)c1CC(=O)OC
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(C#N)cc(C)c1CC(=O)OC
Temperature: 130 °C

Procedure:
7.5 g of methyl 4-bromo-2-ethyl-6-methylphenylacetate were dissolved in 140 ml of dimethylformamide, 5.5 g of copper cyanide were added, and the mixture was heated for 18 hours at 130° C., until the reaction was complete. The mixture was then cooled to room temperature and diluted with water, and the product was extracted repeatedly using tert-butyl methyl ether. The combined organic phases were dried over magnesium sulphate, concentrated and distilled. This gave 3.4 g (52% of theory) of methyl 4-cyano-2-ethyl-6-methylphenylacetate of a boiling point of 123-130° C. and a melting point of 65-72° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:52][CH2:53][NH:54]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:52][CH2:53][NH2:54])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(O)ccc21
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To 1-(phenylsulfonyl)-1 H-indol-5-ol, (Intermediate 8, 8.0 g, 29 mmol) were 1,1′-azobis(N,N-dimethylformamide) (7.6 g, 44 mmol), triphenylphosphine (15.4 g, 580 mmol), tert-butyl N-(2-hydroxy-ethyl)carbamate (9.4 g, 58 mmol) and DCM (200 mL) added. The reaction mixture was heated at 50° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature and TFA (50 mL) was added. The reaction mixture was stirred for 3 hours and evaporated. The crude material was purified with flash chromatography on silica gel (DCM:MeOH, 95:5) to give the title compound (9.6 g). MS m/z 317 [M+H]+.
Reaction SMILES: [Cr](O)(O)(=O)=O.S(=O)(=O)(O)O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[C:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH:32]([OH:34])[CH3:33])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>O.CCOCC>[C:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1ccc(CC(C)O)cc1
Agent: O=[Cr](=O)(O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: CC(=O)Cc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chromic acid solution (11.5 ml, made by adding sulphuric acid [7.3 ml] to sodium dichromate [10.0 g] in water [30 ml] and making up to 50 ml with water) was added to a vigorously stirred solution of 1-(4-acetylphenyl) propan-2-ol (3.8 g) in ether (50 ml) keeping between 25°-30°. The mixture was stirred at ambient temperature for 2 hours, the organic phase was separated, washed with sodium bicarbonate solution and with saturated sodium chloride solution. The dried (MgSO4) solution was evaporated and distilled (2.5 g). b.p. 122°-128°/0.1 mm.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.C(Cl)(=O)C.C(OCC)(=O)C.O1CCCC1>CN(C)C(=O)C.O>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][C:3](=[O:5])[CH3:2])[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: O=C(O)C(F)(F)F
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Solvent: O
Product: CC(=O)NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (350 mg, 0.91 mmol) was dissolved in N,N-dimethylacetamide (10 ml), and acetyl chloride (150 mg, 1.91 mmol) was added thereto. The reaction mixture was stirred at 60° C. for 3 hrs and combined with ethyl acetate, tetrahydrofuran and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (1:10, v/v) were collected, concentrated and recrystallized from methanol-diisopropyl ether to give the titled compound (81 mg, 28%) as white crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1.Cl[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][O:25][CH:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:7][CH:8]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: ClCc1ccccn1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 57 (c)] with 2-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[3-(pyridin-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate as a colourless resin; MS: 583 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([C:10](F)=[O:11])=[C:8]([F:13])[C:7]([F:14])=[C:6]([F:15])[C:5]=1[F:16].O.Cl>O1CCOCC1>[F:3][C:4]1[C:9]([CH2:10][OH:11])=[C:8]([F:13])[C:7]([F:14])=[C:6]([F:15])[C:5]=1[F:16]
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1c(F)c(F)c(F)c(F)c1F
Yield: 211.1 %

Procedure:
38 g of sodium borohydride in 200 ml of dry dioxane are initially introduced into the apparatus at 20° C. and a solution of 86 g of pentafluorobenzoyl fluoride in 100 ml of dioxane is added dropwise, whilst stirring. When the addition has ended, the mixture is subsequently stirred at 20° C. for 2 hours and at 80° C. for 30 minutes and cooled and 75 ml of water are slowly added dropwise, followed by dilute hydrochloric acid until the mixture has a clearly acid reaction. After extraction with methylene chloride, the organic phase is distilled. 168 g of pentafluorobenzyl alcohol are obtained at a boiling point of 87° C./19 mbars.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[CH2:8][CH:7]1[CH2:9][C:10](OCC)=[O:11])=[O:4].[BH4-].[Li+].[NH4+].[Cl-]>O1CCCC1>[OH:11][CH2:10][CH2:9][CH:7]1[CH2:8][C:6]1([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: CCOC(=O)CC1CC1(NC(=O)OC)c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1CCO
Temperature: 23 °C
Reaction time: 6 h
Yield: 86.3 %

Procedure:
Ethyl 2-((1SR,2SR)-2-(methoxycarbonylamino)-2-(3-nitrophenyl)cyclopropyl)acetate (intermediate B10a) (2.45 g, 7.6 mmol, Eq: 1.00) was dissolved in tetrahydrofuran (80 ml) and lithium borohydride (2 M in THF; 8.36 ml, 16.7 mmol, Eq: 2.2) was added dropwise at 5° C. The turbid solution was stirred at 23° C. for 6 hours. The reaction mixture was poured into ice water, sat NH4Cl solution (100 ml) was added slowly and the mixture was stirred vigorously for 45 min (gas evolution finished). Then extraction with EtOAc, the organic layer was dried over Na2SO4, filtration and evaporation of the solvent left a yellow oil (2.5 g; 117%). Crystallization with dichloromethane/cyclohexane gives the methyl (1SR,2SR)-2-(2-hydroxyethyl)-1-(3-nitrophenyl)cyclopropylcarbamate (1.84 g, 6.56 mmol, 86.4% yield) as a light yellow solid. MS (ISP): m/z=281.1 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[C:10]2[NH:9][C:8]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([CH2:35][CH2:36][CH2:37]Br)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:8]2[N:7]([CH2:37][CH2:36][CH2:35][CH:31]3[CH2:32][CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:30]3)[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:37][CH2:36][CH2:35][CH:31]4[CH2:32][CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[CH2:30]4)[C:10]=3[N:9]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCBr)C1
Reactant: Oc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCCN(C(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxy-2-(4-chlorophenoxymethyl)benzimidazole (500 mg, 1.82 mmol) in dry N,N-dimethylformamide (8 ml) was treated with sodium hydride (60% in mineral oil, 162 mg, 4.0 mmol, 2.2 eq). The resulting mixture was stirred at room temperature under a stream of nitrogen for about one hour. To this reaction mixture (RS) 3-[1-(t-butoxycarbonyl)piperidin-3-yl)propyl bromide (4.0 mmol, 2.2 eq) was added and the resulting mixture was stirred for three hours at 70° C. The reaction was quenched by the addition of 10 ml of water. The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined and washed with water (2×10 ml), and then brine (1×10 ml), and then dried over magnesium sulfate. The solvents were removed in vacuo to yield a light brownish crude material. The desired title product was further purified by flash chromatography.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:12]2[CH:13]=[C:14]([NH:22][C:23]([CH2:25][CH2:26][CH2:27][NH:28][C:29](OC(C)(C)C)=[O:30])=[O:24])[CH:15]=[CH:16][C:17]=2[O:18][CH2:19][CH2:20][CH3:21])[NH:6][C:7](=[O:11])[C:8]=1[CH2:9][CH3:10])[CH3:2].F[C:37](F)(F)C(O)=O.C(Cl)(=O)C>ClCCl>[C:29]([NH:28][CH2:27][CH2:26][CH2:25][C:23]([NH:22][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH3:21])=[C:12]([C:5]2[NH:6][C:7](=[O:11])[C:8]([CH2:9][CH3:10])=[C:3]([CH2:1][CH3:2])[N:4]=2)[CH:13]=1)=[O:24])(=[O:30])[CH3:37]
Reactant: CCCOc1ccc(NC(=O)CCCNC(=O)OC(C)(C)C)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CCCOc1ccc(NC(=O)CCCNC(C)=O)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
The compound (200 mg, 0.412 mmol) of example 106 was dissolved in dichloromethane (30 ml) and added with trifluoroacetic acid (2 ml), followed by stirring at room temperature for 0.5 h. The reaction mixture was directly concentrated to dryness. The resultant oil was dissolved in dichloromethane (30 ml) and added with triethylamine (1 ml). Under ice-water both, acetyl chloride (33 mg, 0.42 mmol) was added dropwise thereinto. 0.5 h later, TLC showed that the reaction was complete. The reaction mixture was washed with water (50 ml) and saturated saline (50 ml). The organic layer was dried with anhydrous sodium sulfate, and concentrated, and the residue was passed through a silica gel column to give the white title compound (50 mg, yield: 28%). 1H NMR (CDCl3) δ: 8.79 (1H, br), 8.51 (1H, d), 7.93 (1H, dd), 6.99 (1H, d), 6.05 (1H, br), 4.15 (2H, t), 3.40 (2H, t), 2.68 (2H, q), 2.60 (2H, q), 2.44 (2H, t), 2.03 (3H, s), 1.97 (2H, m), 1.94 (2H, m), 1.32 (3H, t), 1.16 (3H, t), 1.14 (3H, t).
Reaction SMILES: II.[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16]I)[C:12]([O:14][CH3:15])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=3)[S:28][CH:29]=2)=[CH:21][CH:20]=1.C(Cl)Cl>CN(C=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:26]=[C:27]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:34][CH:35]=3)[S:28][CH:29]=2)=[CH:23][CH:24]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Reactant: CCCCCCCOc1ccc(-c2nc(-c3ccc(Br)cc3)cs2)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2nc(-c3ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc3)cs2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a stirring mixture of zinc (182 mg, 2.79 mmol) in DMF (2 mL) was added diiodine (35.4 mg, 0.14 mmol). When the color was discharged, further diiodine (35.4 mg, 0.14 mmol) and (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (306 mg, 0.93 mmol) were added. After 30 min, DMF (1 mL) was added and the mixture de-gassed by bubbling through N2. To the reaction mixture were added 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole (400 mg, 0.93 mmol), Pd2dba3 (21 mg, 0.02 mmol) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (19 mg, 0.05 mmol), the mixture was further de-gassed then heated to 50° C. for 3 h. The reaction mixture was cooled and purified by column chromatography (10-80% EA in iso-hexanes). The product obtained was taken into DCM (4 mL) and washed with water (20 mL) and dried through a hydrophobic frit. The organics were suspended in ACN (4 mL) and concentrated to afford 432 mg (83%) of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)phenyl)propanoate as a yellow foam. LCMS-ESI (m/z) calculated for C31H40N2O5S: 552.7; no ion observed, tR=3.36 min. (Method 4).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([O:16][C:17]([C:19]1[C:20]([C:43](=O)[NH2:44])=[C:21]([CH2:40][CH2:41][CH3:42])[N:22]2[C:27]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:25][C:24]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[N:23]2)=[O:18])[CH3:15].CCN(CC)CC.O>C1COCC1>[CH2:14]([O:16][C:17]([C:19]1[C:20]([C:43]#[N:44])=[C:21]([CH2:40][CH2:41][CH3:42])[N:22]2[C:27]=1[C:26]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[CH:25][C:24]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[N:23]2)=[O:18])[CH3:15]
Reactant: CCCc1c(C(N)=O)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(C#N)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trifluoroacetic anhydride (36 μL, 0.252 mmol) was added dropwise via syringe to a solution of 61 (100 mg, 0.229 mmol) and NEt3 (70 μL, 0.504 mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 48 h. Water was added, the layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were pooled, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to provide a yellow oil. Purification by flash chromatography (silica gel, 20% EtOAc/hexane) provided the title compound. 1H NMR (DMSO-d6) δ 0.74 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H), 1.78 (m, 2H), 3.03 (t, J=7.3 Hz, 2H), 3.59 (m, 6H), 3.75 (m, 4H), 7.02 (s, 1H), 7.48 (m, 5H). Mass Spectrum (ESI+) m/e=419.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:26])=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=1.C1COCC1.[O:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:25][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:37]([C@H:33]2[CH2:34][CH2:35][CH2:36][O:32]2)=[O:38])=[C:4]([F:26])[CH:5]=1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F)[C@H]1CCCO1
Yield: 13.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-107 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-70, 0.090 g, 0.233 mmol), THF:DMF (5 mL:1 mL), (R)-(−)-tetrahydrofuran-2-carboxylic acid (0.040 g, 0.349 mmol), TBTU (0.224 g, 0.699 mmol), and TEA (0.5 mL). The obtained crude was purified with column chromatography using basic alumina as stationary phase and 2% ammonia in 10.0% MeOH:DCM solution as mobile phase to afford 0.015 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.78-1.91 (m, 2H), 2.09-2.15 (m, 1H), 3.74 (m, 1H), 3.88-3.94 (m, 1H), 4.28 (m, 1H), 4.43 (m, 2H), 7.65 (m, 2H), 7.86 (d, J=8.72 Hz, 2H), 8.18 (d, J=8.52 Hz, 2H), 8.45 (d, J=16.0 Hz, 1H), 12.71 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([CH3:27])[CH3:26])=[CH:21][C:20]=1[C:30]([CH2:33][CH3:34])([CH3:32])[CH3:31])=[O:13].[N+:35]([O-])([OH:37])=[O:36].CO>C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:35]([O-:37])=[O:36])=[CH:4][C:3]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([CH3:26])[CH3:27])=[CH:21][C:20]=1[C:30]([CH2:33][CH3:34])([CH3:32])[CH3:31])=[O:13]
Reactant: CCC(C)(C)c1ccc(OCCCNC(=O)c2ccc3ccccc3c2O)c(C(C)(C)CC)c1
Reactant: O=[N+]([O-])O
Solvent: CO
Solvent: CC(=O)O
Product: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc([N+](=O)[O-])c3ccccc3c2O)c(C(C)(C)CC)c1

Procedure:
100 g of 1-hydroxy-N-[γ-(2,4-di-tert-amylphenoxy)propyl]-2-naphthamide was dissolved in 1 liter of acetic acid and nitrated at 15° - 18° C using 23 g of a 60% nitric acid aqueous solution. After conclusion of the reaction, 1 liter of methanol was added thereto and the precipitated crystals were separated by filtration. Thus, 70 g of the object compound were obtained. The melting point was 209° - 210° C.
Reaction SMILES: [Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N=1)=O)(C(C)(C)C)(C)C.[CH2:46]([O:53][C:54]1[C:55]([C:74]([OH:76])=O)=[N:56][C:57]([CH2:61][C:62]2([C:67]3[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=3)[CH2:66][CH2:65][CH2:64][CH2:63]2)=[N:58][C:59]=1[OH:60])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[CH2:77]([NH:84][CH2:85][CH2:86][O:87][Si:88]([C:91]([CH3:94])([CH3:93])[CH3:92])([CH3:90])[CH3:89])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[CH2:77]([N:84]([CH2:85][CH2:86][O:87][Si:88]([C:91]([CH3:94])([CH3:93])[CH3:92])([CH3:89])[CH3:90])[C:74]([C:55]1[C:54]([O:53][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:59]([OH:60])[N:58]=[C:57]([CH2:61][C:62]2([C:67]3[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=3)[CH2:63][CH2:64][CH2:65][CH2:66]2)[N:56]=1)=[O:76])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNCc1ccccc1
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
This compound was prepared by following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) from 5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (324) and benzyl-[2-(tert-butyl-dimethylsilanyloxy)-ethyl]-amine (8I).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:11]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[Cl:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([NH:5][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: COc1c(N)cccc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1c(Cl)cccc1NN
Yield: 110.5 %

Procedure:
To a stirred suspension of 3-chloro-2-methoxyaniline (5 g, 31.7 mmol, 1.0 eq) in conc. HCl (25 mL) was added a solution of NaNO2 (3.28 g, 47.55 mmol, 1.5 eq.) in water (5 mL) dropwise at −5 to 0° C. until the reaction mixture formed a clear solution. The reaction mixture was added drop wise to a stirred solution of SnCl2 (13.24 g, 69.74 mmol, 2.2 eq) in conc. HCl (50 mL) at −5° C. for 30 min. A solid precipitate obtained was filtered out and washed with excess of ice cold water to get (3-chloro-2-methoxyphenyl)hydrazine (6.049 g, 94%, brown solid; TLC system: EtOAc/PE (3:7) Rf: 0.4).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[F:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([F:14])[C:7]=1[CH2:15][C:16]#[N:17].O>C1(C)C(C)=CC=CC=1.C(O)C.C(OCC)(=O)C>[C:2]([CH:15]([C:7]1[C:8]([F:14])=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=1[F:5])[C:16]#[N:17])(=[O:1])[CH3:3]
Reactant: CC[O-]
Reactant: COc1cc(F)c(CC#N)c(F)c1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C(C#N)C(C)=O)c(F)c1
Temperature: 50 °C

Procedure:
Solid sodium ethoxide (4.7 g, 66 mmol) was stirred in a mixture of xylene (20 mL) and ethanol (10 mL) and heated to 50° C. A solution of 2,6-difluoro-4-methoxybenzene-acetonitrile (i.e. the product of Step A) (8.0 g, 44 mmol) in ethyl acetate (10.4 mL) was added dropwise. The reaction mixture was heated at 50° C. for 4 h and then allowed to cool to ambient temperature. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (25 mL). The aqueous phase was acidified with 3 N aqueous HCl to pH 4 and extracted with ethyl acetate (100 mL). This organic phase was washed with water (50 mL), brine (50 mL), then dried over MgSO4, and concentrated to leave the title compound as a tan semisolid (8.0 g).