Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH3:37][S:38]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)[CH2:10]1)(=[O:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N[C@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(t-butoxycarbonyl)amino)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A arid methylsulfonyl chloride in Step B, the title compound can be prepared.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@H:7]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2].Cl.[NH2:21][OH:22]>CCO>[OH:22][NH:21][C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@H:7]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[NH:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2c(C#N)cccc21
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2c(C(=N)NO)cccc21
Temperature: 85 °C
Yield: 85 %

Procedure:
Prepared using General Procedure 3. To (R)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate INT-8 (15.0 g, 58.2 mmol) in EtOH (100 mL) was added hydroxylamine hydrochloride (12.1 g, 174.2 mmol) and TEA (17.6 mL, 174.2 mmol) and the reaction mixture heated at 85° C. for 2 h. The solvents were removed and the resulting white solid was partitioned between water and DCM. The organic layers were dried over Na2SO4, concentrated, and recrystallized from isopropanol (50 mL) to afford 14.4 g (85%) of (R)-tert-butyl 4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-10 as white crystalline solid. LCMS-ESI (m/z) calculated for C15H21N3O3: 291.4; found 292.1 [M+H]+, tR=2.04 min. 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 7.38-7.32 (m, 1H), 7.32-7.12 (m, 3H), 5.68 (s, 2H), 4.97 (q, J=8.5, 1H), 3.07 (ddd, J=16.6, 8.7, 2.6, 1H), 2.86 (dt, J=16.8, 8.4, 1H), 2.30 (ddd, J=12.6, 7.6, 3.6, 1H), 1.75 (dq, J=12.3, 9.0, 1H), 1.44 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN[C@H]2CC[C@H](O)CC2)cc1
Temperature: 80 °C

Procedure:
Methyl 4-(bromomethyl)benzoate (5.0 g, 22 mmol) was dissolved in DMF (50 mL) and trans-4-aminocyclohexanol (3.04 g, 26 mmol) was added followed by addition of potassium carbonate (6.08 g, 44 mmol). The reaction mixture was heated to 80° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and water (200 m) was added. The aqueous phase was extracted with ethyl acetate (100 mL), and the combined organic phases were washed with water (2×100 mL) and dried (MgSO4). The organic phase was concentrated in vacuo to give 2.5 g of trans-4-[(4-hydroxycyclohexylamino)methyl]benzoic acid methyl ester.
Reaction SMILES: O[C:2]1C=C[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=O)/C/2=C\C1NC=CC=1)#C.BrC1[S:46]C=CC=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[NH:22]1[CH:23]=[CH:24][CH:25]=[C:21]1/[CH:20]=[C:13]1\[C:14](=[O:19])[NH:15][C:16]2[C:12]\1=[CH:11][C:10]([C:9]#[C:8][C:5]1[S:46][CH:2]=[CH:3][CH:4]=1)=[CH:18][CH:17]=2
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Reactant: Brc1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(C#Cc3cccs3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (42 mg, 0.18 mmol) (from Example 82) was coupled with 2-bromothiophene (30 mg, 0.18 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst in 1 mL DMF and 1 mL triethylamine at 70° C. for 14 hours to give (Z)-1,3-dihydro-3-[(1H-pyrrol-2-yl)-methylene]-5-(2-thiophenyl)ethynyl-2H-indol-2-one as a yellow powder. (Yield 25 mg, 44%).
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][CH2:7][C@@H:8]([C:13]2[O:14][CH:15]=[C:16]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[N:17]=2)[CH2:9][C:10](O)=[O:11])[CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:40][NH2:41]>O1CCCC1.CO>[CH:1]1([CH2:5][CH2:6][CH2:7][C@@H:8]([C:13]2[O:14][CH:15]=[C:16]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[N:17]=2)[CH2:9][C:10]([NH:41][OH:40])=[O:11])[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: CN(C)C(=O)c1coc([C@H](CCCC2CCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1coc([C@H](CCCC2CCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
A solution of (3R)-6-cyclobutyl-3-{4-[(dimethylamino)carbonyl]-1,3-oxazol-2-yl}hexanoic acid (Preparation 121) (155 mg, 0.50 mmol) and N-methylmorpholine (90 μl, 0.82 mmol) in anhydrous tetrahydrofuran (8 ml) was cooled to 0° C., treated with isobutyl chloroformate (90 μl, 0.70 mmol) and stirred under a nitrogen atmosphere for 2 hours. O-(Trimethylsilyl)hydroxylamine (200 μl, 1.63 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol (2 ml) and stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 98:2 (dichloromethane:methanol) gradually changing to 90:10 (dichloromethane:methanol). The solid was triturated with diethyl ether, filtered and dried under reduced pressure to afford the title compound as a white solid (64 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[OH-].[Na+]>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: Oc1ccccc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: Nc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 48.1 %

Procedure:
A mixture of 1.09 g of 5-chloro-2-nitroaniline, 10 g of phenol and 2.0 g of anhydrous potassium carbonate was heated at 150° C for 4 days. The reaction mixture was diluted with 1N sodium hydroxide and extracted with ethyl acetate. The ethyl acetate layer was washed with 1N sodium hydroxide, water and brine in turn and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was chromatographed on silica gel using chloroform to give 0.70 g of 2-nitro-5-phenoxyaniline.
Reaction SMILES: C([C@H:3]([S:7]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[OH:34][CH2:33][CH2:35][NH:36][C:4](=[O:5])[CH2:3][S:7](=[O:8])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: NCCO
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Product: O=C(CS(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1)NCCO

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (75 mg, 0.17 mmol) and ethanolamine (0.05 mL, 0.84 mmol) were reacted to give the title compound as colorless oil (63 mg, 81
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23](=[O:24])[CH2:22][CH:21]([C:25]([O:27]C)=[O:26])[CH2:20]3)=[CH:15][CH:14]=2)=[C:7]2[C:12]=1[CH:11]=[N:10][CH:9]=[CH:8]2.[OH-].[Na+].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[C:23](=[O:24])[CH2:22][CH:21]([C:25]([OH:27])=[O:26])[CH2:20]3)=[CH:17][CH:18]=2)=[C:7]2[C:12]=1[CH:11]=[N:10][CH:9]=[CH:8]2
Reactant: COC(=O)C1CC(=O)N(c2ccc(-c3ccc(OC)c4cnccc34)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc(N3CC(C(=O)O)CC3=O)cc2)c2ccncc12
Temperature: 80 °C

Procedure:
A mixture of methyl 1-(4-(8-methoxyisoquinolin-5-yl)phenyl)-5-oxopyrrolidine-3-carboxylate (220 mg, 0.58 mmol) in dioxane (2 mL) was treated with NaOH (1N, 1 mL). The mixture was heated to 80° C. for 17 h and the solvents were evaporated to dryness. MS (ESI pos. ion) m/z: 363 (M+H). The acid was dissolved in DMF (2 mL) and was treated with HBTU (450 mg, 1.25 mmol) and Et3N (1 mL). The solution was divided into two equal portions and was used directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[SH2:26]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[S:26])=[CH:11][CH:10]=2)=[CH:17][CH:18]=1
Reactant: S
Reactant: COc1ccc(COc2ccc(C#N)cc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1ccc(COc2ccc(C(N)=S)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To the solution of 4-(p-methoxybenzyl)oxybenzonitrile (7.18 g) in pyridine (100 ml) was added triethylamine (20 ml), and hydrogen sulfide gas was streamed 30 minutes. The mixture was stirred at room temperature for 3 hours followed by 50° C. overnight. After the solvent was evaporated under reduced pressure, the residue was taken into ether, and crystals were collected by filtration and dried to give 8.05 g of 4-(p-methoxybenzyl)oxythiobenzamide (yield, 98%).
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])=[N:4][N:5]([CH3:7])[CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.[Pd]>[CH3:7][N:5]1[CH:6]=[CH:2][C:3]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])=[N:4]1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cn1ccc(-c2cccc(N)c2)n1
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A solution of 3-(4-bromo-1-methyl-1H-pyrazol-3-yl)aniline (1.0 g) (available from Maybridge) in ethanol (20 ml) was added to a pre-hydrogenated suspension of 5% palladium on charcoal (0.5 g) in ethanol (40 ml). The resulting suspension was stirred under an atmosphere of hydrogen for 3 h. The mixture was filtered through ‘hyflo’ filter aid and the filter pad washed with ethanol (50 ml). The combined filtrate was evaporated in vacuo to give a brown gum. This gum was treated with 2M sodium carbonate solution (100 ml) and extracted with ethyl acetate (2×100 ml); the organic layer was dried over magnesium sulphate and the solvent removed in vacuo. Purification by chromatography on silica gel, eluting with diethyl ether, gave the title compound as a white crystalline solid (0.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10]CC)=[O:9])=[N:6][CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 99 %

Procedure:
Dissolve ethyl 5-fluoropyridine-2-carboxylate (4.60 g, 27.2 mmol) in THF (34 mL) and methanol (34 mL). Add 1.0 N NaOH (32.6, 32.6 mmol) and stir at room temperature for 1.3 hours. Concentrate the reaction mixture. Then add 1.0 N HCl (32.6 mL) stir and concentrate. Take the solid up in 20% methanol, 3% AcOH and 77% dichloromethane and filter through a silica plug. Wash the plug with the solvent listed above until all of the product elutes off to give the title compound (3.8 g, 100%): MS ES+ 142.03 (M+H)+, HRMS calcd for C6H5NO2F 142.0304 (M+H)+, found 142.0306, time 0.46 min, 0.51; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=6.3 min, 100% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[C:6]([N:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH3:9])=[O:7].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[C:6]([N:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH3:9])=[O:7]
Reactant: CCOC(=O)CCCCCOc1cc(C)ccc1N(C)C(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)O)ccc1[N+](=O)[O-]
Reaction time: 6 h
Yield: 99.5 %

Procedure:
A solution of 3-methoxy-4-nitro-N-[2-(5-ethoxycarbonylpent-1-yloxy)-4-methylphenyl]-N-methylbenzamide (7.6 g) in ethanol (76 ml) was treated with 1 N sodium hydroxide solution (33 ml) at ambient temperature and the mixture was stirred at the same temperature for 6 hours. The reaction was quenched by the dropwise addition of 1 N hydrochloric acid (35 ml). The mixture was concentrated and the residue was dissolved in a mixture of ethyl acetate and 1 N hydrochloric acid. The extracted organic layer was washed with brine and dried over magnesium sulfate. The suspension was filtered and the solvent was removed by evaporation to give 3-methoxy-4-nitro-N-[2-(5-carboxypent-1-yloxy)-4-methylphenyl]-N-methylbenzamide (7.1 g) as an oil.
Reaction SMILES: BrCCCCC(O)=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.CC[C@H]1OC(=O)[C@H](C)[C@@H]([O:42][C@@H:43]2[O:48][C@@H:47]([CH3:49])[C@H:46]([OH:50])[C@@:45]([O:52][CH3:53])([CH3:51])[CH2:44]2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](O)(C)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@@]1(O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:42]=[CH:43][CH2:44][C@:45]([C@H:46]([C@H:47]([CH3:49])[OH:48])[OH:50])([O:52][CH3:53])[CH3:51]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: CC(C)(C)C(=O)Cl
Agent: O=C(O)CCCCBr
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@](C)(CC=O)[C@@H](O)[C@H](C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.6 %

Procedure:
To a solution of 5-bromovaleric acid (1.282 g; 7.07 mmole) in dry CH2Cl2 (10 ml), 1 ml (7.23 mmole) of triethylamine, 868 mg (7.10 mmole) of 4-dimethyl-aminopyridine and 0.940 ml (7.63 mmole) of pivaloyl chloride were added. The solution was stirred for 2 hours at room temperature in a flow of argon and then a solution of azithromycin (2 g; 2.67 mmole) in 10 ml of dry CH2Cl2 was added. The reaction mixture was stirred for three days at room temperature. Subsequently, 60 ml of saturated NaHCO3 solution were added to the reaction mixture and the layers were separated. The aqueous layer was twice more extracted with 40 ml of CH2Cl2. The combined organic extracts were washed with a saturated NaCl solution, dried over K2CO3 and evaporated in a rotary evaporator. The obtained oily product was purified on a silica gel column (eluant: CH2Cl2:CH3OH:NH4OH=90:9:1.5). 511 mg of the pure product were obtained. MS(ES+): 912 (MH+)
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[O:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(Oc2cccc(C(F)(F)F)c2)c(-c2ccccc2)n1
Yield: 4 %

Procedure:
5-Phenyl-6-[3-(trifluoromethyl)phenoxy]-1,2,4-triazin-3-amine (21 mg, 4%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 3-(trifluoromethyl)phenol (0.52 g, 3.18 mmol) according to the general procedure of Example 3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[C:23]2[OH:28]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:28][C:23]1[C:24]2[C:19](=[C:18]([O:17][CH3:16])[CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc2c(O)cccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3cccc4c(OC)cccc34)c2cc1OC
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 13.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (85 mg) and 5-methoxy-1-naphthol (67 mg) obtained in Example 5 were mixed and stirred at 180° C. for 20 minutes, and the reaction mixture was then purified in the same manner as described in Example 2 to obtain 19 mg of the title compound (yield: 14%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Cl.[CH2:14]([N:21]([CH2:25][CH2:26]Cl)[CH2:22][CH2:23]Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.CS(C)=O>[CH2:14]([N:21]1[CH2:25][CH2:26][C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)([C:11]#[N:12])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: N#CCc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Yield: 84.7 %

Procedure:
To a suspension of 9.8 g of 60% sodium hydride in oil in 140 ml of THF and 60 ml of DMSO is added dropwise, at rt, a solution of 11.3 g of 4-chlorophenylacetonitrile and 20 g of benzyl[bis(2-chloroethyl)]amine hydrochloride in 140 ml of THF and 60 ml of DMSO, and the mixture is then heated at 70-80° C. for 2 hours. After cooling, the reaction mixture is poured onto ice and extracted with ether, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a heptane/EtOAc mixture (90/10; v/v). 19.6 g of the expected compound are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].COC(C)(C)C.S([O:19][CH2:20][CH3:21])(OCC)(=O)=O.[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34][C:35](O)=[O:36])=[CH:25][CH:24]=1>O.CN(C)C=O>[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34][C:35]([O:19][CH2:20][CH3:21])=[O:36])=[CH:25][CH:24]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(O)Cc1ccccc1Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(=O)Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.8 %

Procedure:
After mixing 259.1 g of potassium carbonate (1.88 mol, granular reagent), 985 mL of tert-butyl methyl ether, 493 mL of N,N-dimethylformamide and 202.4 g (1.31 mol) of diethyl sulfate, a mixture of 328.4 g (1.25 mol) of 2-(2-(4-chlorophenoxy)phenyl)acetic acid and 164 mL of N,N-dimethylformamide was added dropwise to the obtained mixture over a period of one hour. The internal temperature of the mixture during the dropwise addition was 25-40° C. Upon completion of the dropwise addition, the obtained mixture was stirred at 25° C. for 12 hours, and completion of the reaction was confirmed by high-performance liquid chromatography. A 1642 mL portion of water was slowly added dropwise to suspend the reaction. The internal temperature of the mixture during the dropwise addition was 25-35° C. The obtained mixture was subjected to liquid separation, and after washing the organic layer with 656 mL of water and 495 mL of brine in that order, the obtained organic layer was subjected to dehydration treatment with anhydrous magnesium sulfate and the treated organic layer was concentrated to obtain 366.4 g of crude ethyl 2-(2-(4-chlorophenoxy)phenyl)acetate as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([NH2:22])[C@H:12]1[OH:13].[C:23]([O:27][C:28]([NH:30][CH:31]([C:42](O)=[O:43])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([NH:22][C:42](=[O:43])[CH:31]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)[NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:29])[C@H:12]1[OH:13]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CCOC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1N
Product: CCOC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1NC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Yield: 46.7 %

Procedure:
Ethyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-β-(4-nitrophenyl)-D,L-alanylamino]-β-D-ribofuranuronate (280 mg) was prepared by reacting ethyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronate (308 mg) prepared in Example 63 with N-tert-butoxycarbonyl-β-(4-nitrophenyl)-D,L-alanine (310 mg) according to a similar manner to that of Example 64, mp. 170°-180° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([C:10](=[O:13])[CH2:11][CH3:12])[CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[C:17]([CH3:30])[C:16]=1[OH:31].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[OH:31][C:16]1[C:17]([CH3:30])=[CH:18][C:19]([C:2]2[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([C:10](=[O:13])[CH2:11][CH3:12])[CH:3]=2)=[CH:20][C:15]=1[CH3:14]
Reactant: CCC(=O)c1cc(Cl)nnc1OC
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCC(=O)c1cc(-c2cc(C)c(O)c(C)c2)nnc1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2 g of 1-(6-chloro-3-methoxy-pyridazin-4-yl)-propan-1-one and 1.73 g of tetrakis(triphenylphosphine) palladium (0) are dissolved in 10 ml DME and the solution is stirred for 5 min at RT (room temperature) under argon. 3 g of 2,6-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol and 10 ml of a 2M aqueous solution of sodium carbonate are added and the reaction solution is stirred at 95° C. for 4 h. The reaction solution is poured into ethyl acetate and ished with saturated aqueous sodium bicarbonate. The organic phase is dried (MgSO4), filtered and evaporated under reduced pressure. The product is purified by silica gel chromatography, eluting with a gradient of ethyl acetate in heptane, followed by purification by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 1.69 g. LC-MS (ES+) 287 (M+H)+.