Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:38][C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]
Reactant: CCN(CC)C(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Nc1ccc(Oc2ncnc3cc(OCc4ccncc4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-diethylurea, 83 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine hydrochloride (49 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC to give 57 mg (yield 56%) of the title compound.
Reaction SMILES: CN1C(NCCCNC2C=CC([N+:19]([O-:21])=[O:20])=CC=2)=CC(=O)N(C)C1=O.[CH3:25][N:26]1[C:31]([NH:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+]([O-])=O)=[CH:40]C=2)=[CH:30][C:29](=[O:47])[N:28]([CH3:48])[C:27]1=[O:49]>>[CH3:25][N:26]1[C:31]([NH:32][CH2:33][CH2:34][NH:35][CH2:36][C:37]2[CH:38]=[CH:43][C:42]([N+:19]([O-:21])=[O:20])=[CH:41][CH:40]=2)=[CH:30][C:29](=[O:47])[N:28]([CH3:48])[C:27]1=[O:49]
Reactant: Cn1c(NCCNCCc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Reactant: Cn1c(NCCCNc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Product: Cn1c(NCCNCc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O

Procedure:
The same procedure as in Example 2 was repeated with the exception that 1,3-dimethyl-6-(piperazin-1-yl)-2,4-(1H,3H)-pyrimidinedione (compound 2) was replaced with 0.45 g of 6-(2-aminoethylamino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 13), in order to obtain 1,3-dimethyl-6-[2-(4-nitrobenzylamino)ethylamino]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: B.CSC.[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15](O)=[O:16])[CH:10]=[C:11]([F:13])[CH:12]=1>C1COCC1>[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][OH:16])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: O=C(O)Cc1cc(F)cc(CBr)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1cc(F)cc(CBr)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Borane-methyl sulfide complex (2M in THF, 17.4 mL) was added dropwise over 10 minutes to a solution of 2-(3-(bromomethyl)-5-fluorophenyl)acetic acid (example 41, step a) (4.3 g) in THF (60 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and then at 20° C. for 1 hour. The reaction mixture was quenched by dropwise addition of methanol and the solvents were removed under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 3.7 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[C:15]3[C:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][N:8]2[C:22](=[O:25])[C:23]=1[OH:24])=O.C[O-].[Na+].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CO>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:3]([C:5]2[N:6]=[C:7]3[C:15]4[C:14]([N:16]5[CH2:17][CH2:18][O:19][CH2:20][CH2:21]5)=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][N:8]3[C:22](=[O:25])[C:23]=2[OH:24])=[O:2])=[CH:32][CH:31]=1
Reactant: COC(=O)c1nc2c3c(N4CCOCC4)cccc3[nH]n2c(=O)c1O
Reactant: NCc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc2c3c(N4CCOCC4)cccc3[nH]n2c(=O)c1O
Temperature: 25 °C
Yield: 38.4 %

Procedure:
The product from Example 21.2 (172 mg, 0.5 mmol), sodium methoxide (54 mg, 1.0 mmol) and 4-fluoro benzylamine (1.87 mg, 1.5 mmol) in methanol (15 mL) were combined and heated with stirring at reflux overnight. The mixture was cooled to room temperature and the resulting solid was collected by filtration and dissolved in dichloromethane (30 mL). The solution was washed with aqueous hydrochloric acid (2.0 M), water, dried and concentrated in vacuo to afford desired compound (84 mg, 38.4).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]([CH2:13][CH:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([CH2:13][CH:14]([C:15]([O:17][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:16])[CH2:18][CH3:19])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(Cc1ccc(C(=O)OC(C)(C)C)s1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(Cc1ccc(C(=O)OC(C)(C)C)s1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
2-(5-tert-Butoxycarbonylthiophen-2-yl)methyl-butanoic acid (20.6 g, 72.2 mmol) was dissolved in N,N-dimethylformamide (100 mL), potassium carbonate (10.4 g, 75.3 mmol) and benzyl bromide (13.0 g, 76.0 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. 0.5 N-Hydrochloric acid solution and ethyl acetate were added to the obtained residue, the organic layer was extracted, and the aqueous layer was extracted three times with ethyl acetate. The organic layers were collected, washed with brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent of the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (27.0 g, 72.1 mmol, 96%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:14][C@H:13]2[CH3:26])=[N:4][N:3]=1.[C:27]1([CH3:36])[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)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>[CH3:26][C@H:13]1[N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:30]3[CH:31]=[CH:32][C:27]([CH3:36])=[CH:28][CH:29]=3)=[N:3][N:4]=2)[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:14]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nnc(N3CCN(C(=O)c4ccccc4)C[C@H]3C)c3ccccc23)cc1
Temperature: 100 °C
Yield: 86.3 %

Procedure:
Compound 20 was prepared as described generally in synthetic Method D. Substrate JK-5 was prepared as described in detail in Example 11. To a reaction flask was added (R)-(4-(4-chlorophthalazin-1-yl)-3-methylpiperazin-1-yl)(phenyl)methanone (JK-5) (200 mg, 0.54 mmol), p-tolyl boronic acid (111 mg, 0.82 mmol, 1.5 eq), and Pd(PPh3)4 (31 mg, 0.027 mmol, 0.05 eq). The flask was fitted with a reflux condenser and purged with nitrogen. Toluene (5.4 mL) and aqueous Na2CO3 (2 M, 0.54 mL, 2 eq) were added and the reaction was heated to 100° C. overnight. The reaction was then cooled to rt and diluted with 75 mL of ethyl acetate. The organic phase was washed with 1×10 mL of sat. NaHCO3 solution, 1×10 mL of H2O, and 1×10 mL of sat. NaCl solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography (60% ethyl acetate in hexanes) afforded 197 mg (86%) of (R)-(3-methyl-4-(4-p-tolylphthalazin-1-yl)piperazin-1-yl)(phenyl)methanone 20 MS (M+H)+=423.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH:27](OCC)OCC)[CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9](=[CH:27][N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: CCOC(OCC)N1CCOCC1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Br)ccc2N1
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2Cl)=NC1=CN1CCOCC1
Temperature: 140 °C

Procedure:
A mixture consisting of 5 gm of 7-bromo-5-(2'-chloro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 17 ml of morpholino-diethoxy-methane was heated for 90 minutes at 140°C, while stirring, and the reaction mixture was then allowed to cool. The cool product was admixed with 150 ml of petroleum ether (b.p. 60°-80°C), the mixture was briefly brought to the boiling point, allowed to cool, and the crystalline substance which had separated out was collected by vacuum filtration and recrystallized from isopropanol, yielding the compound named in the heading, which decomposed slowly between 156° and 185°C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:3].[C:12]1([S:18]([N:21]2[C:29]3[CH:28]=[C:27]([Sn:30]([CH3:33])([CH3:32])[CH3:31])[CH:26]=[C:25]([NH2:34])[C:24]=3[CH:23]=[N:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][CH:2]([N:4]1[C:8]([C:9]([NH:34][C:25]2[CH:26]=[C:27]([Sn:30]([CH3:33])([CH3:32])[CH3:31])[CH:28]=[C:29]3[C:24]=2[CH:23]=[N:22][N:21]3[S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:3]
Reactant: CC(C)n1nccc1C(=O)Cl
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)n1nccc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
1-(1-Methylethyl)-1H-pyrazole-5-carbonyl chloride (152 mg) in DCM (10 ml) was added dropwise to 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (350 mg) in DCM (15 ml) and pyridine (0.07 ml). The reaction was stirred at room temperature for 10 min before addition of further 1-(1-methylethyl)-1H-pyrazole-5-carbonyl chloride (10 mg). The reaction was stirred for 30 min, saturated sodium bicarbonate (aq) (25 ml) was added and stirred vigorously for 10 min before the DCM was separated through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DCM and loaded onto a silica cartridge preconditioned with cyclohexane. The cartridge was eluted with 0-100% ether in cyclohexane. The compound containing fraction was evaporated to dryness to give title compound, 360 mg.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCOCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(morpholin-4-yl-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C28H27N3O4
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:15])=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-:3])=[O:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>CN(C)C1C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[N+:1]([C:4]1[C:5]([NH:15][C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:23])=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-:3])=[O:2]
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1N
Reactant: O=C(Cl)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1NC(=O)c1ccncc1
Yield: 19 %

Procedure:
To a solution of ethyl 3-nitro-2-aminobenzoate (700 mg) in N,N-dimethylaniline (7 ml) was added dropwise isonicotinoyl chloride (2.96 g) at 120° C. for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate and saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give ethyl 3-nitro-2-(4-pyridyl)carbonylaminobenzoate (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:16]3(C(O)=O)[CH2:18][CH2:17]3)[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1(P([N:36]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1COCC1>[NH2:36][C:16]1([C:12]2[CH:11]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)[CH:15]=[N:14][CH:13]=2)[CH2:18][CH2:17]1
Reactant: N#Cc1ccc(-c2cncc(C3(C(=O)O)CC3)c2)cc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2cncc(C3(N)CC3)c2)cc1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)cyclopropanecarboxylic acid (900 mg, 3.01 mmol) in toluene (50 mL) was added TEA (0.63 mL, 4.52 mmol) and diphenylphosphoryl azide (0.977 mL, 4.52 mmol), and the mixture was heated to 100° C. for 4 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was re-dissolved in THF (100 mL) and a solution of KOtBu (2.03 g, 18.08 mmol) in THF (40 mL) was added. The mixture was stirred at 0° C. for 1 h. The mixture was then warmed to room temperature overnight. Silica gel (10 g) was added and the mixture was concentrated in vacuo. The residue was purified by silica chromatography eluting with a 0-10% MeOH-DCM gradient to give 4-(5-(1-aminocyclopropyl)pyridin-3-yl)-2-chlorobenzonitrile. m/z 270.0, 272.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2].[F:17][C:18]([F:29])([F:28])[C:19]1[C:24]([CH:25]=[CH2:26])=[CH:23][N:22]=[C:21]([CH3:27])[CH:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:26][CH2:25][C:24]3[CH:23]=[N:22][C:21]([CH3:27])=[CH:20][C:19]=3[C:18]([F:29])([F:17])[F:28])[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: C=Cc1cnc(C)cc1C(F)(F)F
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCc1ccc2c(c1)c1c(n2CCc2cnc(C)cc2C(F)(F)F)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 8-ethyl-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>>[O:27]=[C:25]1[NH:24][C:23](=[O:28])[C:22](=[CH:21][C:20]2[CH:29]=[CH:30][C:31]([N:32]3[CH2:37][CH2:36][CH:35]([NH:1][CH2:2][CH:3]([C:5]4[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=4)[OH:4])[CH2:34][CH2:33]3)=[C:18]([F:17])[CH:19]=2)[S:26]1
Reactant: O=C1CCN(c2ccc(C=C3SC(=O)NC3=O)cc2F)CC1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(=O)NC4=O)cc3F)CC2)ccc1O

Procedure:
The title compound was prepared from N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) and 5-[3-fluoro-4-(4-oxo-piperidine-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 62) according to the procedure of Example 63 as a yellow solid; mp >225° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.62-1.71 (m, 2H), 2.03-2.12 (m, 2H), 2.70-2.83 (m, 3H), 2.95 (s, 3H), 3.12-3.33 (m, 2H), 3.49-3.52 (m, 2H), 4.72-4.75 (m, 1H), 5.96 (brs, 1H), 6.89 (d, J=8.1 Hz, 1H), 7.05-7.13 (m, 3H), 7.25-7.38 (m, 3H), 8.70 (brs, 1H), 9.8 (brs, 1H); MS (ES) m/z: 551.0 (MH+); HRMS for C24H27FN4O6S2 (MH+): 551.1434. Found: 551.1438.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13].[OH:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])[O:15][CH2:16][CH2:17][OH:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1OCCCl
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCO)cc1OCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 2-(2-chloroethoxy)-4-fluoro-1-nitro-benzene (91.3 g, 6 mmoles), 2-hydroxyethanol (0.57 g, 7.2 mmoles), and cesium carbonate (2.34 g, 7.2 mmoles) in DMF were stirred together at room temperature for 1 hour, diluted with water and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum to afford the title compound (0.63 g, 2.4 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][C@@H:13]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:12]3)[C:4]=2[CH:3]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:33])[C@@H:13]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:12]3)[C:4]=2[CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc2c(c1)C(N1CCN[C@@H](CCc3ccccc3)C1)=Nc1ccccc1N2
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc2c(c1)C(N1CCN(C)[C@@H](CCc3ccccc3)C1)=Nc1ccccc1N2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.6 %

Procedure:
Combine 2-methyl-11-[(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (300.0 mg, 0.76 mmol), formaldehyde (67.5 μL, 0.83 mmol, 37% in water), and 1,2-dichloroethane (25.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (240.5 mg, 1.13 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 279.7 mg (90%) of the title compound as a yellow foam: mp 65°, dec; mass spectrum (ion spray): m/z=411.2 (M+1).
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([C:6]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:7]=1[O:8][CH:9](OCC1C=CC=CC=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])#[N:5]>CO>[NH2:5][C:4]1[C:6]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:7]=2[O:8][C:9]=1[C:10](=[O:11])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[O:2][CH2:1][C:6]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:7]=1
Reactant: C[O-]
Reactant: N#Cc1cc(Cl)ccc1OC(OCc1ccccc1)C(=O)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: Nc1c(C(=O)c2ccccc2OCc2ccccc2)oc2ccc(Cl)cc12

Procedure:
A solution of sodium methanolate (0.07 g, 1.3 mmol) in methanol is added to a solution of ω-(2-cyano-4-chlorophenoxy)-2-benzyloxy-acetophenone (0.5 g, 1.32 mmol) in methanol (30 ml) at 0° C. After 2 h at r.t. the reaction mixture is concentrated under reduced pressure. The residue is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound, having a m.p. of 158-160° C.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:30])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2].[CH:31]1C=CC=C[CH:32]=1.C(O)C>S(=O)(=O)(O)O.O>[C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:30])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH3:27])([CH3:29])[CH3:28])=[CH:24][CH:25]=1)[CH:9]=[CH:8][CH:7]=2)([O:3][CH2:31][CH3:32])=[O:2]
Reactant: CC(C)(C)c1ccc(OCC(O)COc2cccc3oc(C(=O)O)cc(=O)c23)cc1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3ccc(C(C)(C)C)cc3)cccc2o1

Procedure:
1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-t-butylphenoxypropane (10.7 g), benzene (100 ml), ethanol (5 ml) and sulphuric acid (10 drops) were heated under reflux in a Dean and Stark separator until no more water passed over (about 6 hours). After cooling, the solution was washed with saturated sodium bicarbonate solution, and then water. The solvent was removed under reduced pressure to give a very viscous brown oil, from which solid material separated on standing. This solid was filtered off and washed several times with ether to give 1-(2-carbethoxy-chromon-5-yloxy)-2-hydroxy-3-p-t-butylphenoxypropane, 6.1 g, as a cream solid. A portion recrystallized from aqueous ethanol afforded almost colorless flakes m.p. 99°-101.5°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:8](C3CCCCO3)[C:5]2=[CH:6][N:7]=1.[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1>>[C:11]1([C:10]2[C:4]3[C:5](=[CH:6][N:7]=[C:2]([N:23]4[CH:27]=[N:26][CH:25]=[N:24]4)[CH:3]=3)[NH:8][N:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1nc[nH]n1
Reactant: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Product: c1ccc(-c2n[nH]c3cnc(-n4cncn4)cc23)cc1
Yield: 27 %

Procedure:
Following the procedures of Examples 146 and 131, 5-bromo-3-phenyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 1,2,4-triazole were reacted to give 142 as a white solid (20 mg, 27%) over two steps. ESI MS m/z 263.0 (M+1). 1H NMR (400 MHz, DMSO): 14.32 (s, 1H), 9.36 (s, 1H), 9.09 (d, J=1.0 Hz, 1H), 8.38 (d, J=1.0 Hz, 1H), 8.30 (s, 1H), 8.07-8.00 (m, 2H), 7.60 (t, J=7.6 Hz, 2H), 7.48 (t, J=7.4 Hz, 1H)
Reaction SMILES: [ClH:1].[Cl:2][CH:3]=[C:4]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][O:5]1>>[Cl:2][CH2:3][C:4](=[O:5])[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][Cl:1]
Reactant: Cl
Reactant: CC1(C)CCOC1=CCl
Product: CC(C)(CCCl)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A fast stream of hydrogen chloride gas is passed from a pressure cylinder into ice-cooled 476 g (3.25 mols) of 2-chloromethylene-3,3-dimethyltetrahydrofuran. All of the gas is absorbed, and the internal temperature rises to 30°. After the reaction mixture has been completely saturated with hydrogen chloride, it is stirred for 2 hours at room temperature. Excess hydrogen chloride is first distilled off under a water-jet vacuum, and then a distillation in a high vacuum is carried out. 531 g (2.93 mols, 90%) of 1,5-dichloro-3,3-dimethylpentan-2-one are obtained with a boiling point of 85°-90°/0.3.