Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[C:35]1([C:41]2([NH2:44])[CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Br:45][C:46]1[C:54]2[C:49](=[N:50][CH:51]=[C:52]([C:55]3[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=3)[C:58](O)=[O:59])[CH:53]=2)[O:48][C:47]=1[C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1>CN(C=O)C.CCOC(C)=O>[Br:45][C:46]1[C:54]2[C:49](=[N:50][CH:51]=[C:52]([C:55]3[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=3)[C:58]([NH:44][C:41]3([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:43][CH2:42]3)=[O:59])[CH:53]=2)[O:48][C:47]=1[C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1
Reactant: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reactant: NC1(c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC1(c2ccccc2)CC1)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reaction time: 1 h
Yield: 62.5 %

Procedure:
DIEA (286 μL, 1.64 mmol) was added to a stirring solution of HATU (311 mg, 0.819 mmol), 1-phenylcyclopropanamine hydrochloride (111 mg, 0.655 mmol), and 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (225 mg, 0.546 mmol) in DMF (6 mL) at room temperature. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-N-(1-phenylcyclopropyl)benzamide (180 mg, 0.341 mmol, 63% yield) consistent by LCMS. LC-MS retention time: 1.89 min; m/z (MH+): 529. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:16]([NH:24][C:25](=[O:44])[C@H:26]([CH2:40][C:41](=[O:43])[NH2:42])[NH:27][C:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1)=[O:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][NH:4][C:5](=[O:15])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([CH3:14])([CH3:13])[CH3:12].ClC1C=CC=C(C(OO)=[O:53])C=1>ClCCl>[C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[C:5]([NH+:4]([O-:53])[CH2:3][C@@H:2]([OH:1])[C@@H:16]([NH:24][C:25](=[O:44])[C@H:26]([CH2:40][C:41](=[O:43])[NH2:42])[NH:27][C:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1)=[O:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N1CCC[C@H]1C(=O)NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)N1CCC[C@H]1C(=O)[NH+]([O-])C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Yield: 66.7 %

Procedure:
A solution of 0.422 g of N -[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-N1 -tert.butyl-L-prolinamide and 142 mg of 3-chloroperbenzoic acid in 10 ml of dichloromethane was stirred at 20° C. for 1 hour. The solvent was then removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for theelution to give 289 mg of N1 -tert.butyl-N2 -[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]-butyl]L-prolinamide N2 -oxide as a white solid; MS: m/e 619 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][O:12]S(C)(=O)=O.[H-].[Na+].[H][H]>O1CCCC1>[CH:6]1[C:5]2[CH2:10][CH2:11][O:12][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1.[CH2:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)OCCc1ccccc1CCO
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1ccccc1
Product: c1ccc2c(c1)CCOCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonic acid 2-[2-(2-hydroxy-ethyl)-phenyl]-ethyl ester (2.2 g/9.0 mmol) was dissolved in tetrahydrofuran (400 mL). Sodium hydride (540 mg/14.5 mmol) was added (hydrogen evolution) and the reaction allowed to stir at room temperature overnight. The reaction was quenched by the addition of water (10 mL) and the reaction concentrated to a volume of ca. 50 mL by rotary evaporation. The residue was partitioned between water (50 mL) and ethyl ether (50 mL). The aqueous layer was extracted with an additional portion of ethyl ether (50 mL) and the combined organics were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated onto silica gel. Column chromatography on silica gel (eluting with 0→50% ethyl acetate/hexanes) afforded 5,6,8,9-Tetrahydro-7-oxa-benzocycloheptene as a colorless oil (240 mg/18%) along with a styrene by-product formed by mesylate elimination (600 mg/45%). Oxapene: 1H NMR (400 MHz, CDCl3) δ 7.11 (m, 4H), 3.80 (m, 4H), 3.00 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([CH:25]2[CH2:27][CH:26]2[CH2:28][O:29]CC2C=CC=CC=2)(=[O:24])=[O:23])=[C:12]2[O:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16].B(F)(F)F.C(S)C>C(OC(=O)C)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([CH:25]2[CH2:27][CH:26]2[CH2:28][OH:29])(=[O:24])=[O:23])=[C:12]2[O:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2COCc2ccccc2)c2n(c1=O)CCO2
Agent: FB(F)F
Solvent: CCS
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2CO)c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
2-Benzyloxymethyl-cyclopropanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-8-yl]-amide (0.05 g, 0.0001 mol) was added to a stirred solution of BF3.EtO2 (0.34 g, 0.002 mol) in ethane thiol (0.05 g, 0.001 mol) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethylacetate. The organic layer was washed with water, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (2-3% MeOH in DCM) afforded 11 mg of the product (27% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([O:9][C:10]([C:12]1[C:18]2[NH:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][C:25]=3[C:17]=2[C:16]([CH3:28])([CH3:27])[CH2:15][N:14]([C:29](=[O:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:13]=1)=[O:11])[CH3:8].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:7]([O:9][C:10]([C:12]1[C:18]2[NH:19][C:20]3[CH:21]=[C:22]([O:26][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[CH:23]=[CH:24][C:25]=3[C:17]=2[C:16]([CH3:28])([CH3:27])[CH2:15][N:14]([C:29](=[O:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:13]=1)=[O:11])[CH3:8]
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(O)ccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(OC(=O)N(C)C)ccc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
Dimethylcarbamoyl chloride (0.2 mL, 2.17 mmol) was added dropwise to a stirred solution of 3-(4-fluorobenzoyl)-8-hydroxy-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (199 mg, 0.47 mmol), 4-dimethylaminopyridine (DMAP) (20 mg), and triethylamine (0.8 mL, 5.74 mmol) in anhydrous DCM (15 mL) at 0° C. under nitrogen, and the resulting mixture was stirred at 50° C. for 5 hours. The solvents were removed in vacuo, and the residue was purified by chromatography on silica gel eluting with DCM-20% MeOH/DCM (90:10) to give the title compound (171 mg, 74%); 1H-NMR (CDCl3): δ 10.62 (1H, s), 7.78 (s, 1H), 7.74 (1H, d), 7.63-7.59 (2H, m), 7.16-7.10 (3H, m), 6.84 (1H, dd), 4.24 (2H, q), 4.08 (2H, brs), 3.14 (3H, s), 3.03 (3H, s), 1.59 (6H, s), 1.23 (3H, t); MS (ES): 494 (MH+).
Reaction SMILES: [C:1]1([CH2:9][OH:10])[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[N+]([O-])(O)=O.O>C(O)(=O)C>[CH:9](=[O:10])[C:1]1[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:7]=[O:8]
Reactant: OCc1ccccc1CO
Solvent: CC(=O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=Cc1ccccc1C=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
In a 1000-ml three-neck flask equipped with a thermometer, a reflux condenser and a stirrer were placed 50 g of o-xylylene glycol, 39.2 g of 60% by weight nitric acid, 197.6 g of water, and 213.2 g of acetic acid. The mixture was raised in temperature to 70° C. on an oil bath and was stirred under these conditions for 2 hours. After cooling, the reaction mixture was analyzed by gas chromatography to find that the raw material o-xylylene glycol was completely absent and that phthalaldehyde was formed in a yield of 60%. In addition, phthalide (yield: 6%) and an ester of the raw material were formed as by-products. The obtained reaction mixture was extracted with two portions of toluene, the organic layer was distilled and thereby yielded phthalaldehyde in a yield of 45% on the basis of o-xylylene glycol. Gas chromatographic analysis revealed that phthalaldehyde had a purity of 95.0%. In addition, phthalide was formed in a yield of 10%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:16]=1.Cl[C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=4)[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:16]=1
Reactant: Brc1ccc2oc(C3CCNCC3)nc2c1
Reactant: CCc1cnc(Cl)nc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(c3nc4cc(Br)ccc4o3)CC2)nc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 7.2 %

Procedure:
Intermediate 5 (800 mg, 2.85 mmol) and 2-chloro-5-ethylpyrimidine (447 mg, 3.14 mmol) were dissolved in propan-2-ol (25 ml). To this mixture N,N-Diisopropylethyl amine (3.1 ml, 17.12 mmol) added and stirred at 90° C. for 12 h. After completion of the reaction, propan-2-ol was removed to obtain the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (8:92) as eluent to afford the titled compound (80 mg) as a pale-yellow solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.19 (s, 2H), 7.81 (s, 1H), 7.41 (dd, J 1.6, 8.6, 1H), 7.35 (d, J 8.6, 1H), 4.72 (d, J 13.6, 2H), 3.27-3.11 (m, 3H), 2.47 (q, J 7.6, 2H), 2.21 (dd, J 2.6, 13.1, 2H), 2.02-1.90 (m, 2H), 1.19 (t, J 7.6, 3H).
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[CH2:11]([NH:18][S:19]([CH2:22][C:23]#[N:24])(=[O:21])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][S:19](/[C:22](=[CH:9]/[C:6]1[S:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:8][CH:7]=1)/[C:23]#[N:24])(=[O:21])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CCS(=O)(=O)NCc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)NCc1ccccc1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and benzylaminosulfonylacetonitrile as in Example 1 gave (E)-2-(benzylaminosulfonyl)-3-(2-nitrothien-5-yl)acrylonitrile
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:17])=[C:10]2[O:14][CH:13]([O:15][CH3:16])[CH2:12][C:11]=12)=[O:5])C.[OH-].[Na+]>CO.O>[Cl:17][C:9]1[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:11]2[C:10]=1[O:14][CH:13]([O:15][CH3:16])[CH2:12]2
Reactant: CCOC(=O)c1ccc(Cl)c2c1CC(OC)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC1Cc2c(C(=O)O)ccc(Cl)c2O1
Temperature: 55 °C

Procedure:
A mixture of 7-chloro-2-methoxy-2,3-dihydro-benzofuran-4-carboxylic acid ethyl ester (1.17 mmol) and NaOH (1.75 mmol) in MeOH (1.3 mL) and water (1.3 mL) is heated to 55° C. for 90 min. The mixture is concentrated in vacuo and made acidic by addition of aq. HCl (1.0 M). The obtained precipitate is filtered off and dried in vacuo to give the desired product. 1H-NMR (DMSO-d6): δ=13.1 (bs, 1H); 7.45 (d, J=8.3 Hz, 1H); 7.38 (d, J=8.5 Hz, 1H); 5.87 (d, J=6.3 Hz, 1H); 3.67 (dd, J=18.1 Hz, J=6.0 Hz, 1H); 3.47 (s, 3H); 3.30 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH:3]1[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH2:19](O)[CH2:20][OH:21].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[CH2:7][CH2:6][C:5]2([O:21][CH2:20][CH2:19][O:8]2)[CH2:4][CH:3]1[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: OCCO
Reactant: CC1(C)CCC(=O)CC1S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1(C)CCC2(CC1S(=O)(=O)c1ccccc1)OCCO2
Yield: 84 %

Procedure:
To a solution obtained by dissolving 4.4 g of 4,4-dimethyl-3-(phenylsulfonyl) -cyclohexan-1-one in 45 ml of benzene, were added 1.1 nm of 1,2-ethanediol and 0.3 g of anhydrous paratoluenesulfonic acid. The resulting mixture was heated under ref lux for 4 hours. After the reaction, a 2M aqueous sodium bicarbonate solution was added and the resulting mixture was extracted with ethyl acetate three times. The combined organic layers were washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, followed by recrystallization from ethyl ether, whereby 4,4-dimethyl-1,1-(ethylenedioxy)-3-(phenylsulfonyl)-cyclohexane was obtained in the form of white crystals. Yield: 84%
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CS(C)=O.O>[C:17]([N:24]1[CH2:25][CH2:26][N:27]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:28][CH2:29]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a suspension of 1-fluoro-4-nitrobenzene (1.4 mL, 13 mmol) and potassium carbonate (2.5 g, 18 mmol) in DMSO (10 mL) was added 1-Boc-piperazine (2.75 g, 14.8 mmol). The mixture was stirred at 100° C. for 2 hours. After cooing down, the mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried with sodium sulfate (Na2SO4), and concentrated in vacuo to afford a yellow solid. Recrystallization from EtOAC/hexanes gave 4.0 g of 1-(4-Boc-piperazin-1-yl)-4-nitrobenzene, which was reduced via hydrogenation to give the title compound (purple solid, 3 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.68 (d, J=8.8 Hz, 2H), 6.64 (d, J=8.8 Hz, 2H), 3.56 (t, J=5.0 Hz, 4H), 2.96 (t, J=5.0 Hz, 4H), 1.46 (s, 9H).
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32]CS(C)(=O)=O)C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4](OC)[CH:3]=1.CC1(C)C(C)(C)OB(C2C=CC=CC=2[CH2:54][C:55]#[N:56])O1>CCCCCCC.CCOC(C)=O>[CH3:32][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH2:54][C:55]#[N:56]
Reactant: CC1(C)OB(c2ccccc2CC#N)OC1(C)C
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNc1cnccc1-c1ccccc1CC#N

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetonitrile (CAS RN 325141-71-7) after a reaction time of 6 days and using a gradient of n-heptane:EtOAc (100:0 to 20:80) for the chromatographic purification. Light yellow solid (69%). MS (ESI): m/z=224.118 [M+H]+.
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([OH:20])=O)[CH2:13][CH2:12]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[N+:44]([C:47]1[CH:48]=[CH:49][C:50]([O:53][C:54]2[CH:59]=[CH:58][C:57]([NH2:60])=[CH:56][CH:55]=2)=[N:51][CH:52]=1)([O-:46])=[O:45]>CN(C=O)C>[N+:44]([C:47]1[CH:48]=[CH:49][C:50]([O:53][C:54]2[CH:59]=[CH:58][C:57]([NH:60][C:18](=[O:20])[CH2:17][N:14]3[CH2:13][CH2:12][N:11]([CH2:1][C:2]4[CH:10]=[CH:9][C:8]5[O:7][CH2:6][O:5][C:4]=5[CH:3]=4)[CH2:16][CH2:15]3)=[CH:56][CH:55]=2)=[N:51][CH:52]=1)([O-:46])=[O:45]
Reactant: Nc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Reactant: O=C(O)CN1CCN(Cc2ccc3c(c2)OCO3)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(Cc2ccc3c(c2)OCO3)CC1)Nc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (4-piperonylpiperazin-1-yl)acetic acid (13.9 g, 50 mmol) was suspended in DMF (400 mL), and to the resulting suspension were added 1-hydroxybenzotriazole monohydrate (8.42 g, 55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.5 g, 55 mmol) and 4-(5-nitropyridin-2-yloxy)phenylamine (11.6 g, 50 mmol) under ice cooling. The resulting solution was stirred for 6 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was left for standing overnight at room temperature, and the resulting precipitated crystals were collected by suction filtration, to thereby yield 12.8 g of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=3)[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: C[C@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Reactant: COc1cccc(N2CCNCC2)c1
Agent: [Na]
Product: COc1cccc(N2CCN(c3ccc(S(=O)(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)CC2)c1

Procedure:
In a manner similar to Example 3(b), (S)-2-(4-fluoro-benzenesulfonylamino)-propionic acid, sodium salt and 4-(3-methoxy-phenyl)-piperazine were condensed to give the title compound as a pale red-brown solid, mp=137-139° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH2:35]OS(C)(=O)=O)([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:25]OS(C)(=O)=O)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:41])=[N:5]1)([CH3:3])[CH3:2]>C(N)(C)C>[CH2:31]([C:24]1([O:23][C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:41])[N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH2:25][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:35]1)[CH:32]([CH3:33])[CH3:34]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(COS(C)(=O)=O)(COS(C)(=O)=O)CC(C)C)cc2OCC3)n(C(C)C)n1
Solvent: CC(C)N
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(CC(C)C)CN(C(C)C)C4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C

Procedure:
A solution of methanesulfonic acid 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methanesulfonyloxymethyl-4-methylpentyl ester (194 mmol) in isopropylamine (2 mL) was heated at 150° C. for 33 h using microwave irradiation. After cooling to RT, the crude reaction mixture was evaporated and then purified by column chromatography (C18, gradient 30-55% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH affording 301 as a colourless foam (95 mg, 100% over 2 steps). LCMS (Method K): RT 3.29 min [M+H]+ 479.2. 1H NMR (CD3OD, 400 MHz): δ 8.41 (1H, d, J=9.0 Hz), 7.69 (1H, s), 6.67 (1H, bd, J=9.0 Hz), 6.51 (1H, bs), 5.84 (1H, septet, J=6.6 Hz), 4.51 (4H, s), 4.44-4.37 (4H, m), 3.49-3.42 (1H, m), 2.36 (3H, s), 2.17 (2H, d, J=6.9 Hz), 1.72 (1H, nonet, J=6.8 Hz), 1.52 (6H, d, J=6.6 Hz), 1.25 (6H, d, J=6.5 Hz), 0.92 (6H, d, J=6.8 Hz)
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH:22]([CH3:24])[CH3:23])[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].Cl[P:26]([O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C@H:40]([CH3:45])[C:41]([O:43][CH3:44])=[O:42])[CH:34]=[CH:33]2)(Cl)=[O:27].C(Cl)[Cl:47]>>[Cl:47][C:31]1[C:32]2[C:37](=[CH:36][C:35]([C@H:40]([CH3:45])[C:41]([O:43][CH3:44])=[O:42])=[CH:34][CH:33]=2)[CH:38]=[CH:39][C:30]=1[O:29][P:26](=[N:12][C@@H:13]([CH:22]([CH3:24])[CH3:23])[C:14]([O:16][CH2:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:15])=[O:27]
Reactant: COC(=O)[C@@H](C)c1ccc2cc(OP(=O)(Cl)Cl)ccc2c1
Reactant: CC(C)[C@H](N)C(=O)OCC(C)(C)C
Reactant: ClCCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: COC(=O)[C@@H](C)c1ccc2c(Cl)c(O[P+]([O-])=N[C@H](C(=O)OCC(C)(C)C)C(C)C)ccc2c1

Procedure:
Using the general procedure for synthesizing naphthyl (amino acid ester) phosphorochloridates the tosylate salt of (S)-neopentyl 2-amino-3-methylbutanoate (776 mg), and (S)-methyl 2-(6-(dichlorophosphoryloxy)naphthalen-2-yl)propanoate (750 mg), TEA (0.6 mL) and DCM (15 mL) were combined to give 580 mg of desired (2S)-neopentyl 2-(chloro(6-((S)-1-methoxy-1-oxopropan-2-yl)naphthalen-2-yloxy)phosphorylamino)-3-methylbutanoate as gummy solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[O:8][C:9]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:10]=2[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[H][H]>C(O)(=O)C.[C].[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:9]=2[O:8][C:7]1=[O:23])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(C)ccc2oc1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1C(=O)Oc2ccc(C)cc2C1c1ccccc1
Yield: 82.8 %

Procedure:
To a solution of 6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid ethyl ester (15.0 g) in acetic acid (150 ml) was added 10% palladium-carbon (3.0 g), followed by stirring at 80° C. in a hydrogen atmosphere (4 to 5 atm) for 4.5 hours. After the catalyst was filtered off, the filtrate was distilled to remove the solvent, followed by treatment of the residue with isopropyl ether, to yield 3,4-dihydro-6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid ethyl ester as colorless crystals (12.5 g).