Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=CC(C(=O)C(F)(F)F)=CC=1>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:38])[C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=3)=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccc(C(=O)C(F)(F)F)cc2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: O=C(c1ccc(Br)cc1)C(F)(F)F
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2ccc(C(=O)C(F)(F)F)cc2)o1
Yield: 69 %

Procedure:
1-(4-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)phenyl)-2,2,2-trifluoroethanone. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (55 mg, 0.083 mmol) and 1-(4-bromophenyl)-2,2,2-trifluoroethanone following General Procedure A. Flash chromatography (5-20% EtOAc/hexanes) yielded the title compound as a white solid (31 mg, 69%): 1H NMR (CDCl3, 600 MHz) δ 8.13-8.12 (d, 2H, J=7.8 Hz), 7.80-7.79 (d, 2H, J=7.8 Hz), 7.49 (s, 1H), 7.27-7.24 (m, 2H), 7.16-7.15 (m, 3H), 4.86 (t, 1H, J=6.0 Hz), 2.59 (t, 2H, J=7.5 Hz), 1.95-1.91 (m, 2H), 1.61-1.59 (m, 2H), 1.37-1.34 (m, 6H), 0.90 (s, 9H), 0.10 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 180.4 (d, J=35 Hz), 167.5, 150.3, 143.6, 135.1, 131.8, 129.9, 129.2, 129.1, 126.5, 126.1, 125.1, 117.6 (d, J=290 Hz), 69.6, 37.3, 36.8, 32.3, 30.0, 36.6, 26.6, 26.0, 19.1, −4.1, −4.2.
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N+:26]([O-])([OH:28])=[O:27].O>S(=O)(=O)(O)O>[N+:26]([C:21]1[CH:20]=[C:19]([C:16]2[N:17]=[CH:18][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][N:15]=2)[CH:24]=[CH:23][C:22]=1[OH:25])([O-:28])=[O:27]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCCCCCc1cnc(-c2ccc(O)c([N+](=O)[O-])c2)nc1
Yield: 81.7 %

Procedure:
Step i) 2.00 g (5.87 mM) of 4-(5-dodecylpyrimidine-2-yl)phenol was dispersed in 20 ml of conc. sulfuric acid. To the dispersion, 0.50 ml of nitric acid (60%, density=1.38) was gradually added dropwise under cooling and stirring at 2°-8° C. After the addition, the mixture was stirred for 30 min. at about 5° C. After the reaction, the reaction mixture was poured into 150 ml of iced water to precipitate a crystal. The crystal was recovered by filtration, washed with water and recrystallized from ethanol to obtain 1.85 g of 2-nitro-4-(5-dodecylpyrimidine-2-yl)phenol (yield:81.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)=[O:7].[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:33]([N:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[CH2:10][CH2:9][N:8]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:6](=[O:7])[C:5]1[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1cc(C(=O)N(CCC2CCCN2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(=O)N(CCC2CCCN2Cc2ccccc2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Trimethoxy-N-(2-methyl-3-phenyl-allyl)-N-(2-pyrrolidin-2-yl-ethyl)-benzamide 0.11 g (2.5 mmol) and freshly distilled benzaldehyde 0.026 g (2.5 mmol) was taken in 10 ml of dry methanol. Acetic acid 0.022 ml (3.7 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 30 min and sodium cyanoborohydride 0.023 g (3.7 mmol) was added at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 14 hr. The reaction mixture was concentrated, and the residue was diluted with water and extracted with chloroform (3×20 ml). Organic layer was washed with 10% NaHCO3 solution, water and brine, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography over silica gel to yield the pure desired compound. This was converted to its hydrochloride salt using dry HCl in ether to obtain 90 mg of product. Yield: 63%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][NH2:12])=O.[CH2:13]([O:15][C:16](=[O:21])[C:17](Cl)=[N:18][CH3:19])[CH3:14].Cl>ClCCl>[CH2:13]([O:15][C:16]([C:17]1[N:18]([CH3:19])[C:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:11][N:12]=1)=[O:21])[CH3:14]
Reactant: NNC(=O)Cc1ccccc1Cl
Reactant: CCOC(=O)C(Cl)=NC
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1nnc(Cc2ccccc2Cl)n1C
Reaction time: 2 h

Procedure:
14.8 g (80 mmol) of o-chlorophenylacetic acid hydrazide are suspended in 230 ml of dichloromethane. At 5°, 12 g (80 mmol) of 2-chloro-2-(N-methylimino)-acetic acid ethyl ester [Tetrahedron Lett. 30, 2827 (1979)] are added dropwise thereto. The whole is then stirred for 2 hours while cooling with ice and then overnight at room temperature. The reaction mixture is then poured onto ice, 50 ml of 2N hydrochloric acid are added thereto and the whole is extracted twice with dichloromethane. The combined dichloromethane phases are washed twice with water. All the acidic aqueous phases are combined, rendered alkaline with solid sodium carbonate and extracted three times by shaking with dichloromethane. These three organic phases are combined, washed in succession with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 150 ml of xylene and stirred under reflux for 44 hours. The reaction mixture is then concentrated and chromatographed over silica gel using ethyl acetate as eluant. The eluate is concentrated by evaporation and recrystallised from ether. 5-(o-chlorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethyl ester of m.p. 87-88° is obtained in a yield of 12.4 g (55% of the theoretical yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[CH:8][C:7]([OH:18])=[CH:6][CH:5]=2.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[CH:8][C:7]([O:18][S:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])=[O:26])=[CH:6][CH:5]=2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1[nH]c2ccc(O)cc2c1C1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1[nH]c2ccc(OS(=O)(=O)c3ccccc3)cc2c1C1CCN(C)CC1
Yield: 24.2 %

Procedure:
By a method similar to Example 31, using 2-methyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (250 mg, 1.03 mmol), benzenesulfonyl chloride (0.22 g, 1.25 mmol), 0.2N sodium hydroxide and THF (2 mL) gave 96 mg (24%) of the title compound: mass spectrum (ES+)=385.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.C[N:30](C1C=CC=CN=1)C>C(Cl)(Cl)(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH2:30])=[O:23])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Reactant: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 376.8 %

Procedure:
To a suspension of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation E, 50.0 mg, 0.153 mmol) in CCl4 (1.0 mL) was added thionyl chloride (182 mg, 1.53 mmol) and the mixture was heated at reflux for 4 hours (homogeneous after 5 minutes). The mixture was cooled to ambient temperature and was concentrated to give a brittle foam. The foam was dissolved in dry THF (2 mL) and dimethylaminopyridine (DMAP) (3.74 mg, 0.031 mmol) was added. Anhydrous ammonia was bubbled into the mixture with stirring for 5 minutes. The reaction vessel was sealed and the reaction was stirred at ambient temperature for 18 hours. The mixture was added to H2O (4 mL) and extracted with EtOAc. The combined extracts were washed with 1M Na2CO3, H2O and saturated NaCl. The solution was dried over MgSO4/activated carbon and filtered through a SiO2 plug (EtOAc then 10% MeOH/EtOAc for elution). The solution was concentrated to give the title compound as a white solid (38 mg, 76%). MS (apci) m/z=326.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\Cl)/[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[K+]>O1CCOCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CCCCc1ccc(/C(Cl)=C/c2ccc(Br)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCc1ccc(C#Cc2ccc(Br)cc2)cc1
Yield: 89.6 %

Procedure:
To a 1 L flask containing a solution of 1-bromo-4-[(Z) -2-chloro-2-(4-butyl-phenyl) vinyl] benzene (VIe) (100 g; 0.285 mol) in 1,4-dioxane (500 mL; 5 vols) and MeOH (200 mL; 2vols), KOH (32 g; 0.571 mol) was added in one portion. Protocol and work-up was then similar with those described above. Title compound (m=80 g) was obtained in a 89% yield. Melting point: 75.6-76.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30])[CH:11]=[C:12]([C:24]([CH3:26])=[CH2:25])[C:13](=[O:23])[C:14]=1[O:15]CC1C=CC=CC=1)=[O:8].[H][H]>CO.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30])[CH:11]=[C:12]([CH:24]([CH3:25])[CH3:26])[C:13](=[O:23])[C:14]=1[OH:15])=[O:8]
Reactant: C=C(C)c1cn(CC(OC)OC)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(Cn1cc(C(C)C)c(=O)c(O)c1C(=O)NCc1cccc(Cl)c1)OC
Yield: 87.1 %

Procedure:
To a solution of 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-isopropenyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (60 mg) in methanol (1 ml) was added 5% palladium-carbon (20 mg) and the mixture was stirred under an atmospheric pressure of hydrogen for 16 hr. A solid was filtered off and the filtrate was concentrated to give 1-(2,2-dimethoxyethyl)-3-hydroxy-5-isopropyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (43 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([N:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3F)cnc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccccc1-c1cnc2[nH]ccc2c1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
tert-Butyl 4-(5-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.045 g, 0.11 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give 5-(2-fluorophenyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.034 g, 81% yield).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]#[C:11][CH2:12]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[I:19]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Si:1]([O:8][CH2:9][C:10]#[C:11][CH2:12][I:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)OCC#CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC#CCI
Yield: 71.4 %

Procedure:
1-(tert-Butyldimethylsilyloxy)-but-2-yn-4-ol (63, 4.0 g, 19.96 mmol), imidazole (1.80 g, 26.45 mmol), iodine (6.58 g, 25.95 mmol) and triphenylphosphine (6.80 g, 25.95 mmol) are treated in 100 ml dichloromethane according to J. Robertson et al. J. Chem. Soc., Perkin Trans. 1, 3389-3369, 2000. Work-up yields 4.42 g (71%) of a colourless oil. The product is used directly in the next step.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=4[C:21](=[O:29])[N:20]4[CH2:30][CH2:31][CH2:32][C@H:19]4[C:18]=23)[N:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[CH2:1]([N:4]([CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=4[C:21](=[O:29])[N:20]4[CH2:30][CH2:31][CH2:32][C@H:19]4[C:18]=23)[N:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2cc(F)ccc2-3)no1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2cc(F)ccc2-3)no1
Yield: 82.9 %

Procedure:
1.96 g (4.1 mmol) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-11,1 2,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepin-9-one were dissolved in 25 ml of ethyl acetate and hydrogenated at normal pressure and room temperature in the presence of 37 mg of 5% palladium-charcoal. The catalyst was separated and the solution was evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.49 g (83%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-11,12,13, 13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 222°-225°.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]1[CH:13]=[C:12]([N:14]2[C:26]3[C:25]4[CH:24]=[C:23]([C:27]5[CH:28]=[N:29][C:30]([O:36][CH3:37])=[C:31]([CH:35]=5)[C:32](O)=[O:33])[CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:16]([CH3:38])[C:15]2=[O:39])[C:11]([CH3:40])=[N:10]1.[Cl-].[CH3:42][NH2:43].C(O)C>ClCCl.CN(C=O)C>[CH3:8][N:9]1[CH:13]=[C:12]([N:14]2[C:26]3[C:25]4[CH:24]=[C:23]([C:27]5[CH:28]=[N:29][C:30]([O:36][CH3:37])=[C:31]([CH:35]=5)[C:32]([NH:43][CH3:42])=[O:33])[CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:16]([CH3:38])[C:15]2=[O:39])[C:11]([CH3:40])=[N:10]1
Reactant: CN
Reactant: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1C(=O)O
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled with an ice-bath suspension of 5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-nicotinic acid TFA salt (Example 124, 60 mg, 0.089 mmol) in dichloromethane (1.5 ml) containing DMF (0.005 ml) was added oxallyl chloride (0.038 ml, 0.449 mmol). The reaction mixture was stirred for 1 h at rt then cooled with an ice-bath and quenched with 8 M methylamine in ethanol (2.5 ml, 20 mmol). After 5 min stirring, the reaction mixture was evaporated to dryness and the residue purified by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 65:35). The fractions containing products were collected together, basified with NaHCO3, concentrated and the formed precipitate was filtered, washed with water and dried to give the title compound as white solid. (HPLC: tR 2.45 min (Method A); M+H=458 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.52-8.46 (m, 1H), 8.35-8.27 (m, 1H), 8.19-8.07 (m, 3H), 7.99-7.93 (m, 1H), 7.56-7.51 (m, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 3.57 (s, 3H), 2.83 (d, 3H), 1.94 (s, 3H))
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.CO>O.S(N(C1C=C(C(O)=O)C(N(S(=O)(=O)N)C2C=CC=CC=2)=CC=1C(O)=O)C1C=CC=CC=1)(=O)(=O)N.C(N(CC)S(C1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(S(=O)(=O)N(CC)CC)=CC=3)=CC=2C(O)=O)=CC=1)(=O)=O)C>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: CCN(CC)S(=O)(=O)c1ccc(Nc2cc(C(=O)O)c(Nc3ccc(S(=O)(=O)N(CC)CC)cc3)cc2C(=O)O)cc1
Agent: NS(=O)(=O)N(c1ccccc1)c1cc(C(=O)O)c(N(c2ccccc2)S(N)(=O)=O)cc1C(=O)O
Solvent: CO
Solvent: O
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 93 °C
Reaction time: 0.08 h
Yield: 104.4 %

Procedure:
To 720 g of polyphosphoric acid (112%) heated at 85° C. were added 1.6 g of 2,5-di(sulfamoylanilino)terephthalic acid followed by 8 g of 2,5-di[4-(N,N-diethylsulfamoyl)anilino]terephthalic acid. The mixture was stirred for five minutes, after which 160 g of 2,5-di(4-methylanilino)terephthalic acid were added over a period of approximately 65 minutes, the temperature being maintained below 110° C. by adjustment of the addition rate. The reaction mixture was held at 123° C. for two hours, cooled to 93° C., and poured slowly into 1120 g of methanol, the temperature being maintained below reflux using a water bath. The pigment slurry was heated at reflux for one hour, cooled below 65° C., diluted with water, collected by filtration, and washed with water until free of acid. The resultant presscake was reslurried in water and heated to 45° C. After the slurry was acidified to pH 2.5, an emulsion of 4.7 g of an anionic surfactant, 69.6 g of a petroleum distillate, and 160 g of water was added, and the slurry was stirred for three hours. The resultant slurry was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 151 g of 2,9-dimethylquinacridone as a magenta pigment.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:7][CH:6]=1)[CH3:2].[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](Cl)=[N:21][N:20]=1.C(N(CC)CC)C.CN1C(=O)CCC1>O>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:22]3[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]([Cl:18])=[N:20][N:21]=3)[CH2:15][CH2:16]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)nc1
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(c3nnc(Cl)c4ccccc34)CC2)nc1
Temperature: 25 °C
Yield: 49 %

Procedure:
Combine 6-piperazin-1-yl-nicotinic acid ethyl ester (1.30 g, 5.40 mmol), 1,4-dichlorophthalazine (932 mg, 4.59 mmol), triethylamine (1.78 mL, 13.50 mmol), and NMP (8 mL) and heat to 85° C. for 6 h. Cool to room temperature, dilute with H2O (50 mL) and extract organics with EtOAc (3×50 mL). Combined organic layers are dried over MgSO4 and concentrated. Resulting solid is triturated with EtOAc to give the title compound as a fine tan powder (895 mg, 49% yield).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=1)[CH2:20][CH2:21][CH2:22]O.S(Cl)([Cl:39])=O>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=1)[CH2:20][CH2:21][CH2:22][Cl:39]
Reactant: O=S(Cl)Cl
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCO)Cc3cccc(CC(=O)OC)c3)c2n1
Solvent: ClCCl
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCCl)Cc3cccc(CC(=O)OC)c3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-hydroxypropyl)amino]methyl}phenyl)acetate (described in WO2007/1031726, Example 1 step (ix)) (534 mg) was suspended in DCM (5 mL) and thionyl chloride (0.09 mL) added. The reaction mixture was stirred at 25° C. overnight. The reaction was concentrated in vacuo to give the subtitle product (0.55 g); MS multimode (+) 520
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:16])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]3)[CH:10]=[CH:11][C:12]=2[Cl:16])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C[C@@H]1CN(c2ccc(Cl)c(N)c2)C[C@H](C)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(Cl)c(NS(=O)(=O)c3ccc(Br)cc3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-chloroaniline (D34) (108 mg, 0.45 mmol) in pyridine:dichloromethane (1:1, 4 ml) was treated with 4-bromobenzenesulfonyl chloride (138 mg, 0.54 mmol). The solution was stirred at room temperature for 2 hours, quenched with methanol and concentrated in vacuo. The residue was applied to a SCX cartridge (Varian bond-elute, 5 g) and washed with methanol and 2M ammonia in methanol. The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography (FlashMaster) (dichloromethane to 5% methanol:dichloromethane) to afford some pure product. The impure fractions were purified further by MDAP, and combined with the above pure product to afford the title product (D35). MS (ES+) m/e 458/460/462 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
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: [K+]
Product: Cc1nc(-c2ccc(F)cc2F)n2c1c(C)nc1ccc(F)cc12
Yield: 50.1 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 2,4-difluorophenylboronic acid (48 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (41 mg, 50% yield). EIMS 328.0 [M+H]+.