Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][SH:6].Cl[CH2:8][CH:9]=[C:10]([CH3:52])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:51])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:50])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:49])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:48])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:47])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:46])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:45])[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43].O>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[CH3:52][C:10]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:51])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:50])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:49])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:48])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:47])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:46])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:45])[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])=[CH:9][CH2:8][S:6][CH2:5][CH2:4][NH2:3]
Reactant: NCCS
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCSCCN
Yield: 61.3 %

Procedure:
Under an atmosphere of argon, sodium hydride (1.43 g, 35.8 mmol, 60% dispersion in mineral oil) was added to a solution of 2-aminoethanethiol (2.76 g, 35.8 mmol) in 90 ml of tetrahydrofuran. The mixture was heated at reflux temperature for 15 minutes and cooled in an ice bath. To the reaction mixture, 18-crown-6 (20 mg, 0.08 mmol) was added and then a solution of 1-chloro-3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,22,26,30,34-hexatriacontanonaene [23.2 g, 35.7 mmol, prepared as described in Item a) given above] in 90 ml of tetrahydrofuran was added in dropwise for 10 minutes. The reaction mixture was heated at reflux temperature for 4 hours and then cooled. After addition of water (1 ml), the solvent was evaporated in vacuo to dryness. The remaining residue was partitioned between water and n-hexane. The aqueous layer was extracted with n-hexane to combine the n-hexane layers. The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness. The remaining residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (50:1-20:1) to afford 15.1 g (61.3%) of the desired compound, as a pale brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C@@H:30](O)[CH2:31][C@H:32]([OH:34])[CH3:33].C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C@@H:30]([CH3:29])[CH2:31][C@H:32]([OH:34])[CH3:33])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(O[C@@H](C)C[C@@H](C)O)cc1
Reaction time: 17 h

Procedure:
After 4-methoxyphenol (300 mg, 2.41 mmol), triphenylphosphine (762 mg, 2.89 mmol), (2R,4R)-2,4-pentanediol (303 mg, 2.89 mmol), and THF (12 ml) were added to a 50 ml flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (1.53 mL, 2.89 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 17 hours. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml,×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 30% ethyl acetate-hexane solution) to give (4S,2R)-4-(4-methoxyphenoxy)pentane-2-ol containing 1,2-hydrazinedicarboxylic acid diisopropyl ester as 543 mg of a colorless oily substance. Measurement of 1H-NMR showed that 420 mg of (4S,2R)-4-benzoyloxypentane-2-ol (yield: 83%/4-methoxyphenol), and 123 mg of 1,2-hydrazinedicarboxylic acid diisopropyl ester were contained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:34])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:33])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:35][S:36](O)(=[O:38])=[O:37]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:34])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:33])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:36]([Cl:35])(=[O:38])=[O:37])=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)c1cccc(OCC(=O)NCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Solvent: ClCCl
Product: CC(C)c1cc(OCC(=O)NCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)ccc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 57.3 %

Procedure:
To a mixture of 4-(3-isopropylphenoxyactamido)butyric acid 2-(3-nitrobenzenesulfonyl)ethyl ester (Intermediate 25, 4.8 g, 9.75 mmol) and 2 mL of CH2Cl2 was added drop-wise ClSO3H (3.3 mL, 5.8 g, 50 mmol) at 0° C. with vigorous stirring. The mixture was stirred at 0° C. for 40 min. and then was poured onto crushed ice with vigorous stirring resulting in a thick mass. This was extracted with CH2Cl2. The organic layers were dried, and concentrated under reduced pressure. The residual oil was passed through a short silica gel column to remove material that was not moving on TLC. The eluent was concentrated to give Intermediate 26 (3.3 g, 57%) as a light brown foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])[C:35]1[CH:36]=[CH:37][C:32]([O:31][C:28]2[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=2)=[CH:33][CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1ccc(Oc2ccccc2)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(Oc2ccccc2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 1-bromo-4-phenoxy-benzene in analogy to Example 1a): MS (ISP): 472.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[C:19](=[O:20])[CH:18]3[CH:13]([CH2:14][CH:15]=[CH:16][CH:17]3[NH:21]C(=O)OC(C)(C)C)[C:12]2=[O:29])=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:21][CH:17]1[CH:16]=[CH:15][CH2:14][CH:13]2[CH:18]1[C:19](=[O:20])[N:11]([CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[C:12]2=[O:29]
Reactant: CC(C)(C)OC(=O)NC1C=CCC2C(=O)N(CCc3ccc(C#N)cc3)C(=O)C12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CCN2C(=O)C3CC=CC(N)C3C2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.008 g (2.55 mmol) of tert-butyl 2-[2-(4-cyanophenyl)ethyl]-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ylcarbamate are dissolved in 20 ml of dichloromethane, and 0.79 ml (10.2 mmol) of trifluoroacetic acid is added. After 4 h of stirring at room temperature, the reaction mixture is concentrated using a rotary evaporator and worked up using EtOAc and saturated aqueous NaHCO3 solution. The organic phase is dried over magnesium sulfate, filtered and concentrated using a rotary evaporator. The crude product is chromatographed on silica gel (CH2Cl2/EtOH=50/1+0.5% aqueous NH3 solution (25% strength)). This gives 530 mg (70% of theory) of the desired compound. MS=337 (M+H+MeCN), 296 (M+H), rt (Method 4)=2.04 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cn1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2ccc(I)cn2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 4-fluorophenol (1.12 g, 10 mmol), 2-bromo-5-iodopyridine (2.84 g, 10 mmol) and Cs2CO3 (3.83 g, 10 mmol) in DMF was stirred at 120° C. for 4 hrs. The reaction was worked up with EtOAc to give 2-(4-fluoro-phenoxy)-5-iodo-pyridine which was used for next step without further purification (crude yield 100%, yellowish solid). LC/MS: m/z=317 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:48]=[CH:47][C:12]([CH2:13][C@H:14]([NH:28][C:29](=[O:46])[C:30]2[CH:44]=[C:43]([CH3:45])[CH:42]=[C:32]([C:33]([N:35]([CH2:39][CH2:40][CH3:41])[CH2:36][CH2:37][CH3:38])=[O:34])[CH:31]=2)[C@H:15]([OH:27])[CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[OH:27][C@H:15]([CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[C@@H:14]([NH:28][C:29](=[O:46])[C:30]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:32]([C:33]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:39][CH2:40][CH3:41])=[O:34])[CH:31]=1)[CH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:48][CH:47]=1
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)[C@H](O)CNCc2cccc(OC)c2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2ccc(O)cc2)[C@H](O)CNCc2cccc(OC)c2)c1
Reaction time: 5 h

Procedure:
A mixture of N1-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N3,N3-dipropylisophthalamide (140 mg, 0.215 mmol) and palladium on carbon (10%, 140 mg) in absolute glacial acetic acid (5 mL) is shaken under an atmosphere of hydrogen at 35 psi for 5 hours The resulting mixture is filtered through diatomaceous earth and washed with methanol. The combined filtrates are concentrated under reduced pressure. The concentrate is purified by flash column chromatography (silica; methylene chloride/methanol/ammonium hydroxide gradient from 97/3/0.05 to 93/7/0.05) to give the title compound, IR (KEBr) 2962, 2931, 1611, 1594 and 1263 cm−1, ESI-MS (m/z) [M+H]+=562.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([O:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][C:26]([NH:33]C=O)=[N:27][C:28]=2Cl)[CH2:11][O:12][CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])(C(C)(C)C)(C)C.C(O)=[O:37]>>[CH2:17]([O:16][P:14]([CH2:13][O:12][CH2:11][CH:10]([O:22][N:23]1[CH:31]=[N:30][C:29]2[C:28](=[O:37])[NH:27][C:26]([NH2:33])=[N:25][C:24]1=2)[CH2:9][OH:8])([O:19][CH2:20][CH3:21])=[O:15])[CH3:18]
Reactant: O=CO
Reactant: CCOP(=O)(COCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(Cl)nc(NC=O)nc21)OCC
Product: CCOP(=O)(COCC(CO)On1cnc2c(=O)[nH]c(N)nc21)OCC
Temperature: 20 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A solution of 9-(1-t-butyldimethylsilyloxy-3-diethoxyphosphorylmethoxyprop-2-oxy)-6-chloro-2-formamidopurine (280 mg, 0.51 mmol) in 80% aqueous formic acid (5 ml) was stirred at 120° C. for 3 hours. The acid was evaporated, the residue dissolved in methanol (1 ml) and 0.88 ammonia (1 ml) and stirred for 1 hour at 20° C. After evaporation, the residue was dissolved in hot water (5 ml) and extracted with ether (3×5 ml). The aqueous solution was passed down a reverse-phase silica column eluting with up to 15% methanol affording 9-(1-diethoxyphosphorylmethoxy-3-hydroxyprop-2-oxy)guanine (105 mg, 53%) m.p. 238°-240° C. νmax (KBr) 3380, 1700, 1600, 1380, 1380, 1240, 1030 and 960 cm-1 ; δH [(CD3)2SO] 1.24(6H, t, J7.2 Hz, 2×(CH2CH3 ), 3.61(2H, t, J5.2 Hz, CH2OH), 3.81(2H, d, J4.7 Hz, CH2OCH2P), 3.89(2H. d, J8.0 Hz,CH2P), 4.04 (4H, m, 2×CH2CH3, 4.39(1H, t, J4.7 Hz,CHON), 5.06(1H, t, J6.0 Hz, D2O exchangeable, OH), 6.61(2H, br.s, D2O exchangeable, NH2), 7.86(1H, s, H-8), 10.67(1H, br.s, D2O exchangeable, NH); m/z (FAB+veIon), 392(MH+, 2%), 414(MNa+, 100%). Found: C,39.27; H,5.60; N,17.78%; C13H22N5O7P.0.3H2O requires C,39.36; H,5.74; N,17.66%.
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].C(N(CC)CCN[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:28]=[O:29])=[O:18])C>C(Cl)(Cl)Cl>[CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH:7][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:28]=[O:29])=[O:18])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCN(C=O)c1ccccc1COC(=O)NCCN(CC)CC
Reactant: CC(C)N(CCN)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(C=O)c1ccccc1COC(=O)NCCN(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
N,N-Diisopropylethylenediamine (0.79 g) was added to the intermediate (a) (2.62g) obtained in Example 28. After being stirred for 2 hours at 70° C., the reaction mixture, with chloroform added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then filtrated. The solvent was evaporated out and the residue was purified by silica gel column chromatography (silica gel 85 g, chloroform:methanol=100:1), thereby yielding 1.45 g of the aimed compound as white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=[CH:9]2.[NH2:28][C:29]1[C:30]([C:37]([NH:39][C:40](SC)=[NH:41])=[O:38])=[N:31][C:32]([Cl:36])=[C:33]([NH2:35])[N:34]=1.CCN(C(C)C)C(C)C>CCO>[NH2:28][C:29]1[C:30]([C:37]([NH:39][C:40](=[NH:41])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[C:11]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH:10]=[CH:9]3)=[O:38])=[N:31][C:32]([Cl:36])=[C:33]([NH2:35])[N:34]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc2cc(CCCCN)ccc2c1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCOc1ccc2cc(CCCCNC(=N)NC(=O)c3nc(Cl)c(N)nc3N)ccc2c1
Temperature: 70 °C
Yield: 84.2 %

Procedure:
To a solution of carbamate 88 (500 mg, 1.34 mmol) and methyl 3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate (10, 790 mg, 2.01 mmol) in EtOH (30 mL) was added DIPEA (1.75 mL, 9.39 mmol) at room temperature. The reaction mixture was heated at 70° C. in a sealed tube for 2 h, then cooled to room temperature, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 90:9:1 CHCl3/CH3OH/NH4OH) to afford carbamate 89 (660 mg, 84%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 7.65 (d, J=7.5 Hz, 2H), 7.56 (s, 1H), 7.31 (dd, J=8.4, 1.5 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.08 (dd, J=8.7, 2.4 Hz, 1H), 4.10 (t, J=6.3 Hz, 2H), 2.81 (t, J=6.6 Hz, 2H), 2.01-1.97 (m, 2H), 1.83-1.60 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]=[C:7]([O:15][CH:16]([CH3:18])[CH3:17])[C:6]([O:19][CH:20]([CH3:22])[CH3:21])=[N:5]2.P([O-])(O)(O)=O.[Na+].[CH3:29][N:30]([CH3:33])C=O>>[O:15]=[C:16]1[CH:18]=[CH:29][N:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[N:8]=[C:7]([O:15][CH:16]([CH3:18])[CH3:17])[C:6]([O:19][CH:20]([CH3:22])[CH3:21])=[N:5]3)[CH:33]=[CH:17]1
Reactant: CN(C)C=O
Reactant: CC(C)Oc1nc2cc(Cl)c([N+](=O)[O-])cc2nc1OC(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: CC(C)Oc1nc2cc(-n3ccc(=O)cc3)c([N+](=O)[O-])cc2nc1OC(C)C
Temperature: 125 °C
Reaction time: 3 h

Procedure:
A mixture of 4-hydroxypyridine sodium salt 702 mg, the compound 1.63 g obtained in above described (1), and dried dimethylformamide 3.5 mL was stirred at 125° C. for 3 hr. The resultant mixture was added to an ice-cooled solution of sodium dihydrogen phosphate, then the precipitate was collected by filtration with water. The obtained product was dried and crystallized from acetone to give the title compound (pale brown crystal) 1.02 g.
Reaction SMILES: COC1C=CC([O:9][CH2:10][CH2:11][O:12][CH2:13][N:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]=[CH:15]2)=CC=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CCO>CC#N.O>[OH:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]=[CH:15]1
Reactant: COc1ccc(OCCOCn2cnc3ncnc(N)c32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: Nc1ncnc2ncn(COCCO)c12
Yield: 79.9 %

Procedure:
Compound 14 (0.74 g, 3.54 mmol) was prepared in 80% yield from 13 (1.39 g, 4.43 mmol) and CAN (2.43 g, 4.43 mmol) in CH3CN (30 mL) and water (10 mL) by the method used for the synthesis of 9: mp 122-123° C.; Rf(hexanes/EtOAc=1:2) 0.12; UV (EtOH) λmax 265 (ε 14,800); 1H NMR (CD3OD) δ 3.69-3.79 (m, 4 H, O(CH2)2O), 5.79 (s, 2 H, H2C1′), 8.32 (s, 1 H, HC2), 8.60 (s, 1 H, HC8); 13C NMR (CD3OD) δ 61.80 (CH2OH), 72.27 (OCH2) 82.01 (C1′), 119.62 (C5), 144.29 (C2), 147.68 (C8), 150.32 (C4), 152.12 (C6); MS m/z 209 (M+). Anal (C8H11N5O2) C, H, N; calcd (%): 45.93, 5.30, 33.48; found (%): 45.80, 5.45, 33.51.
Reaction SMILES: Br.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][NH:10][CH2:9]2)=[O:5].C(N(CC)CC)C.[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1.C(Cl)(Cl)Cl>C1COCC1>[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:28]([C:25]1[CH:26]=[CH:27][C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:23][CH:24]=1)=[O:29])[CH2:9]2)=[O:5]
Reactant: COC(=O)c1ccc2c(c1)CNC2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)CN(C(=O)c1ccc(-c3ccccc3)cc1)C2
Yield: 85.1 %

Procedure:
2,3-Dihydro-1H-isoindole-5-carboxylic acid methyl ester compound with hydrobromic acid (0.80 g), triethylamine (1.30 mL) and biphenyl-4-carbonyl chloride (0.67 g) are stirred in THF (35 mL) at ambient temperature. After 1.5 h the mixture is treated with CHCl3 washed, dried and evaporated until a solid starts to separate. The product is fully crystallized by adding heptane. 0.94 g of the title compound is obtained with MP 172-180° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:10][CH:11]=1)([CH3:26])[CH3:25]
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccn3)nnn2C)nc1
Yield: 71 %

Procedure:
As described for example 26b, 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (76 mg, 0.24 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (61 mg, 71%) which was obtained as a white solid. MS: m/e=353.2 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:32])=[C:6]([C:14]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)(O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[C:7]([O:12]C)=[C:8]([CH3:11])[C:9]=1[CH3:10])(=[O:3])[CH3:2].B(Br)(Br)Br.O>ClCCl>[C:1]([C:4]1[C:5]([CH3:32])=[C:6]([CH:14]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:7]([OH:12])=[C:8]([CH3:11])[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCCC(O)(c1ccc(F)cc1)c1c(C)c(C(C)=O)c(C)c(C)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1c(C)c(C)c(O)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.4 %

Procedure:
A solution of methyl 7-(3-acetyl-6-methoxy-2,4,5-trimethylphenyl)-7-(4-fluorophenyl)-7-hydroxyheptanoate (1.6 g) in dichloromethane (15 ml) was added dropwise to a solution of boron tribromide (1.4 ml) in dichloromethane (15 ml) at -78° C. The temperature was raised slowly to room temperature and the mixture was stirred for 5 hours. The reaction mixture was ice-cooled and water was added. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to obtain 7-(3-acetyl-6-hydroxy-2,4,5-trimethylphenyl)-7-(4-fluorophenyl)heptanoic acid (0.87 g) (Compound 35). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: B.O1CCCC1.[Br:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([NH2:16])=O)=[CH:10][CH:9]=1>CO>[Br:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[CH2:14][NH2:16])=[CH:10][CH:9]=1
Reactant: CC(Oc1ccc(Br)cc1)C(N)=O
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(CN)Oc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
A 1 M solution of borane in tetrahydrofuran (8.2 ml, 8.2 mmol) was added dropwise to 2-(4-bromo-phenoxy)-propionamide (0.2 g, 0.82 mmol) and the solution was stirred overnight at reflux then subsequently hydrolysed by slow addition of excess of methanol and refluxing for a further 2 hours. The solvent was removed under reduced pressure and aqueous ammonium chloride was added. The aqueous phase was extracted twice with ethyl acetate and the organics were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the desired product. Yield 0.13 g, 68%. LCMS method: 2, RT: 2.74 min; MI: 271-273 [M+1].
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].[Cl:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)=O>C(O)(=O)C>[ClH:5].[CH3:2][C:1]1[S:3][CH:6]=[C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[N:4]=1
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Reactant: CC(N)=S
Solvent: CC(=O)O
Product: Cc1nc(-c2ccc3c(c2)CC(=O)N3)cs1
Product: Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
Thioacetamide (90 mg, 1.2 mmol) was added to a slurry of 5-(2-chloro-acetyl)-1,3-dihydro-indol-2-one (250 mg,1.2 mmol) in acetic acid (3 mL). The reaction temperature was increased to 80° C. and stirred at this temperature for 16 h. The reaction mixture was cooled to room temperature and the resultant precipitate was collected by filtration. The solid was washed with EtOAc (2×20 mL) and ether (2×20 mL) and dried in vacuo to afford a cream colored solid (300 mg, 94% yield). 1H NMR (DMSO-d6) δ2.74 (s, 3H); 3.58 (s, 2H); 6.87 (d, 1H); 7.79 (m, 3H); 10.57 (s, 1H). APCI-MS (−ve) m/z 229 (M−H), APCI-MS (+ve) m/z 231 (M+H).Analytical calculated for C12H10N2OS.HCl: C, 54.02; H, 4.16; N, 10.50; S, 12.02. Found: C, 53.73; H, 4.16; N, 10.17; S, 11.63.