Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.O1CCCC1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2c([N+](=O)[O-])cccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nccc2c(N)cccc12
Yield: 88 %

Procedure:
1-Methyl-5-nitroisoquinoline (prepared according to Rathelot, P. et al. Eur. J. Med. Chem. 1995, 30, 503-508.) (2.19 g, 11.64 mmol) was dissolved in methanol (20 mL) and tetrahydrofuran (20 mL) in a 250 mL stainless steel pressure bottle to which was added 5% Pd—C (0.438 g, 4.12 mmol). The reaction mixture was stirred for 2 h under 30 psi hydrogen at ambient temperature. The mixture was filtered through a nylon membrane and the volatiles evaporated in vacuo. The resulting grayish solid was triturated with 1:1 hexanes-CH2Cl2 (50 mL) and the title compound (1.62 g, 10.24 mmol, 88%) was collected as an off white solid. MS (DCI/NH3) m/z 159 (M+H)+.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:8]([CH2:26][CH2:27][F:28])[CH:7]=1)=O.[NH4+]>CO>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:24])=[O:25])=[C:8]([CH2:26][CH2:27][F:28])[CH:7]=1
Reactant: O=C(Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CCF)c1)C(F)(F)F
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CCF)c1
Yield: 52.9 %

Procedure:
A solution of 2,2,2-trifluoro-N-(3-(2-fluoroethyl)-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide (210 mg, 0.47 mmol) and 7M ammonium in MeOH (10 mL) in 10 mL of MeOH was stirred in a sealed tube at 60° C. for 2 hours. After concentrated, the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a yellow solid (87 mg). MS calcd for (C15H16BFN2O4S): 350.1. MS found (ESI negative): (M−H)−=349.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.05 (s, 1H), 9.2 (bs, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.42 (d, J=2 Hz, 2H), 7.22 (d, J=8 Hz, 1H), 7.12 (dd, J=8, 2 Hz, 1H), 6.46 (d, J=2 Hz, 1H), 6.40 (dd, J=8.4, 2 Hz, 1H), 5.5 (bs, 2H), 4.86 (s, 2H), 4.59 (dt, J=48, 6.4 Hz, 2H), 4.23 (dt, J=23, 6 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20]1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:24]([C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)(=[O:26])=[O:25])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1ccsc1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with thiophene-3-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 8.00 (dd, J=1.2 & 3.3 Hz, 1H), 7.45 (dd, J=0.9 & 5.1 Hz, 1H), 7.35 (m, 2H), 7.27 (m, 2H), 6.91 (dd, J=9.3 & 17.1 Hz, 1H), 6.64 (ddd, J=2.1, 4.8 & 8.7 Hz, 1H), 6.34 (dt, J=5.4, 8.7 & 14.1 Hz, 1H), 5.98 (br d, J=2.1 Hz, D2O exchangeable, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:42])[CH:20]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:21][C:22]([NH:24][C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[CH:14][CH:13]=1)=[O:10].C1COCC1.[Li+].[OH-]>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:42])[CH:20]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:34][CH:35]=2)=[O:23])=[CH:16][CH:17]=1)=[O:10]
Reactant: CCOC(=O)c1ccc(NC(=O)CC(C(=O)Nc2ccc(NC(=O)Nc3ccccc3C)cc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1NC(=O)Nc1ccc(NC(=O)C(CC(=O)Nc2ccc(C(=O)O)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethyl 4-[(4-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]amino}-4-oxo-3-phenylbutanoyl)amino]benzoate (160 mg, 0.28 mmol) was dissolved in water:THF (10 mL; 1:1; v:v) and LiOH (27 mg, 1.13 mmol) was added at 0° C. and the reaction mixture was stirred at r.t. for 24 h. The reaction mixture was acidified, the product was isolated by filtration and purified by flash chromatography (CH2Cl2/MeOH/AcOH; 10/1/0.5) (11 mg, 0.02 mmol). M.p. 169° C. TLC (DCM/MeOH 9/1) Rf 0.27, ESI-MS: 537[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[O:22][CH3:23])[N:3]=1.S(Cl)(Cl)=O.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:28][CH:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:19])=[CH:15][C:14]=2[O:22][CH3:23])[N:3]=1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-benzoic acid (5 g) is suspended in toluene (150 mL) and combined with thionyl chloride (1.77 mL), stirred for 2 h at 110° C. and after cooling the solvent is eliminated in vacuo. The residue is taken up in THF (50 mL), cooled to 0° C. and a solution of 4-amino-1-methylpiperidine (1.396 g) and diisopropylethylamine (4.19 mL) is added dropwise thereto. Then the reaction mixture is left to warm up to RT and stirred overnight. After filtering, the residue is dried overnight at 50° C.
Reaction SMILES: [NH2:1][C:2]([CH3:14])=[CH:3][C:4]([O:6][CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5].[N+:15]([C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[CH:21]=[C:22]([C:27](OC)=[O:28])[C:23]([O:25][CH3:26])=[O:24])([O-:17])=[O:16].C(N(CC)CC)C>CC(O)C>[OH:28][C:27]1[NH:1][C:2]([CH3:14])=[C:3]([C:4]([O:6][CH2:7][CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:5])[CH:21]([C:20]2[CH:31]=[CH:32][CH:33]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC
Reactant: CC(N)=CC(=O)OCCc1cccs1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COC(=O)C1=C(O)NC(C)=C(C(=O)OCCc2cccs2)C1c1cccc([N+](=O)[O-])c1
Yield: 26.5 %

Procedure:
A mixture of 2-(2-thienyl)ethyl 3-amino-2-butenoate (1.8 g) and dimethyl 3-nitrobenzylidenemalonate (2.25 g) was dissolved in anhydrous 2-propanol (80 ml) and, after addition of triethylamine (27 ml), the mixture was refluxed for 21 hours. After the solvent was distilled off under reduced pressure, the residue was purified by thin-layer silica gel chromatography (developing solvent: chloroform/methanol=19/1; elution solvent: chloroform/acetone=2/1) so as to obtain 1.0 g (26%) of the desired compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2Br)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:32][N:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[CH:35][C:34]1=[O:48].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(#N)C>[C:1]([C:4]1[C@@H:5]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[C:37]2[CH:36]=[CH:35][C:34](=[O:48])[N:33]([CH3:32])[CH:38]=2)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)[C@@H]1c1ccc(C#N)cc1-c1ccc(=O)n(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-3-bromo-benzonitrile (intermediate 4)(400 mg, 0.81 mmol) and N-methyl-1H-pyridin-2-one-5-boronic acid pinacol ester (248 mg, 1.06 mmol) are suspended in acetonitrile (15 mL) and are degassed with a stream of argon. Potassium carbonate solution (2 mol/L, 1.22 mL, 2.44 mmol) and 1.1-bis(diphenylphosphino)-ferrocendichloro-palladium(II), complex with dichloromethane (1:1) (6.34 mg, 0.008 mmol) are added and the reaction is stirred at 100° C. overnight. Additional N-methyl-1H-pyridin-2-one-5-boronic acid pinacol ester (100 mg, 0.4 mmol) and 1.1-bis(diphenylphosphino)-ferrocendichloropalladium(II), complex with dichloromethane (1:1) (2 mg, 0.002 mmol) are added and the reaction is continued at 120° C. for 60 min under microwave irradiation. The reaction mixture is filtrated over a layer of silica gel and basic aluminum oxide 1:1 and purified by reversed phase HPLC. Yield: 125 mg; ESI mass spectrum [M+H]+=521; Retention time HPLC: 1.01 min (HPLC method Z018_S04).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[CH:6][NH:7][C:8]=1[C:9](O)=[O:10])([CH3:3])[CH3:2].[O-2].[Ca+2].C=O>>[CH:1]([C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH2:9][OH:10])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc[nH]c1C(=O)O
Agent: C=O
Agent: [Ca+2]
Agent: [O-2]
Product: CC(C)c1nc[nH]c1CO

Procedure:
A mixture of 4-isopropylimidazole-5-carboxylic acid (1.54 g, 0.01 mol), calcium oxide (0.56 g, 0.01 mol) and ~37% aqueous formaldehyde solution (4 ml) is heated at 70°-80° C. for 3 hours, with stirring. After completion of the reaction, the solvent is stripped off, and the residue is extracted with acetone. The acetone extract is concentrated, and the resultant residue is recrystallized from ethyl acetate and filtered to give 4-isopropyl-5-hydroxymethylimidazole as a solid, m.p. 125°-127° C.
Reaction SMILES: [CH2:1]([O:3][CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:27])[CH3:2].[ClH:31]>C1(C)C=CC=CC=1>[ClH:31].[CH2:1]([O:3]/[CH:4]=[C:5]1\[C:6](=[O:27])[C:7]2[C:12]([O:13][C:14]3\1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: Cc1ccccc1
Product: CCO/C=C1\C(=O)c2ccccc2OC12CCNCC2
Temperature: 60 °C
Yield: 63.2 %

Procedure:
To tert-butyl 3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (33.0 g, 78.7 mmol) in toluene (73.33 mL) was added hydrochloric acid (68.8 mL of 4.0 M in dioxane, 275 mmol). The reaction mixture was heated at 60° C. for 15 min. Most of the solvent was removed under vacuum, and the tan slurry was filtered using a medium frit. The solids were washed with 500 mL of toluene. The solids were dried to give (Z)-3-(ethoxymethylene)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (15.4 g, 63%). ESI-MS m/z calc. 273.1, found 274.3 (M+1)+; Retention time: 0.85 minutes (3 min run).
Reaction SMILES: O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:40]([CH:43]1[CH2:49][CH2:48][CH2:47][CH2:46][C:45]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[CH3:56])=[CH:44]1)=[N+]=[N-]>C1COCC1>[CH3:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[C:45]1[CH2:46][CH2:47][CH2:48][CH2:49][CH:43]([NH2:40])[CH:44]=1
Reactant: Cc1ccccc1C1=CC(N=[N+]=[N-])CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C1=CC(N)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 ml of H2O and then 4.23 g (16.1 mmol) of triphenylphosphine PPh3 are added to a solution of the compound obtained in Step D (2.4 g/10.73 mmol) in 60 ml of THF, and then the reaction mixture is stirred at room temperature overnight. The whole is then concentrated to dryness and subsequently chromatographed over silica gel (CH2Cl2, 20% MeOH, 2% NH4OH) to yield the title product in the form of a yellowish oil.
Reaction SMILES: C1(=O)[N:5]([O:6][CH:7]([CH:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22])[CH2:8][N:9]2C(=O)C3=CC=CC=C3C2=O)C(=O)C2=CC=CC=C12.NN>CO>[NH2:5][O:6][CH:7]([CH:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22])[CH2:8][NH2:9]
Reactant: CC(C)(C)C(C(=O)O)C(CN1C(=O)c2ccccc2C1=O)ON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Product: CC(C)(C)C(C(=O)O)C(CN)ON
Temperature: 25 °C

Procedure:
A mixture of 1,3-diphthalimido-2-(t-butylcarboxymethyl)oxapropane(0.50 g, 1.08 mmol) and 55% hydrazine (0.23 mL, 4.6 mmol) in 2 mL of methanol is refluxed for 4 hrs. After cooling the reaction solution to room temperature, the solids are filtered and the filtrate is evaporated under reduced pressure to yield 1,3-diamino-2-(t-butylcarboxymethyl)oxapropane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10](=[O:18])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10](=[O:18])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(=O)[nH]n1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(=O)[nH]n1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl 1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylate (i.e. the product of Step B) (1.0 g, 3.7 mmol) in methanol (15 mL) was added water (3 mL). An aqueous solution of sodium hydroxide (50%, 1.0 g, 12.5 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 3 hours, during which time the reaction mixture turned a clear yellow. Water (20 mL) was added and the reaction mixture was extracted with ethyl ether, which was discarded. The aqueous phase was acidified to pH 2 using concentrated hydrochloric acid and then extracted with ethyl acetate (50 mL). The ethyl acetate extract was washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate and concentrated to give the title compound, isolated as a white solid (0.76 g).
Reaction SMILES: Br.I.C[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:21][C:20]3[C:15](=[C:16]([O:47]C)[C:17]([C:24]4[CH:29]=[C:28]([CH:30]5[O:40][C:39]6[C:34](=[C:35]([O:43]C)[CH:36]=[C:37]([O:41]C)[CH:38]=6)[C:32](=[O:33])[CH2:31]5)[CH:27]=[CH:26][C:25]=4[O:45]C)=[C:18]([O:22]C)[CH:19]=3)[C:13](=[O:14])[CH2:12]2)=[CH:7][CH:6]=1.B(Br)(Br)Br.B(Cl)(Cl)Cl>CC(O)=O.C(Cl)(Cl)Cl>[CH:7]1[C:8]([C:11]2[O:21][C:20]3[CH:19]=[C:18]([OH:22])[C:17]([C:24]4[CH:29]=[C:28]([C:30]5[O:40][C:39]6[CH:38]=[C:37]([OH:41])[CH:36]=[C:35]([OH:43])[C:34]=6[C:32](=[O:33])[CH:31]=5)[CH:27]=[CH:26][C:25]=4[OH:45])=[C:16]([OH:47])[C:15]=3[C:13](=[O:14])[CH:12]=2)=[CH:9][CH:10]=[C:5]([OH:4])[CH:6]=1
Reactant: COc1ccc(C2CC(=O)c3c(cc(OC)c(-c4cc(C5CC(=O)c6c(OC)cc(OC)cc6O5)ccc4OC)c3OC)O2)cc1
Agent: Br
Agent: BrB(Br)Br
Agent: ClB(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=c1cc(-c2ccc(O)c(-c3c(O)cc4oc(-c5ccc(O)cc5)cc(=O)c4c3O)c2)oc2cc(O)cc(O)c12
Yield: 30 %

Procedure:
Deprotection of 10 was initially attempted using standard mineral acid conditions, such as HBr and HI. In all cases, the use of mineral acids resulted in Wessely-Moser rearrangement21, and amentoflavone was the major product isolated. Similar results were obtained using aqueous (HBr and HI) or anhydrous (HBr in HOAc) conditions. Complete demethylation of 10 was achieved by treatment with between about 8 and about 15 equiv BBr3, preferably 12 equivalents BBr3, in a suitable solvent, e.g., CHCl3 at reflux, at a temperature ranging between about 25° C. and about 80° C., preferably about 60-62° C. If desired, BCl3 may be used in place of BBr3. Attempts to deprotect using amounts of BBr3 less than 8 equivalents or at temperatures lower than 50° C., did not achieve complete demethylation, and the resulting products contained significant quantities of partially demethylated materials. Following demethylation, crude robustaflavone was obtained in 88.9% yield. Column chromatography through silica gel (toluene/pyridine/formic acid, 20:10:1) afforded robustaflavone in 30% yield.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12](=[O:18])/[CH:13]=[CH:14]/[N:15](C)C)[CH:2]=[CH2:3].Cl.NO>CO>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]1[O:18][N:15]=[CH:14][CH:13]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C)ccc1C(=O)/C=C/N(C)C
Agent: Cl
Agent: NO
Solvent: CO
Product: C=CCOc1cc(C)ccc1-c1ccno1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a stirred solution of crude (2E)-1-[2-(allyloxy)-4-methylphenyl]-3-(dimethylamino)prop-2-en-1-one (Step 2, 14.1 g, 57.5 mmol) in methanol (70 mL) was added hydroxylamine hydrochloride (4.4 g, 63 mmol) and the reaction was stirred at room temperature for 1 hour. Colourless needle crystals were filtered off and analysed and found to be the title compound, 7.3 g, in a 58% yield. LCMS (2 min acidic) 1.32 min 64-91% pure by UV, ES+/AP+ 216. 1HNMR (400 MHz, CDCl3) δ ppm 2.40 (s, 3H), 4.67 (m, 2H), 5.35 (dq, 1H), 5.46 (dq, 1H), 6.05-6.20 (m, 1H), 6.77 (m, 1H), 6.82 (s, 1H), 6.88-6.92 (m, 1H), 7.88 (d, 1H).
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]3[CH2:18][CH2:19][CH:13]2[CH2:14][CH2:15]3)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[Li+]>CN(C=O)C>[C:1]1([C:7]([C:8]2[NH:28][N:27]=[N:26][N:9]=2)([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH:16]3[CH2:15][CH2:14][CH:13]2[CH2:19][CH2:18]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(CCN1CC2CCC1CC2)(c1ccccc1)c1cccnc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(CCN2CC3CCC2CC3)(c2cccnc2)c2nnn[nH]2)cc1

Procedure:
α-Phenyl-3-pyridylacetonitrile (U.S. Pat. No. 3,225,054) is reacted with 2-(2-chloroethyl)-2-azabicyclo[2.2.2]octane in toluene to provide 2-phenyl-2-(3-pyridyl)-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile. This nitrile is reacted with sodium azide in DMF containing lithium chloride to provide 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-tetrazole. Reaction this tetrazole with acetic anhydride in pyridine provides 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole, the oxalate salt melts at 171°-172° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([NH2:8])[CH:7]=1.[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([NH:8][C:20](=[O:21])[CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1N
Reactant: O=C(Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1NC(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A mixture of 5-chloro-2-methyl-4-nitrophenylamine (0.475 g, 2.55 mmol) and phenylacetyl chloride (0.394 g, 2.55 mmol) in toluene (10 mL) was heated under reflux for 4 h, then cooled to room temperature. A solid crystallized from the reaction mixture upon cooling, and was isolated by vacuum filtration and dried to provide the title compound as a yellow solid (0.330 g, 43%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:20][N:21]([C:34](=[O:37])[CH2:35][Cl:36])[C@@H:22]([C:30](=[O:33])[NH:31][CH3:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH2:20][N:21]([C@H:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]([NH:31][CH3:32])=[O:33])[C:34](=[O:37])[CH2:35][Cl:36]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)C(=O)CCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C[C@H](N)Cc1ccc2ccccc2c1)C(=O)CCl
Reaction time: 0.67 h
Yield: 151.5 %

Procedure:
(R-2-(N-((2R)-2-Amino-3-(2-naphthyl)propyl)-N-chloroacetylamino)-N-methyl-3-phenylpropionamide. ##STR100## ((1R)-1-((N-Chloroacetyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)amino)methyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester (0.56 g, 1.04 mmol) was dissolved in a mixture of trifluoroacetic acid (4 ml) and methylene chloride (4 ml) and stirred for 40 min. The solvent was removed in vacuo and methylene chloride was added and removed in vacuo (3×10 ml) to afford 0.69 g of (2R)-2-(N-((2R)-2-amino-3-(2-naphthyl)propyl)-N-chloroacetylamino)-N-methyl-3-phenylpropionamide as a trifluoroacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O.[CH3:21][C:22]1[CH:27]=[C:26]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH:24][N:23]=1.CS(C)=O>CN(C=O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:7][C:8]=1[C:26]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:21])[CH:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Reactant: COc1cc(CC(=O)O)ccc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1cc(CC(=O)O)ccc1-c1ccnc(C)c1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To the mixture of 2-(3-methoxy-4-(trifluoromethylsulfonyloxy)phenyl)acetic acid 182-2 (590 mg, 1.9 mmol) and 2-methyl-4-(tributylstannyl)pyridine (730 mg, 1.9 mmol) in DMF (2.0 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (33 mg, 0.04 mmol). The reaction was stirred at 110° C. for 20 hours. After cooling down to room temperature, the reaction mixture was diluted into DMSO and purified by reverse-phase HPLC to give 2-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)acetic acid 182-3. MS m/z 258.1 (M+1).
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[C:10]([Br:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1.C(#N)CC>>[Br:11][C:10]1[C:5]([C:2]#[N:3])=[N:6][CH:7]=[C:8]([Cl:12])[CH:9]=1
Reactant: N#C[Cu]
Reactant: Clc1cnc(Br)c(Br)c1
Solvent: CCC#N
Product: N#Cc1ncc(Cl)cc1Br
Yield: 83.2 %

Procedure:
A microwave vial was charged with copper (I) cyanide (1.089 g, 12.16 mmol), 2,3-dibromo-5-chloropyridine (3 g, 11.06 mmol), and propionitrile (15 mL). The vial was capped and irradiated in a microwave reactor at 150° C. for 2.5 hours. The solution was concentrated, diluted with DCM (25 mL), and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography, eluting with 0-30% EtOAc in heptanes, to afford the title compound (2 g, 9.20 mmol). MS m/z=219 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][S:3]([N:6]1[CH2:10][CH2:9][C@H:8]([NH:11]C(=O)OC(C)(C)C)[CH2:7]1)(=[O:5])=[O:4]>>[ClH:1].[CH3:2][S:3]([N:6]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7]1)(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(C)(=O)=O)C1
Agent: Cl
Product: CS(=O)(=O)N1CC[C@H](N)C1

Procedure:
4M HCl solution (in Dioxane) (2 mL) and (S)-tert-butyl (1-(methylsulfonyl)pyrrolidin-3-yl)carbamate (200 mg, 0.99 mmol) was stirred at 20-35° C. for 2 h. The solid precipitate thus obtained was filtered, washed with hexane and dried to afford 120 mg of the title compound.