Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18](F)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.Cl.[CH2:25]([O:27][C:28](=[O:31])[CH2:29][NH2:30])[CH3:26].C1COCC1.CN(C=O)C>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:25]([O:27][C:28](=[O:31])[CH2:29][NH:30][C:18]1[CH:19]=[C:2]([F:1])[C:3]([O:4][C:5]2[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=2)=[CH:16][C:17]=1[N+:21]([O-:23])=[O:22])[CH3:26]
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)c1ccc(Oc2cc([N+](=O)[O-])c(F)cc2F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(F)c(Oc2ccc(C(=O)OCC)cc2)cc1[N+](=O)[O-]
Yield: 60.5 %

Procedure:
A mixture of 2.38 g (7.36 mmol) of ethyl 4-(2,4-difluoro-5-nitrophenoxy)benzoate, 1.03 g of glycine ethyl ester hydrochloride, 30 ml of THF, 10 ml of DMF and 2.06 ml of triethylamine was subjected to heating under reflux for 10 hours. After cooling, the reaction mixture was diluted with ethyl acetate. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate. The resulting solution was washed successively with water and brine, dried over anhydrous sodium sulfate and then, concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (developing solvent: hexane:dichloromethane:ethyl acetate=8:2:1) to give 1.81 g (61%) of N-[4-(4-ethoxycarbonylphenoxy)-5-fluoro-2-nitrophenyl]glycine ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1.N1C=CC=CC=1>ClCCl.CN(C)C=O.O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=2[N+:12]([O-:14])=[O:13])=[N:23][CH:24]=1
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Nc2ccc(Cl)cn2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
To a stirring suspension of 3-methoxy-2-nitrobenzoic acid (14.5 g, 73.5 mmol) in dichloromethane (100 mL) was added a couple of drops of N,N-dimethylformamide followed by oxalyl chloride (6.7 mL, 77.1 mmol). The reaction was stirred at room temperature overnight and the residue transferred slowly to antic cold solution of 2-amino-5-chloropyridine (9 g, 70 mmol) and pyridine (20 mL) in dichloromethane (200 mL). The reaction was stirred overnight, treated with water, and concentrated. The resulting mixture was treated with ethyl acetate, washed consecutively with aqueous citric acid, saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by recrystallization from toluene to give 17 g (79%) of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[O:11]=[S:12]1(=[O:29])[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:14]2=[N:13]1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]3[C:14]4=[N:13][S:12](=[O:29])(=[O:11])[CH2:17][CH2:16][N:15]4[CH:18]=[CH:19][CH:20]=3)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1ccc(F)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(F)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
A mixture of 4-fluorophenylboronic acid (365 mg), 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (240 mg), diacetoxycopper (316 mg), triethylamine (0.60 mL), and powdered 4A MS (1.5 g) in DMF (10 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (139 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:5]=[C:6]([O:8]CC2C=CC(OC)=CC=2)[CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:33]([C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][CH:39]=[CH:38]2)#[N:34].CNCCNC>[Cu]I.C1(C)C=CC=CC=1>[OH:8][C:6]1[CH:7]=[C:2]([N:40]2[C:41]3[C:37](=[CH:36][C:35]([C:33]#[N:34])=[CH:43][CH:42]=3)[CH:38]=[CH:39]2)[CH:3]=[C:4]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:5]=1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: COc1ccc(COc2cc(Br)cc(Nc3cccnc3)c2)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(ccn2-c2cc(O)cc(Nc3cccnc3)c2)c1
Temperature: 110 °C
Yield: 10.8 %

Procedure:
[3-Bromo-5-(4-methoxy-benzyloxy)-phenyl]-pyridin-3-yl-amine (193 mg, ca 0.5 mmol) was placed in a 5 mL glass reactor. Copper (I) iodide (0.5 mmol, 96 mg), potassium phosphate (213 mg, 1 mmol), toluene (3 mL), 5-cyanoindole (1.0 mmol, 142 mg) and N,N′-dimethylethylenediamine (53 mg, 0.6 mmol) were added to the reactor, and the sealed reactor was heated to 110° C. for 24 h. After cooling the reaction mixture to room temperature, the solution was filtered through a short pad of Celite®, and the filtrate was concentrated. The residue was extracted with methylene chloride and aqueous sodium bicarbonate solution. The organic layer was dried, concentrated, and the residue was purified by silica gel column (Biotage) using 2% MeOH in methylene chloride. Pure fractions were treated with 10% dimethylsulfide, 50% TFA in methylene chloride for 2 min. The volatiles were evaporated immediately with a stream of nitrogen with mild heating. The residue was purified by passing through a short pad of silica gel using 15% MeOH in methylene chloride as eluent to give 1-[3-hydroxy-5-(pyridin-3-ylamino)-phenyl]-1H-indole-5-carbonitrile (17.5 mg, 0.054 mmol) which solidified on standing. 1H NMR (400 MHz, CD3OD) δ 8.33 (d, J=2.4, 1H), 8.00-8.30 (m, 2H), 7.65 (d, J=8.8, 1H), 7.61 (m, 1H), 7.54 (d, J=3.2, 1H), 7.43 (dd, J=8.4, 1.2, 1H), 7.28 (dd, J=8.4, 4.8, 1H), 6.74 (d, J=3.2, 1H), 6.48 (m, 1H), 6.20-6.42 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([OH:31])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=1[CH:15]=[CH:16][NH:17][C:18]3=[O:23])[C:7]([OH:28])([C:24]([F:27])([F:26])[F:25])[CH2:6][C:5]2([CH3:30])[CH3:29].[C-:32]#[N:33].[Na+]>CN1CCCC1=O.[Ni](Br)Br>[OH:31][C:3]1[C:4]2[C:5]([CH3:30])([CH3:29])[CH2:6][C:7]([OH:28])([C:24]([F:25])([F:27])[F:26])[CH:8]([NH:12][C:13]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][NH:17][C:18]4=[O:23])[C:9]=2[CH:10]=[CH:11][C:2]=1[C:32]#[N:33]
Reactant: [C-]#N
Reactant: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c(=O)[nH]ccc23)c2ccc(Cl)c(O)c21
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c(=O)[nH]ccc23)c2ccc(C#N)c(O)c21
Yield: 22 %

Procedure:
75 mg (0.166 mmol) of 5-(6-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one is dissolved in 1.3 ml of 1-methyl-2-pyrrolidinone and reacted in the microwave with 16.27 mg (0.332 mmol) of sodium cyanide and 36.27 mg (0.166 mmol) of nickel(II) bromide, as described in Example 160. The black reaction mixture is added via a glass fiber filter. After washing with ethyl acetate, the filtrate is also mixed with an additional 60 ml of ethyl acetate. It is shaken with water and with brine. After drying, the solvent is spun off, and the residue is chromatographed on silica gel (amine plate; mobile solvent: methanol/dichloromethane). 16.2 mg (22.1%) of the desired nitrile is isolated.
Reaction SMILES: C(O[C:4]1[CH2:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:6]=2[N:5]=1)C.CO.O.[NH2:27][NH2:28]>O>[NH:27]([C:4]1[CH2:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:6]=2[N:5]=1)[NH2:28]
Reactant: NN
Reactant: CCOC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Solvent: CO
Solvent: O
Product: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Reaction time: 2.5 h

Procedure:
To a solution of 0.25 part of 2-ethoxy-7-nitro-5-phenyl-3H-1,4-benzodiazepine in 8 parts by volume of methanol is added 0.2 part by volume of hydrazine hydrate (100%) with stirring and the stirring is continued at room temperature for further 2.5 hours. To the reaction mixture is added water, followed by extraction with chloroform. Chloroform layer is washed with water and dried over anhydrous sodium sulfate, followed by distillation of the solvent. Treatment of the residue with n-hexane gives 2-hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine as orange crystalline powder. The product is treated with acetone, whereupon 2-(2-isopropylidenehydrazino)-7-nitro-5-phenyl-3H-1,4-benzodiazepine is obtained as pale yellow crystals melting at 203°-205° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)[N:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH3:45])[C:23]2[O:27][C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32](B4OC(C)(C)C(C)(C)O4)=[CH:31][CH:30]=3)=[N:25][C:24]=2[CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]3)[N:3]=[C:2]([C:32]3[CH:31]=[CH:30][C:29]([NH:28][C:26]4[O:27][C:23]5[C:22]([CH3:45])=[CH:21][C:20]([CH3:19])=[CH:44][C:24]=5[N:25]=4)=[CH:34][CH:33]=3)[C:10]=12
Reactant: CN1CCCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCCN(C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Yield: 12 %

Procedure:
A mixture of 3-iodo-1-(1-methyl-3-piperidyl)-1H-pyrazolo [3,4-d]pyrimidin-4-amine (0.35 g, 0.001 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.44 g, 0.0012 mol), tetrakis(triphenylphosphine)-palladium (0.058 g, 0.00005 mol) and sodium carbonate (0.27 g, 0.0025 mol) in ethylene glycol dimethyl ether (30 mL) and water (6 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 2%-10% methanol/dichloromethane as a mobile phase to give N2-{4-[4-amino-1-(1-methyl-3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}-5,7-dimethyl-1,3-benzoxazol-2-amine (0.055 g, 0.00012 mol). 1H NMR (DMSO-d6, 400 MHz) δ 10.80 (s, 1H), 8.22 (s, 1H), 7.95 (d, 2H), 7.65 (d, 2H), 7.15 (s, 1H), 6.80 (s, 1H), 4.80 (br, 1H), 2.95 (br, 1H), 2.85 (br, 1H), 2.45 (br, 1H), 2.40 (s, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 2.00 (br, 3H), 1.80 (br, 1H), 1.70 (br, 1H). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 9.7 min. MS: MH+ 469
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:13]=[C:14]([O:17][C:18](=[O:22])[C:19](Cl)=[O:20])[CH:15]=[CH:16][C:4]=2[O:3]1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[OH:31]>C1(C)C=CC=CC=1>[O:1]=[C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:13]=[C:14]([O:17][C:18](=[O:22])[C:19]([O:31][C:25]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:23])=[O:20])[CH:15]=[CH:16][C:4]=2[O:3]1
Reactant: O=C(Cl)C(=O)Oc1ccc2c(c1)C(c1ccccc1)C(=O)O2
Reactant: Cc1cccc(C)c1O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1OC(=O)C(=O)Oc1ccc2c(c1)C(c1ccccc1)C(=O)O2
Yield: 38 %

Procedure:
Reaction of chloro-oxo-acetic acid 2-oxo-3-phenyl-2,3-dihydro-benzofuran-5-yl ester prepared as Example 11 reacted in toluene at the reflux with 2,6-dimethylphenol gave after purification oxalic acid (2,6-dimethyl-phenyl) ester (2-oxo-3-phenyl-2,3-dihydro-benzofuran-5-yl) ester (38% yield). Analysis C,70.6; H,4.1; C24H18O6 requires C,71.8; H,4.2%. Mass Spectrometry shows a molecular ion at 402.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:21][NH:22][CH2:23][C:24]1[N:28]=[C:27]([NH2:29])[S:26][N:25]=1>CN(C=O)C.O>[NH2:29][C:27]1[S:26][N:25]=[C:24]([CH2:23][N:22]([CH3:21])[C:6]([C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[O:8])[N:28]=1
Reactant: CNCc1nsc(N)n1
Reactant: O=C(O)[C@H]1CCCO1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1nsc(N)n1)C(=O)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
To a solution of (R)-tetrahydrofuran-2-carboxylic acid (5.0 g, 43 mmol) in DMF (100 mL) was added carbonyl diimidazole (7.68 g, 47 mmol) at 0 C under N2. After 2 hours agitation at 0 C, the product obtained from Step 1 (7.0 g, 49 mmol) in DMF (20 mL) was added and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with water (800 mL), extracted with EA (10×200 mL). The combined organic layers were washed twice with brine (100 mL) and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:3) to afford (R)-tetrahydro-furan-2-carboxylic acid (5-amino-[1,2,4]thiadiazol-3-ylmethyl)-methyl-amide (5.9 g, yield: 59%) as a red syrup. LC-MS (m/z): 243.1 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:25]=1[CH2:26][NH:27][NH2:28]>C(O)C>[NH2:10][C:6]1[NH:28][N:27]([CH2:26][C:25]2[CH:29]=[C:30]([Cl:34])[C:31]([Cl:33])=[CH:32][C:24]=2[Cl:23])[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1cc(Cl)c(Cl)cc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cc(Cl)c(Cl)cc2Cl)[nH]1
Reaction time: 2 h

Procedure:
54.7 g of β-amino-β-ethoxyacrylic acid ethyl ester and 2 g of p-toluenesulphonic acid were dissolved in 400 ml of ethanol. A solution of 77.6 g of 2,4,5-trichlorobenzylhydrazine in 200 ml of ethanol was added dropwise thereto, under nitrogen. After stirring for a further 2 hours, the mixture was left to stand overnight and the precipitate which had separated out was filtered off and dissolved in 2 N sodium hydroxide solution. The alkaline solution was repeatedly extracted with ether and subsequently slightly acidified with dilute acetic acid, whereupon the compound identified above precipitated. After recrystallisation from ethanol, this product melted at 195°-196°. 35 g (38%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Cl:12])=[C:6]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][C:6]=1[O:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23]
Reactant: COC(=O)c1cc(OC)c(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.51 g (1.31 mmol) of 4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-methoxy-benzoic acid methyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1-2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: Cl.Cl.[NH:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:4]1.CC([O-])(C)C.[K+].N1C=CC=CC=1.[CH:26]1([N:32]([CH3:36])[C:33](Cl)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN(C=O)C.CN(C)C1C=CN=CC=1.O>[CH:26]1([N:32]([CH3:36])[C:33]([N:3]2[CH:7]=[C:6]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]=[CH:4]2)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CN(C(=O)Cl)C1CCCCC1
Reactant: c1cncc(-c2c[nH]cn2)c1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN(C(=O)n1cnc(-c2cccnc2)c1)C1CCCCC1
Temperature: 25 °C

Procedure:
To a stirred suspension of 3-(1H-imidazol-4-yl)pyridine dihydrochloride (1.745 g, 8 mmol) in a mixture of tetrahydrofuran (29 mL) and DMF (2.90 mL) was added potassium 2-methylpropan-2-olate (1.795 g, 16.0 mmol) and the mixture was refluxed for 30 minutes. The resulting brown suspension was cooled to room temperature and treated with pyridine (0.979 mL, 12 mmol) and N,N-dimethylpyridin-4-amine (0.098 g, 0.8 mmol), followed by the addition of cyclohexyl(methyl)carbamic chloride (1.476 g, 8.4 mmol). The reaction was heated to 90° C. overnight, whereupon the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried (MgSO4) and filtered. After evaporation, the crude product was chromatographed over silica gel using a dichloromethane/methanol (9:1) mixture. Homogenous fractions were pooled and evaporated to leave a white powder, (160 mg, 7%).
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[C:38]([S:40]([CH3:43])(=[O:42])=[O:41])[CH:37]=[CH:36][C:3]=1[CH2:4][O:5][C:6]1[C:7]([O:33][CH2:34][CH3:35])=[C:8]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si](C(C)C)(C(C)C)C(C)C)[CH:15]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1.[OH-].[K+].[F-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:39]=[C:38]([S:40]([CH3:43])(=[O:41])=[O:42])[CH:37]=[CH:36][C:3]=1[CH2:4][O:5][C:6]1[C:7]([O:33][CH2:34][CH3:35])=[C:8]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOc1c(OCc2ccc(S(C)(=O)=O)cc2Cl)cccc1C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: CCOc1c(OCc2ccc(S(C)(=O)=O)cc2Cl)cccc1C(=O)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2-ethoxy-3-hydroxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (666, 84 mg, 0.054 mmol) in methanol (10 mL) was added potassium hydroxide (6 N solution) until pH of the solution turned to over 10. Potassium fluoride (30 mg, 0.5 mmol) was then added to the reaction mixture and the mixture was stirred at room temperature for 6 hours. The reaction mixture was then poured into saturated sodium carbonate and was extracted with ethyl acetate. The organic layer was collected and washed with brine, dried over magnesium sulfate. After removal of the solvent, the residue was purified by preparative HPLC to provide as a white solid (P-2094, 5 mg, 19%). MS (ESI) [M+H+]+=485.17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:10][CH2:11][O:12][CH2:13][CH2:14]Br.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: BrCCOCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(N2CCOCC2)c1
Temperature: 100 °C
Yield: 42.9 %

Procedure:
3-Bromoaniline (3.0 mL, 4.7 g, 28 mmol), 2-bromoethylether (4.2 mL, 7.7 g, 33 mmol) and diisopropylethylamine (15 mL, 11 g, 86 mmol) were dissolved in anhydrous DMF (20 mL) under inert gas atmosphere and heated to 100° C. for 6 h. After cooling to room temperature the mixture was poured into water (300 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. Purification of the residue by flash chromatography afforded 2.9 g (12 mmol, 43% yield) of 4-(3-bromophenyl)morpholine.
Reaction SMILES: [C:1]([CH:5]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])(=[O:4])[CH2:2][OH:3].[OH-].[K+].Cl>CO.O>[C:1]([CH:5]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])[CH2:2][OH:3]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)OCC)C(=O)CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(=O)CO

Procedure:
A clear, yellow solution of ethyl 8-glycoloyl-12-hydroxyheptadecanoate (7.9 g., 0.02 mole) and potassium hydroxide (2.24 g., 0.04 mole) in 90% aqueous methanol (50 ml.) is stirred at 25° under nitrogen for 20 hours. The reaction solution is evaporated in vacuo at 40° leaving a residual red oil which is dissolved in water (200 ml.). The resulting solution is acidified with concentrated hydrochloric acid (10 ml.) and extracted with ether (2 × 200 ml.). The organic extract is washed with saturated brine (2 × 200 ml.), dried over sodium sulfate, filtered and evaporated in vacuo at 40°-50° providing the title compound as a slightly impure, deep yellow oil (6.3 g., 92%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)[CH:6]=[CH:5]2.[CH2:28]([O:35][CH2:36][C@@H:37]1[CH2:40][C@H:39](O)[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:23]([O:22][C:21](=[O:27])[NH:20][C:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][C@H:39]4[CH2:38][C@H:37]([CH2:36][O:35][CH2:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH2:40]4)[CH:3]=3)[CH:8]=2)[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O[C@H]1C[C@@H](COCc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(O)ccc3c2)COC(C)(C)OC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc3cc(O[C@H]4C[C@H](COCc5ccccc5)C4)ccc3c2)COC(C)(C)OC1
Temperature: 23 °C
Reaction time: 48 h

Procedure:
To a solution of [5-(6-Hydroxynaphthalen-2-yl)-2,2-dimethyl-1,3-dioxinan-5-yl]-carbamic acid tert-butyl ester (Example 13, 30.0 mg, 0.0000723 mol), cis-3-benzyloxymethyl-cyclobutanol (13.9 mg, 0.0000723 mol), and triphenylphosphine (22.8 mg, 0.0000868 mol) in THF (2 mL), a solution of diisopropyl azodicarboxylate (18.7 mg, 0.0000868 mol) in THF (1 mL), was added dropwise at 23° C. The reaction mixture was then allowed to stir at 23° C. for 2 days. Solvent was removed, and the crude mixture was purified via chromatography (SiO2, 4 g, ethyl acetate 0-35%) to give a pure product (18 mg, 45%). MS (ES, M-113): 434.30.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21].NCCC(O)=O.C(O)(=O)C>O>[CH3:18][O:17][C:16]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH:11]=[C:25]2[NH:19][C:20](=[O:21])[NH:22][C:23]2=[O:24])[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(C=O)c1OCc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(C=C2NC(=O)NC2=O)c1OCc1ccccc1
Yield: 84 %

Procedure:
A solution of 96.90 g (0.40 mole) of 2-benzyloxy-3-methoxybenzaldehyde, 48.04 g (0.48 mole) of hydantoin, 8.02 g (0.09 mole) of β-alanine, and 200 mL of glacial acetic acid is stirred at reflux for 6 hours. Water (500 mL) is added and the separated solid is filtered, washed well with water, methanol, and then ether; wt 109.00 g (84% yield); mp 210-212° C.