Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])OC(C)(C)C.[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([NH2:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(OCC)(=O)C>CO.C(OCC)(=O)C>[CH2:13]([N:20]1[CH2:21][CH2:22][N:23]([N:26]2[CH2:2][CH2:3][CH2:4][NH:5][C:6]2=[O:12])[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: NN1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1NCCCN1N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47 %

Procedure:
A solution of tert-butyl (3-oxopropyl)carbamate (4.2 g) and 4-benzylpiperazin-1-amine (4.6 g) in methanol (60 mL) was heated under reflux for 3 hours, and the solvent was distilled off under reduced pressure. After the residue was dissolved in methanol (60 mL), acetic acid (4.1 mL) and sodium triacetoxyborohydride (3.2 g) were added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, made alkaline with 1N sodium hydroxide and potassium carbonate, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was dissolved in ethyl acetate (10 mL). and then a 4N hydrochloric acid-ethyl acetate solution (100 ml) was slowly added at 0° C., followed by stirring at room temperature for 5 hours. The precipitate was collected by filtration, dried, and then suspended in acetonitrile (200 mL). DBU (14.6 g) and CDI (7.8 g) were added thereto, and the mixture was heated under reflux for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and recrystallized from diethyl ether to obtain the title compound (3.1 g, 46%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]=2[CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:3]=1[C:22]([O:24][CH3:25])=[O:23].[H-].[Na+].[CH2:28](I)[CH3:29]>O1CCCC1>[CH2:28]([N:7]1[C:2]([CH3:1])=[C:3]([C:22]([O:24][CH3:25])=[O:23])[CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:5]2[C:10](=[O:11])[O:9][CH2:8][C:6]1=2)[CH3:29]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1C(F)(F)F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(C)=C(C(=O)OC)C(c2ccccc2C(F)(F)F)C2=C1COC2=O
Reaction time: 0.17 h

Procedure:
50 mmol of methyl 2-methyl-4-(2-trifluoromethylphenyl)-5-oxo-1,4,5,7-tetrahydrofuro-[3,4-b]pyridine-3-carboxylate are dissolved in 100 ml of anhydrous tetrahydrofuran, and 50 mmol of sodium hydride are added. After 10 minutes at room temperature, 55 mmol of ethyl iodide are added, and the mixture is boiled under reflux for 1 hour. The mixture is evaporated down, after which the residue is taken up with CH2Cl2, the solution is washed with water, dried and evaporated down, and the residue is recrystallized.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.Br[C:39]1[CH:40]=[CH:41][C:42]([C:45]2([C:51]#[N:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[N:43][CH:44]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:39]2[CH:40]=[CH:41][C:42]([C:45]3([C:51]#[N:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[N:43][CH:44]=2)=[CH:32][CH:31]=1
Reactant: N#CC1(c2ccc(Br)cn2)CCCCC1
Reactant: COc1ccc(CN)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ccc(C3(C#N)CCCCC3)nc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
Palladium (II) acetate (90 mg), 2-(di-tert-butylphosphino)biphenyl (240 mg), sodium tert-butoxide (1.35 g), toluene (20 ml) and p-methoxybenzylamine (1.81 g) were added to 1-(5-bromopyridin-2-yl)cyclohexanecarbonitrile (2.5 g), and stirred at 100° C. for two hours. Water was added to the reaction solution, the resulting precipitate was filtered, the filtrate was extracted with ethyl acetate and the organic layer was concentrated. The residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give 1-{5-[(4-methoxybenzyl)amino]pyridin-2-yl}cyclohexanecarbonitrile (650 mg) as a solid.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14]3[CH2:25][NH:24][C:23]([CH3:27])([CH3:26])[C:15]=3[N:16](C(OCC)=O)[N:17]=2)[C:9]([F:28])=[CH:8][N:7]=1)[CH3:4].C(N(C(C)C)CC)(C)C.[F:38][C:39]1([C:46](Cl)=[O:47])[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>C1COCC1>[CH2:3]([O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14]3[CH2:25][N:24]([C:46]([C:39]4([F:38])[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)=[O:47])[C:23]([CH3:26])([CH3:27])[C:15]=3[NH:16][N:17]=2)[C:9]([F:28])=[CH:8][N:7]=1)[CH3:4]
Reactant: CCOC(=O)n1nc(Nc2nc(OCC)ncc2F)c2c1C(C)(C)NC2
Reactant: CN1CCC(F)(C(=O)Cl)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ncc(F)c(Nc2n[nH]c3c2CN(C(=O)C2(F)CCN(C)CC2)C3(C)C)n1
Temperature: 65 °C

Procedure:
To a solution of ethyl 3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate dihydrochloride (120 mg, 0.27 mmol) in 15 mL THF containing diisopropylethyl amine (0.23 mL, 4 eq) was added a 5 mL THF suspension of 4-fluoro-1-methylpiperidine-4-carbonyl chloride (128 mg, 2.6 eq). After heating for 5 hours at 65° C., the reaction was concentrated to dryness and carried on without further purification. To a solution of ethyl 3-[(2-ethoxy-5-fluoropyrimidin-4-yl)amino]-5-[(4-fluoro-1-methylpiperidin-4-yl)carbonyl]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate in methanol was added 2 mL of a 10% sodium hydroxide solution in methanol. After removing the solvent in vacuo, the residue was purified as in Example K1 above. See Table 1 below for NMR data.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:30])[N:7]2[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[CH2:17][CH2:16]1.Cl>C(O)C.[C].[Pd]>[NH2:27][C:23]1[CH:22]=[C:21]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:7]3[C:8]4[C:3](=[C:2]([Cl:1])[CH:11]=[CH:10][CH:9]=4)[CH2:4][CH2:5][C:6]3=[O:30])[CH2:16][CH2:17]2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CCc2c(Cl)cccc2N1CCCN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(N2CCN(CCCN3C(=O)CCc4c(Cl)cccc43)CC2)c1
Yield: 89.6 %

Procedure:
5-Chloro-1-[3-[4-(3-nitrophenyl)-1-piperazinyl]-propyl]-3,4-dihydrocarbostyril (3 g) was dissolved in 100 ml of ethanol, 2 ml of concentrated hydrochloric acid was added, and catalytic reduction was carried out at 3 atmospheres in the presence of 1.5 g of 5% palladium-carbon. The catalyst was then filtered off, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give 2.5 g of 1-[3-[4-(3-aminophenyl)-l-piperazinyl]propyl]-5-chloro-3,4-dihydrocarbostyril as colorless needles.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:3]1=[O:24].[C:25]1([CH2:31][CH2:32][C@@H:33](OS(C(F)(F)F)(=O)=O)[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:37]([O:36][C:34]([C@@H:33]([NH:1][CH:2]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:3]1=[O:24])[CH2:32][CH2:31][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:35])[CH2:38][CH2:39][CH3:40]
Reactant: CC(C)(C)OC(=O)CN1C[C@H](c2ccc(F)cc2)CC[C@@H](N)C1=O
Reactant: CCCCOC(=O)[C@@H](CCc1ccccc1)OS(=O)(=O)C(F)(F)F
Product: CCCCOC(=O)[C@H](CCc1ccccc1)NC1CCC(c2ccc(F)cc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
According to a similar procedure to that described in Example 1(l), t-butyl α-[3(S*)-amino-6(R*)-(p-fluorophenyl)-2-oxoperhydroazepin-1-yl]acetate [prepared as described in Example 6(e)] was reacted with butyl 4-phenyl-2(R)-trifluoromethanesulfonyloxybutyrate, to give a crude product, which was subjected to column chromatography through silica gel using a 3:1 by volume mixture of cyclohexane and ethyl acetate as eluent.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[CH2:19]=[C:20]1[O:24][C:22](=[O:23])[CH2:21]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:22]([O:1][CH2:2][C:3](=[O:4])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:23])[CH2:21][C:20]([CH3:19])=[O:24]
Reactant: C=C1CC(=O)O1
Reactant: O=C(CO)Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCC(=O)Nc1ccccc1

Procedure:
4.36 g (28.8 mmol)) of 2-hydroxy-N-phenylacetamide, 0.8 ml (5.74 mmol) of triethylamine and 6.5 ml (84.3 mmol) of diketene were heated at 70° C. under stirring in 50 ml of toluene for 7.5 hours. After the addition of a saturated aqueous sodium hydrogencarbonate solution at room temperature followed by the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:23](OC(Cl)(Cl)Cl)=[O:24]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([N:11]1[C:12](=[O:20])[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:19][C:23]1=[O:24])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)[C@@H](NC(=O)c1ccccc1N)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](c1ccccc1)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 90 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
To a solution of (S)-(2-amino-benzoylamino)-phenyl-acetic acid methyl ester (330 mg, 1.16 mmol) in THF (30 mL) is added trichloromethyl chloroformate (115 mg, 0.58 mmol). The mixture is stirred at 90° C. for 16 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (100 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and concentrated to give the (S)-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl-acetic acid methyl ester (110 mg, 31%).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:10]([C@@H:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:50]([O:57][C:58](=[O:72])[NH:59][C@H:60]([C:65](=[O:71])[NH:66][CH2:67][CH2:68][CH:69]=O)[CH2:61][CH:62]([CH3:64])[CH3:63])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)(=O)C>[Si:18]([O:17][C@H:16]1[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13][CH:12]1[C@H:10]([OH:11])[C@@H:2]([C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[NH:1][CH2:69][CH2:68][CH2:67][NH:66][C:65](=[O:71])[C@H:60]([CH2:61][CH:62]([CH3:64])[CH3:63])[NH:59][C:58](=[O:72])[O:57][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(C)C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reaction time: 3.5 h
Yield: 97.1 %

Procedure:
A solution of tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxy-propanoate (200 mg, 0.277 mmol, obtained from Reference Example 6) and [(1S)-3-methyl-1-(3-oxo-propylcarbamoyl)-butyl]-carbamic acid benzyl ester (111 mg, 0.35 mmol, obtained from Reference Example 16) in anhydrous tetrahydrofuran (4 ml) was stirred at room temperature under a nitrogen atmosphere for 15 minutes. Acetic acid (4 drops) and sodium triacetoxyborohydride (117 mg, 0.55 mmol) were added, and the resulting solution was stirred under nitrogen for an additional 3.5 hours. The reaction mixture was basified to pH 9 with sodium carbonate aqueous solution, and the aqueous layer was extracted with ethyl acetate (3×80 ml). The combined extracts were washed with saturated sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 2.5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (276 mg, 97%), as a white amorphous solid.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=O)[C@@H:14]([OH:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(C)C>C1COCC1>[C:1]12([CH2:11][NH:12][CH2:13][C@H:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[OH:21])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)[C@@H](O)c1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: O[C@H](CNCC12CC3CC(CC(C3)C1)C2)c1ccccc1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
To a solution of (S)—N-((1-adamantyl)methyl)-2-hydroxy-2-phenylacetamide (85 mg, 0.28 mmol) in THF (10 mL) was added BH3.Me2S (10 M, 85 μL, 8.5 mmol) under nitrogen. The mixture was heated under reflux overnight and then cooled to rt. The reaction was quenched with methanol. The mixture was concentrated in vacuum to give crude product, which was purified by preparative TLC to afford (S)-2-((1-adamantylmethyl)amino)-1-phenylethanol (40 mg, 50%). 1H NMR (MeOD, 400 MHZ): δ=1.31-2.01 (m, 15H), 2.42 (q, 2H), 2.81 (d, 2H), 4.88 (t, 1H), 7.21-7.43(m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]=[O:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:30]1[CH:31]=[N:32][CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[C:30]4[CH:31]=[N:32][CH:33]=[C:34]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH:35]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1
Reactant: Brc1cncc(-c2ccccc2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cncc(-c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 30, Step 1, using 1-[4′-(4-formyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-phenyl-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[OH:15]O>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=2[O-:15])=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cc2ccccn2)cc1
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 2-p-chlorobenzylpyridine (12.0 g, 0.059 moles) and hydrogen peroxide (33% w/v, 4.02 g, 12.2 ml, 0.118 moles) in glacial acetic acid (40 ml) was heated at 60° for 15 hours. The reaction mixture was cooled to room temperature, the acetic acid evaporated under reduced pressure and the residue dissolved in chloroform. After neutralisation with potassium carbonate (20 g) the chloroform was removed to give 2-p-chlorobenzylpyridine-N-oxide (11.02 g, 85%) as a viscous oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13](I)[C:14]=1[O:15][CH3:16])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[Cu](C#N)[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:19]#[N:20])[C:14]=1[O:15][CH3:16])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C[Cu]C#N
Reactant: COC(=O)c1cc(I)c(OC)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)c(OC)c(C(C)(C)C)c1
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 75.2 %

Procedure:
Methyl 3-t-butyl-5-iodo-4-methoxybenzoate (2.77 g) was dissolved in N,N-dimethylformamide (30 mL), and copper cyanide (965 mg) was added to the solution, and then the mixture was stirred at 150° C. for 2.5 hours. To the reaction solution, 10% potassium carbonate was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (1.48 g) as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:3]1[CH:4]=[C:5]2[C:10](=[N:11][C:2]=1[CH3:1])[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(n1)NCCC2
Solvent: ClCCl
Product: Cc1nc2c(cc1Br)CCCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a vial is added 7-methyl-1,2,3,4-tetrahydro-[1,8]naphthyridine (390 mg, 2.63 mmol) and N-bromosuccinimide (468 mg, 2.63 mmol) in 20 mL of CH2Cl2. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated. The residue is purified by flash column chromatography to give 575 mg of 6-bromo-7-methyl-1,2,3,4-tetrahydro-[1,8]naphthyridine.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:47])[CH2:19][CH2:20][N:21]([C:39]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:16].Cl>ClCCl>[CH2:15]([O:17][C:18](=[O:47])[CH2:19][CH2:20][N:21]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:39]1([C:44](=[O:45])[NH:2][OH:3])[CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:16]
Reactant: CCOC(=O)CCN(C1(C(=O)Cl)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: NO
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCN(C1(C(=O)NO)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.37 g (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0° C. was treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate. The mixture was allowed to warm to ambient temperature overnight. This mixture was then cooled to 0° C. and treated with a solution of 7.54 g (15.1 mmol) of 3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}propionic acid ethyl ester in 73 mL of dichloromethane, prepared as described above, without isolation, causing an exotherm to about 8° C. This mixture was stirred at 0° C. for 30 minutes and at ambient temperature for about one hour. The reaction was then treated with 50 mL of 2N aqueous hydrochloric acid and was stirred at ambient temperature for one hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). This solution of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid ethyl ester in dichloromethane was used for the preparation of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid without isolation. An aliquot was concentrated to a foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=1)[C:6]([CH3:22])=[C:5]2[CH2:23][C:24]([OH:26])=[O:25].ClC1C=CC=C(C(OO)=[O:35])C=1>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])(=[O:35])=[O:20])=[CH:15][CH:14]=1)[C:6]([CH3:22])=[C:5]2[CH2:23][C:24]([OH:26])=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=C(CC(=O)O)c2cc(F)c(F)cc2C1=Cc1ccc(S(C)=O)cc1
Solvent: CC(C)=O
Product: CC1=C(CC(=O)O)c2cc(F)c(F)cc2C1=Cc1ccc(S(C)(=O)=O)cc1

Procedure:
To 5,6-difluoro-2-methyl-1-(ρ-methylsulfinylbenzylidene)-indene-3-aceticacid (0.005 mole) in acetone (15 ml.) is added, slowly with stirring, m-chloroperbenzoic acid (0.005 mole). The mixture is heated and evaporated to near dryness at 40°. The solid is washed with boiling water (4×50 ml.) and dried yielding 5,6-difluoro-2-methyl-1-(ρ-methylsulfonylbenzylidene)-indene-3-acetic acid, M.P. 228°-230°. (R1 =hydrogen; R2 =CH3 ; R3 =5-fluoro; R4 =6-fluoro; R5 =CH3 --SO2 --).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[CH:11]12[C:20](=O)[O:19][C:17](=[O:18])[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]2>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[N:4]1[C:17](=[O:18])[CH:12]2[CH:11]([CH2:16][CH2:15][CH2:14][CH2:13]2)[C:20]1=[O:19]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: O=C1OC(=O)C2CCCCC12
Solvent: CC(=O)O
Product: O=C1C2CCCCC2C(=O)N1c1c(F)cc(F)cc1F

Procedure:
9.54 Parts of 2,4,6-trifluoroaniline were added to a solution of 10 parts of cyclohexane-1,2-dicarboxylic anhydride in 100 parts of glacial acetic acid. The mixture was refluxed for 20 hours and the resulting mixture was poured into 200 parts of ice. The resulting crystals were filtered, dried and recrystallized twice from 70 parts of methanol at -40° C to yield 8.3 parts of white crystals of 2-(2,4,6-trifluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione melting at 129°-131° C.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:20]>>[C:1]1([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([Cl:20])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(Cc1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C(Cc1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
25 g of 2,3-diphenylpropanoic acid was dissolved in 80 mL of SOCl2 (10 eq.). The reaction mixture was stiffed under N2 overnight at room temperature. Extra SOCl2 removed by evaporation. 2,3-Diphenylpropionylchloride (28 g) was obtained as an oil and used without purification. N-(di-BOC-Amidino)-N′-(2,3-diphenylpropionyl)-1,3-diaminoxylene (5′) To a precooled solution (0° C.) of 3 (27.4 g, 72.3 mmol) in 300 mL of CHCl3, Et3N (7.3 g, 72.3 mmol) and 2,3 diphenylpropionylchloride (17.6 g, 72.3 mmol) was added. The mixture was stirred for 1 hour at room temperature. The solution was washed with water and brine and concentrated to dryness. The crude residue was dissolved in minimum amount of EtOAc and 300 mL of hexane was added. 5 (30.1 g, 71% yield) was collected as a white precipitate.