Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:27])[C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=1>Cl[Si](C)(C)C.C(O)CCC>[ClH:1].[CH:12]1([NH:11][C:4]2[N:3]=[C:2]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH3:27])[C:24](=[O:26])[CH3:25])=[CH:21][CH:22]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[CH2:15][CH2:14][CH2:13]1
Reactant: Clc1nc(NC2CCC2)c2nc[nH]c2n1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(NC3CCC3)c3nc[nH]c3n2)cc1
Product: Cl
Temperature: 117 °C
Yield: 61.7 %

Procedure:
A 5 L, 4-neck, round-bottomed flask fitted with a mechanical stirrer, digital thermometer, heating and cooling capabilities, condenser, addition funnel, and nitrogen inlet and outlet, was flushed with nitrogen and charged with 479.8 g (2.15 moles) of 2-chloro-N-cyclobutyl-9H-purin-6-amine, 387.5 g (2.36 moles) of N-(4-aminophenyl)-N-methyl-acetamide, and 3.6 L of dry 1-butanol. The mixture was stirred and 2.72 mL (0.02 moles) of chlorotrimethylsilane was added at 25° C. The mixture was heated to 117° C. over about 50 minutes. The reaction temperature and stirring was maintained for 12.5 hours. The mixture was cooled to 50° C. over a period of 2 hours. A temperature of 50° C. was maintained for an additional hour. The product was filtered and the filter cake was washed three times with a total of 1.2 L of 1-butanol. The filter cake was collected and dried at 50° C./20 mm Hg for 24 hours to give 514.3 g of light yellow crystalline solid. Theoretical yield was 832.0 g. Actual yield was 61.8%.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[CH:6]=1.CS[C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17].[NH2:21][C@H:22]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]([CH2:29][C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])[C:23]1=[O:37]>C(OCC)(=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH:11][C:14]([NH:21][C@H:22]3[CH2:28][CH2:27][CH2:26][CH2:25][N:24]([CH2:29][C:30]([N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)=[O:31])[C:23]3=[O:37])=[CH:15][N+:16]([O-:18])=[O:17])[CH:8]=[CH:7][C:5]=2[CH:6]=1
Reactant: Cc1cc2ccc(N)cc2o1
Reactant: N[C@H]1CCCCN(CC(=O)N2CCCC2)C1=O
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCOC(C)=O
Product: Cc1cc2ccc(NC(=C[N+](=O)[O-])N[C@H]3CCCCN(CC(=O)N4CCCC4)C3=O)cc2o1
Temperature: 25 °C
Yield: 12.3 %

Procedure:
Preparation of title compound. To 2-methyl-6-benzofuranamine (30 mg, 0.16 mmol) in ethyl acetate (1 ML) was added 1,1-bis(methylthio)-2-nitroethylene (26 mg, 0.16 mmol) and the mixture heated at reflux for 30 minutes. After cooling to room temperature, 1-[[(3S)-3-aminohexahydro-2-oxo-1H-azepin-1-yl]acetyl]pyrrolidine (38 mg, 0.16 mmol) was added and the resultant mixture heated for an additional 2 h. The reaction mixture was placed directly on a silica column and the product was eluted with 2% methanol/chloroform. Product-containing fractions were concentrated in vacuo and the residue was then further purified by elution through a reverse-phase cartride (Varian C-18 Mega Bond Elut) with a gradient of 100% water to 100% methanol. Concentration of product-containing fractions in vacuo provided the title compound (9 mg, 12%): MS (ESI, pos. ion spectrum) m/z 456 (M+H); HPLC (method C) tR 3.5 min.
Reaction SMILES: [CH3:1][C:2]1(Br)[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:3]1[O:4][C:5](=[O:7])[CH3:6].[N-:24]=[N+:25]=[N-:26].[Na+].O>CN(C)C=O>[CH3:1][C:2]1([N:24]=[N+:25]=[N-:26])[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:3]1[O:4][C:5](=[O:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)C(C)(Br)O[C@@H]1C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)C(C)(N=[N+]=[N-])O[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
Methyl 2,3,4,-tri-O-acetylglucopyranuronosyl bromide (7.94 g, 20 mmol) was dissolved in 250 ml of dimethylformamide and 2.6 g, that is 40 mmol of sodium azide was added. The mixture was stirred at room temperature for 24 hours and then poured into 500 ml of H2O. The organic soluble material was extracted three times with 150 ml ethyl acetate. The combined ethyl acetate extracts were washed twice with 100 ml H2O, brine, dried over MgSO4, and concentrated to dryness. The residue was recrystallized from ethanol to yield 5.46 g (76%) of methyl 2,3,4,-tri-O-acetylglucopyranuronosyl azide. Methyl 2,3,4,-tri-O-acetylglucopyranuronosyl azide had the melting point of 152°-154°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[N:12]1[C:21]2[CH:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][N:22]([CH:20]2[C:21]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:17][CH2:18][CH2:19]2)[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CC(C)(C)OC(=O)NCCCCNC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCCCN(Cc1cccc2cc[nH]c12)C1CCCc2cccnc21
Yield: 35 %

Procedure:
A heavy-walled Pyrex tube was charged with a solution of indole-7-carboxaldehyde (0.50 g, 3.44 mmol) in 1,2-dichloroethane (5 mL). This solution was treated with tert-butyl 4-(5,6,7,8-tetrahydroquinolin-8-ylamino)butylcarbamate, 3, (1.21 g, 3.78 mmol), sodium triacetoxyborohydride (1.46 g, 6.88 mmol) and a catalytic amount of acetic acid (2 drops). The reaction mixture was exposed to microwave irradiation for 10 min at a temperature of 100° C. After the irradiation, the reaction tube was cooled with high-pressure air until the temperature had fallen below 40° C. The crude reaction mixture was poured onto a saturated aqueous solution of sodium bicarbonate. The product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over potassium carbonate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-5% methanol/CH2Cl2) to afford 0.54 g (35% yield) of the desired product 6: 1H NMR (400 MHz, CDCl3) δ 12.87 (bs, 1H), 8.56 (d, J=3.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.41-7.37 (m, 2H), 7.10 (dd, J=5.2, 7.6 Hz, 1H), 6.97-6.88 (m, 2H), 6.51-6.49 (m, 1H), 4.26-4.20 (m, 2H), 3.96 (d, J=13.2 Hz, 1H), 3.60 (d, J=13.2 Hz, 1H), 2.92-2.72 (m, 3H), 2.65-2.55 (m, 2H), 2.50-2.40 (m, 1H), 2.29-2.20 (m, 1H), 2.14-2.04 (m, 1H), 1.95-1.68 (m, 2H), 1.47-1.15 (m, 2H), 1.39 (s, 9H); ESI+ MS: m/z (rel intensity) 449.2 (100, [M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([O:13][Si](C(C)(C)C)(C)C)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([OH:13])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cnn(Cc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cnn(Cc2ccccc2)c1
Reaction time: 8 h
Yield: 34.8 %

Procedure:
1-Benzyl-4-t-butyldimethylsilyloxypyrazole (3.0 g, 10.4 mmol) was dissolved in THF (20 ml) and tetrabutylammonium fluoride (52 ml of LM solution in THE) was added. The reaction was stirred overnight and the solvent removed in vacuo. The residue was dissolved in water and extracted into diethylether. The organics dried over sodium sulfate, and the ether removed in vacuo. The residue purified by column chromatography (silica gel, chloroform→2% methanol/chloroform) to yield product (0.63 g, 35%). MS
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9](F)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:6]([CH2:19][CH2:20][CH3:21])=[CH:5][C:3]=1[NH2:4].[BH4-].[Na+].C(O)(=O)C>CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([CH:9]([C:10]([F:11])([F:12])[F:13])[C:14]([F:16])([F:17])[F:15])[C:6]([CH2:19][CH2:20][CH3:21])=[CH:5][C:3]=1[NH2:4]
Reactant: CCCc1cc(N)c(C)cc1C(F)(C(F)(F)F)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCc1cc(N)c(C)cc1C(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 5 h
Yield: 98.2 %

Procedure:
2-Methyl-5-n-propyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (1.6 g, 5 mmol) was dissolved in dimethyl sulfoxide (20 ml), sodium borohydride (378 mg, 10 mmol) was added by small portions, and the mixture was stirred at 60° C. for 5 hr. Ice was added to the reaction mixture by small portions, and then acetic acid was added dropwise. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed 4 times with water, dried over magnesium sulfate and concentrated under reduced pressure to give the desired compound (1.47 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]([F:26])([F:25])[F:24])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([OH:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=3)[C:6]=2[CH:22]=1.[Si:27](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.O>ClCCl>[Cl:1][C:2]1[C:3]([C:23]([F:24])([F:26])[F:25])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([OH:12])[CH3:11])[N:7]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][O:21][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:17][CH:18]=3)[C:6]=2[CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
A mixture of 1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol (step 3, 461 mg, 1.19 mmol), tert-Butyldiphenylsilyl chloride (0.35 ml, 1.3 mmol), triethylamine (0.2 ml, 1.4 mmol) and N,N-dimetylaminopyridine (6 mg, 0.05 mmol) in dichloromethane (11 ml) was stirred under nitrogen at room temperature for 4 h. was added water (50 ml) and extracted with dichloromethane (100 ml). The organic layer was washed with water (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (3:1/1:1) to afford 590 mg (80%) of the title compound as white amorphous.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5](=O)[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[N:8]=1.[Cl-:13].[CH3:14]O>>[CH3:14][O:11][C:9]([C:7]1[CH:6]=[C:5]([Cl:13])[N:4]=[C:3]([S:2][CH3:1])[N:8]=1)=[O:10]
Reactant: [Cl-]
Reactant: CSc1nc(C(=O)O)cc(=O)[nH]1
Reactant: CO
Product: COC(=O)c1cc(Cl)nc(SC)n1

Procedure:
In step a of scheme 2, reaction of diethyl diethyl oxalacetate and methylisothiourea provides the 2-methylthio-6-oxo-1,6-dihydro-pyrimidin-4-yl carboxylic acid. In step b, refluxing the carboxylic acid with tionyl chloride in an organic solvent such as tolune, followed by treatment with methanol provides the 2-methylthio-6-chloro-pyrimidin-4-yl carboxylic acid methyl ester. In step c, the methyl ester is converted to the amide using the appropriate amine, such as NHRcRd. In step d, the boronic acid derivative of Ring A (such as [Ring A]-B(OR)2, is coupled to the pyrimidine-4-carboxylic amide using a coupling reagent, such as PdCl2(dppf). The desired compound is produced via synthetic steps e and f, which are similar to steps d and e in scheme 1.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][N:36]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ncnn2c(-c3csc(C4CCNCC4)n3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(c2nc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cs2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 28.2 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(2-piperidin-4-yl-1,3-thiazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.17 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (15 μL, 0.19 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile to provide 28 mg (28%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1 H), 8.38 (s, 1 H), 8.10 (s, 1 H), 7.83 (d, 1 H), 7.67 (s, 1 H), 7.27-7.40 (m, 5H), 7.17-7.24 (m, 2 H), 5.66 (s, 2 H), 3.59-3.69 (m, 2 H), 3.16-3.28 (m, 1 H), 2.85-2.95 (m, 5H), 2.20 (d, 2 H), 1.78 (q, 2 H); ES-MS m/z 585.21 [M+H]+, HPLC RT (min) 2.97.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](Cl)=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4].[C-:30]#[N:31].[Na+].O>CN1CCCC1=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([C:30]#[N:31])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4]
Reactant: [C-]#N
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(C)c(=O)c21
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(C#N)n(C)c(=O)c21
Temperature: 50 °C
Reaction time: 1 h
Yield: 179 %

Procedure:
8 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of N-methylpyrrolidone, and 10 mg of sodium cyanide was added thereto. The mixture was stirred at 50° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to give 14 mg of t-butyl 4-[7-(2-butynyl)-2-cyano-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate. 5 mg of this compound was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.12 mg of the title compound.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([N:18]1[C@@H:23]([C@@H:24]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:25]([N:35]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[CH2:22][O:21][C:20](=[O:58])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].I[CH2:60][CH3:61]>O1CCCC1>[C:11]([O:15][C:16]([N:18]1[C@@H:23]([C@@H:24]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:25]([N:35]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[CH2:22][O:21][C:20](=[O:58])[C@@H:19]1[CH2:60][CH3:61])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CC(=O)OC[C@@H]1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H]1C(=O)OC[C@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
Slowly add lithium hexamethyldisilazide (2.28 mL, 2.28 mmol, 1.0 M in tetrahydrofuran) at −78° C. under nitrogen to a solution of (R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-oxomorpholine-4-carboxylic acid tert-butyl ester) (1 g, 1.52 mmol) and iodoethane (1.24 mL, 15.2 mmol) in anhydrous tetrahydrofuran (10 mL). Stir at −78° C. for 45 minutes, remove the bath and stir for 1.5 hours. Add water and ethyl acetate. Separate the organic layer and extract the aqueous layer with ethyl acetate. Combine the organic layers, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 90:10 hexane:ethyl acetate) to give the desired compound as a white solid (848 mg, 82%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:17][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:9][CH:10]=[C:11]([CH2:13][O:14][C:15]4[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]5[CH:28]=[CH:27][N:26]=[CH:25]5)=[CH:17][CH:16]=4)[N:12]=3)=[CH:6][CH:7]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(C(Oc2ccc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)cc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 43 %

Procedure:
To a solution of 2-(4-hydroxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole (250 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (oily, 60%, 30 mg) and stirred at room temperature for one hour, to which chlorodiphenylmethane (270 mg) was added and stirred at 80° C. for 6 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with 1N-sodium hydroxide and water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-methanol (50:1, v/v), crystals of 2-(4-diphenylmethoxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole (155 mg, 43%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 106-107° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>CN(C)C=O>[OH2:3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: Nc1ccncc1
Solvent: CN(C)C=O
Product: O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)Nc1ccncc1
Temperature: 25 °C
Yield: 18.7 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.43 g, 0.01914 mole) was added dropwise, slowly, to a stirred and chilled solution of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) in dimethylformamide (60 ml). The reaction mixture was stirred at room temperature for 1.5 hour. An additional portion of oxalyl chloride (0.5 ml, 0.0057 mole) was added. After additional stirring at room temperature for 0.5 hr, a solution of 4-aminopyridine (1.81 g, 0.0192 mole) in dimethylformamide (10 ml) was added and the mixture was stirred at room temperature overnight. The mixture was poured into ice water (400 ml) and the resulting solid was collected by filtration, dissolved in hot isopropyl alcohol, filtered hot, and cooled to room temperature to give a solid. The solid was collected by filtration, rinsed with water, and dried under high vacuum to give 1.0 g of title compound, mp>250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)[CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH3:17][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26]([CH2:25][N:22]3[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]3)=[CH:34][CH:33]=2)=[CH:7][C:6]=1[B:8]1[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:11])([CH3:12])[O:9]1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1B1OC(C)(C)C(C)(C)O1
Yield: 23.6 %

Procedure:
A solution of 5-amino-2-methylphenylboronic acid pinacol ester (1.001 g, 4.294 mmol), 4-((4-methylpiperazin-1-yl)methyl)benzoic acid (1.112 g, 4.746 mmol) and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.446 g, 4.691 mmol) in DMF (20 mL) at ambient temperature was added ethyldiisopropylamine (0.98 mL, 5.6 mmol), the mixture stirred at room temperature for 3d and poured into water (100 ml). The aqueous phase was washed with diethyl ether, treated with saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 10-100% ethyl acetate in heptane, and then 0-20% methanol in DCM modified with 1% ammonia) to afford the title compound as a white solid (456 mg, 24%). 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J=8.2, 2.0 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.74 (s, 1H), 7.64 (d, J=2.3 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.3 Hz, 1H), 3.57 (s, 2H), 2.52 (s, 3H), 2.5 (br s, 8H), 2.31 (s, 3H), 1.35 (s, 12H). LCMS: M+H+=450.4.