Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=O)C.[NH3:25]>O1CCOCC1>[C:4]([CH2:6][C:7]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:3])[NH2:25]
Reactant: N
Reactant: CCOC(=O)Cc1cc(OCCN2CCOCC2)ccc1C(=O)O
Solvent: C1COCCO1
Product: NC(=O)Cc1cc(OCCN2CCOCC2)ccc1C(=O)O

Procedure:
A solution of 2-ethoxycarbonylmethyl-4-(2-morpholin-4-yl-ethoxy)-benzoic acid (2.65 g, 10.0 mmole) and saturated ammonia in dioxane (15 mL) in a pressure bottle is stirred and heated using an oil bath at 95° C. overnight. This mixture is cooled and followed by Ic/ms, reaction not complete. The dioxane is evaporated and replaced with 15 mL of 7M ammonia in methanol and heated overnight in a pressure bottle using an oil bath at 70° C., still a small amount of starting material left. The solvent is removed in vacuo and used as is in the next step MS (ESI): m/z 309.3 (M+H).
Reaction SMILES: [C:1]([N:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:24][CH3:25])=[C:17]([CH:23]=1)[C:18]([N:20]=[C:21]=[S:22])=[O:19].II.CO>O1CCCC1.N1C=CC=CC=1>[CH2:8]([C:7]1=[CH:6][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[S:22]/[C:21]/1=[N:20]\[C:18](=[O:19])[C:17]1[CH:23]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=1[O:24][CH3:25])[CH2:9][CH2:10][CH3:11]
Reactant: COc1ccc(Cl)cc1C(=O)N=C=S
Reactant: CCCCCC=NC(C)(C)C
Agent: II
Solvent: c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To the product of Example 1A (1.90 g, 12.2 mmol) in tetrahydrofuran (10 mL) at room temperature under N2 was added the product of Example 1C (2.30 g, 10.1 mmol). After 1 h at room temperature, the reaction was treated with I2 (2.59 g, 10.2 mmol), methanol (30 mL) and pyridine (3 mL) and stirred for 1 hour. The reaction was then partitioned between saturated NaHCO3/diethyl ether with continued stirring overnight. The reaction was diluted further with saturated NaHCO3/diethyl ether, the layers separated and the aqueous phase extracted again with diethyl ether (2×). The organics were combined, dried (MgSO4), filtered and solvent evaporated. Toluene/acetonitrile was added and evaporated 2× to remove excess pyridine and H2O. The crude was flash chromatographed, eluting with diethyl ether:CH2Cl2:hexane (7:3:3) to provide 2.68 g of the desired product with impurities running above and below. This material was dissolved in a minimum of CH2Cl2, hexane added until slightly cloudy and allowed to sit for 4 hours. A white crystalline solid was collected and washed with cold 1:1 CH2Cl2:hexane to provide 962.78 mg of the title compound. The mother liquor was recrystallized from methanol to provide 555 mg additional title compound. The second mother liquor was concentrated to dryness, dissolved in a minimum of CH2Cl2 and flash chromatographed on silica gel, eluting with diethyl ether:CH2Cl2:hexane (7:1:3) to provide an additional 600 mg of the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 0.98 (t, 3H), 1.37-1.49 (m, 2H), 1.65 (s, 9H), 1.67-1.77 (m, 2H), 2.83 (t, 2H), 3.92 (s, 3H), 6.91 (d, 1H), 7.34 (dd, 1H), 7.95 (s, 1H), 8.11 (d, 1H). MS (DCI/NH4+) m/z 381 (M+H)+. Anal. calcd for C19H25ClN2O2S: C, 59.91; H, 6.61; N, 7.35. Found: C, 59.88; H, 6.67; N, 7.42.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6]1.[CH2:21](N(CC)CC)C.S(Cl)(C)(=O)=O>C(Cl)Cl>[OH:2][CH2:3][CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH3:21])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6]1
Reactant: CCN(CC)CC
Reactant: OCCC1Cc2ccccc2C(c2ccccc2)=N1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(c1ccccc1)=NC(CCO)C2
Reaction time: 0.5 h

Procedure:
To a solution cooled to -10° C. of 9 g of the compound of formula (XXXI) obtained in the preceding step and 12.5 ml of triethylamine in 250 ml of methylene chloride are added 5.4 ml of mesyl chloride. Then it is left for 30 minutes at ambient temperature, then washed with water with the help of 1 N hydrochloric acid solution, with water, with a sodium bicarbonate solution, dried on sodium sulfate, filtered and the filtrate is evaporated. An oil is obtained which is then crystallized.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[C:9](=[O:26])[N:10]1[CH2:13][C:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:11]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:9]([N:10]1[CH2:11][C:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:13]1)=[O:26]
Reactant: CCCCCC1(c2ccc(F)cc2)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC1(c2ccc(F)cc2)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reaction time: 1 h

Procedure:
780 mg (1.56 mmol) of tert-butyl[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-(4-fluoro-phenyl)azetidin-1-yl)ethyl]carbamate are solubilized in 10 ml of dichloromethane. 4 ml of trifluoroacetic acid are introduced. The reaction medium is stirred for 1 hour and then concentrated to dryness. The residue is taken up in a 1N aqueous solution of sodium hydroxide and extracted with dichloromethane and then the resulting product is dried over magnesium sulphate, filtered and evaporated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].O[C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH2:14][O:15][C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Cn1ncc(C=O)c1-c1ccc(F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a solution of 5-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (1.02 g, 5.0 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (200 mg, 5.27 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hr. Sodium sulfate decahydrate (1.0 g) was added to the reaction mixture, and the mixture was allowed to warm to room temperature and stirred for 30 min. The insoluble material was filtered off, and the filtrate was concentrated to give a colorless oil. To this oil were added methyl 4-hydroxybenzoate (910 mg, 6.0 mmol), tributylphosphine (1.61 g, 8.0 mmol) and tetrahydrofuran (10 mL), and 1,1′-(azodicarbonyl)dipiperidine (1.50 g, 5.94 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10%-65% ethyl acetate/hexane) to give the title compound (925 mg, yield 54%, 2 steps) as a yellow oil.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:12]([C:24]1[CH:29]=[C:28]([O:30]C)[C:27]([C:32](=[O:47])[NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:36]=2)=[CH:26][N:25]=1)[C:13](=[O:23])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17].CCOCC>FC(F)(F)C(O)=O>[OH:30][C:28]1[C:27]([C:32](=[O:47])[NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:36]=2)=[CH:26][N:25]=[C:24]([NH:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:29]=1
Reactant: COc1ccc(CN(C(=O)CCC(=O)OC(C)(C)C)c2cc(OC)c(C(=O)NCc3cccc(-c4ccccc4)c3)cn2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)CCC(=O)Nc1cc(O)c(C(=O)NCc2cccc(-c3ccccc3)c2)cn1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
A solution of the mixture (345 mg) containing tert-butyl 4-[(2,4-dimethoxyphenyl)methyl-{4-methoxy-5-[(3-phenylphenyl)methylcarbamoyl]-2-pyridyl}amino]-4-oxobutanoate in trifluoroacetic acid (4 mL) was left standing at room temperature for 17 hours. Ether (60 mL) was added to the reaction solution. The resulting suspension was filtered, and the product collected by filtration was washed with ether and dried under reduced pressure. To the obtained residue, a solution of boron tribromide in dichloromethane (1 M, 6 mL) was added at room temperature, and the mixture was stirred at 40° C. for 6 hours. The reaction mixture was cooled to room temperature, and water was then added thereto. The resulting suspension was filtered, and the product collected by filtration was washed with water and ether. The obtained residue was suspended in ethanol, and the suspension was shaken for 15 minutes in an ultrasonic bath and then filtered. The product collected by filtration was dried under reduced pressure to obtain the title compound (56.7 mg).
Reaction SMILES: [F:1][C:2]([F:26])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22]CC)=[O:21])=[CH:12][C:11]=2[CH:25]=1)[C:3]([F:6])([F:5])[F:4].[OH-].[Na+]>C1COCC1.CCO.O>[F:26][C:2]([F:1])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]([C:16]([F:17])([F:18])[F:19])[C:13]([C:20]([OH:22])=[O:21])=[CH:12][C:11]=2[CH:25]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CCOC(=O)C1=Cc2cc(C(F)(F)C(F)(F)F)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(C(F)(F)C(F)(F)F)ccc2OC1C(F)(F)F
Reaction time: 16 h

Procedure:
To a stirred solution of the ethyl ester (Step 1) (0.090 g, 0.231 mmol) in THF:EtOH:H2O (7:2:1) (4 mL) was added aqueous NaOH solution (0.11 mL, 2.5 M). After stirring 16 hours, the reaction was partially concentrated in vacuo to remove the organic solvents, diluted with H2O, and washed with diethyl ether. The resulting aqueous phase was acidified with concentrated HCl, extracted with diethyl ether, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. The oil was purified by flash chromatography (silica, hexanes-ethyl acetate, 3:1 with 5% acetic acid). This procedure yielded the title acid (0.020 g, 24%) as a white powder: mp 162.3–164.7° C. 1H NMR (acetone-d6/300 MHz) 8.05 (s, 1H), 7.90 (s, 1H), 7.74 (d, 1H, J=8.7 Hz), 7.29 (d, 1H, J=8.7 Hz), 5.97 (q, 1H, J=6.8 Hz). FABLRMS m/z 361 (M−H). ESHRMS m/z 361.0111 (M−H, Calc'd 361.0094).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][C:9]=2[C:8]([Br:20])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:21]([O-])([OH:23])=[O:22].CCOC(C)=O.CO>FC(F)(F)C(O)=O>[C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][C:9]=2[C:8]([Br:20])=[CH:7][C:6]=1[N+:21]([O-:23])=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Br)c2c1CC(N1CCCC1)CC2
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CC(N1CCCC1)CC2
Reaction time: 4 h

Procedure:
A mixture of 1-acetamido-4-bromo-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalene (0.3 g) in trifluoroacetic acid (10 mL) was cooled in an icebath and treated with fuming nitric acid (0.5 mL). After stirring for 4 h, the solvent was evaporated and the residue taken up in methylene chloride:water. The mixture was basified with 12.5% NaOH, and the aqueous layer back extracted. The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a solid. Preparative thin layer chromatography (7:3 EtOAc:MeOH) was used to obtain the purified product (0.12 g).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][CH:19]([CH2:21][C:22]([OH:24])=O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[NH:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[NH:28]>>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]4[O:24][N:28]=[C:27]([N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)[N:26]=4)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(NO)N1CCCCC1
Reactant: O=C(O)CC1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Product: c1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](Cc4nc(N5CCCCC5)no4)CS3)cc2c1

Procedure:
[(7-Cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]acetic acid prepared in Example 75 and N-hydroxypiperidinecarboxamidine were reacted according to the same procedure as Example 262 to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[C:13]([CH3:15])[O:12][C:11](=[O:16])[CH:10]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:32](O)(=[O:41])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N#N>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:8][C:9]1[CH:14]=[C:13]([CH3:15])[O:12][C:11](=[O:16])[C:10]=1[C:32](=[O:41])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: O=C(O)CCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O)c(C(=O)CCc2ccccc2)c(=O)o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
Triethylamine (1.12 ml; 8 mmol; Aldrich) was added to 4-hydroxy-6-methyl-2-pyrone (1.01 g; 8 mmol; Aldrich) in 60 ml CH2Cl2, and the reaction mixture was stirred under N2 for 10 min at 0° C. DMAP (293.3 mg; 2.4 mmol; Aldrich) and DCC (1.65 g; 8 mmol; Aldrich) were added, and the reaction mixture was stirred under N2 for 15 min at 0° C. Hydrocinnamic acid (1.20 g; 8 mmol; Aldrich) was added, and the reaction mixture was stirred N2 for 12 h at room temperature. The reaction mixture was filtered on celite to remove urea, acidified to pH ˜2 by addition of by 1 N HCl, diluted by addition of 60 ml water was added, and extracted with CH2Cl2 (2×100 ml). The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated under vacuum. The product was isolated by chromatography on silica gel. Yield: 58%. MS (MALDI): calculated, m/z 259.1 (MH+); found, 259.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:27][O:28][CH3:29].CCOC(C)=O.CCCCCC>C(Cl)Cl>[CH3:27][O:28][CH2:29][O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COCCl
Reactant: O=Cc1ccc(-c2ccc(CO)cc2)cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COCOCc1ccc(-c2ccc(C=O)nc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
To a solution of 5-(4-(hydroxymethyl)phenyl)picolinaldehyde (0.6 g, 2.81 mmol) in DCM (15 mL) at 0° C. was added diisopropylethyl amine (1.5 mL, 8.4 mmol), followed by chloro(methoxy)methane (1.0 mL, 14.08 mmol). The reaction mixture was stirred at 0° C. for 3 h. After completion of the reaction by monitoring with TLC (30% EtOAc\hexane), the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water (100 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by a Biotage Isolera® One column purifier (silica gel 100-200μ) using 13% ethyl acetate in hexane and the product isolated as a yellow viscous liquid (0.36 g, 50% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 9.14 (s, 1H), 8.32 (dd, 1H), 7.996 (d, 1H), 7.83 (d, 2H), 7.50 (d, 2H), 4.67 (s, 2H), 4.60 (s, 2H), 3.28 (s, 3H); LC-MS: m/z 258.1 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)[OH:14])(=O)=O)=CC=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O>[N:26]([CH2:12][C@@H:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=1)[OH:14])=[N+:27]=[N-:28]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)c2ccc(F)c(C(F)(F)F)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H](O)c1ccc(F)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
(R)-2-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-hydroxyethyl 4-methylbenzenesulfonate (3.5 g, 9.25 mmol) was dissolved in 20 mL of DMSO. Sodium azide (1.2 g, 18.5 mmol) was added and the mixture was stirred at 80° C. for 3 h. The clear solution was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was dried and concentrated to give (R)-2-azido-1-(4-fluoro-3-trifluoromethylphenyl)-ethanol as a pale brown oil (2.27 g) which was used as is in the next step.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].N12CCN(CC1)CC2.C(O)(=O)C>C(OCC)C>[CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10](=[CH2:11])[C:9]([O:13][CH3:14])=[O:12]
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Solvent: O=Cc1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: C=C(C(=O)OC)C(O)c1ccccc1
Temperature: 35 °C
Reaction time: 60 h
Yield: 90 %

Procedure:
A mixture of benzaldehyde (82.1 mL, 0.81 mol), methyl acrylate (109.1 mL, 1.211 mol), 1,4-diazabicyclo (2,2,2) octane (13.6 g, 0.12 mol), and acetic acid (1.4 mL, 0.024 mol) was allowed to stir at 35° C. for 60 h, at which point the reaction was determined to have proceeded to 70% completion by 1H NMR. Methyl acrylate (20.9 mL, 0.23 mol) was then added and the solution was allowed to react at 35° C. for an additional 48 h. The mixture was diluted with diethyl ether (1.0 L) and was washed with 2×200 mL portions of a pH 7 phosphate buffer. After concentration in vacuo, the remaining mixture was distilled at reduced pressure (12 mm) to afford 6.5 g of unreacted benzaldehyde and 130.0 g (90%) of the desired product as a colorless oil: b.p. 130° C. (12 mm); IR (film) 1718, 1440 cm-1 ; 1H NMR (CDCl3) δ3.67 (s, 3H), 5.52 (br s, 1H), 5.83-5.85 (m, 1H), 6.29-6.31 (m, 1H), 7.23-7.39 (m, 5H); 13C NMR (75 MHz, CDCl3) δ51.8, 72.9, 125.8, 126.5, 127.7, 128.3, 141.2, 141.9, 166.6.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H](O)C=C2)=C(Cl)N=1.[CH:55]([N:58]1[CH:62]=[C:61]([CH2:63][CH2:64][NH2:65])[N:60]=[CH:59]1)([CH3:57])[CH3:56]>>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:4]2[N:3]=[C:2]([NH:65][CH2:64][CH2:63][C:61]3[N:60]=[CH:59][N:58]([CH:55]([CH3:57])[CH3:56])[CH:62]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)n1cnc(CCN)c1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCc4cn(C(C)C)cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared from N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (compound of Example 4) and 2-(1-isopropyl-1H-imidazol-4-yl)-ethylamine using a procedure analogous to that of Example 9 for the desired salt. MS (ES+) m/e 638 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)c1ccnc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Temperature: -76 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
In a round-bottomed flask, 2-bromo-4-tert-butylpyridine (149 mg, 0.70 mmol) was dissolved in THF (4 mL). The colorless solution was cooled to −76° C. and n-butyllithium (1.6M solution in hexanes, 0.57 mL, 0.91 mmol) was added dropwise. The brown solution was stirred at −76° C. for 30 min then tributylchlorostannane (0.23 mL, 0.85 mmol) was slowly added. The reaction mixture was stirred at −76° C. for 15 min and then warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with 50 mL EtOAc (2×). The combined organic layers were washed with 5 mL water and 5 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 24 g SiO2 with EtOAc/Hexanes (gradient: 0-20% EtOAc). All fractions containing product were combined and concentrated to give 147 mg (30%, purity=60%) of 4-tert-butyl-2-(tributylstannyl)pyridine as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10](O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])[CH:47]=1>CN(C=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([NH:56][CH2:55][CH2:54][CH2:53][CH2:52][C:48]2[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)c(-c2ccccc2)c1
Reactant: NCCCCc1cccnc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCCCc1cccnc1)c1ccc(-c2ccccc2)c(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 0.508 g 1.85 mmol) of 3,4-diphenylbenzoic acid in 10 mL of anhydrous DMF was added 0.44 mL of diphenylphosphoryl azide with stirring. Triethylamine (0.28 mL) was then added and stirring at 3° C. 0 was continued for 1 hour. 3-pyridinebutanamine (0.309 g) was added and stirring was continue for 30 minutes at 3° C. and for 17 hours at room temperature. The solvent was removed under the oil pump vacuum and ethyl acetate was added to the residue. The solution was washed with aqueous 5% sodium bicarbonate. dried (MgSO4) and concentrated in vacuo. The residual oil was chromatographed on 50 g of silica gel, eluting with methylene chloride-methanol-conc.ammonium hydroxide (95:5:0.05). The pure fractions were combined and lyophilized from benzene to yield a 0.708 g of 3,4-Diphenyl-N-[4-(3-pyridinyl)butyl]benzamide 0.25 molar hydrate as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[CH:12]=[N:13]O)[C:5]([CH:19]([CH3:21])[CH3:20])=[C:4]([Cl:22])[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(#N)C.CCOCC>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:12]#[N:13])[C:5]([CH:19]([CH3:20])[CH3:21])=[C:4]([Cl:22])[N:3]=1
Reactant: Cc1cc(C=NO)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1cc(C#N)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a stirred solution of (70) (4.4 g, 12.93 mmol) in acetonitrile (40 ml), was added triphenylphosphine (13.56 g, 51.73 mmol) and carbon tetrachloride (2.5 ml, 25.86 mmol). After 30 min., carbon tetrachloride (5 ml) was added and the mixture was stirred for 1 hr. The mixture was diluted with ether, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:hexanes (1:4)) to afford 3.82 g (94%) of a white solid. m.p. 143-144° C.; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.0 Hz), 2.45 (3H, s), 3.60 (1H, m), 7.18 (1H, m), 7.25 (1H, m), 7.40 (1H, m).