Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])=O.[OH-:22].[Na+].Cl>CO.O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:12]1[C:11]([OH:22])=[CH:4][C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: [OH-]
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: Nc1ccccc1C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1cc2ccccc2nc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
2-Aminobenzaldehyde (360 mg) and 2-chloro-1-(2,4-difluoro-phenyl)-ethanone (585 mg) were dissolved in methanol (15 ml) to prepare a solution. Sodium hydroxide (310 mg) and water (3 ml) were added to the solution, and the mixture was stirred at room temperature overnight. A dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using ethyl acetate-hexane to give 2-(2,4-difluoro-phenyl)-quinolin-3-ol (237 mg, yield 41%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:18](O)=[O:19]>>[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][CH:18]=[O:19])=[CH:5][CH:4]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=CO
Agent: Cl
Solvent: CCN(CC)CC
Product: O=CNCc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
Into a mixture of 9.87 g of 4-bromobenzylamine hydrochloride and 5.04 g of triethylamine, 20 mL of a formic acid solution was dropped and the resultant reaction mixture was stirred at 80° C. for 3.5 hours. After the completion of the reaction, the reaction mixture was charged into 100 mL of ice water and the resultant reaction mixture was extracted with ethyl acetate (30 mL×2). The organic phase was dehydrated and dried over a saturated brine and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The residual solid was washed with hexane to obtain 9.29 g of the objective substance as a white crystal.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[F:23][C:24]([F:43])([F:42])[O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([NH2:41])=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[N:37][C:36]=23)=[CH:28][CH:27]=1>ClCCl.N1C=CC=CC=1>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([NH:41][C:33]2[C:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:43])([F:23])[F:42])=[CH:31][CH:30]=3)=[C:36]3[N:37]=[CH:38][CH:39]=[CH:40][N:35]3[N:34]=2)=[O:11])[CH:3]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cccnc1)Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
3-Pyridylacetic acid hydrochloride (41.6 mg, 0.239 mmol) was suspended in dichloromethane (3.0 mL). Oxalyl chloride (24 μL, 0.28 mmol) and a drop of dimethylformamide were added and the mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was concentrated under vacuum. To this residue was added a solution of the product from Example 1C (59 mg, 0.2 mmol) in pyridine (2.0 mL). The mixture was stirred at ambient temperature for 1 hour and then at 40° C. for 1 hour. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 30-100% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford 24 mg (29%) of the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 8.86 (d, J=5.8 Hz, 1H), 8.52-8.59 (m, 2H), 8.44-8.49 (m, 1H), 7.79-7.89 (m, 1H), 7.71-7.74 (m, 2H), 7.33-7.44 (m, 1H), 7.20-7.23 (m, 2H), 7.07 (dd, J=7.0, 4.1 Hz, 1H), 3.81 (s, 2H); MS (ESI) m/z 414 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:35]=O)=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9].Cl.[NH2:38][OH:39].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:35]=[N:38][OH:39])=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9]
Reactant: NO
Reactant: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C=NO)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (2.44 g), hydroxylamine hydrochloride (377 mg) and sodium acetate (526 mg) in acetic acid (15 ml) was stirred at room temperature for an hour to form 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate. To the reaction mixture was added acetic anhydride (1.66 g) and the mixture was stirred at room temperature for an hour and then heated at 100° C. for 3 hours with stirring. After removal of the acetic acid, the residue was adjusted to pH 7.5 with aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The extracts were washed twice with water, and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residual brown oil (2.6 g) was chromatographed on a column of silica-gel (78 g) and eluted with a mixture of benzene and ethyl acetate (12:1, v/v) to give an oil (1.45 g). The oil was crystallized by triturating with a small amount of mixture of diisopropyl ether and diethyl ether, and recrystallized from a mixture of diisopropyl ether (9 ml) and ethanol (1 ml) to give pure crystals of 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate (840 mg), mp 114° to 115° C. An additional crop (560 mg) was recovered from the filtrate by concentrating the filtrate and allowing to stand the residue in a refrigerator.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1.C(N(CC)CC)C.[CH3:26][C:27]1[O:31][C:30]([C:32](O)=[O:33])=[C:29]([O:35][CH:36]([CH3:38])[CH3:37])[CH:28]=1.C(C1NN=NN=1)(=O)N>C(#N)C>[CH3:26][C:27]1[O:31][C:30]([C:32]([NH:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[O:33])=[C:29]([O:35][CH:36]([CH3:38])[CH3:37])[CH:28]=1
Reactant: Nc1nnn[nH]1
Reactant: Cc1cc(OC(C)C)c(C(=O)O)o1
Agent: NC(=O)c1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OC(C)C)c(C(=O)Nc2nnn[nH]2)o1

Procedure:
Following the procedure described in Example 120, 0.60 g (3.7 mmol, 1.1 equiv) of 1,1'-carbonyl diimidazole, 0.33 g (3.9 mmol, 1.2 equiv) of 5-aminotetrazole and 0.80 g (7.9 mmol, 2.4 equiv) of triethylamine in refluxing (16 hours) acetonitrile (15 mL) are used to convert 0.61 g (3.3 mmol) of the carboxylic acid described above to 0.45 g of the carbamoyltetrazole as a tan solid. Recrystallization gave 0.35 g (1.26 g theo., 28% overall) of analytically pure 5-methyl-3-isopropoxy-N-1H-tetrazol-5-yl-2-furancarboxamide as a tan, crystalline solid; mp 240°-242° C. (dec).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([NH:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([NH2:22])=O)[CH2:16][CH2:15]2)[N:4]=1.Cl>C1COCC1.CCOC(C)=O.CO>[NH2:22][CH2:20][C@@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][C:5]2[N:4]=[C:3]([N:2]([CH3:23])[CH3:1])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=2)[CH2:19][CH2:18]1
Reactant: CN(C)c1nc(N[C@H]2CC[C@@H](C(N)=O)CC2)nc2ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)c1nc(N[C@H]2CC[C@@H](CN)CC2)nc2ccccc12
Temperature: 0 °C

Procedure:
To a solution of cis-4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexanecarboxylic acid amide (18.78 g, 60 mmol) in THF (200 mL) was added a solution of 1 M BH3 in THF (300 mL, 300 mmol). The mixture was stirred at reflux for 2 hr. After cooling the reaction mixture to 0° C., 4 M HCl in EtOAc (100 mL) and MeOH (200 mL) were added. The mixture was concentrated. The mixture was treated with 1 M aqueous sodium hydroxide and the aqueous layer was extracted with CH2Cl2. The organic layer was dried over sodium sulfate, concentrated, and purified by column chromatography (silica gel, 10% 2 M NH3/MeOH in CH2Cl2) to give cis-N2-(4-aminomethyl-cyclohexyl)-N4,N4-dimethyl-quinazoline-2,4-diamine as a white solid (10.6 g, 59%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:4][CH2:3]1.[H][H]>CO.[C].[Pd]>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:21])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O

Procedure:
0.075 g of 10% palladium-carbon was added to a solution of 1.5 g of N-(trans-4-methylcyclohexyl)-4-hydroxy -3-methoxycinnamamide (Example 131) in 100 ml of methanol. The solution was vigorously stirred for 16 hours under normal-pressure hydrogen gas. After reaction, the catalyst was filtered out, and the solvent was removed in vacuo from the flitrate, yielding 1.33 g of N-(trans-4-methylcyclohexyl)-3-(4-hydroxy-3-methoxyphenyl)propionamide (a compound of the present as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][CH2:13][CH2:12][C:11]2=[O:24])=[CH:6][CH:5]=1)([O-])=O.O.N>CO.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][CH2:13][CH2:12][C:11]2=[O:24])=[CH:6][CH:5]=1
Reactant: O=C1CCCC(c2ccc(Cl)c(Cl)c2)N1c1ccc([N+](=O)[O-])cc1
Agent: [Ti+3]
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Nc1ccc(N2C(=O)CCCC2c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 0.67 h
Yield: 76.9 %

Procedure:
A solution of 6.5 g of 1-(4-nitrophenyl)-6-(3,4-dichlorophenyl)-2-piperidone in 180 ml of methanol was cooled to 4° C., and then 110 g of 25% titanium trichloride was added dropwise to the solution. After stirring at 18° to 20° C. for 40 minutes, the reaction mixture was poured into cold ammonia water and the precipitates were filtered off. The filtrate was extracted with chloroform. On the other hand, the precipitate obtained above was throughly washed with chloroform. The chloroform layer was combined with the former, washed with water, dried, and concentrated. The residue was recrystallized from ethanol to give 4.59 g of 1-(4-aminophenyl)-6-(3,4-dichlorophenyl)-2-piperidone as colorless prisms.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH:2]([NH:1][S:13]([C:11]1[S:12][C:8]([Cl:7])=[CH:9][CH:10]=1)(=[O:15])=[O:14])[CH2:5][OH:6]
Reactant: NC(CO)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NC(CO)CO)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a stirred solution of 2-amino-1,3-propanediol (1.26 g, 13.8 mmol) in THF (20 mL) was added at 0° C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (0.96 g, 77%) as an off-white solid. MS (ISP) 272.2 [(M+H)+], mp 101° C.
Reaction SMILES: [C:1](S)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[N:10]=1>O1CCCC1>[C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:10]=1)#[N:16]
Reactant: CC(C)(C)S
Reactant: N#Cc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
tert-Butyl mercaptan (0.72 g, 7.9 mmol) was dissolved in tetrahydrofuran (100 ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7 mmol). The reaction mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure to give the titled compound (1.19 g, 86%) as an oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:38]=[CH:37][C:14]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([S:23]([C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=5)[CH:27]=4)(=[O:25])=[O:24])[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[ClH:36].[NH2:1][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:38]=[CH:37][C:14]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([S:23]([C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=5)[CH:27]=4)(=[O:24])=[O:25])[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: [N-]=[N+]=NCc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cl
Product: NCc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)ccn1
Reaction time: 18 h

Procedure:
At room temperature, 1-[4-(2-azidomethylpyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine (159 mg) was dissolved in tetrahydrofuran (5 ml), followed by the addition of water (0.5 ml) and triphenylphosphine (114 mg). The resulting mixture was stirred for 18 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (10% methanol—dichloromethane), followed by dissolution in dichloromethane. To the resulting solution, 1N hydrochloric acid in ethanol and water were added. The resulting mixture was then concentrated. The crystals were collected by filtration and washed with ethyl acetate, whereby the title compound (53 mg, 30%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][C:20]([CH3:36])=[N:19]1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:22]2[N:18]([CH3:17])[N:19]=[C:20]([CH3:36])[CH:21]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)nn1C
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cc(C)nn2C)c(C(F)(F)F)cc1N
Temperature: 80 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A mixture containing 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (1.0 g, 2.9 mmol), 1,3-dimethyl-5-tributylstannanyl-1H-pyrazole (1.34, 1.2 equiv) and bistriphenylphosphinedichloropalladium (207 mg, 0.1 equiv) in dioxane (15 mL) was stirred for 18 h at 80° C. Bistriphenylphosphinedichloropalladium (0.1 equiv) and another portion of the stannyl derivative (0.4 equiv) were added and the mixture was stirred for 24 h at 80° C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (1:1)) to provide 2-amino-5-(2,5-dimethyl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzoic acid methyl ester (651 mg, 72%) as a yellow paste. (ESI-MS: m/z 314.2 [M+H]+, rt 5.12 min).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10](I)=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[C:16]([Cu])#[N:17].[NH4+].[OH-].[CH3:21][N:22](C=O)C>>[CH:3]1[C:4]2[C:8]3[CH:9]=[C:10]([C:21]#[N:22])[CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:14]=[CH:15][C:2]=1[C:16]#[N:17]
Reactant: N#C[Cu]
Reactant: Ic1ccc2oc3ccc(I)cc3c2c1
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Product: N#Cc1ccc2oc3ccc(C#N)cc3c2c1
Temperature: 160 °C
Yield: 6 %

Procedure:
To a solution of 2,8-Diiodo-dibenzofuran (763 mg, 1.8 mmol) in dry DMF (16 mL) add CuCN (1.1 g, 12.7 mmol), heat the mixture at 160° C. under N2 atmosphere overnight. Cool the mixture at room temperature, add NH4OH and bubble air during 4 hours. Add cool water and extract with EtOAc, dry over Na2SO4. Eliminate the solvent under reduced pressure. Purify by flash chromatography on silica gel (eluent: hexane/EtOAc 3/1) to afford the title compound (25 mg, 6%).
Reaction SMILES: [C:1]([C@@:9]([CH2:41][OH:42])([OH:40])[C@:10]([C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([OH:31])[C@:11]([C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([OH:22])[C:12](C(=O)C1C=CC=CC=1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:43].CC(O)=O>ClCCl>[Br:43][C:12]([C@:11]([C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C@:10]([C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C@:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:41][OH:42])[OH:40])[OH:31])[OH:22])=[O:13]
Reactant: O=C(C(=O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1)c1ccccc1
Reactant: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Br)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Crude tetra-benzoyl-L-ribose 20 (17.0 g, 30.0 mmol) was dissolved in dichloromethane (150 mL) under an atmosphere of argon at 0° C. To this solution was added 33% HBr in AcOH (32.6 mL, 180.0 mmol of HBr) and the reaction was stirred for 30 min at 0° C. then brought to room temperature for 30 min. Dichloromethane (150 mL) was added and the reaction mixture was washed with 125 mL of cold water, dilute NaHCO3, two times with saturated NaHCO3 and brine then dried over Na2SO4 and concentrated in vacuo to give 21 as a off-white solid (13.3 g, 25.3 mmol, 84%). This material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1.[CH2:13]([Li])CCC.IC>O1CCCC1>[CH2:1]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1)[CH3:13]
Reactant: Cc1cc(=O)[nH]c2ccccc12
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCc1cc(=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-methylquinolin-2(1H)-one (5 g, 31 mmol) in anhydrous tetrahydrofuran (100 mL) under a nitrogen atmosphere cooled in an acetone/dry ice bath was added dropwise by syringe a 1.6N solution of n-butyl lithium in hexanes (49 mL, 78 mol). The resulting solution was warmed to r.t. for 2 h at which time iodomethane (3 mL, 47 mmol) was added by syringe. The reaction mixture was stirred at r.t. for 0.5 h then cooled in an ice bath. The reaction mixture was quenched by the addition of aq. 2N HCl and then extracted with excess chloroform. The combined organic extracts were washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and the solvent removed under vacuum to provide a solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:1][N:33]1[C:34](=[O:43])[C:35]2=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]2[C:37]1=[O:38]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCc1ccc2ccccc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
2-(hydroxymethyl)napthalene (1.00 g, 6.33 mmol), triphenyl phosphine (1.73 g, 6.60 mmol, 1.04 equiv) and N-hydroxyphthalimide (1.08 g, 6.63 mmol, 1.05 equiv) were dissolved in 25 mL of dry THF. Diethylazodicarboxylate (1.09 mL, 6.93 mmol, 1.09 equiv) was then added dropwise and the reaction was stirred overnight. The reaction mixture was placed in a freezer for 2 h and then filtered, rinsing with Et2O, to give the proudct (1.38 g) as a white solid. MS(CI) m/e 321 (M+NH4)+.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[C:6]([N:8]([C@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:24]C)=[O:23])[CH:20]=2)[CH2:15][CH2:14]1)[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7]>O.CO.C1COCC1>[Cl:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[C:6]([N:8]([C@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=2)[CH2:15][CH2:14]1)[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N(CC(C)C)C(=O)c1ccccc1Cl)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)c1ccccc1Cl)[C@@H]1CCc2ccc(C(=O)O)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
LiOH (173 mg, 4.156 mmol, 2 eq), dissolved in water (12 ml), was added dropwise to an ice-cooled (0° C.) solution of (R)-methyl 3-(2-chloro-N-isobutylbenzamido)-2,3-dihydro-1H-indene-5-carboxylate (B-29) (0.8 g, 2.078 mmol, 1 eq) in MeOH:THF (1:1, 24 ml), and stirring was carried out for 8 h at RT. After monitoring by thin-layer chromatography, the reaction solution was concentrated and the residue was taken up in water (30 ml) and extracted with ethyl acetate (25 ml). The aqueous phase was adjusted to pH 3 with 2 M HCl and extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. Yield: 78% (600 mg, 1.62 mmol).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][NH2:20].O>CN(C)C=O>[C:1]1([CH:7]2[CH2:8][C:9](=[O:18])[CH2:10][CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:20]2[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Reactant: CN
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(c2ccccc2)CC(=O)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 60.4 %

Procedure:
1,5-Diphenyl-1,4-pentadien-3-one (20b, 4.00 g, 17.1 mmol) was dissolved in dimethyl formamide (60 ml). Methylamine (51, 6.0 ml, 70.0 mmol, 40% in water) was added and the mixture stirred for 96 hr at room temperature. The mixture was poured into water (250 ml) and stirred for 1 hr at room temperature. The resulting mixture was extracted into ethyl ether, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethanol to give 2.74 g (60%) of a white solid: mp 147-149° C. [expected mp 148-150° C.]; 1H NMR δ 1.82 (s, 3H), 2.50, (dd, 2H, J=12.3, 2.5 Hz), 2.82 (t, 2H, J=13.3 Hz), 3.45 (dd, 2H, J=12.9, 2.4 Hz), 7.34, (m, 10H); 13C NMR: δ 40.8, 50.8, 70.2, 127.0, 127.6, 128.8, 143.1, 206.8.