Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C)C=O>[NH:1]=[C:2]1[N:6]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=2[S:3]1
Reactant: ClCCN1CCCCC1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: Cl
Solvent: CN(C)C=O
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CCN1CCCCC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 20.9 %

Procedure:
2-Amino-6-trifluoromethoxybenzothiazole (9.4 g) and N-(2-chloroethyl)piperidine hydrochloride (8.1 g) are heated for 1 hour to 130° C. Dimethylformamide (20 cc) is then added and the reaction is continued for 24 hours at 130° C. After cooling of the mixture to a temperature in the region of 20° C., the precipitate is filtered off and then treated with 1N sodium hydroxide (50 cc) in distilled water (100 cc). The residue obtained by extraction with dichloromethane, drying over magnesium sulphate and concentration to dryness under reduced pressure (20 mm Hg; 2.7 kPa) is purified by chromatography on a silica column, with ethyl acetate and then a mixture of ethyl acetate and methanol (95:5 by volume) as eluents. 2-Imino-3-(2-piperidinoethyl)-6-trifluoromethoxybenzothiazoline (2.9 g) is obtained in the form of a yellow oil, which is converted to a dihydrochloride subliming at about 200° C. after recrystallization in boiling absolute ethanol (20 cc).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:30]>CO.[OH-].[OH-].[Pd+2]>[ClH:30].[CH3:23][N:19]([CH2:20][CH2:21][CH3:22])[C:17]1[CH:16]=[N:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1
Reactant: CCCN(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN(C)c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 8-benzyl-N-methyl-N-propyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (50 mg) in methanol (4 mL) was added 20% Pd(OH)2/C (10 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (2 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (44 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (27 mg, 65%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[CH2:9]3)=[C:4]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH:3]=2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCc2c(cc(NS(=O)(=O)c3ccc(Cl)cc3)cc2-c2ccccc2Cl)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
1-[7-amino-5-(2-chloro-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (80 mgs, 0.2 mmoles) was stirred in dichloromethane (12 mls) and triethylamine (80 ul, 0.58 mmoles) was added, followed by 4-chlorobenzenesulphonyl chloride (75 mgs, 0.36 mmoles). The reaction was flushed with nitrogen and left stirring at room temperature overnight. The reaction was purified by semi-preparative C18 HPLC (47 mgs, 44% yield, 100% pure, CO-AAW00034).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]([O:31][N+:32]([O-:34])=[O:33])[CH2:29][NH2:30])=[CH:24][CH:23]=1)([O-:21])=[O:20].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:30][CH2:29][CH:28]([C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=1)[O:31][N+:32]([O-:34])=[O:33])#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCC(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCC(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 30 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.22 g, 1.2 mmol) was dissolved in methanol (10 ml), and 2-(4-nitrophenyl)-2-nitroxyethylamine nitrate (0.40 g, 1.4 mmol) and sodium methoxide (0.14 g, 2.6 mmol) were added. The mixture was stirred at room temperature for 17 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was extracted with chlofororm (100 ml×3). The chloroform layer was washed with water (150 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (50:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.13 g, 0.36 mmol, yield: 31%) as colorless crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]([C:35]3[C:43]4[C:38](=[CH:39][C:40]([Cl:44])=[CH:41][CH:42]=4)[N:37]([CH3:45])[CH:36]=3)[C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30](OCC)=[O:31])=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1.O1C2C=CC(C(C3C4C(=CC(Cl)=CC=4)N(C)C=3)C(C3C=CC(CC(OCC)=O)=C(S(=O)(=O)N)C=3)=O)=CC=2OC1.Cl>O1CCCC1.C(OCC)(=O)C>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]([C:35]3[C:43]4[C:38](=[CH:39][C:40]([Cl:44])=[CH:41][CH:42]=4)[N:37]([CH3:45])[CH:36]=3)[C:17]([NH:19][S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][OH:31])=[CH:27][CH:28]=3)(=[O:22])=[O:21])=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(Cl)ccc23)cc1
Agent: CCOC(=O)Cc1ccc(C(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(Cl)ccc23)cc1S(N)(=O)=O
Agent: Cl
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(C(C(=O)NS(=O)(=O)c2ccc(CCO)cc2)c2ccc3c(c2)OCO3)c2ccc(Cl)cc21

Procedure:
Lithium aluminium hydride (6 mg, 0.16 mmol) was added to a stirred solution of ethyl 2-(4-[2-(1,3-benzodioxol-5-yl)-2-(6-chloro-1-methyl-1H-3-indolyl)acetyl]sulfamoylphenyl)acetate (the product of Example 89, 80 mg, 0.14 mmol) in tetrahydrofuran (6 ml) at 0° C. under a nitrogen atmosphere. After 40 mins ethyl acetate (1 ml) was slowly added and the reaction mixture was poured into hydrochloric acid (50 ml). The product was extracted into ethyl acetate (2×50 ml), dried (MgSO4) and concentrated. Recrystallisation (methanol/ether) gave the product as a white crystalline solid (50 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].OCC([C@@H]([C@H]([C@@H](CO)O)O)O)=O>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(CO)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C(CO)[C@H](O)[C@@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
A Ca(OH)2 slurry was prepared in a small bucket by carefully mixing 4.66 kg CaO with 14 1 water in an exothermic reaction. A 230 1 capacity stainless steel kettle, equipped with a strong agitator, was charged with 15.0 kg D-galactose and 135 1 deionized water and stirred until the sugar dissolved. With the solution stirring at 20° C., the Ca(OH)2 slurry weighing 18.7 kg was gradually added to the kettle. Addition was complete in hour. The progress of the reaction was monitored by HPLC analysis each 0.5 hour, as described below. After 2 hours the mixture had turned to a thick gel; vigorous stirring was continued. After approximately 4 hours, galactose conversion reached greater than 85% and the reaction was stopped by slowly adding 50% by weight phosphoric acid until the pH was 5.8. In this process, the gel dissolved and calcium phosphate precipitated. The calcium phosphate solids were separated from the reaction mixture by centrifugation. The hydrated calcium salts were then rewashed by stirring them with 25 1 water in the kettle for an additional hour. Using the centrifuge, the washings were separated and combined with the reaction mixture. The reaction mixture of 150 1 was deionized by passing it through columns of AMBERLITE IR-120 (H+ form, 7 1) and then AMBERLITE IRA-68 (free base form, 9 1). AMBERLITE IR-120 is a trademark for a cationic ion exchange resin sold by Rohm and Haas, Philadelphia, PA. AMBERLITE IRA-68 is a trademark for an anionic ion exchange resin sold by Rohm and Haas, Philadelphia, PA. The contact time for each resin was at least 20 minutes. The colorless 200 1 of eluant was analyzed by HPLC, which showed that the dissolved solids contained 72% D-tagatose based on the amount of D-galactose charged. Because of the large volume of solution, the solution was split into several portions for crystallization. Concentration in vacuo of the first portion of deionized solution gave a thick syrup of 5862 g to which 5871 g of 95% EtOH was added. The stirred mixture was heated to dissolve the syrup, then it was cooled and seeded with a few D-tagatose crystals. After stirring 24 hours, crystalline D-tagatose weighing 2390 g, 93% pure by HPLC, was isolated by vacuum filtration. Recrystallization from 95% EtOH gave 1386 g D-tagatose which had a melting point of 127° C.-130° C. and the following composition by HPLC: D-tagatose, 97.5%; D-sorbose, 1.00%; unknown No. 1, 0 65%; and unknown No. 2, 1.00% (estimate, unknown No. 2 not well resolved). The remaining portions of deionized solution were concentrated and crystallized in the same way. Two crops of crystals were obtained from each portion. Syrup containing less than 60% D-tagatose would not yield any more crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:9]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:10]=1)(=[O:3])[CH3:2].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)CCC>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CCCCO
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(-c2ccc(=O)[nH]n2)c1

Procedure:
6-[5-Acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone was reacted with chloranil in boiling butanol to give 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl] -3(2H)-pyridazinone.
Reaction SMILES: [S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[NH2:6][C:7]1[C:8]2[N:9]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13]([NH2:15])=[O:14])[CH:12]=1.[CH3:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([CH3:31])[C:23]=1[CH2:24]Br.C(N(C(C)C)CC)(C)C.[I-].[K+]>CN(C)C=O.C(Cl)Cl.O>[S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[CH3:19][C:17]1[N:18]=[C:8]2[C:7]([NH:6][CH2:24][C:23]3[C:22]([CH3:21])=[CH:29][C:28]([F:30])=[CH:27][C:26]=3[CH3:31])=[CH:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][N:9]2[C:16]=1[CH3:20]
Reactant: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Reactant: Cc1cc(F)cc(C)c1CBr
Agent: CS(=O)(=O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(F)cc(C)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Yield: 23.9 %

Procedure:
8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesylate (5.0 g, 13.4 mmol), 2,6-dimethyl-4-fluorobenzylbromide (2.91 g, 13.4 mmol), diisopropylethylamin (3.8 g, 29.5 mmol) and a cat. amount of potassium iodide were stirred in dimethylformamide (20 ml) at room temperature overnight. Water (70 ml) and methylene chloride (2×50 ml) were added to the reaction mixture and the organic layer was separated, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent. The product was solved in isopropanol and methansulfonic acid (0.3 g) was added. The salt that formed was isolated by filtration and washed with isopropanol and diethyl ether to give 1.4 g (24%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>CN(C)C=O.O.CO>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1.5 g (6.2 mmol) of 7-benzylxanthine from stage b) were dissolved in 50 ml of dimethylformamide at 50° C. and treated in portions with 0.149 g (6.2 mmol) of sodium hydride and stirred at 50° C. for one hour. 0.67 ml (6.2 mmol) of isobutyl bromide was added dropwise and the mixture was heated to 80° C. After 5 hours, a further 0.2 ml (1.86 mmol) of isobutyl bromide was added and the mixture was stirred for a further 5 hours. 12 ml of water and 5 ml of methanol were then added, the mixture was stirred at room temperature for 2 hours, a further 60 ml of water were added and the mixture was extracted three times using methyl tert-butyl ether. The organic phases were washed with water, dried using magnesium sulfate and concentrated under reduced pressure and the residue was purified by flash chromatography on a silica gel column, dichloromethane/methanol (99/1).
Reaction SMILES: Br[C:2]1[N:3]([C:19]#[N:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:21][C:22]1[C:26](B(O)O)=[C:25]([CH3:30])[S:24][N:23]=1.C(=O)([O-])O.[Na+]>COCCOC.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>[CH3:21][C:22]1[C:26]([C:2]2[N:3]([C:19]#[N:20])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[C:25]([CH3:30])[S:24][N:23]=1
Reactant: Cc1nsc(C)c1B(O)O
Reactant: COc1ccc(-c2c(Br)n(C#N)c3ccccc23)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: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2c(-c3c(C)nsc3C)n(C#N)c3ccccc23)cc1
Temperature: 120 °C
Yield: 50.3 %

Procedure:
2-bromo-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile (70.0 mg, 0.21 mmol), tetrakis(triphenylphosphine)palladium (24.7 mg, 0.21 mmol) and 3,5-dimethylisothiazol-4-ylboronic acid (102.3 mg, 0.43 mmol) were mixed in 3.5 ml DME and 0.86 ml sodium hydrogen carbonate (1 M) under nitrogen. The resulting mixture was heated at 120° C. for 20 min in microwave. The solvent was evaporated and the residue was dissolved in DCM. Filtering through a short plug of silica gave a crude product which was purified on silica (EtOAc/n-Heptane 1:4). 38.0 mg 2-(3,5-dimethylisothiazol-4-yl)-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.[OH-].[Na+].Br[C:17]([CH3:22])([CH3:21])[C:18]([NH2:20])=[O:19].[I-].[K+]>CC(N(C)C)=O.O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][C:17]([CH3:22])([CH3:21])[C:18]([NH2:20])=[O:19])[CH:7]=[CH:6]2
Reactant: OCc1ccc2cc(O)ccc2c1
Reactant: CC(C)(Br)C(N)=O
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(Oc1ccc2cc(CO)ccc2c1)C(N)=O
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 6-(hydroxymethyl)-2-naphthol (500 mg, 2.87 mmol) in dimethylacetamide (4 ml) was added sodium hydroxide (344 mg, 8.61 mmol), and the mixture was stirred for 1 hour. 2-bromo-2-methylpropanamide (1.43 g, 8.61 mmol) and potassium iodide (476 mg, 2.87 mmol) were added thereto, and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The extract was washed with a 1N aqueous sodium hydroxide solution and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, 2-[[6-(hydroxymethyl)-2-naphthyl]oxy]-2-methylpropanamide (506 mg) was obtained as a colorless powder from isopropyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](CC(F)(F)F)[C:6]([C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])=[CH:5]2.[Cl:24][CH2:25][CH2:26][CH2:27]OC1C=C2C(=CC=1)NC(C(O)=O)=C2.N1CCOCC1>>[Cl:24][CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:16]([N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)=[O:17])=[CH:5]2
Reactant: O=C(c1cc2cc(O)ccc2n1CC(F)(F)F)N1CCOCC1
Reactant: O=C(O)c1cc2cc(OCCCCl)ccc2[nH]1
Solvent: C1COCCN1
Product: O=C(c1cc2cc(OCCCCl)ccc2[nH]1)N1CCOCC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 4, the title compound was synthesized from 5-(3-chloro-propoxy)-1H-indole-2-carboxylic acid (Example 4, step 2) and morpholine. The desired product was obtained as white solid in 84% yield. MS (m/e): 324.0 (MH+, 100%).
Reaction SMILES: CN(C)C(=O)[O:4][C:5]1[C:14]([C:15]2[C:16]([O:26]C(=O)N(C)C)=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]([CH3:25])[CH2:22][CH2:21][CH2:20]3)=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][N:12]2[CH3:32])=[CH:7][CH:6]=1.[OH-].[K+]>>[CH3:25][N:23]1[C:24]2[C:19](=[CH:18][CH:17]=[C:16]([OH:26])[C:15]=2[C:14]2[C:5]([OH:4])=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]([CH3:32])[CH2:11][CH2:10][CH2:9]3)[CH2:20][CH2:21][CH2:22]1
Reactant: CN(C)C(=O)Oc1ccc2c(c1-c1c(OC(=O)N(C)C)ccc3c1N(C)CCC3)N(C)CCC2
Agent: [K+]
Agent: [OH-]
Product: CN1CCCc2ccc(O)c(-c3c(O)ccc4c3N(C)CCC4)c21
Temperature: 25 °C
Yield: 78.3 %

Procedure:
A solution of 6 (2.0 g, 4.29 mmol) in 10 wt. % methanolic KOH (45 mL) was stirred at reflux for 20 h. The resulting solution was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in H2O and the pH adjusted to a value of 7 by careful addition of 1 M aq. HCl. The aqueous phase was saturated with NaCl and extracted with EtOAc (50 mL×6). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and, concentrated in vacuo. The residue was further purified by column chromatography (eluting with EtOAc/Hexane=4:1) to yield 7 (1.09 g, 76%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:40]1[CH:48]=[CH:47][C:43]([C:44]([NH2:46])=[O:45])=[CH:42][CH:41]=1>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][C:40]1[CH:48]=[CH:47][C:43]([C:44](=[O:45])[NH2:46])=[CH:42][CH:41]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: NC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccc(C(N)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To the solution of 1 (acetylsalicylic acid, 500 mg, 2.77 mmol) in 15 mL of dimethylformamide, hydroxybenzotriazole (412 mg, 3.05 mmol) and DCC (628 mg, 3.05 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (4, 418 mg, 3.05 mmol) was added and stirred for 1 h at 0° C. and 3 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in chloroform; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 5 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9/1), from which 4-carbamoylphenyl 2-acetoxybenzoate (5) was obtained (410 mg, 47% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]1([CH2:23][NH:24][CH2:25][C@@H:26]([NH:31][C:32](=[O:48])[CH2:33][C:34]2[N:38]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=3)[CH:37]=[N:36][CH:35]=2)[C@@H:27]([CH3:30])[CH2:28][CH3:29])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:24]([CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:25][C@@H:26]([NH:31][C:32](=[O:48])[CH2:33][C:34]1[N:38]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=2)[CH:37]=[N:36][CH:35]=1)[C@@H:27]([CH3:30])[CH2:28][CH3:29])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](C)[C@@H](CNCc1cccc2ccccc12)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CC[C@H](C)[C@@H](CN(Cc1cccc2ccccc12)C(=O)CNC(=O)OC(C)(C)C)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1

Procedure:
The title compound was prepared using the protocol described in Example 1 step H using N-t-butoxycarbonyl glycine and N-naphth-1-ylmethyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-ylacetyl}amino-3(S)-methyl pentanamine from Example 2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1.[CH2:38](P(=O)(OCC)OCC)[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42].CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:38]/[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:22][N:21]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: COc1cc(COc2nn(Cc3cccnc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(Cc2cccnc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 88.1 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carbaldehyde (0.17 g), tetraethyl methylenediphosphonate (0.11 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 0.015 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]ethenylphosphonate as a colorless oil (0.19 g, yield 86%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v).