Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:29]([O:36][CH2:37][C@@H:38]1[C@@H:43]([O:44][CH3:45])[C:42]([CH3:47])([CH3:46])[CH2:41][CH2:40][C@H:39]1[CH:48]=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC>[CH3:45][O:44][C@H:43]1[C:42]([CH3:46])([CH3:47])[CH2:41][CH2:40][C@@H:39](/[CH:48]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C@@H:38]1[CH2:37][O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO[C@@H]1[C@@H](COCc2ccccc2)[C@H](C=O)CCC1(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCC/C=C/[C@@H]1CCC(C)(C)[C@H](OC)[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a stirred solution of n-octyltriphenylphosphonium bromide (313 mg) in dry tetrahydrofuran (0.5 ml) and dry HMPA (0.5 ml), n-BuLi (0.44 ml, 1.6M solution in n-hexane) was added at 0° C. After the mixture was stirred at 0° C. for 30 min, a solution of (1R,2R,3R)-2-(benzyloxymethyl)-3-methoxy-4,4-dimethylcyclohexane-1-carbaldehyde (68 mg) in dry tetrahydrofuran (0.5 ml) was added to the resulting orange solution. The mixture was stirred at 0° C. for 30 min, and at room temperature for 2 hrs. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (using n-hexane:ethyl acetate=10:1 as an eluent) to give benzyl [(1R,2R,6S)-2-methoxy-3,3-dimethyl-6-[(E)-1-nonenyl]cyclohexyl]methyl ether (54 mg 61%).
Reaction SMILES: C(=N[NH:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:30]([O:35][CH2:36][CH3:37])(=[O:34])[C:31]([CH3:33])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[CH2:36]([O:35][C:30]([C:31]1[NH:15][C:16]2[C:17]([CH:33]=1)=[C:18]([C:26]([CH3:27])([CH3:28])[CH3:29])[CH:19]=[C:20]([C:22]([CH3:25])([CH3:23])[CH3:24])[CH:21]=2)=[O:34])[CH3:37]
Reactant: CCOC(=O)C(C)=O
Reactant: CC(C)(C)c1cc(NN=C(c2ccccc2)c2ccccc2)cc(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2c(C(C)(C)C)cc(C(C)(C)C)cc2[nH]1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
N-Benzhydrylidene-N′-(3,5-di-tert-butyl-phenyl)-hydrazine (617 mg, 1.6 mmol) was dissolved in ethanol (12 ml). Then, ethyl pyruvate (212 μl, 1.9 mmol) and p-toluene sulfonic acid monohydrate (914 mg, 4.8 mmol) were added thereto. This was heated and stirred at 150° C. by microwave under a nitrogen atmosphere for one hour. After cooling it to room temperature, the reaction mixture was combined with water and an aqueous solution saturated with sodium bicarbonate. The product was extracted into ethyl acetate. The organic layer was isolated, and washed with an aqueous solution saturated with sodium chloride, and dried over magnesium sulfate. The desiccant was removed by filtration, and concentration was performed. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate=100/5). Thus, 4,6-di-tert-butyl-1H-indole-2-carboxylic acid ethyl ester was obtained as a brown solid (268 mg, 56%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([C@H:28]([NH2:30])[CH3:29])=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:30][C@@H:28]([C:25]4[CH:24]=[N:23][C:22]([CH3:21])=[N:27][CH:26]=4)[CH3:29])[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: Cc1ncc([C@@H](C)N)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(N[C@H](C)c4cnc(C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (350 mg, 1.23 mmol) and (R)-1-(2-methylpyrimidin-5-yl)ethanamine (300 mg, 2.19 mmol) in acetonitrile (3 mL) and N,N-diisopropylethylamine (0.86 mL, 4.9 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-55% acetonitrile-water [10 mM Et2NH]) to yield an off-white solid.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1([CH3:24])[C:18]2[C:11]([CH:12]=[C:13]3[C:17]=2[CH:16]=[N:15][N:14]3[CH2:19][C@H:20](O)[CH3:21])=[C:10]([CH3:23])[CH:9]=[CH:8]1.C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([C@@H:20]([CH3:21])[CH2:19][N:14]1[C:13]2=[CH:12][C:11]3[C:18]([C:7]([CH3:24])([CH3:6])[CH:8]=[CH:9][C:10]=3[CH3:23])=[C:17]2[CH:16]=[N:15]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1=C2C=c3c(cnn3C[C@@H](C)O)=C2C(C)(C)C=C1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C2C=c3c(cnn3C[C@H](C)N=[N+]=[N-])=C2C(C)(C)C=C1
Yield: 80.3 %

Procedure:
0.5 ml (6.24 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 0.8 g (3.1 mmol) of (R)-1-(4,4,7-trimethyl-1,4-dihydro-indeno[2,1-c]-pyrazol-1-yl)-propan-2-ol and 1.75 ml (12.5 mmol) of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.41 g (6.3 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 0.7 g (80%) of (S)-1-(2-azido-propyl)-4,4,7-trimethyl-1,4-dihydro-indeno[2,1-c]pyrazole was obtained as a light yellow oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:4](=[O:34])[CH:3]1[CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38](C(C2CSC(=O)N2)=O)[N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O.O>[NH:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:36]([CH2:35][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[N:37]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)C4CSC(=O)N4)c4ccccc34)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
To a stirred solution of 400 mg (0.556 mmol) of 2-{2,4-Dioxo-3-[1-(2-oxo-thiazolidine-4-carbonyl)-1H-indazol-3-yl methyl]-5-pyridin-3-yl-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl}-N-isopropyl-N-(4-methoxyphenyl) acetamide, prepared as in Example 71 in 10 mL methanol is added 154 mg (1.11 mmol, 2 equiv.) of potassium carbonate. The suspension is stirred for 20 min and diluted with 25 mL EtOAc and 25 mL H2O. The organic phase is washed with H2O (2×25 mL) and then dried (MgSO4), and the solvents removed in vacuo. The resulting amorphous solid is swirled in 10 mL ether until a free flowing white solid is produced. The solid is filtered to give 258 mg of the title compound: mp. 214°-215° C.; [a]25 =+47.2; 1H NMR (CDCl3, 400 MHz) δ8.49 (d, br, 2H), 7.79 (d, 2H, J=8.0), 7.29-7.07 (m, 8H) 6.95-6.85 (m, 4H) 4.94 (m, 1H), 4.38 (d, br, 1H, J=15.6) 4.25-4.14 (m, 2H) 3.82 (s, 3H) 3.77 (m, 1H) 3.60 (dd, 1H, J=6.0, 16.1) 1.02 (t, 6H, J=7.7); low resolution MS (FAB)m/e 589 (MH+).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50]O)[CH:46]([O:52]O)[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].N1C=CN=C1.[C:62]([Si:66](Cl)([CH3:68])[CH3:67])([CH3:65])([CH3:64])[CH3:63]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:66]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:68])[CH3:67])[CH:46]([OH:52])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OO)C(OO)C3)C(C)CCC1=O)C(C)CC2OC
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3", 4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (Example 2, 3.01 g) in dry methylene chloride (70 ml) was added an excess of imidazole (809 mg) followed by tertbutyldimethylsilyl chloride (716 mg). After 3 days of stirring at room temperature, the mixture was diluted with ethyl acetate which in turn was washed with 1N HCl, saturated sodium bicarbonate and brine, dried over magnesium sulfate and purified by flash chromatography (ethyl acetate:hexane (1:3)) to give the title compound (941 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH3:15][N:16](C)C=O>[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>[NH2:8][C:6]1[N:7]=[C:2]([C:15]#[N:16])[CH:3]=[CH:4][CH:5]=1
Reactant: CN(C)C=O
Reactant: Nc1cccc(Br)n1
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]
Solvent: CCOC(C)=O
Product: N#Cc1cccc(N)n1
Temperature: 170 °C

Procedure:
340 mg (2.89 mmol, 1 eq) of zinc cyanide are added to 500 mg (2.89 mmol, 1 eq) of 6-bromopyridin-2-ylamine in 10 ml of dimethylformamide in a microwave tube. 170 mg (0.147 mmol, 0.05 eq) of tetrakis(triphenylphosphine)palladium are added. The medium is heated at 170° C. for 1 hour 30 minutes in a microwave oven. 50 ml of ethyl acetate are added to the medium, which is filtered over celite. The filtrate is washed with water and extracted with ethyl acetate. The organic phases are combined and dried over sodium sulphate. The residue is triturated in heptane. 6-Aminopyridine-2-carbonitrile is obtained in the form of an orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[S:19][C:18]([C:20](O)=[O:21])=[C:17]([CH3:23])[CH:16]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[S:19][C:18]([C:20]([NH:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:21])=[C:17]([CH3:23])[CH:16]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cccnc1
Yield: 39 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 5-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 39% yield: mp 165-167° C.; 1H NMR (300 MHz, CDCl3) δ 8.61 (d, J=1.5 Hz, 1H), 8.54 (dd, J=4.7, 1.5 Hz, 1H), 7.71 (dt, J=7.8, 1.5 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.43-7.27 (m, 6H), 6.85 (s, 1H), 6.30 (t, J=5.8 Hz, 1H), 6.15 (dd, J=7.8, 2.7 Hz, 1H), 6.06 (d, J=2.7 Hz, 1H), 5.04 (s, 2H), 4.61 (d, J=5.8 Hz, 2H), 2.54 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.2, 162.6, 160.9, 138.8, 137.5, 135.4, 135.0, 128.5, 128.2, 128.0, 126.9, 120.5, 102.6, 97.3, 70.0, 15.5; MS (ES+) m/z 432.2 (M+1).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[S:13][C:12]([S:14]([NH:17][C@H:18]([C:24]([OH:26])=[O:25])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])(=[O:16])=[O:15])=[CH:11][CH:10]=1>C1COCC1.CO>[CH3:1][O:25][C:24](=[O:26])[C@H:18]([CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[NH:17][S:14]([C:12]1[S:13][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:15])=[O:16]
Reactant: CCC(CC)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(=O)OC
Yield: 94.9 %

Procedure:
Trimethylsilyldiazomethane (3.1 mL, 6.1 mmol) was added to a solution of N-[(5-chloro-2-thienyl)sulfonyl]-3-ethyl-L-norvaline (1.0 g, 3.1 mmol) in THF (20 mL) and MeOH (5 mL). After 2 h the mixture was concentrated to give N-[(5-chloro-2-thienyl)sulfonyl]-3-ethyl-L-norvaline methyl ester as a white solid (1.0 g, 99%). Mass Spectrum (−ESI): 338.00 (M−H)−.
Reaction SMILES: C1(C2OC(C(F)(F)F)=C(C(NC3C=CC(N4CCN(C(C5CCCC5C(O)=O)=O)CC4)=CC=3)=O)N=2)C=CC=CC=1.[C:41]1([C:47]2[O:48][C:49]([C:78]([F:81])([F:80])[F:79])=[C:50]([C:52]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([N:61]4[CH2:66][CH2:65][N:64]([C:67]([CH:69]5[CH2:74][CH2:73][CH2:72][CH:71]([C:75]([OH:77])=[O:76])[CH2:70]5)=[O:68])[CH2:63][CH2:62]4)=[CH:57][CH:56]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.COC(C1CCCC(C(N2CCN(C3C=CC(NC(C4N=C(C5C=CC=CC=5)OC=4C(F)(F)F)=O)=CC=3)CC2)=O)C1)=O.[OH-].[Li+]>>[C:41]1([C:47]2[O:48][C:49]([C:78]([F:79])([F:80])[F:81])=[C:50]([C:52]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([N:61]4[CH2:66][CH2:65][N:64]([C:67]([C@H:69]5[CH2:74][CH2:73][CH2:72][C@@H:71]([C:75]([OH:77])=[O:76])[CH2:70]5)=[O:68])[CH2:63][CH2:62]4)=[CH:57][CH:56]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Nc1ccc(N2CCN(C(=O)C3CCCC(C(=O)O)C3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: COC(=O)C1CCCC(C(=O)N2CCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)C1
Agent: O=C(Nc1ccc(N2CCN(C(=O)C3CCCC3C(=O)O)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: [Li+]
Product: O=C(Nc1ccc(N2CCN(C(=O)[C@H]3CCC[C@@H](C(=O)O)C3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid above, racemic 3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid was prepared from 3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid methyl ester and lithium hydroxide. The crude racemate was purified by chiral supercritical fluid chromatography to yield (1R,3S)-3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid as an off-white solid (first eluting peak). ES-MS calcd for C29H29F3N4O5 (m/e) 570.57, obsd 571.1 (M+H).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=1)=[O:17]
Reactant: CCOC(OCC)c1ccc(C(=O)CC(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)CC(=O)c1ccc(C=O)cc1
Yield: 65.1 %

Procedure:
Dissolve 1-[4-(diethoxymethyl)-phenyl]-3,3-dimethylbutan-1-one (3.49 g, 12.55 mmol) in acetone (50 mL). Add p-toluenesulfonic acid monohydrate (238 mg, 1.256 mmol). Heat the mixture under reflux for 3 h. Concentrate in vacuo and partition the residue between water and EtOAc. Extract the aqueous phase three times with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (1.67 g, 65%).
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH:24]=1>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[O:16])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCOc1cccnc1
Product: CCCc1c(OCCCCCC(=O)NCCCCOc2cccnc2)ccc(C(C)=O)c1O

Procedure:
6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid was allowed to react with 4-(3-pyridinyloxy)butyl amine according to procedure A and the product was purified by HPLC to give 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(3-pyridinyloxy)butyl]hexanamide, the title compound, mp 50°-53° (from ethyl acetate) in 73% yield.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][CH3:19])[N:4]=1.[C:20]1([CH3:46])[CH:25]=[CH:24][C:23]([C:26]([O:28][C@@H:29]2[C@@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)=[O:37])[O:32][C@H:31](Cl)[CH2:30]2)=[O:27])=[CH:22][CH:21]=1.CO.C(Cl)Cl>CC#N.C(Cl)Cl>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:31]2[O:32][C@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=3)=[O:37])[C@@H:29]([O:28][C:26]([C:23]3[CH:22]=[CH:21][C:20]([CH3:46])=[CH:25][CH:24]=3)=[O:27])[CH2:30]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][CH3:19])[N:4]=1
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Reactant: CCCc1nccn1-c1nc(Cl)nc2nc[nH]c12
Agent: [Na]
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: CCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Yield: 84.5 %

Procedure:
The sodium salt of 2-chloro-6-(2-propylimidazol-1-yl)purine (0.13 g, 0.5 mmol) in dried CH3CN (10 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.30 g, 0.8 mmol) in CH2Cl2 (10 mL) by general method 2. No α-nucleoside was detected by 1H NMR. Column chromatography was performed twice (25 g silica gel, MeOH/CH2Cl2, 1:30, and EtOAc/hexanes, 1:1) to give 2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(2-propylimidazol-1-yl)purine (0.26 g, 83%), which was recrystallized (EtOAc) to give analytically pure material (0.17 g, 55%): mp 192-193° C.; UV (MeOH) max 220, 239, 287 nm (∈ 40 700, 38 300, 16 700), min 231, 265 nm (∈ 35 900, 10 300); 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 8.27 (s, 1H), 8.00 (d, J=7.8 Hz, 211), 7.86 (d, J=7.8 Hz, 2H), 7.32 (d, J=7.8 Hz, 2H), 7.28 (d, J=7.8 Hz, 2H), 7.20 (s, 1H), 6.61 (t, J=7.1 Hz, 1H), 5.82-5.83 (m, 1H), 4.84-4.68 (m, 3H), 3.29 (t, J=7.8 Hz, 2H), 2.98-3.01 (m, 2H), 2.47 (s, 3H), 2.38 (s, 3H), 1.86 (sext, J=7.5 Hz, 2H), 1.07 (t, J=7.3 Hz, 3H); NOE difference: H1′ was irradiated, and enhancement of H4′ (small), H8 and H2′,2″ signals was observed; 13C NMR (125 MHz, CDCl3) δ 166.29, 166.23, 154.38, 153.42, 151.47, 148.18, 144.97, 144.65, 142.40, 130.12, 129.78, 129.61, 129.56, 129.20, 126.63, 126.44, 122.95, 120.57, 85.46, 83.82, 75.19, 64.12, 38.88, 33.12, 22.03, 21.91, 21.60, 14.25; HRMS m/z 637.1940 (MNa+[C32H31ClN6O5Na=637.1942]). Anal. Calcd for C32H31ClN6O5: C, 62.49; H, 5.08; N, 13.66. Found: C, 62.44; H, 5.18; N, 13.72.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][OH:8])[C:3]([CH3:6])([CH3:5])[CH3:4].O.[CH2:10]([O:12]C(Cl)=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:3]([C@@H:2]1[CH2:7][O:8][C:10](=[O:12])[NH:1]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[C@@H](N)CO
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[C@@H]1COC(=O)N1
Temperature: 65 °C
Yield: 79.9 %

Procedure:
73 g (containing 0.25 mole (R)-tert-leucinol) of the filtrate cited in example 6 was taken up with 27 ml water and 200 ml toluene. 25 ml (0.26 mole) chloroformic acid ethyl ester were then added dropwise at 20°-25° C., during which the pH was maintained at 7-8.5 by the addition of 10 M sodium hydroxide solution. The mixture was then heated to 60°-65° C. at pH 8.0 and the aqueous phase separated. The toluene phase was dehydrated on a water separator under a slight vacuum and slowly heated after the addition of 0.4 g finely granulated sodium hydroxide at 70° C. A total of 40 ml distillate which contained the ethanol produced during the reaction was separated from 70°-100° C . After cooling of the batch to 65° C. a solution of 0.6 ml glacial acetic acid in 10 ml water was added, the mixture briefly agitated, the aqueous phase separated and the toluene phase compounded again with 15 ml warm water which was separated again after a brief agitation at 65° C. After distilling the organic phase on a water separator the phase was concentrated to 120 ml, filtered hot and slowly cooled off under agitation, during which the product separated in colorless crystals. These crystals were filtered off after 30 min agitation at 5° C., washed with cold toluene and dried in a vacuum at 50° C. 28.6 g (R)-4-tert-butyl-2-oxazolidinone (80% yield) was obtained. A 1H-NMR spectrum corroborated the structure of the product.