Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@H:12]1[CH3:17])[N:7]=[C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][C@H:19]1[CH3:24])[N:5]=2.O.[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[F-].[Cs+]>C(#N)C.C(Cl)Cl.C(O)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:31]1[CH:36]=[CH:35][C:34]([C:2]2[NH:3][C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:7]=[C:6]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH3:24])[N:5]=3)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(-c2ncc[nH]2)cc1
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(Br)[nH]c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(-c3ccc(-c4ncc[nH]4)cc3)[nH]c2n1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
8-Bromo-2,6-bis-((R)-3-methyl-morpholin-4-yl)-9H-purine (99 mg, 250 μmol) was dissolved in 2 mL of acetonitrile and 0.2 mL of water under argon. 4-(1H-imidazol-2-yl)phenyl boronic acid (58.7 mg, 313 μmol), CsF (57 mg, 375 μmol), and Pd(PPh3)4 (28.9 mg, 25 μmol) were added. The suspension was stirred at 50° C. for 10 minutes in a closed microwave vial. Then it was irradiated for 40 minutes in a microwave apparatus at 150° C. The vial was cooled and uncapped, and the reaction mixture was diluted with 50 mL of CH2Cl2 and 10 mL of isopropanol. The organic solvents were washed with brine and aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (40 g SiO2, CH2Cl2/EtOH/aqueous NH3 in a gradient from 100/0/0.1 to 90/10/0.1) to give the product as a solid (58 mg, 48%).
Reaction SMILES: C([CH:3]1[C:7]2=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=[CH:10][CH:11]=[C:6]2[O:5][C:4]1([CH3:16])[CH3:15])C.[OH-].[Na+]>C(O)C>[CH3:15][C:4]1([CH3:16])[CH2:3][C:7]2=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=[CH:10][CH:11]=[C:6]2[O:5]1
Reactant: CCC1c2c(cccc2C(=O)O)OC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)Cc2c(cccc2C(=O)O)O1

Procedure:
Ethyl 2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid (10 g, 45 mmol) was heated to reflux with sodium hydroxide (16.3 ml of 10N, 163 mmol) in ethanol (50 ml) for 2 hr. The mixture was concentrated in vacuo, diluted with water and made acidic with 12N HCl. The precipitate was filtered and air dried (8.6 g, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C@H:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C@H:16]3[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C([C@](C([O-])=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C([O-])=O)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[NH4+:63].[NH4+].[ClH:65]>C(O)C>[ClH:65].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C@H:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C@H:16]3[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)(=[NH:63])[NH2:2]
Reactant: CCOC(=O)C[C@@H]1CN(CC(=O)OCC)CC[C@@H]1N1CCN(c2ccc(C#N)cc2)CC1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)[O-])C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CN(CC(=O)OCC)CC[C@@H]1N1CCN(c2ccc(C(=N)N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
660 mg of (+)-cis-diethyl 4-[4-(4-cyanophenyl)-1-piperazinyl]-1,3-piperidinediacetate-(+)-dibenzoyl-D-tartrate was dissolved in 20 ml of ethanol, into which hydrogen chloride was bubbled at from -10° C. to -20° C. until saturation. This was heated up to room temperature and stirred overnight, and thereafter the solvent was removed by distillation. The residue thus obtained was dissolved in 20 ml of ethanol, and 1.0 g of ammonium carbonate was added thereto and stirred at room temperature overnight. The solvent was removed from the reaction mixture by distillation, and the resulting residue was purified by silica gel column chromatography (using an eluent of chloroform/methanol=10/1) to obtain 300 mg of (+)-cis-diethyl 4-[4-(4-amidinophenyl)-1-piperazinyl]-1,3-piperidinediacetate hydrochloride.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[OH:4].Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[O:12]([C:7]1[CH:6]=[C:5]([C:3](=[O:4])[C:2]([F:1])([F:19])[F:20])[CH:10]=[CH:9][C:8]=1[F:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC(c1ccc(F)c(Oc2ccccc2)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(F)c(Oc2ccccc2)c1)C(F)(F)F

Procedure:
14.37 g (0.05 mol) of 2,2,2-trifluoro-1-(4-fluoro-3-phenoxyphenyl)ethanol and 0.85 g (0.0025 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 200 ml of methylene chloride at room temperature. 31 ml (0.06 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 20 minutes with vigorous stirring and the mixture is stirred for a further 6 hours at room temperature. The reaction mixture is added to 200 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.2 mbar, 150°-165° C. bath temperature), 10.8 g (76% of theory) of 2-phenoxy-4-trifluoroacetylfluorobenzene are obtained. nD20 : 1.5230.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([CH:15]=[O:16])[CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.O.[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31]Cl>CN(C=O)C.C(N(C(C)C)CC)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([CH:15]=[O:16])[CH:12]=[CH:13][C:14]=3[C:5]=2[N:4]([CH2:31][O:30][CH2:29][CH2:28][Si:27]([CH3:34])([CH3:33])[CH3:26])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(Br)n[nH]c12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1nc(Br)c2nc(-c3c(F)cccc3F)c3cc(C=O)ccc3c21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 150 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 780 mg of 3-bromo-5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde in 20 ml of DMF, 2.5 ml of diisopropylethylamine and 0.75 ml of 2-(trimethylsilyl)ethoxymethyl chloride. The mixture is stirred at RT for 24 h and then poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. This gives 1.18 g of a crude product, which is purified by chromatography on silica gel (20-45 μm), eluting with a mixture of DCM and methanol (99.5/0.5 by vol.), to give on one hand 545 mg of 3-bromo-5-(2,6-difluorophenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde in the form of a cream solid: MS (E/I): m/z=388 (M+); 1H NMR: −0.13 (s, 9H); 0.86 (t, J=7.8 Hz, 2H); 3.66 (t, J=7.8 Hz, 2H); 618 (s, 2H); 7.43 (t, J=7.9 Hz, 2H); 7.79 (m, 1H); 8.39 (broad s, 1H) 8.48 (dd, J=8.3, 1.5 Hz, 1H) 8.80 (d, J=8.3 Hz, 1H) 10.17 (s, 1H), and on the other hand 354 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanylethoxymethyl)-2H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde (cream solid). MS (E/I): m/z=388 (M+); 1H NMR: −0.08 (s, 9H); 0.90 (t, J=8.0 Hz, 2H); 3.73 (t, J=8.0 Hz, 2H); 5.91 (s, 2H); 7.41 (t, J=7.8 Hz, 2H); 7.77 (m, 1H); 8.22 (broad s, 1H) 8.42 (dd, J=8.3, 1.5 Hz, 1H) 8.72 (d, J=8.3 Hz, 1H) 10.13 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:6]=1[O:13][CH2:14][CH3:15])[CH3:2].S(=O)(=O)([OH:19])N.Cl([O-])=O.[Na+]>CN(C)C=O.O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[O:13][CH2:14][CH3:15])[C:11]([OH:19])=[O:12])[CH3:2]
Reactant: CCOC(=O)c1cc(C=O)ccc1OCC
Reactant: NS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C(=O)O)ccc1OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirring solution of 2-ethoxy-5-formyl-benzoic acid ethyl ester (1.0 g, 4.5 mmol) in 10 mL of dimethylformamide was added dropwise sulfamic acid (610.4 mg, 6.3 mmol) in 5 mL of water. After addition of sulfamic acid, sodium chlorite (737.2 mg, 8.2 mmol) in 5 mL of water was added dropwise. Reaction was allowed to stir for 2 h at room temperature. Reaction was diluted with brine and extracted with ethyl acetate. Organic extract was dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 4-ethoxy isopthalic acid 3-ethyl ester as a white solid (900 mg, 84%). LC-MS: 239.2 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[S:32](Cl)(=[O:34])=[O:33].CCN(CC)CC.Cl>O1CCOCC1>[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[S:32]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1)(=[O:34])=[O:33]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2nccc(Oc3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)c2c2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
Compound 137 (50 mg, 0.16 mmol), 2,3-dichloro-benzenesulfonyl chloride (45 mg, 0.18 mmol), and Et3N (0.07 mL, 0.49 mmol) were suspended in dioxane (2 mL), and stirred overnight at 80° C. The reaction mixture was acidified with 1M HCl, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 25 to 100% EtOAc in hexanes to provide 173 (14 mg, 17% yield) as a white solid. LC-MS (M+H=512, obsd.=512).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[CH2:14][OH:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1>CC(C)=O.O=[Mn]=O>[N:1]1([C:6]2[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[CH:14]=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: OC/C=C/c1ccc(-n2cccn2)nc1
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: O=C/C=C/c1ccc(-n2cccn2)nc1
Yield: 42.6 %

Procedure:
A mixture of the compound from step C (185 mg, 0.92 mmol) and MnO2 (1.60 g, 18.40 mmol) in acetone (15 mL) was heated to reflux for 1 h. The cooled reaction mixture was filtered through Celite and the filtrate was concentrated. Purification by chromatography (SiO2, 2:1 hexane/ethyl acetate) yielded 78 mg (43%) of the title compound. MS 200 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5](O)=O)[CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:12]=[C:13]([O:18]C)[CH:14]=[CH:15][C:16]=1[NH2:17]>>[OH:18][C:13]1[CH:14]=[CH:15][C:16]2[NH:17][C:5]([CH:4]3[CH2:8][CH2:9][NH:1][CH2:2][CH2:3]3)=[N:10][C:11]=2[CH:12]=1
Reactant: O=C(O)C1CCNCC1
Reactant: COc1ccc(N)c(N)c1
Product: Oc1ccc2[nH]c(C3CCNCC3)nc2c1

Procedure:
The title compound was prepared from isonipecotic acid and 3,4 diamino anisole using the method described in Description 14. MH+ 218.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[CH:18]=[N:17][C:16]([Br:19])=[CH:15][N:14]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:19][C:16]1[N:17]=[CH:18][C:13]([NH:12][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])=[N:14][CH:15]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cnc(Br)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cnc(Br)cn1)c1c(F)cccc1F
Temperature: 0 °C
Yield: 52.8 %

Procedure:
To a 0° C. cooled and stirred, solution of 2,6-difluorobenzoyl chloride (5.7 g, 36.2 mmol, 0.9 eq) in DCM (200 mL) was added drop wise a solution of 2-amino-5-bromopyrazine (7.0 g, 40.2 mmol, 1.0 eq) in DCM (50 mL) followed b pyridine (3.1 g, 36.2 mmol, 0.9 eq). The resulting mixture was stirred at room temperature for 15 h. The reaction was diluted with DCM (100 mL), and washed with 10% hydrochloric acid (100 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, 10% ethyl acetate in hexane) to afford 6.0 g of the title product as a yellow solid. 1HNMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 8.62 (s, 1H, D2O exchangeable), 8.24 (s, 1H), 7.53-7.45 (m, 1H), 7.03 (t, J=8.0 Hz, 2H); ESI-MS (m/z) 314, 316 [(MH)+ Br79,81].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:23][CH:22]([CH2:24][S:25][C:26]4[N:30]=[CH:29][NH:28][N:27]=4)[O:21][C:20]3=[O:31])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH2:32].[OH-].[Li+]>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:22]([OH:32])[CH2:24][S:25][C:26]3[N:30]=[CH:29][NH:28][N:27]=3)[C:20]([OH:21])=[O:31])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)NC3CC(CSc4nc[nH]n4)OC3=O)cc2)cc1
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc[nH]n3)C(=O)O)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of 3-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-5-[(1H-1,2,4-triazol-3-ylthio)methyl]-tetrahydrofuran 20a (0.34 g, 0.68 mmol) in water (5 mL) and THF (5 mL) is added slowly lithium hydroxide monohydrate (290 mg, 4.2 mmol). The reaction mixture is stirred for 4 h, then concentrated to dryness. Diluted with water, the mixture is extracted twice with Et2O. The Et2O layer is discarded and the aqueous layer is neutralized carefully with 1N HCl to pH 6, then extracted three times with EtOAc. The combined EtOAc layer is washed with brine, dried over MgSO4 and concentrated to a solid which is recrystallized from EtOAc/hexane (1:4) to give the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: CCOC(=O)c1cccc(-c2cc(OC)c(OC)c(OC)c2)c1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (3.7 g) and ethyl 3-bromobenzoate (4.02 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:5][CH:6]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:52][CH:53]([CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:54][CH2:55][C:56]([OH:58])=[O:57]>CN(C=O)C.CCOCC>[C:61]1([CH2:60][CH2:59][CH:53]([NH:52][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:54][CH2:55][C:56]([OH:58])=[O:57])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: NC(CCC(=O)O)CCc1ccccc1
Reactant: O=C(O)CCCCCCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=C(O)CCC(CCc1ccccc1)NC(=O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Phenylheptanoic acid (105 mg 0.51 mmol) and BOP (250 mg, 0.56 mmol) were dissolved in dry DMF 2 mL then DIPEA 200 μL was added. After mixing for 3 min the solution was added to (RS)-4-amino-6-phenyl-hexanoic acid (101) (105 mg, 0.51 mmol) and the solution was stirred at room temperature for 1 hr. Ether was added and the solution was washed twice with 1 M HCl and brine then dried over MgSO4. Removal of solvent gave a white solid 200 mg, which was recrystallised from EtOAc-hexane. 1H NMR (300 MHz, CDCl3) δ 7.30-7.22 (m, 4H), 7.21-7.11 (m, 6H), 6.17 (br, 1H, NH), 4.02 (m, 1H), 2.70-2.53 (m, 4H), 2.38 (m, 2H), 2.22 (m, 2H), 2.00-1.52 (m, 8H), 1.44-1.27 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[S:21]>CN(C)C=O.O>[CH3:18][N:19]([CH3:23])[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1)=[S:21]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)CCC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCC(=O)c1ccc(OC(=S)N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from Step B, 25 g, in anhydrous dimethylformamide (DMF) (300 ml) was cooled to 0° and 99% NaH, 3.46 g, was added in two portions. The mixture was stirred for 1 hour at 0° then dimethylthiocarbamoyl chloride, 19.3 g, was added and the mixture heated at 90° under a N2 atmosphere for 1.5 hours. The mixture was cooled to room temperature and diluted with water to 1,200 mL. The resulting solution was then extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine and then dried over Na2SO4 and evaporated to dryness in vacuo to yield a residue which was purified by chromatography on silica gel to Yield the title compound, mp 62°-64°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][OH:15])[CH:6]=[CH:5]2.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1.C(Cl)Cl>>[C:19]([O:15][CH2:14][CH2:13][N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=2[N+:16]([O-:18])=[O:17])[C:8]1=[O:12])(=[O:21])[CH3:20]
Reactant: O=c1c2ccc(Cl)c([N+](=O)[O-])c2ccn1CCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCn1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 6-chloro-2-(2-hydroxyethyl)-5-nitroisoquinolin-1(2H)-one (400.0 mg, 0.00149 mol), acetic anhydride (0.21 mL, 0.0022 mol), pyridine (0.18 mL, 0.0022 mol) and methylene chloride (20 mL, 0.2 mol) and the reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure to afford the product as a yellow solid.
Reaction SMILES: [C:1]1([C:7](=[O:18])[C:8](=[C:12]2[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]2)C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C(O)(=O)C>C(O)C>[NH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1=[CH:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:18]
Reactant: CC(=O)C(C(=O)c1ccccc1)=C1CCCCN1
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(C=C1CCCCN1)c1ccccc1

Procedure:
12.15 g (0.05 mole) of 1-phenyl-2-(2-piperidinylidene)-1,3-butanedione are introduced into a prepared solution of 3.5 g of sodium in 120 ml of ethanol. The reaction mixture is then refluxed for 40 minutes. After cooling, it is neutralised with glacial acetic acid, and filtered off from the sodium acetate. The filtrate is concentrated in the rotary evaporator, and the residue is dissolved in methylene chloride. The solution is repeatedly extracted with water; the organic phase is dried over sodium sulphate, and the solvent is evaporated off in the rotary evaporator. The oily residue is crystallised from ether/hexane to yield 2-(2-piperidinylidene)-acetophenone, m.p. 59°-60°.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[CH2:4][CH2:5][C:6](=[O:17])[C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[O:15]C.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:18])[CH2:4][CH2:5][C:6](=[O:17])[C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:15]
Reactant: CNC(=O)CCC(=O)c1c(OC)cccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CNC(=O)CCC(=O)c1c(O)cccc1OC

Procedure:
N-Methyl 3-(2,6-dimethoxybenzoyl)propionamide was demethylated with aluminium chloride in chlorobenzene to give N-methyl 3-(2-hydroxy-6-methoxybenzoyl)propionamide, m.p. 125° which may also be prepared from a by-product, N-methyl 3-(2,6-dihydroxybenzoyl)propionamide, by selective methylation with methyl iodide and potassium carbonate in acetone. (iii) By subjecting N-methyl 3-(2-hydroxy-6-methoxybenzoyl)-propionamide to a series of reactions similar to those described in Examples 1(i-ii) and 2(i-v), the title compound may be prepared.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:14])[CH:2]=[CH2:3].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.C(=O)(O)[O-].[Na+]>CCCCCC>[CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:2]=[CH2:3]
Reactant: C=CCc1ccc2ccccc2c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCCCCC
Product: C=CCc1ccc2ccccc2c1O[Si](C)(C)C(C)(C)C
Yield: 95 %

Procedure:
A mixture of 2-(2-propenyl)-1-naphthol (Example 118 Part A; 101.9 g, 0.550 mole), t-butyldimethylsilyl chloride (100.0 g, 0.660 mole), and imidazole (93.6 g, 1.375 mole) in N,N"-dimethylformamide was stirred at room temperature for 6.5 hours. It was then poured into saturated aqueous sodium bicarbonate, and the crude product isolated by extraction with hexane. The residue was distilled at reduced pressure to provide the title compound (155.2 g, 95%), bp 135°-140° (0.1 torr).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[C:9]([Si:13]([CH3:23])([CH3:22])[O:14][CH2:15][CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:9]([Si:13]([O:14][CH2:15][CH2:16][C:17]1[S:18][C:19]([Cl:8])=[CH:20][CH:21]=1)([CH3:23])[CH3:22])([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(Cl)s1

Procedure:
NCS (0.826 g) was added portionwise to a solution of tert-butyldimethyl(2-(thiophen-2-yl)ethoxy)silane [WO 2008096129] (1.5 g) in chloroform (50 mL) and the resulting mixture was heated at reflux for 3 days. The mixture was diluted with DCM (100 mL) and washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (100 mL), then dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with isohexane to give the subtitled compound as a clear oil. Yield 1.00 g.