Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19].C1C=CC=CC=1>O>[CH2:16]([N:20]=[C:1]=[C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH2:4]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCOC(=O)COc1ccc(C=O)cc1
Reactant: CCCCN
Solvent: O
Solvent: c1ccccc1
Product: CCCCN=C=C1C=CC(OCC(=O)OCC)=CC1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
Ethyl (4-formylphenoxy)acetate (104.1 g, 0.5 mole), butylamine (36.6 g, 0.5 mole) and benzene (400 ml) were united and refluxed in a flask equipped with a Dean-Stark water separator. After one hour, water ceased to separate. The heating was terminated after 6 hours and the mixture distilled. There was obtained 108.6 g of product boiling at 178°-181° C. at 0.5 mm Hg pressure.
Reaction SMILES: [Cl:1][C:2]1[C:3](C#N)=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:6][CH:7]=1.[C:21](=[O:24])([O-])[O-:22].[Na+].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([C:21]([OH:22])=[O:24])=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
3-chloro-2-cyano-6-[3-(trifluoromethyl)phenoxy] pyridine (2.58 g, 0.086 mol) was dissolved in 30 ml of 90% sulfuric acid. The obtained solution was heated and stirred at 120° C. for 1.5 hours. Thereafter, the obtained reaction solution was poured into ice water, and then treated with sodium carbonate to form a weakly-acidic solution, thereby precipitating solids. The precipitated solids were filtered out, washed with water and then dried.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[CH2:22]([CH:24]1[CH2:32][C:27]2([O:31][CH2:30][CH2:29][O:28]2)[CH2:26][CH:25]1[C:33](O)=[O:34])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:22]([CH:24]1[CH2:32][C:27]2([O:28][CH2:29][CH2:30][O:31]2)[CH2:26][CH:25]1[C:33]([NH:2][NH:1][C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[C:6]2=[N:7][CH:8]=1)=[O:34])[CH3:23]
Reactant: CCC1CC2(CC1C(=O)O)OCCO2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCC1CC2(CC1C(=O)NNc1cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A 50 mL round bottom flask was charged with 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.350 g, 1.16 mmol, Example #1, Step D), 8-ethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid (0.250 g, 1.25 mmol), and DCM (6.0 mL). To the reaction mixture was added HATU (0.483 g, 1.27 mmol) and TEA (0.64 mL, 4.6 mmol) and the resulting yellow suspension was stirred at rt for about 3 h. To the reaction solution was added DCM (25 mL) and the solution was washed with water and brine (20 mL each). The organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give a brown oil. The crude product was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM over 25 min. to give 8-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1,4-dioxaspiro[4.4]nonane-7-carbohydrazide as a foam (0.50 g, 89%): LC/MS (Table 1, Method c) Rt=1.49 min; MS m/z: 486 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[CH:24]=O)([CH3:20])([CH3:19])[CH3:18]>CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:24]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)[C:23]2[CH:22]=[C:21]([C:17]([CH3:18])([CH3:20])[CH3:19])[C:28]([OH:29])=[C:27]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:26]=2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: CO
Product: CC(C)(C)c1cc(SC(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Yield: 86.6 %

Procedure:
The procedure of Example 1 is repeated using 23.84 grams of 2,6-di-tert-butyl-4-mercaptophenol, 11.72 grams of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 150 ml of methyl alcohol. Trituration with methyl alcohol gives 30 grams (87% yield) of white crystals, mp 175°-177° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[NH:18]([C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>C(O)C>[F:12][C:9]1[CH:8]=[CH:7][C:6]2[NH:5][CH:4]=[C:3]3[C:13](=[O:15])[N:18]([C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:19]=[C:2]3[C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1Cl
Reactant: NNc1ncccn1
Solvent: CCO
Product: O=c1c2c[nH]c3ccc(F)cc3c-2nn1-c1ncccn1

Procedure:
A solution of 2.0 of ethyl 4-chloro-6-fluoroquinolin-3-carboxylate and 0.95 g of 2-hydrazinopyrimidine in 40 ml of 95% ethanol is heated under reflux for 16 hours. The reaction mixture is filtered and the resulting solid is taken up in 20 ml of N sodium hydroxide and sufficient water to effect solution. Ammonium chloride (10.7 g) is added, the resulting precipitate is collected, washed with water and dried to yield 8-fluoro-2-(2-pyrimidyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, as a hydrate, m.p. above 350°; IR (KBr) 800, 829, 870, 880 cm-1.
Reaction SMILES: [C:1]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1>O1CCCC1>[C:1]([NH:10][CH2:12][CH2:11][CH2:17][S:14]([OH:16])(=[O:15])=[O:13])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CC(C)(NCCCS(=O)(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of cumylamine (10.5 g, 78 mmol) in tetrahydrofuran (75 mL) was slowly added a solution of 1,3-propane sultone (9.2 g, 74 mmol) in THF (20 mL). The mixture was stirred at reflux for 4 h. The reaction mixture was cooled to room temperature. The solid was collected by filtration, and washed with THF (2×35 mL). The solid was suspended in EtOH (80 mL). The suspension was stirred at reflux for 15 minutes. The solid product was collected by filtration, washed with EtOH (35 mL) and acetone (35 mL). The resulting solid was dried in vacuo, affording compound DM (5.6 g, 30%). 1H NMR (D2O, 500 MHz) 8 ppm 7.41 (m, 5H), 2.74 (m, 4H), 1.88 (m, 2H), 1.66 (s, 6H). 13C NMR (D2O, 125 MHz) 8 ppm 138.36, 129.44, 129.41, 126.52, 61.56, 48.04, 41.21, 24.80, 21.81. ES-MS 256 (M−1).
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[C:9](OC)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:10][CH2:9][C:2]1[S:1][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc2ccsc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cc2ccsc2s1
Reaction time: 3 h

Procedure:
A solution of methyl thieno[2,3-b]thiophene-2-carboxylate (19.8 g. 0.1 mol) in dry ether (75 mL) was added at a rapid drip rate (1 hour, 45 minutes) to a suspension of lithium aluminum hydride (7.59 g, 0.2 mol) in ether (500 mL) cooled in an ice-water bath. During the addition, precipitated material on the inside of the flask was kept suspended in the reaction medium. After the addition was complete stirring was continued at room temperature for 3 hours. The reaction mixture was cooled in an ice-water bath and there was added in succession, slowly, dropwise with vigorous stirring: water (7.6 ml); 20% aqueous NaOH (22.8 mL); water (7.6 mL); water (4 mL); 20sodium hydroxide (12 mL); water (4 ml). Vigorous stirring was continued until a granular precipitate was obtained. The ether was decanted and the solids were washed by decantation three times with ether. The combined ether fractions were dried (MgSO4), filtered, and evaporated in vacuo to leave 16.33 g of white, solid 2-hydroxymethylthieno[2,3-b]thiophene, m.p. 85°-87° C. Recrystallization from hexane gave material with m.p. 86°-87° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:12]3[C:13]([N+:22]([O-:24])=[O:23])=[CH:14][C:15]4[S:19][C:18](=[O:20])[NH:17][C:16]=4[CH:21]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.S([O-])([O-])(=[O:27])=S.[Na+].[Na+]>C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:12]3[C:13]([N+:22]([O-:24])=[O:23])=[CH:14][C:15]4[S:19][C:18](=[O:20])[NH:17][C:16]=4[CH:21]=3)=[O:27])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=c1[nH]c2cc(Sc3cccc4cnccc34)c([N+](=O)[O-])cc2s1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(S(=O)c3cccc4cnccc34)c([N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.6 %

Procedure:
5-(5-Isoquinolylsulfanyl)-6-nitro-2,3-dihydro-benzo[d][1,3]thiazol-2-one 300 mg (0.8 mmol) was dissolved in acetic acid 20 ml, 35% hydrogen peroxide 15 ml was added, and the mixture was stirred for 15 hours at room temperature. Saturated sodium thiosulfate was added to the reaction solution, the resulting precipitates were collected and washed with water, and 5-(5-isoquinolylsulfinyl)-6-nitro-2,3-dihydro-benzo[d][1,3]thiazol-2-one 190 mg (61.6%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CC(C)=O>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:17][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])=[CH:4][CH:3]=1
Reactant: O=c1c2ccccc2sc2c(O)ccc(Cl)c12
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCOc1ccc(Cl)c2c(=O)c3ccccc3sc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.4 %

Procedure:
1-Chloro-4-dodecyloxythioxanthone was prepared as follows. A solution of 1-chloro-4-hydroxythioxanthone (14.0 g, 0.05 mol), K2CO3 (8.09, 0.06 mol) in acetone (250 mL) was stirred and refluxed for 10 min. Bromododecane (20.0 g, 0.08 mol) was added and the resulting mixture was stirred for 24 h under reflux. The reaction was then cooled to room temperature and quenched with water (500 mL). The obtained solid was filtered, washed with water, purified by recrystalized from isopropanol to give the 1-chloro-4-dodecyloxythioxanthone (14.3 g, 62%) with mp 79–80° C. The identity of this compound was shown by 1H NMR to have the following structure:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11]Cl)[C:4]=2[O:3]1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:17][CH:16]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][O:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:19][CH:20]=3)[C:4]=2[O:3]1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Reactant: CC1(C)Cc2cccc(CCl)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Nc1ccc(OCc2cccc3c2OC(C)(C)C3)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
3.0 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranylmethyl chloride and 3.0 g of 1-(4-hydroxyphenyl)-3,3-dimethylurea were dissolved into 20 ml of dried N,N-dimethylformamide, and 2.5 g of anhydrous potassium carbonate was added thereto. After the mixture was stirred at 80° C. for 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/1) as a developer to obtain 4.0 g of Compound No. 7 shown in Table 1.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)([CH3:3])[CH3:2].[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[OH:17]>>[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[O:17][CH2:5][CH:6]([OH:8])[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3]
Reactant: CC(C)N1CC(O)C1
Reactant: Oc1cccc(Cl)c1Cl
Product: CC(C)NCC(O)COc1cccc(Cl)c1Cl
Yield: 54 %

Procedure:
1-(iso-propyl)-3-azetidinol and 2,3-dichlorophenol were reacted in the same manner as in Example 6 to yield 1-(2',3'-dichlorophenoxy)-3-(iso-propylamino)-2-propanol melting at 94°-96° C. The yield was 54%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12]CC)=[O:11])[N:7]([CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]([CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1CC(=O)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)Cn1nc(C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of ethyl 3-tert-butyl-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-5-carboxylate from example B17 (0.48 g, 1.7 mmol) in THF (10 mL) was added a solution of lithium hydroxide (0.21 g, 5.1 mmol) in water (5 mL) and the mixture was stirred for 16 h at RT. Solvents were removed and the residue was acidified with 3M HCl and the product was extracted with EtOAc (2×30 ml). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to afford 3-tert-butyl-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-5-carboxylic acid (0.4, 93% yield) as a pasty mass. 1H NMR (400 MHz, DMSO-d6): δ 6.69 (s, 1H), 5.30 (s, 2H), 3.02 (s, 3H), 2.82 (s, 3H), 1.24 (m, 9H); MS (ESI) m/z: 254.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:23].N#N>CO.C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:14][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][C:7]=2[C:11]([O:13][CH3:23])=[O:12])=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1[nH]c2cc(F)ccc2c1Sc1ccc(Cl)cc1
Agent: N#N
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1[nH]c2cc(F)ccc2c1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of impure 1g product (0.19 g, 0.59 mmol) in a mixture of methanol and toluene (6 mL, 1:2) was added TMSCHN2 (2.0 M solution in diethyl ether) (0.6 mL, 1.2 mmol) dropwise under N2. The reaction was allowed to warm to rt and stirred for 2 h. The reaction mixture was concentrated and purified by flash column chromatography eluting with a linear gradient ranging from 0 to 50% EtOAc-hexanes to provide 0.15 g (75%) of product 34 as an off white solid. 1H NMR (300 MHz, CDCl3) δ 3.93 (s, 3H), 6.88-6.95 (m, 1H), 7.06-7.16 (m, 5H), 7.45-750 (m, 1H), 9.22 (s, 1H). LC-MS (CI): m/z 336.0 [(M+H)+ C16H11ClFNO2S requires 335.02].
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]([OH:16])=[C:14]2[C:9]([C:10](=[O:19])[CH2:11][C:12]([CH3:18])([CH3:17])[O:13]2)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].S(OC)(O[CH3:24])(=O)=O>[OH-].[Na+]>[CH2:1]([O:5][C:6]1[C:15]([O:16][CH3:24])=[C:14]2[C:9]([C:10](=[O:19])[CH2:11][C:12]([CH3:17])([CH3:18])[O:13]2)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc2c(c1O)OC(C)(C)CC2=O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1c(OCC(C)C)ccc2c1OC(C)(C)CC2=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
In 50 ml of a 10% sodium hydroxide solution under nitrogen 5.2 g (20 millimoles) of 7-isobutoxy-8-hydroxy-2,2,-dimethyl-4-chromanone are dissolved, whereupon 2.6 g (2 ml, 21 millimoles) of dimethyl sulfate are added and the reaction mixture is intensively stirred for 3 hours at 50° C. The mixture is diluted with 100 ml of ice cold water, extracted three times with 50 ml of chloroform each, the organic phase is washed twice with 40 ml of water dried over sodium sulfate and the solvent is evaporated. Thus 5.2 g of the desired compound are obtained in the form of yellow oil, yield 93%.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][C:16]([CH2:20][OH:21])([CH3:19])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH2:28]([C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1)[CH3:29]>>[CH2:28]([C:30]1[N:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][C:16]([CH2:20][OH:21])([CH3:19])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:3]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C)(CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C)(CO)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, (1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-4-methylpiperidin-4-yl)methanol and 2-ethyl-1H-benzo[d]imidazole were reacted to give 385. LCMS m/z: 505.3 (MH+)
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.C([BH3-])#N.[Na+].[CH3:38][C:39]([CH3:41])=O>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH:39]([CH3:41])[CH3:38])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: CC(C)=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN(Cc2ccccc2)C(C)C)CC1

Procedure:
4-Amino-N-((1-(5-benzylaminopentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (2.0 g) as starting compound, acetone (0.3 ml) and sodium cyanoborohydride (0.35 g) were reacted and treated in the same manner as in Example 136 to give 0.43 g of 4-amino-5-chloro-N-((1-(5-(N-isopropyl-N-benzylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH:14]2[CH2:16][CH:17]([OH:19])[CH2:18][CH:13]2[CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH:14]2[CH2:16][C:17](=[O:19])[CH2:18][CH:13]2[CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CC3CC(O)CC3C2)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC2CN(c3ccc([N+](=O)[O-])cc3F)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
And, then, the 2-(2-fluoro-4-nitrophenyl)-octahydro-5-hydroxycyclopenta[c]pyrrol (44.4 mmol) prepared in the step 2 was dissolved in 100 ml of methylene chloride and slowly added over 30 minutes, the mixture was stirred for 1 hour while maintaining the temperature, and then, 30.93 ml (221.9 mmol) of triethylamine was slowly added over 20 minutes, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. After the reaction was completed, 100 mL of methylene chloride was added to dilute the mixture, and then, the mixture was washed with water and a saturated aqueous solution of sodium chloride, and the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was recrystallized under ethanol solvent to obtain 11.1 g (95%) of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].C(Cl)CCl.O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:10]1[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:3]=[C:2]([C:11]([O:13][N:19]2[C:23](=[O:24])[CH2:22][CH2:21][C:20]2=[O:25])=[O:12])[N:1]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: O=C1CCC(=O)N1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(ON1C(=O)CCC1=O)c1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-quinoline carboxylic acid (1.2 eq.) in DMF at 0° C. was treated with EDC (1.4 eq.). The mixture was stirred at 0° C. for 1 to 2 h and then N-hydroxysuccinimide (1.0 eq.) was added. After stirring at RT for more than 3 h, the reaction mixture was poured into 60% sat. NaHCO3 and the product filtered: 1H NMR (CDCl3, 300 MHz, ppm) 8.35 (d, 1H), 8.27 (d, 1H), 8.19 (d, 1H), 7.87 (d, 1H), 7.80 (m, 1H), 7.68 (m, 1H), 2.91 (s, 4H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: CN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 60 °C
Yield: 18.3 %

Procedure:
To a solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea (225 mg, 0.427 mmol) from Example 27B in DMF (3 mL) was added N-methyl piperazine (0.142 mL, 1.281 mmol) followed by diisopropyl ethylamine (0.223 mL, 1.281 mmol) and tetrabutyl ammonium iodide (157.72 mg, 0.427 mmol). The reaction mixture was heated at 60° C. for 15 h. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using a phenyl-hexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN). The appropriate fractions were concentrated followed by trituration with ether to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea (46 mg, 18%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.25 (s, 1H), 8.55 (s, 1H), 7.60 (d, 2H), 7.40 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 6.50 (s, 1H), 4.25 (m, 2H), 3.98 (s, 3H), 2.55-2.30 (m, 10H), 2.15 (s, 3H), 1.98 (m, 2H), 1.28 (s, 9H); LC-MS (ESI) m/z 590 (M+H)+.