Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:29])[C:4]1[C:5](=[CH:10][C:11]([N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:6]([O:8]C)=O.[NH3:30]>C(O)CO>[CH3:28][N:21]([C:11]1[CH:10]=[C:5]2[C:6](=[O:8])[NH:30][C:3](=[O:29])[C:4]2=[CH:13][C:12]=1[NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N
Reactant: COC(=O)c1cc(Nc2ccccc2)c(N(C)c2ccccc2)cc1C(=O)OC
Solvent: OCCO
Product: CN(c1ccccc1)c1cc2c(cc1Nc1ccccc1)C(=O)NC2=O

Procedure:
Analogously to Example 1, 160 mg (0.41 mmol) of 4-(N-methyl-N-phenylamino)-5-anilinophthalic acid dimethyl ester in 12 ml of ethylene glycol are heated at 120° and, with stirring, ammonia gas is passed through the mixture for 18 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodiumchloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel withhexane/ethyl acetate 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of slightly yellow crystals, FAB-MS: 344 [M+ +H], 1H-NMR (CDCl3): 3.28 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:15]1([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:21][C:22](=[O:25])[CH2:23][CH2:24][N:11]2[CH2:12][CH2:13][C:14]3=[C:2]([CH3:1])[C:3]4[C:8]([CH:9]3[CH2:10]2)=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=CC(=O)NC1CCCCC1
Reactant: CC1=C2CCNCC2c2ccccc21
Product: CC1=C2CCN(CCC(=O)NC3CCCCC3)CC2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and N-cyclohexyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 8 hours. M.P. of the title compound 162.5°-163.5° from acetone.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][N+:8]=1[O-:15].[N+:16]([O-])([OH:18])=[O:17].C(=O)([O-])O.[NH4+]>O>[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([N+:16]([O-:18])=[O:17])[C:10]([CH3:14])=[CH:9][N+:8]=1[O-:15]
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 0.83 h
Yield: 81.5 %

Procedure:
To 98% sulfuric acid (4.93 kg, 49.3 mol), 2,3,5-trimethylpyridine1-oxide (1.38 kg, 10.1 mol) was added. After 97% nitric acid (1.44 kg) was added dropwise thereto over 50 minutes, the mixture was heated at 85° C. for 4 hours. The reaction mixture was poured to a mixture of ammonium hydrogen carbonate (10.6 kg) and water (9.0 L). The mixture was extracted with ethyl acetate (3.0 L×3). The obtained organic layer was concentrated and dried under vacuum overnight to obtain a desired product (1.50 kg).
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][CH2:8][CH2:9][S:10][C:11]1[N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)=[O:6])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:20][C:17]1[N:16]2[C:11]([S:10][CH2:9][CH2:8][NH:7][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:12][CH:13]=[CH:14][C:15]2=[N:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)OC(=O)NCCSc1cccc2nccn12
Solvent: ClC(Cl)Cl
Product: CC(C)OC(=O)NCCSc1cccc2ncc(Br)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of 5-[2-(isopropyloxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine (279 mg, 1 mmole) in chloroform (5 ml) was added N-bromosuccinimide (187 ml, 1.05 mmoles) and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 296 mg of the desired product (82.7%, colorless solid).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:40]1[CH:41]=[C:42]([C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])[S:43][CH:44]=1>O1CCOCC1.O.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>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:40]4[CH:41]=[C:42]([C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])[S:43][CH:44]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CC(C)C(=O)c1cc(Br)cs1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C(=O)C(C)C)c4)cc23)CC1
Reaction time: 0.33 h

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3 mL) and H2O (1 mL) was added potassium carbonate (89.8 mg, 0.66 mmol), 1-(4-bromo-2-thienyl)-2-methyl-1-propanone (87 mg, 0.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol). The reaction was run in a microwave for 20 min at 150° C. followed by an aqueous work-up with EtOAd and H2O. The reaction was then concentrated and treated with 1 N NaOH and extracted with EtOAc. The compound was purified by flash chromatography using DCM and MeOH to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-methylpropanoyl)-3-thienyl]-1H-indole-7-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O.O.[NH2:18][NH2:19]>C(O)CO>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[N:18][NH2:19]
Reactant: NN
Reactant: COc1cccc(C(=O)c2sccc2Br)c1
Solvent: O
Solvent: OCCO
Product: COc1cccc(C(=NN)c2sccc2Br)c1
Temperature: 130 °C

Procedure:
A mixture of (3-bromothien-2-yl) (3-methoxyphenyl)methanone (10.0 g), hydrazine hydrate (10 ml, above 99% purity), and 75 ml of ethylene glycol was heated at 130° C. for three hours. The reaction mixture was then quenched with water and extracted with ether. The ether solution was washed three times with water and dried over anhydrous magnesium sulfate. The ether was then evaporated to give 5.5 g of an oil. This was then column chromatographed on a silica gel column packed in hexane using 15% ether/hexane as an eluent. The solid from the column was then recrystallized from ether/hexane.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]#[N:21])[CH:15]=[CH:14][N:13]=2)=[N:3]1.C[Si]([N:26]=[N+:27]=[N-:28])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:26]1[C:20]([CH2:19][CH2:18][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([C:4]3[S:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[C:2](=[O:1])[N:3]=3)[CH:17]=2)=[N:21][N:28]=[N:27]1
Reactant: N#CCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cc(CCc3nnn[nH]3)ccn2)sc2ccccc12
Yield: 45.5 %

Procedure:
3-[2-(4-Oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionitrile (0.25 g, 0.85 mmol) and trimethylsilyl azide (0.20 g, 1.7 mmol) were dissolved in toluene (5 ml), and dibutyltin (IV) oxide (0.02 g, 0.08 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs and kept at room temperature. The precipitated crystals were collected by filtration and washed with toluene. The obtained crystals were recrystallized from ethanol to give the titled compound (0.13 g, 44%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>N1C=CC=CC=1>[C:13]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[CH3:1])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy-benzoic acid (3.0 g, 18.05 mmol) in pyridine (7 mL) was added acetic anhydride (2.05 mL, 21.66 mmol) and the reaction mixture was stirred at room temperature for 16 h. Water was added and the mixture was extracted with ethyl acetate, washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid (3.52 g, 94%). To a solution of 4-acetoxy-3,5-dimethyl-benzoic acid (6.02 g, 28.91 mmol) in CH2Cl2 (80 mL), oxalyl chloride (5.04 mL, 57.83 mmol) was added slowly, followed by a drop of dimethyl formamide. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed and acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester was dried under vacuum (6.37 g, 97%). To a solution of N,N,N,N-tetramethyl guanidine (2.77 mL, 22.078 mmol) in CH3CN (50 mL), a solution of 6,8-dimethoxy-isochroman-1,3-dione (4.46 g, 20.07 mmol) in CH3CN (100 mL) was added slowly at <0° C. (bath temperature −20° C.) in 30 min. Then, Et3N was added in one portion, followed by a solution of acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester (6.37 g, 28.1 mmol) in CH3CN (50 mL) and stirred for 30 min. at <0° C. The reaction mixture was stirred at room temperature for 16 h, then heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was quenched with 1 N HCl. The precipitated solid was filtered off to give a mixture of acetic acid 4-(6,8-dimethoxy-1,3-dioxo-isochroman-4-carbonyl)-2,6-dimethyl-phenyl ester and acetic acid 4-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-2,6-dimethyl-phenyl ester (6.0 g).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH3:14][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[Br:1][CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:14])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(C(=O)CBr)cc1

Procedure:
4-(Bromoacetyl)benzoic acid (10 g, 41.3 mmol) was dissolved in 75 mL of MeOH and 75 mL of methylene chloride. Trimethylsilyl diazomethane (2.0 M in ether) was slowly added at 0° C. until a yellow color persisted. The volatiles were evaporated to give the title compound. 1H NMR (500 MHz, (CD3OD): 8.18 (d, 2H), 8.16 (d, 2H), 4.68 (s, 2H), 3.96 (s, 3H). LCMS: m/z 258 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([O:19][CH3:20])=[CH:9][CH:10]=[C:11]3[C:16]=2[O:15][C:14](=[O:17])[CH:13]=[C:12]3O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:25]>C1(C)C=CC=C(C)C=1>[NH2:25][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([O:19][CH3:20])=[CH:9][CH:10]=2)[O:15][C:14](=[O:17])[CH:13]=1
Reactant: [NH4+]
Reactant: COc1ccc2c(O)cc(=O)oc2c1OC1CCCC1
Agent: CC(=O)[O-]
Solvent: Cc1cccc(C)c1
Product: COc1ccc2c(N)cc(=O)oc2c1OC1CCCC1
Reaction time: 3 h

Procedure:
A mixture of 8-(cyclopentyloxy)-4-hydroxy-7-methoxy-2H-chromen-2-one (450 mg, 1.63 mmol, Example 1, Step 2), ammonium acetate (3.0 g, 39 mmol), and anhydrous m-xylene (8 mL) was refluxed under N2. After 3 h, the reaction was concentrated and purified by silica gel chromatography (3:2→0:1; hexanes:ethyl acetate) to give 4-amino-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one: MS (ESI): 275.9.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH:17]=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].CO[C:21](C)(C)[CH3:22]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH2:16][CH:17]=[CH:21][CH3:22]
Reactant: COC(C)(C)C
Reactant: N#Cc1ccc([C@H]2CC[C@H](CCC=O)CC2)cc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC=CCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 14.8 g of ethyltriphenylphosphonium bromide in 150 ml of t-butyl methyl ether was treated with 4.54 g of solid potassium t-butylate at -10° C. within 5 minutes while gassing with argon in a sulphonation flask provided with a mechanical stirrer. The suspension was stirred at room temperature for 1 hour, then treated dropwise at 0° C. over a period of 5 minutes with a solution of 6.4 g of 3-[trans-4-(p-cyanophenyl)cyclohexyl]propionaldehyde in 40 ml of t-butyl methyl ether and stirred at room temperature for another 15 hours. The reaction mixture was subsequently partitioned three times in diethyl ether/water. The organic extracts were washed twice with water, dried over magnesium sulphate, filtered and concentrated. In order to separate triphenylphosphine oxide, the residue was dissolved in ethyl acetate and the solution was diluted with petroleum ether, filtered and concentrated. Chromatographic separation of the resulting, yellowish oil (8.55 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 5.93 g (89%) of p-[trans-4-(3-pentenyl)cyclohexyl]benzonitrile as white crystals.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClCCCl.C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: c1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.4 g) in 1,2-dichloroethane was added rhodium(II) acetate (1 mg) under refluxing. After refluxing for 1 hour, the reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in anhydrous benzene (10 ml) and then evaporated in vacuo. This operation was repeated once again and the residue was dried in vacuo to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The compound obtained above was dissolved in anhydrous acetonitrile (10 ml) and cooled to 0° C. under an atmosphere of nitrogen. To this solution were added N,N-diisopropyl-N-ethylamine (0.21 ml) and diphenyl phosphorochloridate (0.22 ml) successively, and the solution was stirred at 0° C. for 40 minutes. To the resulting solution were added dropwise a solution of (2S,4S)-2-(carbamoylmethyl)thiomethyl-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.45 g) in N,N-dimethylformamide (3 ml) and N,N-diisopropyl-N-ethylamine (0.21 ml) at 0°-2° C. with stirring and the stirring was continued at the same temperature for 2 hours. To the reaction mixture was added ethyl acetate (30 ml). The solution was washed 3 times with saturated aqueous sodium chloride (20 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (1:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(carbamoylmethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.44 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]1([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])(C)(C)C.[K+]>CS(C)=O>[CH:11]1([C:17]2[CH:18]=[CH:19][C:20]([NH:21][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])=[CH:22][CH:23]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(C2CCCCC2)cc1

Procedure:
The product (280 mg) is obtained according to the method of stage 1 of Example 4, by using 400 μL of 2-fluoro-nitrobenzene and 1 g of 4-cyclohexylaniline in the presence of 683 mg of potassium tert-butanolate in 4 mL of DMSO.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]([C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)[OH:22])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CSc1ccc([Mg]Br)cc1
Reactant: O=Cc1ccccc1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
In a nitrogen stream, a solution of 4-methylsulfanyl-phenylmagnesium bromide in THF (0.5 M, 35 mL) was added dropwise to a solution of 2-benzyloxybenzaldehyde (2.60 g, 12.2 mmol) in THF (24 mL) at 0° C. and the mixture was stirred at room temperature for two hours, and then a saturated ammonium chloride aqueous solution was added thereto under cooling with ice and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (3.91 g, 95%).
Reaction SMILES: [OH2:1].O.Cl.O.O.Cl.NC1N=CN=C2C=1N=CN2[C@@H]1O[C@H](C(O)=O)[C@@H](N[C:27](=[O:39])[C@H:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[NH2:29])[C@H]1O.[OH-].[Na+]>O>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C@@H:28]([C:27]([OH:39])=[O:1])[NH2:29])=[CH:36][CH:35]=1
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
A solution of hydrochloride dihydrate of FR-48736 substance [1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-(O-methyl-L-tyrosylamino)-β-D-ribofuranuronic acid hydrochloride dihydrate] (100 mg) prepared by Example 98 in 1N-methanolic sodium hydroxide (10 ml) was refluxed for 20 hours. To the cooled solution was added water (50 ml) and the methanol in the solution was evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH 7 with 1N-hydrochloric acid and applied to a column of activated charcoal (20 ml). The column was washed with water (40 ml) and eluted with a mixture of methanol and water (1:1) (60 ml). The solvent was evaporated under reduced pressure. The residue was chromatographed on a cellulose column and eluted with a mixture of acetonitrile and water (8:2). The first ninhydrin positive and weak UV absorbing fraction was evaporated under reduced pressure to give a powder of O-methyltyrosine (21 mg).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([S:22][CH2:23][CH:24]([OH:31])[CH2:25][S:26][CH2:27][C:28]([OH:30])=[O:29])[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])[CH3:9]>C1C=CC=CC=1>[CH3:1][O:29][C:28](=[O:30])[CH2:27][S:26][CH2:25][CH:24]([OH:31])[CH2:23][S:22][C:13]1[CH:12]=[C:11]([C:8]([CH3:7])([CH3:9])[CH3:10])[C:16]([OH:17])=[C:15]([C:18]([CH3:19])([CH3:20])[CH3:21])[CH:14]=1
Reactant: CC(C)(C)c1cc(SCC(O)CSCC(=O)O)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: COC(=O)CSCC(O)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (3 ml) was added to a solution of the compound of Example 41 (2.3 g) in benzene (50 ml) and stirred for 3 hours at room temperature. The reaction volume was reduced and methyl alcohol (100 ml) added. After evaporation of the solvents, the product (an oil) was purified by chromatography on silica.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(=O)(=O)(O)O>C(OCC)C.O1CCCC1>[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:22])[CH2:3][CH:2]=[CH2:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CC[Mg]Br
Reactant: O=CCCCCCCCCCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(O)CCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a cooled solution of 1M allyl magnesium bromide in diethyl ether was added dropwise, under nitrogen, a solution of 18.2 g of 10-phenyldecanal (prepared as in Step 1) in 200 ml of dry tetrahydrofuran. The reaction mixture was stirred at about 5° for 15 minutes, at room temperature for 1 hour, and then at reflux for 15 minutes. The reaction mixture was cooled to room temperature and poured into a mixture of 400 g of ice and 40 ml of 9M sulfuric acid. Upon standing the mixture separated into aqueous and organic layers. The organic layer was stirred for 15 min with solid sodium bicarbonate and then concentrated. The aqueous layer was extracted with diethyl ether (2×200 ml) and the extracts were combined with the concentrated organic layer. The combined organics were washed with water (300 ml) and a half-saturated aqueous solution of sodium chloride (300 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. High pressure liquid chromatography of the oil using 10% diethyl ether/hexane as the eluent gave 6.98 g (30%) of 13-phenyl-1-tridecen-4-ol as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:33])[NH:18][C:19]1[CH:24]=[C:23]([C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[C:22]([F:31])=[CH:21][C:20]=1[CH3:32])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:27]1[C:28]([CH3:30])=[CH:29][CH:25]([C:23]2[CH:24]=[C:19]([NH:18][C:17]([O:16][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:33])[C:20]([CH3:32])=[CH:21][C:22]=2[F:31])[NH:26]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2cc(NC(=O)OC(C)(C)C)c(C)cc2F)n[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=CC(c2cc(NC(=O)OC(C)(C)C)c(C)cc2F)NN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzylchloroformate (104 mg) was added dropwise to a room temperature solution of [4-fluoro-2-methyl-5-(5-methyl-1H-pyrazol-3-yl)-phenyl]-carbamic acid tert-butyl ester and DIPEA in CH2Cl2 (2 ml). The mixture was stirred at room temperature for one hour, and then 10% aqueous citric acid solution was added. The organic layer was separated dried (Na2SO4), filtered and concentrated under reduced pressure. “Flash chromatography” of the residue (0 to 20% EtOAc in hexanes) gave 210 mg of 3-(5-tert-Butoxycarbonylamino-2-fluoro-4-methyl-phenyl)-5-methyl-2H-pyrazole-1-carboxylic acid benzyl ester as a white solid.