Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([S:12][CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[NH:11][C:6]2=[CH:5][CH:4]=1.N[C@@H]1C2C(=CC=CC=2)C[C@@H]1[OH:34].[O-]O.C1(C(C)C)C=CC=CC=1>CN(C=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:23][C:17]1[C:18]([O:21][CH3:22])=[C:19]([CH3:20])[C:14]([CH2:13][S@@:12]([C:10]2[NH:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:8][C:7]=3[N:9]=2)=[O:34])=[N:15][CH:16]=1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2n1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2n1
Temperature: 22 °C

Procedure:
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]imidazo[4,5-b]pyridine (100 mg, 0.303 mmol) is solubilised in anhydrous DMF (0.65 mL). Titanium isopropoxide (IV) (22 μl, 0.076 mmol) and (1R,2S)-(+)-1-amino-2-indanol (22.8 mg, 0.151 mmol) in anhydrous DMF are added under stirring at 22° C., followed by cumene hydroperoxide (80%, 65 μL, 0.352 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.[CH2:22](I)[CH:23]=[CH2:24]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH2:24]([N:9]1[C:10]2[C@@:11]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@H:14]([CH2:13][CH2:12]3)[C:15]=2[C:16](=[O:17])[N:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH:23]=[CH2:22]
Reactant: C=CCI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c2c(c(=O)n1-c1ccccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
A mixture of a (4S,7R)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 12; 150 mg, 0.52 mmol) and allyl iodide (100 μL, 1.1 mmol) in N,N-dimethylformamide (2 mL) in a microwave reaction tube was heated to 100° C. and stirred for 18 h. The reaction mixture was allowed to cool, diluted with saturated sodium bicarbonate, and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO CombiFlash® Sg100c chromatography system with an Isco 12 g column, eluting with 25-100% ethyl acetate/hexanes to give (4S,7R)-1-allyl-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (56 mg, 33%) as an orange solid. ES(+)-MS (M+H) 327.
Reaction SMILES: C=C(O[C:5](=[O:13])[NH:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)C.C1CCN2[C:17](=[N:18]CCC2)[CH2:16][CH2:15]1.C(N)C#C>O1CCOCC1.[Cl-].[Na+].O>[CH2:17]([NH:18][C:5]([NH:6][CH:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)=[O:13])[C:16]#[CH:15]
Reactant: C1CCC2=NCCCN2CC1
Reactant: C=C(C)OC(=O)NC1CCOCC1
Agent: C#CCN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C#CCNC(=O)NC1CCOCC1
Temperature: 90 °C
Yield: 81 %

Procedure:
A solution of prop-1-en-2-yl(tetrahydro-2H-pyran-4-yl)carbamate (0.50 g, 2.70 mmol) in dioxane (20 mL) was treated with DBU (0.1 mL) and propargylamine (0.149 g, 2.70 mmol) and heated at 90° C. overnight. The mixture was cooled to RT, treated with brine and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated to dryness, treated with Et2O and the resulting solid collected via filtration to afford 1-(prop-2-yn-1-yl)-3-(tetrahydro-2H-pyran-4-yl)urea (400 mg, 81%). 1H NMR (400 MHz, DMSO-d6): δ 6.00 (m, 1 H), 5.99 (m, 1 H), 3.76 (m, 2 H), 3.75 (m, 2 H), 3.56 (m, 1 H), 3.30 (m, 2 H), 3.02 (t, J=2.5 Hz, 1 H), 1.68 (m, 2 H), 1.29 (m, 2H); MS (ESI) m/z: 183.1 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1([C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][NH:17][S:18]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)(=[O:20])=[O:19])[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]=O>CO.[Pd]>[CH2:1]([C:8]1([C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][NH:17][S:18]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)(=[O:20])=[O:19])[CH2:12][CH2:11][N:10]([CH3:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(S(=O)(=O)NCc2cccc(C3(Cc4ccccc4)CCNC3)c2)cn1
Reactant: C=O
Agent: [Pd]
Solvent: CO
Product: CN1CCC(Cc2ccccc2)(c2cccc(CNS(=O)(=O)c3cnn(C)c3)c2)C1
Yield: 37.1 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-4-sulfonic acid 3-(3-benzyl-pyrrolidin-3-yl)benzylamide (example 67, 108 mg, 0.26 mmol) and formaldehyde (37% in water, 0.2 ml, 2.6 mmol) in methanol (10 ml) was added palladium on charcoal (10%, 10 mg). Hydrogenation was performed at room temperature over night. The mixture was filtered and the solvent evaporated. The residue was diluted with dichloromethane, extracted with water, dried over Na2CO3. The solvent was evaporated to give 41 mg of product. Re-extraction of the aqueous layer afforded further 38 mg of product as a clear oil.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]1[C:9]([O:11][C:12](=[O:13])[CH:2]21)=O.[NH2:14][CH:15]([C:19]([OH:21])=[O:20])[CH:16]([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>O>[C:19]([CH:15]([N:14]1[C:12](=[O:13])[CH:2]2[CH:3]([CH:4]3[CH2:7][CH2:8][CH:1]2[CH:6]=[CH:5]3)[C:9]1=[O:11])[CH:16]([CH3:18])[CH3:17])([OH:21])=[O:20]
Reactant: CC(C)C(N)C(=O)O
Reactant: O=C1OC(=O)C2C3C=CC(CC3)C12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)C(C(=O)O)N1C(=O)C2C3C=CC(CC3)C2C1=O
Temperature: 25 °C
Yield: 55 %

Procedure:
To a suspension of bicyclo[2.2.2]oct-5-en-2,3-dicarboxylic anhydride (2.01 g, 11.3 mmol) in H2O (25 mL) was added (dl)-valine (1.58 g, 13.5 mmol) and a solution of K2CO3 (934 mg, 6.8 mmol) in H2O (3 mL). The mixture was heated to reflux temperature and allowed to react for 4 hrs. After cooling to room temperature, the mixture was washed with EtOAc, acidified with conc. HCl until the pH reached 1 and extracted with EtOAc. The organic layer was washed with 5% HCl followed by brine and then dried over Na2SO4. Removal of the solvent gave a beige solid which was recrystallized from EtOAc/hexane to yield the product as off-white crystals: 1.72 g (55% yield), mp=156° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)(=[O:3])[CH3:2].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1CC([O-])=O.[OH-].[Na+].Cl>CO>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:2]1[C:1](=[O:3])[O:4][CH2:5][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)OCC(=O)c1ccccc1
Reactant: O=C([O-])Cc1nc2ccccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1OCC(c2ccccc2)=C1c1nc2ccccc2s1
Temperature: 25 °C

Procedure:
A solution of 2-acetoxyacetophenone (from Example 1) (8.9 g, 0.05M) and α-(benzothiazol-2-yl)-acetate (from Example 3) dissolved in methanol (40 mL) by stirring at room temperature was treated at room temperature with a solution prepared by dissolving sodium hydroxide pellets (2.5 g) in methanol (30 mL) by stirring. A slight exothermic reaction was observed. After being stirred at about room temperature for about 1.0 hour, the reaction mixture was acidified to a pH of about 4 by the dropwise addition of concentrated HCl. The product which was a dark brown colored semi-crystalline mass was washed by decantation and dried in air (yield--12.0 g (81.9% of the theoretical yield). Mass spectrometry indicated that the product largely consisted of the following desired compound: ##STR16##
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([OH:30])=[CH:25][C:24]=3[Cl:31])=[O:15])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:35][CH2:36][OH:37]>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:35][CH2:36][OH:37])=[CH:25][C:24]=3[Cl:31])=[O:15])[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(O)cc1Cl)N1CCN(C2CC2)c2ccccc21
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cnccc1Oc1cc(Cl)c(OCCO)cc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
To a solution of 0.15 g (0.33 mmol) (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone (Example 57) in 2 mL N,N-dimethylformamide was added 0.016 g (0.37 mmol) sodium hydride (60% dispersion in mineral oil, Aldrich). The reaction mixture was stirred for 15 min. at room temperature before 0.03 mL (0.36 mmol) 2-bromoethanol (commercially available, CAS RN 540-51-2) were added. After stirring for 3 hours at room temperature another 0.03 mL (0.36 mmol) 2-bromoethanole were added. After 72 hours the reaction mixture was poured on water and was extracted three times with ethyl acetate. The organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 25:75) to give 0.075 g (46%) of the title compound as a light brown foam. MS (ESI): m/z=500.113 [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][C:18]3[O:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:4]=12)[NH2:2].C([N:25]1[C:29]2=NC=[C:32](C(OCC)=O)[C:33](NN)=[C:28]2C=N1)C>>[CH2:17]([N:14]1[C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:11])[NH:25][C:29]4[N:1]([N:2]=[C:33]([CH3:32])[CH:28]=4)[C:3]=3[C:4]=2[CH:16]=[N:15]1)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1NN
Product: Cc1cc2[nH]c(=O)c3cnc4c(cnn4Cc4ccco4)c3n2n1

Procedure:
By substituting 4-hydrazino-1-furfurylpyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in Example 1 a and proceeding as in parts a and b, 8-furfuryl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained. This compound is now processed as in Example 1, part c, substituting bromobenzene for the methyl iodide. A small amount of copper catalyst is added to obtain 1-furfuryl-1-methyl-4-phenyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido-[3,4-e]pyrimidin-5(8H)-one.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CN(C)C=O.[Cl:14][C:15]1[N:20]=[N:19][C:18]([O:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH:29]2[CH2:31][CH2:30]2)=[C:17]([OH:32])[CH:16]=1.Cl>O>[Br:1][C:16]1[C:17]([OH:32])=[C:18]([O:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH:29]2[CH2:31][CH2:30]2)[N:19]=[N:20][C:15]=1[Cl:14]
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)c(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
108 mg (0.607 mmol) of N-bromosuccinimide was added to a N,N-dimethylformamide (2 mL) solution containing 157 mg (0.567 mmol) of 6-chloro-3-(2-cyclopropyl-6-methyl-phenoxy)-4-pyridazinol, and the resulting mixture was stirred at room temperature for 3 hours and 30 minutes. Water, and then, 4 mol/L hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO. 1.05744, developed by hexane:ethyl acetate=2:1) to obtain 123 mg (0.346 mmol, Yield: 61.0%) of 5-bromo-6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (Compound No. 3843).
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=[CH:10][CH:9]1[OH:22])(=[O:3])[CH3:2].[N+](=[CH2:30])=[N-].N(CNC(N)=O)=O.[OH-].[K+]>C(O)(=O)C.C(OCC)C>[C:1]([O:4][C@@H:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:30])=[O:20])[CH:11]=[CH:10][CH:9]1[OH:22])(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CCCCC[C@@H](/C=C/[C@H]1C(O)C=C[C@@H]1C/C=C\CCCC(=O)O)OC(C)=O
Agent: NC(=O)NCN=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCC[C@@H](/C=C/[C@H]1C(O)C=C[C@@H]1C/C=C\CCCC(=O)OC)OC(C)=O

Procedure:
to a solution of 8 parts of (5Z,13E,15S)-15-acetyloxy-11ξ-hydroxyprosta-5,9,13-trien-1-oic acid in 175 parts of diethyl ether is added an ethereal solution of diazomethane prepared from 30 parts of N-nitrosomethylurea, 90 parts of aqueous 40% potassium hydroxide, and 210 parts of diethyl ether as described in Org. Syn., 15, 4 (1935). The resultant mixture is allowed to stand at 5° for 30 minutes, whereupon 2 parts of acetic acid is introduced and the mixture thus obtained extracted with diethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residual red oil is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvents. From an eluate comprising 30% ethyl acetate in benzene, on evaporation of solvent, methyl (5Z,13E,15S)-15-acetyloxy-11ξ-hydroxyprosta-5,9,13-trien-1-oate is obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:9][CH2:10][C:11]=1[O:12][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
4-Oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (30.9 g, 114 mmol) was dissolved in CH2Cl2 (800 mL). DIPEA (48.7 mL, 285 mmol) was added, and the reaction mixture was cooled to −78° C. A sol. of Tf2O (24.4 mL, 148 mmol) in CH2Cl2 (25 mL) was added slowly, while maintaining the temperature at −78° C. The mixture was stirred for 30 min at −78° C. The mixture was allowed to warm to rt, and aq. 10% Na2CO3 (400 mL) and ice were added. The layers were separated and the aq. layer was extracted with CH2Cl2 (2×). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane→EtOAc/heptane 25:75) yielded the title compound (44.0 g, 91%). LC-MS: tR=1.05 min; ES+: 404.44.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([Cl:46])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.Br[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55][CH2:56][NH:57][C:58](=[O:60])[CH3:59]>>[C:58]([NH:57][CH2:56][CH2:55][CH2:54][C:49]1[CH:48]=[CH:53][CH:52]=[CH:51][C:50]=1[C:28]1[CH:29]=[CH:30][C:25]([CH:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][O:4][C:3]3[C:2]([Cl:1])=[CH:44][C:43]([CH3:45])=[CH:42][C:41]=3[Cl:46])=[CH:13][CH:12]=2)[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[C:26]([CH3:40])[CH:27]=1)(=[O:60])[CH3:59]
Reactant: CC(=O)NCCCc1ccccc1Br
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Product: CC(=O)NCCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and N-[3-(2-bromophenyl)propyl]acetamide (V.15) as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 100% in 15 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(O)(=O)C1C(=CC=CC=1)C(O)=[O:16].C1(=O)OC(=O)C2=CC=CC=C12>Cl>[OH:16][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Agent: O=C1OC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1O
Yield: 70 %

Procedure:
To a flask was added 50 mL of 2N hydrochloric acid, and powdery phthalimide (7.4 g, 0.05 mol) was slowly added thereto with stirring. Then, the mixture was stirred at 97° C. for 3 hours to obtain an aqueous solution containing phthalic acid. Phthalic acid was recovered by condensing and filtering the aqueous solution. Then, to a flask, were added the phthalic acid, 100 mL of pyridine and 0.5 g of sulfuric acid, and stirred for 3 hours at 100° C. with distilling off water formed by reaction to obtain a mixture containing phthalic anhydride. Hydroxylamine hydrochloride NH2OH.HCl (6.9 g, 0.1 mol) was added to the mixture and stirred at 50° C. for 3 hour to form N-hydroxyphthalimide (5.74 g, yield 70%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[O:6][C:5]1=[O:13].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C(#N)C>[N:14]1([CH2:2][CH2:3][N:4]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:7]3[O:6][C:5]2=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: O=c1oc2cccnc2n1CCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=c1oc2cccnc2n1CCN1CCCCC1
Reaction time: 12 h

Procedure:
0.01 mol of 3-(2-bromoethyl)-3H-oxazolo[4,5-b]pyridin-2-one, dissolved in acetonitrile, 0.15 mol of piperidine and 0.015 mol of diisopropylethylamine are introduced into a round-bottomed flask placed under argon and surmounted by a condenser. The mixture is brought to 80° C. for 12 hours. It is cooled, the acetonitrile is evaporated off under vacuum and the residue is taken up with water. The alkalinity of the medium is checked and the medium is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated and the residue is recrystallized.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([NH:64][N:65]2[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]2)=[O:39])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN1CCN(N)CC1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)O)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)NN2CCN(C)CC2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 72.8 %

Procedure:
To a solution of 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-(5-carboxypent-1-yl)oxy-4-methylphenyl]benzamide (250 mg) and N-methylmorpholine (37 mg) in dichloromethane (5 ml) was added pivaloyl chloride (45 mg) at -15° C. After being stirred at the same temperature for 5 minutes, to the mixture was added 1-amino-4-methylpiperazine (47 mg) and the mixture was stirred at -15° C. for 1 hour and then stirred at ambient temperature for additional 2 hours. The resulting mixture was poured into saturated aqueous sodium hydrogen carbonate solution (20 ml) and the solution was extracted with chloroform (15 ml×3). The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified on silica gel column chromatography (SiO3 30 g, 1-15% methanol in chloroform) to give 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(4-methylpiperazine-1-yl)aminocarbonylpent-1-yl]oxy-4-methylphenyl]benzamide (208 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O1CCCC1.O>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cc(C(=O)O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(=O)O)ccc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-amino-4-fluorobenzoic acid (30 g, 193 mmol) in a mixture of tetrahydrofuran (300 mL) and water (300 mL) was added cesium carbonate (157 g, 483 mmol) and benzyl chloroformate (30.4 mL, 213 mmol). This mixture was stirred at ambient temperature for 16 hours, and was concentrated to about 200 mL. The residue was acidified with 2N HCl to a pH 3, and was partitioned between ethyl acetate and brine. The precipitated solid was collected by filtration, washed with ethyl acetate and water, and dried to provide the title compound. MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1C=CC=CC=1.[NH2+]1CCCCC1.O.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:9]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:2][C:1]1=[O:8]
Reactant: O=C([O-])c1ccccc1
Reactant: c1ccccc1
Agent: C1CC[NH2+]CC1
Solvent: O
Product: O=C1Cc2ccccc2O1

Procedure:
A mixture of 9.1 g (0.05 mole) of 4-methyl-3-(3-oxobutyl)-maleic acid anhydride and 11 g (0.053 mole) of piperidinium benzoate in 200 ml of benzene is heated under reflux for 48 hours using a water separator. The benzene is removed in vacuo and the residue that remains is partitioned between methylene chloride and saturated sodium bicarbonate solution. The crude product remaining after drying and after removal of the methylene chloride is chromatographed over silica gel with petroleum ether/ether. Subsequent recrystallisation from ether/petroleum ether yields 3-methyl-6-(piperidin)-1-yl)-benzofuran-2(3H)-one having a melting point of 78°-80° C.