Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[OH:20][CH:21]([CH2:31][OH:32])[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[OH:20][CH:21]([CH2:31][OH:32])[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)=[CH:26][CH:25]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1ccc(OCC(O)CO)cc1
Product: OCC(O)COc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine and 4-(2,3-dihydroxypropoxy)aniline were reacted to produce N2-[4-(2,3-dihydroxypropoxy)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.09 (s, 1H), 8.95 (s, 1H), 7.98 (d, 1H, J=3.5 Hz), 7.51 (d, 2H, J=8.8 Hz), 7.32 (d, 1H, J=2.3 Hz), 7.17 (dd, 1H, J=2.3 and 8.8 Hz), 6.77 (dd, 3H, J=8.8 Hz), 4.90 (d, 1H, J=5.3 Hz), 4.64 (t, 1H, J=5.8 Hz), 4.23-4.19 (m, 4H), 3.91-3.89 (m, 1H), 3.80-3.73 (m, 2H), 3.41 (t, 2H, J=5.3 Hz); LCMS: ret. time: 15.04 min.; purity: 96%; MS (m/e): 429 (MH+).
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5](N2C=CN=C2)[CH:4]=1.CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O>C(O)(=O)C>[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:25])[C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(Cc2ccccc2)c(-n2ccnc2)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In the manner given in Example 24, 1-[4-(trifluoromethyl)-α-phenyl-0-tolyl]imidazole in acetic acid is heated with Jones' reagent to give 5-(trifluoromethyl)-2-imidazo-1-yl)benzophenone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: OCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1

Procedure:
A solution 3-bromobenzyl alcohol (7.1 g, 38 mmol) and tert-butyldimethylsilyl chloride (5.7 g, 38 mmol) in N,N-dimethylformamide (40 mL) was stirred at room temperature for 5 h. Water (40 mL) was added and the mixture was extracted with hexanes. The combined extracts were washed with 10% aqueous hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride, and dried over magnesium sulfate. The desired product was isolated after concentration and purification by silica gel chromatography (hexanes). 1H NMR (CDCl3) 7.48 (s, 1H), 7.34 (m, 1H), 7.24 (m, 2H), 4.72 (s, 2H), 0.95 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[O:7]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Reaction time: 20 h

Procedure:
To a stirred solution of 7.48 g (40 mmoles) of p-bromobenzyl alcohol and 6.07 g (60 mmoles) of triethylamine in 70 mL of sieve dried DMF at 0° C. was added 14.3 g (52 mmoles) of neat t-butyldiphenylsilylchloride. The ice-water bath was removed and the mixture was stirred further for 20 hours.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7](Cl)[N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])=[CH:4][N:3]=1.Cl.[CH3:31][NH:32][CH3:33].C(N(C(C)C)CC)(C)C.O>N1C=CC=CC=1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])=[C:4]([N:32]([CH3:33])[CH3:31])[N:3]=1
Reactant: CNC
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N(C)C)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 67 %

Procedure:
2-amino-chloro-9-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)purine (1) [M. J. Robins and B. Uznanski, Can. J. Chem., 59, 2601-2607 (1981)1(18.6 mmol, 7.96 g) was dehydrated three times azeotropically with anhydrous pyridine, and dissolved in anhydrous pyridine (180 ml), then dimethylamine hydrochloride (55.8 mmol, 4.55 g) and diisopropylethylamine (74.4 mmol, 12.9 ml) were added thereto with stirring at room temperature. The mixture was stirred at room temperature for 15 hours. After confirming completion of the reaction by TLC, water was added to the reaction mixture and concentrated in vacuo. Chloroform was added to the residue, and the organic layer was washed 3 times with water, 2 times with 5% aqueous sodium hydrogen carbonate, once with water and 2 times with 10% aqueous citrate solution, then the organic layer was dried with magnesium sulfate, and dried in vacuo after filtration. The residue was treated with azeotropic distillation with toluene until no odor of pyridine was noted, the product was purified by silica-gel chromatography (dichloromethane-ethanol) to obtain the product (2) 5.42 g (12.4 mmol) (67%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([N:12]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[O:11].[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:28]([C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([N:12]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[O:11])#[N:29]
Reactant: CN(C)C=O
Reactant: COC(CN(C(=O)CCOCCc1cccc(Br)c1)C1CCCCC1)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(CN(C(=O)CCOCCc1cccc(C#N)c1)C1CCCCC1)OC
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To 3-(3-bromophenethoxy)-N-cyclohexyl-N-(2,2-dimethoxyethyl)propanamide (4 g) [Preparation 3] in DMF (30 mL) was added zinc cyanide (1.59 g) and Pd(Ph3P)4 (0.52 g). The reaction flask was flushed with nitrogen then heated to 130° C. with stirring under nitrogen for 1 h. The reaction was worked up by the addition of ethyl acetate, which was washed three times with water, twice with brine, dried over sodium sulphate, filtered and the solvent removed to afford crude product as a yellow oil/gum. Further purification on silica eluting with 10-40% ethyl acetate/isohexane afforded the sub-titled compound as a pale yellow oil (3.44 g). MS [M+H-MeOH]+=357 (MultiMode+)
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]([F:22])([F:21])[F:20])=[CH:11][C:5]=2[N:4]=1.[NH2:25][C:26]1([CH2:32][OH:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O>O1CCOCC1>[F:20][C:19]([F:22])([F:21])[O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:3]([C:2]3[O:33][CH2:32][C:26]4([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[N:25]=3)=[N:4][C:5]=2[CH:11]=1
Reactant: FC(F)(F)Oc1ccccc1-c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Reactant: NC1(CO)CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)Oc1ccccc1-c1ccc2[nH]c(C3=NC4(CCCCC4)CO3)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
2-Trichloromethyl-5-(2-trifluoromethoxy-phenyl)-1H-benzimidazole (241 mg, 0.610 mmol, as prepared in step B of this Example) and (1-amino-cyclohexyl)-methanol (315 mg, 2.44 mmol, as prepared in the previous step) were placed in a 40 mL vial equipped with a magnetic stir bar. Water (8 mL) was added, and the mixture was cooled to 0° C. and stirred at that temperature for 1 h. Complete dissolution of starting materials did not occur, so the mixture was warmed to rt, treated with dioxane (8 mL), and stirred at rt for 14 h. The mixture was extracted three times with EtOAc (20 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography using a 12-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 2:5, v/v over 30 min. The column was repeated under these conditions, yielding 24.6 mg (10%) of the desired compound. 1H-NMR (400 MHz, d6-DMSO) δ: 7.78 (br. s., 1H), 7.46-7.64 (m, 5H), 7.27-7.46 (m, 1H), 4.27 (s, 2H), 1.60-1.82 (m, 6H), 1.47-1.58 (m, 1H), 1.33-1.46 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]2[C:2]([Cl:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=2[N:9]=1)[CH3:29])([CH3:20])([CH3:19])[CH3:18]
Reactant: Nc1ccc(F)c(Cl)c1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(Cl)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-chloro-4-fluoro-N2-phenylbenzene-1,2-diamine (300 mg, 1.26 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (264 mg, 1.39 mmol), HOAt (190 mg, 1.39 mmol), 4-methylmorpholine (0.31 mL, 2.79 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (270 mg, 1.39 mmol) in DCM (5 mL) was stirred at RT for 18 h. The reaction mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with DCM (×3). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in AcOH (5 mL) and the solution heated at 70° C. for 36 h. The volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford impure [(S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester. The product thus obtained was dissolved in 4N HCl in dioxane (7 mL) and heated at 70° C. for 2 h. The volatiles were removed in vacuo to afford (S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride as an off-white foam (368 mg, 80% over three steps). LCMS (Method C): RT 2.28 min [M+H]+ 290.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)=O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CC1C=CC(S([CH2:31][N+:32]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C.COCCOC.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[C:31]#[N:32])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: N#CC(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)(5-fluoropyridin-2-yl)methanone (2.43 g, 8.5 mmol), prepared as described in Procedure 2, in DME (60 mL), was added TosMIC (2.23 g, 11.4 mmol). The reaction mixture was cooled in an ice bath. A solution of potassium tert butoxide (1.0 M potassium tert butoxide in tert butanol, 22.8 mmol) in tert butanol/DME (22 mL t-BuOH, 20 mL DME) was added via a funnel at a slow stream. Upon completion of addition, the ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with water (approx 50 mL). The aqueous phase was extracted with CH2Cl2 (3×50 mL) and the combined organic portions were washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil. The yellow oil was dissolved in CH2Cl2 and loaded directly onto a silica gel ISCO cartridge (120 g) with elution at 40 mL/min gradient 0 to 15% EtOAc in hexane over 30 min (RT=23-29 min). 2-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)acetonitrile (1.8 g, 72% yield) was isolated as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35]C4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH:39](NC)([CH3:41])[CH3:40]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][N:34]([CH:39]([CH3:41])[CH3:40])[CH3:35])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:30])([F:31])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Reactant: CNC(C)C
Product: CC(C)N(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using N-isopropyl-N-methylamine instead of cyclopropylmethylamine. LC-MS: (M+1=531, obsd.=531).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([CH3:13])[C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4]([CH3:14])[CH:3]=1.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])=[C:20]([CH:33]=1)[CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([O:6][CH2:7][C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])=[C:20]([CH:33]=2)[CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:10])=[C:11]([CH3:13])[CH:12]=1
Reactant: CCS(=O)(=O)c1ccc(N)cc1CNC(=O)OCc1ccccc1
Reactant: Cc1cc(Br)cc(C)c1OCC(=O)O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCS(=O)(=O)c1ccc(NC(=O)COc2c(C)cc(Br)cc2C)cc1CNC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 97.6 %

Procedure:
To a solution of 79A (100 mg, 0.386 mmol) and 28A (148 mg, 0.386 mmol) in 2 mL pyridine at −15° C., was added POCl3 (0.040 mL, 0.425 mmol), dropwise. The mixture was stirred at this temperature for 20 min, then was quenched with water. The mixture was diluted with EtOAc, washed with water (2×), 1N HCl, water, sat. NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography to afford 222 mg (98%) of 79B as a colorless oil. MS (ESI) m/z 589.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19](S(C)(=O)=O)[N:18]=1.O>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]([O:12][CH2:13][CH3:14])=[O:11])[N:18]=1
Reactant: CCOC(=O)c1ccccc1O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccccc1Oc1nc(OC)cc(OC)n1
Temperature: 100 °C
Yield: 85.6 %

Procedure:
After washing with petroleum ether, 3.9 grams (0.079 mole) of 60% sodium hydride in mineral oil was suspended in 15 mL of dimethylformamide. The suspension was cooled, and a solution of 10.8 grams (0.065 mole) of ethyl salicylate in 20 mL of dimethylformamide was added dropwise with stirring. Upon completion of addition, the reaction mixture was stirred at ambient temperature for one hour, and then 10.5 grams (0.048 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine (prepared as in Example 1, Steps A-C) was added. Upon completion of addition, the reaction mixture was heated at 100° C. for 2.5 hours. The reaction mixture was cooled and poured into 250 mL of water. The mixture was extracted with ethyl acetate, and the extract was dried with magnesium sulfate. The mixture was filtered, and the filtrate was subjected to column chromatography on silica gel. Elution was accomplished using in succession 25% hexane in methylene chloride and 30% ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure to yield 12.5 grams of ethyl 2-(4,6-dimethoxypyrimidin-2-yloxy)benzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH:18]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]O)([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH:18]([CH3:20])[CH3:19])[CH:23]=2)=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CC(C)Oc1cccc(CO)c1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc(OC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 3-isopropyloxybenzyl alcohol (118 mg, 0.710 mmol) were dissolved in tetrahydrofuran (2 mL), and triphenylphosphine (165 mg, 0.629 mmol) and a diethyl azodicarboxylate toluene solution (2.2 M, 290 μL, 0.640 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 4 hours.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(O)c1cccc(OCc2ccc3ccccc3n2)c1
Solvent: c1ccncc1
Product: CCCCCC(OC(C)=O)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[[3-(1-hydroxyhexyl)phenoxymethyl]quinoline (1.7 g) in pyridine at 0° C. was added acetic anhydride (2.7 ml). The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo to obtain the crude product.
Reaction SMILES: C1(C)C=CC=CC=1.[Si:8]([O:15][CH2:16][C@@H:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].CO[CH:25](O)[C:26]([F:29])([F:28])[F:27]>O>[Si:8]([O:15][CH2:16][C@@H:17](/[N:22]=[CH:25]/[C:26]([F:29])([F:28])[F:27])[CH2:18][CH:19]([CH3:20])[CH3:21])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: COC(O)C(F)(F)F
Reactant: CC(C)C[C@H](N)CO[Si](C)(C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)/N=C/C(F)(F)F

Procedure:
A toluene (300 mL) solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine from Step 1 (50 g) and trifluoroacetaldehyde methyl hemiacetal (35 mL) was heated to reflux for 16 hours during which time water was collected in a Dean-Stark trap. The solvent was evaporated in vacuum and the residue was purified on SiO2 using hexanes and ethyl acetate (9:1) as eluant to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:14]1[C:23]2[C:18](=[C:19]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[O:17][C:16](=[O:32])[CH:15]=1>>[Cl:12][C:11]1[C:2]([NH:1][C:14]2[C:23]3[C:18](=[C:19]([O:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[O:17][C:16](=[O:32])[CH:15]=2)=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Reactant: COC(=O)c1cccc(Cl)c1N
Product: COC(=O)c1cccc(Cl)c1Nc1cc(=O)oc2c(OC3CCCC3)c(OC)ccc12

Procedure:
The title compound was prepared from methyl 2-amino-3-chlorobenzoate and 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one following the procedure outlined in Example 16 (30 min r×n time). 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 7.92 (m, 3H), 7.59 (t, 1H), 7.19 (d, 1H), 4.85 (m, 1H), 4.40 (s, 1H), 3.92 (s, 3H), 3.70 (s, 3H), 1.90-1.50 (m, 8H); MS (ESI): 443.9.
Reaction SMILES: [CH:1](=[CH:10][C:11](=[O:13])[CH3:12])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1>[Pt]=O.C(OCC)(=O)C>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][CH2:10][C:11](=[O:13])[CH3:12]
Reactant: COc1ccccc1C=CC(C)=O
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COc1ccccc1CCC(C)=O
Yield: 45 %

Procedure:
The crude o-anisalacetone is hydrogenated (100 g/l liter of ethyl acetate and 1 g of platinum oxide) and then distilled to give 1.25 moles (45%) of 1-(o-methoxyphenyl)-3-butanone, bp 90°-110° C., 0.15 mm Hg.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:25]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:26][CH2:27][CH2:28]/[C:29](=[N:31]/[OH:32])/[NH2:30])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[CH:22][N:23]=4)[C:8]=3[CH:24]=2)[CH2:3][CH2:2]1.[C:37](N1C=CN=C1)(N1C=CN=C1)=[S:38].N12CCCN=C1CCCCC2.Cl>C(#N)C.C(OCC)(=O)C.O>[CH:1]1([C:4]2[C:5]([N:25]([CH2:26][CH2:27][CH2:28][C:29]3[NH:30][C:37](=[S:38])[O:32][N:31]=3)[S:33]([CH3:36])(=[O:35])=[O:34])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[CH:22][N:23]=4)[C:8]=3[CH:24]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)N(CCC/C(N)=N/O)c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(CCCc1noc(=S)[nH]1)c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1
Yield: 79.6 %

Procedure:
In a 5-mL round bottom flask, a solution of Example 176 (25 mg, 0.049 mmol), 1,1′-thiocarbonyldiimidazole (13.75 mg, 0.073 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (30.1 μL, 0.195 mmol) in anhydrous acetonitrile (490 μL) was stirred under nitrogen at 25° C. for 2 hours. The reaction was diluted with ethyl acetate (50 mL) and H2O (10 mL), and the pH was adjusted to ˜3 with 1 N aqueous HCl. The layers were separated, and the organic phase was washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. The crude material was purified by SiO2 flash chromatography (Alltech Extract-Clean™ column, 10 g bed) eluting with a step gradient of 5% to 7.5% methanol/CH2Cl2 to afford the title compound as a yellow solid (22 mg, 0.039 mmol, 80%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.62 (m, 1H), 0.81-0.91 (m, 1H), 0.94-1.04 (m, 2H), 1.73-1.89 (m, 2H), 2.34-2.42 (m, 1H), 2.56-2.66 (m, 2H), 3.17 (s, 3H), 3.66-3.85 (m, 2H), 7.10 (s, 1H), 7.35 (t, J=8.89 Hz, 2H), 7.40 (s, 2H), 7.90 (s, 1H), 7.95 (dd, J=8.08, 5.80 Hz, 2H); MS (ESI+) m/z 554 (M+H)+, 1107 (2M+H)+; MS (ESI−) m/z 552 (M−H)−, 1105 (2M−H)−.