Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.[NH:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C.[Cl:40][C:41]1[CH:51]=[CH:50][C:44]([O:45][CH2:46][C:47](Cl)=[O:48])=[CH:43][CH:42]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:30][CH2:29][CH2:28][N:27]([C:47](=[O:48])[CH2:46][O:45][C:44]3[CH:50]=[CH:51][C:41]([Cl:40])=[CH:42][CH:43]=3)[CH2:26][CH2:25]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(CCc3ccc(F)cc3)nc12
Reactant: C1CNCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc(N2CCCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in dichloromethane (4 ml) was added homopiperazine (1.4 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was extracted, the organic phase was dried over MgSO4 after which the solvent was removed in vacuo. The residue was dissolved in dichloromethane whereupon diisopropylethylamine (0.28 mmol, 47 μL) followed by 4-chlorophenoxyacetyl chloride (0.14 mmol) were added. The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (38 mg) which was characterized by its mass spectrum: MS m/z (%): 541 ([M+H]+, 100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Br:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([Br:29])=[CH:31][CH:32]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: NCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: Nc1nc2ccccc2c2c1nc(CCCOc1ccccc1)n2CCCNC(=O)c1ccc(Br)cc1
Yield: 60.6 %

Procedure:
Using the general method of Example 189, 1-(3-aminopropyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin4-amine (2.0 g, 5.32 mmol) was reacted with 4-bromobenzoyl chloride (880 mg, 5.86 mmol) to provide 1.8 g of N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl} 4-bromobenzamide as a light yellow solid, m.p. 186.2-186.7° C. Analysis: Calculated for C29H28BrN5O2: % C, 62.37; % H, 5.05; % N, 12.54; Found: % C, 62.18; % H, 5.16; % N, 12.43.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]([CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](O)=[O:31])=[CH:24][CH:23]=1)[CH3:18].ClC(OC)=O.CNC>O1CCCC1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]([CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([N:3]([CH3:4])[CH3:1])=[O:31])=[CH:26][CH:27]=1)[CH3:18]
Reactant: CN(CCOc1ccc(CCC(=O)O)cc1)c1nc2ccccc2o1
Reactant: CCN(CC)CC
Agent: CNC
Agent: COC(=O)Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)CCc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Triethylamine (0.4 mL) was added to an ice-cooled solution of 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]propanoic acid (1.00 g) in dry tetrahydrofuran (20 mL). The mixture was stirred at 0° C. during the addition of freshly distilled methyl chloroformate (0.25 mL), and stirring continued at this temperature for 45 minutes prior to the addition of a solution of dimethylamine in industrial methylated spirit (30% w/v; 20 mL). The mixture was stirred at room temperature for 20 hrs then evaporated. The residue was suspended in water (100 mL). Ethyl acetate (200 mL) and brine (100 mL) were added, the layers were separated and the aqueous layer extracted with ethyl acetate (2×200 mL). The combined ethyl acetate solutions were washed with brine (500 mL), dried (MgSO4) and evaporated. The resulting gum was chromatographed on silica gel with 1% methanol in dichloromethane as eluent to afford a gum which crystallised on standing to afford the title compound, mp 103°-5° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.Br[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]>CN(C)C=O>[O:7]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(C)=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCOc1ccccc1
Reaction time: 4 h
Yield: 7.4 %

Procedure:
A mixture of phenol (18.8 g) and sodium hydroxide (8 g) was stirred at 60°-70° in dimethylformamide (162 ml) and water (18 ml) while 1-bromo-3-methylbut-2-ene (VII, R1 =R2 =CH3, Hal=Br) (29.8 g) was added dropwise over 11/2 h. The mixture was stirred at 60° for 4 h after the addition was complete. It was then poured into water (800 ml) and extracted with ether (3 × 300 ml). The ether extract was washed with 10% sodium hydroxide (200 ml) and then with water (3 × 200 ml) before drying over anhydrous sodium sulphate. The solvent was removed in vacuo, and the residue distilled to give 1-phenoxy-3-methylbut-2-ene (2.4 g, yield 75%) as a clear liquid b.p. 116°-118°/18 mm. Hg.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[N:42]=[CH:41][C:40]([C:43]2([C:46]#[N:47])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:42]=[CH:41][C:40]([C:43]4([C:46]#[N:47])[CH2:45][CH2:44]4)=[CH:39][CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: N#CC1(c2ccc(Cl)nc2)CC1
Product: C[C@@H](c1ccc(-c2ccc(C3(C#N)CC3)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 48 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(6-chloro-pyridin-3-yl)-cyclopropanecarbonitrile following a procedure analogous to that described in Example 1. Yield: 48% of theory; LC (method 3): tR=3.52 min; Mass spectrum (ESI+): m/z=496 [M+H]+.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[CH2:8][C:9]#[N:10].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)=O>C(O)C>[C:14]1(=[C:8]([C:7]2[CH:6]=[C:5]([CH3:4])[CH:13]=[CH:12][CH:11]=2)[C:9]#[N:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCCC1
Reactant: Cc1cccc(CC#N)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=CO
Product: Cc1cccc(C(C#N)=C2CCCCC2)c1
Temperature: 85 °C
Yield: 57.7 %

Procedure:
Sodium methylate (5.40 g, 0.10 mol) is dissolved in ethanol (70 ml) and 3-methyl benzylcyanide (1310 g, 0.10 mol) is added over 2 min. Cyclohexanone (9.80 g, 0.10 mol) is added to the white suspension. The resulting mixture is heated to 85° C. (bath) for 4.5 h. Under icecooling, formic acid (5.0 ml) is added dropwise, upon which the mixture turns colourless. Standard aqueous workup as described in example 1, followed by a short path distillation at 0.05 mbar/157-165° C. yields 12.2 g of product (58% yield), which is further purified by a fine distillation at 0.05 mbar/183° C. to yield 3.95 g (19%) of product as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].BrBr.[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.CC(C)=O.O>[C:13]([CH:15]([CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10])[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]
Reactant: CC(=O)c1ccccc1C
Reactant: CCOC(=O)CC#N
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C#N)CC(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 189.3 %

Procedure:
2′-Methylacetophenone (13.42 g) was dissolved in diethyl ether (100 mL), and bromine (16.0 g) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After dropwise addition, the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 1-bromo-1-(2-methylphenyl)ethanone (21.3 g) as an oil. To ethyl cyanoacetate (79.20 g) was added potassium carbonate (27.64 g), and the mixture was stirred at 43-45° C. for 45 min. A solution (150 mL) of crude 1-bromo-1-(2-methylphenyl)ethanone (21.3 g) in acetone was added dropwise over 30 min. After completion of the dropwise addition, the mixture was stirred at room temperature for 16 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. An excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1→8:1) to give the title compound as a pale-yellow oil (yield 46.44 g, about 100%).
Reaction SMILES: C(NCC)C.[CH2:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[CH2:21]CCCl)=[CH:16][CH:15]=1.O>C(#N)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[CH2:21][CH2:7][CH2:6][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:16][CH:15]=1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Reactant: CCN(CC)CC
Solvent: CCNCC
Solvent: CC#N
Solvent: O
Product: CCN(CC)CCCC(=O)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
Diethylamine (180 mL) and triethylamine (90 mL) were added to a solution of 4′-bromo-4-chlorobutyrophenone (18.13 g) in acetonitrile (90 mL), and the mixture was stirred at 100° C. for one hour. The reaction solution was cooled to room temperature and water was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→ethyl acetate:methanol:triethylamine=40:4:1) to give 1-(4-bromophenyl)-4-(diethylamino)butan-1-one as a brown oil (9.02 g, 44%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[N+]=[N-].CP(C)C.O>O1CCCC1>[C:13]1([C:12]#[C:11][C:9]2[CH:10]=[C:5]([CH2:4][NH2:1])[CH:6]=[N:7][CH:8]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NCc1cncc(C#Cc2ccccc2)c1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: NCc1cncc(C#Cc2ccccc2)c1
Reaction time: 1 h

Procedure:
To a solution of 3-(azidomethyl)-5-(phenylethynyl)pyridine (7.8 g, 33.3 mmol) in tetrahydrofuran (101 mL) at 0° C. was added trimethylphosphine (1M in tetrahydrofuran, 49.9 mL, 49.9 mmol). After evolution of nitrogen had slowed, the ice bath was removed and stirring continued for 1 h. To this was added water (6.0 mL, 333 mmol) and the mixture stirred at room temperature for 2 h. The reaction was concentrated, dissolved in ether, washed with water (5×), then brine, dried over potassium carbonate, filtered, and concentrated to give 5.96 g (77%) as a faint yellow solid which was used without purification. 1H NMR (CDCl3) δ: 8.67 (d, J=1.8 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 7.85 (t, J=2.0 Hz, 1H), 7.53-7.61 (m, 2H), 7.35-7.44 (m, 3H), 3.95 (s, 2H), 1.45 (d, J=5.2 Hz, 2H)1H NMR (CDCl3) δ: 8.67 (d, J=1.8 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 7.85 (t, J=2.0 Hz, 1H), 7.53-7.61 (m, 2H), 7.35-7.44 (m, 3H), 3.95 (s, 2H), 1.45 (d, J=5.2 Hz, 2H). 13C NMR (CDCl3) δ: 150.8, 147.9, 137.8, 137.4, 131.8, 128.9, 128.6, 122.7, 120.3, 92.7, 86.1, 43.7. Mass spec.: 209.1 (MH)+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15](N)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH3:2].[BrH:22].N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O.CC#N>[Br:22][C:15]1[S:16][C:12]2[CH:11]=[C:10]([CH:4]([N:5]3[CH:9]=[CH:8][N:7]=[CH:6]3)[CH:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[CH:19]=[CH:18][C:13]=2[N:14]=1
Reactant: Br
Reactant: CCC(CC)C(c1ccc2nc(N)sc2c1)n1ccnc1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC(CC)C(c1ccc2nc(Br)sc2c1)n1ccnc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (260 mg, 0.866 mmol) and water (4 mL) at 0° C. was added aqueous HBr (0.98 mL, 8.66 mmol) and the mixture was cooled to −10° C. A cold (−10° C.) solution of sodium nitrite (75 mg, 1.08 mmol) in water (1 mL) was added to the reaction mixture over a period of 5 min while maintaining the temperature below −5° C. and the reaction was stirred at −10° C. for 15 min. To a cold (−10° C.) solution of CuBr2 (253 mg, 1.08 mmol) in water (4 mL) was added the reaction mixture and stirred for 10 min at 0° C. MeCN was added to the reaction mixture and then the reaction mixture was stirred for 2.5 h while warming to RT. The reaction was basified with sat. aq. NaHCO3 (pH 7) and then 10 N NaOH (pH 8) followed by celite filtration. The aqueous phase was extracted three times with DCM and the organic extracts were combined and dried over MgSO4, filtered and then concentrated. The crude product was purified by preparative TLC using 5% MeOH in DCM as eluent to afford to 2-bromo-6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole as white solid. MS (ES+): m/z 364 (MH+).
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:14])[C:9]=2[OH:13])[CH:4]1[OH:15].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=O)[CH3:25])=[CH:19][CH:18]=1.[C:27]([O:30]CC)(=[O:29])[CH3:28]>C(O)C>[C:9]([OH:13])(=[O:16])/[CH:10]=[CH:28]/[C:27]([OH:30])=[O:29].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([NH:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([OH:14])[C:9]=3[OH:13])[CH:4]2[OH:15])[CH3:25])=[CH:19][CH:18]=1
Reactant: CCOC(C)=O
Reactant: NC1CCc2c(ccc(O)c2O)C1O
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: Br
Solvent: CCO
Product: CC(Cc1ccc(O)cc1)NC1CCc2c(ccc(O)c2O)C1O
Product: O=C(O)/C=C/C(=O)O

Procedure:
In a manner similar to that of Example 9, 4 parts of 2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide is reacted with 20 parts of 4-hydroxyphenylacetone. The reaction product is dissolved in ethanol and ethyl acetate is added to the solution. The procedure yields 2 parts of 2-(4-hydroxy-α-methylphenethylamino)-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene fumarate as colorless crystals melting at 137°-141° C.
Reaction SMILES: [ClH:1].Cl[C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([NH2:11])=[CH:5][CH:4]=1.[CH2:12]([N:14]([CH2:17]C)CC)[CH3:13].C(OC)(OC)OC.C.COC(OC)CN>C1(C)C=CC=CC=1>[Cl:1][C:5]1[CH:4]=[CH:3][C:8]([O:9][CH3:10])=[CH:7][C:6]=1[N:11]1[CH:13]=[CH:12][N:14]=[CH:17]1
Reactant: COc1cc(N)ccc1Cl
Reactant: Cl
Reactant: CCN(CC)CC
Agent: COC(CN)OC
Solvent: COC(OC)OC
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)c(-n2ccnc2)c1

Procedure:
A mixture of 6-chloro-m-anisidine hydrochloride (21.48 g, 0.11 mole), triethylamine (15.2 ml, 0.11 mole) and 150 ml trimethyl orthoformate was heated at reflux for 3.5 hours. To the mixture was added 150 ml of toluene and some charcoal. After stirring, the mixture was filtered and the filtrate was evaporated to an oil. The oil was redissolved in 150 ml of methanol and reacted with aminoacetaldehyde dimethyl acetal (12 ml, 0.11 mole) at reflux for four hours. The reaction was concentrated and the residue was dissolved in toluene. The toluene solution was extracted twice (total volume 100 ml) with 2N hydrochloric acid solution. The extracts were combined, heated at reflux temperature for five hours, and then concentrated. The residue was dissolved in water and neutralized first with 50% sodium hydroxide and finished up with sodium bicarbonate solution. Some oily material deposited and crystallized upon addition of toluene. The mixture was filtered, the layers of the filtrate were separated, and the aqueous layer extracted three times with toluene-acetonitrile. The organic layers were combined, dried over sodium sulfate, and concentrated to a dark brown oil (15 g). TLC (silica gel eluted with 10% methanol in methylene chloride) of this oil showed mainly two spots at Rf 0.8 and 0.2. The oil was chromatographed on 150 g of silica gel and eluted with 10% methanol in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:13]1([N:19]2[C:23]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:22](=[O:29])[NH:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC=CC=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:10][CH2:9][N:26]2[CH2:25][CH2:24][C:23]3([N:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][NH:21][C:22]3=[O:29])[CH2:28][CH2:27]2)=[O:7])=[CH:11][CH:12]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(c1ccc(Cl)cc1)N1CC1
Solvent: CO
Solvent: c1ccccc1
Product: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1ccc(Cl)cc1

Procedure:
A mixture of 1.82 parts of 1-(4-chlorobenzoyl)aziridine, 2.32 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 10.8 parts of benzene an 1.6 parts of methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and upon scratching, the product solidifies. It is filtered off, washed with benzene and crystallized from 2-propanol, yielding 1.53 parts of 4-chloro-N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)ethyl]benzamide; mp. 200.6° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:15](O)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18].CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=1[C:15]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:23]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)NCCOCCN
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
tert-Butyl 2-(2-aminoethoxy)ethylcarbamate was then taken up in CH2Cl2 (20 mL) along with salicylic acid (576 mg, 4.17 mmol) and EDCI (905 mg. 4.72 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-(2-hydroxybenzamido)ethoxy)ethylcarbamate (450 mg, 33%). Mass, calculated for C16H24N2O5: 324.17; found: [M+H]+=325.
Reaction SMILES: ClCC([C:5]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46]>C(#N)C.C(O)C>[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46].[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:44][C:45]([N:10]4[C:11]5[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=5[CH2:13][CH2:14][C:15]5[CH:5]=[CH:6][CH:7]=[CH:8][C:9]4=5)=[O:46])[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C(CCl)c1cccc2c1CCc1ccccc1N2
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1c2ccccc2CCc2ccccc21

Procedure:
A stirred mixture of 2-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine (6.6 g, 24.3 mmol), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol) and K2CO3 (3.5 g, 40 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The insolubles were filtered, and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography over a silica gel column (100 g of SiO2 ; eluted with dichloromethane (DCM) and 1-2% CH3OH in DCM). The product thus obtained weighed 8.7 g as a yellow oil. A sample (1.5 g) of this material was dissolved in ethanol and was treated with a solution of fumaric acid in ethanol (360 mg/3 ml). The solids collected were recrystallized from acetonitrile to yield 890 mg of white crystals, m.p. 182°-183° C.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[O:30]>C1COCC1>[CH2:33]([O:32][C:28](=[O:31])[CH:29]([OH:30])[CH:14]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][CH:12]=1)[C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:34]
Reactant: CCCCC(=O)Cc1ccc(OC2CCCCC2)cc1
Reactant: CCOC(=O)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)C(c1ccc(OC2CCCCC2)cc1)C(O)C(=O)OCC
Reaction time: 12 h

Procedure:
To a stirred solution of 1-(4-cyclohexyloxy-phenyl)-hexan-2-one (86.4 mmol, 23.7 g) and triethylamine (86.4 mmol, 12.1 mL) in THF (10 mL) was added a solution of ethyl glyoxylate (50% in toluene, 432 mmol, 86 mL) and continued stirring for 12 h during which time the starting material was fully consumed as judged by TLC. After removal of volatiles in vacuo, the crude product was purified on a 300 g SiO2 cartridge with 10-15% ethyl acetate in hexanes to afford 3-(4-cyclohexyloxy-phenyl)-2-hydroxy-4-oxo-octanoic acid ethyl ester
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]2[C:12]3=[N:13]C=[CH:15][C:16](OC4C=CC(N)=CC=4F)=[C:11]3[C:10]([NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH:29]([OH:33])[CH2:28]3)=[N:9]2)=[CH:5][CH:4]=1.FC1C=CC(N2C(=[O:49])C(C(O)=O)=CC=N2)=CC=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C.O.CCN(CC)CC>[CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]2[CH:15]=[CH:16][C:11]([C:12]([NH2:13])=[O:49])=[C:10]([NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH:29]([OH:33])[CH2:28]3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(NC3CCCC(O)C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CN2C=CC(C(N)=O)=C(NC3CCCC(O)C3)N2)cc1
Yield: 97.6 %

Procedure:
A solution of 3-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)cyclohexanol (50 mg, 0.10 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (74 mg, 0.31 mmol, obtained from Example 19 Step C), EDCI (120 mg, 0.63 mmol), Et3N (0.1 mL) and HOBT-H2O (96 mg, 0.63 mmol) was stirred in DMF (1 mL) for 10 hours. The reaction mixture was poured into water and extracted with CH2Cl2. The organic layer washed with saturated aqueous NaHCO3, 10% aqueous LiCl, dried with Na2SO4, filtered and concentrated. The residue was purified with flash silica gel chromatography (5% MeOH in CH2Cl2) to afford the product (35 mg, 48% yield) as a brown solid. LRMS (APCI pos) m/e 694.2 (M+H).