Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>CN(C)C=O>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]1=[O:12]
Reactant: O=C1NCCN1c1cccnc1
Reactant: BrCCCCCCOc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCCOc2nc3ccccc3s2)CCN1c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-pyridyl)-2-imidazolidinone (0.11 g, 0.65 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 31.2 mg, 0.78 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled in ice bath again. 2-[(6-Bromohexyl)oxy]-1,3-benzothiazole (0.20 g, 0.65 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with MeOH, and the solvent was removed under vacuum. A saturated aqueous NH4Cl solution (5 mL) and dichloromethane (10 mL) were successively added to the residue. The dichloromethane layer was separated and dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 4) as a white solid (0.14 g, 88%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[C:8]=1[CH:9]=[O:10])[CH3:6].[Br:17]Br>ClCCl>[Br:17][C:14]1[C:7]([CH2:5][CH3:6])=[C:8]([C:11]([CH2:15][CH3:16])=[CH:12][CH:13]=1)[CH:9]=[O:10]
Reactant: CCc1cccc(CC)c1C=O
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(Br)c(CC)c1C=O
Temperature: 40 °C

Procedure:
To a solution of 8.01 g (60 mmol) aluminum trichloride in 10 ml dichloromethane were added at ambient temperature drop-wise 5.52 g (34 mmol) 2,6-diethyl-benzaldehyde (Example 1 c)); exothermic reaction. To the resulting dark red solution was added slowly drop-wise a solution of 5.5 g (34 mmol) bromine in 7 ml dichloromethane; strong exothermic reaction. Then the mixture was heated to 40° C. for 3 hours. The reaction mixture was cooled to ambient temperature and poured onto ice. The organic phase was separated and the aqueous solution extracted with dichloromethane, the combined extracts washed with 2N HCl solution, saturated sodium bicarbonate solution and brine, dried over MgSO4, filtered and evaporated: 7.0 g 3-bromo-2,6-diethyl-benzaldehyde of 90% purity (HPLC) that did not require further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:26])=[C:4]([C:9]2[C:10]([OH:25])=[N:11][C:12]3[C:17]([C:18]=2[O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=[CH:14][N:13]=3)[C:5]([F:8])=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[F:36][CH:37]([F:47])[CH2:38]OS(C(F)(F)F)(=O)=O>C(#N)C>[Br:1][C:2]1[C:3]([Cl:26])=[C:4]([C:9]2[C:10](=[O:25])[N:11]([CH2:38][CH:37]([F:47])[F:36])[C:12]3[C:17]([C:18]=2[O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=[CH:14][N:13]=3)[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CC(C)C(=O)Oc1c(-c2c(F)ccc(Br)c2Cl)c(O)nc2ncccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)C(=O)Oc1c(-c2c(F)ccc(Br)c2Cl)c(=O)n(CC(F)F)c2ncccc12
Reaction time: 8 h

Procedure:
To a solution of Isobutyric acid 3-(3-bromo-2-chloro-6-fluoro-phenyl)-2-hydroxy-[1,8]naphthyridin-4-yl ester (1.749 g) in acetonitrile (17 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.83 ml) at ambient temperature. The mixture was stirred for 5 minutes at ambient temperature before drop wise addition of a solution of 2,2-difluoroethyltrifluoromethanesulfonate (1.022 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 7 hours when further 2,2-difluoroethyltrifluoromethanesulfonate (0.5 g) and the reaction was stirred overnight. A further portion of 2,2-difluoroethyltrifluoromethanesulfonate (0.5 g) and N,N-diisopropylethylamine (“Hunig's base”) (0.83 ml) was added and the reaction was stirred for 5 hours then left to stand overnight. The reaction was concentrated and partitioned between ethyl acetate and 2M hydrochloric acid. The organic layer was dried and concentrated and the oily residue was purified by column chromatography on silica (eluent: 4:1 hexane:ethyl acetate) to give Compound No. D23 of Table D as a light yellow solid (1.56 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[C:16]([I:17])[C:11]=3[O:10][CH:9]=2)=[CH:4][C:3]=1[O:19][CH3:20].[CH3:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[NH2:18][C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31]([C:23]4[N:22]([CH3:21])[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[N:24]=4)=[O:32])=[C:3]([O:19][CH3:20])[CH:4]=3)=[CH:9][O:10][C:11]=2[C:16]([I:17])=[CH:15][N:14]=1
Reactant: Cn1c(C(=O)Cl)nc2ccccc21
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)c1nc2ccccc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 105.8 %

Procedure:
A solution of 3-(4-amino-3-methoxyphenyl)-7-iodofuro[3,2-c]pyridin-4-amine (1.50 g, 3.94 mmol) in pyridine (18 mL) was cooled to 0° C. and 1-methyl-1H-benzo[d]imidazole-2-carbonyl chloride (0.874 g, 3.33 mmol) was added. The mixture was stirred for 15 minutes at 0° C. and then allowed to rise to ambient temperature over an eighteen hour time period. The solvent was removed in vacuo and the residue was suspended in water (50 mL) and brought to pH 12 with 0.1 N aqueous sodium hydroxide. The suspension was extracted with dichloromethane (4×25 mL) and the combined organic layers were washed with brine (25 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title compound (1.90 g, 90%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz.)δ 10.18 (s, 1H), 8.49 (d, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.85 (d, 1H), 7.76 (d, 1H), 7.46 (t, 1H), 7.39 (t, 1H), 7.30 (s, 1H), 7.19 (d, 1H), 5.77–5.89 (b, 2H), 4.24 (s, 3H), 4.03 (s, 3H); RP-HPLC (Conditions d) Rt 11.89 min.; MS: MH+ 540.
Reaction SMILES: O=[C:2]([NH:7][CH2:8][C:9](=O)[O:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])[C:3]([O:5][CH3:6])=[O:4].N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>ClCCl>[O:10]1[C:9]2=[CH:8][N:7]=[C:2]([C:3]([O:5][CH3:6])=[O:4])[CH:15]=[C:14]2[CH2:13][CH2:12][CH2:11]1
Reactant: C=CCCCOC(=O)CNC(=O)C(=O)OC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc2c(cn1)OCCC2
Temperature: 25 °C

Procedure:
Methyl 2-oxo-2-((2-oxo-2-(pent-4-en-1-yloxy)ethyl)amino)acetate (42.5 g, 1 eq) and dichloromethane (DCM) (425 mL) were added to a vessel with stirring followed by the addition of pyridine (17.6 g, 1.2 eq). Tf2O (78.5 g, 1.5 eq) was added over 45 min to the mixture maintaining an internal temperature of ˜25° C. The mixture was stirred for 6 h at which point the reaction was carefully quenched by the addition of 20 wt % aqueous NaOAc (255 mL) to form a biphasic solution. The aqueous layer was extracted with DCM (85 mL). The combined organic layers were washed first with water (127.5 mL) and 10 wt % citric acid solution (170 mL). 6N HCl (127.5 mL) was added to the mixture to form a biphasic mixture. The two layers were separated and the organic layer was extracted with 6 N HCl (85 mL). The acidic aqueous layers were combined and DCM (127.5 mL) was added. While maintaining the temperature below 25° C., 28 wt % aqueous NH4OH was slowly added until the pH of the aqueous layer reached 3-5. The two layers were separated and the aqueous layer was extracted with DCM (85 mL). The combined organic layers were washed with water (85 mL). The organic solution was concentrated under reduced pressure to provide the title compound as an oil which solidified on standing. 1H NMR (400 MHz, CDCl3) δ ppm 8.17 (s, 1H), 7.80-7.86 (m, 1H), 4.26 (t, J=5.19 Hz, 2H), 3.92 (s, 3H), 2.79 (t, J=6.44 Hz, 2H), 1.97-2.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ ppm 165.11, 154.25, 138.95, 138.64, 130.06, 126.13, 65.55, 51.99, 23.57, 20.67; HRMS (M+Na) m/z, calcd for C10H11NO3Na, 216.0637; found, 216.0643.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(OC)c3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1cccc(-c2cc3c(O)c(C(=O)NCCC(=O)O)ncc3n(Cc3ccccc3)c2=O)c1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.084 mmol), β-alanine (600 mg, 6.7 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 30 mg of the title compound as a yellow solid. MS: (+) m/z 474.36 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.P(=O)(O)(O)O>CC(O)C.[Pd]>[CH3:4][C:3]1[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:2]=1[OH:1]
Reactant: O=Cc1ccc(O)cc1O
Agent: [Pd]
Agent: O=P(O)(O)O
Solvent: CC(C)O
Product: Cc1ccc(O)cc1O
Reaction time: 3 h
Yield: 98.1 %

Procedure:
2,4-Dihydroxybenzaldehyde (33.97 gm, 0.246 mol) (recrystallized from toluene) was dissolved in spectroscopic grade 2-propanol (3L) in a round bottom flask fitted with a gas inlet and a bubbler outlet. 10% Palladium on carbon (1.35 gm) was added followed by phosphoric acid (3 mL) and the mixture was sparged with nitrogen. The nitrogen flow was switched to hydrogen and the mixture was rapidly stirred with ice cooling. After 3 hours hydrogen uptake was complete and the catalyst was removed by filtration. The filtrate was stripped down to 200 mL and 200 mL of ethyl acetate was added. The solution was washed with 4×200 mL of water and the combined water extracts back-extracted with ethyl acetate. These organic extracts were water washed and the combined organic layers dried over sodium sulfate and stripped down to afford the product as a colorless crystalline solid (29.95 gm, 98%). M.p.: 106° C. (Lit. 106°-107° C. [J. C. Bell, W. Bridge, and A. Robertson, J. Chem. Soc., 1542-45 (1937)]). NMR (DMSO-d6): δ1.961 (s, Me), 6.076 (dd, H-6, J[5,6]=8 hz, J[2,6]=2 hz), 6.231 (d, H-2), 6.760 (d, H-5) 8.867 (s, OH), and 9.008 (s, OH).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[F:15])[CH3:2].O[CH:19]=[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][C:21]1=[O:29]>>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]2=[O:29])=[CH:10][C:9]=1[F:15])[CH3:17]
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: CCN(CC)CCCOc1ccc(N)cc1F
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3ccccc32)cc1F
Yield: 23.5 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-Diethylamino-propoxy)-3-fluoro-phenylamine (400 mg, 1.1 equiv.) and 3-hydroxymethylene-1,3-dihydro-indol-2-one (242 mg, 1.5 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (135 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[N:14]=1)[CH:7]=[C:6]2[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[Br:32][C:33]1[C:41]2[C:36](=[N:37][CH:38]=[N:39][C:40]=2Cl)[NH:35][N:34]=1>>[Br:32][C:33]1[C:41]2[C:36](=[N:37][CH:38]=[N:39][C:40]=2[N:29]2[CH2:28][CH2:27][N:26]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=[C:8]([C:13]4[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])[N:14]=4)[CH:7]=3)[CH2:31][CH2:30]2)[NH:35][N:34]=1
Reactant: COc1ccc2cc(-c3ccnc(NCCCN(C)C)n3)cc(N3CCNCC3)c2c1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Product: COc1ccc2cc(-c3ccnc(NCCCN(C)C)n3)cc(N3CCN(c4ncnc5[nH]nc(Br)c45)CC3)c2c1

Procedure:
N1-(4-(4-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-6-methoxynaphthalen-2-yl)pyrimidin-2-yl)-N3,N3-dimethylpropane-1,3-diamine was synthesized according to General Procedure E except N′-[4-(6-methoxy-4-piperazin-1-yl-2-naphthyl)pyrimidin-2-yl]-N,N-dimethylpropane-1,3-diamine and 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine were used. N1-(4-(4-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-6-methoxynaphthalen-2-yl)pyrimidin-2-yl)-N3,N3-dimethylpropane-1,3-diamine 178 was isolated as a solid. M.p.=152-155° C. LC/MS (m/z/): 618 [M+H].
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([O:20][C:21]([N:23]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:26]=2[CH:25]=[CH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44]>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:26]=2[CH:25]=[C:24]1[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)n1ccc2c(C(=O)OCc3ccccc3)cccc21
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C(=O)OCc3ccccc3)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (322 mg) in tetrahydrofuran (5.0 ml) was added dropwise a solution of n-butyllithium (1.6M n-hexane solution 1.3 ml) at −70˜−60° C. and the solution was stirred at 0° C. for 30 minutes. A solution of benzyl 1-tert-butoxycarbonylindole-4-carboxylate (500 mg) in tetrahydrofuran (2.5 ml) was added dropwise to the above solution at −70˜−60° C. and the mixture was stirred at −70° C. for 30 minutes. To the mixture was added a solution of ethyl chloroformate (185 mg) in tetrahydrofuran (2.5 ml) at such a rate as to maintain the temperature below −60° C. The solution was stirred at −70° C. for 2 hours and the reaction was quenched with aqueous saturated ammonium chloride solution at −20° C. The aqueous solution was extracted with ethyl acetate. Drying, filtering and removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (eluent; n-hexane:ethyl acetate=15:1) to give benzyl 1-tert-butoxycarbonyl-2-ethoxycarbonylindole-4-carboxylate (100 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=O)[C:8]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+]>>[F:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[CH:7][C:8]2[NH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11](=[O:13])[C:9]=2[CH:10]=1
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)c1cc2[nH]c3ccccc3c(=O)c2cc1F
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
To a round bottom flask containing polyphosphoric acid (254 g) at 165-172° C. was added finely ground compound 174D (15.0 g, 55.6 mmol) over 30 min. After the addition was complete, the reaction mixture was stirred for 10 min at 165° C. HPLC indicated that the reaction was complete. While at 165° C., the mixture was slowly added to a mixture of ice and sodium bicarbonate. The pH was adjusted to 3.0 with additional solid sodium bicarbonate, and the resulting mixture was filtered through a medium porosity fritted funnel to give a greenish-yellow paste which was washed with water (3×) and air-dried under vacuum. The resulting paste was rinsed with MeOH into a flask. The paste/MeOH mixture was then sonicated to disperse the paste. DCM was added, and the mixture was concentrated under reduced pressure. The azeotrope procedure was repeated 2× to give 12.0 g (84%) of acridone acid 174E as a yellow solid. HPLC retention time=2.35 min. (Condition A) and LC/MS M+1=258.03. 1H-NMR (500 MHz, DMSO) δ 7.30 (t, 1H, J=7.6 Hz), 7.56 (d, 1H, J=7.6 Hz), 7.78 (t, 1H, J=7.6 Hz), 7.93 (d, 1H, J=11.0 Hz), 8.11 (d, 1H, J=6.1 Hz), 8.22 (d, 1H, J=7.6 Hz), and 12.06 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:18]([N:21]1[C:26](=[O:27])[C:25]([Cl:28])=[C:24](Cl)[CH:23]=[N:22]1)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Cl:28][C:25]1[C:26](=[O:27])[N:21]([CH:18]([CH3:19])[CH3:20])[N:22]=[CH:23][C:24]=1[NH:14][CH2:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:11]=1
Reactant: NCc1cccc(OCc2ccccc2)c1
Reactant: CC(C)n1ncc(Cl)c(Cl)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1ncc(NCc2cccc(OCc3ccccc3)c2)c(Cl)c1=O
Reaction time: 4.5 h

Procedure:
A mixture comprising 8.24 g of 3-benzyloxybenzylamine hydrochloride prepared in Reference Example 2A, 3.11 g of 2-i-propyl-4,5-dichloro-3(2H)pyridazinone, 7.26 g of potassium carbonate, 30 ml of 1,4-dioxane and 90 ml of water was refluxed under stirring for 4.5 hours. The majority of 1,4-dioxane was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid, and then treated with cerite to remove the precipitate. The organic layer was separated, and washed with water and a saturated sodium chloride aqueous solution, and then dried over sodium sulfate. Then, the solvent was distilled off. The pale yellow oily substance thereby obtained was crystallized from ether-n-hexane to obtain 2.51 g of the above identified compound having a melting point of from 106° to 108° C. as colorless crystals.
Reaction SMILES: C([N:8]1[C:17](=[O:18])[CH:16]=[C:11]2[S:12][CH2:13][CH2:14][CH2:15][N:10]2[C:9]1=[O:19])C1C=CC=CC=1.B(Br)(Br)Br.CO>C1(C)C=CC=CC=1>[S:12]1[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:19])[NH:8][C:17](=[O:18])[CH:16]=[C:11]12
Reactant: O=c1cc2n(c(=O)n1Cc1ccccc1)CCCS2
Agent: BrB(Br)Br
Solvent: CO
Solvent: Cc1ccccc1
Product: O=c1cc2n(c(=O)[nH]1)CCCS2
Reaction time: 0.5 h

Procedure:
To a solution of 6.31 g (23 mmol) of 7-benzyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione in 200 ml of toluene, 12.5 g (50 mmol) of boron tribromide was added under ice cooling conditions, followed by refluxing for 16 hours. After the reaction mixture was cooled, 50 ml of methanol was added, followed by stirring for 30 minutes. After this mixture was concentrated to dryness, methanoldiethyl ether was added to the residue. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to yield 3.25 g (76.7%, light white powder) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5].[Cl:27][C:28]1[N:32]([CH3:33])[N:31]=[C:30]([CH3:34])[C:29]=1[S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:2]([NH:1][S:35]([C:29]2[C:30]([CH3:34])=[N:31][N:32]([CH3:33])[C:28]=2[Cl:27])(=[O:36])=[O:37])=[C:3]([CH:22]=1)[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:11][CH:12]=1)=[O:5]
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(S(=O)(=O)N2CCSCC2)cc1
Solvent: c1ccncc1
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(Cl)cc1C(=O)Nc1ccc(S(=O)(=O)N2CCSCC2)cc1

Procedure:
250 mg (0.60 mmol) of 2-amino-5-chloro-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide were dissolved in 10 ml of dry pyridine, and a solution of 195 mg (0.85 mmol) 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride in 5 ml of pyridine was added dropwise at 0° C. After 2 h the mixture was poured onto ice, the precipitated solid was filtered off with suction and purified by chromatography over silica with methylene chloride/methanol (98:2). 250 mg (69%) of the title compound having a melting point of 215-216° C. were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:42])[NH:29][C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]#[N:41])[CH:31]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:40]([C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][C:14]4[C:15]5[CH2:16][CH2:17][NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:42])[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=1)#[N:41]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C#N)cc(C(F)(F)F)c3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(NC(=O)n2ccc3cc(Oc4ncnc5c4CCNC5)ccc32)cc(C(F)(F)F)c1

Procedure:
A solution of 4-[1-(3-cyano-5-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (132 mg, 0.28 mmol) in DCM (2 mL) and TFA (2 mL) is stirred at room temperature for 2 h. The reaction is concentrated in vacuo and purified via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 479.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38-8.42 (m, 2 H), 8.35 (s, 1 H), 8.28 (d, J=8.8 Hz, 1 H), 8.07-8.12 (m, 2 H), 7.47 (d, J=2.3 Hz, 1 H), 7.14 (dd, J=8.8, 2.3 Hz, 1 H), 6.83 (d, J=3.3 Hz, 1 H), 3.85 (s, 2 H), 3.06 (t, J=5.8 Hz, 2 H), 2.74 (t, J=5.7 Hz, 2 H).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:25]([P:1]([O:2][CH2:3][CH3:4])(=[O:5])[O:8][CH2:9][CH3:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CCOP(OCC)OCC
Product: CCCCCCCCCCCCCCP(=O)(OCC)OCC

Procedure:
100 g (590 mmol) of triethyl phosphite and 164 g (590 mmol) of 1-bromotetradecane are heated on a column connected to a descending condenser. Bromoethane distills out at a bath temperature of 170° C.; the mixture is then distilled under high vacuum, resulting in the product of boiling point 145° C./0.03 mmHg which is pure by 1H NMR.
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[CH2:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)=O)=[CH:10][CH:9]=2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[NH2:33][OH:34].C(=O)([O-])O.[Na+]>>[OH:34]/[N:33]=[C:16](/[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=1)\[CH2:15][C@H:14]([C:11]1[CH:10]=[CH:9][C:8]([CH:6]2[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:7]2)=[CH:13][CH:12]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: CC(=O)N1CC(c2ccc([C@@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N1CC(c2ccc([C@@H](C/C(=N\O)c3ccnc(C)c3)c3ccccc3C)cc2)C1

Procedure:
In analogy to example 1, step 2, from (R)-3-(4-(1-acetylazetidin-3-yl)phenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=428.1 ([M+H]+).