Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl.[CH2:37]([P:44](Cl)([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.O>[CH2:46]([P:44]([NH:1][C@H:2]([C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7])([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:45])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=P(Cl)(Cc1ccccc1)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CC[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Temperature: -5 °C
Reaction time: 3 h

Procedure:
The thus obtained amorphous L-glutamyl-L-prolyl-L-proline was dissolved in DMF (8 ml) and water (2 ml), and neutralized by addition of triethylamine (0.2 ml) while cooling to -5° C. Dibenzylphosphorylchloride carbon tetrachloride solution (3 m mole) and triethylamine were added dropwise to the mixture while keeping the temperature to not more than 5° C. and usually keeping the pH value to 8-9. The mixture was stirred for 3 hours at room temperature, and the solvent was distilled off under reduced pressure. The residue was dissolved in 5% sodium bicarbonate and then washed with ethyl acetate. The aqueous phase was acidified with 1N hydrochloric acid, and the desired product was extracted with ethyl acetate. The ethyl acetate phase was washed with sodium chloride solution and dried with anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure. The residue was re-precipitated with ethyl acetate-ethyl ether to obtain dibenzylphosphoryl-L-glutamyl-L-prolyl-L-proline (140 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([F:21])=[C:11]([F:20])[CH:12]=[C:13]2[C:17]=1[C:16](=[O:18])[NH:15][CH:14]2[CH3:19].C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:29][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9]2[C:10]([F:21])=[C:11]([F:20])[CH:12]=[C:13]3[C:17]=2[C:16](=[O:18])[NH:15][CH:14]3[CH3:19])=[C:2]([Cl:1])[CH:7]=1
Reactant: CC1NC(=O)c2c1cc(F)c(F)c2Nc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1NC(=O)c2c1cc(F)c(F)c2Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
A mixture of 7-(2-chlorophenylamino)-5,6-difluoro-3-methyl-2,3-dihydro-isoindol-1-one (68 mg, 0.22 mmol, prepared by the procedures described in Example 1) and NBS (46 mg, 0.26 mmol) in DMF (2 mL) was stirred for 3 hours at room temperature. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (100% hexanes to 25% EtOAc in hexanes) to afford 7-(4-bromo-2-chlorophenylamino)-5,6-difluoro-3-methyl-2,3-dihydro-isoindol-1-one (40 mg, 47%). MS APCI (−) m/z 385, 387 (M-, Br, Cl pattern) detected; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.54 (d, 1H), 7.31 (dd, 1H), 6.89 (t, 1H), 6.75 (dd, 1H), 6.05 (s, 1H), 4.63 (q, 1H), 1.49 (d, 3H).
Reaction SMILES: C(I)I.[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([CH3:11])=[CH2:10])[CH3:5].[CH3:13]COC(C)=O>C(OCC)C>[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]1([CH3:13])[CH2:11][CH2:10]1)[CH3:5]
Reactant: C=C(C)CC(=O)OCC
Reactant: CCOC(C)=O
Solvent: CCOCC
Solvent: ICI
Product: CCOC(=O)CC1(C)CC1
Temperature: 60 °C

Procedure:
Zn—Cu couple (10.726 g) suspended in diethyl ether (20 ml) was treated at RT under an argon atmosphere with CH2I2 (14.86 g) and 3-methyl-but-3-enoic acid ethyl ester (3.9 g) and heated in a closed reaction vial at 60° C. for 20 h. The mixture was then cooled to RT, AcOEt (50 ml) were added and reaction mixture was filtered. The filter cake was washed with AcOEt, the combined filtrates washed with water (125 ml), dried over MgSO4 and then evaporated (applying a 40 mbar vacuum). This gave the desired (1-methyl-cyclopropyl)-acetic acid ethyl ester (4.4 g) as a brown liquid that was essentially pure (according to NMR) and used directly in the next reaction step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H]>[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2=CCC3(CC2)OCCO3)cc1
Reactant: [H][H]
Agent: [Pd]
Product: Fc1ccc(C2CCC3(CC2)OCCO3)cc1

Procedure:
8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene is hydrogenated using Pd/C with hydrogen. After filtering-off of the catalyst over celite and evaporating-off of the solvent, 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decane is obtained in a quantitative yield: tR 3.65 min (LC-1); ESI-MS(+): m/z 237.26 [M+H]+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S([O-])(O)(=O)=O.[Na+]>CC(C)=O.O.C(OCC)(=O)C>[C:24]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2)([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1ccc2c(c1)CCC2)OCc1ccccc1
Reaction time: 1 h

Procedure:
Sodium bicarbonate 97.20 g) is added to a solution of 5-aminoindan (XVA, 5.71 g) in acetone (60 ml) and water (30 ml) 0°, followed by the dropwise addition of benzylchloroformate 96.8 ml, 8.07 g) over 5 min. The mixture is stirred at 0° for about 1 hr, then at 20°-25° overnight. The mixture is poured into aqueous sodium hydrogen sulfate (10%, 200 ml), and ethyl acetate (300 ml). The organic extract is washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The oil is purified by column chromatography on 60-200μ silica gel, eluting with ethyl acetate/hexane (10/90). The appropriate fractions are pooled and concentrated to give the title compound, mp 56°-59°; NMR (CDCl3, 300 MHz) 7.40-7.03, 7.11, 7.05, 6.65, 5.18, 2.85 and 2.05 δ; IR (mineral oil mull) 3275, 2925, 1693.5, 1544 and 1236 cm-1 ; MS (m/e) 267, 223, 222 and 91.
Reaction SMILES: C1[C:14]2[C:5](=C[C:7]3[C:12]([CH:13]=2)=CC=CC=3)C=CC=1.CI.[Mg].[CH:18]1[CH2:22][CH:21]=[CH:20][CH:19]=1.[Co+3:23].C/C(/[O-])=C/C(C)=O>C1COCC1>[CH:7]1[CH2:12][CH:13]=[CH:14][CH:5]=1.[CH:19]1([Co:23])[CH:18]=[CH:22][CH:21]=[CH:20]1
Reactant: [Co+3]
Reactant: c1ccc2cc3ccccc3cc2c1
Agent: C1=CCC=C1
Agent: CC(=O)/C=C(/C)[O-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CI
Product: [Co]C1C=CC=C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1.1 g (6.2 mMoles) of anthracene, 300 ml of THF and 0.1 ml of methyliodide are added with stirring in an inert gas atmosphere at 20° C. to 7.2 g (300 mMoles) of magnesium powder (particle size <0.15 mm). After about 2 hours, the reaction mixture is activated for about 3 hours in an ultrasonic bath (cf. Example 1). The mixture is then heated with stirring to 60° C. After the addition of 52.8 g (800 mMoles) of monomeric cyclopentadiene, the heat source is removed and 35.6 g (100 mMoles) of solid cobalt-(III)-acetylacetonate are added over a period of 30 minutes, the reaction mixture changing color to deep red-brown with a vigorous heat effect (65° C.). After cooling to 23° C., the reaction mixture is filtered off from any insoluble fractions through a G-3-glass frit and the deep red-brown filtrate is concentrated to dryness (max. bath temperature 30° C.) in vacuo (10-1Torr). The residue is taken up in 500 ml of pentane and any insoluble fractions eliminated by filtration. The clear deep red filtrate is concentrated to dryness (max. bath temperature 30° C.) in vacuo (10-1Torr) and the residue sublimated at 10-3Torr (bath temperature up to 60° C., sublimation beginning at a bath temperature of 30° C.). The sublimate is dissolved in approximately 100 ml of pentane and the complex crystallized out at -80° C. 11.9 g (62.6 mMoles=62.6% of the theoretical) of η5 -cyclopentadienyl cobalt cyclopentadiene are obtained in the form of wine-red crystals melting at 98° to 99° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[C:3]=1[C:4](OC)=O.C(O)(=O)C.[CH:20](N)=[NH:21]>COCCO>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:2]2[C:3]=1[CH2:4][NH:21][CH:20]=[N:1]2
Reactant: N=CN
Reactant: COC(=O)c1c(N)cc(OC)cc1OC
Solvent: COCCO
Solvent: CC(=O)O
Product: COc1cc2c(c(OC)c1)CNC=N2
Yield: 99.6 %

Procedure:
A mixture of methyl 2-amino-4,6-dimethoxybenzoate (16 g), formamidine acetate (24 g) and 2-methoxyethanol (330 ml) was stirred and heated to reflux until all of the starting material had reacted. The mixture was evaporated and the residue was triturated under water (100 ml). The resultant solid was isolated, washed with water and dried under vacuum to give 5,7-dimethoxy-3,4-dihydroquinazolin one (14.5 g); NMR Spectrum: (DMSOd6) 3.82 (s, 3H), 3.86 (s, 3H), 6.5 (s, 1H), 6.7 (s, 1H), 7.9 (s, 1H), 11.7 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Li]CCCC.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C1COCC1>[C:27]([C:26]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Brc1ccccc1P(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccccc1P(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of (2-bromophenyl)diphenylphosphine (II-a) (0.50 mmol) in dry THF (2 mL) was added dropwise under argon at −78° C. n-BuLi (0.55 mmol). The resulting solution was stirred at this temperature during one hour and pivaloyl chloride (0.80 mmol) was then added dropwise. After stirring at room temperature overnight, the reaction mixture was quenched with water (10 mL) and extracted with methylene chloride (3×10 mL). The organic phases were dried over MgSO4, filtered and the solvent evaporated giving a residue which was purified by column chromatography on silica gel using petroleum ether/ethyl acetate 3:1 as eluent. White solid; Yield 78%; Rf 0.43 (petroleum ether/ethyl acetate 3:1); IR (neat) 3049, 2967, 2928, 2867, 1686, 1585, 1477, 1458, 1431, 1389, 1361, 1283, 1192, 967, 947, 778, 741, 691 cm−1; 1H NMR (300MHz, CDCl3) δ 1.35 (s, 9H, CH3), 7.18-7.22 (m, 1H, Harom), 7.25-7.40 (m, 13H, Harom); 13C NMR (75.5 MHz, CDCl3) δ 27.7 (d, J=3.3 Hz, CH3), 44.7 (C(CH3)3), 124.8 (d, J=8.6 Hz, Carom), 128.3 (Carom), 128.5 (d, J=4.9 Hz, Carom), 128.7 (Carom), 133.3 (Carom), 133.5 (Carom), 134.6 (d, J=15.8 Hz, Carom), 134.8 (d, J=2.2 Hz, Carom), 137.0 (d, J=10.4 Hz, Carom), 148.0 (d, J=35.8 Hz, Carom); 31P NMR (121 MHz, CDCl3) δ −10.4; HRMS calcd for C23H23PONa [M+Na]+369.1379, found 369.1382.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:39])(=[O:38])[C@@H:31]([C@H:33]([C:35]([OH:37])=[O:36])[OH:34])[OH:32]>C(O)C>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([O-:39])(=[O:38])[C@@H:31]([C@H:33]([C:35]([O-:37])=[O:36])[OH:34])[OH:32]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CCO
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 25 °C

Procedure:
Sunitinib (1.35 g, 3.39 mmol) was dissolved in boiling ethanol (140 ml), to which a solution of L-tartaric acid (0.25 g in 10 ml ethanol) was added and left to cool to room temperature to give 1.78 g of sunitinib L-tartarate. Melting point: 233-235° C. (form IV), ratio sunitinib/tartaric acid (according to NMR) 2:1.
Reaction SMILES: [NH2:1][CH:2]([C:6]([CH3:9])([SH:8])[CH3:7])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[C:20]=1[CH2:21]O>C(Cl)Cl>[NH2:1][CH:2]([C:6]([CH3:9])([S:8][CH2:21][C:20]1[C:23]([O:29][CH3:30])=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:19]=1[O:18][CH3:17])[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(S)C(N)C(=O)O
Reactant: COc1cc(OC)c(CO)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(CSC(C)(C)C(N)C(=O)O)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A suspension of 2-amino-3-methyl-3-sulfanylbutanoic acid (D-penicillamine) (5.0 g, 34 mmol) in CH2Cl2 (150 mL) was cooled to 0° C. Trifluoroacetic acid (54 mL, 703 mmol) was added dropwise over a period of 5 minutes. Then 2,4,6-trimethoxybenzyl alcohol (6.64 g, 34 mmol) in CH2Cl2 (137 mL) was added dropwise at 0° C. with stirring. Stirring was continued for 1 hour at 0° C. and 2 hours at room temperature. The solvent was removed in vacuo and the residue was dried under high vacuum for 3 hours. The crude red solid was recrystallized from 1:1:1 CH2Cl2/MeOH/EtOAc to give the title compound as a white solid (10.5 g, 95%). 1H NMR (300 MHz, CDCl3) δ6.10 (s, 2H), 3.84 (s, 6H), 3.76 (s, 3H), 3.40-4.10 (m, 3H), 1.69 (s, 3H), 1.23 (s, 3H). LRMS (EI) m/z 330 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3Cl)[F:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34].C[O-].[Na+:38]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[F:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:38]
Reactant: O=C(NCC(F)c1ccc(Cl)cc1Cl)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NCC(F)c1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of 6-chloro-7-(4-(2-(2,4-dichlorophenyl)-2-fluoroethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.122 g, 0.226 mmol) in methanol (2 ml) was added 0.5 M sodium methanolate in methanol (0.476 ml, 0.238 mmol), and the reaction was stirred overnight. The reaction was concentrated, taken up in dichloromethane and hexanes, and concentrated again to yield 122 mg of the title compound as a white solid (96.1% yield). MS (apci) m/z=537.7 (M-Na+2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:2]1=2.[C:11](Cl)(Cl)=[O:12]>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][CH2:7][CH2:8][CH:9]([N:10]=[C:11]=[O:12])[C:2]1=2
Reactant: NC1CCCc2ccsc21
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=NC1CCCc2ccsc21

Procedure:
A six gram sample of 4,5,6,7-tetrahydrobenzo[b]thiophen-7-amine is stirred in 20 ml. of toluene at 100° C. and phosgene is slowly introduced into the mixture through a gas tube. The flow of phosgene is terminated after most of the solid amine hydrochloride disappears. The mixture is then filtered and the filtrate is evaporated to dryness to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O)[CH3:2].C(O)(=O)C.O.[NH2:30][NH2:31].C([O-])(O)=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:31][N:30]=1)=[O:24])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Yield: 100 %

Procedure:
To a solution of 1-(2-hydroxy-phenyl)-ethanone (5 g, 0.03672 mole) in DMF (75 mL) was added NaH (60% w/w dispersion in oil) (1.66 g, 0.0416 mole) and the resulting mixture was stirred at ambient temperature for 15 minutes. Benzyl bromide (7.23 g, 0.0422 mole) was then added and the mixture as stirred for an additional 4 hours. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 8.4 g (100%) of 1-(2-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 84.14%. To a mixture of THF (200 mL) and NaH (60% w/w dispersion in oil) (4.4 g, 0.11 mole) cooled to 0° C. was added diethyl oxalate (10.73 g, 0.07345 mole). The resulting mixture was heated to reflux for 15 minutes. After cooing to ambient temperature, 1-(2-benzyloxy-phenyl)-ethanone (8.3 g, 0.0376 mole) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 8.7 g (71%) of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 78.6%. A solution of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.75 g, 0.01149 mole), acetic acid (20 mL) and hydrazine hydrate (0.632 g, 0.01264 mole) was heated to reflux for 3 hours. The reaction mixture was then poured into iced water basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 3.703 g (100%) of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 97.14%.
Reaction SMILES: Cl.F[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:11][OH:12].[OH-].[K+]>>[F:9][C:7]1[CH:6]=[CH:5][C:4]2[C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:11][O:12][C:3]=2[CH:8]=1
Reactant: ON=C(c1ccc(F)cc1F)C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Fc1ccc2c(C3CCNCC3)noc2c1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
2,4-difluorophenyl-(4-piperidinyl)-methanone oxime hydrochloride (5.52 g, 20 mmol) is added to 25 ml of 50% potassium hydroxide; reflux for 4 hours, cooled to room temperature, and extracted with toluene (25 ml×2). The combined organic phases are dried over anhydrous magnesium sulfate, filtered, evaporated to dryness under reduced pressure, and recrystallized in diethyl ether, to obtain 3.3 g of a product, with a yield of 75%.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([C:17]2[O:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)[CH:14]=[CH:15][CH:16]=1.FC1C=C(C(=O)C)C=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:58][CH2:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:77])[F:76])[CH:70]=2)[CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[O:61]=[C:60]([N:62]1[CH2:63][CH2:64][CH:65]([O:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:76])[F:77])[CH:70]=2)[CH2:66][CH2:67]1)[CH2:59][NH:58][C:22]([C:19]1[CH:18]=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=2)[O:21][N:20]=1)=[O:24]
Reactant: O=C(O)c1cc(-c2cccc(F)c2)on1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Agent: CC(=O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2cccc(F)c2)on1
Reaction time: 8 h
Yield: 58.9 %

Procedure:
DIPEA (131 mg, 1.0 mmol) was added to a stirred solution of 5-(3-fluoro-phenyl)-isoxazole-3-carboxylic acid (60 mg, 0.29 mmol) (prepared by the method used for the synthesis of Intermediate 25, starting from 3′-fluoroacetophenone) in DMF (2 mL) followed by HOBt (41 mg, 0.3 mmol) and EDCI.HCl (58 mg, 0.3 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (125 mg, 0.37 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by recrystallisation from methanol afforded 84 mg (59.15% Yield) of 5-(3-fluoro-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 492, 70.25%. 1H NMR (300 MHz, DMSO-d6): δ8.6 (t, 1H), 7.8 (m, 2H), 7.5 (m, 3H), 7.24 (m, 4H), 4.7 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:34][CH2:35][N:36]([CH3:79])[C:37](=[O:78])[C:38]1[CH:77]=[CH:76][CH:75]=[C:40]([C:41]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:55][CH2:54]C[CH2:52][CH2:51]3)=[CH:46][C:45]=2[C:56]2[CH:61]=[C:60]([C:62](=[O:74])[NH:63][C@@H:64]3[C:73]4[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=4)[CH2:67][CH2:66][CH2:65]3)[CH:59]=[CH:58][N:57]=2)=[O:42])[CH:39]=1)=[O:28].C(N(CC)C1C=CC(NC(=O)C2C=CC=C(C(N(C)CC=O)=O)C=2)=C(C2C=C(C(=O)N[C@@H]3C4C(=CC=CC=4)CCC3)C=CN=2)C=1)C.C(N)(=O)C1C=CC=C(C(N)=O)C=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:34][CH2:35][N:36]([CH3:79])[C:37](=[O:78])[C:38]1[CH:77]=[CH:76][CH:75]=[C:40]([C:41]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]([CH2:55][CH3:54])[CH2:51][CH3:52])=[CH:46][C:45]=2[C:56]2[CH:61]=[C:60]([C:62](=[O:74])[NH:63][C@@H:64]3[C:73]4[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=4)[CH2:67][CH2:66][CH2:65]3)[CH:59]=[CH:58][N:57]=2)=[O:42])[CH:39]=1)=[O:28]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCNC(=O)[C@@H]1CCCN1CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CC=O)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: NC(=O)c1cccc(C(N)=O)c1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCC[C@H]3C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOC)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of N1-(2-((S)-2-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-ylcarbamoyl)pyrrolidin-1-yl)ethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide Example 195, using (S) —N1-(4-(diethylamino)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)-N3-methyl-N3-(2-oxoethyl)isophthalamide in place of (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide. MS (ES, m/z): 1082.52 [M+H]+.